U.S. patent application number 16/902730 was filed with the patent office on 2021-02-11 for oxysterols and methods of use thereof.
The applicant listed for this patent is Sage Therapeutics, Inc.. Invention is credited to Boyd L. Harrison, Gabriel Martinez Botella, Albert Jean Robichaud, Francesco G. Salituro.
Application Number | 20210040138 16/902730 |
Document ID | / |
Family ID | 1000005169930 |
Filed Date | 2021-02-11 |
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United States Patent
Application |
20210040138 |
Kind Code |
A1 |
Harrison; Boyd L. ; et
al. |
February 11, 2021 |
OXYSTEROLS AND METHODS OF USE THEREOF
Abstract
Compounds are provided according to Formula (I): ##STR00001##
and pharmaceutically acceptable salts thereof, and pharmaceutical
compositions thereof; wherein X, Y, R.sup.1, R.sup.2a, R.sup.2b,
R.sup.4a, R.sup.4b, R.sup.5a, R.sup.5b, R.sup.6a, R.sup.6b,
R.sup.7, and R.sup.8 are as defined herein. Compounds of the
present invention are contemplated useful for the prevention and
treatment of a variety of conditions.
Inventors: |
Harrison; Boyd L.;
(Princeton Junction, NJ) ; Martinez Botella; Gabriel;
(Wayland, MA) ; Robichaud; Albert Jean; (Boston,
MA) ; Salituro; Francesco G.; (Marlborough,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sage Therapeutics, Inc. |
Cambridge |
MA |
US |
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|
Family ID: |
1000005169930 |
Appl. No.: |
16/902730 |
Filed: |
June 16, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16028790 |
Jul 6, 2018 |
10723758 |
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16902730 |
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15319504 |
Dec 16, 2016 |
10259840 |
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PCT/US15/36510 |
Jun 18, 2015 |
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16028790 |
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62107236 |
Jan 23, 2015 |
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62014014 |
Jun 18, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07J 31/006 20130101;
C07J 9/005 20130101; C07J 13/005 20130101; A61K 9/0095 20130101;
C07J 13/007 20130101; A61K 9/4866 20130101; C07J 9/00 20130101;
A61K 9/0019 20130101; A61K 9/2063 20130101; A61K 31/575
20130101 |
International
Class: |
C07J 9/00 20060101
C07J009/00; A61K 9/00 20060101 A61K009/00; A61K 9/20 20060101
A61K009/20; A61K 9/48 20060101 A61K009/48 |
Claims
1. A compound of Formula (I): ##STR00032## or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 is hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, carbocyclyl, or heterocyclyl; each of R.sup.2 and R.sup.2b
is independently hydrogen, C.sub.1-C.sub.6 alkyl, halo, cyano,
--OR.sup.A, or --NR.sup.BR.sup.C, or R.sup.2a and R.sup.2b together
with the carbon atom to which they are attached form a ring (e.g.,
a 3-7-membered ring, e.g., a 5-7-membered ring; a ring containing
at least one heteroatom, e.g., a nitrogen, oxygen, or sulfur atom);
each of R.sup.4a and R.sup.4b is independently absent, hydrogen,
C.sub.1-C.sub.6 alkyl, or halo; X is --C(R.sup.X).sub.2-- or --O--,
wherein R.sup.X is independently hydrogen, halo, or one R.sup.X
group and R.sup.5b are joined to form a double bond; Y is
--OR.sup.Y, wherein R is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, carbocyclyl,
heterocyclyl, aryl, heteroaryl, --C(O)R.sup.A, --C(O)OR.sup.A,
--C(O)NR.sup.BR.sup.C, or --S(O).sub.2R.sup.D; each instance of
R.sup.5a and R.sup.5b is independently hydrogen, halo, or
C.sub.1-C.sub.6 alkyl; each of R.sup.6a and R.sup.6b is
independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, carbocyclyl, heterocyclyl, aryl,
or heteroaryl, or R.sup.6a and R.sup.6b, taken together with the
carbon atom to which they are attached, form a ring (e.g., a
3-6-membered ring, e.g. a 4-6-membered ring containing one
heteroatom); or R.sup.5a and R.sup.6a, together with the carbon
atoms to which they are attached, form a ring (e.g., a 3-6-membered
ring, e.g. a 4-6-membered ring containing one heteroatom); and
R.sup.7 is absent or hydrogen in the alpha configuration; R.sup.8
is hydrogen, halo, C.sub.1-6alkyl, carbocyclyl, or --OR.sup.A;
represents a single or double bond, wherein when one is a double
bond, the other is a single bond; wherein when the between
--CR.sup.7 and --CR.sup.4aR.sup.4b is a double bond, then one of
R.sup.4a or R.sup.4b is absent; and when one of the is a double
bond, R.sup.7 is absent; R.sup.A is hydrogen, C.sub.1-C.sub.6
alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each of
R.sup.B and R.sup.C is independently hydrogen, C.sub.1-C.sub.6
alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or taken
together with the atom to which they are attached form a ring
(e.g., a 3-7-membered ring, e.g., a 5-7-membered ring; a ring
containing at least one heteroatom, e.g., a nitrogen, oxygen, or
sulfur atom); and R.sup.D is hydrogen, C.sub.1-C.sub.6 alkyl,
carbocyclyl, heterocyclyl, aryl, or heteroaryl.
2. The compound of claim 1, or the pharmaceutically acceptable salt
thereof, wherein: a. R.sup.1 is unsubstituted C.sub.1-3 alkyl; b.
R.sup.1 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--CH.sub.2CH.sub.2CH.sub.3; c. R.sup.1 is substituted C.sub.1-3
alkyl; or d. R.sup.1 is haloalkyl (e.g., --CF.sub.3) or
--CH.sub.2OCH.sub.3.
3-5. (canceled)
6. The compound of claim 1, or the pharmaceutically acceptable salt
thereof, wherein: a. R.sup.2a or R.sup.2b is hydrogen; or b.
R.sup.2a and R.sup.2b are both hydrogen.
7. (canceled)
8. The compound of claim 1, or the pharmaceutically acceptable salt
thereof, wherein R.sup.4a is hydrogen.
9. The compound of claim 1, or the pharmaceutically acceptable salt
thereof, wherein X is --CH.sub.2--.
10. The compound of claim 1, or the pharmaceutically acceptable
salt thereof, wherein: a. R is substituted or unsubstituted
C.sub.1-3 alkyl; or b. R.sup.8 is --CH.sub.3.
11. (canceled)
12. The compound of claim 1, or the pharmaceutically acceptable
salt thereof, wherein the compound of Formula (I) is a compound of
Formula (II): ##STR00033##
13. The compound of claim 12, or the pharmaceutically acceptable
salt thereof, wherein the compound of Formula (II) is a compound of
Formula (II-A): ##STR00034##
14. The compound of claim 12, or the pharmaceutically acceptable
salt thereof, wherein the compound of Formula (II) is a compound of
Formula (II-B): ##STR00035##
15. The compound of claim 1, or the pharmaceutically acceptable
salt thereof, wherein: a R.sup.5a or R.sup.5b is hydrogen; or b.
R.sup.5a and R.sup.5b are both hydrogen.
16. (canceled)
17. The compound of claim 1, or the pharmaceutically acceptable
salt thereof, wherein: a. R.sup.6a is a substituted or
unsubstituted C.sub.1-3 alkyl; b. R.sup.6a is --CH.sub.3 or
--CH.sub.2CH.sub.3; or c. R.sup.6a is a substituted or
unsubstituted C.sub.2-4 alkyl, substituted or unsubstituted
C.sub.2-3 alkenyl, substituted or unsubstituted C.sub.2-3 alkynyl,
or substituted or unsubstituted carbocyclyl.
18.-19. (canceled)
20. The compound of claim 1, or the pharmaceutically acceptable
salt thereof, wherein: a. R.sup.6b is substituted or unsubstituted
C.sub.1-3 alkyl; b. R.sup.6b is --CH.sub.3 or --CH.sub.2CH.sub.3;
c. R.sup.6b is hydrogen; or d. R.sup.6b is --CH.sub.3 or
--CF.sub.3.
21.-23. (canceled)
24. The compound of claim 1, or the pharmaceutically acceptable
salt thereof, wherein: a. R.sup.6a and R.sup.6b are both
--CH.sub.3; b. R.sup.6a and R.sup.6b, taken together with the atom
to which they are attached, form a ring; or c. R.sup.6a and
R.sup.6b, taken together with the atom to which they are attached,
form a 3-membered ring.
25.-26. (canceled)
27. The compound of claim 1, or the pharmaceutically acceptable
salt thereof, wherein R.sup.1 is hydrogen or C.sub.1-3 alkyl,
R.sup.6a is substituted or unsubstituted C.sub.1-3 alkyl,
substituted or unsubstituted C.sub.2-3 alkenyl, substituted or
unsubstituted C.sub.2-3 alkynyl, or substituted or unsubstituted
carbocyclyl, and R.sup.6b is --CH.sub.3.
28. The compound of claim 27, or the pharmaceutically acceptable
salt thereof, wherein: a. R.sup.6a is selected from the group
consisting of substituted or unsubstituted C.sub.1-3 alkyl,
unsubstituted C.sub.2-3 alkenyl, unsubstituted C.sub.2-3 alkynyl,
or unsubstituted carbocyclyl; or b. R.sup.6a is selected from a
substituted or unsubstituted C.sub.1-3 alkyl.
29. (canceled)
30. The compound of claim 1, or the pharmaceutically acceptable
salt thereof, wherein R.sup.1 is --CH.sub.3 or --CH.sub.2CH.sub.3
and R.sup.6b is --CH.sub.3 or --CF.sub.3.
31. The compound of claim 1, or the pharmaceutically acceptable
salt thereof, wherein: a. R.sup.Y is substituted or unsubstituted
C.sub.1-3 alkyl; b. R.sup.Y is substituted or unsubstituted
heterocyclyl; c. R is --CH.sub.3; or d. R.sup.Y is --CF.sub.3.
32.-34. (canceled)
35. The compound of claim 1, or the pharmaceutically acceptable
salt thereof, wherein the compound is: ##STR00036##
##STR00037##
36. A pharmaceutical composition comprising a compound or
pharmaceutically acceptable salt thereof according to claim 1, and
a pharmaceutically acceptable carrier.
37. A method of inducing sedation or anesthesia comprising
administering to a subject an effective amount of a compound or
pharmaceutically acceptable salt thereof according to claim 1, or
pharmaceutical composition thereof.
38. A method for treating or preventing a disorder, comprising
administering to a subject in need thereof an effective amount of a
compound of or pharmaceutically acceptable salt thereof according
to claim 1, or pharmaceutical composition thereof; wherein the
disorder is selected from the group consisting of a
gastrointestinal (GI) disorder, inflammatory bowel disease (IBD), a
structural disorder affecting the GI, an anal disorder, a colon
polyp, cancer, diabetes, a sterol synthesis disorder, and
colitis.
39.-41. (canceled)
42. A method for treating or preventing a CNS-related condition
comprising administering to a subject in need thereof an effective
amount of a compound or pharmaceutically acceptable salt thereof
according to claim 1, or pharmaceutical composition thereof.
43. The method according to claim 42, wherein the CNS-related
condition is an adjustment disorder, anxiety disorder, cognitive
disorder, dissociative disorder, eating disorder, mood disorder,
schizophrenia or other psychotic disorder, disorder,
substance-related disorder, personality disorder, autism spectrum
disorders, neurodevelopmental disorder, multiple sclerosis, sterol
synthesis disorders, pain, encephalopathy secondary to a medical
condition, seizure disorder, stroke, traumatic brain injury,
movement disorder, vision impairment, hearing loss, and
tinnitus.
44. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a Continuation Application of U.S.
patent application Ser. No. 16/028,790, filed Jul. 6, 2018, which
is a Continuation Application of U.S. National Phase application
Ser. No. 15/319,504 filed Dec. 16, 2016, which is a National Phase
Application under 35 U.S.C. .sctn. 371 of International Application
No. PCT/US2015/036510 filed Jun. 18, 2015, which claims priority to
U.S. Provisional Application No. 62/014,014 filed Jun. 18, 2014,
and U.S. Provisional Application No. 62/107,236 filed Jan. 23,
2015, the entire contents of which are incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0002] NMDA receptors are heteromeric complexes comprised of NR1,
NR2, and/or NR3 subunits and possess distinct recognition sites for
exogenous and endogenous ligands. These recognition sites include
binding sites for glycine, and glutamate agonists and modulators.
NMDA receptors are expressed in the peripheral tissues and the CNS,
where they are involved in excitatory synaptic transmission.
Activating these receptors contributes to synaptic plasticity in
some circumstances and excitotoxicity in others. These receptors
are ligand-gated ion channels that admit Ca2+ after binding of the
glutamate and glycine, and are fundamental to excitatory
neurotransmission and normal CNS function. Positive modulators may
be useful as therapeutic agents with potential clinical uses as
cognitive enhancers and in the treatment of psychiatric disorders
in which glutamatergic transmission is reduced or defective (see,
e.g., Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325).
In contrast, negative modulators may be useful as therapeutic
agents with potential clinical uses in the treatment of psychiatric
disorders in which glutamatergic transmission is pathologically
increased (e.g., treatment resistant depression).
[0003] Oxysterols are derived from cholesterol and have been shown
to potently and selectively modulate NMDA receptor function. New
and improved oxysterols are needed that modulate the NMDA receptor
for the prevention and treatment of conditions associated with NMDA
expression and function. Compounds, compositions, and methods
described herein are directed toward this end.
SUMMARY OF THE INVENTION
[0004] Provided herein are substituted oxysterols useful for
preventing and/or treating a broad range of disorders, including,
but not limited to, NMDA-mediated disorders. These compounds are
expected to show improved in vivo potency, pharmacokinetic (PK)
properties, oral bioavailability, formulatability, stability,
and/or safety as compared to other oxysterols. Further provided are
pharmaceutical compositions comprising the compounds of the present
invention, and methods of their use and treatment.
[0005] In one aspect, provided herein are compounds according to
Formula (I):
##STR00002##
or a pharmaceutically acceptable salt thereof; wherein: R.sup.1 is
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, carbocyclyl, or heterocyclyl; each of
R.sup.2a and R.sup.2b is independently hydrogen, C.sub.1-C.sub.6
alkyl, halo, cyano, --OR.sup.A, or NR.sup.BR.sup.C, or R.sup.2a and
R.sup.2b together with the carbon atom to which they are attached
form a ring (e.g., a 3-7-membered ring, e.g., a 5-7-membered ring;
a ring containing at least one heteroatom, e.g., a nitrogen,
oxygen, or sulfur atom); each of R.sup.4a and R.sup.4b is
independently absent, hydrogen, C.sub.1-C.sub.6 alkyl, or halo; X
is --C(R.sup.X).sub.2-- or --O--, wherein R.sup.X is independently
hydrogen, halo, or one R.sup.X group and R.sup.5b are joined to
form a double bond; Y is --OR.sup.Y, wherein R is hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl,
--C(O)R.sup.A, --C(O)OR.sup.A, --C(O)NR.sup.BR.sup.C, or
--S(O).sub.2R.sup.D; each instance of R.sup.5a and R.sup.5b is
independently hydrogen, halo, or C.sub.1-C.sub.6 alkyl; each of
R.sup.6a and R.sup.6b is independently hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
carbocyclyl, heterocyclyl, aryl, or heteroaryl, or R.sup.6a and
R.sup.6b, taken together with the carbon atom to which they are
attached, form a ring (e.g., a 3-6-membered ring, e.g. a
4-6-membered ring containing one heteroatom); or R.sup.5a and
R.sup.6a, together with the carbon atoms to which they are
attached, form a ring (e.g., a 3-6-membered ring, e.g. a
4-6-membered ring containing one heteroatom); and R.sup.7 is absent
or hydrogen in the alpha configuration; R.sup.8 is hydrogen, halo,
C.sub.1-6alkyl, carbocyclyl, or --OR.sup.A; represents a single or
double bond, wherein when one is a double bond, the other is a
single bond; wherein when the between --CR.sup.7 and
--CR.sup.4aR.sup.4b is a double bond, then one of R.sup.4a or
R.sup.4b is absent; and when one of the is a double bond, R.sup.7
is absent; R.sup.A is hydrogen, C.sub.1-C.sub.6 alkyl, carbocyclyl,
heterocyclyl, aryl, or heteroaryl; each of R.sup.B and R.sup.C is
independently hydrogen, C.sub.1-C.sub.6 alkyl, carbocyclyl,
heterocyclyl, aryl, heteroaryl, or taken together with the atom to
which they are attached form a ring; and R.sup.D is hydrogen,
C.sub.1-C.sub.6 alkyl, carbocyclyl, heterocyclyl, aryl, or
heteroaryl.
[0006] In another aspect, provided are pharmaceutical compositions
comprising a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
excipient.
[0007] Other objects and advantages will become apparent to those
skilled in the art from a consideration of the ensuing Detailed
Description, Examples, and Claims.
Definitions
Chemical Definitions
[0008] 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.
[0009] Compounds described herein can comprise one or more
asymmetric centers, and thus can exist in various isomeric forms,
e.g., enantiomers and/or diastereomers. For example, the compounds
described herein can be in the form of an individual enantiomer,
diastereomer or geometric isomer, or can be in the form of a
mixture of stereoisomers, including racemic mixtures and mixtures
enriched in one or more stereoisomer. Isomers can be isolated from
mixtures by methods known to those skilled in the art, including
chiral high pressure liquid chromatography (HPLC) and the formation
and crystallization of chiral salts; or preferred isomers can be
prepared by asymmetric syntheses. See, for example, Jacques et al.,
Enantiomers, Racemates and Resolutions (Wiley Interscience, New
York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel,
Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); and
Wilen, Tables of Resolving Agents and Optical Resolutions p. 268
(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.
1972). The invention additionally encompasses compounds described
herein as individual isomers substantially free of other isomers,
and alternatively, as mixtures of various isomers.
[0010] Compound described herein may also comprise one or more
isotopic substitutions. For example, H may be in any isotopic form,
including .sup.1H, .sup.2H (D or deuterium), and .sup.3H (T or
tritium); C may be in any isotopic form, including .sup.12C,
.sup.13C, and .sup.14C; O may be in any isotopic form, including
.sup.16O and .sup.18O; and the like.
[0011] 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.
[0012] 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.
[0013] "Aliphatic" refers to an alkyl, alkenyl, alkynyl, or
carbocyclyl group, as defined herein.
[0014] "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).
[0015] As used herein, "alkylene," "alkenylene," and "alkynylene,"
refer to a divalent radical of an alkyl, alkenyl, and alkynyl
group, respectively. When a range or number of carbons is provided
for a particular "alkylene," "alkenylene," and "alkynylene" group,
it is understood that the range or number refers to the range or
number of carbons in the linear carbon divalent chain. "Alkylene,"
"alkenylene," and "alkynylene" groups may be substituted or
unsubstituted with one or more substituents as described
herein.
[0016] "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.
[0017] "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), 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.
[0018] "Alkenylene" refers to an alkenyl group wherein two
hydrogens are removed to provide a divalent radical, and which may
be substituted or unsubstituted. Exemplary unsubstituted divalent
alkenylene groups include, but are not limited to, ethenylene
(--CH.dbd.CH--) and propenylene (e.g., --CH.dbd.CHCH.sub.2--,
--CH.sub.2--CH.dbd.CH--). Exemplary substituted alkenylene groups,
e.g., substituted with one or more alkyl (methyl) groups, include
but are not limited to, substituted ethylene
(--C(CH.sub.3).dbd.CH--, --CH.dbd.C(CH.sub.3)--), substituted
propylene (e.g., --C(CH.sub.3).dbd.CHCH.sub.2--,
--CH.dbd.C(CH.sub.3)CH.sub.2--, --CH.dbd.CHCH(CH.sub.3)--,
--CH.dbd.CHC(CH.sub.3).sub.2--, --CH(CH.sub.3)--CH.dbd.CH--,
--C(CH.sub.3).sub.2--CH.dbd.CH--, --CH.sub.2--C(CH.sub.3).dbd.CH--,
--CH.sub.2--CH.dbd.C(CH.sub.3)--), and the like.
[0019] "Alkynyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon
triple bonds), and optionally one or more carbon-carbon double
bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C.sub.2-20
alkynyl"). In certain embodiments, alkynyl does not contain any
double bonds. In some embodiments, an alkynyl group has 2 to 10
carbon atoms ("C.sub.2-10 alkynyl"). In some embodiments, an
alkynyl group has 2 to 9 carbon atoms ("C.sub.2-9 alkynyl"). In
some embodiments, an alkynyl group has 2 to 8 carbon atoms
("C.sub.2-8 alkynyl"). In some embodiments, an alkynyl group has 2
to 7 carbon atoms ("C.sub.2-7 alkynyl"). In some embodiments, an
alkynyl group has 2 to 6 carbon atoms ("C.sub.2-6 alkynyl"). In
some embodiments, an alkynyl group has 2 to 5 carbon atoms
("C.sub.2-5 alkynyl"). In some embodiments, an alkynyl group has 2
to 4 carbon atoms ("C.sub.2-4 alkynyl"). In some embodiments, an
alkynyl group has 2 to 3 carbon atoms ("C.sub.2-3 alkynyl"). In
some embodiments, an alkynyl group has 2 carbon atoms ("C.sub.2
alkynyl"). The one or more carbon-carbon triple bonds can be
internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
Examples of C.sub.2-4 alkynyl groups include, without limitation,
ethynyl (C.sub.2), 1-propynyl (C.sub.3), 2-propynyl (C.sub.3),
1-butynyl (C.sub.4), 2-butynyl (C.sub.4), and the like. Examples of
C.sub.2-6 alkenyl groups include the aforementioned C.sub.2-4
alkynyl groups as well as pentynyl (C.sub.5), hexynyl (C.sub.6),
and the like. Additional examples of alkynyl include heptynyl
(C.sub.7), octynyl (C.sub.8), and the like. Unless otherwise
specified, each instance of an alkynyl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
alkynyl") or substituted (a "substituted alkynyl") with one or more
substituents; e.g., for instance from 1 to 5 substituents, 1 to 3
substituents, or 1 substituent. In certain embodiments, the alkynyl
group is unsubstituted C.sub.2-10 alkynyl. In certain embodiments,
the alkynyl group is substituted C.sub.2-10 alkynyl.
[0020] "Alkynylene" refers to a linear alkynyl group wherein two
hydrogens are removed to provide a divalent radical, and which may
be substituted or unsubstituted. Exemplary divalent alkynylene
groups include, but are not limited to, substituted or
unsubstituted ethynylene, substituted or unsubstituted propynylene,
and the like.
[0021] 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_s 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.
[0022] The term "heteroalkenyl," as used herein, refers to an
alkenyl group, as defined herein, which further comprises one or
more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur,
nitrogen, boron, silicon, phosphorus) 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 heteroalkenyl group
refers to a group having from 2 to 10 carbon atoms, at least one
double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC.sub.2-10
alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9
carbon atoms at least one double bond, and 1, 2, 3, or 4
heteroatoms ("heteroC.sub.2-9 alkenyl"). In some embodiments, a
heteroalkenyl group has 2 to 8 carbon atoms, at least one double
bond, and 1, 2, 3, or 4 heteroatoms ("heteroC.sub.2-8 alkenyl"). In
some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at
least one double bond, and 1, 2, 3, or 4 heteroatoms
("heteroC.sub.2-7 alkenyl"). In some embodiments, a heteroalkenyl
group has 2 to 6 carbon atoms, at least one double bond, and 1, 2,
or 3 heteroatoms ("heteroC.sub.2-6 alkenyl"). In some embodiments,
a heteroalkenyl group has 2 to 5 carbon atoms, at least one double
bond, and 1 or 2 heteroatoms ("heteroC.sub.2-5 alkenyl"). In some
embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at
least one double bond, and 1 or 2 heteroatoms ("heteroC.sub.2-4
alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 3
carbon atoms, at least one double bond, and 1 heteroatom
("heteroC.sub.2-3 alkenyl"). In some embodiments, a heteroalkenyl
group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2
heteroatoms ("heteroC.sub.2-6 alkenyl"). Unless otherwise
specified, each instance of a heteroalkenyl group is independently
unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a
"substituted heteroalkenyl") with one or more substituents. In
certain embodiments, the heteroalkenyl group is an unsubstituted
heteroC.sub.2-10 alkenyl. In certain embodiments, the heteroalkenyl
group is a substituted heteroC.sub.2-10 alkenyl.
[0023] The term "heteroalkynyl," as used herein, refers to an
alkynyl group, as defined herein, which further comprises one or
more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur,
nitrogen, boron, silicon, phosphorus) 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 heteroalkynyl group
refers to a group having from 2 to 10 carbon atoms, at least one
triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC.sub.2-10
alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9
carbon atoms, at least one triple bond, and 1, 2, 3, or 4
heteroatoms ("heteroC.sub.2-9 alkynyl"). In some embodiments, a
heteroalkynyl group has 2 to 8 carbon atoms, at least one triple
bond, and 1, 2, 3, or 4 heteroatoms ("heteroC.sub.2-8 alkynyl"). In
some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at
least one triple bond, and 1, 2, 3, or 4 heteroatoms
("heteroC.sub.2-7 alkynyl"). In some embodiments, a heteroalkynyl
group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2,
or 3 heteroatoms ("heteroC.sub.2-6 alkynyl"). In some embodiments,
a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple
bond, and 1 or 2 heteroatoms ("heteroC.sub.2-5 alkynyl"). In some
embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at
least one triple bond, and 1 or 2 heteroatoms ("heteroC.sub.2-4
alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 3
carbon atoms, at least one triple bond, and 1 heteroatom
("heteroC.sub.2-3 alkynyl"). In some embodiments, a heteroalkynyl
group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2
heteroatoms ("heteroC.sub.2-6 alkynyl"). Unless otherwise
specified, each instance of a heteroalkynyl group is independently
unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a
"substituted heteroalkynyl") with one or more substituents. In
certain embodiments, the heteroalkynyl group is an unsubstituted
heteroC.sub.2-10 alkynyl. In certain embodiments, the heteroalkynyl
group is a substituted heteroC.sub.2-10 alkynyl.
[0024] As used herein, "alkylene," "alkenylene," "alkynylene,"
"heteroalkylene," "heteroalkenylene," and "heteroalkynylene," refer
to a divalent radical of an alkyl, alkenyl, alkynyl group,
heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively.
When a range or number of carbons is provided for a particular
"alkylene," "alkenylene," "alkynylene," "heteroalkylene,"
"heteroalkenylene," or "heteroalkynylene," group, it is understood
that the range or number refers to the range or number of carbons
in the linear carbon divalent chain. "Alkylene," "alkenylene,"
"alkynylene," "heteroalkylene," "heteroalkenylene," and
"heteroalkynylene" groups may be substituted or unsubstituted with
one or more substituents as described herein.
[0025] "Aryl" refers to a radical of a monocyclic or polycyclic
(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g.,
having 6, 10, or 14 .pi. electrons shared in a cyclic array) having
6-14 ring carbon atoms and zero heteroatoms provided in the
aromatic ring system ("C.sub.6-14 aryl"). In some embodiments, an
aryl group has six ring carbon atoms ("C.sub.6 aryl"; e.g.,
phenyl). In some embodiments, an aryl group has ten ring carbon
atoms ("C.sub.10 aryl"; e.g., naphthyl such as 1-naphthyl and
2-naphthyl). In some embodiments, an aryl group has fourteen ring
carbon atoms ("C.sub.14 aryl"; e.g., anthracyl). "Aryl" also
includes ring systems wherein the aryl ring, as defined above, is
fused with one or more carbocyclyl or heterocyclyl groups wherein
the radical or point of attachment is on the aryl ring, and in such
instances, the number of carbon atoms continue to designate the
number of carbon atoms in the aryl ring system. Typical aryl groups
include, but are not limited to, groups derived from aceanthrylene,
acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,
chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,
hexalene, as-indacene, s-indacene, indane, indene, naphthalene,
octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,
pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and
trinaphthalene. Particularly aryl groups include phenyl, naphthyl,
indenyl, and tetrahydronaphthyl. Unless otherwise specified, each
instance of an aryl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted aryl") or substituted (a
"substituted aryl") with one or more substituents. In certain
embodiments, the aryl group is unsubstituted C.sub.6-14 aryl. In
certain embodiments, the aryl group is substituted C.sub.6-14
aryl.
[0026] 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.
[0027] Examples of representative substituted aryls include the
following
##STR00003##
wherein one of R.sup.56 and R.sup.57 may be hydrogen and at least
one of R.sup.56 and R.sup.57 is each independently selected from
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 haloalkyl, 4-10 membered
heterocyclyl, alkanoyl, C.sub.1-C.sub.8 alkoxy, heteroaryloxy,
alkylamino, arylamino, heteroarylamino, NR.sup.58COR.sup.59,
NR.sup.58SOR.sup.59NR.sup.58SO.sub.2R.sup.59, COOalkyl, COOaryl,
CONR.sup.58R.sup.59, CONR.sup.58OR.sup.59, NR.sup.8R.sup.9,
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.4haloalkyl, 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.
[0028] "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.
[0029] "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.
[0030] "Heteroaryl" refers to a radical of a 5-10 membered
monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or
10 .pi. 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).
[0031] 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.
[0032] 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.
[0033] Examples of representative heteroaryls include the
following:
##STR00004##
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.
[0034] "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.
[0035] "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.
[0036] 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.
[0037] "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.
[0038] 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.
[0039] 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.
[0040] "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.
[0041] "Acyl" refers to a radical --C(O)R.sup.20, where R.sup.20 is
hydrogen, substituted or unsubstitued alkyl, substituted or
unsubstitued alkenyl, substituted or unsubstitued alkynyl,
substituted or unsubstitued carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstitued 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.
[0042] "Acylamino" refers to a radical --NR.sup.22C(O)R.sup.23,
where each instance of R.sup.22 and R.sup.23 is independently
hydrogen, substituted or unsubstitued alkyl, substituted or
unsubstitued alkenyl, substituted or unsubstitued alkynyl,
substituted or unsubstitued carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstitued heteroaryl, as defined herein, or
R.sup.22 is an amino protecting group. Exemplary "acylamino" groups
include, but are not limited to, formylamino, acetylamino,
cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino,
benzoylamino and benzylcarbonylamino. Particular exemplary
"acylamino" groups are --NR.sup.24C(O)--C.sub.1-C.sub.8 alkyl,
--NR.sup.24C(O)--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--NR.sup.24C(O)--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--NR.sup.24C(O)--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--NR.sup.24C(O)--(CH.sub.2).sub.t(4-10 membered heterocyclyl),
wherein t is an integer from 0 to 4, and each R.sup.24
independently represents H or C.sub.1-C.sub.8 alkyl. In certain
embodiments, R.sup.25 is H, C.sub.1-C.sub.8 alkyl, substituted with
halo or hydroxy; 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; and R.sup.26 is H,
C.sub.1-C.sub.8 alkyl, substituted with halo or hydroxy;
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 hydroxyl; provided at least one of R.sup.25 and
R.sup.26 is other than H.
[0043] "Acyloxy" refers to a radical --OC(O)R.sup.27, where
R.sup.27 is hydrogen, substituted or unsubstitued alkyl,
substituted or unsubstitued alkenyl, substituted or unsubstitued
alkynyl, substituted or unsubstitued carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl, or
substituted or unsubstitued heteroaryl, as defined herein.
Representative examples include, but are not limited to, formyl,
acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and
benzylcarbonyl. In certain embodiments, R.sup.28 is C.sub.1-C.sub.8
alkyl, substituted with halo or hydroxy; 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.
[0044] "Alkoxy" refers to the group --OR.sup.29 where R.sup.29 is
substituted or unsubstituted alkyl, substituted or unsubstitued
alkenyl, substituted or unsubstitued alkynyl, substituted or
unsubstitued carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, or substituted or
unsubstitued 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.
[0045] 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.
[0046] "Amino" refers to the radical --NH.sub.2.
[0047] "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 unsubstitued alkenyl,
substituted or unsubstitued alkynyl, substituted or unsubstitued
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstitued 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.
[0048] 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),
--NR39-(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.
[0049] "Azido" refers to the radical --N.sub.3.
[0050] "Carbamoyl" or "amido" refers to the radical
--C(O)NH.sub.2.
[0051] "Substituted carbamoyl" or "substituted amido" refers to the
radical --C(O)N(R.sup.62).sub.2 wherein each R.sup.62 is
independently hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstitued alkenyl, substituted or unsubstitued
alkynyl, substituted or unsubstitued carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstitued heteroaryl, or an amino protecting
group, wherein at least one of R.sup.62 is not a hydrogen. In
certain embodiments, R.sup.62 is selected from H, 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, aralkyl, 5-10 membered heteroaryl, and
heteroaralkyl; or 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, aralkyl, 5-10 membered
heteroaryl, or heteroaralkyl, 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; provided that at least one
R.sup.62 is other than H.
[0052] Exemplary "substituted carbamoyl" groups include, but are
not limited to, --C(O) NR.sup.64--C.sub.1-C.sub.8 alkyl,
--C(O)NR.sup.64--(CH.sub.2).sub.t(C.sub.6-C.sub.10 aryl),
--C(O)N.sup.64--(CH.sub.2).sub.t(5-10 membered heteroaryl),
--C(O)NR.sup.64--(CH.sub.2).sub.t(C.sub.3-C.sub.10 cycloalkyl), and
--C(O)NR.sup.64--(CH.sub.2).sub.t(4-10 membered heterocyclyl),
wherein t is an integer from 0 to 4, each R.sup.64 independently
represents H or C.sub.1-C.sub.8 alkyl 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.
[0053] "Carboxy" refers to the radical --C(O)OH.
[0054] "Cyano" refers to the radical --CN.
[0055] "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.
[0056] "Hydroxy" refers to the radical --OH.
[0057] "Nitro" refers to the radical --NO.sub.2.
[0058] "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.
[0059] "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.
[0060] "Cycloalkenyl" refers to substituted or unsubstituted
carbocyclyl group having from 3 to 10 carbon atoms and having a
single cyclic ring or multiple condensed rings, including fused and
bridged ring systems and having at least one and particularly from
1 to 2 sites of olefinic unsaturation. Such cycloalkenyl groups
include, by way of example, single ring structures such as
cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.
[0061] "Fused cycloalkenyl" refers to a cycloalkenyl having two of
its ring carbon atoms in common with a second aliphatic or aromatic
ring and having its olefinic unsaturation located to impart
aromaticity to the cycloalkenyl ring.
[0062] "Ethenyl" refers to substituted or unsubstituted
--(C.dbd.C)--.
[0063] "Ethylene" refers to substituted or unsubstituted
--(C--C)--.
[0064] "Ethynyl" refers to --(C.ident.C)--.
[0065] "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.
[0066] "Thioketo" refers to the group .dbd.S.
[0067] 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.
[0068] 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;
[0069] or two geminal hydrogens on a carbon atom are replaced with
the group .dbd.O, .dbd.S, .dbd.NN(R.sup.bb).sub.2,
--NNR.sup.bbC(.dbd.O)R.sup.aa, --NNR.sup.bbC(.dbd.O)OR.sup.aa,
--NNR.sup.bbS(.dbd.O).sub.2R.sup.aa, .dbd.NR.sup.bb, or
.dbd.NOR.sup.cc; 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;
[0070] 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;
[0071] 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;
[0072] each instance of R.sup.dd is, independently, selected from
halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H,
--OH, --OR.sup.ee, --ON(R.sup.ff).sub.2, --N(R.sup.ff).sub.2,
--N(R.sup.ff).sub.3.sup.+X.sup.-, --N(OR.sup.ee)R.sup.ff, --SH,
--SR.sup.ee, --SSR.sup.ee, --C(.dbd.O)R.sup.ee, --CO.sub.2H,
--CO.sub.2R.sup.ee, --OC(.dbd.O)R.sup.ee, --OCO.sub.2R.sup.ee,
--C(.dbd.O)N(R.sup.ff).sub.2, --OC(.dbd.O)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.O)R.sup.ee, --NR.sup.ffCO.sub.2R.sup.ee,
--NR.sup.ffC(.dbd.O)N(R.sup.ff).sub.2, --C(.dbd.NR)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)N(RE).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;
[0073] 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;
[0074] each instance of R.sup.f is, independently, selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl and 5-10 membered heteroaryl, or two
R.sup.f groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups;
and
[0075] 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.6 alkyl).sub.2, --C(.dbd.NH)NH(C.sub.6 alkyl),
--C(.dbd.NH)NH.sub.2, --OC(.dbd.NH)N(C.sub.1-6 alkyl).sub.2,
--OC(NH)NH(C.sub.1-6 alkyl), --OC(NH)NH.sub.2, --NHC(NH)N(C.sub.1-6
alkyl).sub.2, --NHC(.dbd.NH)NH.sub.2, --NHSO.sub.2(C.sub.1-6
alkyl), --SO.sub.2N(C.sub.1-6 alkyl).sub.2, --SO.sub.2NH(C.sub.1-6
alkyl), --SO.sub.2NH.sub.2, --SO.sub.2C.sub.1-6 alkyl,
--SO.sub.2OC.sub.1-6 alkyl, --OSO.sub.2C.sub.1-6 alkyl,
--SOC.sub.1-6 alkyl, --Si(C.sub.1-6 alkyl).sub.3, --OSi(C.sub.1-6
alkyl).sub.3--C(.dbd.S)N(C.sub.1-6 alkyl).sub.2,
C(.dbd.S)NH(C.sub.1-6 alkyl), C(.dbd.S)NH.sub.2,
--C(.dbd.O)S(C.sub.1-6 alkyl), --C(.dbd.S)SC.sub.1-6 alkyl,
--SC(.dbd.S)SC.sub.1-6 alkyl, --P(.dbd.O).sub.2(C.sub.1-6 alkyl),
--P(.dbd.O)(C.sub.1-6 alkyl).sub.2, --OP(.dbd.O)(C.sub.1-6
alkyl).sub.2, --OP(.dbd.O)(OC.sub.1-6 alkyl).sub.2, C.sub.1-6
alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10 membered
heterocyclyl, 5-10 membered heteroaryl; or two geminal R.sup.gg
substituents can be joined to form .dbd.O or .dbd.S; wherein
X.sup.- is a counterion.
[0076] 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,
HSO.sub.4.sup.-, SO.sub.4.sup.-2 sulfonate ions (e.g.,
methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,
benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,
naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic
acid-2-sulfonate, and the like), and carboxylate ions (e.g.,
acetate, ethanoate, propanoate, benzoate, glycerate, lactate,
tartrate, glycolate, and the like).
[0077] 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).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.
[0078] 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
[0079] 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.
[0080] 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.
[0081] Disease, disorder, and condition are used interchangeably
herein.
[0082] 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").
[0083] 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.
[0084] 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.
[0085] As used herein, and unless otherwise specified, a
"prophylactically effective amount" of a compound is an amount
sufficient to prevent a disease, disorder or condition, or one or
more symptoms associated with the disease, disorder or condition,
or prevent its recurrence. A prophylactically effective amount of a
compound means an amount of a therapeutic agent, alone or in
combination with other agents, which provides a prophylactic
benefit in the prevention of the disease, disorder or condition.
The term "prophylactically effective amount" can encompass an
amount that improves overall prophylaxis or enhances the
prophylactic efficacy of another prophylactic agent.
Detailed Description of Certain Embodiments of the Invention
[0086] As generally described herein, the present invention
provides 19-substituted oxysterols useful for preventing and/or
treating a broad range of disorders, including, but not limited to,
NMDA-mediated disorders. These compounds are expected to show
improved in vivo potency, pharmacokinetic (PK) properties, oral
bioavailability, formulatability, stability, and/or safety as
compared to other oxysterols.
Compounds
[0087] In one aspect, provided herein are compounds according to
Formula (I):
##STR00005##
or a pharmaceutically acceptable salt thereof; wherein: R.sup.1 is
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, carbocyclyl, or heterocyclyl; each of
R.sup.2a and R.sup.2b is independently hydrogen, C.sub.1-C.sub.6
alkyl, halo, cyano, --OR.sup.A, or --NR.sup.BR.sup.C, or R.sup.2a
and R.sup.2b together with the carbon atom to which they are
attached form a ring (e.g., a 3-7-membered ring, e.g., a
5-7-membered ring; a ring containing at least one heteroatom, e.g.,
a nitrogen, oxygen, or sulfur atom); each of R.sup.4a and R.sup.4b
is independently absent, hydrogen, C.sub.1-C.sub.6 alkyl, or halo;
X is --C(R.sup.X).sub.2-- or --O--, wherein R.sup.X is
independently hydrogen, halogen, or one R.sup.X group and R.sup.5b
are joined to form a double bond; Y is --OR.sup.Y, wherein R.sup.Y
is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, carbocyclyl, heterocyclyl, aryl,
heteroaryl, --C(O)R.sup.A, --C(O)OR.sup.A, --C(O)NR.sup.BR.sup.C,
or --S(O).sub.2R.sup.D; each instance of R.sup.5a and R.sup.5b is
independently hydrogen, halo, or C.sub.1-C.sub.6 alkyl; each of
R.sup.6a and R.sup.6b is independently hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
carbocyclyl, heterocyclyl, aryl, or heteroaryl, or R.sup.6a and
R.sup.6b, taken together with the carbon atom to which they are
attached, form a ring (e.g., a 3-6-membered ring, e.g. a
4-6-membered ring containing one heteroatom); or R.sup.5a and
R.sup.6a, together with the carbon atoms to which they are
attached, form a ring (e.g., a 3-6-membered ring, e.g. a
4-6-membered ring containing one heteroatom); and R.sup.7 is absent
or hydrogen in the alpha configuration; R.sup.8 is hydrogen, halo,
C.sub.1-6alkyl, carbocyclyl, or --OR.sup.A; represents a single or
double bond, wherein when one is a double bond, the other is a
single bond; wherein when the between --CR.sup.7 and
--CR.sup.4aR.sup.4b is a double bond, then one of R.sup.4a or
R.sup.4b is absent; and when one of the is a double bond, R.sup.7
is absent; R.sup.A is hydrogen, C.sub.1-C.sub.6 alkyl, carbocyclyl,
heterocyclyl, aryl, or heteroaryl; each of R.sup.B and R.sup.C is
independently hydrogen, C.sub.1-C.sub.6 alkyl, carbocyclyl,
heterocyclyl, aryl, heteroaryl, or taken together with the atom to
which they are attached form a ring; and R.sup.D is hydrogen,
C.sub.1-C.sub.6 alkyl, carbocyclyl, heterocyclyl, aryl, or
heteroaryl.
[0088] In certain embodiments, R.sup.1 is hydrogen. In certain
embodiments, R.sup.1 is unsubstituted C.sub.1-3 alkyl. In certain
embodiments, R.sup.1 is --CH.sub.3, --CH.sub.2CH.sub.3, or
--CH.sub.2CH.sub.2CH.sub.3. In certain embodiments, R.sup.1 is
substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is
--CF.sub.3 or --CH.sub.2OCH.sub.3.
[0089] In certain embodiments, R.sup.2a is hydrogen. In certain
embodiments, R.sup.2b is hydrogen. In certain embodiments, R.sup.2a
or R.sup.2b is hydrogen. In certain embodiments, R.sup.2a and
R.sup.2b is hydrogen.
[0090] In certain embodiments, R.sup.4a is hydrogen. In certain
embodiments, R.sup.4b is hydrogen. In certain embodiments, R.sup.4a
or R.sup.4b is hydrogen. In certain embodiments, R.sup.4a and
R.sup.4b is hydrogen.
[0091] In certain embodiments, X is --CH.sub.2--.
[0092] In certain embodiments, R.sup.8 is substituted or
unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.8 is
--CH.sub.3.
[0093] In certain embodiments, the between --CR.sup.7 and
--CR.sup.4aR.sup.4b is a double bond, and one of R.sup.4a or
R.sup.4b is absent.
[0094] In certain embodiments, is a single bond, and R.sup.7 is
hydrogen in the alpha configuration.
[0095] In certain embodiments, the compound of Formula (I) is a
compound of Formula (I-A) or (I-B):
##STR00006##
or a pharmaceutically acceptable salts thereof.
[0096] In certain embodiments, the compound of Formula (I) is a
compound of Formula (II):
##STR00007##
or a pharmaceutically acceptable salt thereof.
[0097] In certain embodiments, the compound of Formula (II) is a
compound of Formula (II-A):
##STR00008##
or a pharmaceutically acceptable salt thereof.
[0098] In certain embodiments, the compound of Formula (I-A) is a
compound of Formula (III):
##STR00009##
or a pharmaceutically acceptable salt thereof.
[0099] In certain embodiments, the compound of Formula (II) is a
compound of Formula (II-B):
##STR00010##
or a pharmaceutically acceptable salt thereof.
[0100] In certain embodiments, R.sup.5a or R.sup.5b is hydrogen. In
certain embodiments, R.sup.5a and R.sup.5b are both hydrogen.
[0101] In certain embodiments, R.sup.6a is a substituted or
unsubstituted C.sub.1-3 alkyl (e.g., C.sub.1-3 haloalkyl). In
certain embodiments, R.sup.6a is --CH.sub.3 or --CH.sub.2CH.sub.3.
In certain embodiments, R.sup.6a is a substituted or unsubstituted
C.sub.2-4 alkyl, substituted or unsubstituted C.sub.2-3 alkenyl,
substituted or unsubstituted C.sub.2-3 alkynyl, or substituted or
unsubstituted carbocyclyl.
[0102] In certain embodiments, R.sup.6b is substituted or
unsubstituted C.sub.1-3 alkyl (e.g., C.sub.1-3 haloalkyl). In
certain embodiments, R.sup.6b is --CH.sub.3 or --CH.sub.2CH.sub.3.
In certain embodiments, R.sup.6b is hydrogen. In certain
embodiments, R.sup.6b is --CH.sub.3 or --CF.sub.3.
[0103] In certain embodiments, R.sup.6a or R.sup.6b is hydrogen. In
certain embodiments, R.sup.6a and R.sup.6b are both hydrogen.
[0104] In certain embodiments, R.sup.6a is hydrogen and R.sup.6b is
substituted or unsubstituted C.sub.1-3 alkyl (e.g., --CH.sub.3,
--CH.sub.2CH.sub.3; C.sub.1-3 haloalkyl (e.g., --CF.sub.3)).
[0105] In certain embodiments, R.sup.6a and R.sup.6b are both
--CH.sub.3. In certain embodiments, R.sup.6a is --CH.sub.3 and
R.sup.6b is --CH.sub.2CH.sub.3. In certain embodiments, R.sup.6a
and R.sup.6b, taken together with the atom to which they are
attached, form a ring. In certain embodiments, the ring is a
3-membered ring.
[0106] In certain embodiments, R.sup.1 is hydrogen or C.sub.1-3
alkyl, R.sup.6a is substituted or unsubstituted C.sub.1-3 alkyl
(e.g., C.sub.1-3 haloalkyl), substituted or unsubstituted C.sub.2-3
alkenyl, substituted or unsubstituted C.sub.2-3 alkynyl, or
substituted or unsubstituted carbocyclyl, and R.sup.6b is
--CH.sub.3.
[0107] In certain embodiments, R.sup.6a is selected from the group
consisting of substituted or unsubstituted C.sub.1-3 alkyl (e.g.,
C.sub.1-3 haloalkyl), unsubstituted C.sub.2-3 alkenyl,
unsubstituted C.sub.2-3 alkynyl, or unsubstituted carbocyclyl. In
certain embodiments, R.sup.6a is selected from a substituted or
unsubstituted C.sub.1-3 alkyl (e.g., C.sub.1-3 haloalkyl).
[0108] In certain embodiments, R.sup.1 is --CH.sub.3 or
--CH.sub.2CH.sub.3 and R.sup.6b is --CH.sub.3 or --CF.sub.3.
[0109] In certain embodiments, R is substituted or unsubstituted
C.sub.1-3 alkyl (e.g., C.sub.1-3 haloalkyl). In certain
embodiments, R is substituted or unsubstituted heterocyclyl. In
certain embodiments, R is --CH.sub.3 or --CH.sub.2CH.sub.3. In
certain embodiments, R is --CF.sub.3.
[0110] In certain embodiments, the compound of Formula (I) is:
##STR00011## ##STR00012##
or a pharmaceutically acceptable salt thereof.
[0111] In one aspect, the present invention provides pharmaceutical
compositions comprising a compound as described herein, e.g., a
compound of Formula (I), or a pharmaceutically acceptable salt or
pharmaceutically acceptable carrier thereof.
[0112] In one aspect, the present invention provides 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), or a pharmaceutically acceptable
salt thereof, or a pharmaceutically acceptable carrier thereof.
[0113] 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), or
pharmaceutically acceptable salt thereof, or pharmaceutical
composition thereof. In some embodiments, the disorder is a
NMDA-mediated disorder. In some embodiments, the disorder is a
disorder mediated by NMDA, e.g., a disorder which benefits from
treatment with a NMDA modulator. In some embodiments, the disorder
is cancer. In some embodiments, the disorder is diabetes. In some
embodiments, the disorder is a sterol synthesis disorder. In some
embodiments, the disorder is a gastrointestinal (GI) disorder e.g.,
constipation, irritable 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.
[0114] 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), or a
pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable carrier 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.
Pharmaceutical Compositions
[0115] In another aspect, the invention provides a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and a
effective amount of a compound of Formula (I).
[0116] 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.
[0117] In one embodiment, with respect to the pharmaceutical
composition, the carrier is a parenteral carrier, oral or topical
carrier.
[0118] The present invention also relates to a compound of Formula
(I) or pharmaceutical composition thereof for use as a
pharmaceutical or a medicament.
[0119] 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.
[0120] 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.
[0121] 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.
[0122] 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.
[0123] 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.
[0124] 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.
[0125] 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.
[0126] 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.
[0127] 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.
[0128] 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.
[0129] 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).
[0130] 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.
[0131] 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.
[0132] Exemplary Formulation 1--Tablets: A compound of Formula (I),
or pharmaceutically acceptable salt thereof, may be admixed as a
dry powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg
of active compound per tablet) in a tablet press.
[0133] Exemplary Formulation 2--Capsules: A compound of Formula
(I), or pharmaceutically acceptable salt thereof, may be admixed as
a dry powder with a starch diluent in an approximate 1:1 weight
ratio. The mixture is filled into 250 mg capsules (125 mg of active
compound per capsule).
[0134] Exemplary Formulation 3--Liquid: A compound of Formula (I),
or pharmaceutically acceptable salt thereof, (125 mg) may be
admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the
resultant mixture may be blended, passed through a No. 10 mesh U.S.
sieve, and then mixed with a previously made solution of
microcrystalline cellulose and sodium carboxymethyl cellulose
(11:89.50 mg) in water. Sodium benzoate (10 mg), flavor, and color
are diluted with water and added with stirring. Sufficient water
may then be added to produce a total volume of 5 mL.
[0135] Exemplary Formulation 4--Tablets: A compound of Formula (I),
or pharmaceutically acceptable salt thereof, may be admixed as a
dry powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 450-900 mg tablets (150-300
mg of active compound) in a tablet press.
[0136] Exemplary Formulation 5--Injection: A compound of Formula
(I), or pharmaceutically acceptable salt thereof, may be dissolved
or suspended in a buffered sterile saline injectable aqueous medium
to a concentration of approximately 5 mg/mL.
[0137] Exemplary Formulation 6--Tablets: A compound of Formula (I),
or pharmaceutically acceptable salt thereof, may be admixed as a
dry powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg
of active compound per tablet) in a tablet press.
[0138] Exemplary Formulation 7--Tablets: A compound of Formula (I),
or pharmaceutically acceptable salt thereof, may be may be admixed
as a dry powder with a dry gelatin binder in an approximate 1:2
weight ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of
active compound per tablet) in a tablet press.
[0139] Exemplary Formulation 8--Tablets: A compound of Formula (I),
or pharmaceutically acceptable salt thereof, may be admixed as a
dry powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg
of active compound per tablet) in a tablet press.
[0140] Exemplary Formulation 9--Tablets: A compound of Formula (I),
or pharmaceutically acceptable salt thereof, may be admixed as a
dry powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg
of active compound per tablet) in a tablet press.
[0141] Exemplary Formulation 10--Tablets: A compound of Formula
(I), or pharmaceutically acceptable salt thereof, may be admixed as
a dry powder with a dry gelatin binder in an approximate 1:2 weight
ratio. A minor amount of magnesium stearate is added as a
lubricant. The mixture is formed into 270-450 mg tablets (90-150 mg
of active compound per tablet) in a tablet press.
[0142] 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.
[0143] 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.
[0144] Transdermal doses are generally selected to provide similar
or lower blood levels than are achieved using injection doses.
[0145] 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
[0146] Compounds of the present invention, e.g., a compound of
Formula (I), and pharmaceutically acceptable salts thereof, as
described herein, are generally designed to modulate NMDA function,
and therefore to act as oxysterols for the treatment and prevention
of, e.g., CNS-related conditions in a subject. In some embodiments,
the compounds described herein, e.g., a compound of Formula (I),
and pharmaceutically acceptable salts thereof, as described herein,
are generally designed to penetrate the blood brain barrier (e.g.,
designed to be transported across the blood brain barrier).
Modulation, as used herein, refers to, for example, the inhibition
or potentiation of NMDA receptor function. In certain embodiments,
the compound of Formula (I), or pharmaceutically acceptable salt
thereof, may act as a negative allosteric modulator (NAM) of NMDA,
and inhibit NMDA receptor function. In certain embodiments, the
present invention, e.g., a compound of Formula (I), or
pharmaceutically acceptable salt thereof, may act as positive
allosteric modulators (PAM) of NMDA, and potentiate NMDA receptor
function. In ceratin embodiments, the compound of Formula (I), or
pharmaceutically acceptable salt thereof, modulates NMDA function,
but does not act as a negative allosteric modulator (NAM) or
positive allosteric modulator (PAM) of N/DA.
[0147] In some embodiments, the disorder is cancer. In some
embodiments, the disorder is diabetes. In some embodiments, the
disorder is a sterol synthesis disorder. In some embodiments, the
disorder is a gastrointestinal (GI) disorder, e.g., constipation,
irritable 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.
[0148] 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.
[0149] 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), or pharmaceutically
acceptable salt thereof, can be used to induce sedation or
anesthesia. In certain embodiments, the compound of Formula (I), or
pharmaceutically acceptable salt thereof, is useful in the
treatment or prevention of adjustment disorders, anxiety disorders,
cognitive disorders, dissociative disorders, eating disorders, mood
disorders, schizophrenia or other psychotic disorders, sleep
disorders, substance-related disorders, personality disorders,
autism spectrum disorders, neurodevelopmental disorders, sterol
synthesis disorders, pain, seizure disorders, stroke, traumatic
brain injury, movement disorders and vision impairment, hearing
loss, and tinnitus.
[0150] In another aspect, provided is a method of treating or
preventing brain excitability in a subject susceptible to or
afflicted with a condition associated with brain excitability,
comprising administering to the subject an effective amount of a
compound of the present invention, e.g., a compound of Formula (I),
or a pharmaceutically acceptable salt thereof.
[0151] In yet another aspect, the present invention provides a
combination of a compound of the present invention, e.g., a
compound of Formula (I), or pharmaceutically acceptable salt
thereof, and another pharmacologically active agent. The compounds
provided herein can be administered as the sole active agent or
they can be administered in combination with other agents.
Administration in combination can proceed by any technique apparent
to those of skill in the art including, for example, separate,
sequential, concurrent and alternating administration.
EXAMPLES
[0152] 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.
Example 1. Synthesis of Compound 1
##STR00013## ##STR00014##
[0153] Synthesis of compound A2. To a solution of reactant A1 (50
g, 127 mmol) in MeOH (500 mL) was added H.sub.2SO.sub.4 (Cat, conc.
5 mL). After heating at reflux for overnight, the solvent was
removed under reduced pressure. The residue was diluted with EtOAc
(1000 mL), washed by NaHCO.sub.3 (150 mL.times.2), brine (150 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated to give
compound A2 (49 g, 94%) as a white solid which was used in the next
step without further purification. .sup.1H NMR (400 MHz,
CDCl.sub.3), .delta. 4.08 (m, 1H), 3.67 (s, 3H), 3.64 (m, 1H),
0.93-0.92 (d, 3H), 0.92 (s, 3H), 0.65 (s, 3H). Synthesis of
compound A3. To a solution of A2 (60 g, 148 mmol) in dry pyridine
(400 ml) was added a solution of 4-toluenesulfonyl chloride (62 g,
325 mmol) in dry pyridine (200 ml). After stirring at room
temperature for 2 days, ice chips were added gradually to the
mixture. The precipitated solid was filtered, then washed with 10%
HCl and water to give crude product A3 (100 g, 95%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3), .delta. 7.80-7.78 (d,
2H), 7.74-7.72 (d, 2H), 7.35 (t, 4H), 4.81 (m, 1H), 4.32 (m, 1H),
2.47 (s, 6H), 0.90-0.88 (d, 3H), 0.81 (s, 3H), 0.60 (s, 3H).
Synthesis of compound A4. A solution of A3 (6.72 g, 9.4 mmol) and
potassium acetate (720 mg, 7.2 mmol) in water (6 mL) and DMF (40
mL) was heated at reflux for overnight. The reaction mixture was
poured into ice-cold water and extracted with EtOAc (100
ml.times.3). The combined organic layers were washed with brine (80
mL.times.2), dried over Na.sub.2SO.sub.4 filtered and concentrated.
The crude product was purified by column chromatography (silica
gel, EA/PE=5:1) to give A4 (1.60 g, 43%) as a white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3), .delta. 5.36 (t, 1H), 3.67 (s, 3H), 3.53
(m, 1H), 1.00 (s, 3H), 0.93-0.92 (d, 3H), 0.68 (s, 3H). Synthesis
of compound A5. A solution of A4 (1.60 g, 4.1 mmol) in acetic
anhydride (40 mL) was heated to 90.degree. C. for overnight. The
solvent was removed by reduced pressure, the residue was diluted
with saturated NaHCO.sub.3 (50 mL) and stirred for 2 h. The mixture
was extracted with EtOAc (50 mL.times.3) and the combined organic
layers were washed with brine (60 mL), dried over Na.sub.2SO.sub.4,
filtered and concentrated. The crude product was purified by column
chromatography (silica gel, EA/PE=1:6) to give A5 (1590 mg, 90%) as
a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3), .delta. 5.39-5.38
(d, 1H), 4.60 (m, 1H), 3.66 (s, 3H), 2.03 (s, 3H), 1.01 (s, 3H),
0.93-0.92 (d, 3H), 0.68 (s, 3H). Synthesis of compound A6. To a
solution of A5 (200 mg, 0.46 mmol) in 1,4-dioxane (10 mL) was added
water (1 mL) and perchloric acid (0.2 mL, 0.78 mmol). The resulting
mixture was protected from light and cooled to -10.degree. C.
N-Bromosuccinimide (125 mg, 0.70 mmol) was added in one portion.
After stirring at -10.degree. C. for 30 min, another portion of
N-bromosuccinimide (42 mg, 0.24 mmol) was added. The reaction
mixture was stirred until TLC showed no SM. The reaction mixture
was quenched with 0.1M of Na.sub.2S.sub.2O.sub.5 solution (40 mL)
and extracted with EtOAc (40 mL.times.3). The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified by column chromatography (PE:EA 10:1, 5:1)
to afford A6 (100 mg, 42%) and A6-a (50 mg, 21%) as a white solid.
A6 .sup.1H NMR (400 MHz, CDCl.sub.3), .delta. 5.09 (m, 1H), 3.98
(s, 1H), 3.67 (s, 3H), 2.06 (s, 3H), 1.36 (s, 3H), 0.94-0.92 (d,
3H), 0.72 (s, 3H); A6-a .sup.1H NMR (400 MHz, CDCl.sub.3), .delta.
5.49 (m, 1H), 4.2 (s, 1H), 2.04 (s, 3H), 1.33 (s, 3H), 0.93-0.91
(d, 3H), 0.68 (s, 3H). Synthesis of compound A7. A solution of
Pd(OAc).sub.4 (1.14 g, 3.32 mmol) and 12 (170 mg, 0.67 mmol) in
cyclohexane (60 mL) was heated to refluxed for 10 min. Then
compound A6 (700 mg, 1.33 mmol) and AIBN (10 mg, 0.08 mmol) were
added and the resulting mixture was refluxed for overnight. The
reaction mixture was allowed to cool to room temperature, filtered
over a plug of celite and washed with EtOAc (100 mL). The organic
layer was washed with a solution of 10% sodium metabisulfite (40
mL.times.2), dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by column chromatography
(silica gel, EA/PE=1:5) to give A7 (500 mg, 83%) as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3), .delta. 5.21 (m, 1H), 4.07-4.06
(d, 1H), 3.94-3.92 (d, 1H), 3.76-3.74 (d, 1H), 3.67 (s, 3H), 2.04
(s, 3H), 0.92-0.91 (d, 3H), 0.70 (s, 3H). Synthesis of compound A8.
To a solution of A7 (500 mg, 0.95 mmol) in EtOH (40 mL) was added
Zn (620 mg, 9.5 mmol), the resulting solution was heated to reflux
for 4 h. The reaction mixture was allowed to cool to room
temperature, filtered over a plug of celite, washed with EtOAc and
concentrated. The residue was purified by column chromatography
(silica gel, EA/PE=5:1) to give A8 (310 mg, 72%) as a white solid
and A8-a (80 mg, 17%) as a white solid. A8 .sup.1H NMR (400 MHz,
CDCl.sub.3), .delta. 5.78 (t, 1H), 4.66 (m, 1H), 3.86-3.83 (d, 1H),
3.67 (s, 3H), 3.64-3.61 (d, 1H), 2.05 (s, 3H), 0.94-0.93 (d, 3H),
0.74 (s, 3H). A8-a .sup.1H NMR (400 MHz, CDCl3), .delta. 5.75 (m,
1H), 3.84-3.81 (d, 1H), 3.67 (s, 3H), 3.62-3.60 (d, 1H), 0.94-0.92
(d, 3H), 0.74 (s, 3H). Synthesis of compound 1. To a solution of
A8-a (70 mg, 0.17 mmol) in THE (5 mL) was added MeMgBr (2 mL, 1M in
THF) dropwise. After stirring at room temperature overnight, the
mixture was quenched with water (20 mL) and extracted with EtOAc
(15 mL.times.3). The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated. The
residue was purified by column chromatography (silica gel,
EA:PE=1:1) to give 1 (20 mg, 30%) as a white solid. .sup.1H NMR
(400 MHz, CD.sub.3OD), .delta. 5.62-5.61 (d, 1H), 3.85-3.82 (d,
1H), 3.59-3.56 (d, 1H), 1.17 (s, 3H), 3.45 (m, 1H), 1.16 (s, 3H),
0.97-0.96 (d, 3H), 0.78 (s, 3H).
Example 2. Synthesis of Compound 2
##STR00015##
[0154] Synthesis of compound B2. To a solution of B1 (140 mg, 0.334
mmol) in DCM (5 mL) was added silica gel (100 mg) and PCC (107 mg,
0.5 mmol). The mixture was stirred at 25.degree. C. for 16 hours.
TLC (PE:EA=3:1) showed the starting material was consumed
completely. The reaction mixture was filtered, and the filtrate was
concentrated. The residue was purified by column chromatography on
silica gel (PE:EA=10:1) to give B2 (120 mg, 86.3%) as white solid.
LCMS Rt=1.157 min in 2 min chromatography, 30-90AB, purity 100%, MS
ESI calcd. for C27H45O3 [M+H].sup.+417, found 399 ([M+H-18].sup.+).
Synthesis of compound 2. To a solution of B2 (140 mg, 0.336 mmol)
in dry THE (5 mL) at 0.degree. C. under N.sub.2 was added EtMgBr (3
M in diethyl ether, 0.56 mL, 1.67 mmol) dropwise. The mixture was
warmed to 25.degree. C. and stirred for 16 hours. LCMS showed the
starting material was consumed completely. The reaction mixture was
quenched with aqueous NH.sub.4Cl (10 mL), extracted with EtOAc (10
mL*3). The combined organic layers were dried over anhydrous sodium
sulfate, filtered and concentrated. The residue was purified by
prep. HPLC to give 2 (3 mg, 2%) as white solid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.=5.57 (d, J=5.02 Hz, 1H), 3.59 (d, J=10.04
Hz, 1H), 3.26-3.32 (m, 4H), 2.47 (d, J=13.05 Hz, 1H), 1.61-2.08 (m,
10H), 1.24-1.49 (m, 9H), 1.05-1.17 (m, 10H), 0.74-1.03 (m, 11H),
0.71 (s, 3H). LCMS Rt=1.239 min in 2 min chromatography, 30-90AB,
purity 100%, MS ESI caled. for C.sub.29H.sub.51O.sub.3
[M+H].sup.+447, found 411 ([M+H-36].sup.+).
Example 3. Synthesis of Compounds 3 and 4
##STR00016##
[0155] Synthesis of compound 3. To a solution of C1 (500 mg, 1.15
mmol) and tetraisopropoxytitanium (326 mg, 1.15 mmol) in dry THE
(20 mL) under N.sub.2 at 25.degree. C. was added EtMgBr (3 M in
diethyl ether, 1.33 mL, 4.02 mmol) dropwise. The mixture was
stirred at 25.degree. C. for 16 hours. LCMS showed the starting
material was consumed. The reaction mixture was quenched with
aqueous NH.sub.4Cl (30 mL), filtered through a pad of celite, and
the filtrate was extracted with EtOAc (20 mL*3). The combined
organic layers were washed with brine (50 mL), dried over sodium
sulfate, filtered and concentrated. The residue was purified by
prep. HPLC to give 3 (211 mg, 42.6%) as white solid and 4 (68 mg,
12.8%) as white solid. 1H NMR (3): (400 MHz, CDCl.sub.3)
.delta.=5.57 (d, J=5.0 Hz, 1H), 3.59 (d, J=10.0 Hz, 1H), 3.32-3.27
(m, 4H), 2.47 (d, J=12.5 Hz, 1H), 2.10-1.94 (m, 4H), 1.91-1.59 (m,
8H), 1.51-0.83 (m, 20H), 0.78-0.66 (m, 5H), 0.47-0.38 (m, 2H). LCMS
(3): Rt=1.142 min in 2 min chromatography, 30-90AB, purity 100%, MS
ESI calcd. for C.sub.28H.sub.47O.sub.3 [M+H].sup.+ 431, found 453
([M+Na].sup.+). 1H NMR (4): (400 MHz, CDCl.sub.3) .delta.=5.56 (d,
J=4.5 Hz, 1H), 5.05-4.93 (m, 1H), 3.59 (d, J=9.5 Hz, 1H), 3.33-3.25
(m, 4H), 2.47 (d, J=12.5 Hz, 1H), 2.36-2.26 (m, 1H), 2.23-2.13 (m,
1H), 2.08-1.73 (m, 8H), 1.70-1.60 (m, 2H), 1.54-1.19 (m, 16H), 1.15
(s, 3H), 1.13-1.00 (m, 4H), 0.96-0.82 (m, 6H), 0.70 (s, 3H). LCMS
(4): Rt=1.317 min in 2 min chromatography, 30-90AB, purity 100%, MS
ESI calcd. for C.sub.30H.sub.53O.sub.3 [M+H].sup.+ 461, found 483
([M+Na].sup.+).
Example 4. Synthesis of Compound 5
##STR00017##
[0156] Synthesis of compound D2. To a solution of D1 (20 g, 63.2
mmol) in DME (200 mL) was added KOH (35.4 g, 0.632 mol). The
mixture was stirred at 25.degree. C. for 16 hours. TLC (PE:EA=2:1)
showed the starting material was remained and the desired compound
was observed. The reaction mixture was quenched with ice chips and
aqueous citric acid (250 mL), extracted with EtOAc (200 mL*3). The
combined organic layers were dried over anhydrous sodium sulfate,
filtered and concentrated. The residue was purified by column
chromatography on silica gel (PE:EA=5:1) to give D2 (3 g, 15.0%) as
a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) J=5.67-5.56 (m,
1H), 3.66 (d, J=10.0 Hz, 1H), 3.48 (d, J=10.0 Hz, 1H), 3.40-3.28
(m, 4H), 2.91 (dd, J=1.5, 16.6 Hz, 1H), 2.52-2.36 (m, 2H),
2.34-2.28 (m, 1H), 2.23-2.02 (m, 4H), 1.98-1.85 (m, 2H), 1.81-1.72
(m, 1H), 1.69-1.63 (m, 1H), 1.61-1.42 (m, 3H), 1.32-1.19 (m, 2H),
1.09-1.02 (m, 1H), 0.93 (s, 3H). Synthesis of compound D3. To a
stirred solution of D2 (24.8 g, 113 mmol) in toluene (100 mL) was
added Me.sub.3Al (2 Min toluene, 28.3 mL, 56.6 mmol) at 0.degree.
C. under N.sub.2 dropwise. The resulting solution was stirred for 1
h at 25.degree. C. It was cooled to -70.degree. C. with
dry-ice/acetone bath, and a slurry of
(8R,9S,10S,13S,14S)-10-(methoxymethyl)-13-methyl-7,8,9,10,11,12,13,
14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,4H)-dione
(6 g, 18.9 mmol) in toluene (150 mL) was added and then stirred for
1 h at -50 to -60.degree. C. MeMgBr in diethyl ether (3M, 18.8 mL,
56.6 mmol) was then added dropwise, while maintaining the
temperature during the addition between -50 to -40.degree. C. The
reaction mixture was then stirred for 3 h at -50 to -60.degree. C.
The mixture was quenched with 10% aqueous citric acid (200 mL),
extracted with EtOAc (200 mL*3). The combined organic layers were
washed with brine (400 mL), dried over anhydrous sodium sulfate,
filtered and concentrated. The residue was purified by column
chromatography on silica gel (PE:EA=8:1) to give D3 (4.5 g, 71.6%)
as white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=5.61 (d,
J=5.0 Hz, 1H), 3.65 (d, J=10.0 Hz, 1H), 3.33-3.26 (m, 4H),
2.54-2.39 (m, 2H), 2.17-2.02 (m, 4H), 1.98-1.81 (m, 3H), 1.72-1.61
(m, 3H), 1.57-1.47 (m, 3H), 1.29-1.17 (m, 2H), 1.16 (s, 3H),
1.12-1.04 (m, 1H), 0.99-0.88 (m, 4H). LCMS Rt=1.412 min in 7 min
chromatography, 30-90AB, purity 100%, MS ESI calcd. for
C.sub.21H.sub.33O.sub.3 [M+H].sup.+333, found 315 ([M+H-18].sup.+).
Synthesis of compound D4. To a solution of
bromo(ethyl)triphenylphosphorane (18.3 g, 49.5 mmol) in THE (100
mL) under N.sub.2 was added a solution of t-BuOK (5.55 g, 49.5
mmol) in THE (60 mL). The mixture was becoming orange and stirred
for 1 hour. A solution of D3 (3.3 g, 9.92 mmol) in THE (40 mL) was
added to this mixture, and the resultant mixture was stirred at
60.degree. C. for additional 16 hours. The reaction mixture was
quenched with aqueous NH.sub.4Cl (200 mL), extracted with EtOAC
(100 mL*2). The combined organic layers were washed with brine (200
mL), dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by column chromatography on
silica gel (PE:EA=10:1) to give D4 (2.5 g, 73.3%) as a white solid.
1H NMR (400 MHz, CDCl.sub.3) .delta.=5.62-5.54 (m, 1H), 5.16-5.10
(m, 1H), 3.61 (d, J=10.0 Hz, 1H), 3.36-3.26 (m, 4H), 2.53-2.27 (m,
3H), 2.23-1.94 (m, 4H), 1.90-1.81 (m, 1H), 1.69-1.64 (m, 3H),
1.63-1.45 (m, 8H), 1.28-1.19 (m, 1H), 1.16 (s, 3H), 1.11-1.01 (m,
2H), 0.97-0.83 (m, 4H). LCMS Rt=1.506 min in 2 min chromatography,
10-80AB, purity 100%, MS ESI calcd. for C.sub.23H.sub.37O.sub.2
[M+H].sup.+ 345, found 327 ([M+H-18].sup.+). Synthesis of compound
D5. To a solution of D4 (1.2 g, 3.48 mmol) and methyl propiolate
(874 mg, 10.4 mmol) in dichloromethane (15 mL) under N.sub.2 at
0.degree. C. was added diethylaluminum chloride (0.9 M in toluene,
15.4 mL, 13.9 mmol) dropwise. The resultant mixture was stirred at
25.degree. C. for 16 hours. TLC (PE:EA=3:1) showed the starting
material was consumed. The reaction mixture was quenched with
aqueous citric acid (100 mL) at 0.degree. C. carefully. The mixture
was extracted with dichloromethane (100 mL*3), and the combined
organic layers were dried over anhydrous sodium sulfate, filtered
and concentrated. The residue was purified with the other batch
(SAGE-LGY-041) together by column chromatography on silica gel
(PE:EA=10:1) to give D5 (3.5 g, 76.4%) as a white solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.=6.98-6.88 (m, 1H), 5.90-5.72 (m,
1H), 5.57 (d, J=4.0 Hz, 1H), 5.45-5.32 (m, 1H), 3.77-3.69 (m, 3H),
3.61 (d, J=10.0 Hz, 1H), 3.36-3.25 (m, 4H), 3.02 (t, J=6.4 Hz, 1H),
2.47 (d, J=12.4 Hz, 1H), 2.10-1.92 (m, 5H), 1.90-1.59 (m, 2H),
1.23-1.14 (m, 7H), 1.10-0.92 (m, 3H), 0.90-0.81 (m, 5H). LCMS
Rt=1.176 min in 2 min chromatography, 30-90AB, purity 100%, MS ESI
calcd. for C.sub.27H.sub.41O.sub.4 [M+H].sup.+429, found 451
([M+Na].sup.+). Synthesis of compound D6. To a solution of D5 (2 g,
4.66 mmol) in EtOAc (50 mL) was added Pd/C (5% on carbon, 0.5 g).
The mixture was degassed and purged with H.sub.2 three times, and
stirred at 25.degree. C. under H.sub.2 balloon for 2 hours. LCMS
showed the starting material was consumed completely. The mixture
was filtered through a pad of celite, and the filtrate was
concentrated to give D6 (2 g, 99.5%) as a white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.=5.56 (d, J=5.0 Hz, 1H), 3.66 (s, 3H),
3.59 (d, J=10.0 Hz, 1H), 3.32-3.26 (m, 4H), 2.46 (d, J=12.5 Hz,
1H), 2.40-2.30 (m, 1H), 2.26-2.17 (m, 1H), 2.08-1.92 (m, 4H),
1.89-1.73 (m, 3H), 1.68-1.59 (m, 2H), 1.54-1.23 (m, 7H), 1.15 (s,
3H), 1.13-0.99 (m, 4H), 0.95-0.83 (m, 5H), 0.70 (s, 3H). LCMS
Rt=1.210 min in 2 min chromatography, 30-90AB, purity 100%, MS ESI
calcd. for C.sub.27H.sub.45O.sub.4 [M+H].sup.+433, found 415
([M+H-18].sup.+). Synthesis of compound 5. To a solution of D6 (100
mg, 0.231 mmol) in dry THE (10 mL) at 0.degree. C. was added
LiAlH.sub.4 (87.2 mg, 2.30 mmol) in portions carefully. The
resultant slurry was stirred at 0.degree. C. for 2 hours. TLC
(PE:EA=3:1) showed the starting material was consumed. The reaction
mixture was quenched with aqueous NH.sub.4Cl (20 mL) at 0.degree.
C. dropwise carefully, filtered through a pad of celite, and the
filtrate was extracted with EtOAc (10 mL*3). The combined organic
layers were dried over anhydrous sodium sulfate and concentrated.
The residue was purified by prep. HPLC to give 5 (32 mg, 34.2%) as
a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) J=5.56 (d, J=4.4
Hz, 1H), 3.65-3.56 (m, 3H), 3.34-3.25 (m, 4H), 2.47 (d, J=12.4 Hz,
1H), 2.08-1.94 (m, 4H), 1.87-1.73 (m, 2H), 1.68-1.56 (m, 4H),
1.50-1.21 (m, 9H), 1.17-1.00 (m, 8H), 0.97-0.84 (m, 5H), 0.71 (s,
3H). LCMS Rt=1.074 min in 2 min chromatography, 30-90AB, purity
100%, MS ESI caled. for C.sub.26H.sub.45O.sub.3 [M+H].sup.+405,
found 427 ([M+Na]*).
Example 5. Synthesis of Compound 6
##STR00018##
[0157] Synthesis of compound 6. To a solution of C.sub.1 (100 mg,
0.231 mmol) in dry THE (10 mL) at 0.degree. C. was added MeLi (1.6
M in diethyl ether, 0.72 mL, 25.2 1.15 mmol) dropwise. The mixture
was stirred at 0.degree. C. for 2 hours. TLC (PE:EA=3:1) showed the
starting material was consumed. The reaction mixture was quenched
with aqueous NH.sub.4Cl (20 mL) at 0.degree. C., extracted with
EtOAc (10 mL*3). The combined organic layers were dried over
anhydrous sodium sulfate, filtered and concentrated. The residue
was purified by prep. HPLC to give 6 (47 mg, 47.0%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3)=5.56 (d, J=5.2 Hz, 1H),
3.59 (d, J=9.6 Hz, 1H), 3.34-3.26 (m, 4H), 2.47 (d, J=12.4 Hz, 1H),
2.08-1.94 (m, 4H), 1.87-1.74 (m, 2H), 1.68-1.55 (m, 4H), 1.51-1.25
(m, 9H), 1.19 (s, 6H), 1.17-1.00 (m, 8H), 0.96-0.84 (m, 5H), 0.70
(s, 3H). LCMS t.sub.R=1.177 min in 2 min chromatography, 30-90AB,
purity 100%, MS ESI calcd. for C.sub.28H.sub.49O.sub.3
[M+H].sup.+433, found 455 ([M+Na].sup.+).
Example 6. Synthesis of Compound 7
##STR00019##
[0158] Synthesis of compound E2. To a solution of E1 (200 mg, 0.491
mmol) in DCM (10 mL) was added silica gel (200 mg) and PCC (212 mg,
0.982 mmol). The mixture was stirred at 25.degree. C. for 16 hours.
TLC (PE:EA=3:1) showed the starting material was consumed. The
reaction mixture was filtered, and the filtrate was concentrated.
The residue was purified by silica gel (PE:EA=10:1) to give E2 (100
mg, 50.5%) as colorless oil. LCMS Rt=1.201 min in 2 min
chromatography, 30-90AB, purity 100%, MS ESI calcd. for
C.sub.26H.sub.45O.sub.3 [M+H].sup.+405, found 387 ([M+H-18].sup.+).
Synthesis of compound 7. To a solution of E2 (100 mg, 0.247 mmol)
and trimethyl(trifluoromethyl)silane (174 mg, 1.23 mmol) in THE (5
mL) was added CsF (3.75 mg, 24.7 .mu.mol). The mixture was stirred
at 25.degree. C. for 1 hour. TLC (PE:EA=3:1) showed the starting
material was consumed. A solution of TBAF (1 M in THF, 1.23 mL,
1.23 mmol) was added to the mixture, and the resulting mixture was
stirred at 25.degree. C. for 16 hours. The reaction mixture was
concentrated, and the residue was purified by column chromatography
on silica gel (PE:EA=10:1) to give 7 (8 mg, 6.83%) as off white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) (=3.92-3.79 (m, 1H),
3.52-3.43 (m, 2H), 3.30 (s, 3H), 2.21-1.91 (m, 4H), 1.89-1.60 (m,
7H), 1.52-1.40 (m, 3H), 1.39-1.18 (m, 9H), 1.16-0.97 (m, 5H),
0.97-0.75 (m, 5H), 0.73-0.62 (m, 4H). LCMS Rt=1.204 min in 2 min
chromatography, 30-90AB, purity 100%, MS ESI calcd. for
C.sub.27H.sub.46F.sub.3O.sub.3 [M+H].sup.+ 475, found 457
([M+H-18].sup.+).
Example 7. Synthesis of Compound 8
##STR00020##
[0159] Synthesis of compound 8. To a solution of D7 (50 mg, 0.124
mmol) and trimethyl(trifluoromethyl)silane (88.1 mg, 0.62 mmol) in
THE (2 mL) was added CsF (1.88 mg, 0.0124 mmol). The mixture was
stirred at 25.degree. C. for 1 hour. TLC (PE:EA=3:1) showed the
starting material was consumed completely, and HCl (1 M in water,
1.24 mL, 1.24 mmol) was added to the reaction mixture. The
resultant mixture was stirred at 25.degree. C. for 16 hours. The
desired compound was detected by TLC (PE:EA=3:1). The reaction
mixture was neutralized with aqueous sodium bicarbonate (5 mL),
extracted with EtOAc (5 mL*3), dried with anhydrous sodium sulfate,
filtered and concentrated. The residue was purified by prep. HPLC
to give 8 (5.5 mg, 9.38%) as white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.=5.57 (d, J=4.0 Hz, 1H), 3.94-3.78 (m, 1H), 3.60
(d, J=10.0 Hz, 1H), 3.39-3.23 (m, 4H), 2.47 (d, J=14.1 Hz, 1H),
2.10-1.92 (m, 5H), 1.89-1.69 (m, 4H), 1.46 (br. s., 4H), 1.38-1.04
(m, 12H), 1.03-0.80 (m, 6H), 0.71 (s, 3H). LCMS Rt=1.168 min in 2
min chromatography, 30-90AB, purity 100%, MS ESI caled. for
C.sub.27H.sub.44F.sub.3O.sub.3 [M+H].sup.+473, found 455
([M+H-18].sup.+).
Example 8. Synthesis of Compound 9
##STR00021##
[0160] Synthesis of compound D7. To a solution of 5 (850 mg, 2.10
mmol) in DCM (15 mL) was added PCC (678 mg, 3.15 mmol) and silica
gel (1 g). The mixture was stirred at 25.degree. C. for 16 hours.
TLC (PE:EA=3:1) showed the starting material was consumed. The
reaction mixture was filtered, and the filtrate was concentrated.
The residue was purified by column chromatography on silica gel
(PE:EA=8:1) to give D7 (250 mg, 29.5%) as white solid. LCMS
Rt=1.089 min in 2 min chromatography, 30-90AB, purity 45.2%, MS ESI
calcd. for C.sub.26H.sub.43O.sub.3 [M+H].sup.+403, found 385
([M+H-18].sup.+). Synthesis of compound 9. To a solution of D7 (200
mg, 0.496 mmol) in dry THE (5 mL) at 0.degree. C. was added MeMgBr
(3 M in dimethyl ether, 0.83 mL, 2.48 mmol). The mixture was
stirred at 25.degree. C. for 2 hours. TLC (PE:EA=3:1) showed the
starting material was consumed. The reaction mixture was quenched
with saturated aqueous ammonium chloride (5 mL), extracted with
EtOAc (5 mL*3), dried over sodium sulfate, filtered and
concentrated to give 9 (190 mg, 91.7%) as white solid. One batch
(140 mg) was used directly in the next step, and the other batch
(50 mg) was purified by prep. HPLC to give desired compound (3 mg).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=5.56 (d, J=5.0 Hz, 1H),
3.77-3.71 (m, 1H), 3.59 (d, J=10.0 Hz, 1H), 3.33-3.25 (m, 4H), 2.47
(d, J=13.1 Hz, 1H), 2.10-1.92 (m, 5H), 1.87-1.73 (m, 3H), 1.69-1.58
(m, 3H), 1.49-1.23 (m, 10H), 1.20-1.00 (m, 11H), 0.96-0.81 (m, 6H),
0.71 (s, 3H). LCMS R=1.126 min in 2 min chromatography, 30-90AB,
purity 100%, MS ESI calcd. for C %14703 [M+H].sup.+419, found 401
([M+H-18]).
Materials and Methods
[0161] 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.
[0162] 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.
[0163] 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
pyrazoles 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.
[0164] .sup.1H-NMR reported herein (e.g., for intermediates) may be
a partial representation of the full NMR spectrum of a compound,
e.g., a compound described herein. For example, the reported
.sup.1H NMR may exclude the region between .delta. (ppm) of about 1
to about 2.5 ppm.
[0165] 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
[0166] 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.
Assay Methods
[0167] Compounds of the present invention can be evaluated using
various in vitro and in vivo assays described in the literature;
examples of which are described below.
[0168] The following examples are offered to illustrate the
biological activity of the compounds, pharmaceutical compositions,
and methods provided herein and are not to be construed in any way
as limiting the scope thereof.
NMDA Potentiation
[0169] NMDA potentiation was assessed using either whole cell patch
clamp of mammalian cells which expressed NMDA receptors, or using
two-electrode voltage clamp (TEVC) of Xenopus Laevis oocytes
expressing NMDA receptors.
Whole-Cell Patch Clamp of Mammalian Cells
[0170] The whole-cell patch-clamp technique was used to investigate
the effects of compounds on the NMDA receptor (GRIN1/GRIN2A
subunits) expressed in HEK cells. NMDA/Glycine peak and
steady-state currents were recorded from stably transfected cells
expressing the NMDA receptor and the modulatory effects of the test
items on these currents were investigated. Results are shown on
Table 1.
[0171] Cells were stably transfected with human GRIN1 (variant
NR1-3). These cells were transiently transfected
(Lipofectamine.TM.) with GRIN2A cDNA and CD8 (pLeu) antigene cDNA.
About 24-72 hours following transfection 1 .mu.l Dynabeads M-45 CD8
was added to identify successfully transfected cells (Jurman et
al., Biotechniques (1994) 17:876-881). Cells were passaged to a
confluence of 50-80%. Cells were seeded onto Poly-L-Lysine coated
cover slips covered with culture complete medium in a 35 mm culture
dish. Confluent clusters of cells are electrically coupled
(Pritchett et al., Science (1988), 242:1306-8). Because responses
in distant cells are not adequately voltage clamped and because of
uncertainties about the extent of coupling (Verdoorn et al., Neuron
(1990), 4:919-28), cells were cultivated at a density that enables
single cells (without visible connections to neighboring cells) to
be measured. Cells were incubated at 37.degree. C. in a humidified
atmosphere with 5% CO.sub.2 (rel. humidity about 95%). The cells
were continuously maintained in and passaged in sterile culture
flasks containing a 1:1 mixture of Dulbecco's modified eagle medium
and nutrient mixture F-12 (D-MEM/F-12 1.times., liquid, with
L-Glutamine) supplemented with 9% fetal bovine serum and 0.9%
Penicillin/Streptomycin solution. The complete medium was
supplemented with 3.0 .mu.g/ml Puromycin.
[0172] Whole cell currents were measured with HEKA EPC-10
amplifiers using PatchMaster software. Cell culture dishes for
recordings were placed on the dish holder of the microscope and
continuously perfused (1 ml/min) with "bath solution" (NaCl 137 mM,
KCl 4 mM, CaCl.sub.2) 1.8 mM, MgCl.sub.2 1 mM, HEPES 10 mM,
D-Glucose 10 mM, pH (NaOH) 7.4). All solutions applied to cells
including the pipette solution were maintained at room temperature
(19.degree. C.-30.degree. C.). After formation of a Gigaohm seal
between the patch electrodes and transfected individual HEK 293
cells (pipette resistance range: 2.5 M.OMEGA.-6.0 M.OMEGA.; seal
resistance range:>1 G) the cell membrane across the pipette tip
was ruptured to assure electrical access to the cell interior
(whole-cell patch-configuration). At this point the bath solution
is switched to "NAMDA bath solution" (NaCl 137 mM, KCl 4 mM,
CaCl.sub.2) 2.8 mM, HEPES 10 mM, D-Glucose 10 mM, Cremophore 0.02%,
pH (NaOH) 7.4). NMDA inward currents were measured upon application
of 30 .mu.M NMDA (and 5.0 M Glycine) to patch-clamped cells (2
applications) for 5 s. The cells were voltage clamped at a holding
potential of -80 mV. For the analysis of test articles, NMDA
receptors were stimulated by 30 M NMDA and 5.0 M Glycine after
sequential pre-incubation of increasing concentrations of the test
article. Pre-incubation duration was 30 s. Stimulation duration was
5 s Test articles were dissolved in DMSO to form stock solutions of
0.1 mM and 1 mM. Test articles were diluted to 0.1 .mu.M and 1
.mu.M in "NMDA bath solution". Both concentrations of test articles
were tested on each cell. The same concentration was applied at
least three times or until the steady state current amplitude was
reached. Every day one cell was tested with 50 .mu.M PREGS
(positive control) using the same application protocol to test
whether cells were successfully transfected with NMDA
receptors.
TABLE-US-00001 TABLE 1 NMDA 1a2A (%) Potentiation Structure 1 .mu.M
##STR00022## A ##STR00023## A ##STR00024## A ##STR00025## B
##STR00026## C For Table 1, "A" indicates >5 to 50%; B: >50%;
C indicates not active in the assay.
Whole-Cell Patch Clamp of Mammalian Cells (IWB)
[0173] The whole-cell patch-clamp technique was used to investigate
the effects of compounds on NR1/NR2A glutamate receptors expressed
in mammalian cells. The results are shown on Table 2. 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 perfomed using Ion
Works Barracuda platform following this procedure:
Electrophysiological Procedures:
[0174] a) Intracellular solution (mM): 50 mM CsCl, 90 mM CsF, 2 mM
MgC.sub.2, 5 mM EGTA, 10 mM HEPES. Adjust to pH 7.2 with CsOH.
[0175] b) Extracellular solution, HB-PS (composition in mM): NaCl,
137; KCl, 1.0; CaC.sub.2, 5; HEPES, 10; Glucose, 10; pH adjusted to
7.4 with NaOH (refrigerated until use). [0176] c) Holding
potential: -70 mV, potential during agonist/PAM application: -40
mV. Recording procedure: [0177] 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. [0178] b) Whole-cell recording
configuration will be established via patch perforation with
membrane currents recorded by on-board patch clamp amplifiers.
[0179] c) Two recordings (scans) will be performed. First, during
pre-application of PAM 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. 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 L/s
(2 second total application time).
TABLE-US-00002 [0179] TABLE 2 GluN2A PCA IWB Ephys % poten- tiation
Structure at 3 .mu.M ##STR00027## A ##STR00028## B ##STR00029## A
##STR00030## A ##STR00031## A For Table 2, "A" indicates 10 to
150%, and "B" indicates potentiation of >150%.
OTHER EMBODIMENTS
[0180] 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.
[0181] 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.
[0182] 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.
[0183] 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.
* * * * *