U.S. patent application number 16/942245 was filed with the patent office on 2021-05-20 for oxysterols and methods of use thereof.
The applicant listed for this patent is Sage Therapeutics, Inc.. Invention is credited to Gabriel Martinez Botella, Albert Jean Robichaud, Francesco G. Salituro.
Application Number | 20210145848 16/942245 |
Document ID | / |
Family ID | 1000005360697 |
Filed Date | 2021-05-20 |
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United States Patent
Application |
20210145848 |
Kind Code |
A1 |
Salituro; Francesco G. ; et
al. |
May 20, 2021 |
OXYSTEROLS AND METHODS OF USE THEREOF
Abstract
Compounds are provided according to Formula (I): Formula (I) and
pharmaceutically acceptable salts thereof, and pharmaceutical
compositions thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.6,
R.sup.7, R.sup.8, and n are as defined herein. Compounds of the
present invention are contemplated useful for the prevention and
treatment of a variety of conditions. ##STR00001##
Inventors: |
Salituro; Francesco G.;
(Marlborough, MA) ; Robichaud; Albert Jean;
(Boston, MA) ; Martinez Botella; Gabriel;
(Wayland, MA) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Sage Therapeutics, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
1000005360697 |
Appl. No.: |
16/942245 |
Filed: |
July 29, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16227099 |
Dec 20, 2018 |
10765685 |
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16942245 |
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15742425 |
Jan 5, 2018 |
10201550 |
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PCT/US2016/041168 |
Jul 6, 2016 |
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16227099 |
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62280394 |
Jan 19, 2016 |
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62189048 |
Jul 6, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/575 20130101;
C07J 9/005 20130101; C07J 7/002 20130101; C07J 9/00 20130101 |
International
Class: |
A61K 31/575 20060101
A61K031/575; C07J 9/00 20060101 C07J009/00 |
Claims
1. A compound of Formula (I): ##STR00075## or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 is C.sub.1-6 alkyl; each
of R.sup.2 and R.sup.3 is independently hydrogen, halogen,
C.sub.1-6 alkyl, or carbocyclyl; or R.sup.2 and R.sup.3, together
with the carbon atom to which they are attached, form a 3-8
membered ring; R.sup.6 is absent or hydrogen; each of R.sup.7 and
R.sup.8 is independently hydrogen, halogen, C.sub.1-6 alkyl, or
carbocyclyl; or each of R.sup.7 and R.sup.8, together with the
carbon atom to which they are attached, form a 3-8 membered ring;
or R.sup.2 and R.sup.7, together with the carbon atoms to which
they are attached, form a 3-8 membered ring; n is 1, 2, or 3; and
represents a single or double bond, wherein when one is a double
bond, the other is a single bond; and when one of the is a double
bond, R.sup.6 is absent.
2. (canceled)
3. The compound of claim 1, wherein R.sup.1 is methyl, substituted
alkyl, ethyl, or isopropyl.
4. The compound of claim 3, wherein R.sup.1 is methyl or ethyl.
5. The compound of claim 1, wherein each of R.sup.2 and R.sup.3 is
independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl, or wherein
R.sup.2 and R.sup.3 are taken together with the carbon atom to
which they are attached form a 3-8 membered ring.
6. The compound of claim 5, wherein the 3-8 membered ring is a
carbocyclyl ring.
7. The compound of claim 5, wherein each of R.sup.2 and R.sup.3 is
independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl.
8. The compound of claim 7, wherein each of R.sup.2 and R.sup.3 is
independently hydrogen, substituted or unsubstituted methyl,
substituted or unsubstituted ethyl, propyl, isopropyl, cyclopropyl,
or butyl.
9. The compound of claim 7, wherein R.sup.2 is hydrogen,
substituted or unsubstituted methyl, or ethyl.
10. The compound of claim 7, wherein R.sup.3 is substituted or
unsubstituted methyl, substituted or unsubstituted ethyl, propyl,
isopropyl, cyclopropyl, or butyl.
11. The compound of claim 7, wherein R.sup.2 is hydrogen and
R.sup.3 is C.sub.1-6 alkyl.
12. The compound of claim 7, wherein R.sup.2 is C.sub.1-6 alkyl and
R.sup.3 is C.sub.1-6 alkyl.
13. (canceled)
14. The compound of claim 1, wherein R.sup.7 and R.sup.8 are
hydrogen.
15. The compound of claim 1, wherein n is 1.
16. The compound of claim 1, wherein n is 1 and R.sup.7 and R.sup.8
are hydrogen.
17. The compound of claim 1, wherein the compound Formula (I) is a
compound of Formula (II): ##STR00076## or a pharmaceutically
acceptable salt thereof.
18. The compound of claim 17, wherein the compound of Formula (I)
is a compound of Formula (II-A) or Formula (II-B): ##STR00077## or
a pharmaceutically acceptable salt thereof.
19. The compound of claim 17, wherein the compound of Formula (I)
is a compound of Formula (II-B-i) or Formula (II-B-ii):
##STR00078## or a pharmaceutically acceptable salt thereof.
20. The compound of claim 17, wherein the compound of Formula (I)
is a compound of Formula (II-B-iii): ##STR00079## or a
pharmaceutically acceptable salt thereof.
21. The compound of claim 1, wherein the compound of Formula (I) is
a compound of Formula (III): ##STR00080## or a pharmaceutically
acceptable salt thereof.
22. The compound of claim 21, wherein the compound of Formula (III)
is a compound of Formula (III-A) or Formula (III-B): ##STR00081##
or a pharmaceutically acceptable salt thereof.
23. The compound of claim 21, wherein the compound of Formula
(III-B) is a compound of Formula (III-C) or Formula (III-D):
##STR00082## or a pharmaceutically acceptable salt thereof.
24. The compound of claim 21, wherein the compound of Formula
(III-A) is a compound of Formula (III-E) or Formula (III-F):
##STR00083## or a pharmaceutically acceptable salt thereof.
25. The compound of claim 21, wherein the compound of Formula (III)
is a compound of Formula (III-A-i-a) or Formula (III-B-i-a):
##STR00084## or a pharmaceutically acceptable salt thereof.
26. The compound of claim 25, wherein R.sup.1 is substituted or
unsubstituted methyl, ethyl, or isopropyl.
27. The compound of claim 21, wherein each of R.sup.2 and R.sup.3
is independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl, or
wherein R.sup.2 and R.sup.3 are taken together with the carbon atom
to which they are attached form a 3-8 membered ring.
28. The compound of claim 27, wherein each of R.sup.2 and R.sup.3
is independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl.
29. The compound of claim 28, wherein each of R.sup.2 and R.sup.3
is independently hydrogen, substituted or unsubstituted methyl,
substituted or unsubstituted ethyl, propyl, isopropyl, cyclopropyl,
or butyl.
30. The compound of claim 29, wherein R.sup.2 is hydrogen,
substituted or unsubstituted methyl, or ethyl.
31. The compound of claim 27, wherein R.sup.3 is substituted or
unsubstituted methyl, substituted or unsubstituted ethyl, propyl,
isopropyl, cyclopropyl, or butyl.
32. The compound of claim 21, wherein the compound is selected from
the group consisting of: ##STR00085## or a pharmaceutically
acceptable salt thereof.
33. The compound of claim 1, wherein the compound of Formula (I) is
a compound of Formula (IV): ##STR00086## or a pharmaceutically
acceptable salt thereof.
34. The compound of claim 33, wherein R.sup.1 is substituted or
unsubstituted methyl, ethyl, or isopropyl.
35. The compound of claim 33, wherein each of R.sup.2 and R.sup.3
is independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl, or
wherein R.sup.2 and R.sup.3 are taken together with the carbon atom
to which they are attached form a 3-8 membered ring.
36. The compound of claim 35, wherein each of R.sup.2 and R.sup.3
is independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl.
37. The compound of claim 36, wherein each of R.sup.2 and R.sup.3
is independently hydrogen, substituted or unsubstituted methyl,
substituted or unsubstituted ethyl, propyl, isopropyl, cyclopropyl,
or butyl.
38. The compound of claim 37, wherein R.sup.2 is hydrogen,
substituted or unsubstituted methyl, or ethyl.
39. The compound of claim 36, wherein R.sup.3 is substituted or
unsubstituted methyl, substituted or unsubstituted ethyl, propyl,
isopropyl, cyclopropyl, butyl.
40. The compound of claim 33, wherein the compound is: ##STR00087##
or a pharmaceutically acceptable salt thereof.
41. The compound of claim 1, wherein the compound Formula (I) is a
compound of Formula (V): ##STR00088## or a pharmaceutically
acceptable salt thereof.
42. The compound of claim 17, wherein the compound of Formula (I)
is a compound of Formula (V-A): ##STR00089## or a pharmaceutically
acceptable salt thereof.
43. The compound of claim 1, wherein the compound of Formula (I) is
a compound of Formula (V-B): ##STR00090## or a pharmaceutically
acceptable salt thereof.
44. The compound of claim 21, wherein the compound of Formula (III)
is a compound of Formula (V-C) or Formula (V-D): ##STR00091## or a
pharmaceutically acceptable salt thereof.
45. The compound of claim 1, wherein the compound of Formula (I) is
a compound of Formula (V-E-i): ##STR00092## or a pharmaceutically
acceptable salt thereof.
46. The compound of claim 1, wherein the compound of Formula (I) is
a compound of Formula (V-E-ii) or (V-E-iii): ##STR00093## or a
pharmaceutically acceptable salt thereof.
47. The compound of claim 1, wherein the compound is selected from:
##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098## or
a pharmaceutically acceptable salt thereof.
48. A pharmaceutical composition comprising a compound of claim 1,
or pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
49. A method of inducing sedation or anesthesia comprising
administering to a subject an effective amount of a compound of
claim 1, or pharmaceutically acceptable salt thereof, or
pharmaceutical composition thereof.
50. (canceled)
51. A method of treating or preventing a disorder, comprising
administering to a subject in need thereof an effective amount of a
compound of claim 1, or pharmaceutically acceptable salt thereof,
or a pharmaceutical composition thereof, wherein the disorder is a
gastrointestinal (GI) disorder, constipation, irritable bowel
syndrome (IBS), inflammatory bowel disease (IBD), structural
disorders affecting the GI, anal disorders, colon polyps, cancer,
colitis.
52.-54. (canceled)
55. A method for treating or preventing a CNS-related condition
comprising administering to a subject in need thereof an effective
amount of a compound of claim 1, or pharmaceutically acceptable
salt thereof, or pharmaceutical composition thereof.
56. The method according to claim 55, wherein the CNS-related
condition is an adjustment disorder, anxiety disorder,
obsessive-compulsive disorder, posttraumatic stress disorder, and
social phobia, cognitive disorder, Alzheimer's disease and other
forms of dementia, dissociative disorder, eating disorder, mood
disorder, depression, postpartum depression, bipolar disorder,
dysthymic disorder, suicidality, schizophrenia or other psychotic
disorder, schizoaffective disorder, sleep disorder, insomnia,
substance-related disorder, personality disorder,
obsessive-compulsive personality disorder, autism spectrum
disorders, autism spectrum disorders involving mutations to the
Shank group of proteins, neurodevelopmental disorder, Rett
syndrome, Tuberous Sclerosis complex, multiple sclerosis, sterol
synthesis disorders, pain, acute pain, chronic pain, encephalopathy
secondary to a medical condition, hepatic encephalopathy, anti-NMDA
receptor encephalitis, seizure disorder, status epilepticus,
monogenic forms of epilepsy such as Dravet's disease, stroke,
traumatic brain injury, movement disorder, Huntington's disease,
Parkinson's disease, vision impairment, hearing loss, and
tinnitus.
57. (canceled)
Description
RELATED APPLICATIONS
[0001] The present application is a Continuation of U.S. Ser. No.
16/227,099 filed Dec. 20, 2018 (now U.S. Pat. No. 10,765,685),
which is a Continuation of U.S. Ser. No. 15/742,425 filed Jan. 5,
2018 (now U.S. Pat. No. 10,201,550), which is a National Phase
Application under 35 U.S.C. .sctn. 371 of International Application
No. PCT/US2016/041168, filed Jul. 6, 2016, which claims the benefit
of and priority to U.S. Provisional Application No. 62/189,048
filed Jul. 6, 2015, and 62/280,394 filed Jan. 19, 2016, the
contents of each of which are incorporated by reference in their
entirety.
BACKGROUND OF THE INVENTION
[0002] NMDA receptors are heteromeric complexes comprised of NR1,
NR2, and/or NR3 subunits and possess distinct recognition sites for
exogenous and endogenous ligands. These recognition sites include
binding sites for glycine, and glutamate agonists and modulators.
NMDA receptors are expressed in the peripheral tissues and the CNS,
where they are involved in excitatory synaptic transmission.
Activating these receptors contributes to synaptic plasticity in
some circumstances and excitotoxicity in others. These receptors
are ligand-gated ion channels that admit Ca2+ after binding of the
glutamate and glycine, and are fundamental to excitatory
neurotransmission and normal CNS function. Positive modulators may
be useful as therapeutic agents with potential clinical uses as
cognitive enhancers and in the treatment of psychiatric disorders
in which glutamatergic transmission is reduced or defective (see,
e.g., Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325).
In contrast, negative modulators may be useful as therapeutic
agents with potential clinical uses in the treatment of psychiatric
disorders in which glutamatergic transmission is pathologically
increased (e.g., treatment resistant depression).
[0003] Oxysterols are derived from cholesterol and have been shown
to potently and selectively modulate NMDA receptor function. New
and improved oxysterols are needed that modulate the NMDA receptor
for the prevention and treatment of conditions associated with NMDA
expression and function. Compounds, compositions, and methods
described herein are directed toward this end.
SUMMARY OF THE INVENTION
[0004] Provided herein are substituted oxysterols useful for
preventing and/or treating a broad range of disorders, including,
but not limited to, NMDA-mediated disorders. These compounds are
expected to show improved in vivo potency, pharmacokinetic (PK)
properties, oral bioavailability, formulatability, stability,
and/or safety as compared to other oxysterols. Further provided are
pharmaceutical compositions comprising the compounds of the present
invention, and methods of their use and treatment.
[0005] In one aspect, provided herein are compounds according to
Formula (I):
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is
C.sub.1-6 alkyl; each of R.sup.2 and R.sup.3 is independently
hydrogen, C.sub.1-6 alkyl, or carbocyclyl; or R.sup.2 and R.sup.3,
together with the carbon atom to which they are attached, form a
3-8 membered ring; R.sup.6 is absent or hydrogen; each of R.sup.7
and R.sup.8 is independently hydrogen, halogen, C.sub.1-6 alkyl, or
carbocyclyl; or each of R.sup.7 and R.sup.8, together with the
carbon atom to which they are attached, form a 3-8 membered ring;
or R.sup.2 and R.sup.7, together with the carbon atoms to which
they are attached, form a 3-8 membered ring; n is 1, 2, or 3; and
represents a single or double bond, wherein when one is a double
bond, the other is a single bond; and when one of the is a double
bond, R.sup.6 is absent.
[0006] In some embodiments, R.sup.1 is substituted C.sub.1-6 alkyl.
In some embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl. In
some embodiments, R.sup.1 is methyl (e.g., --CHF.sub.2, --CH.sub.3,
--CF.sub.3, --CH.sub.2OCH.sub.3, or --CH.sub.2OCH.sub.2CH.sub.3),
ethyl, or isopropyl. In some embodiments, R.sup.1 is --CH.sub.3. In
some embodiments, R.sup.1 is ethyl.
[0007] In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl, or wherein
R.sup.2 and R.sup.3 are taken together with the carbon atom to
which they are attached form a 3-8 membered ring. In some
embodiments, the 3-8 membered ring is a carbocyclyl ring (e.g.,
cyclopropyl). In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl. In some
embodiments, each of R.sup.2 and R.sup.3 is independently hydrogen,
methyl (e.g., --CH.sub.3, --CF.sub.3), ethyl (e.g.,
--CH.sub.2CH.sub.3, CH.sub.2CF.sub.3), propyl, isopropyl,
cyclopropyl, or butyl.
[0008] In some embodiments, R.sup.2 substituted C.sub.1-6 alkyl. In
some embodiments, R.sup.2 unsubstituted C.sub.1-6 alkyl.
[0009] In some embodiments, R.sup.2 is hydrogen, methyl (e.g.,
--CH.sub.3, --CF.sub.3), ethyl, or isopropyl-.
[0010] In some embodiments, R.sup.3 substituted C.sub.1-6 alkyl. In
some embodiments, R.sup.3 unsubstituted C.sub.1-6 alkyl.
[0011] In some embodiments, R.sup.3 is methyl (e.g., --CH.sub.3,
--CF.sub.3), ethyl (e.g., --CH.sub.2CH.sub.3, CH.sub.2CF.sub.3),
propyl, isopropyl, cyclopropyl, or butyl.
[0012] In some embodiments, R.sup.2 and R.sup.3 are hydrogen. In
some embodiments, R.sup.2 is hydrogen and R.sup.3 is C.sub.1-6
alkyl (e.g., methyl (e.g., --CH.sub.3, --CF.sub.3), ethyl,
isopropyl). In some embodiments, R.sup.2 is C.sub.1-6 alkyl and
R.sup.3 is C.sub.1-6 alkyl. In some embodiments, R.sup.2 and
R.sup.3 are --CH.sub.3. In some embodiments, R.sup.2 is --CH.sub.3
and R.sup.3 is --CF.sub.3. In some embodiments, R.sup.2 is
--CH.sub.3 and R.sup.3 is ethyl. In some embodiments, R.sup.2 is
--CH.sub.3 and R.sup.3 is isopropyl.
[0013] In some embodiments, each of is a single bond.
[0014] In some embodiments, R.sup.6 is hydrogen. In some
embodiments, R.sup.6 is in the alpha position. In some embodiments,
R.sup.6 is in the beta position.
[0015] In some embodiments, R.sup.6 is absent.
[0016] In some embodiments, R.sup.7 and R.sup.8 are hydrogen.
[0017] In some embodiments, n is 1. In some embodiments, n is 1 and
R.sup.7 and R.sup.8 are hydrogen.
[0018] In some embodiments, n is 2. In some embodiments, n is 2 and
each of R.sup.7 and R.sup.8 is independently hydrogen, halogen,
C.sub.1-6 alkyl, or carbocyclyl.
[0019] In some embodiments, the compound Formula (I) is a compound
of Formula (II):
##STR00003##
or a pharmaceutically acceptable salt thereof.
[0020] In some embodiments, the compound of Formula (II) is a
compound of Formula (II-A) or Formula (II-B):
##STR00004##
or a pharmaceutically acceptable salt thereof.
[0021] In some embodiments, the compound of Formula (I) is a
compound of Formula (II-B-i) or Formula (II-B-ii):
##STR00005##
or a pharmaceutically acceptable salt thereof.
[0022] In some embodiments, the compound of Formula (I) is a
compound of Formula (II-B-iii):
##STR00006##
or a pharmaceutically acceptable salt thereof.
[0023] In some embodiments, the compound of Formula (I) is a
compound of Formula (III):
##STR00007##
or a pharmaceutically acceptable salt thereof.
[0024] In some embodiments, the compound of Formula (III) is a
compound of Formula (III-A) or Formula (III-B):
##STR00008##
or a pharmaceutically acceptable salt thereof.
[0025] In some embodiments, the compound of Formula (III-B) is a
compound of Formula (III-C) or Formula (III-D):
##STR00009##
or a pharmaceutically acceptable salt thereof.
[0026] In some embodiments, the compound of Formula (III-A) is a
compound of Formula (III-E) or Formula (III-F):
##STR00010##
or a pharmaceutically acceptable salt thereof.
[0027] In some embodiments, the compound of Formula (III) is a
compound of Formula (III-A-i-a) or Formula (III-B-i-a):
##STR00011##
or a pharmaceutically acceptable salt thereof.
[0028] In some embodiments, R.sup.1 is methyl (e.g., --CHF.sub.2,
--CF.sub.3, --CH.sub.2OCH.sub.3, or --CH.sub.2OCH.sub.2CH.sub.3),
ethyl, or isopropyl.
[0029] In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl, or wherein
R.sup.2 and R.sup.3 are taken together with the carbon atom to
which they are attached form a 3-8 membered ring.
[0030] In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl.
[0031] In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, methyl (e.g., --CH.sub.3, --CF.sub.3),
ethyl (e.g., --CH.sub.2CH.sub.3, --CH.sub.2CF.sub.3), propyl,
isopropyl, cyclopropyl, or butyl.
[0032] In some embodiments, R.sup.2 is hydrogen, methyl (e.g.,
--CH.sub.3, --CF.sub.3), or ethyl.
[0033] In some embodiments, R.sup.3 is methyl (e.g., --CH.sub.3,
--CF.sub.3), ethyl (e.g., --CH.sub.2CH.sub.3, --CH.sub.2CF.sub.3),
propyl, isopropyl, cyclopropyl, or butyl.
[0034] In some embodiments, the compound is selected from the group
consisting of:
##STR00012##
or a pharmaceutically acceptable salt thereof.
[0035] In some embodiments, the compound of Formula (I) is a
compound of Formula (IV):
##STR00013##
or a pharmaceutically acceptable salt thereof.
[0036] In some embodiments, R.sup.1 is methyl (e.g., --CHF.sub.2,
--CF.sub.3, --CH.sub.2OCH.sub.3, or --CH.sub.2OCH.sub.2CH.sub.3),
ethyl, or isopropyl.
[0037] In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl, or wherein
R.sup.2 and R.sup.3 are taken together with the carbon atom to
which they are attached form a 3-8 membered ring.
[0038] In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl.
[0039] In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, methyl (e.g., --CH.sub.3, --CF.sub.3),
ethyl (e.g., --CH.sub.2CH.sub.3, CH.sub.2CF.sub.3), propyl,
isopropyl, cyclopropyl, or butyl.
[0040] In some embodiments, R.sup.2 is hydrogen, methyl (e.g.,
--CH.sub.3, --CF.sub.3), or ethyl.
[0041] In some embodiments, R.sup.3 is methyl (e.g., --CH.sub.3,
--CF.sub.3), ethyl (e.g., --CH.sub.2CH.sub.3, --CH.sub.2CF.sub.3),
propyl, isopropyl, cyclopropyl, butyl.
[0042] In some embodiments, the compound is:
##STR00014##
or a pharmaceutically acceptable salt thereof.
[0043] In some embodiments, the compound Formula (I) is a compound
of Formula (V):
##STR00015##
or a pharmaceutically acceptable salt thereof.
[0044] In some embodiments, the compound of Formula (I) is a
compound of Formula (V-A):
##STR00016##
or a pharmaceutically acceptable salt thereof.
[0045] In some embodiments, the compound of Formula (I) is a
compound of Formula (V-B):
##STR00017##
or a pharmaceutically acceptable salt thereof.
[0046] In some embodiments, the compound of Formula (III) is a
compound of Formula (V-C) or Formula (V-D):
##STR00018##
or a pharmaceutically acceptable salt thereof.
[0047] In some embodiments, the compound of Formula (I) is a
compound of Formula (V-E):
##STR00019##
or a pharmaceutically acceptable salt thereof.
[0048] In some embodiments, the compound of Formula (V-E) is a
compound of Formula (V-E-i):
##STR00020##
or a pharmaceutically acceptable salt thereof.
[0049] In some embodiments, the compound of Formula (I) is a
compound of Formula (V-E-ii) or (V-E-iii):
##STR00021##
or a pharmaceutically acceptable salt thereof.
[0050] In some embodiments, the compound is selected from:
##STR00022## ##STR00023## ##STR00024## ##STR00025##
##STR00026##
or a pharmaceutically acceptable salt thereof.
[0051] In an aspect, provided herein is a pharmaceutical
composition comprising a compound described herein, or
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
[0052] In an aspect, provided herein is a method of inducing
sedation or anesthesia comprising administering to a subject an
effective amount of a compound described herein, or
pharmaceutically acceptable salt thereof, or pharmaceutical
composition thereof.
[0053] In an aspect, provided herein is a method for treating or
preventing a disorder described herein, comprising administering to
a subject in need thereof an effective amount of a compound
described herein, or pharmaceutically acceptable salt thereof, or
pharmaceutical composition thereof.
[0054] In some embodiments, the disorder is a metabolic
disorder.
[0055] In some embodiments, the disorder is a gastrointestinal (GI)
disorder e.g., constipation, irritable bowel syndrome (IBS),
inflammatory bowel disease (IBD) (e.g., ulcerative colitis, Crohn's
disease), structural disorders affecting the GI, anal disorders
(e.g., hemorrhoids, internal hemorrhoids, external hemorrhoids,
anal fissures, perianal abscesses, anal fistula), colon polyps,
cancer, colitis.
[0056] In some embodiments, the disorder is inflammatory bowel
disease.
[0057] In some embodiments, the disorder is cancer, diabetes, or a
sterol synthesis disorder.
[0058] In an aspect, provided herein is a method for treating or
preventing a CNS-related condition comprising administering to a
subject in need thereof an effective amount of a compound described
herein, or pharmaceutically acceptable salt thereof, or
pharmaceutical composition thereof. In some embodiments, the
CNS-related condition is an adjustment disorder, anxiety disorder
(including obsessive-compulsive disorder, posttraumatic stress
disorder, and social phobia), cognitive disorder (including
Alzheimer's disease and other forms of dementia (e.g.,
frontotemporal dementia), dissociative disorder, eating disorder,
mood disorder (including depression (e.g., postpartum depression),
bipolar disorder, dysthymic disorder, suicidality), schizophrenia
or other psychotic disorder (including schizoaffective disorder),
sleep disorder (including insomnia), substance-related disorder,
personality disorder (including obsessive-compulsive personality
disorder), autism spectrum disorders (including those involving
mutations to the Shank group of proteins (e.g., Shank3)),
neurodevelopmental disorder (including Rett syndrome, Tuberous
Sclerosis complex), multiple sclerosis, sterol synthesis disorders,
pain (including acute and chronic pain; headaches, e.g., migraine
headaches), encephalopathy secondary to a medical condition
(including hepatic encephalopathy and anti-NMDA receptor
encephalitis), seizure disorder (including status epilepticus and
monogenic forms of epilepsy such as Dravet's disease), stroke,
traumatic brain injury, movement disorder (including Huntington's
disease and Parkinson's disease), vision impairment, hearing loss,
and tinnitus.
[0059] In some embodiments, the disorder is Huntington's disease.
In some embodiments, the disorder is Parkinson's disease. In some
embodiments, the disorder is an inflammatory disease (e.g.,
lupus).
[0060] In some embodiments, the disorder is sterol synthesis
disorder.
[0061] In some embodiments, the disorder is Smith-Lemli-Opitz
Syndrome (SLOS). In some embodiments, the disorder is
desmosterolosis. In some embodiments, the disorder is
sitosterolemia. In some embodiments, the disorder is
cerebrotendinous xanthomatosis (CTX). In some embodiments, the
disorder is Mevalonate Kinase Deficiency (MKD). In some
embodiments, the disorder is SC4MOL gene mutation (SMO Deficiency).
In some embodiments, the disorder is Niemann-Pick disease. In some
embodiments, the disorder is autism spectrum disorder (ASD). In
some embodiments, the disorder is associated with
phenylketomuria.
[0062] Other objects and advantages will become apparent to those
skilled in the art from a consideration of the ensuing Detailed
Description, Examples, and Claims.
Definitions
Chemical Definitions
[0063] Definitions of specific functional groups and chemical terms
are described in more detail below. The chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed.,
inside cover, and specific functional groups are generally defined
as described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity,
are described in Thomas Sorrell, Organic Chemistry, University
Science Books, Sausalito, 1999; Smith and March, March's Advanced
Organic Chemistry, 5.sup.th Edition, John Wiley & Sons, Inc.,
New York, 2001; Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989; and Carruthers, Some Modern
Methods of Organic Synthesis, 3.sup.rd Edition, Cambridge
University Press, Cambridge, 1987.
[0064] Compounds described herein can comprise one or more
asymmetric centers, and thus can exist in various isomeric forms,
e.g., enantiomers and/or diastereomers. For example, the compounds
described herein can be in the form of an individual enantiomer,
diastereomer or geometric isomer, or can be in the form of a
mixture of stereoisomers, including racemic mixtures and mixtures
enriched in one or more stereoisomer. Isomers can be isolated from
mixtures by methods known to those skilled in the art, including
chiral high pressure liquid chromatography (HPLC) and the formation
and crystallization of chiral salts; or preferred isomers can be
prepared by asymmetric syntheses. See, for example, Jacques et al.,
Enantiomers, Racemates and Resolutions (Wiley Interscience, New
York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel,
Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); and
Wilen, Tables of Resolving Agents and Optical Resolutions p. 268
(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.
1972). The invention additionally encompasses compounds described
herein as individual isomers substantially free of other isomers,
and alternatively, as mixtures of various isomers.
[0065] Compound described herein may also comprise one or more
isotopic substitutions. For example, H may be in any isotopic form,
including .sup.1H, .sup.2H (D or deuterium), and .sup.3H (T or
tritium); C may be in any isotopic form, including .sup.12C,
.sup.13C, and .sup.14C; O may be in any isotopic form, including
.sup.16O and .sup.18O; and the like.
[0066] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example
"C.sub.1-6 alkyl" is intended to encompass, C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5,
C.sub.1-4, C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4,
C.sub.2-3, C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5,
and C.sub.5-6 alkyl.
[0067] The following terms are intended to have the meanings
presented therewith below and are useful in understanding the
description and intended scope of the present invention. When
describing the invention, which may include compounds,
pharmaceutical compositions containing such compounds and methods
of using such compounds and compositions, the following terms, if
present, have the following meanings unless otherwise indicated. It
should also be understood that when described herein any of the
moieties defined forth below may be substituted with a variety of
substituents, and that the respective definitions are intended to
include such substituted moieties within their scope as set out
below. Unless otherwise stated, the term "substituted" is to be
defined as set out below. It should be further understood that the
terms "groups" and "radicals" can be considered interchangeable
when used herein. The articles "a" and "an" may be used herein to
refer to one or to more than one (i.e. at least one) of the
grammatical objects of the article. By way of example "an analogue"
means one analogue or more than one analogue.
[0068] "Aliphatic" refers to an alkyl, alkenyl, alkynyl, or
carbocyclyl group, as defined herein.
[0069] "Alkyl" refers to a radical of a straight-chain or branched
saturated hydrocarbon group having from 1 to 20 carbon atoms
("C.sub.1-20 alkyl"). In some embodiments, an alkyl group has 1 to
12 carbon atoms ("C.sub.1-12 alkyl"). In some embodiments, an alkyl
group has 1 to 10 carbon atoms ("C.sub.1-10 alkyl"). In some
embodiments, an alkyl group has 1 to 9 carbon atoms ("C.sub.1-9
alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon
atoms ("C.sub.1-8 alkyl"). In some embodiments, an alkyl group has
1 to 7 carbon atoms ("C.sub.1-7 alkyl"). In some embodiments, an
alkyl group has 1 to 6 carbon atoms ("C.sub.1-6 alkyl", also
referred to herein as "lower alkyl"). In some embodiments, an alkyl
group has 1 to 5 carbon atoms ("C.sub.1-5 alkyl"). In some
embodiments, an alkyl group has 1 to 4 carbon atoms ("C.sub.1-4
alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon
atoms ("C.sub.1-3 alkyl"). In some embodiments, an alkyl group has
1 to 2 carbon atoms ("C.sub.1-2 alkyl"). In some embodiments, an
alkyl group has 1 carbon atom ("C.sub.1 alkyl"). In some
embodiments, an alkyl group has 2 to 6 carbon atoms ("C.sub.2-6
alkyl"). Examples of C.sub.1-6 alkyl groups include methyl
(C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), isopropyl
(C.sub.3), n-butyl (C.sub.4), tert-butyl (C.sub.4), sec-butyl
(C.sub.4), iso-butyl (C.sub.4), n-pentyl (C.sub.5), 3-pentanyl
(C.sub.5), amyl (C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butanyl
(C.sub.5), tertiary amyl (C.sub.5), and n-hexyl (C.sub.6).
Additional examples of alkyl groups include n-heptyl (C.sub.7),
n-octyl (C.sub.8) and the like. Unless otherwise specified, each
instance of an alkyl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a
"substituted alkyl") with one or more substituents; e.g., for
instance from 1 to 5 substituents, 1 to 3 substituents, or 1
substituent. In certain embodiments, the alkyl group is
unsubstituted C.sub.1-10 alkyl (e.g., --CH.sub.3). In certain
embodiments, the alkyl group is substituted C.sub.1-10 alkyl.
Common alkyl abbreviations include Me (--CH.sub.3), Et
(--CH.sub.2CH.sub.3), iPr (--CH(CH.sub.3).sub.2), nPr
(--CH.sub.2CH.sub.2CH.sub.3), n-Bu
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), or i-Bu
(--CH.sub.2CH(CH.sub.3).sub.2).
[0070] "Alkylene" refers to an alkyl group wherein two hydrogens
are removed to provide a divalent radical, and which may be
substituted or unsubstituted. Unsubstituted alkylene groups
include, but are not limited to, methylene (--CH.sub.2--), ethylene
(--CH.sub.2CH.sub.2--), propylene (--CH.sub.2CH.sub.2CH.sub.2--),
butylene (--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), pentylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), hexylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and the
like. Exemplary substituted alkylene groups, e.g., substituted with
one or more alkyl (methyl) groups, include but are not limited to,
substituted methylene (--CH(CH.sub.3)--, (--C(CH.sub.3).sub.2--),
substituted ethylene (--CH(CH.sub.3)CH.sub.2--,
--CH.sub.2CH(CH.sub.3)--, --C(CH.sub.3).sub.2CH.sub.2--,
--CH.sub.2C(CH.sub.3).sub.2--), substituted propylene
(--CH(CH.sub.3)CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3)CH.sub.2--, --CH.sub.2CH.sub.2CH(CH.sub.3)--,
--C(CH.sub.3).sub.2CH.sub.2CH.sub.2--,
--CH.sub.2C(CH.sub.3).sub.2CH.sub.2--,
--CH.sub.2CH.sub.2C(CH.sub.3).sub.2--), and the like. When a range
or number of carbons is provided for a particular alkylene group,
it is understood that the range or number refers to the range or
number of carbons in the linear carbon divalent chain. Alkylene
groups may be substituted or unsubstituted with one or more
substituents as described herein.
[0071] "Alkenyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon
double bonds), and optionally one or more carbon-carbon triple
bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C.sub.2-20
alkenyl"). In certain embodiments, alkenyl does not contain any
triple bonds. In some embodiments, an alkenyl group has 2 to 10
carbon atoms ("C.sub.2-10 alkenyl"). In some embodiments, an
alkenyl group has 2 to 9 carbon atoms ("C.sub.2-9 alkenyl"). In
some embodiments, an alkenyl group has 2 to 8 carbon atoms
("C.sub.2-8 alkenyl"). In some embodiments, an alkenyl group has 2
to 7 carbon atoms ("C.sub.2-7 alkenyl"). In some embodiments, an
alkenyl group has 2 to 6 carbon atoms ("C.sub.2-6 alkenyl"). In
some embodiments, an alkenyl group has 2 to 5 carbon atoms
("C.sub.2-5 alkenyl"). In some embodiments, an alkenyl group has 2
to 4 carbon atoms ("C.sub.2-4 alkenyl"). In some embodiments, an
alkenyl group has 2 to 3 carbon atoms ("C.sub.2-3 alkenyl"). In
some embodiments, an alkenyl group has 2 carbon atoms ("C.sub.2
alkenyl"). The one or more carbon-carbon double bonds can be
internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
Examples of C.sub.2-4 alkenyl groups include ethenyl (C.sub.2),
1-propenyl (C.sub.3), 2-propenyl (C.sub.3), 1-butenyl (C.sub.4),
2-butenyl (C.sub.4), butadienyl (C.sub.4), and the like. Examples
of C.sub.2-6 alkenyl groups include the aforementioned C.sub.2-4
alkenyl groups as well as pentenyl (C.sub.5), pentadienyl
(C.sub.5), hexenyl (C.sub.6), and the like. Additional examples of
alkenyl include heptenyl (C.sub.7), octenyl (C.sub.8), octatrienyl
(C.sub.8), and the like. Unless otherwise specified, each instance
of an alkenyl group is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted alkenyl") or substituted (a
"substituted alkenyl") with one or more substituents e.g., for
instance from 1 to 5 substituents, 1 to 3 substituents, or 1
substituent. In certain embodiments, the alkenyl group is
unsubstituted C.sub.2-10 alkenyl. In certain embodiments, the
alkenyl group is substituted C.sub.2-10 alkenyl.
[0072] "Alkynyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon
triple bonds), and optionally one or more carbon-carbon double
bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C.sub.2-20
alkynyl"). In certain embodiments, alkynyl does not contain any
double bonds. In some embodiments, an alkynyl group has 2 to 10
carbon atoms ("C.sub.2-10 alkynyl"). In some embodiments, an
alkynyl group has 2 to 9 carbon atoms ("C.sub.2-9 alkynyl"). In
some embodiments, an alkynyl group has 2 to 8 carbon atoms
("C.sub.2-8 alkynyl"). In some embodiments, an alkynyl group has 2
to 7 carbon atoms ("C.sub.2-7 alkynyl"). In some embodiments, an
alkynyl group has 2 to 6 carbon atoms ("C.sub.2-6 alkynyl"). In
some embodiments, an alkynyl group has 2 to 5 carbon atoms
("C.sub.2-5 alkynyl"). In some embodiments, an alkynyl group has 2
to 4 carbon atoms ("C.sub.2-4 alkynyl"). In some embodiments, an
alkynyl group has 2 to 3 carbon atoms ("C.sub.2-3 alkynyl"). In
some embodiments, an alkynyl group has 2 carbon atoms ("C.sub.2
alkynyl"). The one or more carbon-carbon triple bonds can be
internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
Examples of C.sub.2-4 alkynyl groups include, without limitation,
ethynyl (C.sub.2), 1-propynyl (C.sub.3), 2-propynyl (C.sub.3),
1-butynyl (C.sub.4), 2-butynyl (C.sub.4), and the like. Examples of
C.sub.2-6 alkenyl groups include the aforementioned C.sub.2-4
alkynyl groups as well as pentynyl (C.sub.5), hexynyl (C.sub.6),
and the like. Additional examples of alkynyl include heptynyl
(C.sub.7), octynyl (C.sub.8), and the like. Unless otherwise
specified, each instance of an alkynyl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
alkynyl") or substituted (a "substituted alkynyl") with one or more
substituents; e.g., for instance from 1 to 5 substituents, 1 to 3
substituents, or 1 substituent. In certain embodiments, the alkynyl
group is unsubstituted C.sub.2-10 alkynyl. In certain embodiments,
the alkynyl group is substituted C.sub.2-10 alkynyl.
[0073] The term "heteroalkyl," as used herein, refers to an alkyl
group, as defined herein, which further comprises 1 or more (e.g.,
1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron,
silicon, phosphorus) within the parent chain, wherein the one or
more heteroatoms is inserted between adjacent carbon atoms within
the parent carbon chain and/or one or more heteroatoms is inserted
between a carbon atom and the parent molecule, i.e., between the
point of attachment. In certain embodiments, a heteroalkyl group
refers to a saturated group having from 1 to 10 carbon atoms and 1,
2, 3, or 4 heteroatoms ("heteroC.sub.1-10 alkyl"). In some
embodiments, a heteroalkyl group is a saturated group having 1 to 9
carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC.sub.1-9
alkyl"). In some embodiments, a heteroalkyl group is a saturated
group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms
("heteroC.sub.1-8 alkyl"). In some embodiments, a heteroalkyl group
is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4
heteroatoms ("heteroC.sub.1-7 alkyl"). In some embodiments, a
heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2,
or 3 heteroatoms ("heteroC.sub.1-8 alkyl"). In some embodiments, a
heteroalkyl group is a saturated group having 1 to 5 carbon atoms
and 1 or 2 heteroatoms ("heteroC.sub.1-5 alkyl"). In some
embodiments, a heteroalkyl group is a saturated group having 1 to 4
carbon atoms and 1 or 2 heteroatoms ("heteroC.sub.1-4 alkyl"). In
some embodiments, a heteroalkyl group is a saturated group having 1
to 3 carbon atoms and 1 heteroatom ("heteroC.sub.1-3 alkyl"). In
some embodiments, a heteroalkyl group is a saturated group having 1
to 2 carbon atoms and 1 heteroatom ("heteroC.sub.1-2 alkyl"). In
some embodiments, a heteroalkyl group is a saturated group having 1
carbon atom and 1 heteroatom ("heteroC.sub.1 alkyl"). In some
embodiments, a heteroalkyl group is a saturated group having 2 to 6
carbon atoms and 1 or 2 heteroatoms ("heteroC.sub.2-6 alkyl").
Unless otherwise specified, each instance of a heteroalkyl group is
independently unsubstituted (an "unsubstituted heteroalkyl") or
substituted (a "substituted heteroalkyl") with one or more
substituents. In certain embodiments, the heteroalkyl group is an
unsubstituted heteroC.sub.1-10 alkyl. In certain embodiments, the
heteroalkyl group is a substituted heteroC.sub.1-10 alkyl.
[0074] "'Aryl" refers to a radical of a monocyclic or polycyclic
(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g.,
having 6, 10, or 14 .pi. electrons shared in a cyclic array) having
6-14 ring carbon atoms and zero heteroatoms provided in the
aromatic ring system ("C.sub.6-14 aryl"). In some embodiments, an
aryl group has six ring carbon atoms ("C.sub.6 aryl"; e.g.,
phenyl). In some embodiments, an aryl group has ten ring carbon
atoms ("C.sub.10 aryl"; e.g., naphthyl such as 1-naphthyl and
2-naphthyl). In some embodiments, an aryl group has fourteen ring
carbon atoms ("C.sub.14 aryl"; e.g., anthracyl). "Aryl" also
includes ring systems wherein the aryl ring, as defined above, is
fused with one or more carbocyclyl or heterocyclyl groups wherein
the radical or point of attachment is on the aryl ring, and in such
instances, the number of carbon atoms continue to designate the
number of carbon atoms in the aryl ring system. Typical aryl groups
include, but are not limited to, groups derived from aceanthrylene,
acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,
chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,
hexalene, as-indacene, s-indacene, indane, indene, naphthalene,
octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,
pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and
trinaphthalene. Particularly aryl groups include phenyl, naphthyl,
indenyl, and tetrahydronaphthyl. Unless otherwise specified, each
instance of an aryl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted aryl") or substituted (a
"substituted aryl") with one or more substituents. In certain
embodiments, the aryl group is unsubstituted C.sub.6-14 aryl. In
certain embodiments, the aryl group is substituted C.sub.6-14
aryl.
[0075] In certain embodiments, an aryl group substituted with one
or more of groups selected from halo, C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 haloalkyl, cyano, hydroxy, C.sub.1-C.sub.8 alkoxy,
and amino.
[0076] Examples of representative substituted aryls include the
following
##STR00027##
wherein one of R.sup.56 and R.sup.57 may be hydrogen and at least
one of R.sup.56 and R.sup.57 is each independently selected from
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 haloalkyl, 4-10 membered
heterocyclyl, alkanoyl, C.sub.1-C.sub.8 alkoxy, heteroaryloxy,
alkylamino, arylamino, heteroarylamino, NR.sup.58COR.sup.59,
NR.sup.58SOR.sup.59NR.sup.58SO.sub.2R.sup.59, COOalkyl, COOaryl,
CONR.sup.58R.sup.59, CONR.sup.58OR.sup.59, NR.sup.58R.sup.59,
SO.sub.2NR.sup.58R.sup.59, S-alkyl, SOalkyl, SO.sub.2alkyl, Saryl,
SOaryl, SO.sub.2aryl; or R.sup.56 and R.sup.57 may be joined to
form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms,
optionally containing one or more heteroatoms selected from the
group N, O, or S. R.sup.60 and R.sup.61 are independently hydrogen,
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.3-C.sub.10
cycloalkyl, 4-10 membered heterocyclyl, C.sub.6-C.sub.10 aryl,
substituted C.sub.6-C.sub.10 aryl, 5-10 membered heteroaryl, or
substituted 5-10 membered heteroaryl.
[0077] "Fused aryl" refers to an aryl having two of its ring carbon
in common with a second aryl or heteroaryl ring or with a
carbocyclyl or heterocyclyl ring.
[0078] "Aralkyl" is a subset of alkyl and aryl, as defined herein,
and refers to an optionally substituted alkyl group substituted by
an optionally substituted aryl group.
[0079] "Heteroaryl" refers to a radical of a 5-10 membered
monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or
10 r electrons shared in a cyclic array) having ring carbon atoms
and 1-4 ring heteroatoms provided in the aromatic ring system,
wherein each heteroatom is independently selected from nitrogen,
oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl
groups that contain one or more nitrogen atoms, the point of
attachment can be a carbon or nitrogen atom, as valency permits.
Heteroaryl bicyclic ring systems can include one or more
heteroatoms in one or both rings. "Heteroaryl" includes ring
systems wherein the heteroaryl ring, as defined above, is fused
with one or more carbocyclyl or heterocyclyl groups wherein the
point of attachment is on the heteroaryl ring, and in such
instances, the number of ring members continue to designate the
number of ring members in the heteroaryl ring system. "Heteroaryl"
also includes ring systems wherein the heteroaryl ring, as defined
above, is fused with one or more aryl groups wherein the point of
attachment is either on the aryl or heteroaryl ring, and in such
instances, the number of ring members designates the number of ring
members in the fused (aryl/heteroaryl) ring system. Bicyclic
heteroaryl groups wherein one ring does not contain a heteroatom
(e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of
attachment can be on either ring, i.e., either the ring bearing a
heteroatom (e.g., 2-indolyl) or the ring that does not contain a
heteroatom (e.g., 5-indolyl).
[0080] In some embodiments, a heteroaryl group is a 5-10 membered
aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms provided in the aromatic ring system, wherein each
heteroatom is independently selected from nitrogen, oxygen, and
sulfur ("5-10 membered heteroaryl"). In some embodiments, a
heteroaryl group is a 5-8 membered aromatic ring system having ring
carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring
system, wherein each heteroatom is independently selected from
nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some
embodiments, a heteroaryl group is a 5-6 membered aromatic ring
system having ring carbon atoms and 1-4 ring heteroatoms provided
in the aromatic ring system, wherein each heteroatom is
independently selected from nitrogen, oxygen, and sulfur ("5-6
membered heteroaryl"). In some embodiments, the 5-6 membered
heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen,
and sulfur. In some embodiments, the 5-6 membered heteroaryl has
1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In
some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom
selected from nitrogen, oxygen, and sulfur. Unless otherwise
specified, each instance of a heteroaryl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
heteroaryl") or substituted (a "substituted heteroaryl") with one
or more substituents. In certain embodiments, the heteroaryl group
is unsubstituted 5-14 membered heteroaryl. In certain embodiments,
the heteroaryl group is substituted 5-14 membered heteroaryl.
[0081] Exemplary 5-membered heteroaryl groups containing one
heteroatom include, without limitation, pyrrolyl, furanyl and
thiophenyl. Exemplary 5-membered heteroaryl groups containing two
heteroatoms include, without limitation, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary
5-membered heteroaryl groups containing three heteroatoms include,
without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
Exemplary 5-membered heteroaryl groups containing four heteroatoms
include, without limitation, tetrazolyl. Exemplary 6-membered
heteroaryl groups containing one heteroatom include, without
limitation, pyridinyl. Exemplary 6-membered heteroaryl groups
containing two heteroatoms include, without limitation,
pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered
heteroaryl groups containing three or four heteroatoms include,
without limitation, triazinyl and tetrazinyl, respectively.
Exemplary 7-membered heteroaryl groups containing one heteroatom
include, without limitation, azepinyl, oxepinyl, and thiepinyl.
Exemplary 5,6-bicyclic heteroaryl groups include, without
limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,
benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,
benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and
purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without
limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
[0082] Examples of representative heteroaryls include the
following:
##STR00028##
wherein each Z is selected from carbonyl, N, NR.sup.65, O, and S;
and R.sup.65 is independently hydrogen, C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.1 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, and 5-10 membered heteroaryl.
[0083] "Heteroaralkyl" is a subset of alkyl and heteroaryl, as
defined herein, and refers to an optionally substituted alkyl group
substituted by an optionally substituted heteroaryl group.
[0084] "Carbocyclyl" or "carbocyclic" refers to a radical of a
non-aromatic cyclic hydrocarbon group having from 3 to 10 ring
carbon atoms ("C.sub.3-10 carbocyclyl") and zero heteroatoms in the
non-aromatic ring system. In some embodiments, a carbocyclyl group
has 3 to 8 ring carbon atoms ("C.sub.3-8 carbocyclyl"). In some
embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 carbocyclyl"). In some embodiments, a carbocyclyl group
has 3 to 6 ring carbon atoms ("C.sub.3-6 carbocyclyl"). In some
embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 carbocyclyl"). Exemplary C.sub.3-6 carbocyclyl groups
include, without limitation, cyclopropyl (C.sub.3), cyclopropenyl
(C.sub.3), cyclobutyl (C.sub.4), cyclobutenyl (C.sub.4),
cyclopentyl (C.sub.5), cyclopentenyl (C.sub.5), cyclohexyl
(C.sub.6), cyclohexenyl (C.sub.6), cyclohexadienyl (C.sub.6), and
the like. Exemplary C.sub.3-8 carbocyclyl groups include, without
limitation, the aforementioned C.sub.3-6 carbocyclyl groups as well
as cycloheptyl (C.sub.7), cycloheptenyl (C.sub.7), cycloheptadienyl
(C.sub.7), cycloheptatrienyl (C.sub.7), cyclooctyl (C.sub.8),
cyclooctenyl (C.sub.8), bicyclo[2.2.1]heptanyl (C.sub.7),
bicyclo[2.2.2]octanyl (C.sub.8), and the like. Exemplary C.sub.3-10
carbocyclyl groups include, without limitation, the aforementioned
C.sub.3-8 carbocyclyl groups as well as cyclononyl (C.sub.9),
cyclononenyl (C.sub.9), cyclodecyl (C.sub.10), cyclodecenyl
(C.sub.10), octahydro-1H-indenyl (C.sub.9), decahydronaphthalenyl
(C.sub.10), spiro[4.5]decanyl (C.sub.10), and the like. As the
foregoing examples illustrate, in certain embodiments, the
carbocyclyl group is either monocyclic ("monocyclic carbocyclyl")
or contain a fused, bridged or spiro ring system such as a bicyclic
system ("bicyclic carbocyclyl") and can be saturated or can be
partially unsaturated. "Carbocyclyl" also includes ring systems
wherein the carbocyclyl ring, as defined above, is fused with one
or more aryl or heteroaryl groups wherein the point of attachment
is on the carbocyclyl ring, and in such instances, the number of
carbons continue to designate the number of carbons in the
carbocyclic ring system. Unless otherwise specified, each instance
of a carbocyclyl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted
(a "substituted carbocyclyl") with one or more substituents. In
certain embodiments, the carbocyclyl group is unsubstituted
C.sub.3-10 carbocyclyl. In certain embodiments, the carbocyclyl
group is a substituted C.sub.3-10 carbocyclyl.
[0085] In some embodiments, "carbocyclyl" is a monocyclic,
saturated carbocyclyl group having from 3 to 10 ring carbon atoms
("C.sub.3-10 cycloalkyl"). In some embodiments, a cycloalkyl group
has 3 to 8 ring carbon atoms ("C.sub.3-8 cycloalkyl"). In some
embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 cycloalkyl"). In some embodiments, a cycloalkyl group
has 5 to 6 ring carbon atoms ("C.sub.5-6 cycloalkyl"). In some
embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 cycloalkyl"). Examples of C.sub.5-6 cycloalkyl groups
include cyclopentyl (C.sub.5) and cyclohexyl (C.sub.5). Examples of
C.sub.3-6 cycloalkyl groups include the aforementioned C.sub.5-6
cycloalkyl groups as well as cyclopropyl (C.sub.3) and cyclobutyl
(C.sub.4). Examples of C.sub.3-8 cycloalkyl groups include the
aforementioned C.sub.3-6 cycloalkyl groups as well as cycloheptyl
(C.sub.7) and cyclooctyl (C.sub.8). Unless otherwise specified,
each instance of a cycloalkyl group is independently unsubstituted
(an "unsubstituted cycloalkyl") or substituted (a "substituted
cycloalkyl") with one or more substituents. In certain embodiments,
the cycloalkyl group is unsubstituted C.sub.3-10 cycloalkyl. In
certain embodiments, the cycloalkyl group is substituted C.sub.3-10
cycloalkyl.
[0086] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3-
to 10-membered non-aromatic ring system having ring carbon atoms
and 1 to 4 ring heteroatoms, wherein each heteroatom is
independently selected from nitrogen, oxygen, sulfur, boron,
phosphorus, and silicon ("3-10 membered heterocyclyl"). In
heterocyclyl groups that contain one or more nitrogen atoms, the
point of attachment can be a carbon or nitrogen atom, as valency
permits. A heterocyclyl group can either be monocyclic ("monocyclic
heterocyclyl") or a fused, bridged or spiro ring system such as a
bicyclic system ("bicyclic heterocyclyl"), and can be saturated or
can be partially unsaturated. Heterocyclyl bicyclic ring systems
can include one or more heteroatoms in one or both rings.
"Heterocyclyl" also includes ring systems wherein the heterocyclyl
ring, as defined above, is fused with one or more carbocyclyl
groups wherein the point of attachment is either on the carbocyclyl
or heterocyclyl ring, or ring systems wherein the heterocyclyl
ring, as defined above, is fused with one or more aryl or
heteroaryl groups, wherein the point of attachment is on the
heterocyclyl ring, and in such instances, the number of ring
members continue to designate the number of ring members in the
heterocyclyl ring system. Unless otherwise specified, each instance
of heterocyclyl is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted heterocyclyl") or substituted (a
"substituted heterocyclyl") with one or more substituents. In
certain embodiments, the heterocyclyl group is unsubstituted 3-10
membered heterocyclyl. In certain embodiments, the heterocyclyl
group is substituted 3-10 membered heterocyclyl.
[0087] In some embodiments, a heterocyclyl group is a 5-10 membered
non-aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms, wherein each heteroatom is independently selected from
nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10
membered heterocyclyl"). In some embodiments, a heterocyclyl group
is a 5-8 membered non-aromatic ring system having ring carbon atoms
and 1-4 ring heteroatoms, wherein each heteroatom is independently
selected from nitrogen, oxygen, and sulfur ("5-8 membered
heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6
membered non-aromatic ring system having ring carbon atoms and 1-4
ring heteroatoms, wherein each heteroatom is independently selected
from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In
some embodiments, the 5-6 membered heterocyclyl has 1-3 ring
heteroatoms selected from nitrogen, oxygen, and sulfur. In some
embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms
selected from nitrogen, oxygen, and sulfur. In some embodiments,
the 5-6 membered heterocyclyl has one ring heteroatom selected from
nitrogen, oxygen, and sulfur.
[0088] Exemplary 3-membered heterocyclyl groups containing one
heteroatom include, without limitation, azirdinyl, oxiranyl,
thiorenyl. Exemplary 4-membered heterocyclyl groups containing one
heteroatom include, without limitation, azetidinyl, oxetanyl and
thietanyl. Exemplary 5-membered heterocyclyl groups containing one
heteroatom include, without limitation, tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl,
pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary
5-membered heterocyclyl groups containing two heteroatoms include,
without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and
oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups
containing three heteroatoms include, without limitation,
triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary
6-membered heterocyclyl groups containing one heteroatom include,
without limitation, piperidinyl, tetrahydropyranyl,
dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl
groups containing two heteroatoms include, without limitation,
piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered
heterocyclyl groups containing two heteroatoms include, without
limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups
containing one heteroatom include, without limitation, azepanyl,
oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups
containing one heteroatom include, without limitation, azocanyl,
oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups
fused to a C.sub.6 aryl ring (also referred to herein as a
5,6-bicyclic heterocyclic ring) include, without limitation,
indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,
benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl
groups fused to an aryl ring (also referred to herein as a
6,6-bicyclic heterocyclic ring) include, without limitation,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
[0089] "Nitrogen-containing heterocyclyl" group means a 4- to
7-membered non-aromatic cyclic group containing at least one
nitrogen atom, for example, but without limitation, morpholine,
piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl),
pyrrolidine (e.g. 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine,
pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline,
pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl
piperazine. Particular examples include azetidine, piperidone and
piperazone.
[0090] "Hetero" when used to describe a compound or a group present
on a compound means that one or more carbon atoms in the compound
or group have been replaced by a nitrogen, oxygen, or sulfur
heteroatom. Hetero may be applied to any of the hydrocarbyl groups
described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g.,
heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g.,
cycloheteroalkenyl, and the like having from 1 to 5, and
particularly from 1 to 3 heteroatoms.
[0091] "Acyl" refers to a radical --C(O)R.sup.20, where R.sup.20 is
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, as defined herein.
"Alkanoyl" is an acyl group wherein R.sup.20 is a group other than
hydrogen. Representative acyl groups include, but are not limited
to, formyl (--CHO), acetyl (--C(.dbd.O)CH.sub.3),
cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl
(--C(.dbd.O)Ph), benzylcarbonyl (--C(.dbd.O)CH.sub.2Ph),
C(O)--C.sub.1-C.sub.8 alkyl,
--C(O)--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--C(O)--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--C(O)--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--C(O)--(CH.sub.2).sub.t(4-10 membered heterocyclyl), wherein t is
an integer from 0 to 4. In certain embodiments, R.sup.21 is
C.sub.1-C.sub.8 alkyl, substituted with halo or hydroxy; or
C.sub.3-C.sub.10 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, arylalkyl, 5-10 membered heteroaryl or
heteroarylalkyl, each of which is substituted with unsubstituted
C.sub.1-C.sub.4 alkyl, halo, unsubstituted C.sub.1-C.sub.4 alkoxy,
unsubstituted C.sub.1-C.sub.4 haloalkyl, unsubstituted
C.sub.1-C.sub.4 hydroxyalkyl, or unsubstituted C1-C.sub.4
haloalkoxy or hydroxy.
[0092] "Alkoxy" refers to the group --OR.sup.29 where R.sup.29 is
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl. Particular alkoxy groups are methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy,
n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy
groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms.
Further particular alkoxy groups have between 1 and 4 carbon
atoms.
[0093] In certain embodiments, R.sup.29 is a group that has 1 or
more substituents, for instance from 1 to 5 substituents, and
particularly from 1 to 3 substituents, in particular 1 substituent,
selected from the group consisting of amino, substituted amino,
C.sub.6-C.sub.10 aryl, aryloxy, carboxyl, cyano, C.sub.3-C.sub.10
cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered
heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol,
alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--. Exemplary `substituted alkoxy` groups include,
but are not limited to, --O--(CH.sub.2).sub.t(C.sub.6-C.sub.10
aryl), --O--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--O--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--O--(CH.sub.2).sub.t(4-10 membered heterocyclyl), wherein t is an
integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or
heterocyclyl groups present, may themselves be substituted by
unsubstituted C.sub.1-C.sub.4 alkyl, halo, unsubstituted
C.sub.1-C.sub.4 alkoxy, unsubstituted C.sub.1-C.sub.4 haloalkyl,
unsubstituted C.sub.1-C.sub.4 hydroxyalkyl, or unsubstituted
C.sub.1-C.sub.4 haloalkoxy or hydroxy. Particular exemplary
`substituted alkoxy` groups are --OCF.sub.3, --OCH.sub.2CF.sub.3,
--OCH.sub.2Ph, --OCH.sub.2-cyclopropyl, --OCH.sub.2CH.sub.2OH, and
--OCH.sub.2CH.sub.2NMe.sub.2.
[0094] "Amino" refers to the radical --NH.sub.2.
[0095] "Substituted amino" refers to an amino group of the formula
--N(R.sup.38).sub.2 wherein R.sup.38 is hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl, or
an amino protecting group, wherein at least one of R.sup.38 is not
a hydrogen. In certain embodiments, each R.sup.38 is independently
selected from hydrogen, C.sub.1-C.sub.5 alkyl, C.sub.3-C.sub.5
alkenyl, C.sub.3-C.sub.8 alkynyl, C.sub.6-C.sub.10 aryl, 5-10
membered heteroaryl, 4-10 membered heterocyclyl, or
C.sub.3-C.sub.10 cycloalkyl; or C.sub.1-C.sub.8 alkyl, substituted
with halo or hydroxy; C.sub.3-C.sub.8 alkenyl, substituted with
halo or hydroxy; C.sub.3-C.sub.8 alkynyl, substituted with halo or
hydroxy, or --(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), or
--(CH.sub.2).sub.t(4-10 membered heterocyclyl), wherein t is an
integer between 0 and 8, each of which is substituted by
unsubstituted C.sub.1-C.sub.4 alkyl, halo, unsubstituted
C.sub.1-C.sub.4 alkoxy, unsubstituted C.sub.1-C.sub.4 haloalkyl,
unsubstituted C.sub.1-C.sub.4 hydroxyalkyl, or unsubstituted
C.sub.1-C.sub.4 haloalkoxy or hydroxy; or both R.sup.38 groups are
joined to form an alkylene group.
[0096] Exemplary "substituted amino" groups include, but are not
limited to, --NR.sup.39--C.sub.1-C.sub.8 alkyl,
--NR.sup.39--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--NR.sup.39--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--NR.sup.39--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--NR.sup.39--(CH.sub.2).sub.t(4-10 membered heterocyclyl), wherein
t is an integer from 0 to 4, for instance 1 or 2, each R.sup.3
independently represents H or C.sub.1-C.sub.8 alkyl; and any alkyl
groups present, may themselves be substituted by halo, substituted
or unsubstituted amino, or hydroxy; and any aryl, heteroaryl,
cycloalkyl, or heterocyclyl groups present, may themselves be
substituted by unsubstituted C.sub.1-C.sub.4 alkyl, halo,
unsubstituted C.sub.1-C.sub.4 alkoxy, unsubstituted C.sub.1-C.sub.4
haloalkyl, unsubstituted C.sub.1-C.sub.4 hydroxyalkyl, or
unsubstituted C.sub.1-C.sub.4 haloalkoxy or hydroxy. For the
avoidance of doubt the term `substituted amino` includes the groups
alkylamino, substituted alkylamino, alkylarylamino, substituted
alkylarylamino, arylamino, substituted arylamino, dialkylamino, and
substituted dialkylamino as defined below. Substituted amino
encompasses both monosubstituted amino and disubstituted amino
groups.
[0097] "Carboxy" refers to the radical --C(O)OH.
[0098] "Cyano" refers to the radical --CN.
[0099] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo
(Br), and iodo (I). In certain embodiments, the halo group is
either fluoro or chloro.
[0100] "Hydroxy" refers to the radical --OH.
[0101] "Nitro" refers to the radical --NO.sub.2.
[0102] "Cycloalkylalkyl" refers to an alkyl radical in which the
alkyl group is substituted with a cycloalkyl group. Typical
cycloalkylalkyl groups include, but are not limited to,
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl,
cyclopropylethyl, cyclobutylethyl, cyclopentylethyl,
cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the
like.
[0103] "Heterocyclylalkyl" refers to an alkyl radical in which the
alkyl group is substituted with a heterocyclyl group. Typical
heterocyclylalkyl groups include, but are not limited to,
pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl,
morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl,
piperazinylethyl, morpholinylethyl, and the like.
[0104] "Thioketo" refers to the group .dbd.S.
[0105] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
and heteroaryl groups, as defined herein, are optionally
substituted (e.g., "substituted" or "unsubstituted" alkyl,
"substituted" or "unsubstituted" alkenyl, "substituted" or
"unsubstituted" alkynyl, "substituted" or "unsubstituted"
carbocyclyl, "substituted" or "unsubstituted" heterocyclyl,
"substituted" or "unsubstituted" aryl or "substituted" or
"unsubstituted" heteroaryl group). In general, the term
"substituted", whether preceded by the term "optionally" or not,
means that at least one hydrogen present on a group (e.g., a carbon
or nitrogen atom) is replaced with a permissible substituent, e.g.,
a substituent which upon substitution results in a stable compound,
e.g., a compound which does not spontaneously undergo
transformation such as by rearrangement, cyclization, elimination,
or other reaction. Unless otherwise indicated, a "substituted"
group has a substituent at one or more substitutable positions of
the group, and when more than one position in any given structure
is substituted, the substituent is either the same or different at
each position. The term "substituted" is contemplated to include
substitution with all permissible substituents of organic
compounds, any of the substituents described herein that results in
the formation of a stable compound. The present invention
contemplates any and all such combinations in order to arrive at a
stable compound. For purposes of this invention, heteroatoms such
as nitrogen may have hydrogen substituents and/or any suitable
substituent as described herein which satisfy the valencies of the
heteroatoms and results in the formation of a stable moiety.
[0106] Exemplary carbon atom substituents include, but are not
limited to, halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H,
--SO.sub.3H, --OH, --OR.sup.aa, --ON(R.sup.bb).sub.2,
--N(R.sup.bb).sub.2, --N(R.sup.bb).sub.3.sup.+X.sup.-,
--N(OR.sup.cc)R.sup.bb, --SH, --SR.sup.aa--, --SSR.sup.cc,
--C(.dbd.O)R.sup.aa, --CO.sub.2H, --CHO, --C(OR.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --OC(.dbd.O)R.sup.aa, --OCO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --OC(.dbd.O)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.O)R.sup.aa, --NR.sup.bbCO.sub.2R.sup.aa,
--NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --OC(.dbd.NR.sup.bb)R.sup.aa,
--OC(.dbd.NR.sup.bb)OR.sup.aa,
--C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbSO.sub.2R.sup.aa,
--SO.sub.2N(R.sup.bb).sub.2, --SO.sub.2R.sup.aa,
--SO.sub.2OR.sup.aa, --OSO.sub.2R.sup.aa, --S(.dbd.O)R.sup.aa,
--OS(.dbd.O)R.sup.aa, --Si(R.sup.aa).sub.3,
--OSi(R.sup.aa).sub.3--C(.dbd.S)N(R.sup.bb).sub.2,
--C(.dbd.O)SR.sup.aa, --C(.dbd.S)SR.sup.aa, --SC(.dbd.S)SR.sup.aa,
--SC(.dbd.O)SR.sup.aa, --OC(.dbd.O)SR.sup.aa,
--SC(.dbd.O)OR.sup.aa, --SC(.dbd.O)R.sup.aa,
--P(.dbd.O).sub.2R.sup.aa, --OP(.dbd.O).sub.2R.sup.aa,
--P(.dbd.O)(R.sup.aa).sub.2, --OP(.dbd.O)(R.sup.aa).sub.2,
--OP(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
--OP(.dbd.O).sub.2N(R.sup.bb).sub.2, --P(.dbd.O)(NR.sup.bb).sub.2,
--OP(.dbd.O)(NR.sup.bb).sub.2--NR.sup.bbP(.dbd.O)(OR.sup.cc).sub.2,
--NR.sup.bbP(.dbd.O)(NR.sup.bb).sub.2, --P(R.sup.cc),
--P(R.sup.cc).sub.3, --OP(R.sup.cc).sub.2, --OP(R.sup.cc).sub.3,
--B(R.sup.aa).sub.2, --B(OR.sup.cc).sub.2,
--BR.sup.aa(OR.sup.cc).sub.2, C.sub.1-10 alkyl, C.sub.1-10
perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently
substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups;
[0107] or two geminal hydrogens on a carbon atom are replaced with
the group .dbd.O, .dbd.S, .dbd.NN(R.sup.bb).sub.2,
--NNR.sup.bbC(.dbd.O)R.sup.aa, .dbd.NNR.sup.bbC(.dbd.O)OR.sup.aa,
--NNR.sup.bbS(.dbd.O).sub.2R.sup.aa, .dbd.NR.sup.bb, or
.dbd.NOR.sup.cc;
[0108] each instance of R.sup.aa is, independently, selected from
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.aa groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0109] each instance of R.sup.bb is, independently, selected from
hydrogen, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2, --CN,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--S.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2,
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.bb groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0110] each instance of R is, independently, selected from
hydrogen, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.cc groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0111] each instance of R.sup.dd is, independently, selected from
halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H,
--OH, --OR.sup.ee, --ON(R.sup.ff).sub.2, --N(R.sup.ff).sub.2,
--N(R.sup.ff).sub.3.sup.+X.sup.-, --N(OR.sup.ee)R.sup.ff, --SH,
--SR.sup.ee, --SSR.sup.ee, --C(.dbd.O)R.sup.ee, --CO.sub.2H,
--CO.sub.2R.sup.ee, --OC(.dbd.O)R.sup.ee, --OCO.sub.2R.sup.ee,
--C(.dbd.O)N(R.sup.ff).sub.2, --OC(.dbd.O)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.O)R.sup.ee, --NR.sup.ffCO.sub.2R.sup.ee,
--NR.sup.ffC(.dbd.O)N(R.sup.ff).sub.2,
--C(.dbd.NR.sup.ff)OR.sup.ee, --OC(.dbd.NR.sup.ff)R.sup.ee,
--OC(.dbd.NR.sup.ff)OR.sup.ee,
--C(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--OC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffSO.sub.2R.sup.ee, --SO.sub.2N(R.sup.ff).sub.2,
--SO.sub.2R.sup.ee, --SO.sub.2OR.sup.ee, --OSO.sub.2R.sup.ee,
--S(.dbd.O)R.sup.ee, --Si(R.sup.ee).sub.3, --OSi(R.sup.ee).sub.3,
--C(.dbd.S)N(R.sup.ff).sub.2, --C(.dbd.O)SR.sup.ee,
--C(.dbd.S)SR.sup.ee, --SC(.dbd.S)SR.sup.ee,
--P(.dbd.O).sub.2R.sup.ee, --P(.dbd.O)(R.sup.ee).sub.2,
--OP(.dbd.O)(R.sup.ee).sub.2--OP(.dbd.O)(OR.sup.ee).sub.2,
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, wherein
each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5
R.sup.gg groups, or two geminal R.sup.dd substituents can be joined
to form .dbd.O or .dbd.S;
[0112] each instance of R.sup.ee is, independently, selected from
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10
membered heterocyclyl, and 3-10 membered heteroaryl, wherein each
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5
R.sup.gg groups;
[0113] each instance of R.sup.ff is, independently, selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl and 5-10 membered heteroaryl, or two
R.sup.f groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups;
and
[0114] each instance of R.sup.gg is, independently, halogen, --CN,
--NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH, --OC.sub.1-6
alkyl, --ON(C.sub.1-6 alkyl).sub.2, --N(C.sub.1-6 alkyl).sub.2,
--N(C.sub.1-6 alkyl).sub.3.sup.+X.sup.-, --NH(C.sub.1-6
alkyl).sub.2.sup.+X.sup.-, --NH.sub.2(C.sub.1-6 alkyl).sup.+X,
--NH.sub.3.sup.+X.sup.-, --N(OC.sub.1-6 alkyl)(C.sub.1-6 alkyl),
--N(OH)(C.sub.1-6 alkyl), --NH(OH), --SH, --SC.sub.1-6 alkyl,
--SS(C.sub.1-6 alkyl), --C(.dbd.O)(C.sub.1-6 alkyl), --CO.sub.2H,
--CO.sub.2(C.sub.1-6 alkyl), --OC(.dbd.O)(C.sub.1-6 alkyl),
--OCO.sub.2(C.sub.1-6 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)N(C.sub.1-6 alkyl).sub.2, --OC(.dbd.O)NH(C.sub.1-6
alkyl), --NHC(.dbd.O)(C.sub.1-6 alkyl), --N(C.sub.1-6
alkyl)C(.dbd.O)(C.sub.1-6 alkyl), --NHCO.sub.2(C.sub.1-6 alkyl),
--NHC(.dbd.O)N(C.sub.1-6 alkyl).sub.2, --NHC(.dbd.O)NH(C.sub.1-6
alkyl), --NHC(.dbd.O)NH.sub.2, --C(.dbd.NH)O(C.sub.1-6 alkyl),
--OC(.dbd.NH)(C.sub.1-6 alkyl), --OC(.dbd.NH)OC.sub.1-6 alkyl,
--C(.dbd.NH)N(C.sub.1-6 alkyl).sub.2, --C(.dbd.NH)NH(C.sub.1-6
alkyl), --C(.dbd.NH)NH.sub.2, --OC(.dbd.NH)N(C.sub.1-6
alkyl).sub.2, --OC(NH)NH(C.sub.1-6 alkyl), --OC(NH)NH.sub.2,
--NHC(NH)N(C.sub.1-6 alkyl).sub.2, --NHC(.dbd.NH)NH.sub.2,
--NHSO.sub.2(C.sub.1-6 alkyl), --SO.sub.2N(C.sub.1-6 alkyl).sub.2,
--SO.sub.2NH(C.sub.1-6 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2C.sub.1-6 alkyl, --SO.sub.2OC.sub.1-6 alkyl,
--OSO.sub.2C.sub.1-6 alkyl, --SOC.sub.1-6 alkyl, --Si(C.sub.1-6
alkyl).sub.3, --OSi(C.sub.1-6 alkyl).sub.3-C(.dbd.S)N(C.sub.1-6
alkyl).sub.2, C(.dbd.S)NH(C.sub.1-6 alkyl), C(.dbd.S)NH.sub.2,
--C(.dbd.O)S(C.sub.1-6 alkyl), --C(.dbd.S)SC.sub.1-6 alkyl,
--SC(.dbd.S)SC.sub.1-6 alkyl, --P(.dbd.O).sub.2(C.sub.1-6 alkyl),
--P(.dbd.O)(C.sub.1-6 alkyl).sub.2, --OP(.dbd.O)(C.sub.1-6
alkyl).sub.2, --OP(.dbd.O)(OC.sub.1-6 alkyl).sub.2, C.sub.1-6
alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10 membered
heterocyclyl, 5-10 membered heteroaryl; or two geminal R.sup.gg
substituents can be joined to form .dbd.O or .dbd.S; wherein
X.sup.- is a counterion.
[0115] A "counterion" or "anionic counterion" is a negatively
charged group associated with a cationic quaternary amino group in
order to maintain electronic neutrality. Exemplary counterions
include halide ions (e.g., F.sup.-, Cl.sup.-, Br.sup.-, I.sup.-),
NO.sub.3.sup.-, ClO.sub.4.sup.-, OH.sup.-, H.sub.2PO.sub.4.sup.-,
HSO.sub.4.sup.-, SO.sub.4.sup.-2 sulfonate ions (e.g.,
methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,
benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,
naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic
acid-2-sulfonate, and the like), and carboxylate ions (e.g.,
acetate, ethanoate, propanoate, benzoate, glycerate, lactate,
tartrate, glycolate, and the like).
[0116] Nitrogen atoms can be substituted or unsubstituted as
valency permits, and include primary, secondary, tertiary, and
quaternary nitrogen atoms. Exemplary nitrogen atom substitutents
include, but are not limited to, hydrogen, --OH, --OR.sup.aa,
--N(R.sup.cc).sub.2, --CN, --C(.dbd.O)R.sup.aa,
--C(.dbd.O)N(R.sup.cc).sub.2, --CO.sub.2R.sup.aa,
--SO.sub.2R.sup.aa, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2,
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.cc groups attached to a nitrogen atom are joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.dd groups, and wherein R.sup.aa, R.sup.bb, R.sup.cc
and R.sup.dd are as defined above.
[0117] These and other exemplary substituents are described in more
detail in the Detailed Description, Examples, and claims. The
invention is not intended to be limited in any manner by the above
exemplary listing of substituents.
Other Definitions
[0118] The term "pharmaceutically acceptable salt" refers to those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well known in the art.
For example, Berge et al., describes pharmaceutically acceptable
salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.
Pharmaceutically acceptable salts of the compounds of this
invention include those derived from suitable inorganic and organic
acids and bases. Examples of pharmaceutically acceptable, nontoxic
acid addition salts are salts of an amino group formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid and perchloric acid or with organic
acids such as acetic acid, oxalic acid, maleic acid, tartaric acid,
citric acid, succinic acid or malonic acid or by using other
methods used in the art such as ion exchange. Other
pharmaceutically acceptable salts include adipate, alginate,
ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Pharmaceutically acceptable salts derived from appropriate bases
include alkali metal, alkaline earth metal, ammonium and
N.sup.+(C.sub.1-4alkyl).sub.4 salts. Representative alkali or
alkaline earth metal salts include sodium, lithium, potassium,
calcium, magnesium, and the like. Further pharmaceutically
acceptable salts include, when appropriate, nontoxic ammonium,
quaternary ammonium, and amine cations formed using counterions
such as halide, hydroxide, carboxylate, sulfate, phosphate,
nitrate, lower alkyl sulfonate, and aryl sulfonate.
[0119] A "subject" to which administration is contemplated
includes, but is not limited to, humans (i.e., a male or female of
any age group, e.g., a pediatric subject (e.g, infant, child,
adolescent) or adult subject (e.g., young adult, middle-aged adult
or senior adult)) and/or a non-human animal, e.g., a mammal such as
primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs,
horses, sheep, goats, rodents, cats, and/or dogs. In certain
embodiments, the subject is a human. In certain embodiments, the
subject is a non-human animal. The terms "human," "patient," and
"subject" are used interchangeably herein.
[0120] Disease, disorder, and condition are used interchangeably
herein.
[0121] As used herein, and unless otherwise specified, the terms
"treat," "treating" and "treatment" contemplate an action that
occurs while a subject is suffering from the specified disease,
disorder or condition, which reduces the severity of the disease,
disorder or condition, or retards or slows the progression of the
disease, disorder or condition ("therapeutic treatment"), and also
contemplates an action that occurs before a subject begins to
suffer from the specified disease, disorder or condition
("prophylactic treatment").
[0122] In general, the "effective amount" of a compound refers to
an amount sufficient to elicit the desired biological response. As
will be appreciated by those of ordinary skill in this art, the
effective amount of a compound of the invention may vary depending
on such factors as the desired biological endpoint, the
pharmacokinetics of the compound, the disease being treated, the
mode of administration, and the age, health, and condition of the
subject. An effective amount encompasses therapeutic and
prophylactic treatment.
[0123] As used herein, and unless otherwise specified, a
"therapeutically effective amount" of a compound is an amount
sufficient to provide a therapeutic benefit in the treatment of a
disease, disorder or condition, or to delay or minimize one or more
symptoms associated with the disease, disorder or condition. A
therapeutically effective amount of a compound means an amount of
therapeutic agent, alone or in combination with other therapies,
which provides a therapeutic benefit in the treatment of the
disease, disorder or condition. The term "therapeutically effective
amount" can encompass an amount that improves overall therapy,
reduces or avoids symptoms or causes of disease or condition, or
enhances the therapeutic efficacy of another therapeutic agent.
[0124] As used herein, and unless otherwise specified, a
"prophylactically effective amount" of a compound is an amount
sufficient to prevent a disease, disorder or condition, or one or
more symptoms associated with the disease, disorder or condition,
or prevent its recurrence. A prophylactically effective amount of a
compound means an amount of a therapeutic agent, alone or in
combination with other agents, which provides a prophylactic
benefit in the prevention of the disease, disorder or condition.
The term "prophylactically effective amount" can encompass an
amount that improves overall prophylaxis or enhances the
prophylactic efficacy of another prophylactic agent.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[0125] As generally described herein, the present invention
provides substituted oxysterols useful for preventing and/or
treating a broad range of disorders, including, but not limited to,
NMDA-mediated disorders. These compounds are expected to show
improved in vivo potency, pharmacokinetic (PK) properties, oral
bioavailability, formulatability, stability, and/or safety as
compared to other oxysterols.
Compounds
[0126] In one aspect, the present invention features a compound of
Formula (I):
##STR00029##
or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is
C.sub.1-6 alkyl; each of R.sup.2 and R.sup.3 is independently
hydrogen, C.sub.1-6 alkyl, or carbocyclyl; or R.sup.2 and R.sup.3,
together with the carbon atom to which they are attached, form a
3-8 membered ring; R.sup.6 is absent or hydrogen; each of R.sup.7
and R.sup.8 is independently hydrogen, halogen, C.sub.1-6 alkyl, or
carbocyclyl; or each of R.sup.7 and R.sup.8, together with the
carbon atom to which they are attached, form a 3-8 membered ring;
or R.sup.2 and R.sup.7, together with the carbon atoms to which
they are attached, form a 3-8 membered ring; n is 1, 2, or 3; and
represents a single or double bond, wherein when one is a double
bond, the other is a single bond; and when one of the is a double
bond, R.sup.6 is absent.
[0127] In some embodiments, R.sup.1 is substituted C.sub.1-6 alkyl.
In some embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl. In
some embodiments, R.sup.1 is methyl (e.g., --CHF.sub.2, --CH.sub.3,
--CF.sub.3, --CH.sub.2OCH.sub.3, or --CH.sub.2OCH.sub.2CH.sub.3),
ethyl, or isopropyl. In some embodiments, R.sup.1 is --CH.sub.3. In
some embodiments, R.sup.1 is ethyl.
[0128] In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl, or wherein
R.sup.2 and R.sup.3 are taken together with the carbon atom to
which they are attached form a 3-8 membered ring. In some
embodiments, the 3-8 membered ring is a carbocyclyl ring (e.g.,
cyclopropyl). In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl. In some
embodiments, each of R.sup.2 and R.sup.3 is independently hydrogen,
methyl (e.g., --CH.sub.3, --CF.sub.3), ethyl (e.g.,
--CH.sub.2CH.sub.3, CH.sub.2CF.sub.3), propyl, isopropyl,
cyclopropyl, or butyl.
[0129] In some embodiments, R.sup.2 substituted C.sub.1-6 alkyl. In
some embodiments, R.sup.2 unsubstituted C.sub.1-6 alkyl.
[0130] In some embodiments, R.sup.2 is hydrogen, methyl (e.g.,
--CH.sub.3, --CF.sub.3), ethyl, or isopropyl.
[0131] In some embodiments, R.sup.3 substituted C.sub.1-6 alkyl. In
some embodiments, R.sup.3 unsubstituted C.sub.1-6 alkyl.
[0132] In some embodiments, R.sup.3 is methyl (e.g., --CH.sub.3,
--CF.sub.3), ethyl (e.g., --CH.sub.2CH.sub.3, --CH.sub.2CF.sub.3),
propyl, isopropyl, cyclopropyl, or butyl.
[0133] In some embodiments, R.sup.2 and R.sup.3 are hydrogen. In
some embodiments, R.sup.2 is hydrogen and R.sup.3 is C.sub.1-6
alkyl (e.g., methyl (e.g., --CH.sub.3, --CF.sub.3), ethyl,
isopropyl). In some embodiments, R.sup.2 is C.sub.1-6 alkyl and
R.sup.3 is C.sub.1-6 alkyl. In some embodiments, R.sup.2 and
R.sup.3 are --CH.sub.3. In some embodiments, R.sup.2 is --CH.sub.3
and R.sup.3 is --CF.sub.3. In some embodiments, R.sup.2 is
--CH.sub.3 and R.sup.3 is ethyl. In some embodiments, R.sup.2 is
--CH.sub.3 and R.sup.3 is isopropyl.
[0134] In some embodiments, each of is a single bond.
[0135] In some embodiments, R.sup.6 is hydrogen. In some
embodiments, R.sup.6 is in the alpha position. In some embodiments,
R.sup.6 is in the beta position.
[0136] In some embodiments, R.sup.6 is absent.
[0137] In some embodiments, R.sup.7 and R.sup.8 are hydrogen.
[0138] In some embodiments, n is 1. In some embodiments, n is 1 and
R.sup.7 and R are hydrogen.
[0139] In some embodiments, n is 2. In some embodiments, n is 2 and
each of R.sup.7 and R.sup.8 is independently hydrogen, halogen,
C.sub.1-6 alkyl, or carbocyclyl.
[0140] In some embodiments, the compound Formula (I) is a compound
of Formula (II):
##STR00030##
or a pharmaceutically acceptable salt thereof.
[0141] In some embodiments, the compound of Formula (II) is a
compound of Formula (II-A) or Formula (II-B):
##STR00031##
or a pharmaceutically acceptable salt thereof.
[0142] In some embodiments, the compound of Formula (I) is a
compound of Formula (II-B-i) or Formula (II-B-ii):
##STR00032##
or a pharmaceutically acceptable salt thereof.
[0143] In some embodiments, the compound of Formula (I) is a
compound of Formula (II-B-iii):
##STR00033##
or a pharmaceutically acceptable salt thereof.
[0144] In some embodiments, the compound of Formula (I) is a
compound of Formula (III):
##STR00034##
or a pharmaceutically acceptable salt thereof.
[0145] In some embodiments, the compound of Formula (III) is a
compound of Formula (III-A) or Formula (III-B):
##STR00035##
or a pharmaceutically acceptable salt thereof.
[0146] In some embodiments, the compound of Formula (III-B) is a
compound of Formula (III-C) or Formula (III-D):
##STR00036##
or a pharmaceutically acceptable salt thereof.
[0147] In some embodiments, the compound of Formula (III-A) is a
compound of Formula (III-E) or Formula (III-F):
##STR00037##
or a pharmaceutically acceptable salt thereof.
[0148] In some embodiments, the compound of Formula (III) is a
compound of Formula (III-A-i-a) or Formula (III-B-i-a):
##STR00038##
or a pharmaceutically acceptable salt thereof.
[0149] In some embodiments, R.sup.1 is methyl (e.g., --CHIF.sub.2,
--CF.sub.3, --CH.sub.2OCH.sub.3, or --CH.sub.2OCH.sub.2CH.sub.3),
ethyl, or isopropyl.
[0150] In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl, or wherein
R.sup.2 and R.sup.3 are taken together with the carbon atom to
which they are attached form a 3-8 membered ring.
[0151] In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl.
[0152] In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, methyl (e.g., --CH.sub.3, --CF.sub.3),
ethyl (e.g., --CH.sub.2CH.sub.3, --CH.sub.2CF.sub.3), propyl,
isopropyl, cyclopropyl, or butyl.
[0153] In some embodiments, R.sup.2 is hydrogen, methyl (e.g.,
--CH.sub.3, --CF.sub.3), or ethyl.
[0154] In some embodiments, R.sup.3 is methyl (e.g., --CH.sub.3,
--CF.sub.3), ethyl (e.g., --CH.sub.2CH.sub.3, --CH.sub.2CF.sub.3),
propyl, isopropyl, cyclopropyl, or butyl.
[0155] In some embodiments, the compound is selected from the group
consisting of:
##STR00039##
or a pharmaceutically acceptable salt thereof.
[0156] In some embodiments, the compound of Formula (I) is a
compound of Formula (IV):
##STR00040##
or a pharmaceutically acceptable salt thereof.
[0157] In some embodiments, R.sup.1 is methyl (e.g., --CHF.sub.2,
--CF.sub.3, --CH.sub.2OCH.sub.3, or --CH.sub.2OCH.sub.2CH.sub.3),
ethyl, or isopropyl.
[0158] In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl, or wherein
R.sup.2 and R.sup.3 are taken together with the carbon atom to
which they are attached form a 3-8 membered ring.
[0159] In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, C.sub.1-6 alkyl, or carbocyclyl.
[0160] In some embodiments, each of R.sup.2 and R.sup.3 is
independently hydrogen, methyl (e.g., --CH.sub.3, --CF.sub.3),
ethyl (e.g., --CH.sub.2CH.sub.3, CH.sub.2CF.sub.3), propyl,
isopropyl, cyclopropyl, or butyl.
[0161] In some embodiments, R.sup.2 is hydrogen, methyl (e.g.,
--CH.sub.3, --CF.sub.3), or ethyl.
[0162] In some embodiments, R.sup.3 is methyl (e.g., --CH.sub.3,
--CF.sub.3), ethyl (e.g., --CH.sub.2CH.sub.3, --CH.sub.2CF.sub.3),
propyl, isopropyl, cyclopropyl, butyl.
[0163] In some embodiments, the compound is:
##STR00041##
or a pharmaceutically acceptable salt thereof.
[0164] In some embodiments, the compound Formula (I) is a compound
of Formula (V):
##STR00042##
or a pharmaceutically acceptable salt thereof.
[0165] In some embodiments, the compound of Formula (I) is a
compound of Formula (V-A):
##STR00043##
or a pharmaceutically acceptable salt thereof.
[0166] In some embodiments, the compound of Formula (I) is a
compound of Formula (V-B):
##STR00044##
or a pharmaceutically acceptable salt thereof.
[0167] In some embodiments, the compound of Formula (III) is a
compound of Formula (V-C) or Formula (V-D):
##STR00045##
or a pharmaceutically acceptable salt thereof.
[0168] In some embodiments, the compound of Formula (I) is a
compound of Formula (V-E):
##STR00046##
or a pharmaceutically acceptable salt thereof.
[0169] In some embodiments, the compound of Formula (V-E) is a
compound of Formula (V-E-i):
##STR00047##
or a pharmaceutically acceptable salt thereof.
[0170] In some embodiments, the compound of Formula (I) is a
compound of Formula (V-E-ii) or (V-E-iii):
##STR00048##
or a pharmaceutically acceptable salt thereof.
[0171] In some embodiments, the compound is selected from:
##STR00049## ##STR00050## ##STR00051## ##STR00052##
##STR00053##
or a pharmaceutically acceptable salt thereof.
Pharmaceutical Compositions
[0172] In another aspect, the invention provides a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and an
effective amount of a compound of Formula (I).
[0173] When employed as pharmaceuticals, the compounds provided
herein are typically administered in the form of a pharmaceutical
composition. Such compositions can be prepared in a manner well
known in the pharmaceutical art and comprise at least one active
compound.
[0174] In one embodiment, with respect to the pharmaceutical
composition, the carrier is a parenteral carrier, oral or topical
carrier.
[0175] The present invention also relates to a compound of Formula
(I) or pharmaceutical composition thereof for use as a
pharmaceutical or a medicament.
[0176] Generally, the compounds provided herein are administered in
a therapeutically effective amount. The amount of the compound
actually administered will typically be determined by a physician,
in the light of the relevant circumstances, including the condition
to be treated, the chosen route of administration, the actual
compound administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[0177] The pharmaceutical compositions provided herein can be
administered by a variety of routes including oral, rectal,
transdermal, subcutaneous, intravenous, intramuscular, and
intranasal. Depending on the intended route of delivery, the
compounds provided herein are preferably formulated as either
injectable or oral compositions or as salves, as lotions or as
patches all for transdermal administration.
[0178] The compositions for oral administration can take the form
of bulk liquid solutions or suspensions, or bulk powders. More
commonly, however, the compositions are presented in unit dosage
forms to facilitate accurate dosing. The term "unit dosage forms"
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient. Typical unit dosage forms include
prefilled, premeasured ampules or syringes of the liquid
compositions or pills, tablets, capsules or the like in the case of
solid compositions. In such compositions, the compound is usually a
minor component (from about 0.1 to about 50% by weight or
preferably from about 1 to about 40% by weight) with the remainder
being various vehicles or carriers and processing aids helpful for
forming the desired dosing form.
[0179] Liquid forms suitable for oral administration may include a
suitable aqueous or nonaqueous vehicle with buffers, suspending and
dispensing agents, colorants, flavors and the like. Solid forms may
include, for example, any of the following ingredients, or
compounds of a similar nature: a binder such as microcrystalline
cellulose, gum tragacanth or gelatin; an excipient such as starch
or lactose, a disintegrating agent such as alginic acid, Primogel,
or corn starch; a lubricant such as magnesium stearate; a glidant
such as colloidal silicon dioxide; a sweetening agent such as
sucrose or saccharin; or a flavoring agent such as peppermint,
methyl salicylate, or orange flavoring.
[0180] Injectable compositions are typically based upon injectable
sterile saline or phosphate-buffered saline or other injectable
carriers known in the art. As before, the active compound in such
compositions is typically a minor component, often being from about
0.05 to 10% by weight with the remainder being the injectable
carrier and the like.
[0181] Transdermal compositions are typically formulated as a
topical ointment or cream containing the active ingredient(s),
generally in an amount ranging from about 0.01 to about 20% by
weight, preferably from about 0.1 to about 20% by weight,
preferably from about 0.1 to about 10% by weight, and more
preferably from about 0.5 to about 15% by weight. When formulated
as a ointment, the active ingredients will typically be combined
with either a paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream
with, for example an oil-in-water cream base. Such transdermal
formulations are well-known in the art and generally include
additional ingredients to enhance the dermal penetration of
stability of the active ingredients or the formulation. All such
known transdermal formulations and ingredients are included within
the scope provided herein.
[0182] The compounds provided herein can also be administered by a
transdermal device. Accordingly, transdermal administration can be
accomplished using a patch either of the reservoir or porous
membrane type, or of a solid matrix variety.
[0183] The above-described components for orally administrable,
injectable or topically administrable compositions are merely
representative. Other materials as well as processing techniques
and the like are set forth in Part 8 of Remington's Pharmaceutical
Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa.,
which is incorporated herein by reference.
[0184] The above-described components for orally administrable,
injectable, or topically administrable compositions are merely
representative. Other materials as well as processing techniques
and the like are set forth in Part 8 of Remington's The Science and
Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott
Williams & Wilkins, which is incorporated herein by
reference.
[0185] The compounds of this invention can also be administered in
sustained release forms or from sustained release drug delivery
systems. A description of representative sustained release
materials can be found in Remington's Pharmaceutical Sciences.
[0186] The present invention also relates to the pharmaceutically
acceptable formulations of a compound of Formula (I). In one
embodiment, the formulation comprises water. In another embodiment,
the formulation comprises a cyclodextrin derivative. The most
common cyclodextrins are .alpha.-, .beta.- and
.gamma.-cyclodextrins consisting of 6, 7 and 8 .alpha.-1,4-linked
glucose units, respectively, optionally comprising one or more
substituents on the linked sugar moieties, which include, but are
not limited to, methylated, hydroxyalkylated, acylated, and
sulfoalkylether substitution. In certain embodiments, the
cyclodextrin is a sulfoalkyl ether .beta.-cyclodextrin, e.g., for
example, sulfobutyl ether .beta.-cyclodextrin, also known as
Captisol.RTM.. See, e.g., U.S. Pat. No. 5,376,645. In certain
embodiments, the formulation comprises
hexapropyl-.beta.-cyclodextrin. In a more particular embodiment,
the formulation comprises hexapropyl-.beta.-cyclodextrin (10-50% in
water).
[0187] The present invention also relates to the pharmaceutically
acceptable acid addition salt of a compound of Formula (I). The
acid which may be used to prepare the pharmaceutically acceptable
salt is that which forms a non-toxic acid addition salt, i.e., a
salt containing pharmacologically acceptable anions such as the
hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate,
bisulfate, phosphate, acetate, lactate, citrate, tartrate,
succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and
the like.
[0188] The following formulation examples illustrate representative
pharmaceutical compositions that may be prepared in accordance with
this invention. The present invention, however, is not limited to
the following pharmaceutical compositions.
[0189] Exemplary Formulation 1--Tablets: A compound of Formula (I),
or pharmaceutically acceptable salt thereof, may be admixed as a
dry powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg
of active compound per tablet) in a tablet press.
[0190] Exemplary Formulation 2--Capsules: A compound of Formula
(I), or pharmaceutically acceptable salt thereof, may be admixed as
a dry powder with a starch diluent in an approximate 1:1 weight
ratio. The mixture is filled into 250 mg capsules (125 mg of active
compound per capsule).
[0191] Exemplary Formulation 3--Liquid: A compound of Formula (I),
or pharmaceutically acceptable salt thereof, (125 mg) may be
admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the
resultant mixture may be blended, passed through a No. 10 mesh U.S.
sieve, and then mixed with a previously made solution of
microcrystalline cellulose and sodium carboxymethyl cellulose
(11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color
are diluted with water and added with stirring. Sufficient water
may then be added to produce a total volume of 5 mL.
[0192] Exemplary Formulation 4--Tablets: A compound of Formula (I),
or pharmaceutically acceptable salt thereof, may be admixed as a
dry powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 450-900 mg tablets (150-300
mg of active compound) in a tablet press.
[0193] Exemplary Formulation 5--Injection: A compound of Formula
(I), or pharmaceutically acceptable salt thereof, may be dissolved
or suspended in a buffered sterile saline injectable aqueous medium
to a concentration of approximately 5 mg/mL.
[0194] Exemplary Formulation 6--Tablets: A compound of Formula (I),
or pharmaceutically acceptable salt thereof, may be admixed as a
dry powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg
of active compound per tablet) in a tablet press.
[0195] Exemplary Formulation 7--Tablets: A compound of Formula (I),
or pharmaceutically acceptable salt thereof, may be may be admixed
as a dry powder with a dry gelatin binder in an approximate 1:2
weight ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of
active compound per tablet) in a tablet press.
[0196] Exemplary Formulation 8--Tablets: A compound of Formula (I),
or pharmaceutically acceptable salt thereof, may be admixed as a
dry powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg
of active compound per tablet) in a tablet press.
[0197] Exemplary Formulation 9--Tablets: A compound of Formula (I),
or pharmaceutically acceptable salt thereof, may be admixed as a
dry powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg
of active compound per tablet) in a tablet press.
[0198] Exemplary Formulation 10--Tablets: A compound of Formula
(I), or pharmaceutically acceptable salt thereof, may be admixed as
a dry powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 270-450 mg tablets (90-150 mg
of active compound per tablet) in a tablet press.
[0199] Injection dose levels range from about 0.1 mg/kg/hour to at
least 10 mg/kg/hour, all for from about 1 to about 120 hours and
especially 24 to 96 hours. A preloading bolus of from about 0.1
mg/kg to about 10 mg/kg or more may also be administered to achieve
adequate steady state levels. The maximum total dose is not
expected to exceed about 2 g/day for a 40 to 80 kg human
patient.
[0200] For the prevention and/or treatment of long-term conditions
the regimen for treatment usually stretches over many months or
years so oral dosing is preferred for patient convenience and
tolerance. With oral dosing, one to five and especially two to four
and typically three oral doses per day are representative regimens.
Using these dosing patterns, each dose provides from about 0.01 to
about 20 mg/kg of the compound provided herein, with preferred
doses each providing from about 0.1 to about 10 mg/kg, and
especially about 1 to about 5 mg/kg.
[0201] Transdermal doses are generally selected to provide similar
or lower blood levels than are achieved using injection doses.
[0202] When used to prevent the onset of a CNS-disorder, the
compounds provided herein will be administered to a subject at risk
for developing the condition, typically on the advice and under the
supervision of a physician, at the dosage levels described above.
Subjects at risk for developing a particular condition generally
include those that have a family history of the condition, or those
who have been identified by genetic testing or screening to be
particularly susceptible to developing the condition.
Methods of Treatment and Use
[0203] Compounds of the present invention, e.g., a compound of
Formula (I), and pharmaceutically acceptable salts thereof, as
described herein, are generally designed to modulate NMDA function,
and therefore to act as oxysterols for the treatment and prevention
of, e.g., CNS-related conditions in a subject. In some embodiments,
the compounds described herein, e.g., a compound of Formula (I),
and pharmaceutically acceptable salts thereof, as described herein,
are generally designed to penetrate the blood brain barrier (e.g.,
designed to be transported across the blood brain barrier).
Modulation, as used herein, refers to, for example, the inhibition
or potentiation of NMDA receptor function. In certain embodiments,
the compound of Formula (I), or pharmaceutically acceptable salt
thereof, may act as a negative allosteric modulator (NAM) of NMDA,
and inhibit NMDA receptor function. In certain embodiments, the
present invention, e.g., a compound of Formula (I), or
pharmaceutically acceptable salt thereof, may act as positive
allosteric modulators (PAM) of NMDA, and potentiate NMDA receptor
function. In certain embodiments, the compound of Formula (I), or
pharmaceutically acceptable salt thereof, modulates NMDA function,
but does not act as a negative allosteric modulator (NAM) or
positive allosteric modulator (PAM) of NMDA.
[0204] In some embodiments, the disorder is cancer. In some
embodiments, the disorder is diabetes. In some embodiments, the
disorder is a sterol synthesis disorder. In some embodiments, the
disorder is a gastrointestinal (GI) disorder, e.g., constipation,
irritable bowel syndrome (IBS), inflammatory bowel disease (IBD)
(e.g., ulcerative colitis, Crohn's disease), structural disorders
affecting the GI, anal disorders (e.g., hemorrhoids, internal
hemorrhoids, external hemorrhoids, anal fissures, perianal
abscesses, anal fistula), colon polyps, cancer, colitis. In some
embodiments, the disorder is inflammatory bowel disease.
[0205] In some embodiments, the disorder is Smith-Lemli-Opitz
Syndrome (SLOS). In some embodiments, the disorder is
desmosterolosis. In some embodiments, the disorder is
sitosterolemia. In some embodiments, the disorder is
cerebrotendinous xanthomatosis (CTX). In some embodiments, the
disorder is Mevalonate Kinase Deficiency (MKD). In some
embodiments, the disorder is SC4MOL gene mutation (SMO Deficiency).
In some embodiments, the disorder is Niemann-Pick disease. In some
embodiments, the disorder is autism spectrum disorder (ASD). In
some embodiments, the disorder is associated with
phenylketomuria.
[0206] Exemplary conditions related to NMDA-modulation includes,
but are not limited to, gastrointestinal (GI) disorder, e.g.,
constipation, irritable bowel syndrome (IBS), inflammatory bowel
disease (IBD) (e.g., ulcerative colitis, Crohn's disease),
structural disorders affecting the GI, anal disorders (e.g.,
hemorrhoids, internal hemorrhoids, external hemorrhoids, anal
fissures, perianal abscesses, anal fistula), colon polyps, cancer,
colitis, and CNS conditions, e.g., as described herein.
[0207] Exemplary CNS conditions related to NMDA-modulation include,
but are not limited to, adjustment disorders, anxiety disorders
(including obsessive-compulsive disorder, posttraumatic stress
disorder, social phobia, generalized anxiety disorder), cognitive
disorders (including Alzheimer's disease and other forms of
dementia (e.g., frontotemporal dementia)), dissociative disorders,
eating disorders, mood disorders (including depression (e.g.,
postpartum depression), bipolar disorder, dysthymic disorder,
suicidality), schizophrenia or other psychotic disorders (including
schizoaffective disorder), sleep disorders (including insomnia),
substance abuse-related disorders, personality disorders (including
obsessive-compulsive personality disorder), autism spectrum
disorders (including those involving mutations to the Shank group
of proteins (e.g., Shank3)), neurodevelopmental disorders
(including Rett syndrome), multiple sclerosis, sterol synthesis
disorders, pain (including acute and chronic pain; headaches, e.g.,
migraine headaches), seizure disorders (including status
epilepticus and monogenic forms of epilepsy such as Dravet's
disease, and Tuberous Sclerosis Complex (TSC)), stroke, traumatic
brain injury, movement disorders (including Huntington's disease
and Parkinson's disease) and tinnitus. In certain embodiments, the
compound of the present invention, e.g., a compound of Formula (I),
or pharmaceutically acceptable salt thereof, can be used to induce
sedation or anesthesia. In certain embodiments, the compound of
Formula (I), or pharmaceutically acceptable salt thereof, is useful
in the treatment or prevention of adjustment disorders, anxiety
disorders, cognitive disorders, dissociative disorders, eating
disorders, mood disorders, schizophrenia or other psychotic
disorders, sleep disorders, substance-related disorders,
personality disorders, autism spectrum disorders,
neurodevelopmental disorders, sterol synthesis disorders, pain,
seizure disorders, stroke, traumatic brain injury, movement
disorders and vision impairment, hearing loss, and tinnitus. In
some embodiments, the disorder is Huntington's disease. In some
embodiments, the disorder is Parkinson's disease. In some
embodiments, the disorder is an inflammatory disease (e.g.,
lupus).
[0208] In another aspect, provided is a method of treating or
preventing brain excitability in a subject susceptible to or
afflicted with a condition associated with brain excitability,
comprising administering to the subject an effective amount of a
compound of the present invention, e.g., a compound of Formula (I),
or a pharmaceutically acceptable salt thereof.
[0209] In yet another aspect, the present invention provides a
combination of a compound of the present invention, e.g., a
compound of Formula (I), or pharmaceutically acceptable salt
thereof, and another pharmacologically active agent. The compounds
provided herein can be administered as the sole active agent or
they can be administered in combination with other agents.
Administration in combination can proceed by any technique apparent
to those of skill in the art including, for example, separate,
sequential, concurrent and alternating administration.
Diseases and Disorders
[0210] Described herein are methods of treating a sterol synthesis
disorder. Exemplary disorders are described herein. The methods
include administering to a subject, e.g., a subject suffering from
a sterol synthesis disorder such as SLOS, a NMDA receptor
modulating compound. Exemplary compounds are described herein.
Sterol Synthesis Disorders
[0211] In one aspect, described herein are methods for treating a
sterol synthesis disorder. Cholesterol has an essential rule in
growth and development. It is a membrance lipid and a precursor to
many molecules that play important roles in cellular growth and
differentiation, protein glycosylation, and signaling pathways.
Biosynthesis of cholesterol involves a number of enzymes and
intermediates. Disorders resulting from a deficiency in any of the
enzymes involved in cholesterol biosynthesis lead to the
accumulation of intermediates and imbalance in biomolecules,
resulting in disorders including congenital skeletal malformations,
dysmorphic facial features, psychomotor retardation, and failure to
thrive. In an embodiment, a sterol synthesis disorder or symptom of
a sterol synthesis disorder can be treated by administering to a
subject suffering from a sterol synthesis disorder a compound
described herein, such as a NMDA receptor modulating compound as
described herein. Additional disorders are described below.
Smith-Lemli-Opitz Syndrome
[0212] In one aspect, described herein are methods for treating
Smith-Lemli-Opitz Syndrome (or SLOS, or 7-dehydrocholesterol
reductase deficiency). SLOS is an inborn error of cholesterol
synthesis. In addition to microcephaly, moderate to severe
intellectual disability, sensory hypersensitivity, stereotyped
behaviors, dysmorphic facial features, and syndactyly of the
second/third toes, a feature of the disease is reduced
cerebrosterol (24(S)-hydroxycholesterol) levels. SLOS is an
autosomal recessive genetic condition resulting from deficiency in
the final enzyme of the cholesterol synthesis pathway, and causes
low or low-normal plasma cholesterol levels and increased 7- and
8-dehydrocholesterol (DHC; 7DHC and 8DHC) levels. Common therapies
currently used include dietary cholesterol supplementation,
treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase
inhibitors (HMG CoA reductase inhibitors, also known as statins),
and treatment with agents that enhance cholesterol production
and/or accretion; and to decrease the accumulation of 7DHC and
8DHC, the potentially toxic precursors of cholesterol.
Desmosterolosis
[0213] Desmosterolosis is a deficiency in desmosterol reductase and
has a similar phenotype to SLOS. In one aspect, described herein
are methods for treating desmosterolosis with compounds described
herein.
Sitosterolemia
[0214] Sitosterolemia is a rare autosomal recessive disorder caused
by mutations in two ATP-binding cassette (ABC) transporter genes
(ABCG5 and ABCG8). Sitosterolemia enhances the absorption of plant
sterols and cholesterol from the intestines. Patients typically
present with tendon and tuberous xanthomas and premature coronary
artery disease. In one aspect, described herein are methods for
treating sitosterolemia with compounds described herein.
Cerebrotendinous Xanthomatosis (CTX)
[0215] In one aspect, described herein are methods for treating
cerebrotendinous xanthomatosis (also referred to as cerebral
cholesterosis, or Van Bogaert-Scherer-Epstein syndrome) with
compounds described herein. CTX can be caused by a mutation in the
CYP27A1 gene, which produces the sterol 27-hydroxylase enzyme.
Sterol 27-hydroxylase metabolizes cholesterol into bile acids
(e.g., chenodeoxycholic acid) that are important in the absorption
of fats in the intestine. Enzyme dysfunction can lead to
cholesterol accumulation in tissues. CTX is characterized by
childhood diarrhea, cataracts, tendon xanthomas, reduced mental
capability and abnormal movements in adults.
Mevalonate Kinase Deficiency Syndromes (MKD)
[0216] Mevalonate Kinase Deficiency (also referred to as mevalonic
aciduria (a more severe form of MKD), or Hyper IgD Syndrome (HIDS,
or hyperimmunoglobulinemia D) with period fever syndrome (a more
benign form of MKD)) causes an accumulation of mevalonic acid in
the urine as a result of insufficient activity of mevalonate
kinase. MKD can result in developmental delay, hypotonia, anemia,
hepatosplenomegaly, dysmorphic features, mental retardation, and
overall failure to thrive. Mevalonic aciduria is characterized by
delayed physical and mental development, failure to thrive,
recurrent episodes of fever with vomiting and diarrhea, enlarged
liver, spleen and lymph nodes, microcephaly (small head size),
cataract, low muscle tone, short statute, distinctfacial features,
ataxia, and anemia. HIDS is characterized by recurrent episodes of
fever associated with swollen lymph nodes, joint pain,
gastrointestinal issues and skin rash. In one aspect, described
herein are methods for treating MKD with the compounds described
herein.
SC4MOL Gene Mutation (SMO Deficiency)
[0217] SC4MOL gene deficiency is a genetic disorder in the
cholesterol biosynthesis pathway (e.g., mutations in the SC4MOL
gene encoding a novel sterol oxidase). SC$MOL deficiency is
characterized by the accumulation of dimethyl and monomethyl
sterols that can be detected in blood, skin flakes or primary skin
fibroblasts. In one aspect, described herein are methods for
treating SMO deficiency with compounds described herein.
Niemann-Pick Disease
[0218] Niemann-Pick disease is a lysosomal storage disease
resulting from a genetic mutation that affects metabolism.
Niemann-Pick disease leads to abnormal accumulation of cholesterol
and other fatty substances (lipids) due to an inability of the body
to transport the substances. The accumulation damages the affected
areas.
Autism
[0219] In one aspect, described herein are methods for treating
autism spectrum disorder or autism. Autism spectrum disorder (ASD)
and autism refer to a group of complex disorders of brain
development. Autism is typically characterized by difficulties in
social interaction, for example in verbal and nonverbal
communication. Repetitive behaviors are also often seen in
individuals having autism. Autism can be associated with
intellectual disability, difficulties in motor coordination and
attention and physical health issues, e.g., sleep and
gastrointestinal disturbances. Individuals having autism can also
excel in visual skills, music, math and art. Autism can refer to
autistic disorder, childhood disintegrative disorder, pervasive
developmental disorder-not otherwise specified (PDD-NOS), and
Asperger syndrome. Autism also refers to monogenetic causes of
autism such as synaptophathy's, e.g., Rett syndrome, Fragile X
syndrome, Angelman syndrome.
Disorders Associated with Phenylketonuria
[0220] In one aspect, described herein are methods for treating
disorders associated with phenylketonuria (e.g., cognitive
disorders) with compounds described herein. Phenylketonuria can
lead to hypochesterolemia and lowered vitamin D status. Total and
low-density cholesterols and 25-hydroxy vitamin D have been found
to be decreased in subjects suffering from phenylketonuria as
compared with subjects not suffering from phenylketonuria (Clin.
Chim. Acta 2013, 416: 54-59). 24S-hydroxycholesterol and
27S-hydroxycholesterol and 7.alpha.-hydroxycholesterol (e.g.,
representing peripheral and hepatic cholesterol elimination,
respectively) have been shown to be significantly decreased in
subjects suffering from phenylketonuria, while
70-hydroxycholesterol (e.g., reflecting oxidative stress) was
increased significantly in subjects suffering from phenylketonuria.
Changes in the levels of 24S--OHC and 7.beta.-hydroxycholesterol
correlate with phenylalanine level, and 27S-hydroxycholesterol
levels may correlate with the 25-hydroxy vitamin D level in
subjects suffering from phenylketonuria.
Abbreviations
[0221] PCC: pyridinium chlorochromate; t-BuOK: potassium
tert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane;
Pd(t-Bu.sub.3P).sub.2: bis(tri-tert-butylphosphine)palladium(0);
AcCl: acetyl chloride; i-PrMgCl: Isopropylmagnesium chloride;
TBSCl: tert-Butyl(chloro)dimethylsilane; (i-PrO).sub.4Ti: titanium
tetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me:
methyl; Ph: phenyl; Et: ethyl; Bz: benzoyl; DCC:
dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP:
4-dimethylaminopyridine; DMP: Dess-Martin periodinane; EtOAc: ethyl
acetate; TEA: triethylamine; AlaOH: alanine; Boc: t-butoxycarbonyl.
Py: pydidine; TBAF: tetra-n-butylammonium fluoride; THF:
tetrahydrofuran; TMS: trimethylsilyl. MAD: methyl aluminum
bis(2,6-di-t-butyl-4-methylphenoxide); Na.sub.2SO.sub.4: sodium
sulfate; Na.sub.2S.sub.2O.sub.3: sodium thiosulfate; PE: petroleum
ether; MeCN: acetonitrile; MeOH: methanol; Py: pyridine, Boc:
t-butoxycarbonyl; MTBE: methyl tert-butyl ether.
EXAMPLES
[0222] In order that the invention described herein may be more
fully understood, the following examples are set forth. The
synthetic and biological examples described in this application are
offered to illustrate the compounds, pharmaceutical compositions,
and methods provided herein and are not to be construed in any way
as limiting their scope.
[0223] The stereochemistry assigned herein (e.g., the assignment of
"R" or "S" to the C25 or C27 position of the steroid) may be
tentatively (e.g., randomly) assigned. For example, a C25 position
may be drawn in the "R" configuration when the absolute
configuration is "S." A C25 position may also be drawn in the "S"
configuration when the absolute configuration is "R."
Example 1. Synthesis of Compound 1
##STR00054##
[0225] Step 1. To a solution of reactant A1 (700 mg, 1.73 mmol) in
dry CH.sub.2Cl.sub.2 (5 mL) was added Dess-Martin reagent (1.09 g,
2.59 mmol) in portions at 0.degree. C. The reaction mixture was
stirred at 25.degree. C. for 3 h. The mixture was quenched with
saturated aqueous NaHC.sub.3/Na.sub.2S.sub.2O.sub.3 (1:3, 15 mL)
and extracted with EtOAc (2.times.50 mL). The organic phase was
then washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and
concentrated to afford A2 as a crude residue (700 mg), which was
directly used in the next step without further purification.
[0226] Step 2. To a solution of BHT (2.29 g, 10.4 mmol) in toluene
(10 mL) was added a solution of AlMe.sub.3 (2.61 mL, 5.22 mmol) in
2 M in toluene at 25.degree. C. The resulting mixture was stirred
at 25.degree. C. for 1 h, after which a solution of A2 (700 mg,
1.74 mmol) in toluene (5 mL) was added at -78.degree. C. under
nitrogen. The mixture was stirred for an additional for 30 min,
after which MeMgBr (3.0 M in Et.sub.2O, 1.74 mL, 5.22 mmol) was
added dropwise at -78.degree. C. The reaction mixture was stirred
at this temperature for 3 h, then quenched with saturated aqueous
NH.sub.4Cl solution (30 mL) at -78.degree. C. The resulting
suspension was filtered and the filter cake was washed with EtOAc
(2.times.50 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4, concentrated and purified by silica gel
(PE/EtOAc=10/1 to 8/1) to afford Compound 1 (120 mg, 17%) as an off
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.30 (d,
J=3.6 Hz, 1H), 2.40-2.30 (m, 1H), 1.99-1.98 (m, 3H), 1.70-1.57 (m,
4H), 1.46-1.17 (m, 28H), 1.11-0.92 (m, 8H), 0.67 (s, 3H). LCMS
Rt=1.503 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for
C.sub.28H.sub.49O.sub.2 [M+H].sup.+ 417, found C.sub.28H.sub.45
[M-2H.sub.2O+H].sup.+ 381.
Example 2. Synthesis of Compounds 2 and 3
##STR00055##
[0228] Step 1. To a solution of Compound 1 (55 mg, 0.131 mmol) in
EtOAc (10 mL) was added Pd/C (50 mg). The reaction mixture was
stirred under hydrogen (50 psi) at 50.degree. C. for 12 h, after
which time it was filtered through a pad of celite. The filtrate
was concentrated under reduced pressure and the resulting residue
was purified by silica gel (PE/EtOAc=10/1) to afford both Compound
2 (5 mg, 9%) and Compound 3 (47.8 mg, 87%), each as an off white
solid. Compound 2: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.96
(d, J=12.4 Hz, 1H), 1.80-1.62 (m, 1H), 1.60-1.57 (m, 3H), 1.46-1.24
(m, 28H), 1.21-0.92 (m, 10H), 0.90 (s, 3H), 0.70-0.64 (m, 4H). LCMS
Rt=1.568 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for
C.sub.28H.sub.51O.sub.2 [M+H].sup.+ 419, found C.sub.28H.sub.47
[M-2H.sub.2O+H].sup.+ 383 Compound 3: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.98-1.79 (m, 5H), 1.75-1.57 (m, 2H), 1.55-0.98
(m, 34H), 0.96 (s, 3H), 0.91 (d, J 8.4 Hz, 3H), 0.64 (s, 3H). LCMS
Rt=1.590 min in 2 min chromatography, 10-80 AB, MS ESI calcd. for
C.sub.28H.sub.51O.sub.2 [M+H].sup.+ 419, found C.sub.28H.sub.47
[M-2H.sub.2O+H].sup.+ 383.
Example 3. Synthesis of Compounds 4, 5, and 6
##STR00056## ##STR00057## ##STR00058##
[0230] Step 1. A mixture of propiolic acid B1 (20 g, 285 mmol) in
40% HBr (150 mL) was stirred at 110.degree. C. for 2 hrs. The
mixture was cooled in ice water. The precipitated solid was
filtered out and washed with excess water to give B2 (25 g, 58%) as
a brown solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.69 (br.
s., 1H), 7.76 (d, J=14.4 Hz, 1H), 6.54 (d, J=13.6 Hz, 1H).
[0231] Step 2. To a suspension of B2 (8.5 g, 56.3 mmol) in MeOH (15
mL) was added 98% H.sub.2SO.sub.4 (2.80 g, 28.1 mmol). The mixture
was stirred at 25.degree. C. for 24 hrs. The reaction mixture was
evaporated in vacuum. The distillation was washed with water (20
mL). The organic layer was separated and dried over
Na.sub.2SO.sub.4 to give B3 (7 g, 75%) as colorless oil.
[0232] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.61 (d, J=14.0
Hz, 1H), 6.53 (d, J=14.0 Hz, 1H), 3.76 (s, 3H).
[0233] Step 3. To a suspension of Ph.sub.3PMeBr (67.5 g, 189 mmol)
in anhydrous THE (300 mL) under N.sub.2 was added t-BuOK (21.2 g,
189 mmol). After stirred at 60.degree. C. for 30 min, A3 (20 g,
63.1 mmol) was added. The resulting mixture was stirred at
60.degree. C. for 4 hrs. The reaction mixture was poured into ice
water (500 mL), extracted with EtOAc (2.times.500 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by column chromatography on
silica gel (PE/EtOAc=15/1) to give A4 (18 g, 91%) as an off white
solid.
[0234] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.39-5.32 (m, 1H),
4.85 (s, 1H), 4.71 (s, 1H), 3.59-3.47 (m, 1H), 2.36-2.17 (m, 2H),
2.07-1.94 (m, 2H), 1.89-1.65 (m, 9H), 1.60-1.39 (m, 6H), 1.26-0.92
(m, 8H), 0.59 (s, 3H).
[0235] Step 4. To a solution of A4 (18 g, 57.2 mmol) in anhydrous
DCM (150 mL) was added Ac.sub.2O (8.75 g, 85.8 mmol) and DMAP (13.9
g, 114 mmol). The mixture was stirred at 25.degree. C. for 2 hrs.
The reaction mixture was diluted with water (200 mL), extracted
with DCM (3.times.150 mL). The combined organic layer was washed
with saturated NaHCO.sub.3 (150 mL) and brine (150 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give A5
(20 g, 99%) as an off white solid.
[0236] Step 5. To solution of A5 (30 g, 84.1 mmol) in anhydrous TH
(150 mL) under nitrogen atmosphere at 30.degree. C. was added 9-BBN
(0.5 M in THF, 185 mL, 92.5 mmol). The mixture was stirred at
75.degree. C. for 3 hrs. The reaction mixture was cooled to
30.degree. C., and (E)-methyl 3-bromoacrylate (15.2 g, 92.5 mmol),
CsF (25.5 g, 168 mmol) and Pd(t-Bu.sub.3P).sub.2 (4.55 g, 8.40
mmol) were added. The resulting mixture was stirred at 75.degree.
C. for 16 hrs. The reaction was cooled, quenched with water (300
mL), extracted with EtOAc (3.times.300 mL). The combined organic
layer was dried over Na.sub.2SO.sub.4, filtered through a pad of
silica gel and concentrated. The residue was triturated from MeOH
to give A6 (20 g, 54%) as an off white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.00-6.90 (m, 1H), 5.81 (d, J=15.6 Hz, 1H),
5.37 (d, J=4.5 Hz, 1H), 4.66-4.53 (m, 1H), 3.73 (s, 3H), 2.36-2.24
(m, 3H), 2.03 (s, 3H), 2.00-1.79 (m, 6H), 1.65-1.38 (m, 8H),
1.34-1.05 (m, 6H), 1.01 (s, 3H), 0.95 (d, J=6.5 Hz, 3H), 0.69 (s,
3H).
[0237] Step 6. To suspension of A6 (20 g, 45.1 mmol) in anhydrous
MeOH (250 mL) was added AcCl (2.82 g, 36.0 mmol). The mixture was
stirred at 25.degree. C. for 16 hrs. The reaction mixture was
concentrated to remove most of MeOH, diluted with EtOAc (500 mL),
washed with saturated NaHCO.sub.3 (500 mL), brine (300 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The
residue was purified by column chromatography on silica gel
(PE/EtOAc/DCM=8/1/1) to give A7 (12 g, 67%) as a off white
solid.
[0238] Step 7. To a solution of A7 (12 g, 29.9 mmol) in TH (150 mL)
was added 5% Pt/C (2 g). The mixture was degassed and purged with
H.sub.2 several times, stirred under a H.sub.2 balloon at
25.degree. C. for 4 hrs. The reaction mixture was filtered through
a pad of Celite, and the filtrate was concentrated to give A8 (12
g, 100%) as an off white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 5.34 (d, J=5.0 Hz, 1H), 3.66 (s, 3H), 3.57-3.45 (m, 1H),
2.33-2.21 (m, 4H), 2.05-1.65 (m, 7H), 1.48-1.32 (m, 6H), 1.31-0.88
(m, 17H), 0.67 (s, 3H).
[0239] Step 8. To a solution of A8 (27 g, 67.0 mmol) in DCM (300
mL) was added DMP (85.2 g, 201 mmol) at 25.degree. C. The reaction
was stirred at 25.degree. C. for 1 h. The reaction was stirred at
25.degree. C. for 1 h. The mixture was poured into saturated
Na.sub.2S.sub.2O.sub.3 (400 ml) at 0.degree. C. and extracted with
EtOAc (3.times.300 mL). The combined organic layers were washed
with saturated NaHCO.sub.3 (2.times.250 mL), brine (200 mL), dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give
A9 (27 g, crude) as an oil, which was used for next step directly
without further purification.
[0240] Step 9. To a solution of BHT (88.8 g, 403 mmol) in toluene
(250 mL) was added AlMe.sub.3 (100 mL, 201 mmol, 2 M in toluene)
dropwise below 25.degree. C. The solution was stirred at 25.degree.
C. for 1 h. A solution of A9 (27 g, 67.3 mmol) in toluene (250 mL)
was added dropwise at -78.degree. C. After stirring at -78.degree.
C. for 1 h, MeMgBr (67.0 mL, 201 mmol, 3M in ethyl ether) was added
dropwise at -78.degree. C. The resulting solution was stirred
between -78.degree. C. and -50.degree. C. for 3 hrs. The reaction
was quenched by saturated citric acid solution (400 mL) at
-78.degree. C. After stirring at 25.degree. C. for 0.5 h, the
resulting mixture was filtered and the filtrate was extracted with
EtOAc (3.times.300 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum. The crude
product was purified by a silica gel column (PE/EtOAc=5/1) to give
the product (18.5 g, 66%) and 70 mg of the product was
recrystallized (PE/EtOAc=10 mL/2 mL) to give A27 (67 mg) as an off
white solid. A27: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.30-5.28 (m, 1H), 3.65 (s, 3H), 2.40-0.91 (m, 37H), 0.66 (s, 3H).
LCMS Rt=1.562 min in 2 min chromatography, 10-80 AB, MS ESI calcd.
for C.sub.27H.sub.43O.sub.2 [M+H-H.sub.2O].sup.+ 399, found
399.
[0241] Step 10. To a solution of LiAlH.sub.4 (6.11 g, 161 mmol) in
THE (135 mL) was added dropwise a solution of A27 (27 g, 64.8 mmol)
in THF (135 mL) at 0.degree. C. The mixture was stirred at
25.degree. C. for 1 h. H.sub.2O (100 mL) was added at 0.degree. C.
The reaction mixture was filtered, washed with THE (2.times.100
mL). The filtrate was concentrated under vacuum to give crude
product, which was washed with EtOAc (100 mL) to give Compound 4
(25 g, 100%) and 30 mg of the product was recrystallized (EtOAc, 3
mL) to give Compound 4 (27 mg) as an off white solid. Compound 4:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.31-5.29 (m, 1H),
3.70-3.60 (m, 2H), 2.43-2.40 (m, 1H), 2.20-0.90 (m, 37H), 0.67 (s,
3H). LCMS Rt=1.402 min in 2 min chromatography, 10-80 AB, MS ESI
calcd. for C.sub.26H.sub.45O.sub.2 [M+H].sup.+ 389, found 371
C.sub.26H.sub.43O [M+H-H.sub.2O].
[0242] Step 11. To a solution of Compound 4 (18 g, 46.3 mmol) in
DCM (180 mL) was added DMP (58.5 g, 138 mmol) at 0.degree. C. The
reaction was stirred at 25.degree. C. for 1 h. The mixture was
poured into saturated Na.sub.2S.sub.2O.sub.3 (100 mL) at 0.degree.
C. The mixture was extracted with EtOAc (3.times.100 mL). The
combined organic layers was washed with saturated NaHCO.sub.3
(2.times.150 mL), brine (100 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuum to give crude product, which
was purified by a silica gel column (PE/EtOAc=5/1) to give A10 (13
g, 73%) as an off white solid.
[0243] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.76 (t, J=1.8 Hz,
1H), 5.33-5.27 (m, 1H), 2.46-2.31 (m, 3H), 2.10-0.72 (m, 34H), 0.67
(s, 3H).
[0244] Step 12. To a solution of A10 (10 g, 25.8 mmol) in TH (100
mL) was added MeMgBr (51 mL, 154 mmol) at 0.degree. C. under
N.sub.2. The reaction was stirred at 25.degree. C. for 1 h. The
reaction was quenched by saturated. NH.sub.4Cl (30 mL) and
extracted with EtOAc (3.times.100 mL). The combined organic layers
were washed with brine (50 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuum to give crude product, which
was purified by a silica gel column (PE/EtOAc=10/1) to give A11
(4.1 g, 40%) as an off white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 5.30-5.29 (m, 1H), 3.81-3.77 (m, 1H), 2.43-2.39
(m, 1H), 1.99-0.76 (m, 40H), 0.67 (s, 3H).
[0245] Step 13. A mixture of A11 (400 mg, 0.993 mmol) was purified
by SFC separation (Column: Chiralpak AD 250.times.30 mm I.D., 5
.mu.m; Mobile phase: Supercritical
CO.sub.2/MeOH+NH.sub.3H.sub.2O=55/45; Flow rate: 60 ml/min;
Wavelength: 220 nm) to give Compound 5 (Peak 1, 120 mg, 30%) as an
off white solid and Compound 6 (Peak 2, 150 mg, 38%) as an off
white solid.
[0246] Compound 5: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.32-5.27 (m, 1H), 3.85-3.72 (m, 1H), 2.45-2.40 (m, 1H), 2.06-1.91
(m, 3H), 1.88-1.65 (m, 3H), 1.54-1.33 (m, 12H), 1.32-0.87 (m, 22H),
0.68 (s, 3H). LCMS Rt=1.267 min in 2 min chromatography, 30-90 AB,
MS ESI calcd. for C.sub.27H.sub.47O.sub.2 [M+H].sup.+ 403, found
C.sub.27H.sub.45O [M-H.sub.2O+H].sup.+ 385.
[0247] Compound 6: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.33-5.27 (m, 1H), 3.84-3.75 (m, 1H), 2.45-2.40 (m, 1H), 2.06-1.92
(m, 3H), 1.89-1.64 (m, 3H), 1.56-0.79 (m, 34H), 0.67 (s, 3H). LCMS
Rt=1.262 min in 2 min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.27H.sub.47O.sub.2 [M+H].sup.+ 403, found C.sub.27H.sub.45O
[M-H.sub.2O+H].sup.+ 385.
Example 4. Synthesis of Compounds 7 and 8
##STR00059##
[0249] Step 1. To a solution of A11 (3.6 g, 8.94 mmol) in DCM (40
mL) was added DMP (11.3 g, 26.8 mmol) at 0.degree. C. The reaction
was stirred at 25.degree. C. for 1 h. The mixture was poured into
saturated Na.sub.2S.sub.2O.sub.3 (60 ml) at 0.degree. C. and
extracted with EtOAc (3.times.50 mL). The combined organic layers
were washed with saturated aqueous NaHCO.sub.3 (2.times.50 mL),
brine (50 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuum to give crude product, which was purified by
a silica gel column (PE/EtOAc=15/1) to give A13 (1.4 g, 39%) as an
off white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.33-5.31 (m, 1H), 2.50-2.30 (m, 3H), 2.16 (s, 3H), 2.02-0.94 (m,
34H), 0.69 (s, 3H).
[0250] Step 2. To a solution of A13 (288 mg, 0.718 mmol) in
anhydrous THE (10 mL) at -10.degree. C. under N.sub.2 was added
EtMgBr (3 M in diethyl ether, 1.43 mL, 4.30 mmol) dropwise. The
mixture was stirred at 25.degree. C. for 3 hrs. The mixture was
quenched with saturated NH.sub.4Cl (10 mL), extracted with EtOAc
(3.times.10 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by silica gel column chromatography, eluting with DCM to
give A14 (105 mg, 34%) as an off white solid.
[0251] Step 3. A14 (105 mg, 0.244 mmol) was separated by SFC
(Column: Chiralpak AD 250.times.30 mm I.D., 5 .mu.m; Mobile phase:
Supercritical CO.sub.2/EtOH+NH.sub.3H.sub.2O=70/30; Flow rate: 60
ml/min; Wavelength: 220 nm) to give Compound 7 (Peak 1, 21.4 mg,
28%) as an off white solid and Compound 8 (Peak 2, 12.4 mg, 16%) as
an off white solid.
[0252] Compound 7: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.32-5.28 (m, 1H), 2.45-2.40 (m, 1H), 2.04-1.93 (m, 3H), 1.81-1.65
(m, 3H), 1.52-0.79 (m, 39H), 0.68 (s, 3H). LCMS Rt=1.378 min in 2
min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.29H.sub.51O.sub.2 [M+H]+ 431, found C.sub.29H.sub.47
[M+H-2H.sub.2O].sup.+ 395.
[0253] Compound 8: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.32-5.28 (m, 1H), 2.45-2.40 (m, 1H), 2.05-1.94 (m, 3H), 1.88-1.63
(m, 4H), 1.52-0.83 (m, 38H), 0.68 (s, 3H). LCMS Rt=1.374 min in 2
min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.29H.sub.51O.sub.2 [M+H].sup.+ 431, found C.sub.29H.sub.47
[M+H-2H.sub.2O].sup.+ 395.
Example 5. Synthesis of Compounds 9 and 10
##STR00060##
[0255] Step 1. To a solution of A13 (500 mg, 1.24 mmol) in
anhydrous THE (5 mL) at 0.degree. C. under N.sub.2 was added
i-PrMgCl (2 M in THF, 6.2 mL, 12.3 mmol) dropwise. The reaction
mixture was stirred at 25.degree. C. for 16 hrs. The reaction
mixture was cooled to 0.degree. C., quenched with saturated
NH.sub.4Cl (10 mL), extracted with EtOAc (3.times.10 mL). The
combined organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated. The residue was purified by column chromatography
on silica gel (DCM/Acetone=500/1) to give A16 (160 mg, 29%) as an
off white solid.
[0256] Step 2. A16 (100 mg, 0.224 mmol) was separated by SFC
(Column: Chiralpak AD 250.times.30 mm I.D., 5 um; Mobile phase:
Supercritical CO.sub.2/EtOH+NH.sub.3H.sub.2O=65/35; Flow rate: 60
ml/min; Wavelength: 220 nm) to give Compound 9 (Peak 1, 26.2 mg,
26%) as an off white solid and Compound 10 (Peak 2, 18.8 mg, 19%)
as an off white solid.
[0257] Compound 9: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.33-5.27 (m, 1H), 2.45-2.40 (m, 1H), 2.06-1.92 (m, 3H), 1.88-1.64
(m, 5H), 1.52-0.78 (m, 39H), 0.68 (s, 3H). LCMS Rt=1.444 min in 2
min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.30H.sub.53O.sub.2 [M+H].sup.+ 445, found C.sub.3H.sub.49
[M+H-2H.sub.2O].sup.+ 409.
[0258] Compound 10: .sup.1HNMR (400 MHz, CDCl.sub.3) .delta.
5.32-5.28 (m, 1H), 2.45-2.40 (m, 1H), 2.05-1.93 (m, 3H), 1.88-1.65
(m, 5H), 0.84-1.52 (m, 39H), 0.68 (s, 3H). LCMS Rt=1.442 min in 2
min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.3H.sub.53O.sub.2 [M+H].sup.+ 445, found C.sub.30H.sub.49
[M+H-2H.sub.2O].sup.+ 409.
Example 6. Synthesis of Compounds 11 and 12
##STR00061##
[0260] Step 1. To a solution of A13 (300 mg, 0.748 mmol) in THF (5
mL) was added TMSCF.sub.3 (106 mg, 0.748 mmol) at 25.degree. C. The
reaction was stirred at 25.degree. C. for 1 h. TBAF (271 mg, 1.04
mmol) was added at 25.degree. C. The reaction was poured into
water, extracted with EtOAc (2.times.10 mL). The combined organic
layers was washed with saturated NaHCO.sub.3 (2.times.20 mL), brine
(20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuum to give A18 (100 mg) as an off white solid.
[0261] Step 2. A18 (100 mg. 212 .mu.mol) was purified by SFC
separation (Column: Chiralpak AD 250.times.30 mm I.D., 5 .mu.m;
Mobile phase: Supercritical CO.sub.2/MeOH+NH.sub.3H.sub.2O=70/30;
Flow rate: 60 ml/min; Wavelength: 220 nm) to give Compound 11 (Peak
1, 25.6 mg, 26%) and Compound 12 (Peak 2, 30 mg, 30%) as off white
solids.
[0262] Compound 11: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.33-5.28 (m, 1H), 2.45-2.40 (m, 1H), 2.06-1.93 (m, 3H), 1.90-1.61
(m, 6H), 1.56-1.38 (m, 9H), 1.35 (s, 3H), 1.32-0.82 (m, 19H), 0.68
(s, 3H). LCMS Rt=1.327 min in 2 min chromatography, 30-90 AB, MS
ESI calcd. for C.sub.28H.sub.44F.sub.3O [M-H.sub.2O+H].sup.+ 453,
found 453. Compound 12: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.34-5.28 (m, 1H), 2.45-2.40 (m, 1H), 2.06-1.92 (m, 3H), 1.90-1.66
(m, 5H), 1.56-1.33 (m, 13H), 1.31-0.87 (m, 19H), 0.68 (s, 3H). LCMS
Rt=1.320 min in 2 min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.28H.sub.44F.sub.3O [M-H.sub.2O+H].sup.+ 453, found 453.
Example 7. Synthesis of Compounds 13 and 14
##STR00062##
[0264] Step 1. To a solution A10 (400 mg, 1.03 mmol) in TH (5 mL)
was added TMSCF.sub.3 (365 mg, 2.57 mmol) at 25.degree. C. The
mixture was stirred at 25.degree. C. for 1 h. TBAF (806 mg, 3.09
mmol) was added. The mixture was stirred at 25.degree. C. for 1 h.
The mixture was poured into water (30 mL), washed with saturated
brine (2.times.20 mL), dried over Na.sub.2SO.sub.4 and concentrated
in vacuum to give A20 (190 mg, 40%) as an off white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 5.33-5.28 (m, 1H), 4.00-3.85 (m,
1H), 2.50-2.35 (m, 1H), 2.11-1.93 (m, 4H), 1.89-1.61 (m, 5H),
1.53-1.35 (m, 8H), 1.31-1.05 (m, 11H), 1.01 (s, 9H), 0.68 (s, 3H).
LCMS Rt=1.301 min in 2 min chromatography, 30-90 AB, MS ESI calcd.
for C.sub.27H.sub.42F.sub.3O [M-H.sub.2O+H].sup.+ 439, found
439.
[0265] Step 2. A20 (190 mg, 0.416 mmol) was purified by SFC
(Column: Chiralpak AD 250.times.30 mm I.D., 5 um; Mobile phase:
Supercritical CO.sub.2/MeOH+NH.sub.3H.sub.2O=65/35; Flow rate: 60
ml/min; Wavelength: 220 nm) at 25.degree. C. to give Compound 13
(Peak 1, 38.4 mg, 20%) and Compound 14 (Peak 2, 47.6 mg, 25%) as
off white solids.
[0266] Compound 13: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.34-5.27 (m, 1H), 3.98-3.84 (m, 1H), 2.45-2.40 (m, 1H), 2.08-1.92
(m, 4H), 1.89-1.64 (m, 6H), 1.53-1.36 (m, 7H), 1.33-1.21 (m, 3H),
1.21-1.08 (m, 7H), 1.07-0.90 (m, 10H), 0.68 (s, 3H). LCMS Rt=1.302
min in 2 min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.27H.sub.44F.sub.3O.sub.2 [M+H].sup.+ 457, found
C.sub.27H.sub.42F.sub.3O [M+H-H.sub.2O].sup.+ 439. Compound 14:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.34-5.28 (m, 1H),
3.95-3.89 (m, 1H), 2.45-2.40 (m, 1H), 2.06-1.92 (m, 4H), 1.89-1.59
(m, 7H), 1.54-1.34 (m, 8H), 1.32-1.21 (m, 2H), 1.20-1.05 (m, 8H),
1.04-0.90 (m, 8H), 0.68 (s, 3H). LCMS Rt=1.299 min in 2 min
chromatography, 30-90 AB, MS ESI calcd. for
C.sub.27H.sub.44F.sub.3O.sub.2 [M+H].sup.+ 457, found
C.sub.27H.sub.42F.sub.3O [M+H-H.sub.2O].sup.+ 439.
Example 8. Synthesis of Compound 17
##STR00063##
[0268] Step 1. To a solution of A27 (500 mg, 1.20 mmol) and
(i-PrO).sub.4Ti (341 mg, 1.20 mmol) in anhydrous THE (10 mL) under
N.sub.2 at 25.degree. C. was added EtMgBr (3 M in diethyl ether,
1.39 mL, 4.19 mmol) dropwise. The mixture was stirred at 25.degree.
C. for 16 hrs. The reaction mixture was quenched with brine (15
mL), diluted with EtOAc (20 mL), filtered through a pad of Celite
and the filtrate was extracted with EtOAc (2.times.20 mL). The
combined organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified by column
chromatography on silica gel (PE/EtOAc=20/1) to give Compound 17
(220 mg, 44%) as an off white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 5.33-5.27 (m, 1H), 2.50-2.40 (m, 1H), 2.06-1.92
(m, 3H), 1.88-1.63 (m, 5H), 1.54-1.34 (m, 10H), 1.29-0.90 (m, 19H),
0.76-0.65 (m, 5H), 0.47-0.40 (m, 2H). LCMS Rt=1.294 min in 2 min
chromatography, 30-90 AB, MS ESI calcd. for C.sub.28H.sub.47O.sub.2
[M+H].sup.+ 415, found C.sub.28H.sub.45O [M+H-H.sub.2O].sup.+
397.
Example 9. Synthesis of Compounds 18, 19, and 20
##STR00064##
[0270] Step 1. To a solution of A8 (1.4 g, 3.47 mmol) in DCM (20
mL) was added DMP (2.94 g, 6.94 mmol) at 25.degree. C. The mixture
was stirred at 25.degree. C. for 2 hrs. The mixture was poured into
saturated Na.sub.2S.sub.2O.sub.3 (100 ml) at 0.degree. C. and
extracted with EtOAc (2.times.100 mL). The combined organic layers
was washed with saturated NaHCO.sub.3 (2.times.80 mL), brine (100
mL), dried over Na.sub.2SO.sub.4 and concentrated in vacuum to give
A9 (1.5 g, crude) as an off white solid.
[0271] Step 2. To a solution of BHT (4.93 g, 22.4 mmol) in toluene
(20 mL) was added AlMe.sub.3 (5.60 mL, 2 M in toluene, 11.2 mmol)
dropwise at 0.degree. C. The reaction mixture was stirred at
25.degree. C. for 1.5 hrs. A solution of A9 (1.5 g, 3.74 mmol) in
toluene (20 mL) was added at -70.degree. C. The resulting mixture
was stirred at -70.degree. C. for 1 hour. EtMgBr (3.73 mL, 3.0 M in
diethyl ether, 11.2 mmol) at -70.degree. C. was added. The reaction
mixture was stirred at -70.degree. C. for another 1 hour. The
reaction was quenched with NH.sub.4Cl (100 mL), extracted with
EtOAc (2.times.100 mL). The combined organic layers were washed
with brine (100 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to give crude product, which was purified by silica gel
chromatography eluted with PE/EtOAc=10/1 to give A30 (600 mg, 35%)
as white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.31-5.26
(m, 1H), 3.67 (s, 3H), 2.41-2.19 (m, 3H), 2.07-1.91 (m, 3H),
1.88-1.61 (m, 5H), 1.55-1.33 (m, 11H), 1.31-1.01 (m, 10H),
1.00-0.80 (m, 7H), 0.67 (s, 3H).
[0272] Step 3. To a solution of A30 (550 mg, 1.27 mmol) in TH (5
mL) was added MeLi (3.17 mL, 5.08 mmol) at -70.degree. C. The
mixture was stirred at -70.degree. C. for 10 mins. The reaction was
quenched with saturated NH.sub.4Cl (20 mL), extracted with EtOAc
(2.times.20 mL). The combined organic layers were washed with brine
(30 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure. This mixture was combined with another
batch synthesized from 50 mg of the starting material. The residue
was purified by silica gel chromatography (PE/EtOAc=10/1) to give
Compound 18 (270 mg, 49% yield) as white solid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 5.28 (d, J=5.0 Hz, 1H), 2.36 (d, J=13.1
Hz, 1H), 2.08-1.91 (m, 3H), 1.89-1.69 (m, 3H), 1.65-1.60 (m, 3H),
1.51-1.32 (m, 8H), 1.30-1.17 (m, 11H), 1.15-1.01 (m, 8H), 0.99-0.81
(m, 9H), 0.68 (s, 3H). LCMS Rt=1.372 min in 2 min chromatography,
30-90 AB, MS ESI calcd. for C.sub.29H.sub.51O.sub.2 [M+H].sup.+
431, found C.sub.29H.sub.47 [M+H-2H.sub.2O].sup.+ 395.
[0273] Step 4. To a solution of Compound 18 (200 mg, 0.464 mmol) in
EtOAc (10 mL) was added Pd/C (100 mg) at 25.degree. C. The mixture
was stirred under H.sub.2 at 55.degree. C. for 12 hrs. The reaction
mixture was filtered and the filtered cake was washed with EtOAc
(2.times.40 mL). The mixture was concentrated under reduced
pressure to give crude product, which was purified by silica gel
chromatography eluted with PE/EtOAc=10/1 to give Compound 19 (6.6
mg) and Compound 20 (10.2 mg) as off white solids.
[0274] Compound 19: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
2.02-1.95 (m, 1H), 1.94-1.72 (m, 4H), 1.52-1.31 (m, 14H), 1.27-1.16
(m, 14H), 1.14-0.99 (m, 7H), 0.97 (s, 3H), 0.95-0.89 (m, 6H), 0.65
(s, 3H). LCMS Rt=1.432 min in 2 min chromatography, 30-90 AB, MS
ESI calcd. for C.sub.29H.sub.53O.sub.2 [M+H].sup.+ 433, found
C.sub.29H.sub.49 [M+H-2H.sub.2O].sup.+ 397.
[0275] Compound 20: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.96
(d, J=12.5 Hz, 1H), 1.86-1.75 (m, 1H), 1.58-1.50 (m, 5H), 1.49-1.29
(m, 10H), 1.21 (s, 13H), 1.13-0.95 (m, 8H), 0.94-0.84 (m, 7H), 0.82
(s, 3H), 0.64 (s, 4H). LCMS Rt=1.431 min in 2 min chromatography,
30-90 AB, MS ESI calcd. for C.sub.29H.sub.53O.sub.2 [M+H].sup.+
433, found C.sub.29H.sub.49 [M+H-2H.sub.2O].sup.+ 397.
Example 10. Synthesis of Compound 22
##STR00065##
[0277] Step 1. To a solution of A7 (3 g, 7.48 mmol) in TH (30 mL)
was added Pd/C (10%, 600 mg). The mixture was degassed and purged
with H.sub.2 three times. The resulting mixture was stirred at
25.degree. C. under H.sub.2 for 16 hrs. The reaction mixture was
filtered through a pad of Celite, and the filtrate was concentrated
to give A32 (3 g, 99%) as an off white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) (33.66 (s, 3H), 3.63-3.53 (m, 1H), 2.34-2.18 (m, 2H),
1.99-1.91 (m, 1H), 1.82-1.62 (m, 5H), 1.56-1.43 (m, 3H), 1.42-1.18
(m, 10H), 1.14-0.77 (m, 15H), 0.68-0.57 (m, 4H).
[0278] Step 2. To a solution of A32 (3 g, 7.41 mmol) in DCM (30 mL)
was added PCC (3.19 g, 14.8 mmol) and silica gel (4 g, 66.6 mmol)
at 25.degree. C. The mixture was stirred at 25.degree. C. for 1.5
hrs. The mixture was filtered. The filtrate was concentrated in
vacuum, purified by column chromatography on silica gel
(PE/EtOAc=50/1 to 10/1) to give A33 (2.4 g) as an off white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.66 (s, 3H), 2.44-2.19
(m, 5H), 2.13-1.94 (m, 3H), 1.89-1.64 (m, 3H), 1.53-0.82 (m, 24H),
0.76-0.66 (m, 4H).
[0279] Step 3. To a solution of BHT (7.88 g, 35.7 mmol) in toluene
(25 mL) was added AlMe.sub.3 (8.9 mL, 17.8 mmol, 2 M in toluene) at
0.degree. C. under N.sub.2. The mixture was stirred at 25.degree.
C. for 1 h. A solution of A33 (2.4 g, 5.96 mmol) in toluene (5 mL)
at -70.degree. C. was added. The mixture was stirred at -78.degree.
C. for 1 h. MeMgBr (5.93 mL, 17.8 mmol, 3M in diethyl ether) was
added at -78.degree. C. The mixture was stirred at -78.degree. C.
for 1 h. The reaction mixture was quenched with saturated citric
acid (100 mL). The mixture was extracted with EtOAc (3.times.100
mL), washed with brine (3.times.300 mL), dried over
Na.sub.2SO.sub.4, concentrated in vacuum to give a crude product,
which was purified by column chromatography on silica gel
(PE/EtOAc=30/1 to 10/1) to give A34 (2 g) as a yellow solid. A34:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.67 (s, 3H), 2.36-2.18
(m, 2H), 2.01-1.92 (m, 1H), 1.86-1.77 (m, 1H), 1.72-1.61 (m, 3H),
1.55-1.46 (m, 4H), 1.40-1.21 (m, 13H), 1.18-0.99 (m, 7H), 0.95-0.86
(m, 5H), 0.81 (s, 3H), 0.70-0.60 (m, 4H). LCMS Rt=1.372 min in 2
min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.27H.sub.47O.sub.2 [M+H].sup.+ 418.3, found 401
[M+H-H.sub.2O].
[0280] Step 4. To a solution of A34 (300 mg, 0.716 mmol) and
Ti(i-PrO).sub.4 (203 mg, 0.716 mmol) in THF (10 ml) was added
EtMgBr (3 M in diethyl ether, 713 .mu.L, 2.14 mmol). The mixture
was stirred at 25.degree. C. for 16 hours. The reaction mixture was
quenched with saturated NH.sub.4Cl (5 mL). The mixture was filtered
through a pad of celite. The filtrate was extracted with EtOAc
(2.times.20 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by column chromatography on silica gel
(PE/EtOAc=20/1-10/1) to give Compound 22 (77 mg, 26%) as an off
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.00-1.92
(m, 1H), 1.84-1.61 (m, 6H), 1.53-0.83 (m, 30H), 0.80 (s, 3H),
0.76-0.71 (m, 2H), 0.69-0.60 (m, 4H), 0.47-0.40 (m, 2H). LCMS
Rt=1.317 min in 2 min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.28H.sub.49O.sub.2 [M+H].sup.+ 417, found C.sub.28H.sub.47O
[M+H-H.sub.2O].sup.+ 399.
Example 11. Synthesis of Compounds 23 and 24
##STR00066##
[0282] Step 1. To a solution of Compound 6 (50 mg, 0.124 mmol) in
MeOH (10 mL) was added Pd/C (10% wt, 26.6 mg, 24.8 mmol). After
degassing for three times with H.sub.2, the reaction mixture was
stirred for 72 hrs at 50.degree. C. under H.sub.2 (55 Psi). The
reaction was filtered and the filtrate was concentrated to give
crude product, which was purified by a silica gel column
(PE/EtOAc=15/1) to give Compound 23 (10 mg, 20%) as white solid and
Compound 24 (10 mg, 20%) as white solid. Compound 23: .sup.1HNMR
(400 MHz, CDCl.sub.3) .delta. 3.81-3.75 (m, 1H), 1.96-0.90 (m,
38H), 0.92 (s, 3H), 0.90 (d, J=6.4 Hz, 3H), 0.64 (s, 3H). LCMS
Rt=1.293 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.27H.sub.49O.sub.2 [M+H].sup.+ 405, found C.sub.27H.sub.45
[M-2H.sub.2O+H].sup.+369.
[0283] Compound 24: .sup.1HNMR (400 MHz, CDCl.sub.3) .delta.
3.80-3.75 (m, 1H), 2.00-1.90 (m, 1H), 1.90-1.75 (m, 1H), 1.75-0.70
(m, 38H), 0.80 (s, 3H), 0.70-0.60 (m, 4H). LCMS Rt=1.282 min in 2.0
min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.27H.sub.49O.sub.2 [M+H].sup.+ 405, found C.sub.27H.sub.45
[M-2H.sub.2O+H].sup.+369.
Example 12. Synthesis of Compounds 25 and 26
##STR00067##
[0285] Step 1. To a solution of t-BuOK (838 mg, 7.47 mmol) in TH
(10 mL) was added Ph.sub.3PMeBr (2.66 g, 7.47 mmol) at 60.degree.
C. The mixture was stirred at 60.degree. C. for 1 hour. A13 (1 g,
2.49 mmol) was added at 60.degree. C. The mixture was stirred at
60.degree. C. for 2 hrs. The reaction was poured into water (30 mL)
at 0.degree. C. The mixture was extracted with EtOAc (2.times.20
mL), washed with brine (30 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to give A36 (0.9
g, 90%) as an off white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 5.33-5.28 (m, 1H), 4.70-4.65 (m, 2H), 2.45-2.40 (m, 1H),
2.06-1.91 (m, 5H), 1.89-1.74 (m, 2H), 1.74-1.67 (m, 4H), 1.56-1.20
(m, 11H), 1.19-1.06 (m, 6H), 1.06-0.99 (m, 5H), 0.99-0.78 (m, 6H),
0.68 (s, 3H).
[0286] Step 2. To a solution of A36 (800 mg, 2 mmol) in THF (5 mL)
was added 9-BBN (40 mL, 20.0 mmol) at 0.degree. C. The mixture was
stirred at 25.degree. C. for 1 hour. NaOH (13.3 mL, 40 mmol, 3M)
and H.sub.2O.sub.2 (1.2 mL, 40 mmol) was added at 0.degree. C. The
mixture was stirred at 25.degree. C. for 2 hrs. The reaction was
poured into water. The mixture was extracted with EtOAc (2.times.50
mL). The combined organic layers was washed with saturated
Na.sub.2S.sub.2O.sub.3 (2.times.50 mL), brine (50 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give A37
(400 mg) as an off white solid.
[0287] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.35-5.27 (m, 1H),
4.00-3.90 (m, 1H), 3.90-3.80 (m, 1H), 2.45-2.40 (m, 1H), 2.04-1.91
(m, 3H), 1.88-1.66 (m, 5H), 1.53-1.21 (m, 10H), 1.20-0.87 (m, 23H),
0.68 (s, 3H). Step 3. To a solution of A37 (500 mg, 1.19 mmol) in
DCM (10 mL) was added TEA (240 mg, 2.38 mmol) and Ac.sub.2O (181
mg, 1.78 mmol) at 25.degree. C. The reaction was stirred at
25.degree. C. for 2 hrs. The reaction was quenched by saturated
NaHCO.sub.3 (10 mL). The mixture was extracted with DCM (2.times.10
mL) washed with brine (2.times.10 mL), dried over Na.sub.2SO.sub.4,
and concentrated to give A38 (450 mg, 82%) as an off white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.35-5.25 (m, 1H),
3.56-3.38 (m, 2H), 2.45-2.40 (m, 1H), 2.07-1.91 (m, 3H), 1.89-1.67
(m, 3H), 1.65-1.53 (m, 5H), 1.49-1.32 (m, 8H), 1.32-1.09 (m, 10H),
1.09-0.97 (m, 7H), 0.97-0.87 (m, 7H), 0.68 (s, 3H).
[0288] Step 4. A38 (450 mg) was purified by SFC (Column: Chiralpak
AD 250.times.30 mm I.D., 5 .mu.m; Mobile phase: Supercritical
CO.sub.2/MeOH+NH.sub.3H.sub.2O=60/40; Flow rate: 60 ml/min;
Wavelength: 220 nm) to give A39 (200 mg) and A40 (150 mg) as off
white solids.
[0289] Step 5. To a solution of A39 (200 mg, 0.435 mmol) in MeOH
(10 mL) was added AcCl (17.0 mg, 0.217 mmol) at 25.degree. C. The
mixture was stirred at 25.degree. C. for 2 hrs. The reaction was
poured into water (10 mL), extracted with THE (2.times.20 mL). The
organic layer was washed with brine (30 mL), dried over
Na.sub.2SO.sub.4 and concentrated to give Compound 25 (100 mg, 55%)
as an off white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.33-5.28 (m, 1H), 3.57-3.36 (m, 2H), 2.46-2.38 (m, 1H), 2.05-1.92
(m, 3H), 1.87-1.57 (m, 6H), 1.52-1.34 (m, 7H), 1.28-1.20 (m, 3H),
1.18-0.89 (m, 22H), 0.68 (s, 3H). LCMS Rt=1.328 min in 2 min
chromatography, 30-90 AB_E, MS ESI calcd. for
C.sub.28H.sub.49O.sub.2 [M+H].sup.+ 417, found C.sub.28H.sub.47O
[M+H-H.sub.2O].sup.+ 399.
[0290] Step 6. To a solution of A40 (150 mg, 0.326 mmol) in MeOH
(10 mL) was added AcCl (12.7 mg, 0.163 mmol) at 25.degree. C. The
mixture was stirred at 25.degree. C. for 2 hrs. The reaction was
poured into water (10 mL), extracted with THE (2.times.20 mL). The
organic layer was washed with brine (30 mL), dried over
Na.sub.2SO.sub.4 and concentrated to give crude product, which was
purified by column chromatography on silica gel (PE/EtOAc=20/1 to
8/1) to give Compound 26 (90 mg, 66%) as an off white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.33-5.28 (m, 1H),
3.55-3.38 (m, 2H), 2.46-2.38 (m, 1H), 2.05-1.93 (m, 3H), 1.87-1.58
(m, 5H), 1.51-0.89 (m, 33H), 0.68 (s, 3H). LCMS Rt=1.320 min in 2
min chromatography, 30-90 AB_E, MS ESI calcd. for
C.sub.2H.sub.49O.sub.2 [M+H].sup.+ 417, found C.sub.28H.sub.47O
[M+H-H.sub.2O].sup.+ 399.
Example 13. Synthesis of Compound 33
##STR00068##
[0292] Step 1. To a solution of BHT (32.6 g, 148 mmol) in toluene
(100 mL) was added trimethylaluminum (37.2 mL, 2 M in toluene, 74.4
mmol) dropwise at 0.degree. C. The reaction mixture was stirred at
15.degree. C. for 1.5 hrs. A33 (10 g, 24.8 mL) in toluene (100 mL)
was added dropwise at -70.degree. C. The resulting mixture was
stirred at -70.degree. C. for 1 h. EtMgBr (28.4 mL, 3.0 M in
diethyl ether, 74.4 mmol) was added dropwise at -70.degree. C. The
reaction mixture was stirred at -70.degree. C. for another 1 h. The
reaction mixture was poured into saturated aqueous critic acid (2
L). The aqueous was extracted with EtOAc (3.times.1.5 L). The
combined organic was washed with brine (2 L), dried over
Na.sub.2SO.sub.4, filtered and concentrated under vacuum to give
crude product, which was purified by silica gel chromatography
eluted with PE:EtOAc=10:1 to give A41 (8 g, 75%) as a yellow solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.66 (s, 3H), 2.30-2.15
(m, 2H), 2.00-1.90 (m, 1H), 1.85-1.60 (m, 5H), 1.50-1.15 (m, 15H),
1.14-0.80 (m, 18H), 0.69-0.55 (m, 4H). LCMS Rt=1.376 min in 2.0 min
chromatography, 30-90 AB, purity 100%, MS ESI calcd. for
C.sub.2H.sub.47O.sub.2 [M+H-H.sub.2O].sup.+ 415, found 415.
[0293] Step 2. To a solution of A41 (2 g, 4.62 mmol) in TH (50 mL)
under N.sub.2 at 0.degree. C. was added LiAlH.sub.4 (263 mg, 6.93
mmol) in portions. The reaction was stirred at 0.degree. C. for 30
mins. The reaction was quenched with 1 M HCl (30 mL) at 0.degree.
C., extracted with EtOAc (3.times.30 mL). The combined organic
phase was washed with brine (100 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated to give crude Compound 33 (1.3 g, 70%) as
an off white solid. 100 mg of crude Compound 33 was recrystallized
from MeCN/DCM (10 mL/10 mL) to afford Compound 33 (30 mg) as an off
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.68-3.60
(m, 2H), 2.00-1.91 (m, 1H), 1.86-1.74 (m, 1H), 1.70-1.58 (m, 4H),
1.56-1.44 (m, 6H), 1.42-1.31 (m, 6H), 1.30-1.18 (m, 7H), 1.14-0.95
(m, 7H), 0.93-0.81 (m, 9H), 0.93-0.79 (m, 1H), 0.68-0.58 (m, 4H).
LCMS Rt=1.279 min in 2.0 min chromatography, 30-90 AB, MS ESI
calcd. for C.sub.27H.sub.47O [M+H-H.sub.2O].sup.+ 387, found
387.
Example 14. Synthesis of Compounds 34, 35, and 36
##STR00069##
[0295] Step 1. To a solution of A30 (2 g, 4.64 mmol) in TH (30 mL)
was added LiAlH.sub.4 (260 mg, 6.85 mmol) at 0.degree. C. The
mixture was stirred at 20.degree. C. for 10 mins. Water/THF (20 mL,
1/1) was added. The mixture was extracted with EtOAc (2.times.30
mL), washed with brine (2.times.100 mL), dried over
Na.sub.2SO.sub.4, filtered, concentrated in vacuum to give a crude
product A42 (1.7 g) as an off white solid, which was used in the
next step without further purification. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 5.35-5.25 (m, 1H), 3.70-3.60 (m, 2H), 2.40-2.30
(m, 1H), 2.05-1.60 (m, 7H), 1.60-1.35 (m, 10H), 1.25-1.15 (m, 5H),
1.10-0.80 (m, 17H), 0.67 (s, 3H).
[0296] Step 2. To a solution of A42 (1.7 g, 4.22 mmol) in DCM (150
mL) was added DMP (3.2 g, 7.6 mmol) at 30.degree. C. The mixture
was stirred at 30.degree. C. for 30 mins. Water (100 mL) was added,
following by adding NaHCO.sub.3 (4 g, solid). The organic phase was
separated and washed with Sat. Na.sub.2S.sub.2O.sub.3 (2.times.200
mL), brine (2.times.200 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuum to give a crude product A43 (2.1 g) as a
yellow solid.
[0297] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.77 (s, 1H),
5.35-5.25 (m, 1H), 2.45-2.30 (m, 3H), 2.05-1.90 (m, 4H), 1.85-0.90
(m, 28H), 0.85-0.75 (m, 4H), 0.68 (s, 3H).
[0298] Step 3. To a solution of A43 (1 g, crude) in TH (20 mL) was
added methylmagnesium bromide (2.5 mL, 7.5 mmol, 3M in ether) at
-70.degree. C. under N.sub.2. The mixture was stirred at 20.degree.
C. for 1 h. To the mixture was added Sat. NH.sub.4Cl (20 mL), EtOAc
(20 mL) and H.sub.2O (10 mL). The mixture was extracted with EtOAc
(3.times.20 mL), washed with Sat. NaCl (2.times.60 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuum to give crude
product, which was purified by column chromatography on silica gel
(PE:EtOAc=100:1 to 12:1) to give Compound 34 (520 mg, impure) as an
off white solid. Compound 34 (520 mg, impure) was triturated with
CH.sub.3CN (50 mL) at 80.degree. C. to give 27 mg of pure Compound
34 as an off white solid and 400 mg of impure Compound 34 was used
for SFC.
[0299] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.35-5.25 (m, 1H),
3.85-3.75 (m, 1H), 2.40-2.30 (m, 1H), 2.05-1.90 (m, 3H), 1.85-1.55
(m, 6H), 1.55-1.30 (m, 10H), 1.25-0.90 (m, 20H), 0.85-0.75 (m, 3H),
0.67 (s, 3H). LCMS Rt=1.295 min in 2 min chromatography, 30-90
AB_E, MS ESI calcd. for C.sub.28H.sub.47O [M-H.sub.2O+H].sup.+ 399,
found 399.
[0300] Step 3. Compound 35 (400 mg, impure) was purified by SFC
(Column: AD (250 mm*30 mm, 5 um); Condition: 0.1% NH.sub.3H.sub.2O
MeOH, 40% B; FlowRate (ml/min): 60) to give Compound 35 (79 mg) and
Compound 36 (59 mg) as an off white solid.
[0301] Compound 35: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.30-5.25 (m, 1H), 3.85-3.75 (m, 1H), 2.40-2.30 (m, 1H), 2.10-1.95
(m, 3H), 1.90-1.60 (m, 4H), 1.45-1.28 (m, 11H), 1.25-0.90 (m, 17H),
0.88-0.82 (m, 4H), 0.78 (t, J=7.2 Hz, 3H), 0.67 (s, 3H). LCMS
Rt=1.295 min in 2 min chromatography, 30-90 AB_E, MS ESI calcd. for
[M-H.sub.2O+H].sup.+ 399, found 399.
[0302] Compound 36: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.30-5.25 (m, 1H), 3.85-3.75 (m, 1H), 2.40-2.30 (m, 1H), 2.10-1.95
(m, 3H), 1.90-1.60 (m, 4H), 1.50-1.17 (m, 11H), 1.14-0.90 (m, 17H),
0.88-0.82 (m, 4H), 0.78 (t, J=7.2 Hz, 3H), 0.67 (s, 3H). LCMS
Rt=1.295 min in 2 min chromatography, 30-90 AB_E, MS ESI calcd. for
C.sub.28H.sub.47O [M-H.sub.2O+H].sup.+ 399, found 399.
Example 16. Synthesis of Compounds 37, 37-A, and 37-B
##STR00070##
[0304] Step 1. To a solution of Compound 33 (500 mg, 1.23 mmol) in
DCM (20 mL) was added DMP (1.04 g, 2.46 mmol) at 20.degree. C. The
reaction mixture was stirred at 20.degree. C. for 1.5 hrs. The
reaction mixture was quenched with saturated NaHCO.sub.3 (10 mL) at
20.degree. C. The mixture was filtered and separated. The aqueous
phase was extracted with DCM (20 mL). The combined organic phase
was washed with saturated Na.sub.2S.sub.2O.sub.3 (50 mL), brine (50
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give
A44 (500 mg, crude) as yellow solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.76 (s, 1H), 2.44-2.34 (m, 2H), 1.99-1.92 (m,
1H), 1.63-1.51 (m, 9H), 1.43-1.31 (m, 6H), 1.30-1.18 (m, 6H),
1.12-0.97 (m, 7H), 0.94-0.85 (m, 7H), 0.82 (s, 3H), 0.66-0.62 (m,
4H).
[0305] Step 2. To a solution of A44 (500 mg, 1.24 mmol) in TH (20
mL) under N.sub.2 was added MeMgBr (2.06 mL, 3.0 M, 6.19 mmol) at
0.degree. C. in one portion. After stirring at 20.degree. C. for 30
min, the mixture was quenched by 50 mL of saturated NH.sub.4Cl and
extracted with 50 mL of EtOAc. The separated organic phase was
washed with 100 mL of brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated. The residue was purified by Combi-flash (EtOAc in
PE, 0%40%) to afford Compound 37 (350 mg, 67%) as an off white
solid. 27 mg was delivered. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 3.85-3.72 (m, 1H), 1.99-1.91 (m, 1H), 1.86-1.74 (m, 1H),
1.69-1.59 (m, 3H), 1.56-1.50 (m, 3H), 1.50-1.27 (m, 11H), 1.26-1.16
(m, 8H), 1.14-0.95 (m, 7H), 0.93-0.79 (m, 11H), 0.67-0.59 (m, 4H).
LCMS Rt=1.297 min in 2.0 min chromatography, 30-90 AB, MS ESI
calcd. for C.sub.28H.sub.47 [M+H-2H.sub.2O].sup.+ 383, found
383.
[0306] Step 3. To a solution of Compound 37 (300 mg, 0.716 mmol) in
pyridine (10 mL) was added benzoyl chloride (501 mg, 3.57 mmol).
The reaction was stirred at 20.degree. C. for 2 h. The reaction was
diluted with H.sub.2O (50 mL), extracted with EtOAc (3.times.20
mL). The combined organic phase was washed with 1N HCl (100 mL),
brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by Combi-flash (0%15% of
EtOAc in PE) to afford A45 (270 mg, 72%) as clear oil. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.10-8.00 (m, 2H), 7.60-7.50 (m, 1H),
7.50-7.40 (m, 2H), 5.70-5.55 (m, 1H), 2.00-1.90 (m, 1H), 1.85-1.15
(m, 23H), 1.10-0.75 (m, 20H), 0.70-0.50 (m, 4H).
[0307] Step 4. A45 (270 mg, 0.516 mmol) was purified by SFC
(Column: AD (250 mm*30 mm, 5 um); Condition: 0.1% NH.sub.3.H.sub.2O
EtOH; Gradient 35% B; Gradient Time (min): 30; FlowRate (ml/min):
60) to afford A46 (peak 1, 90 mg) as white solid and A47 (peak 2,
100 mg) as white solid
[0308] A46: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.10-8.00 (m,
2H), 7.60-7.50 (m, 1H), 7.50-7.40 (m, 2H), 5.70-5.55 (m, 1H),
2.00-1.60 (m, 6H), 1.55-1.25 (m, 14H), 1.20-1.10 (m, 7H), 1.10-0.75
(m, 17H), 0.70-0.50 (m, 4H).
[0309] A47: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.10-8.00 (m,
2H), 7.60-7.50 (m, 1H), 7.50-7.40 (m, 2H), 5.70-5.55 (m, 1H),
2.00-1.60 (m, 7H), 1.55-1.20 (m, 20H), 1.20-0.80 (m, 17H),
0.70-0.50 (m, 4H).
[0310] Step 5. To a solution of A46 (0 mg, 0.17 mmol) in TH (5 mL)
was added MeOH (2 mL) and a solution of LiOH.H.sub.2O (72 mg, 1.72
mmol) at 25.degree. C. The mixture was stirred at 25.degree. C. for
17 hours. Water (5 mL) was added. The mixture was extracted with
EtOAc (2.times.8 mL), washed with brine (2.times.10 mL), dried over
Na.sub.2SO.sub.4, filtered, concentrated in vacuum to give a crude
product, which was purified by flash-column (0-30% of EtOAc in PE,
50 mins) to give Compound 37-A (28 mg, 39%) as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.90-3.70 (m, 1H),
2.00-1.60 (m, 5H), 1.55-1.40 (m, 5H), 1.35-1.20 (m, 17H), 1.20-0.80
(m, 18H), 0.70-0.50 (m, 4H). HPLC Rt=6.82 min in 8 min
chromatography, 30-90_AB_1.2 ml_E, MS MS ESI calcd. For
C.sub.2H.sub.47 [M+H-2H.sub.2O].sup.+ 383, found 383.
[0311] Step 6. To a solution of A47 (100 mg, 0.19 mmol) in THF (5
mL) was added MeOH (2 mL) and a solution of LiOH.H.sub.2O (80 mg,
1.91 mmol) at 25.degree. C. The mixture was stirred at 25.degree.
C. for 17 hours. Water (5 mL) was added. The mixture was extracted
with EtOAc (2.times.8 mL), washed with brine (2.times.10 mL), dried
over Na.sub.2SO.sub.4, filtered, concentrated in vacuum to give a
crude product, which was purified by flash-column (0-30% of EtOAc
in PE, 50 mins) to give Compound 37-B (57 mg, 71%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.90-3.70 (m, 1H),
2.00-1.60 (m, 7H), 1.55-1.30 (m, 11H), 1.25-1.15 (m, 9H), 1.10-0.75
(m, 18H), 0.70-0.50 (m, 4H). HPLC Rt=6.78 min in 8 min
chromatography, 30-90_AB_1.2 ml_E, MS MS ESI calcd. For
C.sub.28H.sub.47 [M+H-2H.sub.2O].sup.+ 383, found 383.
Example 17. Synthesis of Compounds 38, 39 and 40
##STR00071##
[0313] Step 1. To a solution of A43 (1 g, crude) and CsF (200 mg,
1.31 mmol) in THF (15 mL) was added TMSCF.sub.3 (1.76 g, 12.4 mmol)
at 0.degree. C. under nitrogen. The mixture was stirred at
20.degree. C. for 1 h. TBAF (15 mL, 1M in THF) was added. The
mixture was stirred at 20.degree. C. for another 16 hours. The
mixture was concentrated to 10 mL of the mixture in vacuum and DCM
(30 mL) was added. The mixture was washed with water (3.times.50
mL), brine (2.times.50 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuum to give a crude product, which was
purified by flash column (0-25% of EtOAc in PE, 80 mins) to give
Compound 38 (400 mg, crude) as an off white solid. Compound 38 (400
mg, crude) was triturated with CH.sub.3CN (30 mL) at 80.degree. C.
to give Compound 38 (310 mg) as an off white solid.
[0314] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.32-5.25 (m, 1H),
3.95-3.85 (m, 1H), 2.40-2.30 (m, 1H), 2.10-1.60 (m, 10H), 1.55-1.30
(m, 9H), 1.25-0.90 (m, 17H), 0.85 (t, J=7.6 Hz, 3H), 0.67 (s, 3H).
LCMS Rt=1.308 min in 2 min chromatography, 30-90 AB_E, MS ESI
calcd. for C.sub.28H.sub.44F.sub.3O [M-H.sub.2O+H].sup.+ 453, found
453.
[0315] Step 2. Compound 38 (300 mg) was purified by SFC (Column: AD
(250 mm*30 mm, 5 um; Condition: 0.1% NH.sub.3H.sub.2O IPA, 35% B;
FlowRate (ml/min): 60) to give Compound 39 (68 mg, 23%) and
Compound 40 (39 mg, 13%) as an off white solid.
[0316] Compound 39: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.32-5.25 (m, 1H), 3.95-3.85 (m, 1H), 2.40-2.30 (m, 1H), 2.10-1.60
(m, 10H), 1.55-1.30 (m, 10H), 1.25-0.90 (m, 16H), 0.85 (t, J=7.6
Hz, 3H), 0.68 (s, 3H). LCMS Rt=1.307 min in 2 min chromatography,
30-90 AB_E, MS ESI calcd. for C.sub.28H.sub.44F.sub.3O
[M-H.sub.2O+H].sup.+ 453, found 453.
[0317] Compound 40: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
5.32-5.25 (m, 1H), 3.95-3.85 (m, 1H), 2.40-2.30 (m, 1H), 2.10-1.60
(m, 10H), 1.55-1.25 (m, 13H), 1.20-0.90 (m, 13H), 0.85 (t, J=7.2
Hz, 3H), 0.68 (s, 3H). LCMS Rt=1.302 min in 2 min chromatography,
30-90 AB_E, MS ESI calcd. for C.sub.28H.sub.44F.sub.3O
[M-H.sub.2O+H].sup.+ 453, found 453.
Example 18. Synthesis of Compound 41
##STR00072##
[0319] To a suspension of A30 (100 mg, 0.232 mmol) and
Ti(i-PrO).sub.4 (65.9 mg, 0.232 mmol) in THF (10 mL) under N.sub.2
was added EtMgBr (0.27 mL, 0.812 mmol) at 20.degree. C. dropwise.
After stirring at 20.degree. C. for 1 h, the mixture was quenched
by 0.4 mL of saturated NH.sub.4Cl. The mixture was filtered. The
filtrate was concentrated. The residue was purified by Combi-flash
(EtOAc in PE, 0%30%) to afford Compound 41 (42 mg, 42%) as an off
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.33-5.23
(m, 1H), 2.41-2.31 (m, 1H), 2.07-1.91 (m, 3H), 1.88-1.67 (m, 3H),
1.66-1.57 (m, 3H), 1.53-1.35 (m, 11H), 1.33-1.00 (m, 11H),
0.99-0.81 (m, 8H), 0.76-0.71 (m, 2H), 0.67 (s, 3H), 0.47-0.41 (m,
2H). LCMS Rt=1.309 min in 2.0 min chromatography, 30-90 AB, MS ESI
calcd. for C.sub.29H.sub.47O [M+H-H.sub.2O].sup.+ 411, found
411.
Example 19. Synthesis of Compound 42
##STR00073##
[0321] To a suspension of A41 (150 mg, 0.346 mmol) and
Ti(i-PrO).sub.4 (98.3 mg, 0.346 mmol) in THF (10 mL) under N.sub.2
was added EtMgBr (0.4 mL, 1.21 mmol) at 20.degree. C. dropwise.
After stirring at 20.degree. C. for 1 h, the mixture was quenched
by 0.4 mL of saturated NH.sub.4Cl. The mixture was filtered. The
filtrate was concentrated. The residue was purified by Combi-flash
(EtOAc in PE, 0%30%) to afford Compound 42 (78 mg, 52%) as an off
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.00-1.92
(m, 1H), 1.86-1.71 (m, 2H), 1.69-1.56 (m, 6H), 1.53-1.33 (m, 10H),
1.29-1.16 (m, 5H), 1.14-0.96 (m, 7H), 0.94-0.81 (m, 11H), 0.75-0.71
(m, 2H), 0.67-0.60 (m, 4H), 0.46-0.42 (m, 2H). LCMS Rt=1.343 min in
2.0 min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.29H.sub.47 [M+H-2H.sub.2O].sup.+ 395, found 395.
Example 20. Synthesis of Compounds 43, 43-A, and 43-B
##STR00074##
[0323] Step 1. To a suspension of A44 (800 mg, 1.98 mmol) and CsF
(150 mg, 0.99 mmol) in THF (20 mL) under N.sub.2 was added
TMSCF.sub.3 (843 mg, 5.93 mmol) at 0.degree. C. in one portion.
After stirring at 20.degree. C. for 1 h, TBAF (9.89 mL, 9.89 mmol,
1M in THF) was added. The mixture was stirred at 20.degree. C. for
another 16 hrs. The mixture was quenched by 50 mL of saturated
NH.sub.4Cl and extracted with 50 mL of EtOAc. The separated organic
phase was washed with 100 mL of brine twice, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by Combi-flash (EtOAc in PE, 0%40%) to afford Compound 43
(400 mg, 42%) as an off white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 3.98-3.85 (m, 1H), 1.99-1.92 (m, 2H), 1.87-1.74
(m, 1H), 1.69-1.56 (m, 7H), 1.53-1.31 (m, 10H), 1.28-1.16 (m, 5H),
1.15-0.95 (m, 7H), 0.94-0.85 (m, 7H), 0.82 (s, 3H), 0.68-0.60 (m,
4H). LCMS Rt=1.351 min in 2.0 min chromatography, 30-90 AB, MS ESI
calcd. for C.sub.28H.sub.46F.sub.3O [M+H-H.sub.2O].sup.+ 455, found
455.
[0324] Step 2. To a solution of Compound 43 (350 mg, 0.740 mmol) in
pyridine (10 mL) was added benzoyl chloride (416 mg, 2.96 mmol).
The reaction was stirred at 50.degree. C. for 48 h. The reaction
was diluted with H.sub.2O (50 mL), extracted with EtOAc (3.times.20
mL). The combined organic phase was washed with 1N HCl (100 mL),
brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by Combi-flash (0%20% of
EtOAc in PE) to afford A48 (200 mg, 47%) as clear oil. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.20-8.05 (m, 2H), 7.15-7.05 (m, 1H),
7.50-7.40 (m, 2H), 5.60-5.50 (m, 1H), 2.00-1.70 (m, 3H), 1.55-1.40
(m, 12H), 1.35-1.15 (m, 9H), 1.10-0.90 (m, 8H), 0.90-0.75 (m, 9H),
0.70-0.50 (m, 4H).
[0325] Step 3. A48 (200 mg) was purified by SFC (Column: AD (250
mm*30 mm, 5 um); Condition: 0.1% NH.sub.3H.sub.2O MeOH, 40% B;
FlowRate (ml/min): 60) to give A49 (40 mg, 20%) as a oil and A50
(70 mg, 35%) as an off-white solid.
[0326] Step 4. To a solution of A49 (40 mg) in THE (2 mL) was added
MeOH (1 mL) and a solution of LiOH.H.sub.2O (16.6 mg, 0.69 mmol) in
H.sub.2O (1 mL) at 25.degree. C. The mixture was stirred at
25.degree. C. for 17 hours. The mixture as extracted with EtOAc
(2.times.5 mL), washed with brine (2.times.10 mL), dried over
Na.sub.2SO.sub.4, filtered, purified by flash column (0-30% of
EtOAc in PE) to give 43-A (20 mg, impure) as an off-white solid,
which was triturated with CH.sub.3CN (2 mL) at 25.degree. C. then
filter cake was dissolved in CH.sub.3CN (20 mL) at 80.degree. C.
The solution was concentrated in vacuum to give 43-A (6 mg, 31%) as
an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
4.00-3.85 (m, 1H), 2.10-1.75 (m, 3H), 1.70-1.60 (m, 5H), 1.55-1.20
(m, 16H), 1.15-0.75 (m, 18H), 0.70-0.55 (m, 4H).
[0327] LCMS Rt=1.319 min in 2 min chromatography, 30-90 AB_E, MS
ESI calcd. For C.sub.28H.sub.46F.sub.3O [M+H-H.sub.2O].sup.+455,
found 455.
[0328] Step 5. To a solution of A50 (70 mg) in THF (3 mL) was added
MeOH (2 mL) and a solution of LiOH.H.sub.2O (50.7 mg, 1.2 mmol) in
H.sub.2O (2 mL) a 25.degree. C., The mixture was stirred at
25.degree. C. for 17 hours. The mixture as extracted with EA
(2.times.6 mL), washed with brine (2.times.10 mL), dried over
Na.sub.2SO.sub.4 filtered, purified by flash column (0-30% of EtOAc
in PE, 1 h) to give 43-B (40 mg, impure) as oil, which was
re-crystallized from 4 mL of CH.sub.3CN at 80.degree. C. to give
43-B (23 mg, 58%) as an off-white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 4.00-3.85 (m, 1H), 2.10-1.75 (m, 3H), 1.70-1.60
(m, 5H), 1.55-1.20 (m, 16H), 1.15-0.75 (m, 18H), 0.70-0.55 (m, 4H).
LCMS R.sub.t=1.315 min in 2 min chromatography, 30-90 AB_E, MS ESI
calcd. For C.sub.28H.sub.46F.sub.3O [M+H-H.sub.2O]+455, found
455.
Materials and Methods
[0329] The compounds provided herein can be prepared from readily
available starting materials using the following general methods
and procedures. It will be appreciated that where typical or
preferred process conditions (i.e., reaction temperatures, times,
mole ratios of reactants, solvents, pressures, etc.) are given,
other process conditions can also be used unless otherwise stated.
Optimum reaction conditions may vary with the particular reactants
or solvent used, but such conditions can be determined by one
skilled in the art by routine optimization.
[0330] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group as well as suitable conditions for protection and
deprotection are well known in the art. For example, numerous
protecting groups, and their introduction and removal, are
described in T. W. Greene and P. G. M. Wuts, Protecting Groups in
Organic Synthesis, Second Edition, Wiley, New York, 1991, and
references cited therein.
[0331] The compounds provided herein may be isolated and purified
by known standard procedures. Such procedures include (but are not
limited to) recrystallization, column chromatography, HPLC, or
supercritical fluid chromatography (SFC). The following schemes are
presented with details as to the preparation of representative
neuroactive steroids that have been listed herein. The compounds
provided herein may be prepared from known or commercially
available starting materials and reagents by one skilled in the art
of organic synthesis. Exemplary chiral columns available for use in
the separation/purification of the enantiomers/diastereomers
provided herein include, but are not limited to, CHIRALPAK.RTM.
AD-10, CHIRALCEL.RTM. OB, CHIRALCEL.RTM. OB-H, CHIRALCEL.RTM. OD,
CHIRALCEL.RTM. OD-H, CHIRALCEL.RTM. OF, CHIRALCEL.RTM. OG,
CHIRALCEL.RTM. OJ and CHIRALCEL.RTM. OK.
[0332] .sup.1H-NMR reported herein (e.g., for the region between
.delta. (ppm) of about 0.5 to about 4 ppm) will be understood to be
an exemplary interpretation of the NMR spectrum (e.g., exemplary
peak integratations) of a compound. Exemplary general method for
preparative HPLC: Column: Waters RBridge prep 10 .mu.m C18, 19*250
mm. Mobile phase: acetonitrile, water (NH.sub.4HCO.sub.3) (30 L
water, 24 g NH.sub.4HCO.sub.3, 30 mL NH.sub.3.H.sub.2O). Flow rate:
25 mL/min
[0333] Exemplary general method for analytical HPLC: Mobile phase:
A: water (10 mM NH.sub.4HCO.sub.3), B: acetonitrile Gradient:
5%-95% B in 1.6 or 2 min Flow rate: 1.8 or 2 mL/min; Column:
XBridge C18, 4.6*50 mm, 3.5 .mu.m at 45 C.
NMDA Potentiation
[0334] NMDA potentiation was assessed using either whole cell patch
clamp of mammalian cells which expressed NMDA receptors.
Whole-Cell Patch Clamp of Mammalian Cells (Ionworks Barracuda
(IWB)
[0335] The whole-cell patch-clamp technique was used to investigate
the effects of compounds on GlunN1/GluN2A glutamate receptors
expressed in mammalian cells. The results are shown on Table 1.
[0336] HEK293 cells were transformed with adenovirus 5 DNA and
transfected with cDNA encoding the human GRIN1/GRIN2A genes. Stable
transfectants were selected using G418 and Zeocin-resistance genes
incorporated into the expression plasmid and selection pressure
maintained with G418 and Zeocin in the medium. Cells were cultured
in Dulbecco's Modified Eagle Medium/Nutrient Mixture (D-MEM/F-12)
supplemented with 10% fetal bovine serum, 100 .mu.g/ml penicillin G
sodium, 100 .mu.g/ml streptomycin sulphate, 100 .mu.g/ml Zeocin, 5
.mu.g/ml blasticidin and 500 .mu.g/ml G418.
[0337] Test article effects were evaluated in 8-point
concentration-response format (4 replicate wells/concentration).
All test and control solutions contained 0.3% DMSO and 0.01%
Kolliphor.RTM. EL (C5135, Sigma). The test article formulations
were loaded in a 384-well compound plate using an automated liquid
handling system (SciClone ALH3000, Caliper LifeScienses). The
measurements were performed using Ion Works Barracuda platform
following this procedure:
Electrophysiological Procedures:
[0338] a) Intracellular solution (mM): 50 mM CsCl, 90 mM CsF, 2 mM
MgCl.sub.2, 5 mM EGTA, 10 mM HEPES. Adjust to pH 7.2 with CsOH.
[0339] b) Extracellular solution, HB-PS (composition in mM): NaCl,
137; KCl, 1.0; CaCl.sub.2, 5; HEPES, 10; Glucose, 10; pH adjusted
to 7.4 with NaOH (refrigerated until use). [0340] c) Holding
potential: -70 mV, potential during agonist/PAM application: -40
mV.
Recording Procedure:
[0340] [0341] a) Extracellular buffer will be loaded into the PPC
plate wells (11 .mu.L per well). Cell suspension will be pipetted
into the wells (9 .mu.L per well) of the PPC planar electrode.
[0342] b) Whole-cell recording configuration will be established
via patch perforation with membrane currents recorded by on-board
patch clamp amplifiers. [0343] c) Two recordings (scans) will be
performed. First, during pre-application of test article alone
(duration of pre-application--5 min) and second, during test
articles and agonist (EC.sub.20 L-glutamate and 30 .mu.M glycine)
co-application to detect positive modulatory effects of the test
article.
[0344] Test Article Administration: The first pre-application will
consist of the addition of 20 .mu.L of 2.times. concentrated test
article solution and, second, of 20 .mu.L of 1.times. concentrated
test article and agonist at 10 .mu.L/s (2 second total application
time).
TABLE-US-00001 TABLE 1 GluN2A PCA IWB Ephys % potentiation
Structure at 3 .mu.M Compound 1 B Compound 2 A Compound 4 A
Compound 5 A Compound 6 B Compound 7 A Compound 8 A Compound 9 A
Compound 10 B Compound 11 A Compound 12 A Compound 13 A Compound 14
B Compound 15 A Compound 17 A Compound 18 B Compound 19 B Compound
22 B Compound 23 A Compound 24 B Compound 25 A Compound 26 A
[0345] For Table 1, "A" indicates 10 to 100%, and "B" indicates
potentiation of >100%; and "ND" indicates not determinable or
not determined.
OTHER EMBODIMENTS
[0346] In the claims articles such as "a," "an," and "the" may mean
one or more than one unless indicated to the contrary or otherwise
evident from the context. Claims or descriptions that include "or"
between one or more members of a group are considered satisfied if
one, more than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or process
unless indicated to the contrary or otherwise evident from the
context. The invention includes embodiments in which exactly one
member of the group is present in, employed in, or otherwise
relevant to a given product or process. The invention includes
embodiments in which more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process.
[0347] Furthermore, the invention encompasses all variations,
combinations, and permutations in which one or more limitations,
elements, clauses, and descriptive terms from one or more of the
listed claims is introduced into another claim. For example, any
claim that is dependent on another claim can be modified to include
one or more limitations found in any other claim that is dependent
on the same base claim. Where elements are presented as lists,
e.g., in Markush group format, each subgroup of the elements is
also disclosed, and any element(s) can be removed from the group.
It should it be understood that, in general, where the invention,
or aspects of the invention, is/are referred to as comprising
particular elements and/or features, certain embodiments of the
invention or aspects of the invention consist, or consist
essentially of, such elements and/or features. For purposes of
simplicity, those embodiments have not been specifically set forth
in haec verba herein. It is also noted that the terms "comprising"
and "containing" are intended to be open and permits the inclusion
of additional elements or steps. Where ranges are given, endpoints
are included. Furthermore, unless otherwise indicated or otherwise
evident from the context and understanding of one of ordinary skill
in the art, values that are expressed as ranges can assume any
specific value or sub-range within the stated ranges in different
embodiments of the invention, to the tenth of the unit of the lower
limit of the range, unless the context clearly dictates
otherwise.
[0348] This application refers to various issued patents, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference. If there is a
conflict between any of the incorporated references and the instant
specification, the specification shall control. In addition, any
particular embodiment of the present invention that falls within
the prior art may be explicitly excluded from any one or more of
the claims. Because such embodiments are deemed to be known to one
of ordinary skill in the art, they may be excluded even if the
exclusion is not set forth explicitly herein. Any particular
embodiment of the invention can be excluded from any claim, for any
reason, whether or not related to the existence of prior art.
[0349] Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation many
equivalents to the specific embodiments described herein. The scope
of the present embodiments described herein is not intended to be
limited to the above Description, but rather is as set forth in the
appended claims. Those of ordinary skill in the art will appreciate
that various changes and modifications to this description may be
made without departing from the spirit or scope of the present
invention, as defined in the following claims.
* * * * *