U.S. patent application number 16/089896 was filed with the patent office on 2019-10-31 for oxysterols and methods of use thereof.
This patent application is currently assigned to Sage Therapeutics, Inc.. The applicant listed for this patent is Sage Therapeutics, Inc.. Invention is credited to Boyd L. Harrison, Gabriel Martinez Botella, John Gregory Reid, Albert Jean Robichaud, Francesco G. Salituro.
Application Number | 20190330259 16/089896 |
Document ID | / |
Family ID | 59965335 |
Filed Date | 2019-10-31 |
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United States Patent
Application |
20190330259 |
Kind Code |
A1 |
Robichaud; Albert Jean ; et
al. |
October 31, 2019 |
OXYSTEROLS AND METHODS OF USE THEREOF
Abstract
Compounds are provided according to Formula (I), and
pharmaceutically acceptable salts thereof, and pharmaceutical
compositions thereof; wherein A, R.sup.1, and R.sup.5 are as
defined herein. Compounds of the present invention are contemplated
useful for the prevention and treatment of a variety of conditions.
##STR00001##
Inventors: |
Robichaud; Albert Jean;
(Boston, MA) ; Salituro; Francesco G.;
(Marlborough, MA) ; Martinez Botella; Gabriel;
(Wayland, MA) ; Harrison; Boyd L.; (Princeton
Junction, NJ) ; Reid; John Gregory; (Wellington,
FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sage Therapeutics, Inc. |
Cambridge |
MA |
US |
|
|
Assignee: |
Sage Therapeutics, Inc.
Cambridge
MA
Sage Therapeutics, Inc.
Cambridge
MA
|
Family ID: |
59965335 |
Appl. No.: |
16/089896 |
Filed: |
March 31, 2017 |
PCT Filed: |
March 31, 2017 |
PCT NO: |
PCT/US17/25535 |
371 Date: |
September 28, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62317002 |
Apr 1, 2016 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07J 17/00 20130101;
A61P 3/06 20180101; A61P 25/00 20180101; C07J 9/00 20130101; A61P
35/00 20180101; A61P 1/00 20180101; A61P 3/10 20180101; A61P 25/20
20180101; C07J 43/003 20130101 |
International
Class: |
C07J 9/00 20060101
C07J009/00; C07J 17/00 20060101 C07J017/00; C07J 43/00 20060101
C07J043/00 |
Claims
1. A compound of Formula (I-A): ##STR00074## or a pharmaceutically
acceptable salt thereof, wherein: A is carbocyclyl or heterocyclyl;
R.sup.1 is C.sub.1-6 alkyl; R.sup.5 is absent or hydrogen;
represents a single or double bond, wherein when one is a double
bond, then the other is a single bond and R.sup.5 is absent.
2. A compound of Formula (I-B): ##STR00075## or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 is hydrogen or C.sub.1-6
alkyl; R.sup.5 is absent or hydrogen; Z is --C(R.sup.A).sub.2--,
--NR.sup.B--, --O--, or --S--; X is halogen, C.sub.1-6 alkyl, or
--OR.sup.C; R.sup.A is hydrogen, halogen, or C.sub.1-6 alkyl;
R.sup.B is hydrogen, C.sub.1-6 alkyl, --C(O)R.sup.C,
--C(O)OR.sup.C, --C(O)N(R.sup.D).sub.2, or --S(O).sub.2R.sup.C;
R.sup.C is hydrogen or C.sub.1-6 alkyl; each R.sup.D is
independently hydrogen, C.sub.1-6 alkyl, aryl, or heteroaryl; m is
an integer selected from 1, 2, and 3; n is an integer selected from
1, 2, and 3; p is an integer selected from 0, 1, 2, 3, 4, and 5;
and represents a single or double bond, wherein when one is a
double bond, then the other is a single bond and R.sup.5 is
absent.
3. The compound of claim 2, wherein the compound is a compound of
Formula (II-A), Formula (II-B), or Formula (II-C): ##STR00076##
4-7. (canceled)
8. The compound of claim 3, wherein the compound is of Formula
(II-D), Formula (II-E), or Formula (II-F): ##STR00077##
9-11. (canceled)
12. The compound of claim 2, wherein the compound is of Formula
(II-G) or Formula (II-H): ##STR00078##
13. The compound of claim 2, wherein the compound is of Formula
(II-I) or Formula (II-J): ##STR00079##
14-26. (canceled)
27. The compound of claim 2, wherein the compound is selected from
the group consisting of: ##STR00080## ##STR00081## ##STR00082##
##STR00083##
28. A pharmaceutically acceptable salt of the compound of claim 2,
wherein the compound is selected from the group consisting of:
##STR00084## ##STR00085## ##STR00086## ##STR00087##
29. A pharmaceutical composition comprising a compound according to
claim 1, and a pharmaceutically acceptable carrier.
30. A method of inducing sedation or anesthesia comprising
administering to a subject an effective amount of a compound
according to claim 1 or pharmaceutical composition thereof.
31. A method for treating or preventing a disorder described
herein, comprising administering to a subject in need thereof an
effective amount of a compound according to claim 1 or
pharmaceutical composition thereof.
32. The method according to claim 31, wherein the disorder is a
gastrointestinal (GI) disorder, structural disorders affecting the
GI, anal disorders, colon polyps, cancer, colitis.
33. The method according to claim 31, wherein the disorder is
inflammatory bowel disease.
34. The method according to claim 31, wherein the disorder is
cancer, diabetes, or a sterol synthesis disorder.
35. The method according to claim 31, wherein the disorder is a
metabolic disorder.
36. A method for treating or preventing a CNS-related condition
comprising administering to a subject in need thereof an effective
amount of a compound according to claim 1 or pharmaceutical
composition thereof.
37-38. (canceled)
39. A method for treating or preventing Smith-Lemli-Opitz Syndrome
(SLOS), Desmosterolosis, Sitosterolemia, Cerebrotendinous
xanthomatosis (CTX), Mevalonate Kinase Deficiency Syndromes (MKD),
SC4MOL gene mutation (SMO Deficiency), Niemann-Pick disease, Autism
Disorders Associated with Phenylketonuria, comprising administering
to a subject in need thereof an effective amount of a compound
according to claim 1 or pharmaceutical composition thereof.
Description
CLAIM OF PRIORITY
[0001] This application claims priority to U.S. Ser. No. 62/317,002
filed Apr. 1, 2016, which is incorporated herein by reference in
its 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 of
these receptors 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 of
these receptors 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 cholesterol analogs that are modulators of
NMDA receptor function. There is a need for new oxysterols 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 new oxysterols useful for preventing
and/or treating a broad range of disorders, including, but not
limited to, NMDA-mediated disorders. 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-A):
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein: A is
carbocyclyl or heterocyclyl (e.g., unsubstituted or substituted
carbocyclyl or heterocyclyl, e.g., heterocyclyl substituted with at
least one heteroatom (e.g., 1, 2, or 3 heteroatoms)); R.sup.1 is
C.sub.1-6 alkyl (e.g., --CH.sub.3 or --CH.sub.2CH.sub.3); R.sup.5
is absent or hydrogen; represents a single or double bond, wherein
when one is a double bond, then the other is a single bond and
R.sup.5 is absent.
[0006] In one aspect, provided herein are compounds according to
Formula (I-B):
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein: R is
hydrogen or C.sub.1-6 alkyl (e.g., --CH.sub.3 or
--CH.sub.2CH.sub.3); R.sup.5 is absent or hydrogen; Z is
--C(R.sup.A).sub.2--, --NR.sup.B--, --O--, or --S--; X is halogen,
C.sub.1-6 alkyl, or --OR.sup.C; R.sup.A is hydrogen, halogen, or
C.sub.1-6 alkyl; R.sup.B is hydrogen, C.sub.1-6 alkyl,
--C(O)R.sup.C, --C(O)OR.sup.C, --C(O)N(R.sup.D).sub.2, or
--S(O).sub.2R.sup.C; R.sup.C is hydrogen or C.sub.1-6 alkyl; each
R.sup.D is independently hydrogen, C.sub.1-6 alkyl, aryl, or
heteroaryl; m is an integer selected from 1, 2, and 3; n is an
integer selected from 1, 2, and 3; p is an integer selected from 0,
1, 2, 3, 4, and 5; and represents a single or double bond, wherein
when one is a double bond, then the other is a single bond and
R.sup.5 is absent.
[0007] In some embodiments, the compound is a compound of Formula
(II-A), Formula (II-B), or Formula (II-C):
##STR00004##
[0008] In some embodiments, p is an integer selected from 0, 1, or
2. In some embodiments, p is 0. In some embodiments, p is 1. In
some embodiments, p is 1 and X is halogen.
[0009] In some embodiments, the compound is of Formula (II-D),
Formula (II-E), or Formula (II-F):
##STR00005##
[0010] In some embodiments, the compound is of Formula (II-G) or
Formula (II-H):
##STR00006##
[0011] In some embodiments, the compound is of Formula (II-I) or
Formula (II-J):
##STR00007##
[0012] In some embodiments, R.sup.1 is C.sub.1-6 alkyl. In some
embodiments, R.sup.1 is methyl or ethyl. In some embodiments,
R.sup.1 is --CH.sub.3, --CF.sub.3, --CH.sub.2CH.sub.3.
[0013] In some embodiments, Z is --C(R.sup.A).sub.2--, --O--, or
--NR.sup.B--. Or, Z is --CH.sub.2--. Or, Z is O. Or, Z is
--NR.sup.B--, wherein R.sup.B is --NH--, --N--(C.sub.1-C.sub.4
alkyl)-, or --NC(O)--(C.sub.1-C.sub.4 alkyl). In some embodiments,
R.sup.A is halogen (e.g., --F). In some embodiments, Z is
--CH.sub.2--, --CF.sub.2--, or --C(CH.sub.3).sub.2--.
[0014] In some embodiments, the compound is:
##STR00008##
[0015] In some embodiments, the compound is:
##STR00009##
[0016] In some embodiments, Z is --O-- or --NR.sup.B--.
[0017] In some embodiments, the compound is:
##STR00010##
[0018] In some embodiments, the compound is:
##STR00011##
[0019] In some embodiments, the compound is:
##STR00012##
[0020] In some embodiments, Z is --NH--, --NMe-, or --NAc--.
[0021] In some embodiments, the compound is:
##STR00013##
[0022] In some embodiments, Z is --CH.sub.2--. In some embodiments,
Z is --C(CH.sub.3).sub.2--. In some embodiments, Z is --CF.sub.2--.
In some embodiments, m is 1, n is 2, and Z is --O--. In some
embodiments, m is 2 and n is 2. In some embodiments, m is 3 and n
is 1. In some embodiments, m is 3, n is 1, and Z is --O--. In some
embodiments, m is 2, n is 2, and Z is --O-- or --NR.sup.B--.
[0023] In some embodiments, the compound is:
##STR00014## ##STR00015## ##STR00016## ##STR00017##
[0024] In some embodiments, the compound is a pharmaceutically
acceptable salt of:
##STR00018## ##STR00019## ##STR00020## ##STR00021##
[0025] In one aspect, provided herein is a pharmaceutical
composition comprising a compound as described herein (e.g., a
compound of Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D),
(II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)), or
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
[0026] In another aspect, provided herein is a method of inducing
sedation or anesthesia comprising administering to a subject an
effective amount of a compound as described herein (e.g., a
compound of Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D),
(II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)), or
pharmaceutically acceptable salt thereof, or pharmaceutical
composition thereof.
[0027] In one 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 as
described herein (e.g., a compound of Formula (I-A) (I-B), (II-A),
(II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or
(II-J)), or pharmaceutically acceptable salt thereof, or
pharmaceutical composition thereof.
[0028] In some embodiments, the disorder is a gastrointestinal (GI)
disorder e.g., constipation, irritable blowel 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.
[0029] In some embodiments, the disorder is inflammatory bowel
disease.
[0030] In some embodiments, the disorder is cancer, diabetes, or a
sterol synthesis disorder.
[0031] In some embodiments, the disorder is a metabolic
disorder.
[0032] In one 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 as
described herein (e.g., a compound of Formula (I-A) (I-B), (II-A),
(II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or
(II-J)), or pharmaceutically acceptable salt thereof, or
pharmaceutical composition thereof.
[0033] 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), 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), 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.
[0034] In some embodiments, the disorder is sterol synthesis
disorder.
[0035] In one aspect, provided herein is a method for treating or
preventing Smith-Lemli-Opitz Syndrome (SLOS), Desmosterolosis,
Sitosterolemia, Cerebrotendinous xanthomatosis (CTX), Mevalonate
Kinase Deficiency Syndromes (MKD), SC4MOL gene mutation (SMO
Deficiency), Niemann-Pick disease, Autism Disorders Associated with
Phenylketonuria, comprising administering to a subject in need
thereof an effective amount of a compound as described herein
(e.g., a compound of Formula (I-A) (I-B), (II-A), (II-B), (II-C),
(II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)), or a
pharmaceutically acceptable salt thereof, or pharmaceutical
composition thereof.
[0036] In some embodiments, the disorder is cancer, diabetes, or a
sterol synthesis disorder.
[0037] 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 (e.g., a compound of Formula (I-A) (I-B), (II-A), (II-B),
(II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)),
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), 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), 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.
Definitions
Chemical Definitions
[0038] 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.
[0039] 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), supercritical
fluid chromatography (SFC), 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.
[0040] In one embodiment, a stereoisomer described herein is
enriched in the stereoisomeric form depicted for that compound. For
example, the stereoisomer can have an enantiomeric excess or
diastereomeric excess of at least about 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,
96%, 97%, 98%, or 99%.
[0041] 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.
[0042] 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.
[0043] "Aliphatic" refers to an alkyl, alkenyl, alkynyl, or
carbocyclyl group, as defined herein.
[0044] "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).
[0045] "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.
[0046] "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.
[0047] "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.28 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.
[0048] 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.1-6 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.
[0049] "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.1-4 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.
[0050] 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.
[0051] Examples of representative substituted aryls include the
following
##STR00022##
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.59 NR.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.
[0052] "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.
[0053] "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.
[0054] "Heteroaryl" refers to a radical of a 5-10 membered
monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or
10 n 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).
[0055] 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.
[0056] 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.
[0057] Examples of representative heteroaryls include the
following:
##STR00023##
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.10 cycloalkyl, 4-10 membered heterocyclyl,
C.sub.6-C.sub.10 aryl, and 5-10 membered heteroaryl.
[0058] "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.
[0059] "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.
[0060] 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.
[0061] "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.
[0062] 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.
[0063] 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.
[0064] "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.
[0065] "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.
[0066] "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 C.sub.1-C.sub.4
haloalkoxy or hydroxy.
[0067] "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.
[0068] 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.
[0069] "Amino" refers to the radical --NH.sub.2.
[0070] "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.8 alkyl, C.sub.3-C.sub.8
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.
[0071] 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.39
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.
[0072] "Carboxy" refers to the radical --C(O)OH.
[0073] "Cyano" refers to the radical --CN.
[0074] "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.
[0075] "Hydroxy" refers to the radical --OH.
[0076] "Nitro" refers to the radical --NO.sub.2.
[0077] "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.
[0078] "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.
[0079] "Thioketo" refers to the group .dbd.S.
[0080] 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.
[0081] 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).sub.2,
--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),
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;
[0082] or two geminal hydrogens on a carbon atom are replaced with
the group .dbd.O, .dbd.S, .dbd.NN(R.sup.bb).sub.2,
.dbd.NNR.sup.bbC(.dbd.O)R.sup.aa,
.dbd.NNR.sup.bbC(.dbd.O)OR.sup.aa,
.dbd.NNR.sup.bbS(.dbd.O).sub.2R.sup.aa, .dbd.NR.sup.bb, or
.dbd.NOR.sup.cc;
[0083] 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;
[0084] 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,
--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.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;
[0085] each instance of R.sup.cc 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;
[0086] 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, --C, --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;
[0087] 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;
[0088] 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.ff 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
[0089] 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.sup.-, --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 is a
counterion.
[0090] 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.-2sulfonate 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).
[0091] Nitrogen atoms can be substituted or unsubstituted as
valency permits, and include primary, secondary, tertiary, and
quarternary 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.
[0092] 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
[0093] 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.
[0094] 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.
[0095] Disease, disorder, and condition are used interchangeably
herein.
[0096] 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").
[0097] 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.
[0098] 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.
[0099] 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.
Abbreviations
[0100] AcCl: acetyl chloride; 9-BBN: 9-borabicyclo[3.3.1]nonane;
BHT: 2,6-di-t-butyl-p-cresol (butylated hydroxytoluene); Boc:
t-butoxycarbonyl; DCE: dichloroethane; DCM: dichloromethane; DMF:
N,N-dimethylformamide; DMP: Dess-Martin periodinane; DMSO:
dimethylsulfoxide; EtOAc: ethylacetate; i-PrMgCl:
Isopropylmagnesium chloride; MAD: methyl aluminum
bis(2,6-di-t-butyl-4-methylphenoxide); m-CPBA: meta
chloroperbenzoic acid; Me.sub.3SI: Trimethylsulfonium iodide; MTBE:
methyl tert-butyl ether; Na.sub.2SO.sub.4: sodium sulfate; n-BuLi:
n-Butyl lithium; PCC: pyridinium chlorochromate;
Pd(t-Bu.sub.3P).sub.2: bis(tri-tert-butylphosphine)palladium(0);
PE: petroleum ether; py: pyridine; TBAF: tetra-n-butylammonium
fluoride; t-BuOK: potassium tert-butoxide; TBSCl:
tert-Butyl(chloro)dimethylsilane; TFA: trifluoroacetic acid; THF:
tetrahydrofuran; Ts: p-toluenesulfonyl; (i-PrO).sub.4Ti: titanium
tetraisopropoxide.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[0101] As generally described herein, the present invention
provides new oxysterols useful for preventing and/or treating a
broad range of disorders, including, but not limited to,
NMDA-mediated disorders.
Compounds
[0102] In one aspect, provided herein are compounds according to
Formula (I-A):
##STR00024##
or a pharmaceutically acceptable salt thereof, wherein: A is
carbocyclyl or heterocyclyl (e.g., unsubstituted or substituted
carbocyclyl or heterocyclyl, e.g., heterocyclyl substituted with at
least one heteroatom (e.g., 1, 2, or 3 heteroatoms)); R.sup.1 is
C.sub.1-6 alkyl (e.g., --CH.sub.3 or --CH.sub.2CH.sub.3); R.sup.5
is absent or hydrogen; represents a single or double bond, wherein
when one is a double bond, then the other is a single bond and
R.sup.5 is absent.
[0103] In one aspect, provided herein are compounds according to
Formula (I-B):
##STR00025##
or a pharmaceutically acceptable salt thereof, wherein: R is
hydrogen or C.sub.1-6 alkyl (e.g., --CH.sub.3 or
--CH.sub.2CH.sub.3); R.sup.5 is absent or hydrogen; Z is
--C(R.sup.A).sub.2--, --NR.sup.B--, --O--, or --S--; X is halogen,
C.sub.1-6 alkyl, or --OR.sup.C; R.sup.A is hydrogen, halogen, or
C.sub.1-6 alkyl; R.sup.B is hydrogen, C.sub.1-6 alkyl,
--C(O)R.sup.C, --C(O)OR.sup.C, --C(O)N(R.sup.D).sub.2, or
--S(O).sub.2R.sup.C; R.sup.C is hydrogen or C.sub.1-6 alkyl; each
R.sup.D is independently hydrogen, C.sub.1-6 alkyl, aryl, or
heteroaryl; m is an integer selected from 1, 2, and 3; n is an
integer selected from 1, 2, and 3; p is an integer selected from 0,
1, 2, 3, 4, and 5; and represents a single or double bond, wherein
when one is a double bond, then the other is a single bond and
R.sup.5 is absent.
[0104] In some embodiments, the compound is a compound of Formula
(II-A), Formula (II-B), or Formula (II-C):
##STR00026##
[0105] In some embodiments, p is an integer selected from 0, 1, or
2. In some embodiments, p is 0. In some embodiments, p is 1. In
some embodiments, p is 1 and X is halogen.
[0106] In some embodiments, the compound is of Formula (II-D),
Formula (II-E), or Formula (II-F):
##STR00027##
[0107] In some embodiments, the compound is of Formula (II-G) or
Formula (II-H):
##STR00028##
[0108] In some embodiments, the compound is of Formula (II-I) or
Formula (II-J):
##STR00029##
[0109] In some embodiments, R.sup.1 is C.sub.1-6 alkyl. In some
embodiments, R.sup.1 is methyl or ethyl. In some embodiments,
R.sup.1 is --CH.sub.3, --CF.sub.3, --CH.sub.2CH.sub.3.
[0110] In some embodiments, Z is --C(R.sup.A).sub.2--, --O--, or
--NR.sup.B--. Or, Z is --CH.sub.2--. Or, Z is O. Or, Z is
--NR.sup.B--, wherein R.sup.B is --NH--, --N--(C.sub.1-C.sub.4
alkyl)-, or --NC(O)--(C.sub.1-C.sub.4 alkyl). In some embodiments,
R.sup.A is halogen (e.g., --F). In some embodiments, Z is
--CH.sub.2--, --CF.sub.2--, or --C(CH.sub.3).sub.2--.
[0111] In some embodiments, the compound is:
##STR00030##
[0112] In some embodiments, the compound is:
##STR00031##
[0113] In some embodiments, Z is --O-- or --NR.sup.B--.
[0114] In some embodiments, the compound is:
##STR00032##
[0115] In some embodiments, the compound is:
##STR00033##
[0116] In some embodiments, the compound is:
##STR00034##
[0117] In some embodiments, Z is --NH--, --NMe-, or --NAc--.
[0118] In some embodiments, the compound is:
##STR00035##
[0119] In some embodiments, Z is --CH.sub.2--. In some embodiments,
Z is --C(CH.sub.3).sub.2--. In some embodiments, Z is --CF.sub.2--.
In some embodiments, m is 1, n is 2, and Z is --O--. In some
embodiments, m is 2 and n is 2. In some embodiments, m is 3 and n
is 1. In some embodiments, m is 3, n is 1, and Z is --O--. In some
embodiments, m is 2, n is 2, and Z is --O-- or --NR.sup.B--.
[0120] In some embodiments, the compound is:
##STR00036## ##STR00037## ##STR00038## ##STR00039##
[0121] In some embodiments, the compound is a pharmaceutically
acceptable salt of:
##STR00040## ##STR00041## ##STR00042## ##STR00043##
Pharmaceutical Compositions
[0122] In another aspect, the invention provides a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and a
effective amount of a compound as described herein (e.g., Formula
(I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F),
(II-G), (II-H), (II-I), or (II-J)).
[0123] 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.
[0124] In one embodiment, with respect to the pharmaceutical
composition, the carrier is a parenteral carrier, oral or topical
carrier.
[0125] The present invention also relates to a compound as
described herein (e.g., Formula (I-A) (I-B), (II-A), (II-B),
(II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)),
or pharmaceutical composition thereof for use as a pharmaceutical
or a medicament.
[0126] 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.
[0127] 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.
[0128] 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.
[0129] 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.
[0130] 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.
[0131] 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.
[0132] 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.
[0133] 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.
[0134] 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.
[0135] 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.
[0136] 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).
[0137] 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.
[0138] 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.
[0139] Exemplary Formulation 1--Tablets:
[0140] A compound of Formula (I-A), 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.
[0141] Exemplary Formulation 2--Capsules:
[0142] A compound of Formula (I-A), 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).
[0143] Exemplary Formulation 3--Liquid:
[0144] A compound of Formula (I-A), 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.
[0145] Exemplary Formulation 4--Tablets:
[0146] A compound of Formula (I-A), 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.
[0147] Exemplary Formulation 5--Injection:
[0148] A compound of Formula (I-A), 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.
[0149] Exemplary Formulation 6--Tablets:
[0150] A compound of Formula (I-A), 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.
[0151] Exemplary Formulation 7--Tablets:
[0152] A compound of Formula (I-A), 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.
[0153] Exemplary Formulation 8--Tablets:
[0154] A compound of Formula (I-A), 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.
[0155] Exemplary Formulation 9--Tablets:
[0156] A compound of Formula (I-A), 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.
[0157] Exemplary Formulation 10--Tablets:
[0158] A compound of Formula (I-A), 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.
[0159] 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.
[0160] 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.
[0161] Transdermal doses are generally selected to provide similar
or lower blood levels than are achieved using injection doses.
[0162] 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
[0163] Compounds of the present invention, e.g., a compound of
Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E),
(II-F), (II-G), (II-H), (II-I), or (II-J), 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-A) (I-B), (II-A),
(II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or
(II-J), 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 as described herein (e.g., Formula (I-A) (I-B),
(II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G), (II-H),
(II-I), or (II-J)), 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-A) (I-B), (II-A), (II-B),
(II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J),
or pharmaceutically acceptable salt thereof, may act as positive
allosteric modulators (PAM) of NMDA, and potentiate NMDA receptor
function. In ceratin embodiments, the compound of Formula (I-A)
(I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F), (II-G),
(II-H), (II-I), or (II-J), 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.
[0164] In some embodiments, the disorder is cancer. In some
embodiments, the disorder is diabetes. In some embodiments, the
disorder is a metabolic disorder. In some embodiments, the disorder
is a sterol synthesis disorder. In some embodiments, the disorder
is a gastrointestinal (GI) disorder, e.g., constipation, irritable
blowel 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.
[0165] 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.
[0166] Exemplary conditions related to NMDA-modulation includes,
but are not limited to, gastrointestinal (GI) disorder, e.g.,
constipation, irritable blowel 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.
[0167] 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), 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), 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-A) (I-B), (II-A), (II-B),
(II-C), (II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J),
or pharmaceutically acceptable salt thereof, can be used to induce
sedation or anesthesia. In certain embodiments, the compound of
Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E),
(II-F), (II-G), (II-H), (II-I), or (II-J), 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.
[0168] 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-A) (I-B), (II-A), (II-B), (II-C), (II-D), (II-E), (II-F),
(II-G), (II-H), (II-I), or (II-J), or a pharmaceutically acceptable
salt thereof.
[0169] In yet another aspect, the present invention provides a
combination of a compound of the present invention, e.g., a
compound of Formula (I-A) (I-B), (II-A), (II-B), (II-C), (II-D),
(II-E), (II-F), (II-G), (II-H), (II-I), or (II-J), 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
[0170] 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
[0171] 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
diffierentiation, 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
[0172] 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
[0173] 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
[0174] 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)
[0175] 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)
[0176] 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 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)
[0177] SC4MOL gene deficiency is a genetic disorder in the
cholesterol biosynthesis pathway (e.g., mutations in the SC4MOL
gene encoding a novel sterol oxidase). SC4MOL 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
[0178] 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
[0179] 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
[0180] 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
7.beta.-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.
Alternative Embodiments
[0181] In an alternative embodiment, a compound described herein
(e.g., a compound of Formula (I-A) (I-B), (II-A), (II-B), (II-C),
(II-D), (II-E), (II-F), (II-G), (II-H), (II-I), or (II-J)) may also
comprise one or more isotopic substitutions. In some embodiments,
hydrogen may be .sup.2H (D or deuterium), or .sup.3H (T or
tritium). In some embodiments, carbon may be .sup.13C or .sup.14C.
In some embodiments, oxygen may .sup.18O). In some embodiments,
nitrogen may be .sup.15N. In a further embodiment, a compound may
comprise one or more isotopic substitutions where the site of
isotopic substitution is enriched with a particular isotope. For
example, a compound described herein can comprise hydrogen enriched
as .sup.2H or .sup.3H, carbon enriched as 1.sup.3C or .sup.14C,
oxygen enriched as .sup.18O, or nitrogen enriched as .sup.15N.
EXAMPLES
[0182] 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.
Materials and Methods
[0183] 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.
[0184] 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.
[0185] 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.
[0186] 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.
[0187] 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
[0188] NMDA potentiation was assessed using the whole cell patch
clamp of mammalian cells which expressed NMDA receptors.
Whole-Cell Patch Clamp of Mammalian Cells (Ionworks Barracuda
(IWB)
[0189] 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 in Table 1.
[0190] 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.
[0191] 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:
[0192] 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.
[0193] 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). [0194] c) Holding
potential: -70 mV, potential during agonist/PAM application: -40
mV.
Recording Procedure:
[0194] [0195] 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.
[0196] b) Whole-cell recording configuration will be established
via patch perforation with membrane currents recorded by on-board
patch clamp amplifiers. [0197] 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.
[0198] 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).
[0199] Synthetic Methods
Example 1. Synthesis of Intermediate A-6
##STR00044## ##STR00045##
[0200] Step 1. Synthesis of Intermediate A-1.
[0201] To a suspension of PPh.sub.3MeBr (2.13 kg, 5.97 mol) in THF
(3000 mL) was added t-BuOK (688 g, 6.14 mol) at 20.degree. C. The
color of the suspension changed to yellow. After stirring at
50.degree. C. for 1 h, Pregnenolone (630 g, 2.05 mol) was added at
50.degree. C. and the reaction mixture was stirred at 50.degree. C.
for 2 h. After cooling to 20.degree. C., the mixture was treated
with NH.sub.4Cl (10% aq., 5 L) and heptane (3.5 L) and stirred for
15 minutes. The organic layer was separated and concentrated in
vacuo to give the crude material as a thick oil, which was poured
into MTBE (10 L) with vigorous stirring and allowed to stir at room
temperature for 16 hours. The resulting off-white solid was
collected by filtration and washed with MTBE (3 L). The combined
filtrate was mixed with MeOH (10 L) and concentrated to 6 L in
vacuo. The resulting off-white solid was collected by filtration,
washed with MeOH (3 L), and air-dried to give 700 g of wet
off-white solid. The combined MeOH filtrate was concentrated in
vacuo to give a thick oil. The oil was poured into MTBE (3 L) with
vigorous stirring and the mixture was allowed to stir for 3 hours.
The resulting white solid was collected by filtration and washed
with MTBE (1 L). The combined filtrate was mixed with MeOH (3 L)
and concentrated to 1.5 L in vacuo. The resulting white solid was
collected by filtration, washed with MeOH (500 mL) and air-dried to
give 150 g of a wet off-white solid. The previous 700 g and 150 g
batch were combined and vacuum-dried to give Intermediate A-1 (552
g, 88%) as an off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 5.40-5.30 (m, 1H), 4.85 (s, 1H), 4.71 (s, 1H), 3.60-3.50
(m, 1H), 2.36-2.18 (m, 2H), 2.08-1.96 (m, 2H), 1.92-1.78 (m, 3H),
1.76 (s, 3H), 1.73-1.48 (m, 9H), 1.38-1.03 (m, 4H), 1.01 (s, 3H),
1.00-0.91 (m, 1H), 0.58 (s, 3H).
Step 2. Synthesis of Intermediate A-2.
[0202] To a solution of Intermediate A-1 (184 g, 585 mmol) in DCM
(2000 mL) was added DMP (496 g, 1.17 mol) at 25.degree. C. in
portions, followed by water (42 mL). The mixture was stirred at
25.degree. C. for 30 min. Water (1500 mL) and NaHCO.sub.3(750 g)
were added in portions (gas evolution was observed). The mixture
was filtered through a pad of Celite and the solid was washed with
DCM (500 mL). The organic layer in the filtrate was separated,
washed with Na.sub.2S.sub.2O.sub.3 (1000 mL, saturated), dried over
Na.sub.2SO.sub.4, filtered, concentrated in vacuo below 30.degree.
C. to give Intermediate A-2 (250 g, crude) as a light yellow gum.
The crude was used in the next step directly without further
purification or analysis.
Step 3. Synthesis of Intermediate A-3.
[0203] To a solution of BHT (769 g, 3.49 mol) in toluene (1500 mL)
was added AlMe.sub.3 (870 mL, 2M in toluene, 1.74 mol) at 0.degree.
C. After stirring at 0.degree. C. for 1 h, the reaction mixture was
cooled to -78.degree. C. and a solution of Intermediate A-2 (250 g
crude, theoretical mass: 182 g, 582 mmol) in toluene (1000 mL) was
added. After stirring at -78.degree. C. for 1 h, MeMgBr (580 mL, 3
M in ether, 1.74 mmol) was added and the mixture was stirred at
-78.degree. C. for another 1 h. The mixture was quenched by pouring
into citric acid (4000 mL, 20% aq.) in portions (gas evolution was
observed). Another two batches were conducted and combined. The
mixture was extracted with EtOAc (10 L). The organic layer was
separated, washed with brine (5 L, 10%), NaHCO.sub.3(5 L, saturated
aq.), brine (5 L, saturated), dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The resulting residue was purified by silica
gel chromatography (PE to EtOAc) to give Intermediate A-3 (440 g,
impure, containing Intermediate A-i) as a light yellow solid. To a
solution of impure Intermediate A-3 (440 g) in DCM (6 L) was added
DMAP (24.4 g) and Ac.sub.2O (51 g). The mixture was stirred at
20.degree. C. for 1 h. NaHCO.sub.3 (1 L, saturated aq.) was added
and the mixture was stirred for 10 min. The organic layer was
separated, concentrated in vacuo and the residue was triturated
with PE (2 L). The solid was washed with PE (3.times.500 mL) and
dried in vacuo to give A-3 (262 g) as an off-white solid. The
combined filtrate was concentrated, purified by silica gel
chromatography (PE/EtOAc=50/1 to 8/1) and triturated with PE (1 L)
to give A-3 (30 g). Total yield for the two steps was 51%. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 5.35-5.28 (m, 1H), 4.85 (s, 1H),
4.71 (s, 1H), 2.48-2.37 (m, 1H), 2.08-1.94 (m, 3H), 1.92-1.85 (m,
1H), 1.82-1.33 (m, 14H), 1.29-1.08 (m, 7H), 1.02 (s, 3H), 1.00-0.93
(m, 1H), 0.59 (s, 3H).
Step 4. Synthesis of Intermediate A-4.
[0204] Intermediate A-3 (100 g, 304 mmol) was dissolved in 9-BBN
(1.21 L, 0.5 M in THF, 608 mmol) at 0.degree. C. under N.sub.2. The
solution was heated and stirred at 65.degree. C. for 1 hour and
re-cooled to 10.degree. C. to generate a off-white precipitate.
Ethanol (279 g, 6080 mmol) and aqueous NaOH (304 mL, 5 M, 1520
mmol) were added dropwise below 10.degree. C. to give a clear
solution. Hydrogen peroxide (343 g, 30% in water, 3040 mmol) was
added dropwise below 10.degree. C. and the reaction mixture was
heated and stirred at 75.degree. C. for 1 hour. The mixture was
cooled to 20.degree. C., and the resulting off-white precipitate
was collected by filtration. The filter cake was washed with water
(3.times.500 mL) and dried in vacuo to give an off-white solid,
which was triturated with ethanol (1.5 L) at reflux to give
Intermediate A-4 (92 g, 88%) as an off-white solid.
[0205] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.31-5.29 (m, 1H),
3.65-3.63 (m, 1H), 3.38-3.37 (m, 1H), 2.42 (d, J=12.4, 1H),
2.05-1.92 (m, 3H), 1.88-1.63 (m, 4H), 1.63-1.40 (m, 8H), 1.40-0.90
(m, 16H), 0.70 (s, 3H).
Step 5. Synthesis of Intermediate A-5.
[0206] To a solution of Intermediate A-4 (124.5 g, 357 mmol) in
chloroform (1 L) and pyridine (700 mL) was added TsCl (204 g, 1071
mmol) at 15.degree. C. and the mixture was stirred at 15.degree. C.
for 2 hrs. The mixture was concentrated in vacuo to remove most of
the chloroform. The pyridine mixture was poured into water (6 L)
and the resulting off-white solid was collected by filtration, and
the filter cake was washed with water (6.times.1 L). The off-white
solid was dissolved in DCM (3.5 L), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to give Intermediate A-5 (163 g,
92%) as an off-white solid.
[0207] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.78 (d, J=8.0 Hz,
2H), 7.34 (d, J=8.4 Hz, 2H), 5.29-5.28 (m, 1H), 3.96 (dd, J=3.2,
9.6 Hz, 1H), 3.79 (dd, J=6.4, 9.2 Hz, 1H), 2.45 (s, 3H), 2.41 (d,
J=13.6 Hz, 1H), 1.99-1.91 (m, 3H), 1.77-1.39 (m, 11H), 1.26-0.86
(m, 16H), 0.64 (s, 3H).
Step 6. Synthesis of Intermediate A-6.
[0208] To a solution of Intermediate A-5 (163 g, 325 mmol) in DMF
(1.7 L) was added KI (258 g, 1560 mmol) at 15.degree. C. The
mixture was heated and stirred at 60.degree. C. for 2 hours. Sodium
benzenesulfinate (195 g, 975 mmol) was added and stirring was
continued at 60.degree. C. for 2 hours. The reaction mixture was
cooled to 25.degree. C. and combined with another batch of 83 g of
Intermediate A-5. The combined mixture was poured into water (20 L)
to give a yellow solid which was collected by filtration and washed
with water (3.times.2 L). The resulting filter cake was dissolved
in DCM (5 L), washed with water (2.times.1 L), brine (2.times.1 L),
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
give a yellow solid residue, which was re-crystallized from toluene
(2.5 L) to give Intermediate A-6 (150 g, 65%) as a light yellow
solid. The re-crystallization filtrate was concentrated in vacuo to
give crude Intermediate A-6 (30 g) as a yellow solid.
[0209] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.91 (d, J=7.2 Hz,
2H), 7.69-7.61 (m, 1H), 7.60-7.50 (m, 2H), 5.28-5.27 (m, 1H), 3.14
(d, J=14.0 Hz, 1H), 2.85 (dd, J=9.6, 14.0 Hz, 1H), 2.41 (d, J=12.8
Hz, 1H), 2.17-2.03 (m, 1H), 2.02-1.87 (m, 3H), 1.81-1.65 (m, 3H),
1.60-1.32 (m, 8H), 1.25-0.85 (m, 15H), 0.65 (s, 3H). LCMS Rt=2.057
min in 3.0 min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.29H.sub.41O.sub.2S [M+H-H.sub.2O].sup.+ 453, found 453.
Example 2. Synthesis of Intermediate .alpha.-4
##STR00046##
[0210] Step 1. Synthesis of Intermediate .alpha.-1.
[0211] To a solution of BHT (191 g, 866 mmol) in toluene (500 mL)
was added AlMe.sub.3 (2 M in toluene, 216 mL, 433 mmol) at
10.degree. C. and the solution was stirred for 1 h. To the mixture
was added a solution of Intermediate A-2 (Theoretical Mass: 44.6 g)
in DCM (100 mL) at -78.degree. C. The mixture was stirred at
-78.degree. C. for 1 h. EtMgBr (141 mL, 426 mmol) was added at
-78.degree. C. and the mixture was stirred at -78.degree. C. for 20
mins. Saturated citric acid (1 L) was added. The organic phase was
separated, washed with brine (600 mL), dried over Na.sub.2SO.sub.4
and concentrated in vacuo to give a residue, which was purified by
column chromatography on silica gel (PE:EtOAc=50:1 to 30:1) to give
Intermediate .alpha.-1 (27 g, 55%) as a yellow solid.
[0212] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.35-5.25 (m, 1H),
4.85 (s, 1H), 4.71 (s, 1H), 2.40-2.30 (m, 1H), 2.10-1.60 (m, 14H),
1.50-0.75 (m, 17H), 0.58 (s, 3H).
Step 2. Synthesis of Intermediate B-2.
[0213] To 9-BBN (200 mL, 0.5 M in THF, 100 mL) was added
Intermediate B-1 (13 g, 37.9 mmol) at 0.degree. C. under N.sub.2.
The mixture was heated and stirred at 65.degree. C. for 2 hrs then
cooled to 10.degree. C. EtOH (46.5 g) was added, followed by
aqueous NaOH (51 mL, 5 M) and H.sub.2O.sub.2 (57 g, 30% in water)
and the resulting mixture was stirred at 75.degree. C. for 1 h. The
mixture was concentrated in vacuo to give a solution (100 mL),
which was extracted with EtOAc (2.times.150 mL), washed with
NH.sub.4Cl (2.times.300 mL) and brine (2.times.300 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a
residue, which was purified by column chromatography on silica gel
(PE:EtOAc=50:1 to 3:1) to give Intermediate B-2 (9.86 g, 72%) as an
off-white solid.
[0214] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.31-5.29 (m, 1H),
3.70-3.60 (m, 1H), 3.40-3.30 (m, 1H), 2.40-2.30 (m, 1H), 2.10-1.90
(m, 3H), 1.75-1.65 (m, 1H), 1.65-1.55 (m, 2H), 1.50-1.26 (m, 6H),
1.25-0.95 (m, 15H), 0.90-0.75 (m, 6H), 0.70 (s, 3H).
Step 3. Synthesis of Intermediate B-3.
[0215] To a solution of Intermediate B-2 (9.86 g, 27.3 mmol) in
CHCl.sub.3 (100 mL) and pyridine (20 mL) was added TsCl (15.6 g,
81.9 mmol) at 15.degree. C. The mixture was stirred at 15.degree.
C. for 1 h. The reaction mixture was concentrated in vacuo to give
60 mL of the mixture, which was poured into 600 mL of water to give
an off-white precipitate. The mixture was filtered, the filter cake
was washed with water, dissolved in DCM (150 mL), dried over
Na.sub.2SO.sub.4, filtered, concentrated under vacuum to give
Intermediate B-3 as an off-white solid (9.9 g, 70%).
[0216] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.78 (d, J=8.4 Hz,
2H), 7.34 (d, J=8.0 Hz, 2H), 5.30-5.20 (m, 1H), 4.00-3.90 (m, 1H),
3.80-3.70 (m, 1H), 2.45 (s, 3H), 2.40-2.30 (m, 1H), 2.10-1.90 (m,
3H), 1.75-1.60 (m, 6H), 1.55-1.30 (m, 5H), 1.25-0.95 (m, 13H),
0.90-0.80 (m, 5H), 0.65-0.50 (m, 3H).
Step 4. Synthesis of Intermediate B-4.
[0217] To a solution of Intermediate B-3 (9.9 g, 19.2 mmol) in DMF
(150 mL) was added KI (15.2 g, 92.1 mmol) at 15.degree. C. The
mixture was heated and stirred at 60.degree. C. for 2 hrs. Sodium
benzenesulfinate (9.43 g, 57.5 mmol) was added and the mixture was
stirred at 60.degree. C. for 2 hrs. The mixture was poured into
water (200 mL) and the resulting yellow precipitate was collected
by filtration. The filter cake was washed with water (2.times.100
L), dissolved in DCM (500 mL), washed with water (2.times.500 mL)
and brine (2.times.1 L), dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to give a yellow solid residue, which was
purified by silica gel chromatography (0-35% EtOAc in PE) to give
Intermediate B-4 (8 g, 89%).
[0218] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.95-7.88 (m, 2H),
7.68-7.62 (m, 1H), 7.61-7.53 (m, 2H), 5.30-5.22 (m, 1H), 3.20-3.08
(m, 1H), 2.91-2.79 (m, 1H), 2.40-2.30 (m, 1H), 2.09-1.87 (m, 4H),
1.74-1.60 (m, 4H), 1.50-1.36 (m, 7H), 1.24-0.98 (m, 13H), 0.90-0.80
(m, 4H), 0.65 (s, 3H).
Example 3. Synthesis of Intermediate C-8
##STR00047## ##STR00048##
[0219] Step 1. Synthesis of Intermediate C-1.
[0220] To a solution of Intermediate A-1 (4 kg, 12.7 mol) in DCM
(30 L) was added imidazole (1.72 kg, 25.4 mol) and TBSCl (2.86 kg,
19.0 mol) at 25.degree. C. After stirring at 25.degree. C. for 16
hrs, water (10 L) was added and the organic phase was separated and
concentrated to give a residue which was triturated with MeOH (15
L) at reflux to give Intermediate C-1 (5.02 kg, 92%) as an
off-white solid.
[0221] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.38-5.28 (m, 1H),
4.85 (s, 1H), 4.71 (s, 1H), 3.57-3.41 (m, 1H), 2.33-2.11 (m, 2H),
2.10-1.94 (m, 2H), 1.90-1.61 (m, 8H), 1.60-1.38 (m, 6H), 1.28-1.03
(m, 4H), 1.00 (s, 3H), 0.98-0.91 (m, 1H), 0.89 (s, 9H), 0.58 (s,
3H), 0.06 (s, 6H).
Step 2. Synthesis of Intermediate C-2.
[0222] To a solution of Intermediate C-1 (1.69 kg, 3.94 mol) in THF
(8 L) was added 9-BBN dimer (671 g, 2.75 mol) and the resulting
mixture was stirred at 25.degree. C. under N.sub.2 for 1 h
(formation of an off-white precipitate was observed). Ethanol (2.26
L, 39.4 mol) and NaOH (3.94 L, 5 M, 19.7 mol) were added and the
resulting clear solution was treated dropwise with H.sub.2O.sub.2
(3.94 L, 10 M, 39.4 mol) at 25.degree. C. (the inner temperature
raised to reflux). After addition was complete, the mixture was
cooled to 25.degree. C. and stirred for 16 hrs, followed by
addition of Na.sub.2SO.sub.3 (2.5 L, 20% aq.) and water (5 L) at
25.degree. C. After stirring for 1 hr, the mixture was allowed to
settle to a clear lower layer and an upper suspension layer. The
upper suspension layer was collected and treated with water (20 L).
The mixture was stirred for 15 mins and filtered. The solid was
washed with water to pH<9 to give the wet product, which was
combined with two other batches of product from a previous
synthesis. The wet product was dissolved in DCM (100 L) and the
organic layer was separated, dried over Na.sub.2SO.sub.4, filtered
and concentrated to 20 L. The residue was used in the next step
directly.
[0223] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.40-5.23 (m, 1H),
3.70-3.60 (m, 1H), 3.55-3.42 (m, 1H), 3.41-3.31 (m, 1H), 2.31-2.20
(m, 1H), 2.20-2.11 (m, 1H), 2.06-1.91 (m, 2H), 1.89-1.67 (m, 3H),
1.65-1.39 (m, 7H), 1.38-1.08 (m, 6H), 1.05 (d, J=6.4 Hz, 3H), 1.00
(s, 3H), 0.99-0.91 (m, 2H), 0.88 (s, 9H), 0.70 (s, 3H), 0.05 (s,
6H).
Step 3. Synthesis of Intermediate C-3.
[0224] To a solution of Intermediate C-2 (theoretical mass: 5.2 kg,
11.6 mol) in DCM (15 L) was added N-methyl-imidazole (1.37 L, 17.4
mol) and TEA (3.2 L, 23.2 mol) at 25.degree. C. TsCl (2.53 kg, 13.3
mol) was added portionwise to the above solution, maintaining the
inner temperature between 25-30.degree. C. The reaction mixture was
stirred at 25.degree. C. for 1 h. To the mixture was added water
(10 L), citric acid (20%, 1 L) and HCl (1 M) to adjust the pH to
.about.3. The organic layer was separated, washed with water
(2.times.10 L), NaHCO.sub.3 (saturated aq. 5 L) and brine (5 L),
dried over Na.sub.2SO.sub.4, filtered and concentrated to give
Intermediate C-3 (6.63 kg, 95% for 2 steps) as an off-white
solid.
[0225] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.78 (d, J=8.4 Hz,
2H), 7.34 (d, J=8.0 Hz, 2H), 5.37-5.25 (m, 1H), 3.96 (dd, J=2.8,
9.2 Hz, 1H), 3.79 (dd, J=6.4, 9.2 Hz, 1H), 3.53-3.41 (m, 1H), 2.45
(s, 3H), 2.32-2.20 (m, 1H), 2.20-2.11 (m, 1H), 2.01-1.88 (m, 2H),
1.84-1.61 (m, 4H), 1.56-1.31 (m, 6H), 1.23-1.02 (m, 5H), 1.02-0.95
(m, 7H), 0.93-0.90 (m, 1H), 0.88 (s, 9H), 0.63 (s, 3H), 0.05 (s,
6H).
Step 4. Synthesis of Intermediate C-4.
[0226] To a suspension of Intermediate C-3 (2.69 kg, 4.47 mol) in
DMF (25 L) was added KI (1.48 g, 8.94 mol) at 70.degree. C. and the
mixture was stirred at 70.degree. C. for 1 h. PhSO.sub.2Na (2.19
kg, 13.4 mol) was added and stirring was continued at 70.degree. C.
for 1 h. The mixture was poured into water (50 L) and filtered. The
filter cake was washed with water (2.times.10 L) to give the wet
product, which was combined with two other batches from previous
syntheses. Half of the wet product was triturated with MeCN (20 L)
at 80.degree. C. and cooled to 30.degree. C. The heating and
cooling process was repeated two more times and the residue was
collected by filtration and further triturated with MeCN/toluene
(20 L, 10:1) at 80.degree. C., filtered, washed with MeCN
(3.times.5 L), dried in vacuo to give Intermediate C-4 (2.21 kg) as
a white solid. Another half of the wet product was triturated with
MeCN (20 L) at 80.degree. C. and cooled to 50.degree. C. The
heating and cooling process was repeated two more times and the
precipitate was collected by filtration to give Intermediate C-4
(1.92 kg) as an off-white solid. Totally 4.13 kg of the product was
obtained (67% yield).
[0227] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.00-7.82 (m, 2H),
7.69-7.61 (m, 1H), 7.60-7.49 (m, 2H), 5.37-5.20 (m, 1H), 3.57-3.39
(m, 1H), 3.14 (d, J=14.0 Hz, 1H), 2.85 (dd, J=9.6, 14.0 Hz, 1H),
2.35-2.05 (m, 3H), 2.02-1.88 (m, 2H), 1.85-1.62 (m, 3H), 1.61-1.32
(m, 7H), 1.29-0.91 (m, 12H), 0.88 (s, 9H), 0.65 (s, 3H), 0.05 (s,
6H).
Step 5. Synthesis of Intermediate C-5.
[0228] To a suspension of Intermediate C-4 (2.21 kg, 3.87 mol) in
THF (10 L) was added TBAF.3H.sub.2O (1.87 kg, 5.92 mol). The
mixture was heated and stirred at 65.degree. C. for 1 h to give a
clear solution, which was treated with water (25 L) and stirred at
80.degree. C. for 2 h. After cooling, the mixture was filtered and
the filter cake was washed with water (3.times.10 L) and air-dried
to give Intermediate C-5 (1.83 kg, crude) as an off-white
solid.
[0229] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.98-7.88 (m, 2H),
7.69-7.61 (m, 1H), 7.60-7.51 (m, 2H), 5.40-5.28 (m, 1H), 3.58-3.44
(m, 1H), 3.14 (d, J=13.2 Hz, 1H), 2.85 (dd, J=9.6, 14.0 Hz, 1H),
2.36-2.18 (m, 2H), 2.18-2.04 (m, 1H), 2.03-1.90 (m, 2H), 1.89-1.79
(m, 2H), 1.78-1.68 (m, 1H), 1.62-1.48 (m, 6H), 1.38-0.84 (m, 14H),
0.65 (s, 3H).
Step 6. Synthesis of Intermediate C-6.
[0230] To a solution of Intermediate C-5 (50 g, 109 mmol) in THF
(500 mL) was added Pd/C (wet, 10%, 11.7 g, 10.9 mmol) under Ar.
After degassing three times with N.sub.2, the reaction mixture was
purged three times with H.sub.2. The reaction mixture was stirred
for 72 h at 25.degree. C. under a hydrogen atmosphere (50 Psi).
Formation of the desired product and consumption of starting
material was confirmed by NMR. The catalyst was removed by
filtration and the filtrate was concentrated to give Intermediate
C-6 (39 g, crude) as an off-white solid, which was used in next
step directly without further purification.
[0231] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.85-7.82 (m, 2H),
7.58-7.55 (m, 1H), 7.52-7.47 (m, 2H), 3.54-3.47 (m, 1H), 3.09-3.04
(m, 1H), 2.80-2.74 (m, 1H), 2.03-1.83 (m, 2H), 1.63-1.46 (m, 2H),
1.30-1.21 (m, 8H), 1.20-1.17 (m, 7H), 1.16-1.10 (m, 6H), 1.09-0.92
(m, 2H), 0.72 (s, 3H), 0.60-0.48 (m, 4H).
Step 7. Synthesis of Intermediate C-7.
[0232] To a solution of Intermediate C-6 (196 g, 427 mmol) in DCM
(2 L) was added PCC (137 g, 640 mmol) and the reaction mixture was
stirred at 25.degree. C. for 2 h, then filtered and concentrated in
vacuo to give a residue which was purified by silica gel
chromatography (DCM) to give Intermediate C-7 (145 g, 74%) as an
off-white solid.
[0233] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.95-7.85 (m, 2H),
7.70-7.60 (m, 1H), 7.60-7.50 (m, 2H), 3.20-3.10 (m, 1H), 2.90-2.80
(m, 1H), 2.45-2.20 (m, 3H), 2.15-1.90 (m, 4H), 1.75-1.60 (m, 2H),
1.55-1.00 (m, 16H), 0.99 (s, 3H), 0.95-0.70 (m, 2H), 0.66 (s,
3H).
Step 8. Synthesis of Intermediate C-8.
[0234] To a solution of BHT (499 g, 2.27 mmol) in anhydrous toluene
(1 L) under N.sub.2 at 0.degree. C. trimethylaluminum (2 M in
toluene, 525 mL, 1.05 mmol) was added dropwise. The mixture was
stirred at 25.degree. C. for 1 hour and cooled to -70.degree. C.
Intermediate C-7 (160 g, 350 mmol) in toluene (500 mL) was added
maintaining the temperature below -60.degree. C. The resulting
mixture was stirred at -70.degree. C. for 1 hour. Ethylmagnesium
bromide (350 mL, 3.0 M in diethyl ether, 1.05 mmol) was added
dropwise maintaining the temperature below -60.degree. C. and
stirring was continued at -70.degree. C. for another 1 hour. The
reaction mixture was quenched with saturated citric acid (2 L) at
-70.degree. C., warmed slowly to 25.degree. C., and extracted with
ethyl acetate (500 mL.times.3). The combined organic layers were
washed with brine (200 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated. The residue was purified by silica gel
chromatography (0%-30% EtOAc in PE) to afford Intermediate C-8 (153
g, 90%) as an off-white solid. A small sample of this material (300
mg) was purified by re-crystallization from MeCN (2 mL) to give
Intermediate C-8 (200 mg) as an off-white solid.
[0235] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.95-7.85 (m, 2H),
7.70-7.60 (m, 1H), 7.60-7.50 (m, 2H), 3.20-3.10 (m, 1H), 2.90-2.80
(m, 1H), 2.15-2.05 (m, 1H), 1.95-1.85 (m, 1H), 1.75-1.60 (m, 3H),
1.55-1.40 (m, 6H), 1.40-1.15 (m, 11H), 1.15-0.95 (m, 7H), 0.88 (t,
J=7.2 Hz, 3H), 0.81 (s, 3H), 0.65-0.55 (m, 4H).
[0236] LCMS Rt=1.194 min in 2.0 min chromatography, 30-90 AB,
purity 100%, MS ESI calcd. for
C.sub.30H.sub.48O.sub.4S[M+H.sub.2O]+504, found 504.
Example 4. Synthesis of Compound 1
##STR00049##
[0237] Step 1. Synthesis of Intermediate 1-2.
[0238] To a suspension of Me.sub.3SI (3.93 g, 19.3 mmol) in THF (20
mL) was added a solution of t-BuOK (3.33 g, 29.8 mmol) in THF (10
mL) under N.sub.2 at 15.degree. C. and the resulting suspension was
stirred at 15.degree. C. for 30 mins. A solution of Intermediate
1-1 (2 g, 14.9 mmol) in THF (5 mL) was added dropwise at 15.degree.
C. and the mixture was stirred at 15.degree. C. for 16 hrs. The
mixture was quenched with saturated NH.sub.4Cl (50 mL) and
extracted with EtOAc (3.times.20 mL). The combined organic phases
were dried over Na.sub.2SO.sub.4, filtered, and concentrated to
give Intermediate 1-2 (1.8 g, 82%) as a brown solid.
[0239] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.72 (s, 2H),
2.20-1.85 (m, 8H).
Step 2. Synthesis of Intermediate 1-3.
[0240] To a flask containing THF (5 mL) was added n-BuLi (2.5 M,
1.59 mmol, 0.636 mL) under N.sub.2 at -70.degree. C. A suspension
of A-6 (0.637 mmol, 300 mg) in THF (4 mL) was added dropwise to
give a light yellow suspension. After stirring at -70.degree. C.
for 30 mins, a solution of Intermediate 1-2 (0.764 mmol, 113 mg) in
THF (1 mL) was added dropwise and the reaction was stirred at
15.degree. C. for 12 hrs. The reaction was quenched with saturated
NH.sub.4Cl (30 mL) and extracted with EtOAc (10 mL.times.3). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated to give Intermediate 1-3 (400 mg, crude) as light
yellow solid, which was used directly for the next step.
Step 3. Synthesis of Compound 1.
[0241] To a solution of Intermediate 1-3 (400 mg, 0.646 mmol) in
MeOH (5 mL) was added Mg powder (930 mg, 38.76 mmol) at 60.degree.
C. and the mixture was stirred at 60.degree. C. for 16 hrs. The
reaction was quenched with HCl (50 mL, 1N) and extracted with DCM
(2.times.30 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered, concentrated and the residue was
purified by silica gel chromatography (0-10% EtOAc in PE) to give
50 mg impure product, which was purified by SFC (column: AD(250
mm*30 mm, 5 um), gradient: 0-40% B (A=0.05% NH.sub.3/H.sub.2O,
B=MeOH); FlowRate(mL/min): 60) to give Compound 1 (32 mg, 10%) as
an off-white solid.
[0242] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.31-5.29 (m, 1H),
2.43-2.40 (m, 1H), 2.20-2.02 (m, 4H), 2.00-1.73 (m, 5H), 1.72-1.61
(m, 5H), 1.60-1.46 (m, 10H), 1.45-1.22 (m, 3H), 1.21-1.06 (m, 8H),
1.05-0.96 (m, 3H), 0.95-0.90 (m, 5H), 0.68 (s, 3H). LCMS Rt=1.256
min in 2.0 min chromatography, 30-90AB_ELSD, purity 100%, MS ESI
calcd. for C.sub.30H.sub.45F.sub.2[M+H-2H.sub.2O].sup.+ 443, found
443.
Example 5. Synthesis of Compound 2
##STR00050##
[0243] Step 1. Synthesis of Intermediate 2-2.
[0244] To a solution of Me.sub.3SI (13.4 g, 66.1 mmol) in DMSO (100
mL) was added NaH (2.63 g, 66.1 mmol, 60%) in portions at 0.degree.
C. After stirring at 25.degree. C. for 30 min, a solution of
Intermediate 2-1 (5 g, 50.9 mmol) in 50 ml of DMSO was added
dropwise and the mixture was stirred at 25.degree. C. for 1 h,
poured into ice-water (300 mL) and extracted with EtOAc
(2.times.100 mL). The combined organic phases were washed with
brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue was purified by silica gel
chromatography (PE/EtOAc=10/1) to afford Intermediate 2-2 (0.6 g,
10%) as a colorless oil.
[0245] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.59 (s, 2H),
1.78-1.71 (m, 4H), 1.59-1.51 (m, 6H).
Step 2. Synthesis of Intermediate 2-3.
[0246] To a flask containing THF (4 mL) under N.sub.2 at
-70.degree. C. was added n-BuLi (2.5 M, 3.17 mmol, 1.26 mL, 2.5
eq.) followed by dropwise addition of a suspension of A-6 (600 mg,
1.27 mmol) in THF (6 mL). After stirring at -70.degree. C. for 30
min, a solution of Intermediate 2-2 (227 mg, 2.03 mmol) was added.
The reaction was stirred at 25.degree. C. for 16 hours, poured into
ice-water (100 mL) and extracted with EtOAc (2.times.50 mL). The
combined organic layers were washed with brine (30 mL), dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was
purified by silica gel chromatography (PE/EtOAc=5/1) to afford
Intermediate 2-3 (400 mg, impure) as a light yellow solid. LCMS
Rt=1.066 min in 1.5 min chromatography, 5-95 AB, MS ESI calcd. for
C.sub.3-6H.sub.53O.sub.3S [M+H-H.sub.2O].sup.+ 565, found 565.
Step 3. Synthesis of Compound 2.
[0247] To a solution of Intermediate 2-3 (400 mg, 0.69 mmol) in 10
mL of dry methanol, magnesium turnings (492 mg, 20.5 mmol)
(activated with 0.5% aqueous HCl, water, dry ethanol, and MTBE) and
NiCl.sub.2 (44.4 mg, 0.34 mmol) were added under N.sub.2 and the
reaction was stirred at 50.degree. C. for 1 h. The reaction was
quenched at 10.degree. C. by dropwise addition of 2M HCl (50 mL)
until the complete dissolution of all solids. The mixture was
extracted with EtOAc (50 mL) and the organic layer was washed with
saturated NaHCO.sub.3 (50 mL), brine (50 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by silica gel chromatography (PE/EtOAc=10/1) to afford
Compound 2 (42 mg, 14%) as an off-white solid.
[0248] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.31-5.30 (m, 1H),
2.44-2.41 (m, 1H), 2.02-1.93 (m, 3H), 1.86-1.58 (m, 6H), 1.52-1.36
(m, 16H), 1.32-1.25 (m, 3H), 1.18-1.07 (m, 9H), 1.03-0.92 (m, 8H),
0.68 (s, 3H). LCMS Rt=1.353 min in 2.0 min chromatography, 30-90
AB, MS ESI calcd. for C.sub.30H.sub.47 [M+H-2H.sub.2O].sup.+ 407,
found 407.
Example 6. Synthesis of Compound 3
##STR00051##
[0249] Step 1. Synthesis of Intermediate 3-2.
[0250] To a mixture of trimethylsulfoxonium iodide (47.1 g, 231
mmol) in 100 mL of DMSO was added NaH (9.23 g, 60% in mineral oil,
231 mmol) portionwise at 10.degree. C. under N.sub.2. The mixture
was stirred at 10.degree. C. for 30 mins. Intermediate 3-1 (15 g,
178 mmol) in DMSO (50 mL) was added dropwise below 15.degree. C.
and the reaction mixture was stirred at 15.degree. C. for 20 hrs.
The reaction was quenched at 10.degree. C. with water (200 mL) and
extracted with MTBE (2.times.300 mL). The combined organic phases
were washed with water (2.times.400 mL), brine (200 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a
residue, which was purified by silica gel chromatography (DCM) to
give Intermediate 3-2 (11 g, impure) as a colorless oil.
[0251] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.83 (s, 2H),
1.95-1.77 (m, 4H), 1.74-1.60 (m, 4H).
Step 2. Synthesis of Intermediate 3-3.
[0252] To a flask containing THF (4 mL) under N.sub.2 at
-70.degree. C. was added n-BuLi (2.5 M, 5.30 mmol, 2.11 mL),
followed by dropwise addition of a suspension of A-6 (2.12 mmol, 1
g) in THF (10 mL). After stirring at -70.degree. C. for 30 mins, a
solution of Intermediate 3-2 (4.24 mmol, 416 mg) in THF (4 mL) was
added and the reaction was stirred at -70.degree. C. for 10 mins
and at 25.degree. C. for 16 hrs. The reaction was quenched with
water (10 mL) and extracted with EtOAc (3.times.50 mL). The
combined organic phases were washed with brine (100 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give
Intermediate 3-3 (1.2 g, crude) as a yellow solid. LCMS Rt=1.161
min & 1.222 min in 2.0 min chromatography, 30-90 AB, 28%, MS
ESI calcd. for C.sub.35H.sub.52O.sub.4SNa [M+Na].sup.+ 591, found
591.
Step 3. Synthesis of Compound 3.
[0253] To a solution of Intermediate 3-3 (1.2 g, 2.10 mmol) in 50
mL of dry MeOH and 25 mL of THF, magnesium turnings (3.06 g, 126
mol) (activated with 0.5% aqueous HCl, water, dry ethanol, and
MTBE) and NiCl.sub.2 (54.4 mg, 0.42 mmol) were added under N.sub.2
at 50.degree. C. to initiate continuous hydrogen generation. The
reaction was quenched at 10.degree. C. by addition of 1 M HCl (200
mL) until the complete dissolution of all solids. The mixture was
extracted with EtOAc (2.times.200 mL). The combined organic layers
were washed with saturated NaHCO.sub.3 (500 mL), brine (500 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
give Compound 3 (600 mg, crude), which was purified by column
chromatography on silica gel (PE/EtOAc=5/1) to give a product (150
mg, impure) as an off-white solid. The impure product was purified
by SFC (Column: AD(250 mm*30 mm, 5 um); Condition: Base-ETOH, 40%
B; FlowRate(ml/min): 60 mL/min) to give 30 mg of the product. The
product was washed with n-hexane (5 mL) to give Compound 3 (3 mg,
0.3%).
[0254] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.34-5.28 (m, 1H),
2.46-2.35 (m, 1H), 2.05-1.93 (m, 3H), 1.89-1.59 (m, 12H), 1.53-1.24
(m, 11H), 1.21-0.99 (m, 13H), 0.96-0.89 (m, 4H), 0.68 (s, 3H).
[0255] LCMS Rt=1.161 min & 1.295 min in 2.0 min chromatography,
30-90 AB_E, MS ESI calcd. for C.sub.29H.sub.45
[M+H-2H.sub.2O].sup.+ 393, found 393.
Example 7. Synthesis of Compound 4
##STR00052##
[0256] Step 1. Synthesis of Intermediate 4-2.
[0257] To a solution of Intermediate 4-1 (1 g, 14.6 mmol) in DCM
(30 mL) was added m-CPBA (3.77 g, 21.9 mmol) and the mixture was
stirred at 25.degree. C. for 16 hrs. The reaction mixture was
filtered, and the filtrate was distilled in vacuo to give a
solution of Intermediate 4-2 in DCM. The solution was distilled
under normal pressure to give a solution of Intermediate 4-2 (5 g,
2% solution in DCM calculated from .sup.1HNMR, 8% yield calculated
from HNMR).
[0258] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.67 (s, 2H),
2.54-2.43 (m, 2H), 2.30-2.20 (m, 2H), 1.89-1.72 (m, 2H).
Step 2. Synthesis of Intermediate 4-3.
[0259] To a solution of n-BuLi (2.5 M in hexane, 1.1 mL, 2.65 mmol)
in anhydrous THF (8 mL) under nitrogen at -78.degree. C., A-6 (500
mg, 1.06 mmol) was added in one portion and the mixture was stirred
at -78.degree. C. for 0.5 hr. A solution of Intermediate 4-2 (5 g,
2% in DCM, 1.18 mmol) was added dropwise to the above mixture and
the reaction was gradually warmed to 15.degree. C. After stirring
for 16 hrs the reaction was quenched with saturated NH.sub.4Cl (20
mL) and extracted with EtOAC (3.times.30 mL). The combined organic
layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by column chromatography on
silica gel (PE:EtOAc=9:1) to give Intermediate 4-3 (100 mg, 17%) as
an off-white solid. LCMS Rt=1.131 min in 2.0 min chromatography,
30-90 AB, MS ESI calcd. for C.sub.34H.sub.49O.sub.3S
[M+H-H.sub.2O].sup.+ 537, found 537.
Step 3. Synthesis of Compound 4.
[0260] To a solution of Intermediate 4-3 (100 mg, 0.180 mmol) in
anhydrous MeOH (5 mL) under nitrogen was added magnesium powder
(260 mg, 10.7 mmol). The mixture was stirred at 60.degree. C. for 2
hrs, cooled to room temperature, neutralized with 1 M HCl and
extracted with EtOAc (4.times.20 mL). The combined organic layers
were washed with water (40 mL) and brine (40 mL), dried over
anhydrous sodium sulfate, filtered and concentrated. The residue
was purified by column chromatography on silica gel (PE:EtOAc=10:1)
to afford a residue, which was triturated with n-hexane to give
Compound 4 (23 mg, 31%) as an off-white solid.
[0261] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.34-5.26 (m, 1H),
2.46-2.37 (m, 1H), 2.09-1.57 (m, 14H), 1.54-1.23 (m, 11H),
1.21-1.05 (m, 8H), 1.04-0.90 (m, 8H), 0.69 (s, 3H). LCMS Rt=1.230
min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.28H.sub.43 [M+H-2H.sub.2O].sup.+ 379, found 379.
Example 8. Synthesis of Compound 5
##STR00053##
[0262] Step 1. Synthesis of Intermediate 5-2.
[0263] To a mixture of trimethylsulfoxonium iodide (28.3 g, 139
mmol) in DMSO (60 mL) was added NaH (5.55 g, 60% in mineral oil,
139 mmol) in portions at 5.degree. C. under N.sub.2 and the mixture
was stirred at 5.degree. C. for 30 mins. Dihydrofuran-3 (2H)-one
(10 g, 116 mmol) in DMSO (40 mL) was added dropwise while
maintaining the temperature below 15.degree. C. and the resulting
mixture was stirred at 15.degree. C. for 20 hrs. The reaction was
quenched at 10.degree. C. with water (200 mL) and extracted with
MTBE (2.times.200 mL). The combined organic phases were washed with
brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated and the residue was purified by silica gel
chromatography (0%-40% EtOAc in PE) to afford Intermediate 5-2 (100
mg, 1%) as a colorless oil.
[0264] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.12-3.93 (m, 3H),
3.68 (d, J=10.4 Hz, 1H), 3.05 (d, J=4.4 Hz, 1H), 2.96 (d, J=4.4 Hz,
1H), 2.37-2.25 (m, 1H), 2.02-1.92 (m, 1H).
Step 2. Synthesis of Intermediate 5-3.
[0265] To a flask containing THF (2 mL) under N.sub.2 at
-78.degree. C. was added n-BuLi (0.9 mL, 2.22 mmol, 2.5 M) followed
by a suspension of A-6 (300 mg, 0.637 mmol) in THF (4 mL), giving a
light yellow suspension. After stirring at -78.degree. C. for 30
mins, a solution of Intermediate 5-2 (100 mg, 1.01 mmol) in THF (2
mL) was added and the reaction was stirred at -78.degree. C. for 10
mins and at 15.degree. C. for 16 hrs. The reaction was quenched
with saturated NH.sub.4Cl (20 mL), extracted with EtOAc (3.times.20
mL) and the combined organic phases were washed with brine (50 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated to give
crude Intermediate 5-3 (300 mg) as a yellow solid, which was used
directly in next step. LCMS Rt=0.907 min in 1.5 min chromatography,
5-95 AB, MS ESI calcd. for C.sub.34H.sub.49O.sub.4S
[M+H-H.sub.2O].sup.+553, found 553.
Step 3. Synthesis of Compound 5.
[0266] To a solution of Intermediate 5-3 (300 mg, 0.525 mmol) in 20
mL of dry MeOH under N.sub.2, magnesium turnings (127 mg, 5.24
mmol) (activated with 0.5% aqueous HCl, water, dry EtOH, and MTBE)
and NiCl.sub.2 (13.6 mg, 0.10 mmol) were added with stirring at
55.degree. C. to initiate continuous hydrogen generation. After
four batches of 127 mg of magnesium turnings were added most of the
starting material was consumed. The reaction was quenched by adding
2M HCl (50 mL) until the complete dissolution of all solids. The
mixture was extracted with DCM (3.times.20 mL) and the combined
organic phases were washed with brine (50 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by silica gel chromatography (0%-50% EtOAc in PE) to
afford Compound 5 (34 mg, 15%) as an off-white solid.
[0267] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.37-5.24 (m, 1H),
4.08-3.98 (m, 1H), 3.94-3.84 (m, 1H), 3.74-3.65 (m, 1H), 3.59-3.51
(m, 1H), 2.48-2.37 (m, 1H), 2.06-1.67 (m, 9H), 1.66-1.38 (m, 13H),
1.34-1.07 (m, 8H), 1.06-0.90 (m, 7H), 0.68 (s, 3H). LCMS Rt=1.111
min in 2 min chromatography, 30-90AB_E, MS ESI calcd. for
C.sub.30H.sub.49O.sub.3NNa [M+MeCN+Na].sup.+ 494, found 494.
Example 9. Preparation of Compound 5-A and 5-B
##STR00054##
[0269] Racemic Compound 5 (1.4 g) was purified by SFC (Column: AD
(250 mm*30 mm, 5 um)); Condition: 0.1% NH.sub.3H.sub.2O IPA;
Gradient 40% B; Gradient Time(min):30; FlowRate(ml/min): 60.) to
afford Compound 5-A (350 mg, 15%) as an off-white solid and
Compound 5-B (310 mg, 14%) as a an off-white solid.
Compound 5-A
[0270] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.33-5.28 (m, 1H),
4.10-4.00 (m, 1H), 3.93-3.85 (m, 1H), 3.69 (d, J=9.2 Hz, 1H), 3.54
(d, J=9.2 Hz, 1H), 2.46-2.38 (m, 1H), 2.04-1.88 (m, 5H), 1.87-1.56
(m, 9H), 1.53-1.23 (m, 7H), 1.21-1.09 (m, 7H), 1.08-0.89 (m, 9H),
0.68 (s, 3H).
[0271] LCMS Rt=1.091 min in 2 min chromatography, 30-90AB_E, purity
100%, MS ESI calcd. for C.sub.28H.sub.46O.sub.3Na [M+Na].sup.+ 453,
found 453.
Compound 5-B
[0272] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.32-5.28 (m, 1H),
4.10-4.00 (m, 1H), 3.93-3.85 (m, 1H), 3.70 (d, J=9.2 Hz, 1H), 3.55
(d, J=9.2 Hz, 1H), 2.45-2.39 (m, 1H), 2.04-1.83 (m, 6H), 1.81-1.63
(m, 4H), 1.61-1.54 (m, 5H), 1.52-1.37 (m, 6H), 1.26-1.08 (m, 8H),
1.05-0.92 (m, 8H), 0.68 (s, 3H). LCMS Rt=1.093 min in 2 min
chromatography, 30-90AB_E, purity 100%, MS ESI calcd. for
C.sub.28H.sub.43O [M+H-2H.sub.2O].sup.+ 395, found 395.
Example 10. Synthesis of Compound 6
##STR00055##
[0273] Step 1. Synthesis of Intermediate 6-2.
[0274] To a mixture of trimethylsulfoxonium iodide (12.2 g, 59.8
mmol) in DMSO (40 mL) at 5.degree. C. under N.sub.2, NaH (2.38 g,
60% in mineral oil, 59.8 mmol) was added portionwise and the
mixture was stirred at 5.degree. C. for 30 mins. Intermediate 6-1
(5 g, 49.9 mmol) in DMSO (40 mL) was added dropwise maintaining the
temperature below 15.degree. C. and the reaction mixture was
stirred at 15.degree. C. for 20 hrs. The reaction was quenched at
10.degree. C. with water (200 mL) and extracted with MTBE
(2.times.200 mL). The combined organic phases were washed with
brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated and the resulting residue was purified by silica gel
chromatography (0%-50% EtOAc in PE) to afford Intermediate 6-2 (1.5
g, 26%) as colorless oil.
[0275] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.93-3.76 (m, 4H),
2.69 (s, 2H), 1.94-1.81 (m, 2H), 1.58-1.48 (m, 2H).
Step 2. Synthesis of Intermediate 6-3.
[0276] To a flask containing THF (5 mL) under N.sub.2 at
-78.degree. C., n-BuLi (2.96 mL, 7.42 mmol, 2.5 M) was added,
followed by dropwise addition of a suspension of A-6 (1 g, 2.12
mmol) in THF (10 mL) to give a light yellow suspension. After
stirring at -78.degree. C. for 30 mins, a solution of Intermediate
6-2 (483 mg, 4.24 mmol) in THF (5 mL) was added and the reaction
was stirred at -78.degree. C. for 10 min and at 15.degree. C. for
16 hrs. The reaction was quenched with saturated NH.sub.4Cl (50 mL)
and extracted with EtOAc (3.times.30 mL). The combined organic
phases were washed with brine (50 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated to give crude
Intermediate 6-3 (1 g) as a yellow solid, which was used directly
in next step. LCMS Rt=2.423 min in 3.0 min chromatography, 10-80
AB, MS ESI calcd. for C.sub.35H.sub.52O.sub.5SNa [M+Na].sup.+ 607,
found 607.
Step 3. Synthesis of Compound 6.
[0277] To a solution of Intermediate 6-3 (1 g, 1.70 mmol) in 20 mL
of anhydrous MeOH under N.sub.2, magnesium turnings (410 mg, 16.9
mmol) (activated with 0.5% aqueous HCl, water, anhydrous ethanol,
and MTBE) and NiCl.sub.2 (44.0 mg, 0.34 mmol) were added with
stirring at 55.degree. C. to initiate continuous hydrogen
generation. After four batches of magnesium turnings (410 mg
overall) were added, the reaction was quenched at 10.degree. C. by
dropwise addition of 2M HCl (80 mL) until the complete dissolution
of all solids. The mixture was extracted with DCM (3.times.50 mL)
and the combined organic phases were washed with brine (80 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated. The
resulting residue was purified by silica gel chromatography (0%-70%
EtOAc in PE) to afford Compound 6 (200 mg, 26%) as an off-white
solid.
[0278] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 5.24-5.15 (m,
1H), 4.34 (s, 1H), 4.02 (s, 1H), 3.64-3.47 (m, 4H), 2.30-2.23 (m,
1H), 2.00-1.75 (m, 5H), 1.70-1.24 (m, 14H), 1.20-0.83 (m, 18H),
0.63 (s, 3H). LCMS Rt=2.043 min in 3.0 min chromatography, 10-80
AB, MS ESI calcd. for C.sub.29H.sub.45O [M+H-2H.sub.2O].sup.+ 409,
found 409.
Example 11. Synthesis of Compound 7
##STR00056##
[0279] Step 1. Synthesis of Intermediate 7-2.
[0280] To a solution of trimethylsulfoxonium iodide (26.5 g, 130
mmol) in 50 mL of DMSO at 10.degree. C. under N.sub.2, NaH (5.18 g,
60% in mineral oil, 130 mmol) was added portionwise and the mixture
was stirred at 10.degree. C. for 30 mins. Intermediate 7-1 (20 g,
100 mmol) in DMSO (50 mL) was added dropwise maintaining the
temperature below 15.degree. C. and stirring was continued at
15.degree. C. for 20 hrs. The reaction was quenched at 10.degree.
C. with water (200 mL) and extracted with MTBE (2.times.300 mL).
The combined organic phases were washed with water (2.times.400
mL), brine (200 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to give a residue, which was purified by
silica gel chromatography (PE:EtOAc=6:1) to give Intermediate 7-2
(15 g, 70%) as an off-white solid.
[0281] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.77-3.66 (m, 2H),
3.43 (m, 2H), 2.69 (s, 2H), 1.86-1.72 (m, 2H), 1.52-1.39 (m,
11H).
Step 2. Synthesis of Intermediate 7-3.
[0282] To a solution of n-BuLi (2.5 M in hexane, 4.2 mL, 10.6 mmol)
in anhydrous THF (20 mL) at -70.degree. C. under nitrogen A-6 (2 g,
4.24 mmol) was added in one portion and the mixture was stirred at
-70.degree. C. for 30 mins. Intermediate 7-2 (1.80 g, 8.48 mmol)
was added and the resulting mixture was gradually warmed to
15.degree. C. and stirred for an additional 16 hours. The reaction
was quenched with saturated NH.sub.4Cl (30 mL) and extracted with
EtOAc (3.times.40 mL). The combined organic layers were dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue
was purified by column chromatography on silica gel (PE:THF=5:1) to
give Intermediate 7-3 (2.3 g, 79%) as an off-white solid.
[0283] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.96-7.87 (m, 2H),
7.72-7.55 (m, 3H), 5.31-5.24 (m, 1H), 4.00-3.83 (m, 2H), 3.43-3.32
(m, 1H), 3.30-3.06 (m, 2H), 2.44-2.24 (m, 2H), 1.99-1.87 (m, 3H),
1.80-1.50 (m, 11H), 1.49-1.42 (m, 12H), 1.40-1.25 (m, 4H),
1.18-0.80 (m, 15H), 0.43 (s, 3H).
Step 3. Synthesis of Intermediate 7-4.
[0284] To a solution of Intermediate 7-3 (2.3 g, 3.36 mmol) and
nickel(II) chloride (435 mg, 3.36 mmol) in anhydrous MeOH (30 mL)
and THF (10 mL) under nitrogen at 45.degree. C. was added a single
portion of magnesium turnings (3.25 g, 134 mmol). The internal
temperature rose to 60.degree. C. and vigorous gas evolution was
observed. The mixture was stirred at 60.degree. C. for 3 hrs,
cooled to room temperature, quenched with 1 M HCl (100 mL) and
extracted with EtOAc (2.times.100 mL). The combined organic layers
were washed with saturated NaHCO.sub.3 (100 mL) and brine (100 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue
was purified by column chromatography on silica gel (PE:THF=6:1) to
give Intermediate 7-4 (1.1 g, 60%) as an off-white solid.
[0285] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.34-5.27 (m, 1H),
3.91-3.66 (m, 2H), 3.23-3.07 (m, 2H), 2.47-2.38 (m, 1H), 2.03-1.91
(m, 3H), 1.88-1.65 (m, 4H), 1.60-1.54 (m, 4H), 1.47-1.42 (m, 12H),
1.38-1.24 (m, 4H), 1.20-0.97 (m, 14H), 0.97-0.77 (m, 7H), 0.68 (s,
3H).
Step 4. Synthesis of Compound 7.
[0286] To a solution of Intermediate 7-4 (1 g, 1.83 mmol) in EtOAc
(8 mL) and DCM (8 mL) were added ethanol (843 mg, 18.3 mmol) and
acetyl chloride (1.43 g, 18.3 mmol). The mixture was stirred at
15.degree. C. for 16 hrs. The precipitated solid was collected by
filtration and dried in vacuo to afford crude product (720 mg),
which was triturated with methanol to give the hydrochloride of
Compound 7 (260 mg, 30%) as an off-white solid.
[0287] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.70-8.38 (m,
1H), 5.24-5.15 (m, 1H), 4.52-4.24 (m, 2H), 3.11-2.94 (m, 4H),
2.35-2.25 (m, 1H), 1.98-1.77 (m, 4H), 1.71-1.50 (m, 8H), 1.47-1.31
(m, 7H), 1.28-0.98 (m, 8H), 0.97-0.86 (m, 10H), 0.65 (s, 3H). LCMS
Rt=1.054 min in 2.0 min chromatography, 10-80 AB, MS ESI calcd. for
C.sub.29H.sub.50NO.sub.2[M+H].sup.+ 444, found 444.
Example 12. Synthesis of Compound 8
##STR00057##
[0289] To a suspension of Compound 7 hydrochloride (50 mg, 0.104
mmol) in DCE (4 mL) were added Et.sub.3N (21.0 mg, 0.208 mmol),
paraformaldehyde (18.7 mg, 0.208 mmol) and NaBH.sub.3CN (16.3 mg,
0.260 mmol) and the mixture was stirred at 25.degree. C. for 16
hrs. The reaction mixture was neutralized with 1 M HCl and purified
by preparative HPLC (Column: DuraShell 150*25 mm*5 um. Mobile
phase: A: Water (0.1% TFA), B: ACN. Gradient: 35-60% B, 25 Min.
Flow rate: 30 mL/min) to give Compound 8 (3 mg, 6%) as an off-white
solid.
[0290] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.34-5.26 (m, 1H),
3.44-3.32 (m, 2H), 3.19-3.04 (m, 2H), 2.78 (d, J=4.0 Hz, 3H),
2.48-2.37 (m, 1H), 2.16-1.92 (m, 5H), 1.86-1.56 (m, 9H), 1.51-1.35
(m, 7H), 1.31-1.04 (m, 10H), 1.04-0.87 (m, 8H), 0.67 (s, 3H). LCMS
Rt=0.748 min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.30H.sub.52NO.sub.2 [M+H].sup.+ 458, found 458.
Example 13. Synthesis of Compound 9
##STR00058##
[0292] To a suspension of Compound 7 hydrochloride (50 mg, 0.104
mmol) in DCM (4 mL) were added Et.sub.3N (31.5 mg, 0.312 mmol) and
AcCl (16.3 mg, 0.208 mmol) and the mixture was stirred at
25.degree. C. for 16 hrs. The reaction mixture was neutralized with
1 M HCl and purified by preparative HPLC (Column: DuraShell 150*25
mm*5 um. Mobile phase: A: Water (0.1% TFA), B: ACN. Gradient:
51-76% B, 25 Min. Flow rate: 30 mL/min) to give Compound 9 (15 mg,
30%) as an off-white solid.
[0293] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.35-5.25 (m, 1H),
4.43-4.27 (m, 1H), 3.65-3.38 (m, 2H), 3.12-2.94 (m, 1H), 2.48-2.37
(m, 1H), 2.11 (s, 11H), 1.89-1.57 (m, 6H), 1.52-1.21 (m, 9H),
1.20-1.03 (m, 8H), 1.03-0.89 (m, 8H), 0.68 (s, 3H). LCMS Rt=1.036
min in 2.0 min chromatography, 30-90 AB, MS ESI calcd. for
C.sub.31H.sub.52NO.sub.3 [M+H].sup.+ 486, found 486.
Example 14. Synthesis of Compound 10
##STR00059##
[0294] Step 1. Synthesis of Intermediate 10-2.
[0295] To a suspension of t-BuOK (3.53 g, 31.6 mmol) in THF (30 mL)
was added Me.sub.3SI (4.18 g, 20.5 mmol) under N.sub.2 and the
suspension was stirred at 15.degree. C. for 30 min. A solution of
Intermediate 10-1 (2 g, 15.8 mmol) in 10 ml of THF was added
dropwise and stirring was continued at 15.degree. C. for 16 hrs.
The reaction was quenched with saturated NH.sub.4Cl (100 mL) and
extracted with EtOAc (3.times.150 mL). The combined organic phases
were dried over Na.sub.2SO.sub.4, filtered, and concentrated in
vacuo to give Intermediate 10-2 (1.8 g, 81%) as a yellow
liquid.
[0296] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.58 (s, 2H),
1.90-1.80 (m, 1H), 1.70-1.55 (m, 2H), 1.54-1.45 (m, 3H), 1.40-1.30
(m, 2H), 1.00-0.90 (m, 6H).
Step 2. Synthesis of Intermediate 10-3.
[0297] To a flask containing THF (0.5 mL) under N.sub.2 at
-70.degree. C. was added n-BuLi (1.05 mL, 2.5 M, 2.65 mmol),
followed by dropwise addition of a suspension of Intermediate A-6
(500 mg, 1.06 mmol) in THF (1 mL) to give a light yellow
suspension. After stirring at -70.degree. C. for 30 min, a solution
of Intermediate 10-2 (178 mg, 1.27 mmol) in THF (1 mL) was added
dropwise and the reaction was stirred at 15.degree. C. for 12 hrs.
The reaction was quenched with saturated NH.sub.4Cl (10 mL) and
extracted with EtOAc (3.times.10 mL). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered and concentrated to give
Intermediate 10-3 (500 mg, crude) as a yellow solid, which was used
directly for the next step.
Step 3. Synthesis of Compound 10.
[0298] To a solution of Intermediate 10-3 (500 mg, 0.818 mmol) and
nickel (II) chloride (26.4 mg, 0.204 mmol) in dry methanol under
N.sub.2 (20 mL) was added magnesium powder (794 mg, 32.7 mmol) with
stirring at 50.degree. C. to initiate continuous hydrogen
generation. After stirring at 60.degree. C. for 1 hour the reaction
was quenched at 10.degree. C. by dropwise addition of 2M HCl (100
mL) until the complete dissolution of all solids. After extraction
with EtOAc (2.times.150 mL), the combined organic layers were
washed with sat. NaHCO.sub.3 aq. (300 mL), brine (300 mL), dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give a
yellow solid, which was purified by silica gel chromatography
(PE/THF=4/1) to give 150 mg of white solid. 72 mg of the solid was
purified by SFC (column: AD(250 mm*30 mm, 10 um)), gradient: 55-55%
B (A=0.1% NH.sub.3/H.sub.2O, B=EtOH), flow rate: 80 mL/min) to give
Compound 10 (39 mg) as an off-white solid.
[0299] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.35-5.30 (m, 1H),
2.45-2.40 (m, 2H), 2.10-1.95 (m, 3H), 1.90-1.65 (m, 7H), 1.60-1.40
(m, 14H), 1.39-1.10 (m, 11H), 1.09-1.00 (m, 4H), 0.09-0.88 (m, 6H),
0.87 (s, 3H), 0.67 (m, 3H).
[0300] LCMS Rt=1.481 min in 2.0 min chromatography, 30-90 AB,
purity 100%, MS ESI calcd. for C.sub.32H.sub.51
[M+H-2H.sub.2O].sup.- 435, found 435.
Example 15. Synthesis of Compound 11
##STR00060##
[0301] Step 1. Synthesis of Intermediate 11-2.
[0302] To a mixture of trimethylsulfoxonium iodide (12.2 g, 59.8
mmol) in DMSO (40 mL) was added NaH (2.38 g, 60% in mineral oil,
59.8 mmol) portionwise at 5.degree. C. under N.sub.2 and the
mixture was stirred at 5.degree. C. for 30 mins. Intermediate 11-1
(5 g, 49.9 mmol) in DMSO (40 mL) was added dropwise maintaining the
temperature below 15.degree. C. and stirring was continued at
15.degree. C. for 20 hrs. The reaction was quenched at 10.degree.
C. with water (200 mL) and extracted with DCM (2.times.200 mL). The
combined organic phases were washed with brine (200 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
purified by silica gel chromatography (0%-50% EtOAc in PE) to
afford Intermediate 11-2 (2 g, 35%) as a colorless oil.
[0303] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.81-3.60 (m, 3H),
3.49 (d, J=12.0 Hz, 1H), 2.73-2.65 (m, 2H), 2.03-1.82 (m, 2H),
1.81-1.62 (m, 2H).
Step 2. Synthesis of Intermediate 11-3.
[0304] To a flask containing THF (3 mL) under N.sub.2 at
-78.degree. C. was added n-BuLi (1.48 mL, 3.71 mmol, 2.5 M),
followed by dropwise addition of a suspension of Intermediate A-6
(500 mg, 1.06 mmol) in THF (5 mL) to give a light yellow
suspension. After stirring at -78.degree. C. for 30 min, a solution
of Intermediate 11-2 (362 mg, 3.18 mmol) in THF (2 mL) was added
and the reaction was stirred at -78.degree. C. for 10 min and at
15.degree. C. for 16 hrs. The reaction was quenched with
aq.NH.sub.4Cl (50 mL) and extracted with EtOAc (3.times.30 mL). The
combined organic phases were washed with brine (50 mL), dried over
anhydrous sodium sulfate, filtered and concentrated to give crude
Intermediate 11-3 (500 mg) as a yellow solid, which was used
directly in next step.
[0305] LCMS Rt=0.939 min in 1.5 min chromatography, 5-95 AB, purity
79%, MS ESI calcd. for C.sub.35H.sub.51O.sub.4S
[M+H-H.sub.2O].sup.+ 567, found 567.
Step 3. Synthesis of Compound 11.
[0306] To a solution of Intermediate 11-3 (500 mg, 0.85 mmol) in 20
mL of dry MeOH under N.sub.2, magnesium turnings (828 mg, 34.1
mmol) (activated with 0.5% aqueous HCl, water, dry ethanol, and
MTBE) and NiCl.sub.2 (22 mg, 0.17 mmol) were added with stirring at
55.degree. C. to initiate continuous hydrogen generation. After two
batches of magnesium turnings (828 mg) were added, most of the
starting material was consumed. The reaction mixture was quenched
at 10.degree. C. by addition of 2M HCl (40 mL) until the complete
dissolution of all solids. The resulting solution was extracted
with DCM (3.times.50 mL) and the combined organic phases were
washed with brine (80 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated. The resulting residue was purified by silica gel
chromatography (0%-20% MeOH in DCM) to afford the crude product,
which was recrystallized from MeCN (20 mL) to afford Compound 11
(150 mg, 40%) as a white solid.
[0307] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.25-5.22 (m, 1H),
3.84-3.75 (m, 1H), 3.50-3.40 (m, 1H), 3.36-3.21 (m, 2H), 2.39-2.32
(m, 1H), 2.19-2.14 (m, 1H), 1.96-1.86 (m, 3H), 1.85-1.51 (m, 6H),
1.49-1.40 (m, 3H), 1.44-1.26 (m, 8H), 1.25-1.14 (m, 2H), 1.13-0.97
(m, 8H), 0.96-0.82 (m, 8H), 0.61 (s, 3H).
[0308] LCMS Rt=1.226 min in 2 min chromatography, 30-90AB_E, purity
100%, MS ESI calcd. for C.sub.29H.sub.45O [M+H-2H.sub.2O].sup.+
409, found 409.
Example 16. Synthesis of Compound 12
##STR00061##
[0309] Step 1. Synthesis of Intermediate 12-1.
[0310] To a flask containing THF (5 mL) was added BuLi (4.12 mL,
2.5 M in hexane, 10.3 mmol) and the solution was cooled to
-70.degree. C. and treated with a solution of Intermediate B-4 (2
g, 4.12 mmol) in THF (10 mL). The mixture was stirred at
-70.degree. C. for 1 h and treated with a solution of Intermediate
1-2 (1.89 g, 6.18 mmol, 50% purity) in THF (5 mL) at -70.degree. C.
The reaction was warmed to 25.degree. C. and allowed to stir for 16
hrs. NH.sub.4Cl (40 mL, saturated aq.) was added and the mixture
was extracted with EtOAc (30 mL). The organic layer was separated,
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The crude
residue was purified by silica gel chromatography (0-25% EtOAc in
PE) to give Intermediate 12-1 (150 mg, 6%) as an off-white
solid.
[0311] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.96-7.90 (m, 2H),
7.70-7.62 (m, 1H), 7.62-7.55 (m, 2H), 5.30-5.26 (m, 1H), 3.58 (m,
1H), 2.40-2.28 (m, 3H), 2.10-2.00 (m, 2H), 1.99-1.76 (m, 6H),
1.75-1.58 (m, 7H), 1.56-1.31 (m, 8H), 1.30-1.15 (m, 4H), 1.14-1.03
(m, 3H), 1.01 (s, 3H), 0.96-0.75 (m, 8H), 0.58 (s, 3H).
Step 2. Synthesis of Compound 12.
[0312] To a solution of Intermediate 12-1 (170 mg, 0.268 mmol) in
MeOH (15 mL) was added Mg powder (256 mg, 10.7 mmol) at 55.degree.
C. After stirring at 60.degree. C. for 16 hrs., the reaction was
quenched by addition of HCl (50 mL, 1 N) until the reaction became
clear and the resulting solution was extracted with DCM (2.times.30
mL). The combined organic phases were dried over Na.sub.2SO.sub.4,
filtered, concentrated and purified by silica gel chromatography
(0-10% EtOAc in PE) to give Compound 12 (50 mg, 38%) as an
off-white solid.
[0313] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.30-5.26 (m, 1H),
2.38-2.31 (m, 1H), 2.18-1.76 (m, 8H), 1.75-1.58 (m, 8H), 1.56-1.41
(m, 9H), 1.40-1.20 (m, 3H), 1.18-1.05 (m, 5H), 1.02 (s, 3H),
1.00-0.90 (m, 6H), 0.88-0.80 (m, 3H), 0.68 (s, 3H).
[0314] LCMS Rt=1.268 min in 2.0 min chromatography, 30-90 AB,
purity 100%, MS ESI calcd. for
C.sub.31H.sub.47F.sub.2[M+H-2H.sub.2O].sup.+ 457, found 457.
Example 17. Synthesis of Compound 13
##STR00062##
[0315] Step 1. Synthesis of Intermediate 13-1.
[0316] To a solution of diisopropylamine (526 mg, 5.20 mmol) in THF
(1 mL) was added n-BuLi (1.93 mL, 2.5 M in hexane, 4.84 mmol) under
N.sub.2 at -70.degree. C. and the mixture was allowed to warm to
25.degree. C. After cooling to -70.degree. C., a suspension of
Intermediate B-4 (588 mg, 1.21 mmol) in THF (5 mL) was added
dropwise under N.sub.2 and stirring was continued at -70.degree. C.
for 30 min. Intermediate 10-2 (339 mg, 2.42 mmol) was added at
-70.degree. C. and the reaction was allowed to slowly warm to
25.degree. C. After stirring for 16 hours, the reaction was
quenched with saturated aqueous NH.sub.4Cl (15 mL) and the
resulting mixture was extracted with EtOAc (2.times.15 mL). The
combined organic phases were washed with brine (2.times.20 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
give Intermediate 13-1 (840 mg, crude) as a yellow oil which was
used directly for next step without further purification.
Step 2. Synthesis of Compound 13.
[0317] A solution of Intermediate 13-1 (840 mg, 1.34 mmol) in MeOH
(40 mL) was heated to 65.degree. C. NiCl.sub.2 (34.2 mg, 268
.mu.mol) and Mg powder (1.28 g, 53.6 mmol) were added in one
portion and the mixture was allowed to stir at 65.degree. C. for 1
h. After cooling, the mixture was quenched by addition of HCl (40
mL, 2N) until the reaction became clear and the resulting solution
was extracted with DCM (2.times.40 mL). The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered, concentrated and
purified by silica gel chromatography (0-10% EtOAc in PE) to give
Compound 13 (240 mg, 37%) as an off-white solid.
[0318] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.31-5.26 (m, 1H),
2.42-2.31 (m, 1H), 2.07-1.92 (m, 3H), 1.92-1.78 (m, 1H), 1.77-1.68
(m, 1H), 1.68-1.58 (m, 3H), 1.52-1.44 (m, 10H), 1.44-1.34 (m, 4H),
1.34-1.23 (m, 3H), 1.22-1.14 (m, 3H), 1.14-1.05 (m, 5H), 1.04-0.96
(m, 5H), 0.96-0.89 (m, 7H), 0.89-0.82 (m, 6H), 0.68 (s, 3H).
[0319] LCMS Rt=1.475 min in 2 min chromatography, 30-90AB, purity
100%, MS ESI calcd. For C.sub.33H.sub.53 [M+H-2H.sub.2O].sup.+ 449,
found 449.
Example 18. Synthesis of Compound 14
##STR00063##
[0320] Step 1. Synthesis of Intermediate 14-1.
[0321] To a flask containing THF (3 mL) under N.sub.2 at
-78.degree. C. was added n-BuLi (1.44 mL, 3.60 mmol, 2.5 M),
followed by dropwise addition of a suspension of Intermediate B-4
(500 mg, 1.03 mmol) in THF (5 mL) to give a light yellow
suspension. After stirring at -78.degree. C. for 30 min, a solution
of Intermediate 6-2 (352 mg, 3.09 mmol) in THF (2 mL) was added,
and the reaction was stirred at -78.degree. C. for 10 min at
15.degree. C. for 16 hours. The reaction was quenched with
saturated NH.sub.4Cl (50 mL) and extracted with DCM (3.times.50
mL). The combined organic phases were washed with brine (100 mL),
dried over anhydrous sodium sulfate, filtered and concentrated to
give crude Intermediate 14-1 (500 mg) as a yellow solid, which was
used directly in next step.
[0322] LCMS Rt=0.953 min in 1.5 min chromatography, 5-95 AB, purity
36%, MS ESI calcd. for C.sub.3-6H.sub.54O.sub.5SNa [M+Na].sup.+
621, found 621.
Step 2. Synthesis of Compound 14.
[0323] To a solution of Intermediate 14-1 (500 mg, 0.834 mmol) in
20 mL of anhydrous MeOH under N.sub.2, magnesium turnings (809 mg,
33.3 mmol) (activated with 0.5% aqueous HCl, water, anhydrous EtOH,
and MTBE) and NiCl.sub.2 (21.5 mg, 0.17 mmol) were added with
stirring at 55.degree. C. to initiate continuous hydrogen
generation. After two batches of 809 mg of magnesium turnings were
added, most of the starting material was consumed. The reaction
mixture was quenched at 10.degree. C. by addition of 2M HCl (40 mL)
until the complete dissolution of all solids and the resulting
solution was extracted with DCM (3.times.50 mL). The combined
organic phases were washed with brine (80 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated. The resulting residue
was purified by silica gel chromatography (0%-20% MeOH in DCM), to
afford the crude product, which was recrystallized from MeCN (20
mL) to afford Compound 14 (150 mg, 39%) as an off-white solid.
[0324] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.26-5.18 (m, 1H),
3.78-3.61 (m, 4H), 2.34-2.25 (m, 1H), 2.02-1.85 (m, 4H), 1.83-1.71
(m, 1H), 1.69-1.49 (m, 7H), 1.47-1.35 (m, 9H), 1.27-1.15 (m, 4H),
1.12-0.96 (m, 9H), 0.90-0.77 (m, 7H), 0.61 (s, 3H).
[0325] LCMS Rt=1.227 min in 2.0 min chromatography, 30-90 AB,
purity 100%, MS ESI calcd. for C.sub.30H.sub.47O
[M+H-2H.sub.2O].sup.+ 423, found 423.
Example 19. Synthesis of Compound 15
##STR00064##
[0326] Step 1. Synthesis of Intermediate 15-1.
[0327] To a flask containing THF (3 mL) under N.sub.2 at
-78.degree. C. was added n-BuLi (1.44 mL, 3.60 mmol, 2.5 M),
followed by dropwise addition of a suspension of Intermediate B-4
(500 mg, 1.03 mmol) in THF (5 mL) to give a light yellow
suspension. After stirring at -78.degree. C. for 30 min, a solution
of Intermediate 11-2 (352 mg, 3.09 mmol) in THF (2 mL) was added.
The reaction was stirred at -78.degree. C. for 10 mins and at
15.degree. C. for 16 hrs. The reaction was quenched with
aq.NH.sub.4Cl (50 mL) and extracted with DCM (3.times.50 mL). The
combined organic phases were washed with brine (100 mL), dried over
anhydrous sodium sulfate, filtered and concentrated to give crude
Intermediate 15-1 (500 mg) as a yellow solid, which was used
directly in next step.
[0328] LCMS Rt=0.973 min in 1.5 min chromatography, 5-95 AB, purity
47%, MS ESI calcd. for C.sub.36H.sub.53O.sub.4S
[M+H-H.sub.2O].sup.+ 581, found 581.
Step 2. Synthesis of Compound 15.
[0329] To a solution of Intermediate 15-1 (500 mg, 0.834 mmol) in
20 mL of dry MeOH under N.sub.2, magnesium turnings (809 mg, 33.3
mmol) (activated with 0.5% aqueous HCl, water, dry ethanol, and
MTBE) and NiCl.sub.2 (21.5 mg, 0.17 mmol) were added with stirring
at 55.degree. C. to initiate continuous hydrogen generation. After
two batches of magnesium turnings (809 mg) were added, most of the
starting material was consumed. The reaction mixture was quenched
at 10.degree. C. by addition of 2M HCl (40 mL) until the complete
dissolution of all solids. The resulting solution was extracted
with DCM (3.times.50 mL) and the combined organic phases were
washed with brine (80 mL), dried over Na.sub.2SO.sub.4, filtered
and concentrated. The resulting residue was purified by silica gel
chromatography (0%-20% MeOH in DCM) to provide the product which
was recrystallized from MeCN (20 mL) to afford Compound 15 (150 mg,
39%) as an off-white solid.
[0330] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.25-5.18 (m, 1H),
3.84-3.74 (m, 1H), 3.50-3.41 (m, 1H), 3.35-3.21 (m, 2H), 2.33-2.26
(m, 1H), 2.20-2.12 (m, 1H), 2.00-1.64 (m, 7H), 1.63-1.47 (m, 6H),
1.44-1.31 (m, 9H), 1.26-1.14 (m, 3H), 1.10-0.94 (m, 8H), 0.89-0.75
(m, 7H), 0.61 (s, 3H).
[0331] LCMS Rt=1.284 min in 2.0 min chromatography, 30-90 AB,
purity 100%, MS ESI calcd. for C.sub.30H.sub.47O
[M+H-2H.sub.2O].sup.+ 423, found 423.
Example 20. Synthesis of Compound 16
##STR00065##
[0333] To a solution of Compound 1 (300 mg, 0.626 mmol) in MeOH (20
mL) was added Pd(OH).sub.2 (100 mg, dry). The mixture was
hydrogenated at 50.degree. C., 50 Psi for 48 hrs. The mixture was
filtered, washed with DCM (100 mL) and the filtrate was
concentrated. The resulting residue was purified by silica gel
chromatography (0-15% EtOAc in PE) to give Compound 16 (114 mg,
38%) as an off-white solid.
[0334] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.20-2.00 (m, 2H),
1.99-1.75 (m, 4H), 1.70-1.60 (m, 5H), 1.59-1.42 (m, 8H), 1.41-1.23
(m, 6H), 1.22-1.16 (m, 6H), 1.15-0.96 (m, 8H), 0.95-0.82 (m, 4H),
0.80 (s, 3H), 0.70-0.60 (m, 4H).
[0335] LCMS Rt=1.275 min in 2.0 min chromatography, 30-90 AB,
purity 100%, MS ESI calcd. for
C.sub.30H.sub.47F.sub.2[M+H-2H.sub.2O].sup.+ 445, found 445.
Example 21. Synthesis of Compound 17
##STR00066##
[0337] To a solution of Compound 5-A (100 mg, 0.232 mmol) in MeOH
(10 mL) was added dry Pd/C (100 mg) at 15.degree. C. The mixture
was degassed and purged several times with H.sub.2 and was allowed
to stir under 50 psi H.sub.2 at 55.degree. C. for 48 hrs. The
reaction mixture was filtered to remove the Pd/C and the filtrate
was concentrated. The resulting residue was purified by silica gel
chromatography (0%-30%) EtOAc in PE/DCM(v/v=1/1)) to afford
Compound 17 (30 mg, 30%) as an off-white solid.
[0338] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.06-3.98 (m, 1H),
3.93-3.85 (m, 1H), 3.69 (d, J=9.2 Hz, 1H), 3.54 (d, J=9.2 Hz, 1H),
1.99-1.75 (m, 4H), 1.74-1.58 (m, 5H), 1.55-1.37 (m, 7H), 1.35-1.18
(m, 10H), 1.17-0.95 (m, 7H), 0.94-0.83 (m, 4H), 0.80 (s, 3H),
0.70-0.60 (m, 4H).
[0339] LCMS Rt=1.114 min in 2.0 min chromatography, 30-90 AB,
purity 100%, MS ESI calcd. for C.sub.28H.sub.45O
[M+H-2H.sub.2O].sup.+ 397, found 397.
Example 22. Synthesis of Compound 18
##STR00067##
[0341] To a solution of Compound 6 (100 mg, 0.224 mmol) in MeOH (10
mL) was added dry Pd/C (100 mg) at 15.degree. C. The mixture was
degassed and purged several times with H.sub.2 and was allowed to
stir under 50 psi H.sub.2 at 50.degree. C. for 48 hrs. The reaction
mixture was filtered to remove the Pd/C and the filtrate was
concentrated. The resulting residue was purified by silica gel
chromatography (0%-30% EtOAc in PE/DCM(v/v=1/1)) to afford Compound
18 (32 mg, 32.0%) as an off-white solid.
[0342] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.75-3.61 (m, 4H),
1.92-1.84 (m, 1H), 1.81-1.70 (m, 1H), 1.66-1.49 (m, 7H), 1.48-1.36
(m, 7H), 1.34-1.22 (m, 5H), 1.20-1.12 (m, 7H), 1.09-0.98 (m, 5H),
0.96-0.77 (m, 6H), 0.81 (s, 3H), 0.64-0.53 (m, 4H).
[0343] LCMS Rt=1.216 min in 2.0 min chromatography, 30-90 AB,
purity 100%, MS ESI calcd. for C.sub.29H.sub.47O
[M+H-2H.sub.2O].sup.+ 411, found 411.
Example 23. Synthesis of Compound 19
##STR00068##
[0345] To a solution of Compound 11 (100 mg, 0.224 mmol) in MeOH
(10 mL) was added dry Pd/C (100 mg) at 15.degree. C. The mixture
was degassed and purged several times with H.sub.2 and was allowed
to stir under 50 psi H.sub.2 at 50.degree. C. for 48 hrs. The
reaction mixture was filtered to remove the Pd/C and the filtrate
was concentrated. The resulting residue was purified by silica gel
chromatography (0%-30% EtOAc in PE/DCM(v/v=1/1)) to afford Compound
19 (35.0 mg, 35%) as an off-white solid.
[0346] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.84-3.74 (m, 1H),
3.49-3.42 (m, 1H), 3.35-3.20 (m, 2H), 2.18-2.14 (m, 1H), 1.93-1.71
(m, 3H), 1.68-1.49 (m, 5H), 1.47-1.34 (m, 7H), 1.33-1.21 (m, 4H),
1.21-1.10 (m, 8H), 1.10-0.89 (m, 7H), 0.88-0.68 (m, 7H), 0.63-0.52
(m, 4H).
[0347] LCMS Rt=1.249 min in 2 min chromatography, 30-90AB_E, purity
100%, MS ESI calcd. for C.sub.29H.sub.47O [M+H-2H.sub.2O].sup.+
411, found 411.
Example 24. Synthesis of Compound 20
##STR00069##
[0348] Step 1. Synthesis of Intermediate 20-1.
[0349] To a solution of 2, 6-di-tert-butyl-4-methylphenol (14.4 mg,
65.4 mmol) in toluene (100 mL) was added AlMe.sub.3 (16.3 mL, 32.7
mmol, 2 M in toluene) dropwise at 0.degree. C. The mixture was
stirred at 25.degree. C. for 1 h to give a MAD solution. A solution
of Intermediate C-7 (5 g, 10.9 mmol) in toluene (50 mL) was added
dropwise to the MAD (116 ml, 0.28 M in toluene) reaction mixture at
-65.degree. C. After stirring at -65.degree. C. for 1 h, MeMgBr
(10.8 mL, 32.6 mmol, 3M in ethyl ether) was added dropwise at
-65.degree. C. and the resulting solution was stirred at
-65.degree. C. for 1 hr. The reaction was quenched at -65.degree.
C. with saturated aqueous NH.sub.4Cl (100 mL) and the mixture was
allowed to warm to 25.degree. C. After stirring for 10 min, the
resulting suspension was filtered through a Celite pad and the pad
was washed with EtOAc (100 mL). The combined organic layers were
separated, washed with brine (50 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to afford Intermediate 20-1 (4.5
g crude) as an off-white solid.
[0350] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.95-7.83 (m, 2H),
7.66-7.60 (m, 1H), 7.58-7.51 (m, 2H), 3.17-3.08 (m, 1H), 2.88-2.68
(m, 1H), 2.15-2.03 (m, 1H), 1.94-1.86 (m, 1H), 1.73-1.40 (m, 9H),
1.40-0.90 (m, 19H), 0.90-0.80 (m, 1H), 0.79 (s, 3H), 0.62 (s,
3H).
Step 2. Synthesis of Intermediate 20-2.
[0351] To a solution of n-BuLi (504 .mu.L, 2.5 M in hexane, 1.26
mmol) in THF (1 mL) at -65.degree. C. under N.sub.2, a suspension
of Intermediate 20-1 (200 mg, 0.423 mmol) in THF (3 mL) was added
dropwise. After stirring for 30 minutes at -65.degree. C., a
solution of diisopropylamine (127 mg, 1.26 mmol) was added
dropwise, followed by the dropwise addition of a solution of
Intermediate 10-2 (176 mg, 1.26 mmol). The mixture was stirred for
another 30 min at -65.degree. C. and then gradually warmed to
25.degree. C. and allowed to stir for 16 hours. The reaction was
quenched with saturated aqueous NH.sub.4Cl (10 mL) and extracted
with EtOAc (3.times.10 mL). The combined organic layers were dried
over Na.sub.2SO.sub.4, filtered and concentrated to give
Intermediate 20-2 (270 mg, crude), which was used directly for the
next step.
Step 3. Synthesis of Compound 20.
[0352] A solution of Intermediate 20-2 (270 mg, 0.44 mmol) in MeOH
(50 mL) was heated to 60.degree. C. One portion of NiCl.sub.2 (2.83
mg, 0.022 mmol) was added, followed by four portions of Mg (420 mg,
17.5 mmol). After stirring at 60.degree. C. for 1 h, the reaction
was quenched by addition of HCl (10 mL, 2 M) until a clear solution
was obtained and the solution was extracted with DCM (2.times.20
mL). The combined organic phases were dried over Na.sub.2SO.sub.4,
filtered, concentrated and purified by silica gel chromatography
(0-20% EtOAc in PE) to give Compound 20 (100 mg, 48%). The product
was dissolved in MeCN (25 mL), vacuum concentrated at 70.degree.
C., triturated with water (5 mL), filtered and concentrated to give
Compound 20 as an off-white solid (56 mg).
[0353] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.00-1.91 (m, 1H),
1.89-1.78 (m, 1H), 1.70-1.51 (m, 3H), 1.51-1.19 (m, 13H), 1.19-1.04
(m, 13H), 1.18-1.06 (m, 5H), 1.06-0.96 (m, 3H), 0.95-0.86 (m, 10H),
0.82-0.79 (m, 3H), 0.70-0.60 (m, 4H).
[0354] LCMS Rt=1.442 min in 2 min chromatography, 30-90AB_2MIN_E,
purity 100%, MS ESI calcd. for C.sub.32H.sub.53
[M+H-2H.sub.2O].sup.+ 437, found 437.
Example 25. Synthesis of Compound 21
##STR00070##
[0355] Step 1. Synthesis of Intermediate 21-1.
[0356] To a solution of diisopropylamine (173 mg, 1.72 mmol) in THF
(0.5 mL) cooled to -70.degree. C. was added butyllithium (0.616 mL,
1.54 mmol, 2.5 M in n-hexane) and the mixture was stirred at
-70.degree. C. for 30 minutes. A solution of Intermediate C-8 (300
mg, 0.616 mmol) in THF (3 mL) was added and the mixture was stirred
at -70.degree. C. for 30 minutes. Intermediate 1-2 (182 mg, 1.23
mmol) was added at -70.degree. C. and the mixture was warmed to
25.degree. C. and stirred at this temperature for 17 hours. The
mixture was quenched with saturated NH.sub.4Cl (30 mL), extracted
with EtOAc (3.times.10 mL), washed with brine (2.times.30 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
give Intermediate 21-1 (350 mg) as a yellow solid, which was used
directly in the next step.
Step 2. Synthesis of Compound 21.
[0357] A solution of Intermediate 21-1 (350 mg, 0.551 mmol) in MeOH
(15 mL) was heated to 55.degree. C., treated with one portion of Mg
powder (547 mg, 22.8 mmol) and heated to reflux for 1 h. The
reaction was quenched with HCl (50 mL, 1N) and the resulting clear
solution was extracted with DCM (2.times.30 mL). The combined
organic phases were dried over Na.sub.2SO.sub.4, filtered,
concentrated and purified by silica gel chromatograpy (0-10% EtOAc
in PE) to give impure Compound 21 (120 mg, 44% yield, containing
22,23-olefin) as an off-white solid. The 120 mg of impure sample
was dissolved in THF (5 mL) and treated with Pd/C (100 mg, wet).
The mixture was hydrogenated (15 Psi, 25.degree. C.) for 2 hrs,
filtered, concentrated and purified by silica gel chromatography
(0-15% EtOAc in PE) to give Compound 21 (86 mg, 72%) as an
off-white solid.
[0358] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.20-2.01 (m, 2H),
1.98-1.72 (m, 4H), 1.70-1.58 (m, 10H), 1.56-1.41 (m, 6H), 1.40-1.30
(m, 5H), 1.29-1.18 (m, 4H), 1.17-1.05 (m, 4H), 1.04-0.96 (m, 3H),
0.95-0.80 (m, 10H), 0.68-0.58 (m, 4H).
[0359] LCMS Rt=1.325 min in 2.0 min chromatography, 30-90 AB,
purity 100%, MS ESI calcd. for
C.sub.31H.sub.49F.sub.2[M+H-2H.sub.2O].sup.+ 459, found 459.
Example 26. Synthesis of Compound 22
##STR00071##
[0361] To a solution of Compound 13 (160 mg, 0.391 mmol) in MeOH
(15 mL) and THF (15 mL) was added Pd(OH).sub.2/C (dry, 350 mg)
under N.sub.2. The suspension was degassed and purged with H.sub.2
three times. The mixture was stirred under H.sub.2 (50 psi) at
50.degree. C. for 48 hours to give a black suspension. The reaction
mixture was filtered through a pad of Celite, washed with THF
(3.times.20 mL) and the filtrate was concentrated in vacuo to give
Compound 22 (12 mg, 8%) as an off-white solid.
[0362] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.00-1.91 (m, 1H),
1.91-1.73 (m, 1H), 1.69-1.56 (m, 5H), 1.54-1.44 (m, 9H), 1.44-1.41
(m, 1H), 1.41-1.32 (m, 4H), 1.32-1.15 (m, 9H), 1.15-1.04 (m, 5H),
1.04-0.95 (m, 3H), 0.95-0.91 (m, 5H), 0.91-0.89 (m, 2H), 0.89-0.85
(m, 6H), 0.85-0.79 (m, 3H), 0.69-0.60 (m, 4H)
[0363] LCMS Rt=1.515 min in 2 min chromatography, 30-90AB, purity
100%, MS ESI calcd. For C.sub.33H.sub.55 [M+H-2H.sub.2O].sup.+ 451,
found 451.
Example 27. Synthesis of Compound 23
##STR00072##
[0365] To a solution of Compound 14 (100 mg, 0.217 mmol) in MeOH
(10 mL) was added dry Pd/C (100 mg) at 15.degree. C. The mixture
was degassed and purged with H.sub.2 several times and was stirred
under 50 psi H.sub.2 at 55.degree. C. for 48 hrs. The reaction
mixture was filtered to remove the Pd/C, the filtrate was
concentrated and the residue was purified by silica gel
chromatography (0%-30% EtOAc in PE/DCM(v/v=1/1)) to afford Compound
23 (36.0 mg, 36%) as an off-white solid.
[0366] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.82-3.69 (m, 4H),
1.99-1.91 (m, 1H), 1.87-1.75 (m, 1H), 1.73-1.57 (m, 7H), 1.55-1.42
(m, 7H), 1.40-1.17 (m, 10H), 1.16-0.95 (m, 8H), 0.94-0.84 (m, 7H),
0.82 (s, 3H), 0.70-0.55 (m, 4H).
[0367] LCMS Rt=1.208 min in 2.0 min chromatography, 30-90 AB,
purity 100%, MS ESI calcd. for C.sub.30H.sub.49O
[M+H-2H.sub.2O].sup.+ 425, found 425.
Example 28. Synthesis of Compound 24
##STR00073##
[0369] To a solution of Compound 15 (100 mg, 0.217 mmol) in MeOH
(10 mL) was added dry Pd/C (100 mg) at 15.degree. C. The mixture
was degassed and purged with H.sub.2 several times and stirred
under 50 psi H.sub.2 at 50.degree. C. for 48 hours. The reaction
mixture was filtered to remove the Pd/C, the filtrate was
concentrated and the residue was purified by silica gel
chromatography (0%-30% EtOAc in PE/DCM(v/v=1/1)) to afford Compound
24 (27 mg, 27%) as a white solid.
[0370] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.89-3.81 (m, 1H),
3.55-3.48 (m, 1H), 3.43-3.25 (m, 2H), 2.25-2.20 (m, 1H), 1.99-1.77
(m, 3H), 1.73-1.57 (m, 6H), 1.54-1.41 (m, 7H), 1.40-1.18 (m, 10H),
1.15-0.96 (m, 7H), 0.93-0.80 (m, 10H), 0.70-0.57 (m, 4H).
[0371] LCMS Rt=1.270 min in 2.0 min chromatography, 30-90 AB,
purity 100%, MS ESI calcd. for C.sub.30H.sub.49O
[M+H-2H.sub.2O].sup.+ 425, found 425.
TABLE-US-00001 TABLE 1 NMDA Potentiation GluN2A PCA IWB Ephys %
Compound potentiation at 3 .mu.M 1 C 2 C 3 C 4 B 5 C 5-A B 5-B C 6
B 7 B 8 A 9 C 10 A 11 C 12 C 13 A 14 C 15 C 16 A 17 C 18 C 19 C 20
A 21 C 22 A 23 C 24 C For Table 1, "A" indicates 10 to 100%,"B"
indicates potentiation of >100% to 150%; and "C" indicates
potentiation of >150%.
[0372] The data in Table 1 demonstrate the ability of the
exemplified compounds to modulate the NMDA receptor as positive
allosteric modulators (PAMs).
Other Embodiments
[0373] 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.
[0374] 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.
[0375] 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.
[0376] 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.
* * * * *