U.S. patent application number 17/554808 was filed with the patent office on 2022-04-07 for heterodimer compositions and methods for the treatment of ocular disorders.
The applicant listed for this patent is Ripple Therapeutics Corporation. Invention is credited to Kyle Giovanni BATTISTON, Wendy Alison NAIMARK, Ian Charles PARRAG, Georgios RIZIS, Matthew Alexander John STATHAM.
Application Number | 20220106351 17/554808 |
Document ID | / |
Family ID | 1000006038695 |
Filed Date | 2022-04-07 |
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United States Patent
Application |
20220106351 |
Kind Code |
A1 |
PARRAG; Ian Charles ; et
al. |
April 7, 2022 |
HETERODIMER COMPOSITIONS AND METHODS FOR THE TREATMENT OF OCULAR
DISORDERS
Abstract
Described herein are processable compositions comprising at
least one moiety that is processable in its free form. Also
described herein are compositions and methods for the treatment of
ocular diseases or disorders including glaucoma, blepharitis,
ocular inflammation, diabetic macular edema, posterior
inflammation, anterior inflammation, macular degeneration (e.g.,
wet macular degeneration (AMD) or dry AMD), post-cataract surgery,
and retinal vein occlusion. Said compositions and methods comprise
steroids and prostaglandins which demonstrate anti-inflammatory
activity, intraocular pressure (IOP) lowering, and/or other
desirable activities. Injection of said compositions in the eye
provides therapeutic benefit to patients suffering from ocular
disorders.
Inventors: |
PARRAG; Ian Charles;
(Mississauga, CA) ; NAIMARK; Wendy Alison;
(Toronto, CA) ; STATHAM; Matthew Alexander John;
(Milton, CA) ; RIZIS; Georgios; (Toronto, CA)
; BATTISTON; Kyle Giovanni; (Toronto, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ripple Therapeutics Corporation |
Toronto |
|
CA |
|
|
Family ID: |
1000006038695 |
Appl. No.: |
17/554808 |
Filed: |
December 17, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17350888 |
Jun 17, 2021 |
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17554808 |
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PCT/IB2021/000332 |
Apr 29, 2021 |
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17350888 |
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63019182 |
May 1, 2020 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0024 20130101;
C07J 7/008 20130101 |
International
Class: |
C07J 7/00 20060101
C07J007/00; A61K 9/00 20060101 A61K009/00 |
Claims
1. A compound represented by the structure of Formula (VI-C):
##STR00136## or a pharmaceutically acceptable salt thereof,
wherein, L is a linker; and PG is selected from the group
consisting of: (i) a prostaglandin radical represented by a
structure of Formula (VII): ##STR00137## wherein is a single bond
or a double bond; G is OH and Y.sup.1 is hydrogen; or G together
with Y.sup.1 form --O--CH.sub.2--; Y.sup.2 is a bond or
--CH.sub.2--; g is 1 or 2; Z is --O-- or --CH.sub.2--; R.sup.6 and
R.sup.6' are each independently hydrogen, halogen, OH, or L of
Formula (VI-C); R.sup.11 is OR.sup.13, NR.sup.13'R.sup.13'', or L
of Formula (VI-C); each R.sup.12 is independently halogen or
haloalkyl; R.sup.13, R.sup.13' and R.sup.13'' are each
independently hydrogen or C.sub.1-C.sub.3 alkyl; and u is 0-5; and
(ii) a radical of a prostaglandin, wherein the prostaglandin is
selected from the group consisting of latanoprost, latanoprost
acid, travoprost, travoprost acid, tafluprost, tafluprost acid,
bimatoprost, bimatoprost acid, sepetaprost, and sepetaprost
acid.
2. The compound of claim 1, wherein PG is a prostaglandin radical
represented by a structure of Formula (VII).
3. The compound of claim 2, wherein R.sup.6 and R.sup.6' are each
independently fluoro.
4. The compound of claim 2, wherein R.sup.6 is OH and R.sup.6' is
hydrogen.
5. The compound of claim 2, wherein Z is --O--.
6. The compound of claim 2, wherein Z is --CH.sub.2--.
7. The compound of claim 2, wherein R.sup.12 is F and u is 2.
8. The compound of claim 2, wherein R.sup.12 is CF.sub.3 and u is
1.
9. The compound of claim 2, wherein u is 0.
10. The compound of claim 2, wherein R.sup.6 is L of Formula (VI-C)
and R.sup.6' is hydrogen.
11. The compound of claim 2, wherein R.sup.11 is OH,
--NHCH.sub.2CH.sub.3, or --OCH(CH.sub.3).sub.2.
12. The compound of claim 2, wherein R.sup.11 L of Formula
(VI-C).
13. The compound of claim 1, wherein PG is a prostaglandin radical
represented by a structure of Formula (VII-A): ##STR00138##
14. The compound of claim 1, wherein PG is a prostaglandin radical
represented by the structure of Formula (VII-B) ##STR00139##
15. The compound of claim 1, wherein PG is a radical of
latanoprost.
16. The compound of claim 1, wherein PG is a radical of
bimatoprost.
17. The compound of claim 1, wherein L is a bond.
18. The compound of claim 1, wherein L is alkylene, cycloalkylene,
or C.dbd.O.
19. The compound of claim 1, wherein L comprises one or more linker
groups, each linker group being independently selected from the
group consisting of alkyl, cycloalkyl, heteroalkyl, and alkoxy,
wherein the alkyl, cycloalkyl, heteroalkyl, or alkoxy is optionally
substituted.
20. A pharmaceutical implant comprising at least 50 wt. % of the
compound of claim 1.
21. A method of treating an ophthalmic disease or disorder in an
individual in need thereof, the method comprising administering to
the individual a compound or claim 1 or a pharmaceutically
acceptable salt thereof, or an implant, article, or composition
comprising the compound of claim 1.
Description
CROSS-REFERENCES
[0001] This application is a continuation of U.S. patent
application Ser. No. 17/350,888, filed on Jun. 17, 2021, which is a
continuation of International Application No. PCT/1132021/000332
filed on Apr. 29, 2021, which claims the benefit of U.S.
Provisional Application No. 63/019,182, filed May 1, 2020, which
are hereby incorporated by reference in their entirety herein.
BACKGROUND OF THE INVENTION
[0002] Prostaglandins (prostaglandin analogs) are a front-line
medication in the treatment of glaucoma and can be used in the
treatment of other ocular disorders. In some instances,
prostaglandins are useful for lowering intraocular pressure (IOP),
a major risk factor in glaucoma. Typically, prostaglandins are
ophthalmically formulated and delivered in the form of eye drops.
To provide efficacy, however, frequent ophthalmic administration of
prostaglandins is often required. For example, latanoprost given
once a day has been reported to have a mean IOP lowering of about
35%.
SUMMARY OF THE INVENTION
[0003] Provided in certain embodiments herein are compounds
comprising a first radical (D1) and a second radical (D2) (e.g.,
having the formula: D1-L-D2). In certain instances, D1 is a
processable group (also referred to herein as a processable
radical), L is a linker, and D2 is a drug (also referred herein as
a drug radical). In certain embodiments, L is a hydrolyzable linker
or bond, such that when the compound of formula D1-L-D2 is (e.g.,
ophthalmically) administered (or when present in or otherwise
exposed to an aqueous environment, such as a buffering solution,
tears, serum, or the like), D1 and D2 are released (e.g., in their
free, non-radical form). In certain instances, the (e.g., covalent)
joining of a group D1 to an active agent D2 (e.g., non-processable
active agent) through a linker L (e.g., D1-L-D2), provides a
compound comprising an otherwise non-processable drug (e.g.,
D2-L-D2 (e.g., D2-D2)) in a processable form. In certain instances,
a drug (such as a prostaglandin) is joined with a processable group
(such as a steroid or other radical of a formula described herein,
such as Formula (I)). In certain instances, the processable group
D1 may or may not itself be processable when in free form, but when
combined with D2 (e.g., through a linker L) provides a solid (e.g.,
at a physiological temperature) that is processable (e.g., at a
temperature above a physiological temperature).
[0004] Provided in certain instances herein is a platform for
providing compounds and implants (e.g., with high drug content, low
excipient content (e.g., that would otherwise need to be removed),
and other benefits, such as described herein) that provide
long-lasting release of therapeutics (e.g., prostaglandins,
steroids, beta-blockers, and/or the like) in biological and
therapeutic applications, such as in ocular (e.g., implant)
administration.
[0005] In some instances, compounds provided herein (e.g., joining
a non-processable drug, such as a prostaglandin, radical to a
processable, such as a steroid, radical, such as through a (e.g.,
hydrolyzable) linker) are processable into forms (e.g., implants,
coatings, or other bodies), such as that are capable of being
administered to (e.g., an eye of) an individual in need thereof. In
some instances, such compounds are processable without the need for
additional excipients or materials (e.g., controlled release
polymers, matrices, or other components). In certain instances, the
no or low amounts of additional excipients or materials facilitates
high levels of drug delivery, while limiting impact of drug
delivery (e.g., a small implant can have high quantities of
drug).
[0006] In certain instances, such compounds (or implants comprising
such compounds) are administered to (e.g., implanted into) an
individual, such that sustained and/or otherwise controlled (e.g.,
local) delivery of the drug is achieved. In some instances,
delivery of the compounds (e.g., in the form of an implant,
coating, etc.) facilitate delivery of a drug component or radical
thereof for an extended period of time, such as for weeks, months,
or more. In certain instances, compounds, formulations, and
implants provided herein facilitate the long term delivery of drugs
to an individual in need thereof, such as without the need for
frequent dosing. For example, as discussed herein, prostaglandins
are often formulated and administered as eye drops, such as with
daily administration. In some instances, without rigid compliance
to frequent administration is required to maintain (e.g., optimal)
therapeutic efficacy. With the compounds provided herein, however,
long term delivery of such drugs can be achieved from weeks,
months, or more, with infrequent administration (e.g., once a year,
twice a year, or the like).
[0007] In some embodiments, the group D1 is also an active agent or
drug (e.g., radical thereof). In certain embodiments, D1 and D2 are
both effective in the treatment of a single indication, such that
administration of a compound herein provides a combination
therapeutic effect. For example, in some embodiments, D1 is a
steroid and D2 is a prostaglandin. In certain embodiments, such as
in therapies for the treatment of glaucoma, the anti-inflammatory
effect of the steroid and the ocular pressure lowering effect of
the prostaglandin both provide therapeutic effect. In some
embodiments, such as wherein the compound is formulated as or with
an implant, D1 is an anti-inflammatory (e.g., steroid) and reduces
or minimizes an inflammatory response to the implant.
[0008] Provided in certain embodiments herein are compounds, such
as described herein, (e.g., pharmaceutical) compositions comprising
compounds described herein, and methods of making and using
compounds provided herein. In some embodiments, methods of using
the compounds provided herein include methods of treating disorders
in individuals in need thereof, such as disorders treatable by a
drug D2 (e.g., in its free form). In some embodiments, methods of
treatment provided herein comprise methods of treating ocular
disorders, such as glaucoma. It is to be understood that
disclosures of methods provided herein explicitly include
disclosures of pharmaceutical compositions comprising (e.g., an
effective amount) of a compound provided herein for such uses.
[0009] Provided in certain embodiments herein is a compound
comprising a first radical and a second radical, the first radical
comprising the structure of Formula (I):
##STR00001##
[0010] In certain embodiments, is a single bond or a double bond.
In some embodiments, each R.sup.a, R.sup.b, and R.sup.c is
independently selected from the group consisting of oxo, halogen,
--CN, --NO.sub.2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,
alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino),
hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or
heterocycloalkyl is optionally substituted. In certain embodiments,
any one of R.sup.a, R.sup.b, or R.sup.c are taken together with
another of R.sup.a, R.sup.b, or R.sup.c to form a substituted or an
unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments,
X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are each independently
selected from the group consisting of a bond and Q.sub.y, wherein
each Q is independently selected from the group consisting of
--O--, --NR--, --S(R).sub.x--, and --C(R).sub.z--. In some
embodiments, y is 1-3. In certain embodiments, each x is
independently 0-5. In some embodiments, each z is independently 1
or 2 (e.g., depending on degree of saturation). In certain
embodiments, each of m, n, and o are independently 0-6. In certain
embodiments, each R is independently selected from the group
consisting of hydrogen, halogen, alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or
arylamino), hydroxy, and thiol (e.g., wherein the alkyl,
heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally
substituted), or each R is taken together with another R to form an
oxo. In some embodiments, the second radical is a therapeutically
active agent (or drug). In certain embodiments, the first radical
(e.g., steroid) is different than the second radical (e.g.,
prostaglandin). In some embodiments, either the first radical, the
second radical, or both the first radical and the second radical is
not a steroid. Also provided in certain embodiments herein are
pharmaceutically-acceptable salts or solvates of a compound of
Formula (I).
[0011] In some embodiments, the second radical is a drug. In some
embodiments, the drug is a prostaglandin. In some embodiments, the
prostaglandin is selected from the group consisting of latanoprost,
latanoprost acid, travoprost, travoprost acid, tafluprost,
tafluprost acid, bimatoprost, bimatoprost acid, sepetaprost, and
sepetaprost acid, or a fragment or radical of any of the
foregoing.
[0012] In some embodiments, X.sup.1 is Q.sub.1. In some
embodiments, X.sup.2 is a bond. In some embodiments, X.sup.3 is
Q.sub.2. In some embodiments, X.sup.4 is Q.sub.1. In some
embodiments, X.sup.1 and X.sup.4 are each Q.sub.1. In some
embodiments, X.sup.2 is a bond and X.sup.3 is Q.sub.2. In some
embodiments, Q is --C(R).sub.1-- or --C(R).sub.2--. In some
embodiments, X.sup.1 and X.sup.4 are each independently
--C(R).sub.1-- or --C(R).sub.2--. In some embodiments, X.sup.2 is a
bond and X.sup.3 is --C(R).sub.2C(R).sub.2--, --C(R)C(R).sub.2--,
or --C(R)C(R)--. In some embodiments, X.sup.1 and X.sup.4 are each
--C(R).sub.2--, and X.sup.2 is a bond and X.sup.3 is
--C(R).sub.2C(R).sub.2-- or --C(R)C(R).sub.2--.
[0013] In some embodiments, each R is independently hydrogen,
halogen, alkyl, heteroalkyl, hydroxy, amino (e.g., dihydroamino,
alkylamino, or arylamino), or taken together with another R to form
an oxo. In some embodiments, each R is independently hydrogen,
halogen, alkyl, hydroxy, or taken together with another R to form
an oxo. In some embodiments, each R is independently hydrogen or
halogen. In some embodiments, each R is independently hydrogen or
alkyl. In some embodiments, each R is independently hydrogen or
hydroxy. In some embodiments, each R is independently hydrogen or
taken together with another R to form an oxo.
[0014] In some embodiments, the alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or
arylamino), hydroxy, or thiol of R is optionally substituted. In
some embodiments, R combines with one of R.sup.a, R.sup.b, or
R.sup.c to form an optionally substituted cycloalkyl or an
optionally substituted heterocycloalkyl. In some embodiments, R is
amino and combines with one of R.sup.a, R.sup.b, or R.sup.c to form
an optionally substituted heterocycloalkyl. In some embodiments, R
is amino and combines with one of R.sup.a or R.sup.c to form a
heterocycloalkyl substituted with optionally substituted alkyl.
[0015] In some embodiments, provided herein is a compound
comprising a first radical and a second radical, the first radical
comprising a structure of Formula (IA):
##STR00002##
[0016] In some embodiments, is a single bond or a double bond). In
some embodiments, each R.sup.a, R.sup.b, and R.sup.c are
independently selected from the group consisting of oxo, halogen,
--CN, --NO.sub.2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,
alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino),
hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or
heterocycloalkyl is optionally substituted. In some embodiments,
each of m, n, and o are independently 0-6. In some embodiments, any
one of R.sup.a, R.sup.b, or R.sup.c are taken together with another
of R.sup.a, R.sup.b, or R.sup.c to form a substituted or an
unsubstituted cycloalkyl or heterocycloalkyl. In some embodiments,
the second radical is a therapeutically active agent (or drug) and
the first radical (e.g., steroid) being different than the second
radical (e.g., prostaglandin). In some embodiments, either the
first radical, the second radical, or both the first radical and
the second radical is not a steroid. Also provided in certain
embodiments herein are pharmaceutical salts or solvates of a
compound of Formula (IA).
[0017] In some embodiments, both the first radical and the second
radical have a structure of Formula (I) or Formula (IA). In some
embodiments, the first radical has a structure of Formula (I) or
Formula (IA) and the second radical does not have a structure of
Formula (I) or Formula (IA). In some embodiments, the structure of
Formula (I) or Formula (IA) has a melt and/or glass transition
temperature at a temperature of at least 20.degree. C. (e.g., at
least 25.degree. C., at least 30.degree. C., at least 37.degree.
C., at least 40.degree. C., at least 50.degree. C., at least
100.degree. C., or more) in its free form.
[0018] In some embodiments, n is 4. In some embodiments, n is 3. In
some embodiments, n is 2. In some embodiments, n is 1. In some
embodiments, each R.sup.b is independently hydrogen, halogen,
alkyl, heteroalkyl, hydroxy, amino (e.g., dihydroamino, alkylamino,
or arylamino), or taken together with another R.sup.b to form an
oxo. In some embodiments, each R.sup.b is independently hydrogen,
halogen, alkyl, hydroxy, or taken together with another R.sup.b to
form an oxo. In some embodiments, each R.sup.b is independently
hydrogen or halogen. In some embodiments, each R.sup.b is
independently hydrogen or alkyl. In some embodiments, each R.sup.b
is independently hydrogen or hydroxy. In some embodiments, each
R.sup.b is independently hydrogen or taken together with another
R.sup.b to form an oxo.
[0019] In some embodiments, the alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or
arylamino), hydroxy, or thiol of R.sup.b is optionally substituted.
In some embodiments, R.sup.b combines with one of R.sup.a, R.sup.b,
or R.sup.c to form an optionally substituted cycloalkyl or an
optionally substituted heterocycloalkyl. In some embodiments,
R.sup.b is amino and combines with one of R.sup.a or R.sup.c to
form an optionally substituted heterocycloalkyl. In some
embodiments, R.sup.b is amino and combines with one of R.sup.a or
R.sup.c to form a heterocycloalkyl substituted with optionally
substituted alkyl.
[0020] In some embodiments, one of R.sup.c is taken together with
another R.sup.c to form an optionally substituted cycloalkyl or an
optionally substituted heterocycloalkyl. In some embodiments, one
of R.sup.c is taken together with another R.sup.c to form an
optionally substituted cycloalkyl. In some embodiments, one of
R.sup.c is taken together with another R.sup.c to form a cycloalkyl
substituted with one or more substituent, each substituent selected
from the group consisting of oxo, halogen, alkyl, heteroalkyl,
cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino,
alkylamino, or arylamino), hydroxy, or thiol, wherein the alkyl,
heteroalkyl, cycloalkyl, alkoxy, amino, thiol, or heterocycloalkyl
is optionally substituted.
[0021] In some embodiments, R.sup.a, R.sup.b, and R.sup.c (e.g., of
Formula (I) or Formula (IA)) are each optionally and independently
substituted with one or more groups, each group independently
selected from --OH, oxo, alkyl (e.g., alkenyl), heteroalkyl,
cycloalkyl, or alkoxy, wherein the alkyl, heteroalkyl, cycloalkyl,
or alkoxy, is further optionally substituted. In certain
embodiments, the alkyl, heteroalkyl, cycloalkyl, or
heterocycloalkyl of each R.sup.a, R.sup.b, or R.sup.c (e.g., of
Formula (I) or Formula (IA)) is, independently, substituted or not
substituted. In some embodiments, each group is independently not
substituted or substituted with any one or more substituent
described herein. In specific embodiments, each group is
independently not substituted or substituted with one or more
substituent, wherein each substituent is selected from the group
consisting of --OH, oxo, alkyl, heteroalkyl, cycloalkyl, or alkoxy,
wherein the alkyl, heteroalkyl, cycloalkyl, or alkoxy, is further
optionally substituted.
[0022] In some embodiments, the substituted or unsubstituted
cycloalkyl or heterocycloalkyl (e.g., of Formula (I) or Formula
(IA)) are each optionally and independently substituted with one or
more groups, each group independently selected from --OH, oxo,
alkyl (e.g., alkenyl, alkynyl), --S-alkyl, --NH-alkyl, halogen,
heteroalkyl, cycloalkyl, or alkoxy, wherein the alkyl (e.g.,
--S-alkyl, --NH-- alkyl), heteroalkyl, cycloalkyl, or alkoxy, is
further optionally substituted. In certain embodiments, substituted
or unsubstituted cycloalkyl or heterocycloalkyl are, independently,
substituted or not substituted. In some embodiments, each group is
independently not substituted or substituted with any one or more
substituent described herein. In specific embodiments, each group
is independently not substituted or substituted with one or more
substituent, wherein each substituent is selected from the group
consisting of --OH, oxo, alkyl (e.g., alkenyl, alkynyl), --S-alkyl,
--NH-alkyl, halogen, heteroalkyl, cycloalkyl, or alkoxy, wherein
the alkyl (e.g., --S-alkyl, --NH-alkyl), heteroalkyl, cycloalkyl,
or alkoxy, is further optionally substituted. In some embodiments,
the cycloalkyl (e.g., of Formula (I) or Formula (IA)) is
substituted with oxo, --OH, optionally substituted alkyl, or
optionally substituted alkoxy. In some embodiments, the alkyl is
substituted with one or more halogen, oxo, --OH, alkyl (e.g.,
alkenyl), --S-alkyl, --NH-alkyl, alkoxy, wherein the alkyl (e.g.,
--S-- alkyl, --NH-alkyl) or alkoxy is further optionally
substituted. In some embodiments, the alkyl is methyl.
[0023] In some embodiments, provided herein is a compound
comprising a first radical and a second radical, the first radical
comprising a structure of Formula (IB):
##STR00003##
[0024] In some embodiments, is a single bond or a double bond). In
some embodiments, each R.sup.a, R.sup.b, R.sup.c, and R.sup.d are
independently selected from the group consisting of oxo, halogen,
--CN, --NO.sub.2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,
alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino),
hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or
heterocycloalkyl is optionally substituted. In some embodiments,
each of m, n, o, and p are independently 0-6. In some embodiments,
any one of R.sup.a, R.sup.b, R.sup.c, and R.sup.d are taken
together with another of R.sup.a, R.sup.b, R.sup.c, and R.sup.d to
form a substituted or an unsubstituted cycloalkyl or
heterocycloalkyl. In some embodiments, the second radical is a
therapeutically active agent (or drug) and the first radical (e.g.,
steroid) being different than the second radical (e.g.,
prostaglandin). In some embodiments, either the first radical, the
second radical, or both the first radical and the second radical is
not a steroid. Also provided in certain embodiments herein are
pharmaceutical salts or solvates of a compound of Formula (IB).
[0025] In some embodiments, Ring B of any one of Formula (I),
Formula (IA), or Formula (IB) is an optionally substituted
cycloalkyl. In some embodiments, Ring B of any one of Formula (I),
Formula (IA), or Formula (IB) does not comprise a heteroatom within
the ring (e.g., Ring B is optionally substituted cycloalkyl). In
some embodiments, Ring B of any one of Formula (I), Formula (IA),
or Formula (IB) comprises only single bonds. In some embodiments,
Ring B of any one of Formula (I), Formula (IA), or Formula (IB)
comprises at least one double bond. In some embodiments, Ring B of
any one of Formula (I), Formula (IA), or Formula (IB) is attached
to at least one ring (e.g., Ring A and/or Ring C) that comprises at
least one double bond. In some embodiments, Ring A comprises at
least one double bond. In some embodiments, Ring C comprises at
least one double bond. In some embodiments, Ring A and Ring C each
independently comprise at least one double bond. In some
embodiments, Ring B of any one of Formula (I), Formula (IA), or
Formula (IB) is attached to at least one ring (e.g., Ring A and or
Ring C) that is aromatic. In some embodiments, Ring B of any one of
Formula (I) or Formula (IA) is aromatic. In some embodiments, Ring
A, Ring B, and Ring C of any one of Formula (I) or Formula (IA) are
each aromatic.
[0026] In some embodiments, m is 4. In some embodiments, m is 3. In
some embodiments, m is 2. In some embodiments, m is 1. In some
embodiments, n is 3. In some embodiments, n is 2. In some
embodiments, n is 1. In some embodiments, n is 0. In some
embodiments, o is 5. In some embodiments, o is 4. In some
embodiments, o is 3. In some embodiments, o is 2. In some
embodiments, o is 1. In some embodiments, p is 3. In some
embodiments, p is 2. In some embodiments, p is 1.
[0027] In some embodiments, each R.sup.a, R.sup.b, R.sup.c, and
R.sup.d are independently selected from the group consisting of
oxo, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,
alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino),
hydroxy, or thiol, wherein the alkyl, heteroalkyl, cycloalkyl,
alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino),
hydroxy, thiol, or heterocycloalkyl is optionally substituted. In
some embodiments, each R.sup.a is independently selected from --OH,
oxo, halogen, alkyl, or alkoxy, wherein the alkyl or alkoxy is
optionally substituted. In some embodiments, each R.sup.b is
independently selected from --OH, oxo, halogen, or optionally
substituted alkyl. In some embodiments, each R.sup.c is
independently selected from --OH, oxo, or optionally substituted
alkyl. In some embodiments, each R.sup.d is independently selected
from --OH, oxo, alkyl (e.g., alkenyl or alkynyl), heteroalkyl, or
each R.sup.d is taken together to form an oxo, wherein the alkyl or
heteroalkyl is optionally substituted. In some embodiments, the
substituted alkyl of R.sup.d is --COOH, --(C.dbd.O)alkyl,
--(C.dbd.O)Oalkyl, --O(C.dbd.O)Oalkyl, --(C.dbd.O)Salkyl, wherein
the alkyl is optionally substituted with --OH or halogen. In some
embodiments, one R.sup.d is taken together with another R.sup.d to
form a substituted or unsubstituted cycloalkyl or
heterocycloalkyl.
[0028] In some embodiments, the alkyl of any one of R.sup.a,
R.sup.b, R.sup.c, or R.sup.d is C.sub.1-C.sub.3 alkyl. In some
embodiments, the alkyl of any one of R.sup.a, R.sup.b, R.sup.c, or
R.sup.d is substituted with oxo and further optionally substituted
with alkyl, hydroxy, halogen, heteroalkyl, alkoxy, thioether,
wherein the alkyl, alkoxy, thioether, or heteroalkyl is further
optionally substituted. In some embodiments, the alkoxy of any one
of R.sup.a, R.sup.b, R.sup.c, or R.sup.d is C.sub.1-C.sub.3
alkoxy.
[0029] In some embodiments, Ring A is aromatic. In some
embodiments, Ring A comprises at least one double bond. In some
embodiments, Ring A comprises one double bond. In some embodiments,
Ring A comprises two double bonds. In some embodiments, Ring B
comprises at least one double bond. In some embodiments, Ring B
comprises one double bond. In some embodiments, Ring C comprises
one double bond. In some embodiments, Ring D comprises one double
bond. In some embodiments, Ring A comprises at least one double
bond and each of Ring B, Ring C, and Ring D consist of single
bonds. In some embodiments, Ring A is aromatic and each of Ring B,
Ring C, and Ring D consist of single bonds. In some embodiments,
Ring A comprises at least one double bond and at least one of Ring
B, Ring C, or Ring D comprises a double bond. In some embodiments,
Ring A is aromatic and at least one of Ring B, Ring C, or Ring D
comprises a double bond. In some embodiments, Ring A comprises at
least one double bond and Ring B comprises a double bond. In some
embodiments, Ring A comprises at least one double bond and Ring C
comprises a double bond. In some embodiments, Ring A comprises at
least one double bond and Ring D comprises a double bond.
[0030] In some embodiments, provided herein is a compound
comprising a first radical and a second radical, the first radical
comprising a structure of Formula (IC):
##STR00004##
[0031] In some embodiments, is a single bond or a double bond. In
some embodiments, R.sup.a is hydrogen, --OH, or oxo. In some
embodiments, each R.sup.d' is independently selected from hydrogen,
--OH, halogen, C.sub.1-C.sub.3 alkyl, and alkoxy. In some
embodiments, R.sup.a'' is absent, hydrogen, or C.sub.1-C.sub.3
alkyl. In some embodiments, R.sup.b is absent, hydrogen, halogen,
or C.sub.1-C.sub.3 alkyl. In some embodiments, R.sup.b' is
hydrogen, halogen, --OH, oxo, or C.sub.1-C.sub.3 alkyl. In some
embodiments, R.sup.b'' is hydrogen or --OH. In some embodiments,
each R.sup.c is independently hydrogen, --OH, oxo, or
C.sub.1-C.sub.3 alkyl. In some embodiments, each R.sup.c' is
independently hydrogen or C.sub.1-C.sub.3 alkyl. In some
embodiments, R.sup.c'' is hydrogen, --OH, C.sub.1-C.sub.3 alkyl, or
--C(.dbd.O)H. In some embodiments, each R.sup.d is independently
hydrogen, --OH, --COOH, alkyl (e.g., alkylene, alkenyl, or
alkynyl), heteroalkyl, or each R.sup.d is taken together to form an
oxo, wherein the alkyl or heteroalkyl is optionally substituted. In
some embodiments, R.sup.d' is hydrogen, --OH, C.sub.1-C.sub.3 alkyl
(e.g., alkylene or alkenyl), or heteroalkyl. In some embodiments,
one R.sup.d is taken together with R.sup.d' to form a substituted
or unsubstituted cycloalkyl or heterocycloalkyl. In some
embodiments, either the first radical, the second radical, or both
the first radical and the second radical is not a steroid. In some
embodiments, the second radical is a therapeutically active agent
(or drug) and the first radical (e.g., steroid) being different
than the second radical (e.g., prostaglandin. Also provided in
certain embodiments herein are pharmaceutical salts or solvates of
a compound of Formula (IC).
[0032] In some embodiments, the structure of any one of Formula
(I), Formula (IA), Formula (IB), or Formula (IC) consists of single
bonds. In some embodiments, the structure of any one of Formula
(I), Formula (IA), Formula (IB), or Formula (IC) comprises at least
one double bond. In some embodiments, the structure of any one of
Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises
one double bond. In some embodiments, the structure of any one of
Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises
two double bonds. In some embodiments, the structure of any one of
Formula (I), Formula (IA), Formula (IB), or Formula (IC) comprises
three double bonds. In some embodiments, the structure of any one
of Formula (I), Formula (IA), Formula (IB), or Formula (IC)
comprises at least one aromatic ring. In some embodiments, the
structure of any one of Formula (I), Formula (IA), Formula (IB), or
Formula (IC) comprises one aromatic ring.
[0033] In some embodiments, R.sup.d is --OH. In some embodiments,
R.sup.a is --OH and attached to a fully saturated cycloalkyl. In
some embodiments, R.sup.a is --OH and attached to an aryl. In some
embodiments, R.sup.a is oxo. In some embodiments, R.sup.a is oxo
and is adjacent to at least one double bond. In some embodiments,
R.sup.a is oxo and is adjacent to one double bond. In some
embodiments, R.sup.a is oxo and is adjacent to two double
bonds.
[0034] In some embodiments, each R.sup.a' is independently hydrogen
or halogen (e.g., fluoro or chloro). In some embodiments, each
R.sup.a, is independently hydrogen or C.sub.1-C.sub.3 alkyl. In
some embodiments, each R.sup.a, is independently hydrogen or
C.sub.1-C.sub.3 alkoxy. In some embodiments, each R.sup.a' is
attached to a single bond. In some embodiments, each R.sup.a, is
hydrogen. In some embodiments, at least one R.sup.a' is attached to
a double bond. In some embodiments, one R.sup.a, is attached to a
double bond. In some embodiments, each R.sup.a, is attached to a
double bond. In some embodiments, each R.sup.a, is independently
hydrogen or C.sub.1-C.sub.3 alkyl and attached to a single bond. In
some embodiments, each R.sup.a' is independently hydrogen or
halogen, and one R.sup.a, is attached to a double bond. In some
embodiments, each R.sup.a, is hydrogen and attached to a single
bond. In some embodiments, each R.sup.a, is hydrogen and attached
to a double bond. In some embodiments, each R.sup.a, is attached to
an aryl and independently hydrogen or C.sub.1-C.sub.3 alkoxy. In
some embodiments, each R.sup.a, is hydrogen and attached to an
aryl.
[0035] In some embodiments, R.sup.a'' is absent. In some
embodiments, R.sup.a'' is hydrogen. In some embodiments, R.sup.a''
is C.sub.1-C.sub.3 alkyl. In some embodiments, R.sup.a is --OH or
oxo, each R.sup.a, is independently hydrogen or C.sub.1-C.sub.3
alkyl, and R.sup.a'' is C.sub.1-C.sub.3 alkyl. In some embodiments,
R.sup.a is --OH or oxo, each R.sup.a, is independently hydrogen or
C.sub.1-C.sub.3 alkoxy, and R.sup.a'' is C.sub.1-C.sub.3 alkyl. In
some embodiments, R.sup.a is oxo, each R.sup.a, is independently
hydrogen or halogen (e.g., fluoro or chloro), and R.sup.a'' is
C.sub.1-C.sub.3 alkyl (e.g., methyl). In some embodiments, R.sup.a
is oxo, each R.sup.a' is independently hydrogen or C.sub.1-C.sub.3
alkyl (e.g., methyl), and R.sup.a'' is C.sub.1-C.sub.3 alkyl (e.g.,
methyl). In some embodiments, R.sup.a is oxo, each R.sup.a, is
hydrogen, and R.sup.a'' is C.sub.1-C.sub.3 alkyl (e.g., methyl). In
some embodiments, R.sup.a is --OH, each R.sup.a, is independently
hydrogen or C.sub.1-C.sub.3 alkoxy (e.g., methoxy), and R.sup.a''
is absent. In some embodiments, R.sup.a is --OH, each R.sup.a, is
hydrogen, and R.sup.a'' is C.sub.1-C.sub.3 alkyl (e.g., methyl). In
some embodiments, R.sup.a is --OH, each R.sup.a' is hydrogen, and
R.sup.a'' is absent.
[0036] In some embodiments, R.sup.b is absent. In some embodiments,
R.sup.b is hydrogen. In some embodiments, R.sup.b is halogen (e.g.,
fluoro or chloro). In some embodiments, R.sup.b' is hydrogen. In
some embodiments, R.sup.b' is halogen (e.g., fluoro or chloro). In
some embodiments, R.sup.b' is --OH. In some embodiments, R.sup.b'
is -oxo. In some embodiments, R.sup.b' is C.sub.1-C.sub.3 alkyl
(e.g., methyl). In some embodiments, R.sup.b' is hydrogen, halogen
(e.g., fluoro or chloro), or C.sub.1-C.sub.3 alkyl (e.g., methyl)
and attached to a single bond. In some embodiments, R.sup.b' is
hydrogen or C.sub.1-C.sub.3 alkyl (e.g., methyl) and attached to a
double bond. In some embodiments, R.sup.b'' is hydrogen. In some
embodiments, R.sup.b'' is --OH.
[0037] In some embodiments, R.sup.b is hydrogen or halogen (e.g.,
fluoro or chloro), R.sup.b' is hydrogen, halogen (e.g., fluoro or
chloro), or C.sub.1-C.sub.3 alkyl (e.g., methyl), and R.sup.1' is
hydrogen. In some embodiments, R.sup.b is hydrogen or halogen
(e.g., fluoro or chloro), R.sup.b' is hydrogen or halogen (e.g.,
fluoro or chloro), and R.sup.b'' is hydrogen. In some embodiments,
R.sup.b is halogen (e.g., fluoro or chloro), R.sup.b' is halogen
(e.g., fluoro or chloro), and R.sup.b'' is hydrogen. In some
embodiments, R.sup.b is halogen (e.g., fluoro or chloro), R.sup.b'
is hydrogen, and R.sup.b'' is hydrogen. In some embodiments,
R.sup.b is hydrogen, R.sup.b' is halogen (e.g., fluoro or chloro),
and R.sup.1' is hydrogen. In some embodiments, R.sup.b is hydrogen,
R.sup.b' is C.sub.1-C.sub.3 alkyl (e.g., methyl), and R.sup.1' is
hydrogen. In some embodiments, R.sup.b is hydrogen, R.sup.b' is
hydrogen, and R.sup.1' is --OH. In some embodiments, R.sup.b is
hydrogen, R.sup.b' is oxo, and R.sup.b'' is hydrogen. In some
embodiments, R.sup.b, R.sup.b', and R.sup.b'' are each
hydrogen.
[0038] In some embodiments, each R.sup.c is independently hydrogen
or --OH. In some embodiments, each R.sup.c is independently
hydrogen or oxo. In some embodiments, each R.sup.c is hydrogen. In
some embodiments, each R.sup.c' is hydrogen. In some embodiments,
each R.sup.c' is C.sub.1-C.sub.3 alkyl. In some embodiments,
R.sup.c' is hydrogen. In some embodiments, R.sup.c' is
C.sub.1-C.sub.3 alkyl. In some embodiments, R.sup.c'' is
--C(.dbd.O)H.
[0039] In some embodiments, each R.sup.c is hydrogen, each R.sup.c'
is hydrogen, and R.sup.c' is C.sub.1-C.sub.3 alkyl. In some
embodiments, each R.sup.c is independently hydrogen or --OH, each
R.sup.c' is hydrogen, and R.sup.c'' is C.sub.1-C.sub.3 alkyl. In
some embodiments, each R.sup.c is independently hydrogen or oxo,
each R.sup.c' is hydrogen, and R.sup.c'' is C.sub.1-C.sub.3 alkyl.
In some embodiments, each R.sup.c is independently hydrogen or
--OH, each R.sup.c' is hydrogen, and R.sup.c'' is --C(.dbd.O)H. In
some embodiments, each R.sup.c is independently hydrogen or --OH,
each R.sup.c' is C.sub.1-C.sub.3 alkyl, and R.sup.c' is
hydrogen.
[0040] In some embodiments, one R.sup.d is absent and R.sup.d' and
the other R.sup.d are attached to a double bond. In some
embodiments, the R.sup.d' and the other R.sup.d attached to a
double bond are each hydrogen.
[0041] In some embodiments, one R.sup.d is hydrogen and the other
R.sup.d is --OH, --COOH, alkyl (e.g., alkylene, alkenyl, or
alkynyl), heteroalkyl, wherein the alkyl or heteroalkyl is
optionally substituted. In some embodiments, one R.sup.d is alkyl
and the other R.sup.d is --OH, --COOH, alkyl (e.g., alkylene,
alkenyl, or alkynyl), heteroalkyl, wherein the alkyl or heteroalkyl
is optionally substituted. In some embodiments, one R.sup.d is
optionally substituted alkoxy and the other R.sup.d is --OH,
--COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl,
wherein the alkyl or heteroalkyl is optionally substituted. In some
embodiments, one R.sup.d is --OH and the other R.sup.d is --COOH,
alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl, wherein
the alkyl or heteroalkyl is optionally substituted. In some
embodiments, each R.sup.d is independently hydrogen or --OH. In
some embodiments, each R.sup.d is independently optionally
substituted alkyl or --OH. In some embodiments, each R.sup.d is
independently --COOH or --OH. In some embodiments, each R.sup.d is
independently --COOH or optionally substituted alkoxy. In some
embodiments, each R.sup.d is taken together to form an oxo. In some
embodiments, each R.sup.d is taken together to form an optionally
substituted alkenyl. In some embodiments, the alkenyl is
substituted with --COOH and alkyl. In some embodiments, the alkyl
comprises saturated and unsaturated carbon bonds. In some
embodiments, each R.sup.d is independently optionally substituted
alkyl or hydrogen. In some embodiments, the alkyl consists of
saturated carbon bonds. In some embodiments, the alkyl is
substituted with C.sub.1-C.sub.3 alkyl and alkyl further
substituted with --COOH. In some embodiments, the alkyl is
substituted with C.sub.1-C.sub.3 alkyl and alkyl further
substituted with --OH.
[0042] In some embodiments, R.sup.d' is hydrogen. In some
embodiments, R.sup.d' is --OH. In some embodiments, R.sup.d' is
C.sub.1-C.sub.3 alkyl (e.g., alkylene or alkenyl). In some
embodiments, the C.sub.1-C.sub.3 alkyl is methyl. In some
embodiments, the C.sub.1-C.sub.3 alkyl is CHCH. In some
embodiments, R.sup.d' is heteroalkyl. In some embodiments, the
heteroalkyl is --O(C.dbd.O)C.sub.1-C.sub.3 alkyl.
[0043] In some embodiments, one R.sup.d is taken together with
R.sup.d' to form an optionally substituted cycloalkyl or optionally
substituted heterocycloalkyl. In some embodiments, one R.sup.d is
taken together with R.sup.d' to form a heterocycloalkyl substituted
with one or more alkyl groups. In some embodiments, one R.sup.d is
optionally substituted alkyl and the other R.sup.d is taken
together with R.sup.d' to form a heterocycloalkyl substituted with
one or more alkyl groups. In some embodiments, the alkyl is
substituted with oxo and --OH. In some embodiments, the alkyl is
substituted with oxo and alkyl further substituted with halogen
(e.g., fluoro or chloro). In some embodiments, the heterocycloalkyl
is an optionally substituted dioxolane. In some embodiments, the
optionally substituted dioxolane is 2,2-dimethyl-1,3-dioxolane. In
some embodiments, the optionally substituted dioxolane is
1,4-dioxaspiro[4.4]nonane.
[0044] In some embodiments, each R.sup.d is independently hydrogen
or optionally substituted alkyl and R.sup.d' is hydrogen. In some
embodiments, each R.sup.d is independently hydrogen or optionally
substituted alkyl and R.sup.d' is C.sub.1-C.sub.3 alkyl. In some
embodiments, each R.sup.d is independently optionally substituted
alkyl and R.sup.d' is hydrogen. In some embodiments, each R.sup.d
is independently --OH or optionally substituted alkyl and R.sup.d'
is hydrogen. In some embodiments, each R.sup.d is independently
--COOH or optionally substituted alkoxy and R.sup.d' is hydrogen.
In some embodiments, each R.sup.d is independently --OH or
optionally substituted alkyl and R.sup.d' is C.sub.1-C.sub.3 alkyl.
In some embodiments, each R.sup.d is independently --OH or
optionally substituted alkyl and R.sup.d' is --OH. In some
embodiments, each R.sup.d is independently --OH or optionally
substituted alkyl and R.sup.d' is alkyl (e.g., alkenyl). In some
embodiments, each R.sup.d is independently hydrogen or --OH and
R.sup.d' is hydrogen. In some embodiments, each R.sup.d is
independently --OH or --COOH and R.sup.d' is hydrogen. In some
embodiments, each R.sup.d and R.sup.d' are hydrogen. In some
embodiments, each R.sup.d is optionally substituted alkenyl and
R.sup.d' is optionally substituted alkoxy. In some embodiments,
each R.sup.d is taken together to form an oxo and R.sup.d' is
hydrogen. In some embodiments, one R.sup.d is optionally
substituted alkyl and the other R.sup.d is taken together with
R.sup.d' is to form an optionally substituted heterocycloalkyl.
[0045] In some embodiments, the alkyl or heteroalkyl of R.sup.d or
R.sup.d' is substituted with one or more of the group consisting of
--SH, --OH, --COOH, oxo, halogen, amino (e.g., dihydroamino,
alkylamino, or arylamino), alkyl (e.g., alkenyl, alkynyl),
heteroalkyl, ester, amide, sulfonic acid, and sulfone. In some
embodiments, one R.sup.d is taken together with R.sup.d' to form
substituted heterocycloalkyl.
[0046] In some embodiments, the alkyl of R.sup.d is substituted
with oxo and alkyl further substituted with hydroxyl. In some
embodiments, the alkyl of R.sup.d is substituted with oxo and alkyl
further substituted with halogen (e.g., fluorine or chlorine). In
some embodiments, the alkyl of R.sup.d is substituted with oxo and
C.sub.1-C.sub.3 alkyl. In some embodiments, the alkyl of R.sup.d is
substituted with oxo and alkyl further substituted with alkoxy
further substituted with oxo and C.sub.1-C.sub.3 alkyl. In some
embodiments, the alkyl of R.sup.d is substituted with alkyl and
alkyl further substituted with oxo and amino further substituted
with alkyl further substituted with sulfonic acid. In some
embodiments, the alkyl of R.sup.d is substituted with oxo and thiol
(e.g., thioether) further substituted with C.sub.1-C.sub.3 alkyl
further substituted with halogen (e.g., fluorine or chlorine). In
some embodiments, the alkyl of R.sup.d is substituted with --OH. In
some embodiments, the alkyl of R.sup.d is substituted with oxo and
hydroxyl (e.g., ether) further substituted with C.sub.1-C.sub.3
alkyl further substituted with halogen (e.g., fluorine or
chlorine). In some embodiments, the alkoxy of R.sup.d is
substituted with oxo and alkoxy further substituted with alkyl.
[0047] In some embodiments, the C.sub.1-C.sub.3 alkyl is methyl,
ethyl, propyl, isopropyl, butyl, or tert-butyl. In some
embodiments, the C.sub.1-C.sub.3 alkyl is methyl. In some
embodiments, the C.sub.1-C.sub.3 alkoxy is methoxy, ethyoxy,
propyoxy, or isopropoxy. In some embodiments, the C.sub.1-C.sub.3
alkyl is methoxy.
[0048] In some embodiments, the first radical and the second
radical are joined by a linker (e.g., a bond). In some embodiments,
the first radical is joined to the second radical through any one
of R.sup.a, R.sup.b, R.sup.c, or R.sup.d of the first radical. In
some embodiments, the first radical is joined to the second radical
through any one of R.sup.a, R.sup.b, R.sup.c, or R.sup.d, and the
R.sup.a, R.sup.b, R.sup.c, or R.sup.d through which the first
radical is joined to the second radical comprises a hydroxyl
radical (e.g., when together with the linker or second radical
(where the linker is a bond), forms an ether), a thiol radical
(e.g., when together with the linker or second radical (where the
linker is a bond), forms a thioether), or a carboxylate radical
(e.g., when taken together with the linker or second radical (where
the linker is a bond), forms an ester or carbonate). In some
embodiments, the connection between the thiol radical forms a
thioester, a disulfide, or a thiocarbonate. In some embodiments,
the connection between the carboxylate radical forms an anhydride.
In some embodiments, the first radical is joined to the second
radical through any one of R.sup.a, R.sup.b, R.sup.c, or R.sup.d,
and the R.sup.a, R.sup.b, R.sup.c, or R.sup.d through which the
first radical is joined to the second radical comprises an amino
radical (e.g., when together with the linker or second radical
(where the linker is a bond), forms an amide, carbamate, or
thiocarbamate).
[0049] In some embodiments, the R.sup.a, R.sup.b, R.sup.c, or
R.sup.d through which the first radical is joined to the second
radical comprises a hydroxyl radical which together with the linker
or with the second radical forms an ether. In some embodiments, the
R.sup.a, R.sup.b, R.sup.c, or R.sup.d through which the first
radical is joined to the second radical comprises a thiol radical
which together with the linker or the second radical forms a
thioether. In some embodiments, the R.sup.a, R.sup.b, R.sup.c, or
R.sup.d through which the first radical is joined to the second
radical comprises a carboxylate radical which together with the
linker or the second radical forms an ester or a carbonate.
[0050] In some embodiments, the first radical has a structure of
Formula (I), Formula (IA), Formula (IB), or Formula (IC) and the
second radical does not have a structure of Formula (I), Formula
(IA), Formula (IB), or Formula (IC). In some embodiments, the
structure of Formula (I), Formula (IA), Formula (IB), or Formula
(IC) has a melt and/or glass transition temperature at a
temperature of at least 20.degree. C. (e.g., at least 25.degree.
C., at least 30.degree. C., at least 37.degree. C., at least
40.degree. C., at least 50.degree. C., at least 100.degree. C., or
more) in its free form.
[0051] In some embodiments, both the first radical and the second
radical consist of the three-membered ring system of Formula (I),
Formula (IA), Formula (IB), or Formula (IC). In some embodiments,
the first radical is a central nervous system (CNS) agent. In some
embodiments, the radical of Formula (I), Formula (IA), Formula
(IB), or Formula (IC) is a steroid, an opioid agonist, an opioid
antagonist, an adrenergic receptor antagonist (e.g.,
.beta.-blocker, .alpha.-1 blocker), or a serotonergic antagonist
(e.g., serotonin 5-HT3 receptor antagonist). In some embodiments,
the first radical is an anti-inflammatory agent, an anti-psychotic
agent (e.g., typical anti-psychotic, a typical antipsychotic,
schizophrenia, or the like), or the like. In some embodiments, the
IOP lowering agent is a beta-blocker. In some embodiments, the
beta-blocker is timolol.
[0052] In some embodiments, the second radical is an intraocular
pressure (IOP) lowering agent. In some embodiments, the first
radical is an anti-inflammatory agent and the second radical is an
intraocular pressure (IOP) lowering agent. In some embodiments, the
first radical is an IOP lowering steroid (e.g., anecortave) or
benign steroid (e.g., cholesterol) and the second radical is an IOP
lowering agent. In some embodiments, the IOP lowering agent is a
prostaglandin.
[0053] In some embodiments, the first radical is a solid (e.g.,
having a melting point of at least 30.degree. C.) in its free form.
In some embodiments, the second radical is a liquid (e.g., having a
melting point of less than 30.degree. C.) in its free form. In some
embodiments, the first radical is a steroid (e.g., dexamethasone,
anecortave, etc.). In some embodiments, the steroid is a
corticosteroid (e.g., glucocorticoid or mineral corticoid), a sex
steroid, a neurosteroid, an aminosteroid, or a secosteroid. In some
embodiments, the second radical is not a steroid (or does not have
a structure of any one of Formula (I), Formula (IA), Formula (IB),
or Formula (IC)). In some embodiments, the first radical is a
steroid and the second radical is a prostaglandin.
[0054] In some embodiments, the second radical has a structure of
Formula (II):
##STR00005##
[0055] In some embodiments, is a single bond or a double bond. In
some embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5
are each independently selected from one or more of the group
consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or
arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl,
cycloalkyl, and heterocycloalkyl is optionally substituted. In some
embodiments, any one of R.sup.1, R.sup.2, R.sup.3, R.sup.4, or
R.sup.5 are taken together to form an optionally substituted
cycloalkyl or heterocycloalkyl. In some embodiments, X is selected
from the group consisting of --O--, --NR--, --S(R).sub.a--, and
--C(R).sub.b--. In some embodiments, a is independently 0-2. In
some embodiments, b is independently 1 or 2. Also provided in
certain embodiments herein are pharmaceutical salts or solvates of
a compound of Formula (II).
[0056] In some embodiments, X is S, --C(R).sub.1--, or
--C(R).sub.2--. In some embodiments, X is S attached to a single
bond. In some embodiments, X is --CH-- or --CH.sub.2--.
[0057] In some embodiments, R.sup.4 is alkyl substituted with one
or more groups, each group being independently selected from
--C(.dbd.O)OC.sub.1-C.sub.3alkyl, --COOH, --CONH.sub.2,
--CONHC.sub.1-C.sub.3alkyl, and/or alkyl (e.g., alkylene or
alkenyl). In some embodiments, R.sup.4 is alkyl substituted with
--COOH. In some embodiments, R.sup.4 is alkyl substituted with
--C(.dbd.O)OC.sub.1-C.sub.3alkyl. In some embodiments, R.sup.4 is
alkyl substituted with --CONH.sub.2. In some embodiments, R.sup.4
is alkyl substituted with --CONHC.sub.1-C.sub.3alkyl. In some
embodiments, the alkyl of R.sup.4 comprises at least one double
bond. In some embodiments, the alkyl of R.sup.4 comprises one
double bond. In some embodiments, the alkyl of R.sup.4 comprises
two double bonds. In some embodiments, the two double bonds form an
allene.
[0058] In some embodiments, R.sup.5 is alkyl substituted with one
or more groups, each group being independently selected from
halogen, --OH, oxo, alkyl (e.g., alkynyl), alkoxy, aryl, and
aryloxy, wherein alkyl (e.g., alkynyl), aryl, or aryloxy is
optionally substituted. In some embodiments, the alkyl is
substituted with one or more groups, each group being independently
selected from halogen, --OH, oxo, alkyl (e.g., alkynyl), aryl, or
aryloxy, wherein the alkyl (e.g., alkynyl), aryl, or aryloxy is
optionally substituted. In some embodiments, the aryl or aryloxy is
substituted with one or more halogen groups. In some embodiments,
the aryl or aryloxy is unsubstituted.
[0059] In some embodiments, the second radical has a structure of
Formula (IIA):
##STR00006##
[0060] In some embodiments, each is independently a single bond or
a double bond. In some embodiments, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are each independently selected from one or
more of the group consisting of hydrogen, oxo, halo, alkyl,
heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g.,
dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol,
wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is
optionally substituted.
[0061] In some embodiments, Formula (IIA) comprises three double
bonds. In some embodiments, Formula (IIA) comprises two double
bonds. In some embodiments, Formula (IIA) comprises one double
bond.
[0062] In some embodiments, R.sup.1 and R.sup.3 are each
independently --OH or oxo. In some embodiments, R.sup.1 is oxo,
R.sup.2 is hydrogen, and R.sup.3 is --OH. In some embodiments,
R.sup.3 is oxo, R.sup.2 is hydrogen, and R.sup.1 is --OH. In some
embodiments, R.sup.1 and R.sup.3 are each --OH and R.sup.2 is
hydrogen.
[0063] In some embodiments, R.sup.4 is
--C(.dbd.O)OC.sub.1-C.sub.3alkyl, --COOH, --CONH.sub.2, or
--CONHC.sub.1-C.sub.3alkyl. In some embodiments, R.sup.4 is --COOH.
In some embodiments, R.sup.4 is --CONH.sub.2.
[0064] In some embodiments, R.sup.5 is alkyl or aryloxy, wherein
the alkyl and aryloxy are optionally substituted. In some
embodiments, R.sup.5 is alkyl. In some embodiments, the alkyl is
butyl or hexyl. In some embodiments, R.sup.5 is alkyl substituted
with optionally substituted aryl or optionally substituted alkyl.
In some embodiments, the alkyl is substituted with unsubstituted
aryl. In some embodiments, the alkyl is substituted with alkyl
(e.g., but-2-yne). In some embodiments, R.sup.5 is unsubstituted
aryloxy. In some embodiments, R.sup.5 is aryloxy substituted with
one or more alkyl (e.g., --CF.sub.3) or halo (fluoro or chloro)
groups. In some embodiments, the aryloxy is substituted with
--CF.sub.3.
[0065] In some embodiments, R.sup.6 and R.sup.6' are each fluoro.
In some embodiments, R.sup.6 is H or methyl and R.sup.6' is --OH.
In some embodiments, R.sup.6 is H and R.sup.6' is --OH. In some
embodiments, R.sup.6 is methyl and R.sup.6' is --OH. In some
embodiments, R.sup.6 and R.sup.6' are taken together to form an
oxo.
[0066] In some embodiments, R.sup.3 and R.sup.4 of Formula (II) are
taken together to form an optionally substituted cycloalkyl or
heterocycloalkyl. In some embodiments, R.sup.3 and R.sup.4 of
Formula (II) are taken together to form heterocycloalkyl
substituted with optionally substituted alkyl (e.g., alkenyl). In
some embodiments, R.sup.3 and R.sup.4 of Formula (II) are taken
together to form a heterocycloalkyl substituted with alkyl (e.g.,
alkenyl) substituted with --COOH or
--C(.dbd.O)OC.sub.1-C.sub.3alky. In some embodiments, the
heterocycloalkyl is substituted with alkyl further substituted with
--COOH or --C(.dbd.O)OC.sub.1-C.sub.3alkyl. In some embodiments,
the heterocycloalkyl is substituted with alkenyl further
substituted with alkyl, which is further substituted with --COOH or
--C(.dbd.O)OC.sub.1-C.sub.3alkyl. In some embodiments the alkyl or
alkenyl is substituted with --COOH.
[0067] In some embodiments, the second radical has a structure of
Formula (IIB):
##STR00007##
[0068] In some embodiments, is a single bond or a double bond. In
some embodiments, R.sup.1, R.sup.2, and R.sup.5 are each
independently selected from one or more of the group consisting of
hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or
arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl,
cycloalkyl, and heterocycloalkyl is optionally substituted. In some
embodiments, R.sup.6'' is oxo or --OH. In some embodiments, Y.sup.1
and Y.sup.2 are each independently a bond or alkylene. In some
embodiments, G is O or CH.sub.2. In some embodiments, g is 1 or 2.
In some embodiments, R.sup.10 is alkyl or H. Also provided in
certain embodiments herein are pharmaceutical salts or solvates of
a compound of Formula (IIB).
[0069] In some embodiments, G is O and Y.sup.1 is a bond. In some
embodiments, Y.sup.2 is methylene. In some embodiments, g is 1. In
some embodiments, G is O and Y.sup.1 is a alkylene. In some
embodiments, Y.sup.2 is a bond. In some embodiments, g is 2.
[0070] In some embodiments, R.sup.1 is oxo or --OH. In some
embodiments, R.sup.1 is --OH. In some embodiments, R.sup.1 is --OH
and R.sup.2 is hydrogen. In some embodiments, R.sup.6'' is --OH. In
some embodiments, R.sup.5 is alkyl. In some embodiments, R.sup.5 is
substituted aryl.
[0071] In some embodiments, G is O, Y.sup.1 is a bond, Y.sup.2 is
methylene, g is 1, R.sup.1 is --OH, R.sup.2 is hydrogen, R.sup.5 is
alkyl, R.sup.6'' is --OH, and R.sup.10 is H. In some embodiments, G
is O, Y.sup.1 is a methylene, Y.sup.2 is a bond, g is 2, R.sup.1 is
--OH, R.sup.2 is hydrogen, R.sup.5 is substituted aryl, R.sup.6''
is --OH, and R.sup.10 is H or C.sub.1-C.sub.3alkyl.
[0072] In some embodiments, R.sup.5 is selected from one or more of
the group consisting of --O--, --OH, halogen, alkyl (e.g.,
alkynyl), aryl, wherein the alkyl (e.g., alkynyl) and aryl are
optionally substituted with one or more of alkyl (e.g.,
fluoroalkyl), halogen, and --OH. In some embodiments, R.sup.5 is
optionally substituted aryl or optionally substituted --O-aryl. In
some embodiments, R.sup.5 is alkyl or aryloxy, wherein the alkyl
and optionally substituted aryloxy. In some embodiments, R.sup.5 is
alkyl. In some embodiments, the alkyl is butyl or hexyl. In some
embodiments, R.sup.5 is unsubstituted aryloxy. In some embodiments,
the aryloxy is substituted with one or two --F. In some
embodiments, R.sup.5 is an aryl or O-aryl, each of which is
unsubstituted. In some embodiments, R.sup.5 is an aryl or O-aryl,
each of which is substituted with one or more of halogen or
haloalkyl (e.g., trifluoroalkyl, e.g., trifluoromethyl).
[0073] In certain embodiments, provided herein is a compound
comprising a first radical or a second radical, wherein the first
radical has a structure of any one of Formula (I), Formula (IA),
Formula (IB), or Formula (IC) and the second radical has a
structure of any one of Formula (II), Formula (IIA), or Formula
(IIB). In some embodiments, the first radical (e.g., having a
structure of any one of Formula (I), Formula (IA), Formula (IB), or
Formula (IC)) and the second radical (e.g., Formula (II), Formula
(IIA), or Formula (IIB)) are joined by a linker (e.g., hydrolyzable
linker). In some embodiments, the linker is a bond.
[0074] In certain embodiments, provided herein is a compound
comprising a steroid. In some embodiments, provided herein is a
compound comprising a prostaglandin. In some embodiments, provided
herein is a compound comprising a linker (e.g., hydrolyzable
linker). In some embodiments, the linker adjoins (e.g., covalently)
the steroid and the prostaglandin. Also provided in certain
embodiments herein are pharmaceutical salts or solvates of a
compound.
[0075] In certain aspects, provided herein is a compound having the
structure of Formula (III):
##STR00008##
[0076] In some embodiments, is a single bond or a double bond. In
some embodiments, each R.sup.d, R.sup.b, R.sup.c, and R.sup.d are
independently selected from the group consisting of oxo, halogen,
--CN, --NO.sub.2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,
alkoxy, amino (e.g., dihydroamino, alkylamino, or arylamino),
hydroxy, or thiol, wherein the alkyl, alkynyl, heteroalkyl,
cycloalkyl, or heterocycloalkyl is optionally substituted. In some
embodiments, any one of R.sup.a, R.sup.b, R.sup.c, and R.sup.d are
taken together with another of R.sup.d, R.sup.b, R.sup.c, and
R.sup.d to form an substituted or unsubstituted cycloalkyl or
heterocycloalkyl. In some embodiments, each of m, n, o, and p are
independently 0-6. In some embodiments, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are each independently selected from one or
more of the group consisting of hydrogen, oxo, halo, alkyl,
heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g.,
dihydroamino, alkylamino, or arylamino), hydroxyl, and thiol,
wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is
optionally substituted. In some embodiments, L is a linker. Also
provided in certain embodiments herein are pharmaceutical salts or
solvates of a compound of Formula (III).
[0077] In some embodiments, the optional substitution of any one of
the groups of Formula (III) are as provided elsewhere herein (e.g.,
as in for Formula (IB) or Formula (II)).
[0078] In certain aspects, provided herein is a compound having the
structure of Formula (IV):
##STR00009##
[0079] In some embodiments, is a single bond or a double bond. In
some embodiments, R.sup.a is hydrogen, --OH, or oxo. In some
embodiments, each R.sup.a' is independently selected from hydrogen,
--OH, halogen, C.sub.1-C.sub.3 alkyl, and alkoxy. In some
embodiments, R.sup.a'' is absent, hydrogen, or C.sub.1-C.sub.3
alkyl. In some embodiments, R.sup.b is absent, hydrogen, halogen,
or C.sub.1-C.sub.3 alkyl. In some embodiments, R.sup.b' is
hydrogen, halogen, --OH, oxo, or C.sub.1-C.sub.3 alkyl. In some
embodiments, R.sup.b'' is hydrogen or --OH. In some embodiments,
each R.sup.c is independently hydrogen, --OH, oxo, or
C.sub.1-C.sub.3 alkyl. In some embodiments, each R.sup.c' is
independently hydrogen or C.sub.1-C.sub.3 alkyl. In some
embodiments, R.sup.c'' is hydrogen, --OH, C.sub.1-C.sub.3 alkyl, or
--C(.dbd.O)H. In some embodiments, each R.sup.d is independently
hydrogen, --OH, --COOH, alkyl (e.g., alkylene, alkenyl, or
alkynyl), heteroalkyl, or each R.sup.d is taken together to form an
oxo, wherein the alkyl or heteroalkyl is optionally substituted. In
some embodiments, R.sup.d' is hydrogen, --OH, C.sub.1-C.sub.3 alkyl
(e.g., alkylene or alkenyl), or heteroalkyl. In some embodiments,
one R.sup.d is taken together with R.sup.d' to form a substituted
or unsubstituted cycloalkyl or heterocycloalkyl. In some
embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.6 are
each independently selected from one or more of the group
consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino, or
arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl,
cycloalkyl, and heterocycloalkyl is optionally substituted. In some
embodiments, R.sup.6 and R.sup.6' are each independently hydrogen,
halogen, alkyl, or R.sup.6 and R.sup.6' are taken together to form
an oxo. Also provided in certain embodiments herein are
pharmaceutical salts or solvates of a compound of Formula (IV).
[0080] In certain aspects, provided herein is a compound having the
structure of Formula (V):
##STR00010##
[0081] In some embodiments, is a single bond or a double bond. In
some embodiments, R.sup.a is hydrogen, --OH, or oxo. In some
embodiments, each R.sup.d' is independently selected from hydrogen,
--OH, halogen, C.sub.1-C.sub.3 alkyl, and alkoxy. In some
embodiments, R.sup.d'' is absent, hydrogen, or C.sub.1-C.sub.3
alkyl. In some embodiments, R.sup.b is absent, hydrogen, halogen,
or C.sub.1-C.sub.3 alkyl. In some embodiments, R.sup.b' is
hydrogen, halogen, --OH, oxo, or C.sub.1-C.sub.3 alkyl. In some
embodiments, R.sup.b'' is hydrogen or --OH. In some embodiments,
each R.sup.c is independently hydrogen, --OH, oxo, or
C.sub.1-C.sub.3 alkyl. In some embodiments, each R.sup.c' is
independently hydrogen or C.sub.1-C.sub.3 alkyl. In some
embodiments, R.sup.c'' is hydrogen, --OH, C.sub.1-C.sub.3 alkyl, or
--C(.dbd.O)H. In some embodiments, each R.sup.d is independently
hydrogen, --OH, --COOH, alkyl (e.g., alkylene, alkenyl, or
alkynyl), heteroalkyl, or each R.sup.d is taken together to form an
oxo, wherein the alkyl or heteroalkyl is optionally substituted. In
some embodiments, R.sup.d' is hydrogen, --OH, C.sub.1-C.sub.3 alkyl
(e.g., alkylene or alkenyl), or heteroalkyl. In some embodiments,
one R.sup.d is taken together with R.sup.d' to form a substituted
or unsubstituted cycloalkyl or heterocycloalkyl. In some
embodiments, R.sup.1, R.sup.2, and R.sup.5 are each independently
selected from one or more of the group consisting of hydrogen, oxo,
halo, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy,
amino (e.g., dihydroamino, alkylamino, or arylamino), hydroxyl, and
thiol, wherein the alkyl, heteroalkyl, cycloalkyl, and
heterocycloalkyl is optionally substituted. In some embodiments,
R.sup.6'' is oxo or --OH. In some embodiments, Y.sup.1 and Y.sup.2
are each independently a bond or alkylene. In some embodiments, G
is O or CH.sub.2. In some embodiments, g is 1 or 2. In some
embodiments, R.sup.1' is alkyl or H. In some embodiments, L is a
linker. Also provided in certain embodiments herein are
pharmaceutical salts or solvates of a compound of Formula (V).
[0082] In some embodiments, a hydroxyl radical or a carboxylate
radical of any one of Formula (I), Formula (IA), Formula (IB), or
Formula (IC) is attached to a hydroxyl radical or a carboxylate
radical of another of any one of Formula (I), Formula (IA), Formula
(IB), or Formula (IC) through a linker. In some embodiments, a
hydroxyl radical or a carboxylate radical of any one of Formula
(I), Formula (IA), Formula (IB), or Formula (IC) is attached to a
hydroxyl radical or a carboxylate radical of any one of Formula
(II), Formula (IIA), or Formula (IIB) through a linker. In some
embodiments, a hydroxyl radical of any one of Formula (I), Formula
(IA), Formula (IB), or Formula (IC) is attached to a hydroxyl
radical of any one of Formula (II), Formula (IIA), or Formula (IIB)
through a linker. In some embodiments, a hydroxyl radical of any
one of Formula (I), Formula (IA), Formula (IB), or Formula (IC) is
attached to a carboxylate radical of any one of Formula (II),
Formula (IIA), or Formula (IIB) through a linker. In some
embodiments, a carboxylate radical of any one of Formula (I),
Formula (IA), Formula (IB), or Formula (IC) is attached to a
hydroxyl radical of any one of Formula (II), Formula (IIA), or
Formula (IIB) through a linker. In some embodiments, a carboxylate
radical of any one of Formula (I), Formula (IA), Formula (IB), or
Formula (IC) is attached to a carboxylate radical of any one of
Formula (II), Formula (IIA), or Formula (IIB) through a linker. In
some embodiments, the linker is a bond. In some embodiments, the
linker is oxo.
[0083] In some embodiments, any one of R.sup.a, R.sup.a', R.sup.b,
R.sup.b', R.sup.b'', R.sup.c, R.sup.c'', R.sup.d, or R.sup.d' is an
ester radical, a hydroxyl radical, or a carboxylate radical, and
any one of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.6', R.sub.6'', or R.sub.10 is an amide radical, a thiol
radical, a hydroxyl radical, or a carboxylate radical. In some
embodiments, any one of R.sup.a, R.sup.a', R.sup.b, R.sup.b',
R.sup.b'', R.sup.c, R.sup.c'', R.sup.d, or R.sup.d' is an ester
radical, a hydroxyl radical, or a carboxylate radical, and any one
of R.sup.1, R.sub.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.6',
R.sup.6'', or R.sup.10 is a hydroxyl radical or a carboxylate
radical. In some embodiments, any radical of R.sup.a, R.sup.a',
R.sup.b, R.sup.b', R.sup.b'', R.sup.c, R.sup.c'', R.sup.d, or
R.sup.d' is adjoined to any radical of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.6', R.sup.6'', or R.sup.10 by a
linker. In some embodiments, any radical of R.sup.a, R.sup.a',
R.sup.b, R.sup.b', R.sup.b'', R.sup.c, R.sup.c'', R.sup.d, or
R.sup.d' is adjoined to any radical of R.sup.4, R.sup.5, R.sup.6,
R.sup.6', R.sup.6'', or R.sup.10 by a linker. In some embodiments,
any radical of R.sup.a, R.sup.b, R.sup.c, or R.sup.d is adjoined to
any radical of R.sup.4, R.sup.5, R.sup.6, R.sup.6', R.sup.6'', or
R.sup.10 by a linker. In some embodiments, any radical of R.sup.d
or R.sup.d' is adjoined to any radical of R.sup.4, R.sup.5,
R.sup.6, R.sup.6', R.sup.6'', or R.sup.10 by a linker. In some
embodiments, a radical of R.sup.d is adjoined to any radical of
R.sup.4, R.sup.6, R.sup.6', R.sup.6'', or R.sup.10 by a linker. In
some embodiments, a radical of R.sup.d is adjoined to a radical of
R.sup.4 or R.sup.10 by a linker. In some embodiments, a radical of
of R.sup.d is adjoined to any radical of R.sup.6, R.sup.6', or
R.sup.6'' by a linker. In some embodiments, the linker is oxo. In
some embodiments, the linker is a bond.
[0084] In some embodiments, the linker is a bond, alkyl,
heteroalkyl, or alkoxy, wherein the alkyl, heteroalkyl, or alkoxy
is optionally substituted. In some embodiments, the alkyl,
heteroalkyl, or alkoxy are each independently substituted with one
or more groups, each group being independently selected from the
group consisting of --O--, --S--, silicone, amino, optionally
substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g.,
polypropylene), haloalkyl), optionally substituted heteroalkyl
(e.g, polyTHF), and optionally substituted cycloalkyl. In some
embodiments, the linker is alkyl (alkylene) and the alkyl
(alkylene) is substituted with one or more groups selected from
--OH, halo, oxo, alkyl, heteroalkyl, cycloalkyl, and
heterocycloalkyl. In some embodiments, the linker is an
unsubstituted alkyl (alkylene). In some embodiments, the linker is
heteroalkyl (heteroalkylene) and the heteroalkyl (heteroalkylene)
is substituted with one or more groups selected from halo or alkyl.
In some embodiments, the linker is unsubstituted heteroalkyl
(heteroalkylene). In some embodiments, the linker is a bond.
[0085] In some embodiments, the linker comprises one or more linker
group, each linker group being independently selected from a bond,
alkyl, cycloalkyl, heteroalkyl, or alkoxy, wherein the alkyl,
cycloalkyl, heteroalkyl, or alkoxy is optionally substituted. In
some embodiments, the linker is a bond, alkyl, cycloalkyl,
heteroalkyl, or alkoxy, wherein the alkyl, cycloalkyl, heteroalkyl,
or alkoxy is optionally substituted. In some embodiments, the
alkyl, cycloalkyl, heteroalkyl, or alkoxy are each independently
substituted with one or more substitutent, each substituent being
independently selected from the group consisting of --O-- (e.g.,
--OH), --S-- (e.g., --SH), silicone, amino, optionally substituted
alkyl (e.g., alkenyl, alkynyl, branched (e.g., polypropylene),
haloalkyl), optionally substituted heteroalkyl (e.g, polyTHF), and
optionally substituted cycloalkyl. In some embodiments, the linker
comprises one or more linker group, each linker group being
independently selected from alkyl (alkylene) and cycloalkyl
(cycloalkylene). In some embodiments, the linker is alkyl
(alkylene) or cycloalkyl (cycloalkylene). In some embodiments, the
alkyl (alkylene) or cycloalkyl (cycloalkylene) is unsubstituted or
substituted with one or more substituent, each substituent being
independently selected from the group consisting of --OH, halo,
oxo, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl. In some
embodiments, the linker comprises an unsubstituted or substituted
alkylene-cycloalkylene-alkylene.
[0086] In some embodiments, the linker comprises at least one oxo.
In some embodiments, the linker is oxo. In some embodiments, the
linker comprises at least one carbamate. In some embodiments, the
linker is a carbamate. In some embodiments, the linker comprises at
least one ester. In some embodiments, the linker is an ester.
[0087] In some embodiments, the linker comprises one or more linker
groups selected from oxo, --O--, --S--, unsubstituted alkylene,
C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O, C.dbd.O(CHCH).sub.nC.dbd.O,
C.dbd.O(OCH.sub.2CH.sub.2O).sub.nC.dbd.O,
O(CH.sub.2CH.sub.2O).sub.n, and C.dbd.O(CH.sub.2CH.sub.2O).sub.n,
(CH(CH.sub.3)C(.dbd.O)O).sub.n, wherein n is 1-20. In some
embodiments, the linker is a bond, unsubstituted alkylene,
C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O, C.dbd.O(CHCH).sub.nC.dbd.O,
C.dbd.O(OCH.sub.2CH.sub.2O).sub.nC.dbd.O,
O(CH.sub.2CH.sub.2O).sub.n, C.dbd.O(CH.sub.2CH.sub.2O).sub.n,
(CH(CH.sub.3)C(.dbd.O)O).sub.n, and
C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O(CH(CH.sub.3)C(.dbd.O)O).sub.n,
wherein n is 1-20. In some embodiments, n is 1-10. In some
embodiments, n is 6. In some embodiments, n is 5. In some
embodiments, n is 4. In some embodiments, n is 3. In some
embodiments, n is 2. In some embodiments, n is 1.
[0088] In some embodiments, the linker comprises one or more linker
group, each linker group being independently selected from the
group consisting of a bond, --O--, --O(C.dbd.O)--,
--O(C.dbd.O)--O--, --S--, unsubstituted alkylene, unsubstituted
cycloalkylene, C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O,
C.dbd.O(CHCH).sub.nC.dbd.O,
C.dbd.O(OCH.sub.2CH.sub.2O).sub.nC.dbd.O,
O(CH.sub.2CH.sub.2O).sub.n, and C.dbd.O(CH.sub.2CH.sub.2O).sub.n,
and (CH(CH.sub.3)C(.dbd.O)O).sub.n, wherein n is 1-20. In some
embodiments, the linker is a bond, unsubstituted alkylene,
unsubstituted alkylene-cycloalkylene-alkylene,
C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O, C.dbd.O(CHCH).sub.nC.dbd.O,
C.dbd.O(OCH.sub.2CH.sub.2O).sub.nC.dbd.O,
O(CH.sub.2CH.sub.2O).sub.n, and C.dbd.O(CH.sub.2CH.sub.2O).sub.n,
(CH(CH.sub.3)C(.dbd.O)O).sub.n,
C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O(CH(CH.sub.3)C(.dbd.O)O).sub.n,
wherein n is 1-20. In some embodiments, n is 1-10. In some
embodiments, n is 6. In some embodiments, n is 5. In some
embodiments, n is 4. In some embodiments, n is 3. In some
embodiments, n is 2. In some embodiments, n is 1.
[0089] In some embodiments, the linker is hydrolyzed in a buffered
solution. In some embodiments, the linker is hydrolytically labile.
In some embodiments, the linker is hydrolyzed by water. In some
embodiments, the linker is hydrolyzed by an enzyme. In some
embodiments, the enzyme is a hydrolase (e.g., a protease or an
esterase). In some embodiments, the enzyme is an esterase.
[0090] In some embodiments, the first radical is a (e.g., hydroxyl
or carboxyl) radical of a compound selected from the group
consisting of:
##STR00011## ##STR00012## ##STR00013## ##STR00014##
##STR00015##
[0091] In some embodiments, the first radical is a (e.g., hydroxyl
or carboxyl) radical of a compound selected from the group
consisting of:
##STR00016## ##STR00017## ##STR00018## ##STR00019##
##STR00020##
[0092] In some embodiments, the second radical is a (e.g., hydroxyl
or carboxyl) radical of a compound selected from the group
consisting of:
##STR00021## ##STR00022## ##STR00023## ##STR00024##
[0093] In some embodiments, the second radical is a (e.g., hydroxyl
or carboxyl) radical of a compound selected from the group
consisting of:
##STR00025## ##STR00026##
[0094] In some embodiments, the first radical is a hydroxyl radial.
In some embodiments, the second radical is a hydroxyl radial. In
some embodiments, the first radical is a carboxyl radical. In some
embodiment, the second radical is a carboxyl radical.
[0095] In certain embodiments, provided herein is a compound having
the structure of Formula (VI):
##STR00027##
[0096] In some embodiments, is a single bond or a double bond. In
some embodiments, R.sup.7 is hydrogen or halogen. In some
embodiments, R.sup.7 is hydrogen. In some embodiments, R.sup.7 is
fluoro. In some embodiments, R.sup.8 is a hydrogen or a
C.sub.1-C.sub.4 alkyl. In some embodiments, R.sup.8 is hydrogen. In
some embodiments, R.sup.8 is methyl, ethyl, propyl or butyl. In
some embodiments, R.sup.8 is methyl, ethyl, or butyl. In some
embodiments, R.sup.8 is methyl. In some embodiments, R.sup.7 is
hydrogen and R.sup.8 is methyl. In some embodiments, R.sup.9 is
absent, hydrogen or hydroxyl. In some embodiments, R.sup.9 is
hydrogen. In some embodiments, R.sup.9 is hydroxyl. In some
embodiments, R.sup.9 is absent. In some embodiments, L is a linker.
In some embodiments, L is a linker described herein. In some
embodiments, L is a bond. In some embodiments, L comprises one or
more linker group, each linker group being independently selected
from the group consisting of an alkylene, cycloalkylene and --O--.
In some embodiments, PG is a prostaglandin radical. Also provided
in certain embodiments herein are pharmaceutically-acceptable salts
or solvates of a compound of Formula (VI).
[0097] In some embodiments, a compound provided herein has the
structure of formula (VI-A):
##STR00028##
[0098] In some embodiments, is a single bond or a double bond. In
some embodiments, R.sup.7 is hydrogen or halogen. In some
embodiments, R.sup.7 is hydrogen. In some embodiments, R.sup.7 is
fluoro. In some embodiments, R.sup.8 is a hydrogen or a
C.sub.1-C.sub.4 alkyl. In some embodiments, R.sup.8 is hydrogen. In
some embodiments, R.sup.8 is methyl, ethyl, propyl or butyl. In
some embodiments, R.sup.8 is methyl, ethyl, or butyl. In some
embodiments, R.sup.8 is methyl. In some embodiments, R.sup.7 is
hydrogen and R.sup.8 is methyl. In some embodiments, L is a linker.
In some embodiments, L is a bond. In some embodiments, L comprises
one or more linker group, each linker group being independently
selected from the group consisting of an alkylene, cycloalkylene or
--O--. In some embodiments, PG is a prostaglandin radical. Also
provided in certain embodiments herein are
pharmaceutically-acceptable salts or solvates of a compound of
Formula (VI-A).
[0099] In some embodiments, a compound provided herein has the
structure of formula (VI-B):
##STR00029##
[0100] In some embodiments, is a single bond or a double bond. In
some embodiments, R.sup.7 is hydrogen or halogen. In some
embodiments, R.sup.7 is hydrogen. In some embodiments, R.sup.7 is
fluoro. In some embodiments, R.sup.8 is a hydrogen or a
C.sub.1-C.sub.4 alkyl. In some embodiments, R.sup.8 is hydrogen. In
some embodiments, R.sup.8 is methyl, ethyl, propyl or butyl. In
some embodiments, R.sup.8 is methyl, ethyl, or butyl. In some
embodiments, R.sup.8 is methyl. In some embodiments, R.sup.7 is
hydrogen and R.sup.8 is methyl. In some embodiments, R.sup.9 is
absent, hydrogen or hydroxyl. In some embodiments, R.sup.9 is
hydrogen. In some embodiments, R.sup.9 is hydroxyl. In some
embodiments, R.sup.9 is absent. In some embodiments, L is a linker.
In some embodiments, L is a bond. In some embodiments, L comprises
one or more linker group, each linker group being independently
selected from the group consisting of an alkylene, cycloalkylene or
--O--. In some embodiments, PG is a prostaglandin radical. Also
provided in certain embodiments herein are
pharmaceutically-acceptable salts or solvates of a compound of
Formula (VI-B).
[0101] In some embodiments, a compound provided herein has the
structure of formula (VI-C):
##STR00030##
[0102] In some embodiments, L is a linker. In some embodiments, L
is a bond. In some embodiments, L comprises one or more linker
group, each linker group being independently selected from the
group consisting of an alkylene, cycloalkylene or --O--. In some
embodiments, PG is a prostaglandin radical. Also provided in
certain embodiments herein are pharmaceutically-acceptable salts or
solvates of a compound of Formula (VI-B).
[0103] In certain embodiments, provided herein is a compound having
a prostaglandin (PG) radical of the formula (VII).
##STR00031##
[0104] In some embodiments, is a single bond or a double bond. In
some embodiments, G is OH and Y.sup.1 is hydrogen. In some
embodiments, G together with Y.sup.1 form --O--CH.sub.2--. In some
embodiments, Y.sup.2 is a bond or --CH.sub.2--. In some
embodiments, g is 1 or 2. In some embodiments, Z is --O-- or
--CH.sub.2--. In some embodiments, R.sup.6 and R.sup.6' are each
independently hydrogen, halogen or OH. In some embodiments,
R.sup.11 is --OR.sup.13, or --NR.sup.13'R.sup.13''. In some
embodiments, R.sup.13, R.sup.13' and R.sup.13'' are each
independently hydrogen or a C.sub.1-C.sub.3 alkyl. In some
embodiments, each R.sup.12 is independently halogen or haloalkyl.
In some embodiments, u is 0-5. In some embodiments, R.sup.6 and
R.sup.6' are each fluoro. In some embodiments, R.sup.6 is OH and
R.sup.6' is hydrogen. In some embodiments, Z is --O--. In some
embodiments, Z is --CH.sub.2--. In some embodiments, each R.sup.12
is F and u is 2. In some embodiments, CF.sub.3 and u is 1. In some
embodiments, u is 0. In some embodiments, u is 1. In some
embodiments, u is 2. In some embodiments, u is 3. In some
embodiments, u is 4. In some embodiments, u is 5. In some
embodiments, R.sup.11 is OH. In some embodiments, R.sup.11 is
--NHCH.sub.2CH.sub.3. In some embodiments, R.sup.11 is
--OCH(CH.sub.3).sub.2.
[0105] In some embodiments, the prostaglandin (PG) radical provided
herein has the formula (VII-A):
##STR00032##
[0106] In some embodiments, Z is --O-- or --CH.sub.2--. In some
embodiments, R.sup.6 and R.sup.6' are each independently hydrogen,
halogen or OH. In some embodiments, R.sup.11 is --OR.sup.13, or
--NR.sup.13, R.sup.13''. In some embodiments, R.sup.13, R.sup.13'
and R.sup.13'' are each independently hydrogen or a C.sub.1-C.sub.3
alkyl. In some embodiments, each R.sup.12 is independently halogen
or haloalkyl. In some embodiments, u is 0-5. In some embodiments,
R.sup.6 and R.sup.6' are each independently fluoro. In some
embodiments, R.sup.6 is OH and R.sup.6' is hydrogen. In some
embodiments, Z is --O--. In some embodiments, Z is --CH.sub.2--. In
some embodiments, R.sup.12 is F and u is 2. In some embodiments,
CF.sub.3 and u is 1. In some embodiments, u is 0. In some
embodiments, u is 1. In some embodiments, u is 2. In some
embodiments, u is 3. In some embodiments, u is 4. In some
embodiments, u is 5. In some embodiments, R.sup.11 is OH. In some
embodiments, R.sup.11 is --NHCH.sub.2CH.sub.3. In some embodiments,
R.sup.11 is --OCH(CH.sub.3).sub.2.
[0107] In some embodiments, the prostaglandin (PG) radical has the
formula (VII-B):
##STR00033##
[0108] In some embodiments, Z is --O-- or --CH.sub.2--. In some
embodiments, R.sup.6 and R.sup.6' are each independently hydrogen,
halogen or OH. In some embodiments, R.sup.11 is --OR.sup.13, or
--NR.sup.13'R.sup.13''. In some embodiments, R.sup.13, R.sup.13'
and R.sup.13'' are each independently hydrogen or a C.sub.1-C.sub.3
alkyl. In some embodiments, each R.sup.12 is independently halogen
or haloalkyl. In some embodiments, u is 0-5. In some embodiments,
R.sup.6 and R.sup.6' are each independently fluoro. In some
embodiments, R.sup.6 is OH and R.sup.6' is hydrogen. In some
embodiments, Z is --O--. In some embodiments, Z is --CH.sub.2--. In
some embodiments, R.sup.12 is F and u is 2. In some embodiments,
CF.sub.3 and u is 1. In some embodiments, u is 0. In some
embodiments, u is 1. In some embodiments, u is 2. In some
embodiments, u is 3. In some embodiments, u is 4. In some
embodiments, u is 5. In some embodiments, R.sup.11 is OH. In some
embodiments, R.sup.11 is --NHCH.sub.2CH.sub.3. In some embodiments,
R.sup.11 is --OCH(CH.sub.3).sub.2.
[0109] In some embodiments, the radical (e.g., a PG radical) is
attached to a linker (e.g., L) provided herein. In some
embodiments, the PG radical is attached to a linker (e.g., L) and
the linker is further attached to a steroid radical (e.g., provided
herein). In some embodiments, R.sup.11 is a radical (e.g., a
hydroxyl radical or an amino radical) attached to a linker (e.g., a
radical of a linker) provided herein (e.g., and the linker (e.g.,
another radical of the linker) is further attached to a steroid
radical provided herein). In some embodiments, R.sup.6 or R.sup.6'
is a radical (e.g., a hydroxyl radical) attached to a linker (e.g.,
a radical of a linker) provided herein (e.g., and the linker (e.g.,
another radical of the linker) is further attached to a steroid
radical provided herein).
[0110] In certain embodiments, provided herein is a compound having
the structure of Formula (VIII):
##STR00034##
[0111] In some embodiments, is a single bond or a double bond. In
some embodiments, L is a linker. In some embodiments, A is a
steroid radical. In some embodiments, G is OH and Y.sup.1 is
hydrogen. In some embodiments, G together with Y.sup.1 form
--O--CH.sub.2--. In some embodiments, Y.sup.2 is a bond or
--CH.sub.2--. In some embodiments, g is 1 or 2. In some
embodiments, Z is --O-- or --CH.sub.2--. In some embodiments,
R.sup.6 and R.sup.6' are each independently hydrogen, halogen or
OH. In some embodiments, R.sup.n is --OR.sup.13 or
--NR.sup.13'R.sup.13''. In some embodiments, each R.sup.12 is
independently halogen or haloalkyl. In some embodiments, R.sup.13,
R.sup.13' and R.sup.13'' are each independently hydrogen or a
C.sub.1-C.sub.3 alkyl. In some embodiments, u is 0-5. In some
embodiments, R.sup.6 and R.sup.6' are each independently fluoro. In
some embodiments, R.sup.6 is OH and R.sup.6' is hydrogen. In some
embodiments, Z is --O--. In some embodiments, Z is --CH.sub.2--. In
some embodiments, R.sup.12 is F and u is 2. In some embodiments,
R.sup.12 is CF.sub.3 and u is 1. In some embodiments, u is 0. In
some embodiments, u is 1. In some embodiments, u is 2. In some
embodiments, u is 3. In some embodiments, u is 4. In some
embodiments, u is 5. In some embodiments, R.sup.11 is OH. In some
embodiments, R.sup.11 is --NHCH.sub.2CH.sub.3. In some embodiments,
R.sup.11 is --OCH(CH.sub.3).sub.2. Provided in certain embodiments
herein are pharmaceutically-acceptable salts or solvates of a
compound of Formula (VIII).
[0112] In certain embodiments, provided herein is a compound having
the structure of Formula (VIII-A):
##STR00035##
[0113] In some embodiments, L is a linker. In some embodiments, A
is a steroid radical. In some embodiments, Z is --O-- or
--CH.sub.2--. In some embodiments, R.sup.6 and R.sup.6' are each
independently hydrogen, halogen or OH; R.sup.11 is --OR.sup.13, or
--NR.sup.13'R.sup.13''. In some embodiments, each R.sup.12 is
independently halogen or haloalkyl. In some embodiments, R.sup.13,
R.sup.13' and R.sup.13'' are each independently hydrogen or a
C.sub.1-C.sub.3 alkyl. In some embodiments, u is 0-5. In some
embodiments, R.sup.6 and R.sup.6' are each independently fluoro. In
some embodiments, R.sup.6 is OH and R.sup.6' is hydrogen. In some
embodiments, Z is --O--. In some embodiments, Z is --CH.sub.2--. In
some embodiments, R.sup.12 is F and u is 2. In some embodiments,
R.sup.12 is CF.sub.3 and u is 1. In some embodiments, u is 0. In
some embodiments, u is 1. In some embodiments, u is 2. In some
embodiments, u is 3. In some embodiments, u is 4. In some
embodiments, u is 5. In some embodiments, R.sup.11 is OH. In some
embodiments, R.sup.11 is --NHCH.sub.2CH.sub.3. In some embodiments,
R.sup.11 is --OCH(CH.sub.3).sub.2. Provided in certain embodiments
herein are pharmaceutically-acceptable salts or solvates of a
compound of Formula (VIII-A).
[0114] In certain embodiments, provided herein is a compound having
the structure of Formula (VIII-B):
##STR00036##
[0115] In some embodiments, L is a linker. In some embodiments, A
is a steroid radical. In some embodiments, Z is --O-- or
--CH.sub.2--. In some embodiments, R.sup.6 and R.sup.6' are each
independently hydrogen, halogen or OH. In some embodiments,
R.sup.11 is --OR.sup.13, or --NR.sup.13'R.sup.13''. In some
embodiments, each R.sup.12 is independently halogen or haloalkyl.
In some embodiments, R.sup.13, R.sup.13' and R.sup.13'' are each
independently hydrogen or a C.sub.1-C.sub.3 alkyl. In some
embodiments, u is 0-5. In some embodiments, R.sup.6 and R.sup.6'
are each independently fluoro. In some embodiments, R.sup.6 is OH
and R.sup.6' is hydrogen. In some embodiments, Z is --O--. In some
embodiments, Z is --CH.sub.2--. In some embodiments, R.sup.12 is F
and u is 2. In some embodiments, R.sup.12 is CF.sub.3 and u is 1.
In some embodiments, u is 0. In some embodiments, u is 1. In some
embodiments, u is 2. In some embodiments, u is 3. In some
embodiments, u is 4. In some embodiments, u is 5. In some
embodiments, R.sup.11 is OH. In some embodiments, R.sup.11 is
--NHCH.sub.2CH.sub.3. In some embodiments, R.sup.11 is
--OCH(CH.sub.3).sub.2. Provided in certain embodiments herein are
pharmaceutically-acceptable salts or solvates of a compound of
Formula (VIII-B).
[0116] In some embodiments, R.sup.11 is a radical (e.g., a hydroxyl
radical or an amino radical) attached to L. In some embodiments,
R.sup.6 or R.sup.6' is a radical (e.g., a hydroxyl radical)
attached to L. In some embodiments, L is a bond. In some
embodiments, L comprises one or more linker group, each linker
group being independently selected from the group consisting of an
alkylene, cycloalkylene or --O--.
[0117] In certain embodiments, A has the structure:
##STR00037##
[0118] In some embodiments, is a single bond or a double bond. In
some embodiments, R.sup.7 is hydrogen or halogen. In some
embodiments, R.sup.8 is a hydrogen or a C.sub.1-C.sub.4 alkyl. In
some embodiments, R.sup.9 is absent, hydrogen or hydroxyl. In some
embodiments, R.sup.7 is hydrogen. In some embodiments, R.sup.7 is
fluoro. In some embodiments, R.sup.8 is hydrogen. In some
embodiments, R.sup.8 is methyl, ethyl, propyl or butyl. In some
embodiments, R.sup.8 is methyl, ethyl or butyl. In some
embodiments, R.sup.8 is methyl. In some embodiments, R.sup.9 is
hydroxyl.
[0119] In certain embodiments, A has the structure:
##STR00038##
[0120] In some embodiments, is a single bond or a double bond. In
some embodiments, R.sup.7 is hydrogen or halogen. In some
embodiments, R.sup.8 is a hydrogen or a C.sub.1-C.sub.4 alkyl. In
some embodiments, R.sup.9 is absent, hydrogen or hydroxyl. In some
embodiments, R.sup.7 is hydrogen. In some embodiments, R.sup.7 is
fluoro. In some embodiments, R.sup.8 is hydrogen. In some
embodiments, R.sup.8 is methyl, ethyl, propyl or butyl. In some
embodiments, R.sup.8 is methyl, ethyl or butyl. In some
embodiments, R.sup.8 is methyl.
[0121] In certain embodiments, A has the structure:
##STR00039##
[0122] In some embodiments, is a single bond or a double bond. In
some embodiments, R.sup.7 is hydrogen or halogen. In some
embodiments, R.sup.8 is a hydrogen or a C.sub.1-C.sub.4 alkyl. In
some embodiments, R.sup.9 is absent, hydrogen or hydroxyl. In some
embodiments, R.sup.7 is hydrogen. In some embodiments, R.sup.7 is
fluoro. In some embodiments, R.sup.8 is hydrogen. In some
embodiments, R.sup.8 is methyl, ethyl, propyl or butyl. In some
embodiments, R.sup.8 is methyl, ethyl or butyl. In some
embodiments, R.sup.8 is methyl. In some embodiments, R.sup.9 is
hydroxyl.
[0123] In certain embodiments, A has the structure:
##STR00040##
[0124] In certain embodiments, provided herein is a compound having
the structure of Formula (IX):
##STR00041##
[0125] In certain embodiments, each is independently a single bond
or a double bond. In some embodiments, G is OH and Y.sup.1 is
hydrogen. In some embodiments, G together with Y.sup.1 form
--O--CH.sub.2--. In some embodiments, Y.sup.2 is a bond or
--CH.sub.2--. In some embodiments, g is 1 or 2. In some
embodiments, Z is --O-- or --CH.sub.2--. In some embodiments,
R.sup.6 and R.sup.6' are each independently hydrogen, halogen or
OH. In some embodiments, each R.sup.12 is independently halogen or
haloalkyl. In some embodiments, u is 0-5. In some embodiments, Z is
--O-- or --CH.sub.2--. In some embodiments, R.sup.6 and R.sup.6'
are each independently hydrogen, halogen or OH. In some
embodiments, each R.sup.12 is independently halogen or haloalkyl.
In some embodiments, R.sup.6 and R.sup.6' are each fluoro. In some
embodiments, R.sup.6 is OH and R.sup.6' is hydrogen. In some
embodiments, Z is --O--. In some embodiments, Z is --CH.sub.2--. In
some embodiments, R.sup.12 is F and u is 2. In some embodiments,
R.sup.12 is CF.sub.3 and u is 1. In some embodiments, u is 0. In
some embodiments, u is 1. In some embodiments, u is 2. In some
embodiments, u is 3. In some embodiments, u is 4. In some
embodiments, u is 5. Also provided in certain embodiments herein
are pharmaceutically-acceptable salts or solvates of a compound of
Formula (IX).
[0126] In certain embodiments, provided herein is a compound having
the structure of Formula (X):
##STR00042##
[0127] In certain embodiments, each is independently a single bond
or a double bond. In some embodiments, L is a linker. In some
embodiments, L is a bond. In some embodiments, L is --(C.dbd.O)--,
or --O-- (C.dbd.O)--. In some embodiments, G is OH and Y.sup.1 is
hydrogen. In some embodiments, G together with Y.sup.1 form
--O--CH.sub.2--. In some embodiments, Y.sup.2 is a bond or
--CH.sub.2--. In some embodiments, g is 1 or 2. In some
embodiments, Z is --O-- or --CH.sub.2--. In some embodiments,
R.sup.6 and R.sup.6' are each independently hydrogen, halogen or
OH. In some embodiments, each R.sup.12 is independently halogen or
haloalkyl. In some embodiments, u is 0-5. In some embodiments, Z is
--O-- or --CH.sub.2--. In some embodiments, R.sup.6 and R.sup.6'
are each independently hydrogen, halogen or OH. In some
embodiments, each R.sup.12 is independently halogen or haloalkyl.
In some embodiments, R.sup.6 and R.sup.6' are each independently
fluoro. In some embodiments, R.sup.6 is OH and R.sup.6' is
hydrogen. In some embodiments, Z is --O--. In some embodiments, Z
is --CH.sub.2--. In some embodiments, R.sup.12 is F and u is 2. In
some embodiments, R.sup.12 is CF.sub.3 and u is 1. In some
embodiments, u is 0. In some embodiments, u is 1. In some
embodiments, u is 2. In some embodiments, u is 3. In some
embodiments, u is 4. In some embodiments, u is 5. Also provided in
certain embodiments herein are pharmaceutically-acceptable salts or
solvates of a compound of Formula (X).
[0128] In some embodiments, a compound provided herein comprises a
steroid attached to a second agent (e.g., a prostaglandin) through
an optional linker (e.g., travoprost-anecortave), as such, forming
a heteroalkyl bond (e.g., an ester, a carbonate, etc.), such as,
whereby upon cleavage (e.g., hydrolysis) of the heteroalkyl bond,
the steroid and/or second agent are released in their free form. In
some embodiments, a steroid radical (e.g., a first radical)
provided herein (e.g., a hydroxyl radical (e.g., anecortave
desacetate radical)) is attached to an optional linker or a second
radical (e.g., a prostaglandin radical) (e.g., a hydroxyl radical,
a carboxylic radical, etc.) provided herein to form a compound
provided herein.
[0129] In some aspects, provided herein is a pharmaceutical
composition comprising any compound provided herein, such as a
compound having the structure of any one of Formula (I), Formula
(IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA),
Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula
(VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula
(VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula
(VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), or a
pharmaceutically-acceptable salt thereof. In some embodiments, the
pharmaceutical composition comprises at least one pharmaceutically
acceptable excipient. Another embodiment provides the
pharmaceutical composition, wherein the pharmaceutical composition
is suitable for ophthalmic administration. Another embodiment
provides the pharmaceutical composition, wherein the pharmaceutical
composition is suitable for intraocular ophthalmic administration.
In some embodiments, intraocular ophthalmic administration is
administration in the eye, such as intraocular, intracameral,
intravitreal, suprachoroidal, punctal, retrobulbar, or
subconjunctival.
[0130] Another embodiment provides the pharmaceutical composition,
wherein the pharmaceutical composition is suitable for subcutaneous
administration. Another embodiment provides the pharmaceutical
composition, wherein the pharmaceutical composition is suitable for
intraspinal administration.
[0131] Another embodiment provides a pharmaceutical implant or
article comprising any compound provided herein, such as a compound
having the structure of any one of Formula (I), Formula (IA),
Formula (IB), Formula (IC), Formula (II), Formula (IIA), Formula
(IIB), Formula (III), Formula (IV), or Formula (V), or a
pharmaceutically acceptable salt thereof.
[0132] In some embodiments, the implant or article comprises at
least 50 wt. % (at least 60 wt. %, at least 70 wt. %, at least 80
wt. %, at least 90 wt. %, at least 95 wt. %, at least 98 wt. %, or
the like) of the compound and/or pharmaceutically acceptable salt
thereof. In some instances, an article or implant provided herein
comprises at least 50 wt. % of a compound as described herein. In
some instances, an article or implant provided herein comprises at
least 70 wt. % of a compound as described herein. In some
instances, an article or implant provided herein comprises at least
90 wt. % of a compound as described herein. In some instances, an
article or implant provided herein comprises at least 95 wt. % of a
compound as described herein. In some instances, an article or
implant provided herein comprises at least 99 wt. % of a compound
as described herein. In some instances, an article or implant
provided herein comprises an additional component, such as up to 20
wt. %, 15 wt. %, 10 wt. %, 5 wt. %, 1 wt. %, 0.1 wt. %, 0.01 wt. %,
or less of the additional component. In some embodiments, an
article or implant provided herein comprises up to 5 wt. % (e.g.,
up to 1 wt. %, up to 0.1 wt. %, or less) a first radical in its
free form (e.g., a steroid (such as described herein)), a second
radical in its free form (e.g., a prostaglandin (such as described
herein), or a combination thereof (e.g., as an impurity, such as
residual from a manufacturing process, such as provided herein). In
some embodiments, an article or implant provided herein comprises
up to 5 wt. % (e.g., up to 1 wt. %, up to 0.1 wt. %, or less) of an
impurity, such as residual from a manufacturing process, such as
provided herein. In some embodiments, an article or implant
provided herein comprises up to 5 wt. % (e.g., up to 1 wt. %, up to
0.1 wt. %, or less) of a steroid (as described herein).
[0133] In certain embodiments, the implant or article releases a
(e.g., active) group therefrom, such as when implanted into or
otherwise administered to an individual (or when placed into an
aqueous medium (e.g., aqueous buffer solution), serum, or other
physiological medium, such as at a physiological temperature, such
as 37.degree. C.). In some instances, a (e.g., active) group
released is the free form of the first radical and/or the second
radical. In certain instances, a (e.g., active) group released from
the compound is an active fragment or metabolite of the first
and/or second radical. In some embodiments, the implant or article
undergoes surface erosion to release the compound, the first
radical, and/or the second radical (or an (e.g., active) fragment
or radical thereof). In some embodiments, first radical and the
second radical are released from the pharmaceutical implant or
article at near zero-order in solution (e.g., buffer solution,
serum, biological environment, in vivo, or the like). In some
embodiments, the first radical and the second radical (or an (e.g.,
active) fragment or metabolite thereof) are released from the
pharmaceutical implant or article at 37.degree. C. in 100% bovine
serum or at 37.degree. C. in phosphate buffered saline (PBS) at a
rate such that t.sub.10 is greater than or equal to 1/10 of
t50.
[0134] In some embodiments, a compound or a pharmaceutical
composition comprising any compound provided herein, such as a
compound having the structure of any one of Formula (I), Formula
(IA), Formula (IB), Formula (IC), Formula (II), Formula (IIA),
Formula (IIB), Formula (III), Formula (IV), or Formula (V), or a
pharmaceutically acceptable salt thereof. In certain embodiments,
the composition further comprises an amount of a free form of any
radical provided herein, or a combination thereof, such as a free
form of a radical having the (e.g., steroid) structure of any one
of Formula (I), Formula (IA), Formula (IB), Formula (IC), Formula
(II), Formula (IIA), Formula (IIB), Formula (IC), Formula (II),
Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula
(V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C),
Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII),
Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X)
(such as wherein the free form is the structure, wherein the free
form (e.g., --COO-- or --O-- thereof) has a negative charge (e.g.,
as --O.sup.-) or an H (e.g., as --OH), rather than being connected
to a linker and/or other (first or second) radical). In some
embodiments, a composition provided herein comprises a (e.g.,
weight or molar) ratio of a compound provided herein to a free form
of any radical provided herein, or a combination thereof, such as a
free form of a radical having the structure of any one of Formula
(I), Formula (IA), Formula (IB), Formula (IC), Formula (II),
Formula (IIA), Formula (IIB), Formula (IC), Formula (II), Formula
(IIA), Formula (IIB), Formula (III), Formula (IV), Formula (V),
Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C),
Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII),
Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X),
or a pharmaceutically acceptable salt thereof (e.g., wherein the
free form is the structure, wherein the free form (e.g., --COO-- or
--O-- thereof) has a negative charge (e.g., as --O.sup.-) or an H
(e.g., as --OH)), rather than being connected to a linker and/or
other (first or second) radical, of about 1:99 to about 100:0
(e.g., the amount of the free form of the radical relative to the
overall amount of free form of the radical plus the conjugate is
between 0% (weight or molar) and 99%). In some embodiments, the
relative amount of the free form of the radical is 0% to about 50%,
such 0% to about 20%, 0% to about 10%, about 0.1% to about 10%,
about 0.1% to about 5%, less than 5%, less than 2.5%, less than 2%,
or the like (percentages being weight/weight or mole/mole
percentages). Further, in some instances, compounds provided herein
release free form of any radical provided herein, or a combination
thereof, such as a free form of a structure of a compound having
the structure of any one of Formula (I), Formula (IA), Formula
(IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB),
Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula
(III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A),
Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A),
Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula
(VIII-B), Formula (IX), or Formula (X) (e.g., wherein the free form
(e.g., --COO-- or --O-- thereof) has a negative charge (e.g., as
--O.sup.-) or H (e.g., as --OH), rather than being connected to a
linker and/or other (first or second) radical)), such as when
administered to an individual (e.g., ocular (e.g., intraocular),
subcutaneous, or intraspinal administration).
[0135] In certain embodiments, provided herein is a method of
treating an ophthalmic disease or disorder in a patient in need
thereof, comprising administering to the patient a composition
comprising any compound provided herein, such as a compound having
the structure of any one of Formula (I), Formula (IA), Formula
(IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB),
Formula (III), Formula (IV), or Formula (V), or a pharmaceutically
acceptable salt thereof. Another embodiment provides the method
wherein the ophthalmic disease or disorder is glaucoma. Another
embodiment provides the method wherein the ophthalmic disease or
disorder is selected from the group consisting of ocular
inflammation, diabetic macular edema, posterior inflammation,
anterior inflammation, macular degeneration (e.g., wet macular
degeneration (AMD)), post-cataract surgery, and retinal vein
occlusion.
[0136] In certain embodiments, provided herein is a method of
treating a medical indication or abnormality (e.g., ocular or
neurological disease and/or disorder), the method comprising
administering a therapeutically effective amount of a compound or
composition provided herein. In some embodiments, a composition
provided herein (e.g., used in a method provided herein) comprises
a compound provided herein in a therapeutically effective amount
(e.g., at a concentration effective to treat an ophthalmic disease
or disorder in an individual in need thereof, the method comprising
administering to the individual a compound, pharmaceutically
acceptable salt, implant, article, or composition having the
structure of any one of Formula (I), Formula (IA), Formula (IB),
Formula (IC), Formula (II), Formula (IIA), Formula (IIB), Formula
(III), Formula (IV), Formula (V), Formula (VI), Formula (VI-A),
Formula (VI-B), Formula (VI-C), Formula (VII), Formula (VII-A),
Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula
(VIII-B), Formula (IX), or Formula (X). In some embodiments, a
composition provided herein (e.g., used in a method provided
herein) comprises a compound provided herein in a therapeutically
effective amount (e.g., at a concentration effective to treat
glaucoma, inflammation, and/or lower intraocular pressure) in the
eye. In certain embodiments, a (e.g., pharmaceutical and/or
ophthalmic) composition provided herein comprises about 0.1 wt. %
to about 10 wt. % of a compound provided herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0137] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized, and the accompanying drawings (also "Figure" and
"FIG." herein), of which:
[0138] FIG. 1 shows the chemical structure for a prodrug ester and
an active pharmaceutical ingredient for a prostaglandin (e.g.,
travaprost (FIG. 1A) and travoprost acid (FIG. 1B), respectively)
and a steroid (e.g., anecortave acetate (FIG. 1C) and anecortave
desacetate (FIG. 1D), respectively) exemplified herein.
[0139] FIG. 2 shows the chemical structure (FIG. 2A) and the heat
processed pellet (FIG. 2B) of a steroid-prostaglandin heterodimer
(travoprost-anecortave, Compound 1) exemplified herein. FIG. 2C
shows the drug release profile for Compound 1 (pellet) in fetal
bovine serum (FBS) over 15 days. FIG. 2D represents the 15-day
progression of the surface erosion drug release profile for the
pellet of Compound 1 in FBS.
[0140] FIG. 3 shows the chemical structure (FIG. 3A) and the heat
processed pellet (FIG. 3B) of a steroid-prostaglandin heterodimer
(travoprost-dexamethasone, Compound 2) exemplified herein. FIG. 3C
shows the drug release profile for Compound 2 (pellet) in
phosphate-buffered saline (PBS) over 30 days. FIG. 3D represents
the 30-day progression of the (e.g., surface erosion) drug release
profile and swelling profile for the pellet of Compound 2 in
PBS.
[0141] FIG. 4 shows the chemical structure for a prodrug ester and
an active pharmaceutical ingredient for a prostaglandin (e.g.,
latanoprost (FIG. 4A) and latanoprost acid (FIG. 4B), respectively)
exemplified herein.
[0142] FIG. 5 shows the chemical structure (FIG. 5A) and the heat
processed pellet (FIG. 5B) of a steroid-prostaglandin heterodimer
(latanoprost-dexamethasone, Compound 3) exemplified herein. FIG. 5C
shows the drug release profile for Compound 3 (pellet) in fetal
bovine serum (FBS) over 30 days. FIG. 5D represents the 30-day
progression of the (e.g., surface erosion) drug release profile and
swelling profile for the pellet of Compound 3 in FBS.
[0143] FIG. 6 shows the chemical structure (FIG. 6A) of a
steroid-prostaglandin heterodimer (latanoprost-estrone, Compound 4)
exemplified herein. FIG. 6B shows the drug release profile for
Compound 4 (coating on polymeric substrate) in fetal bovine serum
(FBS) over 8 days. FIG. 6C represents the 7-day progression of the
surface coating drug release of Compound 4 in FBS.
[0144] FIG. 7 shows the chemical structure (FIG. 7A) and the heat
processed pellet (FIG. 7B) of a steroid-prostaglandin heterodimer
(bimatoprost-anecortave, Compound 5) exemplified herein. FIG. 7C
shows the drug release profile for Compound 5 (pellet) in fetal
bovine serum (FBS) over 25 days. FIG. 7D represents the 28-day
progression of the (e.g., surface erosion) drug release profile for
the pellet of Compound 5 in FBS.
[0145] FIG. 8 shows the chemical structure (FIG. 8A) and the heat
processed pellet (FIG. 8B) of a steroid-prostaglandin heterodimer
(latanoprost-anecortave, Compound 6) exemplified herein. FIG. 8C
shows the drug release profile for each of latanoprost acid
(.circle-solid.) and anecortave desacetate (o) (pellet) in fetal
bovine serum (FBS) over 30 days. FIG. 8D represents the 28-day
progression of the (e.g., surface erosion) drug release profile for
the pellet of Compound 6 in FBS.
[0146] FIG. 9 shows the chemical structure (FIG. 9A) and the heat
processed pellet (FIG. 9B) of a steroid-prostaglandin heterodimer
(tafluprost-anecortave, Compound 7) exemplified herein. FIG. 9C
shows the drug release profile for Compound 7 (pellet) in fetal
bovine serum (FBS) over 30 days. FIG. 9D represents the 28-day
progression of the (e.g., surface erosion) drug release profile for
the pellet of Compound 7 in FBS.
[0147] FIG. 10 shows an extruded rod of a steroid-prostaglandin
heterodimer (bimatoprost-anecortave, Compound 5) exemplified herein
(FIG. 10A). FIG. 10B shows the drug release profile of Compound 5
(extruded rod) in fetal bovine serum (FBS) over 30 days. FIG. 10C
represents the 30-day progression of the (e.g., surface erosion)
drug release profile for the extruded rod of Compound 5 in FBS.
[0148] FIG. 11 shows an extruded rod of a steroid-prostaglandin
heterodimer (travoprost-anecortave, Compound 1) exemplified herein
(FIG. 11A). FIG. 11B shows the drug release profile of Compound 1
(extruded rod) in fetal bovine serum (FBS) over 30 days.
[0149] FIG. 12 shows an extruded rod of a steroid-prostaglandin
heterodimer (latanoprost-anecortave, Compound 6) exemplified herein
(FIG. 12A). FIG. 12B shows the drug release profile of Compound 6
(extruded rod) in fetal bovine serum (FBS) over 70 days. FIG. 12C
represents the 70-day progression of the (e.g., surface erosion)
drug release profile for the extruded rod of Compound 6 in FBS.
[0150] FIG. 13 shows an extruded rod of a steroid-prostaglandin
heterodimer (tafluprost-anecortave, Compound 7) exemplified herein
(FIG. 13A). FIG. 13B shows the drug release profile of Compound 7
(extruded rod) in fetal bovine serum (FBS) over 100 days. FIG. 13C
represents the 100-day progression of the (e.g., surface erosion)
drug release profile for the extruded rod of Compound 7 in FBS.
[0151] FIG. 14 shows an extruded rod of a steroid-prostaglandin
heterodimer (bimatoprost-anecortave, Compound 5) exemplified herein
in a rabbit eye.
[0152] FIG. 15 shows the chemical structure (FIG. 15A) and the heat
processed pellet (FIG. 15B) of a steroid-prostaglandin heterodimer
(travoprost-cyclohexanedimethanol-anecortave, Compound 8)
exemplified herein. FIG. 15C shows the drug release profile for
Compound 8 (pellet) in fetal bovine serum (FBS) over 8 days.
[0153] FIG. 16 shows the chemical structure of a
steroid-prostaglandin heterodimer (travoprost-naltrexone, Compound
9) exemplified herein.
[0154] FIG. 17 shows the chemical structure of a
steroid-prostaglandin heterodimer (timolol-deoxycholic acid,
Compound 10) exemplified herein.
[0155] FIG. 18 shows purity of Compound 5 before
(pre-sterilization) or post sterilization of Compound 5 in ethylene
oxide, or by gamma-radiation or E-beam.
[0156] FIG. 19 shows the chemical structure (FIG. 19A) and the heat
processed pellet (FIG. 19B) of a steroid-prostaglandin heterodimer
(Bimatoprost (C.sub.15)-anecortave, Compound 11) exemplified
herein.
DETAILED DESCRIPTION OF THE INVENTION
Certain Definitions
[0157] As used herein and in the appended claims, the singular
forms "a," "and," and "the" include plural referents unless the
context clearly dictates otherwise. Thus, for example, reference to
"an agent" includes a plurality of such agents, and reference to
"the cell" includes reference to one or more cells (or to a
plurality of cells) and equivalents thereof known to those skilled
in the art, and so forth. When ranges are used herein for physical
properties, such as molecular weight, or chemical properties, such
as chemical formulae, all combinations and subcombinations of
ranges and specific embodiments therein are intended to be
included. The term "about" when referring to a number or a
numerical range means that the number or numerical range referred
to is an approximation within experimental variability (or within
statistical experimental error), and thus the number or numerical
range may vary between 1% and 15% of the stated number or numerical
range. The term "comprising" (and related terms such as "comprise"
or "comprises" or "having" or "including") is not intended to
exclude that in other certain embodiments, for example, an
embodiment of any composition of matter, composition, method, or
process, or the like, described herein, may "consist of" or
"consist essentially of" the described features.
[0158] "Amino" refers to the --NH.sub.2 radical (dihydroamino).
"Alkylamino" refers to an amino group which is substituted by one
or more alkyl groups as defined herein. "Arylamino" referrers to an
amino group which substituted by one or more aryl groups as defined
herein.
[0159] "Cyano" refers to the --CN radical.
[0160] "Nitro" refers to the --NO.sub.2 radical.
[0161] "Oxa" refers to the --O-- radical.
[0162] "Oxo" refers to the .dbd.O radical.
[0163] "Thioxo" refers to the .dbd.S radical.
[0164] "Imino" refers to the .dbd.N--H radical.
[0165] "Oximo" refers to the .dbd.N--OH radical.
[0166] "Hydrazino" refers to the .dbd.N--NH.sub.2 radical.
[0167] "Hydrogen" refers to the "H" radical.
[0168] "Alkyl" generally refers to a straight or branched
hydrocarbon chain radical consisting solely of carbon and hydrogen
atoms, such as having from one to fifteen carbon atoms (e.g.,
C.sub.1-C.sub.15 alkyl). Unless otherwise stated, alkyl is
saturated or unsaturated (e.g., an alkenyl, which comprises at
least one carbon-carbon double bond, or alkynyl, which comprises at
least one carbon-carbon triple bond). Disclosures provided herein
of an "alkyl" are intended to include independent recitations of a
saturated "alkyl," or unsaturated alkyl (alkenyl, alkynyl), unless
otherwise stated. Alkyl groups described herein are generally
monovalent, but may also be divalent (which may also be described
herein as "alkylene" or "alkylenylene", or alkynylene groups). In
certain embodiments, an alkyl comprises one to thirteen carbon
atoms (e.g., C.sub.1-C.sub.13 alkyl). In certain embodiments, an
alkyl comprises one to eight carbon atoms (e.g., C.sub.1-C.sub.8
alkyl). In other embodiments, an alkyl comprises one to five carbon
atoms (e.g., C.sub.1-C.sub.5 alkyl). In other embodiments, an alkyl
comprises one to four carbon atoms (e.g., C.sub.1-C.sub.4 alkyl).
In other embodiments, an alkyl comprises one to three carbon atoms
(e.g., C.sub.1-C.sub.3 alkyl). In other embodiments, an alkyl
comprises one to two carbon atoms (e.g., C.sub.1-C.sub.2 alkyl). In
other embodiments, an alkyl comprises one carbon atom (e.g.,
C.sub.1 alkyl). In other embodiments, an alkyl comprises five to
fifteen carbon atoms (e.g., C.sub.5-C.sub.15 alkyl). In other
embodiments, an alkyl comprises five to eight carbon atoms (e.g.,
C.sub.5-C.sub.8alkyl). In other embodiments, an alkyl comprises two
to five carbon atoms (e.g., C.sub.2-C.sub.5 alkyl). In other
embodiments, an alkyl comprises three to five carbon atoms (e.g.,
C.sub.3-C.sub.5 alkyl). In other embodiments, the alkyl group is
selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl
(iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl),
2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl),
1-pentyl (n-pentyl). The alkyl is attached to the rest of the
molecule by a single bond. In general, alkyl groups are each
independently substituted or unsubstituted. Each recitation of
"alkyl" provided herein, unless otherwise stated, includes a
specific and explicit recitation of an unsaturated "alkyl" group.
Similarly, unless stated otherwise specifically in the
specification, an alkyl group is optionally substituted by one or
more of the following substituents: halo, cyano, nitro, oxo,
thioxo, imino, oximo, trimethylsilanyl, --OR.sup.a, --SR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)OR.sup.a,
--OC(O)--N(R.sup.a).sub.2, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2), --S(O).sub.tR.sup.a
(where t is 1 or 2) and --S(O).sub.tN(R.sup.a).sub.2 (where t is 1
or 2) where each R.sup.a is independently hydrogen, alkyl
(optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl),
carbocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), aryl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heterocyclylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heteroaryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl), or heteroarylalkyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl).
[0169] "Alkoxy" refers to a radical bonded through an oxygen atom
of the formula --O-alkyl, where alkyl is an alkyl chain as defined
above.
[0170] "Alkenyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one carbon-carbon double bond, and having from
two to twelve carbon atoms. In certain embodiments, an alkenyl
comprises two to eight carbon atoms. In other embodiments, an
alkenyl comprises two to four carbon atoms. The alkenyl is
optionally substituted as described for "alkyl" groups.
[0171] "Alkynyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one carbon-carbon triple bond, and having from
two to twelve carbon atoms. In certain embodiments, an alkynyl
comprises two to eight carbon atoms. In other embodiments, an
alkynyl comprises two to four carbon atoms. The alkenyl is
optionally substituted as described for "alkyl" groups.
[0172] "Alkylene" or "alkylene chain" generally refers to a
straight or branched divalent alkyl group linking the rest of the
molecule to a radical group, such as having from one to twelve
carbon atoms, for example, methylene, ethylene, propylene,
i-propylene, n-butylene, and the like. Unless stated otherwise
specifically in the specification, an alkylene chain is optionally
substituted as described for alkyl groups herein.
[0173] The term "article," as used herein, generally refers to a
pharmaceutical composition that is machined, molded,
heat-processed, emulsion-processed, electrospun, electrosprayed,
blow molded, or extruded to form a fiber, fiber mesh, woven fabric,
non-woven fabric, film, surface coating, pellet, cylinder, rod,
microparticle, nanoparticle, or another shaped article.
[0174] "Aryl" refers to a radical derived from an aromatic
monocyclic or multicyclic hydrocarbon ring system by removing a
hydrogen atom from a ring carbon atom. The aromatic monocyclic or
multicyclic hydrocarbon ring system contains only hydrogen and
carbon from five to eighteen carbon atoms, where at least one of
the rings in the ring system is fully unsaturated, i.e., it
contains a cyclic, delocalized (4n+2) .pi.-electron system in
accordance with the Huckel theory. The ring system from which aryl
groups are derived include, but are not limited to, groups such as
benzene, fluorene, indane, indene, tetralin and naphthalene. Unless
stated otherwise specifically in the specification, the term "aryl"
or the prefix "ar-" (such as in "aralkyl") is meant to include aryl
radicals optionally substituted by one or more substituents
independently selected from alkyl, alkenyl, alkynyl, halo,
fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted carbocyclyl,
optionally substituted carbocyclylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.b--OR.sup.a, --R.sup.b--OC(O)--R.sup.a,
--R.sup.b--OC(O)--OR.sup.a, --R.sup.b--OC(O)--N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a).sub.2, --R.sup.b--C(O)R.sup.a,
--R.sup.b--C(O)OR.sup.a, --R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aryl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aralkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heteroaryl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), each R.sup.b is independently a
direct bond or a straight or branched alkylene or alkenylene chain,
and R.sup.c is a straight or branched alkylene or alkenylene chain,
and where each of the above substituents is unsubstituted unless
otherwise indicated.
[0175] "Aralkyl" or "aryl-alkyl" refers to a radical of the formula
--R.sup.c-aryl where R.sup.c is an alkylene chain as defined above,
for example, methylene, ethylene, and the like. The alkylene chain
part of the aralkyl radical is optionally substituted as described
above for an alkylene chain. The aryl part of the aralkyl radical
is optionally substituted as described above for an aryl group.
[0176] "Carbocyclyl" or "cycloalkyl" refers to a stable
non-aromatic monocyclic or polycyclic hydrocarbon radical
consisting solely of carbon and hydrogen atoms, which includes
fused or bridged ring systems, having from three to fifteen carbon
atoms. In certain embodiments, a carbocyclyl comprises three to ten
carbon atoms. In other embodiments, a carbocyclyl comprises five to
seven carbon atoms. The carbocyclyl is attached to the rest of the
molecule by a single bond. Carbocyclyl or cycloalkyl is saturated
(i.e., containing single C--C bonds only) or unsaturated (i.e.,
containing one or more double bonds or triple bonds). Examples of
saturated cycloalkyls include, e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An
unsaturated carbocyclyl is also referred to as "cycloalkenyl."
Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl,
cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic
carbocyclyl radicals include, for example, adamantyl, norbornyl
(i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,
7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise
stated specifically in the specification, the term "carbocyclyl" is
meant to include carbocyclyl radicals that are optionally
substituted by one or more substituents independently selected from
alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted carbocyclyl, optionally substituted
carbocyclylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.b--OR.sup.a,
--R.sup.b--OC(O)--R.sup.a, --R.sup.b--OC(O)--OR.sup.a,
--R.sup.b--OC(O)--N(R.sup.a).sub.2, --R.sup.b--N(R.sup.a).sub.2,
--R.sup.b--C(O)R.sup.a, --R.sup.b--C(O)OR.sup.a,
--R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)O R.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,--R.sup.b--N(R.sup.a)S(O).sub.t-
R.sup.a (where t is 1 or 2), --R.sup.b--S(O).sub.tR.sup.a (where t
is 1 or 2), --R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aryl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aralkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heteroaryl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), each R.sup.b is independently a
direct bond or a straight or branched alkylene or alkenylene chain,
and R.sup.c is a straight or branched alkylene or alkenylene chain,
and where each of the above substituents is unsubstituted unless
otherwise indicated.
[0177] "Carbocyclylalkyl" refers to a radical of the formula
--R.sup.c-carbocyclyl where R.sup.c is an alkylene chain as defined
above. The alkylene chain and the carbocyclyl radical is optionally
substituted as defined above.
[0178] "Carbocyclylalkenyl" refers to a radical of the formula
--R.sup.c-carbocyclyl where R.sup.c is an alkenylene chain as
defined above. The alkenylene chain and the carbocyclyl radical is
optionally substituted as defined above.
[0179] "Carbocyclylalkynyl" refers to a radical of the formula
--R.sup.c-carbocyclyl where R.sup.c is an alkynylene chain as
defined above. The alkynylene chain and the carbocyclyl radical is
optionally substituted as defined above.
[0180] "Carbocyclylalkoxy" refers to a radical bonded through an
oxygen atom of the formula --O--R.sup.c-carbocyclyl where R.sup.c
is an alkylene chain as defined above. The alkylene chain and the
carbocyclyl radical is optionally substituted as defined above.
[0181] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo
substituents.
[0182] "Fluoroalkyl" refers to an alkyl radical, as defined above,
that is substituted by one or more fluoro radicals, as defined
above, for example, trifluoromethyl, difluoromethyl, fluoromethyl,
2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
In some embodiments, the alkyl part of the fluoroalkyl radical is
optionally substituted as defined above for an alkyl group.
[0183] The term "heteroalkyl" refers to an alkyl group as defined
above in which one or more skeletal carbon atoms of the alkyl are
substituted with a heteroatom (with the appropriate number of
substituents or valencies--for example, --CH.sub.2-- may be
replaced with --NH-- or --O--). For example, each substituted
carbon atom is independently substituted with a heteroatom, such as
wherein the carbon is substituted with a nitrogen, oxygen,
selenium, or other suitable heteroatom. In some instances, each
substituted carbon atom is independently substituted for an oxygen,
nitrogen (e.g. --NH--, --N(alkyl)-, or --N(aryl)- or having another
substituent contemplated herein), or sulfur (e.g. --S--,
--S(.dbd.O)--, or --S(.dbd.O).sub.2--). In some embodiments, a
heteroalkyl is attached to the rest of the molecule at a carbon
atom of the heteroalkyl. In some embodiments, a heteroalkyl is
attached to the rest of the molecule at a heteroatom of the
heteroalkyl. In some embodiments, a heteroalkyl is a
C.sub.1-C.sub.18 heteroalkyl. In some embodiments, a heteroalkyl is
a C.sub.1-C.sub.12 heteroalkyl. In some embodiments, a heteroalkyl
is a C.sub.1-C.sub.6 heteroalkyl. In some embodiments, a
heteroalkyl is a C.sub.1-C.sub.4 heteroalkyl. Representative
heteroalkyl groups include, but are not limited to --OCH.sub.2OMe,
or --CH.sub.2CH.sub.2OMe. In some embodiments, heteroalkyl includes
alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, aminoalkyl,
heterocycloalkyl, heterocycloalkyl, and heterocycloalkylalkyl, as
defined herein. Unless stated otherwise specifically in the
specification, a heteroalkyl group is optionally substituted as
defined above for an alkyl group.
[0184] "Heteroalkylene" refers to a divalent heteroalkyl group
defined above which links one part of the molecule to another part
of the molecule. Unless stated specifically otherwise, a
heteroalkylene is optionally substituted, as defined above for an
alkyl group.
[0185] "Heterocyclyl" refers to a stable 3- to 18-membered
non-aromatic ring radical that comprises two to twelve carbon atoms
and from one to six heteroatoms selected from nitrogen, oxygen and
sulfur. Unless stated otherwise specifically in the specification,
the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or
tetracyclic ring system, which optionally includes fused or bridged
ring systems. The heteroatoms in the heterocyclyl radical are
optionally oxidized. One or more nitrogen atoms, if present, are
optionally quaternized. The heterocyclyl radical is partially or
fully saturated. The heterocyclyl is attached to the rest of the
molecule through any atom of the ring(s). Examples of such
heterocyclyl radicals include, but are not limited to, dioxolanyl,
thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,
imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,
octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,
piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,
quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,
tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,
1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated
otherwise specifically in the specification, the term
"heterocyclyl" is meant to include heterocyclyl radicals as defined
above that are optionally substituted by one or more substituents
selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted carbocyclyl,
optionally substituted carbocyclylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.b--OR.sup.a, --R.sup.b--OC(O)--R.sup.a,
--R.sup.b--OC(O)--OR.sup.a, --R.sup.b--OC(O)--N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a).sub.2, --R.sup.b--C(O)R.sup.a,
--R.sup.b--C(O)OR.sup.a, --R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aryl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aralkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heteroaryl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), each R.sup.b is independently a
direct bond or a straight or branched alkylene or alkenylene chain,
and R.sup.c is a straight or branched alkylene or alkenylene chain,
and where each of the above substituents is unsubstituted unless
otherwise indicated.
[0186] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a
heterocyclyl radical as defined above containing at least one
nitrogen and where the point of attachment of the heterocyclyl
radical to the rest of the molecule is through a nitrogen atom in
the heterocyclyl radical. An N-heterocyclyl radical is optionally
substituted as described above for heterocyclyl radicals. Examples
of such N-heterocyclyl radicals include, but are not limited to,
1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl,
pyrazolidinyl, imidazolinyl, and imidazolidinyl.
[0187] "C-heterocyclyl" or "C-attached heterocyclyl" refers to a
heterocyclyl radical as defined above containing at least one
heteroatom and where the point of attachment of the heterocyclyl
radical to the rest of the molecule is through a carbon atom in the
heterocyclyl radical. A C-heterocyclyl radical is optionally
substituted as described above for heterocyclyl radicals. Examples
of such C-heterocyclyl radicals include, but are not limited to,
2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or
3-pyrrolidinyl, and the like.
[0188] "Heterocyclylalkyl" refers to a radical of the formula
--R.sup.c-heterocyclyl where R.sup.c is an alkylene chain as
defined above. If the heterocyclyl is a nitrogen-containing
heterocyclyl, the heterocyclyl is optionally attached to the alkyl
radical at the nitrogen atom. The alkylene chain of the
heterocyclylalkyl radical is optionally substituted as defined
above for an alkylene chain. The heterocyclyl part of the
heterocyclylalkyl radical is optionally substituted as defined
above for a heterocyclyl group.
[0189] "Heterocyclylalkoxy" refers to a radical bonded through an
oxygen atom of the formula --O--R.sup.c-heterocyclyl where R.sup.c
is an alkylene chain as defined above. If the heterocyclyl is a
nitrogen-containing heterocyclyl, the heterocyclyl is optionally
attached to the alkyl radical at the nitrogen atom. The alkylene
chain of the heterocyclylalkoxy radical is optionally substituted
as defined above for an alkylene chain. The heterocyclyl part of
the heterocyclylalkoxy radical is optionally substituted as defined
above for a heterocyclyl group.
[0190] "Heteroaryl" refers to a radical derived from a 3- to
18-membered aromatic ring radical that comprises two to seventeen
carbon atoms and from one to six heteroatoms selected from
nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical
is a monocyclic, bicyclic, tricyclic or tetracyclic ring system,
wherein at least one of the rings in the ring system is fully
unsaturated, i.e., it contains a cyclic, delocalized (4n+2)
.pi.-electron system in accordance with the Huckel theory.
Heteroaryl includes fused or bridged ring systems. The
heteroatom(s) in the heteroaryl radical is optionally oxidized. One
or more nitrogen atoms, if present, are optionally quaternized. The
heteroaryl is attached to the rest of the molecule through any atom
of the ring(s). Examples of heteroaryls include, but are not
limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl,
1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl,
benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl,
1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl,
benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl,
benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl),
benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,
benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,
cyclopenta[d]pyrimidinyl,
6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,
5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl,
dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl,
furo[3,2-c]pyridinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl,
imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl,
isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,
5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,
1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
oxiranyl, 5,6,6.alpha.,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,
1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,
phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,
pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl,
pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl,
pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,
tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,
5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,
5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl,
thiadiazolyl, triazolyl, tetrazolyl, triazinyl,
thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl,
thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless
stated otherwise specifically in the specification, the term
"heteroaryl" is meant to include heteroaryl radicals as defined
above which are optionally substituted by one or more substituents
selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,
haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally
substituted aryl, optionally substituted aralkyl, optionally
substituted aralkenyl, optionally substituted aralkynyl, optionally
substituted carbocyclyl, optionally substituted carbocyclylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl, optionally substituted heteroaryl, optionally
substituted heteroarylalkyl, --R.sup.b--OR.sup.a,
--R.sup.b--OC(O)--R.sup.a, --R.sup.b--OC(O)--OR.sup.a,
--R.sup.b--OC(O)--N(R.sup.a).sub.2, --R.sup.b--N(R.sup.a).sub.2,
--R.sup.b--C(O)R.sup.a, --R.sup.b--C(O)OR.sup.a,
--R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R.sup.c--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aryl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aralkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heteroaryl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), each R.sup.b is independently a
direct bond or a straight or branched alkylene or alkenylene chain,
and R.sup.c is a straight or branched alkylene or alkenylene chain,
and where each of the above substituents is unsubstituted unless
otherwise indicated.
[0191] "N-heteroaryl" refers to a heteroaryl radical as defined
above containing at least one nitrogen and where the point of
attachment of the heteroaryl radical to the rest of the molecule is
through a nitrogen atom in the heteroaryl radical. An N-heteroaryl
radical is optionally substituted as described above for heteroaryl
radicals.
[0192] "C-heteroaryl" refers to a heteroaryl radical as defined
above and where the point of attachment of the heteroaryl radical
to the rest of the molecule is through a carbon atom in the
heteroaryl radical. A C-heteroaryl radical is optionally
substituted as described above for heteroaryl radicals.
[0193] "Heteroarylalkyl" refers to a radical of the formula
--R.sup.c-heteroaryl, where R.sup.c is an alkylene chain as defined
above. If the heteroaryl is a nitrogen-containing heteroaryl, the
heteroaryl is optionally attached to the alkyl radical at the
nitrogen atom. The alkylene chain of the heteroarylalkyl radical is
optionally substituted as defined above for an alkylene chain. The
heteroaryl part of the heteroarylalkyl radical is optionally
substituted as defined above for a heteroaryl group.
[0194] "Heteroarylalkoxy" refers to a radical bonded through an
oxygen atom of the formula --O--R.sup.c-heteroaryl, where R.sup.c
is an alkylene chain as defined above. If the heteroaryl is a
nitrogen-containing heteroaryl, the heteroaryl is optionally
attached to the alkyl radical at the nitrogen atom. The alkylene
chain of the heteroarylalkoxy radical is optionally substituted as
defined above for an alkylene chain. The heteroaryl part of the
heteroarylalkoxy radical is optionally substituted as defined above
for a heteroaryl group.
[0195] The compounds disclosed herein, in some embodiments, contain
one or more asymmetric centers and thus give rise to enantiomers,
diastereomers, and other stereoisomeric forms that are defined, in
terms of absolute stereochemistry, as (R)- or (S)-. Unless stated
otherwise, it is intended that all stereoisomeric forms of the
compounds disclosed herein are contemplated by this disclosure.
When the compounds described herein contain alkene double bonds,
and unless specified otherwise, it is intended that this disclosure
includes both E and Z geometric isomers (e.g., cis or trans.)
Likewise, all possible isomers, as well as their racemic and
optically pure forms, and all tautomeric forms are also intended to
be included. The term "geometric isomer" refers to E or Z geometric
isomers (e.g., cis or trans) of an alkene double bond. The term
"positional isomer" refers to structural isomers around a central
ring, such as ortho-, meta-, and para-isomers around a benzene
ring.
[0196] In general, optionally substituted groups are each
independently substituted or unsubstituted. Each recitation of an
optionally substituted group provided herein, unless otherwise
stated, includes an independent and explicit recitation of both an
unsubstituted group and a substituted group (e.g., substituted in
certain embodiments, and unsubstituted in certain other
embodiments). Unless otherwise stated, substituted groups may be
substituted by one or more of the following substituents: halo,
cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,
--OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2,
--C(O)R.sup.a, --C(O)OR.sup.a, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --OC(O)--N(R.sup.a).sub.2,
--N(R.sup.a)C(O)R.sup.a, --N(R.sup.a)S(O).sub.tR.sup.a (where t is
1 or 2), --S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tR.sup.a (where t is 1 or 2) and
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2) where each R.sup.a
is independently hydrogen, alkyl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl,
carbocyclyl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl), carbocyclylalkyl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aralkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), heterocyclyl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl
(optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), heteroaryl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl
(optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl).
[0197] The compounds disclosed herein, reference to any atom
includes reference to isotopes thereof. For example, reference to H
includes reference to any isotope thereof, such as a .sup.1H,
.sup.2H, .sup.3H, or mixtures thereof.
[0198] Generally, recitations of "anecortave" herein refer to
"anecortave" in the desacetate form of FIG. 1D; however, where
applicable, recitations of "anecortave" include disclosure of each
of the "desacetate" and "acetate" forms.
[0199] The term "opioid" or "opiate," as used interchangeably
herein, generally refers to a ligand that binds to an opioid
receptor, such as, for example, the delta (.delta.)-opioid receptor
(DOR), the kappa (.kappa.)-opioid receptor (KOR), mu (.mu.)-opioid
receptor (MOR), nociceptin opioid receptor (NOR), zeta
(.zeta.)-opioid receptor (ZOR), or any combination thereof. In some
embodiments, the opioid is an opioid agonist, an opioid antagonist,
or a mixed opioid agonist/antagonist of an opioid receptor. In some
embodiments, the opioid agonist is a partial opioid agonist or an
inverse opioid agonist. In some embodiments, the opioid is an
opioid radical. In some embodiments, the opioid radical is joined
to a radical of a therapeutically active agent by a linker, as
described herein, forming an opioid dimer. In some embodiments, the
opioid dimer is a heterodimer as described above. In some
embodiments, an opioid radical is joined to a second radical, which
is not an opioid radical, such as, for example, a radical of a
therapeutically active agent (e.g., a steroid), by a linker
described herein, forming an opioid heterodimer. In some
embodiments, a first opioid radical, such as, for example, a
partial opioid agonist, is joined to a second opioid radical, which
is a different opioid radical than the first opioid radical, such
as, for example, an opioid antagonist, by a linker described
herein, forming a heterodimer.
[0200] The term "pellet," as used herein, refers to the shape of
the pharmaceutical compositions of the disclosure that is rounded,
spherical, cylindrical, or a combination thereof. In some
embodiments, the pellet has a mean diameter from about 0.2 to 5 mm,
e.g., from about 0.2 to 1 mm, from about 0.2 to 2 mm, from about
0.3 to 3 mm, from about 1.5 to 5 mm, from about 2 to 5 mm, from
about 2.5 to 5 mm, from about 3 to 5 mm, from about 3.5 to 5 mm,
from about 4 to 5 mm, or from about 4.5 to 5 mm.
[0201] "Pharmaceutically acceptable salt" includes both acid and
base addition salts. A pharmaceutically acceptable salt of any one
of the pharmacological agents described herein is intended to
encompass any and all pharmaceutically suitable salt forms.
Preferred pharmaceutically acceptable salts of the compounds
described herein are pharmaceutically acceptable acid addition
salts and pharmaceutically acceptable base addition salts.
[0202] "Pharmaceutically acceptable acid addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free bases, which are not biologically or
otherwise undesirable, and which are formed with inorganic acids
such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, hydroiodic acid, hydrofluoric acid,
phosphorous acid, and the like. Also included are salts that are
formed with organic acids such as aliphatic mono- and dicarboxylic
acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,
alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic
acids, etc. and include, for example, acetic acid, trifluoroacetic
acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,
maleic acid, malonic acid, succinic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid, and the like. Exemplary salts thus include
sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates,
phosphates, monohydrogenphosphates, dihydrogenphosphates,
metaphosphates, pyrophosphates, chlorides, bromides, iodides,
acetates, trifluoroacetates, propionates, caprylates, isobutyrates,
oxalates, malonates, succinate suberates, sebacates, fumarates,
maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates,
dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,
phenylacetates, citrates, lactates, malates, tartrates,
methanesulfonates, and the like. Also contemplated are salts of
amino acids, such as arginates, gluconates, and galacturonates
(see, for example, Berge S. M. et al., "Pharmaceutical Salts,"
Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition
salts of basic compounds are, in some embodiments, prepared by
contacting the free base forms with a sufficient amount of the
desired acid to produce the salt according to methods and
techniques with which a skilled artisan is familiar.
[0203] "Pharmaceutically acceptable base addition salt" refers to
those salts that retain the biological effectiveness and properties
of the free acids, which are not biologically or otherwise
undesirable. These salts are prepared from addition of an inorganic
base or an organic base to the free acid. Pharmaceutically
acceptable base addition salts are, in some embodiments, formed
with metals or amines, such as alkali and alkaline earth metals or
organic amines. Salts derived from inorganic bases include, but are
not limited to, sodium, potassium, lithium, ammonium, calcium,
magnesium, iron, zinc, copper, manganese, aluminum salts and the
like. Salts derived from organic bases include, but are not limited
to, salts of primary, secondary, and tertiary amines, substituted
amines including naturally occurring substituted amines, cyclic
amines and basic ion exchange resins, for example, isopropylamine,
trimethylamine, diethylamine, triethylamine, tripropylamine,
ethanolamine, diethanolamine, 2-dimethylaminoethanol,
2-diethylaminoethanol, dicyclohexylamine, lysine, arginine,
histidine, caffeine, procaine, N,N-dibenzylethylenediamine,
chloroprocaine, hydrabamine, choline, betaine, ethylenediamine,
ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine,
theobromine, purines, piperazine, piperidine, N-ethylpiperidine,
polyamine resins and the like. See Berge et al., supra.
[0204] The terms "treat," "treating," or "treatment" as used
herein, include reducing, alleviating, abating, ameliorating,
relieving, or lessening the symptoms associated with a disease,
disease state, or indication (e.g., glaucoma) in either a chronic
or acute therapeutic scenario. In one embodiment, treatment
includes a reduction of intraocular pressure. Also, treatment of a
disease or disease state described herein includes the disclosure
of use of such compound or composition for the treatment of such
disease, disease state, or indication.
[0205] Often the final hurdle of drug development, producing a
final medicinal product from an active pharmaceutical ingredient
(API) that is a solid or a liquid at room temperature is an
extensive and costly process. Pharmaceutical formulation of an API
that is a liquid at room temperature often requires, for example,
excipients (e.g., stabilizers, additives, adjuvants, etc.) or
conjugation to another molecule (e.g., a polymer) to stabilize
and/or produce a processable and/or storable product. Instead, APIs
that are solids at room temperature are often used for
pharmaceutical formulations, avoiding the additional processing and
formulation for producing medicinal products from liquid APIs;
albeit, still incurring significant cost to formulation to a final
medicinal product. Therefore, the cost of formulating solid or
liquid APIs as well as the limited processability of liquid APIs
limit the efficacy and/or adoption of potentially beneficial
therapeutics.
[0206] Furthermore, patient compliance is an often unresolved issue
in the clinic. In some instances, modified-release pharmaceuticals
can improve patient compliance. For example, extended-release (ER)
dosage forms, such as sustained-release (SR) or controlled-release
(CR) dosage forms, may facilitate compliance with a therapeutic
regimen in some instances. SR and CR dosage forms are generally
designed to liberate an API at a certain rate, such as to maintain
a particular drug concentration over a period of time. For example,
SR maintains drug release over a sustained period but not at a
constant rate, while CR maintains drug release over a sustained
period at a more consistent (e.g., nearly constant) rate (e.g.,
zero-order). Despite their ability to extend the dosing of an
active, such dosage forms can be difficult to develop. Moreover,
such dosage forms often include controlled release excipients
(e.g., polymers) and/or controlled release matrices to facilitate
controlled release. In the case of liquid or otherwise low melting
point active agents, controlled release formulations can be even
more difficult to develop. Moreover, even in the best
circumstances, many controlled release forms have limited durations
of active release (e.g., 24-hour release windows), so patient
compliance remains an issue.
[0207] Provided in certain embodiments herein are processable
compounds that address the burden of medicinal product formulation
as well as patient compliance. In certain embodiments, compounds
described herein are solids at body temperature (e.g., about
37.degree. C., or lower). In certain embodiments, compounds
provided herein comprise a first group or radical (e.g., a
structure provided in any one of Formula (I), Formula (IA), Formula
(IB), Formula (IB') Formula (IC), Formula (II), Formula (IIA),
Formula (IIB), Formula (III), Formula (IV), or Formula (V)) (e.g.,
covalently) joined (e.g., conjugated) to a second group. In some
embodiments, the first group is a radical of Formula (I), Formula
(IA), Formula (IB), Formula (IB') or Formula (IC). In some
embodiments, the second group is a group that is itself not
processable itself in free form (e.g., has a melting temperature
that is higher than its degradation temperature, is generally
insoluble, such as in aqueous media, or is otherwise not suited for
processing). In certain embodiments, the second group is a group
that is not processable in dimer form (e.g., when conjugated
directly to itself or via a linker, such as described herein). In
some embodiments, the second group is a group that has a melting
point and/or glass transition temperature of less than 50.degree.
C., less than 40.degree. C., less than 37.degree. C., or the like.
Generally, such compounds, even if solid at room temperature, may
not be suitable for use as implants due to the possibility of
melting or deformation in a physiological environment. In some
embodiments, the compound is formed into an implantable article
(e.g., a pellet), such as using methods described herein (e.g., as
described in the examples). In some embodiments, the implantable
article has a (e.g., zero-order) controlled release rate over an
extended period (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks,
12 weeks, 52 weeks, or more) in an aqueous medium (e.g., a buffer
solution, serum, biological environment (e.g., in the eye), in
vivo, or the like). In some embodiments, a compound provided herein
(or implant comprising such a compound) is administered to an
individual suffering an acute or a chronic disease or condition
(e.g., as a therapy for the acute or chronic disease or condition)
in any suitable manner (e.g., route of administration, such as by
implanting, and/or frequency of dosing), such as a single dose or a
series of doses (e.g., once or twice every 1 week, 2 weeks, 3
weeks, 4 weeks, 6 weeks, 12 weeks, 52 weeks, or more).
[0208] In certain instances, compounds (e.g., conjugates) provided
herein are used to improve treatment options and/or patient
compliance for acute diseases and/or disorders. In some instances,
processable compounds described herein are used to improve
treatment options and/or patient compliance for chronic diseases
and/or disorders. In some embodiments, the processable compounds
described herein are used to improve treatment options and/or
patient compliance for ophthalmology, neurology, post-surgical
medicine, orthopedics, and pain management.
[0209] Provided herein are compounds (e.g., conjugates) that are
processable (e.g., into an article). A processable compound is a
compound that can be processed with heat or solvent to form a
solid, such as with little (e.g., less than 20 wt. %, less than 10
wt. %, or less than 5 wt. %) or no addition of further excipient.
In certain instances, the solid prepared following processing is an
amorphous solid or a solid having a highly amorphous morphology
(e.g., as discussed in more detail herein). In certain instances, a
processable compound provided herein is a solid at room (e.g.,
20.degree. C.) and/or physiological temperature (e.g., 37.degree.
C.). In some instances, the compound is thermally processable, such
as having a melt or glass transition temperature of at least
37.degree. C., at least 40.degree. C., at least 50.degree. C., at
least 60.degree. C., at least 70.degree. C., at least 100.degree.
C., or the like. In some embodiments, it is beneficial for the
compound to be solid at room temperature, but processable at a
temperature that is not prohibitively high. In some embodiments, a
compound provided herein has a melt and/or glass transition
temperature of less than 200.degree. C., less than 150.degree. C.,
less than 140.degree. C., less than 130.degree. C., less than
125.degree. C., less than 120.degree. C., or the like.
[0210] In some embodiments, the compounds have any suitable
morphology, such as to facilitate processing and/or pharmacodynamic
effects (e.g., release profile). In certain embodiments, the
compound (or implant or pharmaceutical composition comprising the
compound) is amorphous (or comprises a highly amorphous content).
In some embodiments, a compound (e.g., morphology) provided herein
is a solid, such as at a physiological temperature (e.g., having a
melting point (T.sub.m) and/or glass transition temperature
(T.sub.g) of at least 37.degree. C.). In some embodiments, the
compound is a crystalline solid, film, glass, or amorphous solid
(e.g., at a temperature of at least 37.degree. C.). In some
embodiments, the compound (or composition, article, or coating
comprising the compound) has a crystallinity of at most 15% (e.g.,
determined by PXRD, DSC, or polarized light microscopy). In some
embodiments, the compound (or composition, article, or coating
comprising the compound) is substantially non-crystalline (e.g.,
determined by PXRD, DSC, or polarized light microscopy). In some
embodiments, the compound (or composition, article, or coating
comprising the compound) is amorphous (e.g., determined by PXRD,
DSC, or polarized light microscopy). In some embodiments, the
compound (e.g., morphology) has a thermal melting point (T.sub.m)
that is greater than or equal to the glass transition temperature
(T.sub.g). In some embodiments, the compound has a melting point of
at least 37.degree. C. In some embodiments, the compound (e.g.,
morphology) has a melting point of at least 100.degree. C. In some
embodiments, either one or both of the first and/or second radicals
(or (e.g., active) fragments or metabolites thereof) of the
compounds (e.g., drug conjugates) and (e.g., active) agents are
released (e.g., in their free form), the release being controlled
release and/or extended release. In some embodiments, either one or
both of the first and/or second radicals of the compounds and
agents are released (e.g., in their free form) for at least 15 days
(e.g., in solution, buffer solution, serum, biological environment,
in vivo, or the like).
[0211] Described in certain embodiments herein are processable
agents (e.g., compounds) formed from a processable group (e.g., a
radical that makes a non-processable radical processable when
linked or joined thereto) and a non-processable moiety (e.g., a
radical that, if in its free form, would not be processable, such
as by thermal techniques, e.g., because of a melting point that is
below a physiological temperature). In some embodiments, the
processable agents described herein are processable into a solid
(e.g., at a temperature of at least 20.degree. C., 25.degree. C.,
30.degree. C., 37.degree. C., or more). In some embodiments,
provided herein are compounds useful in therapies for treating
acute, chronic, or both disease or condition. In some instances,
the conjugates provided herein represent a significant advance in
the art, e.g., as processable compounds suitable for being formed
into or formulated into controlled and/or extended release
articles, coatings, or other pharmaceutical compositions that are
beneficial for treating acute and/or chronic diseases or disorders,
such as with infrequent (e.g., a single, or weekly, monthly, or
less frequent) administration.
[0212] In certain aspects, provided herein is a compound comprising
a first radical and a second radical, the first radical comprising
the structure of Formula (I):
##STR00043## [0213] wherein: [0214] is a single bond or a double
bond; [0215] each R.sup.a, R.sup.b, and R.sup.c are independently
selected from the group consisting of oxo, halogen, --CN,
--NO.sub.2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,
alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy,
or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or
heterocycloalkyl is optionally substituted; [0216] or any one of
R.sup.a, R.sup.b, or R.sup.c are taken together with another of
R.sup.a, R.sup.b, or R.sup.c to form a substituted or an
unsubstituted cycloalkyl or heterocycloalkyl; [0217] X.sup.1,
X.sup.2, X.sup.3, and X.sup.4 are each independently selected from
the group consisting of a bond and Q.sub.y, wherein each Q is
independently selected from the group consisting of --O--, --NR--,
--S(R).sub.x--, and --C(R).sub.z--; [0218] each of m, n, and o are
independently 0-6; [0219] each x is independently 0-5; [0220] each
y is independently 1-3; [0221] each z is independently 1 or 2;
[0222] each R is independently selected from the group consisting
of hydrogen, halogen, alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino,
arylamino), hydroxy, and thiol (e.g., wherein the alkyl,
heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally
substituted), or one R is taken together with another R to form an
oxo; and [0223] the second radical being a therapeutically active
agent (or drug) and the first radical (e.g., steroid) being
different than the second radical (e.g., prostaglandin); [0224]
wherein, either the first radical, the second radical, or both the
first radical and the second radical is not a steroid, [0225] or a
pharmaceutically-acceptable salt or solvate thereof.
[0226] In some embodiments, provided herein is a compound
comprising a first radical and a second radical, the first radical
comprising a structure of Formula (IA):
##STR00044## [0227] wherein: [0228] is a single bond or a double
bond; [0229] each R.sup.a, R.sup.b, and R.sup.c are independently
selected from the group consisting of oxo, halogen, --CN,
--NO.sub.2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,
alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy,
or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or
heterocycloalkyl is optionally substituted; [0230] or any one of
R.sup.a, R.sup.b, or R.sup.c are taken together with another of
R.sup.a, R.sup.b, or R.sup.c to form a substituted or an
unsubstituted cycloalkyl or heterocycloalkyl; [0231] each of m, n,
and o are independently 0-6; and [0232] the second radical being a
therapeutically active agent (or drug) and the first radical (e.g.,
steroid) being different than the second radical (e.g.,
prostaglandin); [0233] wherein, either the first radical, the
second radical, or both the first radical and the second radical is
not a steroid, [0234] or a pharmaceutically-acceptable salt or
solvate thereof.
[0235] In some embodiments, provided herein is a compound
comprising a first radical and a second radical, the first radical
or the second radical comprising a structure of Formula (IB'):
##STR00045## [0236] wherein: [0237] is a single bond or a double
bond; [0238] each G.sup.a is independently selected from the group
consisting of oxo, halogen, --CN, --NO.sub.2, azide, alkyl,
heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryloxy, ester,
amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy,
hydrazone, oxime, or thiol, wherein the alkyl, heteroalkyl,
cycloalkyl, alkoxy, aryloxy, hydrazone, or heterocycloalkyl is
optionally substituted; [0239] or a first G.sup.a is taken together
with another R.sup.a to form an optionally substituted cycloalkyl,
heterocycloalkyl, aryl, or heteroaryl; [0240] each G.sup.1 is
independently hydrogen, alkyl, heteroalkyl, cycloalkyl, or
heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl, or
heterocycloalkyl are optionally substituted; [0241] G.sup.2 is
hydrogen, hydroxy, alkyl, heteroalkyl, alkoxy, cycloalkyl, or
heterocycloalkyl, wherein the alkyl, heteroalkyl, cycloalkyl,
alkoxy, or heterocycloalkyl are optionally substituted; [0242] s is
0-8; and [0243] q is 1 or 2, [0244] or a
pharmaceutically-acceptable salt or solvate thereof.
[0245] In some embodiments, provided herein is a compound
comprising a first radical and a second radical, the first radical
comprising a structure of Formula (IB):
##STR00046## [0246] wherein: [0247] is a single bond or a double
bond; [0248] each R.sup.a, R.sup.b, R.sup.c, and R.sup.d are
independently selected from the group consisting of oxo, halogen,
--CN, --NO.sub.2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,
alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy,
or thiol, wherein the alkyl, heteroalkyl, cycloalkyl, or
heterocycloalkyl is optionally substituted; [0249] or any one of
R.sup.a, R.sup.b, R.sup.c, and R.sup.d are taken together with
another of Re, R.sup.b, R.sup.c, and R.sup.d to form a substituted
or an unsubstituted cycloalkyl or heterocycloalkyl; [0250] each of
m, n, o, and p are independently 0-6; and [0251] the second radical
being a therapeutically active agent (or drug) and the first
radical (e.g., steroid) being different than the second radical
(e.g., prostaglandin); [0252] wherein, either the first radical,
the second radical, or both the first radical and the second
radical is not a steroid, [0253] or a pharmaceutically-acceptable
salt or solvate thereof.
[0254] In some embodiments, Ring A, B, C, or D of Formula (I),
Formula (IA), or Formula (IB), each optionally and independently
comprise one or more heteroatom (e.g., O, S, or N) within the
ring.
[0255] In some embodiments, provided herein is a compound
comprising a first radical and a second radical, the first radical
comprising a structure of Formula (IC):
##STR00047## [0256] wherein: [0257] is a single bond or a double
bond; R.sup.a is hydrogen, --OH, or oxo; [0258] each R.sup.a' is
independently selected from hydrogen, --OH, halogen,
C.sub.1-C.sub.3 alkyl, and alkoxy; [0259] R.sup.a'' is absent,
hydrogen, or C.sub.1-C.sub.3 alkyl; [0260] R.sup.b is absent,
hydrogen, halogen, or C.sub.1-C.sub.3 alkyl; [0261] R.sup.b' is
hydrogen, halogen, --OH, oxo, or C.sub.1-C.sub.3 alkyl; [0262]
R.sup.b'' is hydrogen or --OH; [0263] each R.sup.c is independently
hydrogen, --OH, oxo, or C.sub.1-C.sub.3 alkyl; [0264] each R.sup.c'
is independently hydrogen or C.sub.1-C.sub.3 alkyl; [0265]
R.sup.c'' is hydrogen, --OH, C.sub.1-C.sub.3 alkyl, or
--C(.dbd.O)H; [0266] each R.sup.d is independently hydrogen, --OH,
--COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl,
or each R.sup.d is taken together to form an oxo, wherein the alkyl
or heteroalkyl is optionally substituted; [0267] R.sup.d' is
hydrogen, --OH, C.sub.1-C.sub.3 alkyl (e.g., alkylene or alkenyl),
or heteroalkyl; [0268] or one R.sup.d is taken together with
R.sup.d' to form a substituted or unsubstituted cycloalkyl or
heterocycloalkyl; and [0269] the second radical being a
therapeutically active agent (or drug) and the first radical (e.g.,
steroid) being different than the second radical (e.g.,
prostaglandin); [0270] wherein, either the first radical, the
second radical, or both the first radical and the second radical is
not a steroid, [0271] or a pharmaceutically-acceptable salt or
solvate thereof.
[0272] In some embodiments, the alkyl or heteroalkyl of R.sup.d is
substituted with one or more of the group consisting of --SH, --OH,
--COOH, oxo, halogen, amino, alkyl (e.g., alkenyl, alkynyl),
heteroalkyl, ester, amide, sulfonic acid, and sulfone. In some
embodiments, one R.sup.d is taken together with R.sup.d' to form
substituted heterocycloalkyl.
[0273] In some embodiments, the first radical and the second
radical are joined by a linker (e.g., a bond). In some embodiments,
the first radical is joined to the second radical through any one
of R.sup.a, R.sup.b, R.sup.c, or R.sup.d of the first radical. In
some embodiments, the first radical is joined to the second radical
through any one of R.sup.a, R.sup.b, R.sup.c, or R.sup.d, and the
R.sup.a, R.sup.b, R.sup.c, or R.sup.d through which the first
radical is joined to the second radical comprises a hydroxyl
radical (e.g., when together with the linker or second radical
(where the linker is a bond), forms an ether), a thiol radical
(e.g., when together with the linker or second radical (where the
linker is a bond), forms a thioether), or a carboxylate radical
(e.g., when taken together with the linker or second radical (where
the linker is a bond), forms an ester or carbonate).
[0274] In some embodiments, the R.sup.a, R.sup.b, R.sup.c, or
R.sup.d through which the first radical is joined to the second
radical comprises a hydroxyl radical which together with the linker
or with the second radical forms an ether. In some embodiments, the
R.sup.a, R.sup.b, R.sup.c, or R.sup.d through which the first
radical is joined to the second radical comprises a thiol radical
which together with the linker or the second radical forms a
thioether. In some embodiments, the R.sup.a, R.sup.b, R.sup.c, or
R.sup.d through which the first radical is joined to the second
radical comprises a carboxylate radical which together with the
linker or the second radical forms an ester or a carbonate.
[0275] In some embodiments, both the first radical and the second
radical have the structure of any one of Formula (I), Formula (IA),
Formula (IB'), Formula (IB), or Formula (IC). In some embodiments,
both the first radical and the second radical have the structure of
any one of Formula (I), Formula (IA), or Formula (IB'). In some
embodiments, both the first radical and the second radical have the
structure of Formula (I) or Formula (IA). In some embodiments, both
the first radical and the second radical have the structure of
Formula (I). In some embodiments, both the first radical and the
second radical have the structure of Formula (IA). In some
embodiments, the first radical and the second radical (e.g., that
have the structure of any one of Formula (I), Formula (IA), Formula
(IB'), Formula (IB), or Formula (IC)) are joined by a linker (e.g.,
a hydrolysable linker). In some embodiments, the linker (e.g., a
hydrolysable linker) is a bond.
[0276] In some embodiments, the first radical has a structure of
any one of Formula (I), Formula (IA), Formula (IB'), Formula (IB),
or Formula (IC). In some embodiments, the second radical has a
structure of any one of Formula (I), Formula (IA), Formula (IB'),
Formula (IB), or Formula (IC). In some embodiments, the second
radical (e.g., which is not processable in its free form, not
processable in dimer form, and/or is liquid or malleable at
physiological temperature) does not have a structure of any one of
a structure of any one of Formula (I), Formula (IA), Formula (IB'),
Formula (IB), or Formula (IC).
[0277] In some embodiments, the radical of Formula (I), Formula
(IA), Formula (IB'), Formula (IB), or Formula (IC) is a steroid, an
opioid agonist, an opioid antagonist, an adrenergic receptor
antagonist (e.g., .beta.-blocker, .alpha.-1 blocker), or a
serotonergic antagonist (e.g., serotonin 5-HT3 receptor
antagonist). In some embodiments, the first radical and/or the
second radical is an anti-inflammatory agent, an anti-psychotic
agent (e.g., typical anti-psychotic, a typical antipsychotic,
schizophrenia, or the like), or the like.
[0278] In some embodiments, the first radical and/or the second
radical is a beta-blocker, which may be used to treat intra-ocular
pressure in the eye. In some embodiments, the beta-blocker is
timolol. In other embodiments, the beta-blocker is levobunolol,
metipranolol or carteolol. In some embodiments, the beta-blocker is
selected from the group consisting of Dichloroisoprenaline,
Propranolol, Bucindolol, Carteolol, Carvedilol, Labetalol, Nadolol,
Oxprenolol, Penbutolol, Pindolol, Sotalol, Timolol, Acebutolol,
Atenolol, Betaxolol, Bisoprolol, Celiprolol, Metoprolol, Nebivolol,
Esmolol, Butaxamine, ICI-118,551, SR 59230A, Nebivolol, Acebutolol,
pindolol, labetalol, mepindolol, oxprenolol, celiprolol, and
penbutolol. In some embodiments, the beta-blocker is selected from
the group consisting of Betaxolol, carteolol, levobunolol, timolol,
metipranolol.
[0279] In some embodiments, the first radical is a solid (e.g.,
having a melting point of at least 30.degree. C.) in its free form.
In some embodiments, the second radical is a liquid (e.g., having a
melting point of less than 30.degree. C.) in its free form.
[0280] In some embodiments, the first radical or the second radical
is a steroid (e.g., dexamethasone, anecortave (e.g., anecortave
desacetate), etc.). In some embodiments, the first radical is or is
derived from anecortave (e.g., anecortave acetate or anecortave
desacetate). In some embodiments, the first radical is a steroid
(e.g., dexamethasone, anecortave (e.g., anecortave desacetate),
etc.). In some embodiments, the steroid is a corticosteroid (e.g.,
glucocorticoid or mineral corticoid), a sex steroid, a
neurosteroid, an aminosteroid, or a secosteroid. In some
embodiments, the second radical is not a steroid. In certain
embodiments, the second radical is a radical that does not have a
structure of Formula (I), Formula (IA), Formula (IB'), Formula
(IB), or Formula (IC).
[0281] In some embodiments, the steroid is a glucocorticoid. In
some embodiments, the glucocorticoid is selected from the group
consisting of medrysone, alclometasone, alclometasone dipropionate,
amcinonide, beclometasone, beclomethasone dipropionate,
betamethasone, betamethasone benzoate, betamethasone valerate,
budesonide, ciclesonide, clobetasol, clobetasol butyrate,
clobetasol propionate, clobetasone, clocortolone, loprednol,
cortisol, cortisone, cortivazol, deflazacort, desonide,
desoximetasone, desoxycortone, desoxymethasone, dexamethasone,
diflorasone, diflorasone diacetate, diflucortolone, diflucortolone
valerate, difluorocortolone, difluprednate, fluclorolone,
fluclorolone acetonide, fludroxycortide, flumetasone, flumethasone,
flumethasone pivalate, flunisolide, flunisolide, fluocinolone,
fluocinolone acetonide, fluocinonide, fluocortin, fluocoritin
butyl, fluocortolone, fluorocortisone, fluorometholone,
fluperolone, fluprednidene, fluprednidene acetate, fluprednisolone,
fluticasone, fluticasone propionate, formocortal, halcinonide,
halometasone, hydrocortisone, hydrocortisone acetate,
hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone
butyrate, loteprednol, meprednisone, 6a-methylprednisolone,
methylprednisolone, methylprednisolone acetate, methylprednisolone
aceponate, mometasone, mometasone furoate, mometasone furoate
monohydrate, paramethasone, prednicarbate, prednisolone,
prednisone, prednylidene, rimexolone, tixocortol, triamcinolone,
triamcinolone acetonide, and ulobetasol, or the like.
[0282] In some embodiments, the steroid is a mineralocorticoid. In
some embodiments, the mineralocorticoid is selected from the group
consisting of aldosterone, fludrocortisone, deoxycorticosterone,
and corticosterone, or the like. In some embodiments, the
mineralocorticoid is canrenone (e.g., potassium canrenoate),
drospirenone, eplerenone, spirolactone, or a metabolite thereof
(e.g., 7.alpha.-thiomethylspironolactone, canrenone,
6.beta.-hydroxy-7.alpha.-thiomethylspironolactone, and
7.alpha.-thiospironolactone).
[0283] In some embodiments, the steroid is an anabolic steroid. In
some embodiments, the anabolic steroid is selected from the group
consisting of androisoxazole, androstenediol, bolandiol,
bolasterone, clostebol, ethylestrenol, formyldienolone,
4-hydroxy-19-nortestosterone, methandriol, methenolone,
methyltrienolone, nandrolone, norbolethone, oxymesterone,
stenbolone, and trenbolone, or the like.
[0284] In some embodiments, the steroid is an androgenic steroid.
In some embodiments, the androgenic steroid is selected from the
group consisting of boldenone, fluoxymesterone, mestanolone,
mesterolone, methandrostenolone, 17-methyltestosterone,
17-.alpha.-methyltestosterone 3-cyclopentyl enol ether,
norethandrolone, normethandrone, oxandrolone, oxymesterone,
oxymetholone, prasterone, stanlolone, stanozolol, testosterone,
testosterone 17-chloral hemiacetal, testosterone proprionate,
testosterone enanthate tiomesterone dehydroepiandrosterone (DHEA),
androstenedione, androstenediol, androsterone, dihydrotestosterone
(DHT), and androstanolone, or the like.
[0285] In some embodiments, the steroid is a progestin steroid. In
some embodiments, the progestin steroid is selected from the group
consisting of progesterone, norethisterone, norethisterone acetate,
gestodene, levonorgestrel, allylestrenol, anagestone, desogestrel,
dimethisterone, dydrogesterone, ethisterone, ethynodiol, ethynodiol
diacetate, etonogestrel, gestodene, ethinylestradiol,
haloprogesterone, 17-hydroxy-16-methylene-progesterone,
17-alpha-hydroxyprogesterone, lynestrenol, medroxyprogesterone,
melengestrol, norethindrone, norethynodrel, norgesterone,
gestonorone, norgestimate, norgestrel, levonorgestrel,
norgestrienone, norvinisterone, pentagestrone, M ENT
(7-methyl-19-testosterone); norelgestromin, and trimigestone
drospirenone, tibolone, and megestrol, or the like.
[0286] In some embodiments, the steroid is an estrogen steroid. In
some embodiments, the estrogen steroid is selected from the group
consisting of estradiol, estrone, eguilenin, equilin, estradiol
benzoate, estriol, ethinyl estradiol, mestranol, moxestrol,
mytatrienediol, quinestradiol, and quinestrol, or the like.
[0287] In some embodiments, the steroid is selected from the group
consisting of abiraterone, cyproterone acetate, dutasteride,
enzalutamide, finasteride, galeterone, fusidic acid, cholesterol,
11-deoxycortisol, 11-deoxycorticosterone, pregnenolone, cholic
acid, chenodeoxycholic acid, ursodeoxycholic acid, obeticholic
acid, tetrahydrocortisone, tetrahydrodeoxycortisol,
tetrahydrocorticosterone, 5.alpha.-dihydrocorticosterone,
5.alpha.-dihydropregesterone, flugestone, prebediolone,
chlormadinone acetate, medrogestone, and segesterone acetate, or
the like.
[0288] In some embodiments, the steroid is an anti-angiogenic or an
intraocular pressure (IOP) lowering steroid. In some embodiments,
the anti-angiogenic or intraocular pressure (IOP) lowering steroid
is selected from the group consisting of anecortave acetate,
anecortave (e.g., anecortave desacetate), 11-epicortisol,
17.alpha.-hydroxyprogesterone, tetrahydrocortexolone, and
tetrahydrocortisol, or the like. In some embodiments, the
anti-angiogenic or IOP lowering steroid is anecortave
desacetate.
[0289] In some embodiments, the steroid is a cholic acid-related
bile acid steroid. In some embodiments, the cholic acid-related
bile acid steroid is selected from the group consisting of
deoxycholic acid, apocholic acid, dehydrocholic acid,
glycochenodeoxycholic acid, glycocholic acid, glycodeoxycholic
acid, hyodeoxycholic acid, lithocholic acid, .alpha.-muricholic
acid, .beta.-muricholic acid, .gamma.-muricholic acid, w-muricholic
acid, taurochenodeoxycholic acid, taurocholic acid,
taurodeoxycholic acid, taurolithocholic acid, and
tauroursodeoxycholic acid, or the like.
[0290] In some embodiments, the steroid is a neurosteroid. In some
embodiments, the neurosteroid is selected from the group consisting
of alphaxalone, alphadolone, hydroxydione, minaxolone,
tetrahydrodeoxycorticosterone, allopregnanolone, pregnanolone,
ganoxolone, 3.alpha.-androstanediol, epipregnanolone,
isopregnanolone, and 24(S)-hydroxycholesterol, or the like.
[0291] In some embodiments, the steroid is a steroid pheromone. In
some embodiments, the steroid pheromone is selected from the group
consisting of androstadienol, androstadienone, androstenol,
androstenone, estratetraenol, 5-dehydroprogesterone,
6-dehydro-retroprogesterone, allopregnanolone, and
hydroxyprogesterone caproate, or the like.
[0292] In some embodiments, the steroid is a steroid metabolite. In
some embodiments, the steroid metabolite is selected from the group
consisting of tetrahydrotriamcinolone, cortienic acid,
11-dehydrocorticosterone, 11.beta.-hydroxypregnenolone,
ketoprogesterone, 17-hydroxypregnenolone,
17,21-dihydroxypregnenolone, 18-hydroxycorticosterone,
deoxycortisone, 21-hydroxypregnenolone, and progesterone, or the
like.
[0293] In some embodiments, the steroid is a progestin. In some
embodiments, the progestin is selected from the group consisting of
allopregnone-3.alpha.,20.alpha.-diol,
allopregnone-3.beta.,20.beta.-diol,
allopregnane-3.beta.,21-diol-11,20-dione,
allopregnane-3.beta.,17.alpha.-diol-20-one, 3,20-allopregnanedione,
3.beta.,11.beta.,17.alpha.,20.beta.,21-pentol,
allopregnane-3.beta.,17.alpha.,20.beta.,21-tetrol,
allopregnane-3.alpha.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,11.beta.,17.alpha.,21-tetrol-20-one,
allopregnane-3.beta.,17.alpha.,20.beta.-triol,
allopregnane-3.beta.,17.alpha.,21-triol-11,20-dione,
allopregnane-3.beta.,11.beta.,21-triol-20-one,
allopregnane-3.beta.,17.alpha.,21-triol-20-one,
allopregnane-3.alpha.-ol-20-one, allopregnane-3.beta.-ol-20-one,
pregnanediol, 3,20-pregnanedione, 4-pregnene-20,21-diol-3,11-dione,
4-pregnene-11.beta.,17.alpha.,20,21-tetrol-3-one,
4-pregnene-17.alpha.,20.beta.,21-triol-3,11-dione,
4-pregnene-17.alpha.,20.beta.,21-triol-3-one, and pregnenolone, or
the like.
[0294] In some embodiments, the first radical and the second
radical are joined by a linker (e.g., hydrolyzable linker). In some
embodiments, the first radical and the second radical are joined by
a bond.
[0295] In some embodiments, the linker is a bond, alkyl,
heteroalkyl, or alkoxy, wherein the alkyl, heteroalkyl, or alkoxy
is optionally substituted. In some embodiments, the alkyl,
heteroalkyl, or alkoxy are each independently substituted with one
or more groups, each group being independently selected from the
group consisting of a bond, --O--, --S--, silicone, amino,
optionally substituted alkyl (e.g., alkenyl, alkynyl, branched
(e.g., polypropylene), haloalkyl), optionally substituted
heteroalkyl (e.g, polyTHF), and optionally substituted cycloalkyl.
In some embodiments, the linker is a bond. In some embodiments, the
linker is alkyl (alkylene) and the alkyl (alkylene) is substituted
with one or more groups selected from --OH, halo, oxo, alkyl,
heteroalkyl, cycloalkyl, and heterocycloalkyl. In some embodiments,
the linker is alkyl (alkylene) and the alkyl (alkylene) is an
unsubstituted alkylene. In some embodiments, the linker is
heteroalkyl (heteroalkylene) and the heteroalkyl (heteroalkylene)
is substituted with one or more groups selected from halo or alkyl.
In some embodiments, the linker is heteroalkyl (heteroalkylene) and
is the heteroalkyl (heteroalkylene) an unsubstituted
heteroalkylene. In some embodiments, the linker comprises one or
more linker groups selected from a bond, --O--, --S--,
unsubstituted alkylene, C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O,
C.dbd.O(CHCH).sub.nC.dbd.O,
C.dbd.O(OCH.sub.2CH.sub.2O).sub.nC.dbd.O,
O(CH.sub.2CH.sub.2O).sub.n, and C.dbd.O(CH.sub.2CH.sub.2O).sub.n,
(CH(CH.sub.3)C(.dbd.O)O).sub.n, wherein n is 1-20. In some
embodiments, the linker is a bond, unsubstituted alkylene,
C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O, C.dbd.O(CHCH).sub.nC.dbd.O,
C.dbd.O(OCH.sub.2CH.sub.2O).sub.nC.dbd.O,
O(CH.sub.2CH.sub.2O).sub.n, and C.dbd.O(CH.sub.2CH.sub.2O).sub.n,
(CH(CH.sub.3)C(.dbd.O)O).sub.n,
C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O(CH(CH.sub.3)C(.dbd.O)O).sub.n,
wherein n is 1-20. In some embodiments, the linker is a bond.
[0296] In some embodiments, the linker is hydrolyzed in a buffered
solution. In some embodiments, the linker is hydrolyzed by an
enzyme. In some embodiments, the enzyme is a hydrolase (e.g., a
protease or an esterase).
[0297] In some embodiments, the first radical is a (e.g., hydroxyl
or carboxyl) radical of a compound selected from the group
consisting of:
##STR00048## ##STR00049## ##STR00050## ##STR00051##
[0298] In some embodiments, the first radical is a (e.g., hydroxyl
or carboxyl) radical of a compound selected from the group
consisting of:
##STR00052## ##STR00053## ##STR00054## ##STR00055##
##STR00056##
[0299] In certain embodiments, the disclosure provides a compound,
or pharmaceutically acceptable salt thereof, having a structure
provided in Table 1. In some embodiments, the compound, or
pharmaceutically acceptable salt thereof, provided in Table 1 is a
solid at a temperature of at least 20.degree. C. (e.g., at least 30
C, at least 37 C, at least 40 C, at least 50 C, at least 70 C, at
least 100 C, or the like). In some embodiments, the compound, or
pharmaceutically acceptable salt thereof, provided in Table 1 is
processable at a temperature of at least 20.degree. C. (e.g., as
described in the examples). In some embodiments, the compound, or
pharmaceutically acceptable salt thereof, provided in Table 1 is
processable into an article (e.g., machined, molded,
emulsion-processed, electrospun, electrosprayed, blow molded, or
extruded to form a fiber, fiber mesh, woven fabric, non-woven
fabric, film, surface coating, pellet, cylinder, rod,
microparticle, nanoparticle, or another shaped article) at a
temperature of at least 20.degree. C. In some embodiments, the
compound, or pharmaceutically acceptable salt thereof, provided in
Table 1 comprises both a first radical and a second radical. In
some embodiments, the compound in Table 1 is processable when the
first radical, and the second radical are joined by a linker. In
some embodiments, the linker is a bond.
TABLE-US-00001 TABLE 1 Compound Number Structure Name 1
##STR00057## 2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13-
dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7-
((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3-
(trifluoromethyl)phenoxy) but-1-en-1- yl)cyclopentyl)hept-5- enoate
2 ##STR00058## 2- ((8S,9R,10S,11S,13S,14S, 16R,17R)-9-fluoro-11,17-
dihydroxy-10,13,16- trimethyl-3-oxo- 6,7,8,9,10,11,12,13,14,
15,16,17-dodecahydro- 3H- cyclopenta[a]phenanthren-
17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3-
hydroxy-4-(3- (trifluoromethyl)phenoxy) but-1-en-1-
yl)cyclopentyl)hept-5- enoate 3 ##STR00059## 2-
((8S,9R,10S,11S,13S,14S, 16R,17R)-9-fluoro-11,17-
dihydroxy-10,13,16- trimethyl-3-oxo- 6,7,8,9,10,11,12,13,14,
15,16,17-dodecahydro- 3H- cyclopenta[a]phenanthren-
17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3-
hydroxy-5- phenylpentyl)cyclopentyl) hept-5-enoate 4 ##STR00060##
(8R,9S,13S,14S)-13- methyl-17-oxo- 7,8,9,11,12,13,14,15,16,
17-decahydro-6H- cyclopenta[a]phenanthren- 3-yl(Z)-7-
((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5-
phenylpentyl)cyclopentyl) hept-5-enoate 5 ##STR00061##
2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo-
2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7-
((1R,2R,3R,5S)-3,5- dihydroxy-2-((S,E)-3- hydroxy-5-phenylpent-1-
en-1-yl)cyclopentyl)hept- 5-enoate 6 ##STR00062##
2-((8S,14S,17R)-17- hydroxy-10,13-dimethyl- 3-oxo-
2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7-
((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5-
phenylpentyl)cyclopentyl) hept-5-enoate 7 ##STR00063##
2-((8S,14S,17R)-17- hydroxy-10,13-dimethyl- 3-oxo-
2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7-
((1R,2R,3R,5S)-2-((E)-3,3- difluoro-4-phenoxybut-1- en-1-yl)-3,5-
dihydroxycyclopentyl) hept-5-enoate 8 ##STR00064##
(4-((((2-((8S,14S,17R)-17- hydroxy-10,13-dimethyl- 3-oxo-
2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2- oxoethoxy)carbonyl)oxy)
methyl)cyclohexyl)methyl (Z)-7-((1R,2R,3R,5S)-3,5-
dihydroxy-2-((R,E)-3- hydroxy-4-(3- (trifluoromethyl)phenoxy)
but-1-en-1- yl)cyclopentyl)hept-5- enoate 9 ##STR00065##
(4R,4aS,7aR,12bS)-3- (cyclopropylmethyl)-4a- hydroxy-7-oxo-
2,3,4,4a,5,6,7,7a- octahydro-1H-4,12- methanobenzofuro[3,2-
e]isoquinolin-9-yl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3-
hydroxy-4-(3- (trifluoromethyl)phenoxy) but-1-en-1-
yl)cyclopentyl)hept-5- enoate 10 ##STR00066##
(S)-1-(tert-butylamino)- 3-((4-morpholino-1,2,5- thiadiazol-3-
yl)oxy)propan-2-yl(R)-4- ((3R,5R,8R,9S,10S,12S,13 R,14S,17R)-3,12-
dihydroxy-10,13- dimethylhexadecahydro- 1H-
cyclopenta[a]phenanthren- 17-yl)pentanoate 11 ##STR00067##
(S,E)-1-((1R,2R,3S,5R)-2- ((Z)-7-(ethylamino)-7-
oxohept-2-en-1-yl)-3,5- dihydroxycyclopentyl)-5-
phenylpent-1-en-3-yl(2- ((8S,10S,13S,14S,17R)- 17-hydroxy-10,13-
dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl) carbonate 12
##STR00068## 2-((8S,14S,17R)-17- hydroxy-10,13-dimethyl- 3-oxo-
2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7-
((1R,2R,3R,5S)-3,5- dihydroxy-2-(3- oxodecyl)cyclopentyl)
hept-5-enoate 13 ##STR00069## 2-((8S,10S,13S,14S,17R)-
17-hydroxy-10,13- dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15,
16,17-dodecahydro-1H- cyclopenta[a]phenanthren-
17-yl)-2-oxoethyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((S,E)-3-
hydroxyoct-1-en-1- yl)cyclopentyl)hept-5- enoate 14 ##STR00070##
2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo-
2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl 4-
((3R,5aS,6S,7S,8aR)-6- ((S,E)-4-(2,5- difluorophenoxy)-3-
hydroxybut-1-en-1-yl)-7- hydroxyoctahydro-2H-
cyclopenta[b]oxepin-3- yl)butanoate 15 ##STR00071##
(8R,9S,13S,14S)-13- methyl-17-oxo- 7,8,9,11,12,13,14,15,16,
17-decahydro-6H- cyclopenta[a]phenanthren- 3-yl(Z)-7-
((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3-
(trifluoromethyl)phenoxy) but-1-en-1- yl)cyclopentyl)hept-5- enoate
16 ##STR00072## 1-(tert-butylamino)-3- ((4-morpholino-1,2,5-
thiadiazol-3- yl)oxy)propan-2-yl(2- ((8S,10S,13S,14S,17R)-
17-hydroxy-10,13- dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15,
16,17-dodecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl)
carbonate 17 ##STR00073## (4R,4aS,7aR,12bS)-3-
allyl-4a-hydroxy-7-oxo- 2,3,4,4a,5,6,7,7a- octahydro-1H-4,12-
methanobenzofuro[3,2- e]isoquinolin-9-yl(2-
((8S,9S,10R,11S,13S,14S, 17R)-11,17-dihydroxy-
10,13-dimethyl-3-oxo- 2,3,6,7,8,9,10,11,12,13,14, 15,16,17-
tetradecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl)
carbonate 18 ##STR00074## 1-((4R,4aS,7aR,12bS)-3-
allyl-4a-hydroxy-7-oxo- 2,3,4,4a,5,6,7,7a- octahydro-2H-4,12-
methanobenzofuro[3,2- e]isoquinolin-9-yl)8-(2-
((8S,9S,10R,11S,13S,14S, 17R)-11,17-dihydroxy-
10,13-dimethyl-3-oxo- 2,3,6,7,8,9,10,11,12,13,14, 15,16,17-
tetradecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl)
octanedioate 19 ##STR00075## 1-(tert-butylamino)-3-
((4-morpholino-1,2,5- thiadiazol-3- yl)oxy)propan-2-yl(4R)- 4-
((3R,5S,7R,8R,9S,10S, 12S,13R,14S,17R)-3,7,12- trihydroxy-10,13-
dimethylhexadecahydro- 1H- cyclopenta[a]phenanthren-
17-yl)pentanoate 20 ##STR00076## 1-(tert-butylamino)-3-
((4-morpholino-1,2,5- thiadiazol-3- yl)oxy)propan-2-yl(Z)-2-
((3R,4S,5S,8S,9S,10S,11R, 13R,14S,16S)-16- acetoxy-3,11-dihydroxy-
4,8,10,14- tetramethylhexadecahydro- 17H- cyclopenta[a]phenanthren-
17-ylidene)-6- methylhept-5-enoate 21 ##STR00077##
2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo-
2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(E)-4-
(2-((5-bromoquinoxalin- 6-yl)amino)-4,5-dihydro-
1H-imidazol-1-yl)but-3- enoate 22 ##STR00078##
2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo-
2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(E)-4-
((((4S,6S)-4-(ethylamino)- 6-methyl-7,7-dioxido- 5,6-dihydro-4H-
thieno[2,3-b]thiopyran- 2- yl)sulfonyl)imino) butanoate 23
##STR00079## 2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13-
dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15, 16,17-dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(E)-4-
(4-(isoquinolin-5- ylsulfonyl)-1,4-diazepan- 1-yl)but-3-enoate 24
##STR00080## (Z)-4-(4-(4- chlorophenyl)-4-
hydroxypiperidin-1-yl)-1- (4-fluorophenyl)but-1- en-1-yl(2-
((8S,9S,10R,11S,13S,14S, 17R)-11,17-dihydroxy-
10,13-dimethyl-3-oxo- 2,3,6,7,8,9,10,11,12,13, 14,15,16,17-
tetradecahydro-1H- cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl)
carbonate
[0300] In some embodiments, the disclosure provides a compound
(e.g., conjugate, such as a heterodimeric conjugate), or
pharmaceutically acceptable salt thereof, having a structure
provided in Table 2. In other embodiments, parent conjugate
compounds that do not form a processable solid are shown in Table
2. In some embodiments, the compound, or pharmaceutically
acceptable salt thereof, provided in Table 2 is not a solid at a
temperature of at least 20.degree. C. In some embodiments, the
compound, or pharmaceutically acceptable salt thereof, provided in
Table 2 is not processable at a temperature of at least 20.degree.
C. In some embodiments, the compound, or pharmaceutically
acceptable salt thereof, provided in Table 2 is not processable
into an article, as described herein, at a temperature of at least
20.degree. C.
[0301] In some embodiments, the compound, or pharmaceutically
acceptable salt thereof, provided in Table 2 comprises both a first
radical and a second radical. In some embodiments, the
heterodimeric conjugate in Table 2 is not processable when the
first radical and the second radical are joined by a linker. In
some embodiments, the linker is not a bond. In some embodiments,
the linker is alkyl, heteroalkyl, or alkoxy, wherein the alkyl,
heteroalkyl, or alkoxy is optionally substituted with one or more
groups, each group being independently selected from the group
consisting of a bond, --O--, --S--, silicone, amino, optionally
substituted alkyl (e.g., alkenyl, alkynyl, branched (e.g.,
polypropylene), haloalkyl), optionally substituted heteroalkyl
(e.g, polyTHF), and optionally substituted cycloalkyl.
TABLE-US-00002 TABLE 2 Compound Number Structure Name 25
##STR00081## 1- ((8S,9R,10S,11S,13S,14S, 16R,17R)-9-fluoro-11,17-
dihydroxy-10,13,16- trimethyl-3-oxo- 6,7,8,9,10,11,12,13,14,
15,16,17-dodecahydro- 3H- cyclopenta[a]phenanthren-
17-yl)-1,4-dioxo- 3,5,8,11- tetraoxatridecan-13-yl
(Z)-7-((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5-
phenylpentyl)cyclopentyl) hept-5-enoate 26 ##STR00082##
4-acetamidophenyl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3-
hydroxy-4-(3- (trifluoromethyl)phenoxy) but-1-en-1-
yl)cyclopentyl)hept-5- enoate 27 ##STR00083##
((3R,5R,7R)-adamantan- 1-yl)methyl(Z)-7- ((1R,2R,3R,5S)-3,5-
dihydroxy-2-((R,E)-3- hydroxy-4-(3- (trifluoromethyl)phenoxy)
but-1-en-1- yl)cyclopentyl)hept-5- enoate 28 ##STR00084##
2-(2-(2-(((Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5-
phenylpentyl)cyclopentyl) hept-5- enoyl)oxy)ethoxy)ethoxy)
ethyl(Z)-7- ((1S,2S,3S,5R)-3,5- dihydroxy-2-((S)-3- hydroxy-5-
phenylpentyl)cyclopentyl) hept-5-enoate 29 ##STR00085##
propyl(Z)-7- ((1R,2R,3R,5S)-2- ((3R,18S)-20- ((1S,2S,3R,5S)-3,5-
dihydroxy-2-((Z)-7-oxo-7- propoxyhept-2-en-1- yl)cyclopentyl)-5,16-
dioxo-3,18-diphenethyl- 4,6,9,12,15,17- hexaoxaicosyl)-3,5-
dihydroxycyclopentyl) hept-5-enoate 30 ##STR00086## propyl(Z)-7-
((1R,2R,3R,5S)-2-((R)-3- ((ethoxycarbonyl)oxy)-5-
phenylpentyl)-3,5- dihydroxycyclopentyl) hept-5-enoate
Ocular Diseases or Disorders
[0302] Intraocular diseases are a group of diseases including, but
not limited to, glaucoma, ocular inflammation, diabetic macular
edema, posterior inflammation, anterior inflammation, macular
degeneration (e.g., wet macular degeneration (AMD) and dry AMD),
post-cataract surgery, and retinal vein occlusion. Prominent
aspects of intraocular diseases are increased intraocular pressure
and inflammation. In some embodiments, the intraocular disease is a
macular degeneration. In some embodiments, the intraocular disease
is wet AMD. In some embodiments, the intraocular disease is dry
AMD.
Glaucoma
[0303] In some embodiments, glaucoma is a group of eye diseases,
which result in damage to the optic nerve and cause vision loss.
Glaucoma is one of the leading causes of blindness globally, and
there is currently no cure for glaucoma. Glaucoma management is
limited to avoiding glaucomatous damage and nerve damage as well as
preserving visual field and total quality of life. This management
system relies on diagnostic techniques and follow-up examinations
as well as judicious selection of treatments for the individual
patient.
[0304] Therapeutic strategies for glaucoma are limited to
pharmaceutical agents (e.g., intraocular pressure (IOP) lowering
agents, e.g., prostaglandins), surgery (e.g., implants), laser
therapy, or any combination thereof. The reported rates of
nonadherence to topical glaucoma medication vary widely from 16% to
67%, and it is estimated that less than a third of patients
remained on their initial therapy after 12 months (Robin et al,
Exp. Rev. Ophth. (2019); 14:4-5, 199-210). Poor compliance with
medications and follow-up visits is a major reason for vision loss
in glaucoma patients.
[0305] Ocular hypertension (increased intraocular pressure (IOP))
is one of the major risk factors for glaucoma, and lowering it is a
major goal of glaucoma treatment. Intraocular pressure is a
function of the production of aqueous humor by the ciliary
processes of the eye as well as it's drainage through the
trabecular meshwork. In glaucoma, the drainage mechanisms are
hindered and/or blocked, causing an increase in IOP. Furthermore,
inflammation blocks outflow of aqueous humor through the trabecular
meshwork, causing secondary glaucoma. This inflammation is often
difficult to treat because anti-inflammatory steroids (e.g.,
corticosteroids), which restrict blood flow to the eye, often raise
the IOP further. Described herein are compounds that navigate the
balance between reducing the IOP (e.g., with an IOP lowering agent
such as a prostaglandin or an IOP lowering steroid) as well as
reducing inflammation (e.g., with a corticosteroid). In some
embodiments, described herein are compounds that significantly
increase patient compliance by reducing the number of
administrations of API (e.g., once per month).
[0306] Described herein are processable agents for glaucoma formed
from a processable moiety and a non-processable moiety. The
processable agents for glaucoma described herein are processable
into a solid (e.g., at a temperature of at least 20.degree. C.,
25.degree. C., 30.degree. C., 37.degree. C., or more). The
processable agents for glaucoma described herein have a controlled
release profile (e.g., zero order) and/or an extended release
profile (e.g., at least 1 day, 2 days, 3 days, 4 days, 5 days, 6
days, 7 days, 15 days, 30 days, or more) in solution (e.g., buffer
solution, serum, biological environment, in vivo, or the like). The
compounds for glaucoma described herein are useful to treat both
acute and chronic diseases or disorders. The compounds for glaucoma
are tested, in certain embodiments, using the assays and methods
described herein (e.g., as described in the examples). The
compounds for glaucoma described herein represent a significant
advance in the art as the processable agents produce a controlled
and extended release profile that is beneficial for treating acute
and/or chronic forms of glaucoma with a single administration.
[0307] Provided herein is a heteromeric conjugate comprising a
first radical and a second radical. In some embodiments, both the
first radical and the second radical have the structure of any one
of Formula (I), Formula (IA), Formula (IB'), Formula (IB), or
Formula (IC). In some embodiments, the first radical is an
anti-inflammatory agent. In some embodiments, the second radical is
selected from the group consisting of a non-steroidal
anti-inflammatory (NSAID), an intraocular pressure (IOP) lowering
agent, a beta blocker, a Rho kinase inhibitor, a carbonic anhydrase
inhibitor, an .alpha.-adrenergic agonist, tyrosine kinase
inhibitor, neuroprotective agent, anti-oxidant, anti-microbial,
anti-viral, or the like. In some embodiments, the second radical is
an IOP lowering agent. In some embodiments, the first radical is an
anti-inflammatory agent and the second radical is an IOP lowering
agent. In some embodiments, the first radical is an IOP lowering
steroid (e.g., anecortave (e.g., anecortave desacetate)) or benign
steroid (e.g., cholesterol) and the second radical is an IOP
lowering agent. In some embodiments, the IOP lowering agent is a
prostaglandin. In some embodiments, the first radical is a steroid
and the second radical is a prostaglandin.
[0308] In certain aspects, the first radical has the structure of
any one of Formula (I), Formula (IA), Formula (IB'), Formula (IB),
or Formula (IC).
[0309] In some embodiments, the second radical has a structure of
Formula (II):
##STR00087## [0310] wherein: [0311] R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are each independently selected from one or
more of the group consisting of hydrogen, oxo, halo, alkyl,
heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g.,
dihydroamino, alkylamino, arylamino), hydroxyl, and thiol, wherein
the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is
optionally substituted; [0312] or any one of R.sup.1, R.sup.2,
R.sup.3, R.sup.4, or R.sup.5 are taken together to form an
optionally substituted cycloalkyl or heterocycloalkyl; [0313] X is
selected from the group consisting of --O--, --NR--,
--S(R).sub.a--, and --C(R).sub.b--; [0314] a is independently 0-2;
and [0315] b is independently 1 or 2, [0316] or a pharmaceutically
acceptable salt or solvate thereof.
[0317] In some embodiments, R.sup.4 is alkyl substituted with one
or more of --COOH, --CONH.sub.2, and alkyl (e.g., alkylene or
alkenyl). In some embodiments, X is S, --C(R).sub.1--, or
--C(R).sub.2--. In some embodiments, X is --CH-- or
--CH.sub.2--.
[0318] In some embodiments, the second radical has a structure of
Formula (IIA):
##STR00088## [0319] wherein: [0320] R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 are each independently selected from one or
more of the group consisting of hydrogen, oxo, halo, alkyl,
heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g.,
dihydroamino, alkylamino, arylamino), hydroxyl, and thiol, wherein
the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is
optionally substituted; and [0321] R.sup.6 and R.sup.6' are each
independently hydrogen, halogen, alkyl, or R.sup.6 and R.sup.6' are
taken together to form an oxo, [0322] or a pharmaceutically
acceptable salt or solvate thereof.
[0323] In some embodiments, R.sup.6 and R.sup.6' are each
independently fluoro. In some embodiments, R.sup.6 is H or methyl
and R.sup.6' is --OH. In some embodiments, R.sup.6 and R.sup.6' are
taken together to form an oxo. In some embodiments, R.sup.1 and
R.sup.3 are each independently --OH or oxo. In some embodiments,
R.sup.3 and R.sup.4 are taken together to form a heterocycloalkyl
substituted with alkyl (e.g., alkenyl) substituted with --COOH.
[0324] In some embodiments, the second radical has a structure of
Formula (IIB):
##STR00089## [0325] wherein: [0326] R.sup.1, R.sup.2, and R.sup.5
are each independently selected from one or more of the group
consisting of hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino,
arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl,
cycloalkyl, and heterocycloalkyl is optionally substituted; [0327]
R.sup.6'' is oxo or --OH; [0328] Y.sup.1 and Y.sup.2 are each
independently a bond or alkylene; [0329] G is O or CH.sub.2; [0330]
g is 1 or 2; and [0331] R.sup.10 is alkyl or hydrogen, [0332] or a
pharmaceutically acceptable salt or solvate thereof.
[0333] In some embodiments, R.sup.1 is oxo or --OH. In some
embodiments, R.sup.2 is hydrogen. In some embodiments, R.sup.5 is
selected from one or more of the group consisting of --O--, --OH,
halogen, alkyl (e.g., alkynyl), aryl, wherein the alkyl (e.g.,
alkynyl) and aryl are optionally substituted with one or more of
alkyl (e.g., fluoroalkyl), halogen, and --OH. In some embodiments,
R.sup.5 is optionally substituted aryl or optionally substituted
--O-aryl.
[0334] In some embodiments, the first radical and the second
radical are joined by a linker (e.g., hydrolyzable linker). In some
embodiments, the first radical and the second radical are joined by
a bond.
[0335] In certain aspects, provided herein is a compound
comprising: [0336] a) a steroid; [0337] b) a prostaglandin; and
[0338] c) a linker (e.g., hydrolyzable linker), wherein the linker
adjoins (e.g., covalently) the steroid and the prostaglandin,
[0339] or a pharmaceutically acceptable salt or solvate
thereof.
[0340] In certain aspects, provided herein is a compound having the
structure of Formula (III):
##STR00090## [0341] wherein: [0342] is a single bond or a double
bond; [0343] each R.sup.a, R.sup.b, R.sup.c, and R.sup.d are
independently selected from the group consisting of oxo, halogen,
--CN, --NO.sub.2, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,
alkoxy, amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy,
or thiol, wherein the alkyl, alkynyl, heteroalkyl, cycloalkyl, or
heterocycloalkyl is optionally substituted; [0344] or any one of
R.sup.a, R.sup.b, R.sup.c, and R.sup.d are taken together with
another of R.sup.a, R.sup.b, R.sup.c, and R.sup.d to form an
substituted or unsubstituted cycloalkyl or heterocycloalkyl; [0345]
each of m, n, o, and p are independently 0-6; [0346] each R is
independently selected from the group consisting of hydrogen,
halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy,
amino (e.g., dihydroamino, alkylamino, arylamino), hydroxy, and
thiol, or is taken together with another R to form an oxo; [0347]
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are each
independently selected from one or more of the group consisting of
hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino,
arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl,
cycloalkyl, and heterocycloalkyl is optionally substituted; and
[0348] L is a linker, [0349] or a pharmaceutically-acceptable salt
or solvate thereof.
[0350] In certain aspects, provided herein is a compound having the
structure of Formula (IV):
##STR00091## [0351] wherein: [0352] is a single bond or a double
bond; [0353] R.sup.d is hydrogen, --OH, or oxo; [0354] each
R.sup.a' is independently selected from hydrogen, --OH, halogen,
C.sub.1-C.sub.3 alkyl, and alkoxy; [0355] R.sup.a'' is absent,
hydrogen, or C.sub.1-C.sub.3 alkyl; [0356] R.sup.b is absent,
hydrogen, halogen, or C.sub.1-C.sub.3 alkyl; [0357] R.sup.b' is
hydrogen, halogen, --OH, oxo, or C.sub.1-C.sub.3 alkyl; [0358]
R.sup.b'' is hydrogen or --OH; [0359] each R.sup.c is independently
hydrogen, --OH, oxo, or C.sub.1-C.sub.3 alkyl; [0360] each R.sup.c'
is independently hydrogen or C.sub.1-C.sub.3 alkyl; [0361]
R.sup.c'' is hydrogen, --OH, C.sub.1-C.sub.3 alkyl, or
--C(.dbd.O)H; [0362] each R.sup.d is independently hydrogen, --OH,
--COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl,
or each R.sup.d is taken together to form an oxo, wherein the alkyl
or heteroalkyl is optionally substituted; [0363] R.sup.d' is
hydrogen, --OH, C.sub.1-C.sub.3 alkyl (e.g., alkylene or alkenyl),
or heteroalkyl; [0364] or one R.sup.d is taken together with
R.sup.d' to form a substituted or unsubstituted cycloalkyl or
heterocycloalkyl; [0365] R.sup.1, R.sup.2, R.sup.3, R.sup.4, and
R.sup.5 are each independently selected from one or more of the
group consisting of hydrogen, oxo, halo, alkyl, heteroalkyl,
cycloalkyl, heterocycloalkyl, alkoxy, amino (e.g., dihydroamino,
alkylamino, arylamino), hydroxyl, and thiol, wherein the alkyl,
heteroalkyl, cycloalkyl, and heterocycloalkyl is optionally
substituted; and [0366] R.sup.6 and R.sup.6' are each independently
hydrogen, halogen, alkyl, or R.sup.6 and R.sup.6' are taken
together to form an oxo, [0367] or a pharmaceutically acceptable
salt or solvate thereof.
[0368] In certain aspects, provided herein is a compound having the
structure of Formula (V):
##STR00092## [0369] wherein: [0370] is a single bond or a double
bond; [0371] R.sup.d is hydrogen, --OH, or oxo; [0372] each
R.sup.a' is independently selected from hydrogen, --OH, halogen,
C.sub.1-C.sub.3 alkyl, and alkoxy; [0373] R.sup.a'' is absent,
hydrogen, or C.sub.1-C.sub.3 alkyl; [0374] R.sup.b is absent,
hydrogen, halogen, or C.sub.1-C.sub.3 alkyl; [0375] R.sup.b' is
hydrogen, halogen, --OH, oxo, or C.sub.1-C.sub.3 alkyl; [0376]
R.sup.b'' is hydrogen or --OH; [0377] each R.sup.c is independently
hydrogen, --OH, oxo, or C.sub.1-C.sub.3 alkyl; [0378] each R.sup.c'
is independently hydrogen or C.sub.1-C.sub.3 alkyl; [0379]
R.sup.c'' is hydrogen, --OH, C.sub.1-C.sub.3 alkyl, or
--C(.dbd.O)H; [0380] each R.sup.d is independently hydrogen, --OH,
--COOH, alkyl (e.g., alkylene, alkenyl, or alkynyl), heteroalkyl,
or each R.sup.d is taken together to form an oxo, wherein the alkyl
or heteroalkyl is optionally substituted; [0381] R.sup.d' is
hydrogen, --OH, C.sub.1-C.sub.3 alkyl (e.g., alkylene or alkenyl),
or heteroalkyl; [0382] or one R.sup.d is taken together with
R.sup.d' to form a substituted or unsubstituted cycloalkyl or
heterocycloalkyl; [0383] R.sup.1, R.sup.2, and R.sup.5 are each
independently selected from one or more of the group consisting of
hydrogen, oxo, halo, alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, alkoxy, amino (e.g., dihydroamino, alkylamino,
arylamino), hydroxyl, and thiol, wherein the alkyl, heteroalkyl,
cycloalkyl, and heterocycloalkyl is optionally substituted; [0384]
R.sup.6'' is oxo or --OH; [0385] Y.sup.1 and Y.sup.2 are each
independently a bond or alkylene; [0386] G is O or CH.sub.2; [0387]
g is 1 or 2; [0388] R.sup.10 is alkyl or H; and [0389] L is a
linker, [0390] or a pharmaceutically acceptable salt or solvate
thereof.
[0391] In some embodiments, any one of Re, R.sup.a', R.sup.b,
R.sup.b', R.sup.b'', R.sup.c, R.sup.c'', R.sup.d, or R.sup.d' is an
ester radical, a hydroxyl radical, or a carboxylate radical, and
any one of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.6', R.sup.6'', or R.sup.10 is a thiol radical, a hydroxyl
radical, or a carboxylate radical. In some embodiments, any one of
Re, R.sup.a', R.sup.b, R.sup.b', R.sup.b'', R.sup.c, R.sup.c',
R.sup.d, or R.sup.d' is adjoined to any one of R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.6', R.sup.6'', or R.sup.10 by a
linker. In some embodiments, any one of R.sup.d, R.sup.a', R.sup.b,
R.sup.b', R.sup.b'', R.sup.c'', R.sup.d, or R.sup.d' is adjoined to
any one of R.sup.4, R.sup.5, R.sup.6, R.sup.6', R.sup.6'', or
R.sup.10 by a linker. In some embodiments, any one of R.sup.d or
R.sup.d' is adjoined to any one of R.sup.4, R.sup.5, R.sup.6,
R.sup.6', R.sup.6'', or R.sup.10 by a linker. In some embodiments,
the linker is a bond.
[0392] In some embodiments, the linker is a bond, alkyl,
heteroalkyl, or alkoxy, wherein the alkyl, heteroalkyl, or alkoxy
is optionally substituted. In some embodiments, the alkyl,
heteroalkyl, or alkoxy are each independently substituted with one
or more groups, each group being independently selected from the
group consisting of a bond, --O--, --S--, silicone, amino,
optionally substituted alkyl (e.g., alkenyl, alkynyl, branched
(e.g., polypropylene), haloalkyl), optionally substituted
heteroalkyl (e.g, polyTHF), and optionally substituted cycloalkyl.
In some embodiments, the linker is a bond. In some embodiments, the
linker is alkyl (alkylene) and the alkyl (alkylene) is substituted
with one or more groups selected from --OH, halo, oxo, alkyl,
heteroalkyl, cycloalkyl, and heterocycloalkyl. In some embodiments,
the linker is alkyl (alkylene) and the alkyl (alkylene) is an
unsubstituted alkylene. In some embodiments, the linker is
heteroalkyl (heteroalkylene) and the heteroalkyl (heteroalkylene)
is substituted with one or more groups selected from halo or alkyl.
In some embodiments, the linker is heteroalkyl (heteroalkylene) and
is the heteroalkyl (heteroalkylene) an unsubstituted
heteroalkylene. In some embodiments, the linker comprises one or
more linker groups selected from a bond, --O--, --S--,
unsubstituted alkylene, C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O,
C.dbd.O(CHCH).sub.nC.dbd.O,
C.dbd.O(OCH.sub.2CH.sub.2O).sub.nC.dbd.O,
O(CH.sub.2CH.sub.2O).sub.n, and C.dbd.O(CH.sub.2CH.sub.2O).sub.n,
(CH(CH.sub.3)C(.dbd.O)O).sub.n, wherein n is 1-20. In some
embodiments, the linker is a bond, unsubstituted alkylene,
C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O, C.dbd.O(CHCH).sub.nC.dbd.O,
C.dbd.O(OCH.sub.2CH.sub.2O).sub.nC.dbd.O,
O(CH.sub.2CH.sub.2O).sub.n, and C.dbd.O(CH.sub.2CH.sub.2O).sub.n,
(CH(CH.sub.3)C(.dbd.O)O).sub.n,
C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O(CH(CH.sub.3)C(.dbd.O)O).sub.n,
wherein n is 1-20.
[0393] In some embodiments, the linker comprises one or more linker
group, each linker group being independently selected from the
group consisting of a bond, alkyl, cycloalkyl, heteroalkyl, or
alkoxy, wherein the alkyl, cycloalkyl, heteroalkyl, or alkoxy is
optionally substituted. In some embodiments, the alkyl, cycloalkyl,
heteroalkyl, or alkoxy are each independently substituted with one
or more substituent, each substituent being independently selected
from the group consisting of --O-- (e.g., --OH), --S-- (e.g.,
--SH), silicone, amino, optionally substituted alkyl (e.g.,
alkenyl, alkynyl, branched (e.g., polypropylene), haloalkyl),
optionally substituted heteroalkyl (e.g, polyTHF), and optionally
substituted cycloalkyl. In some embodiments, the linker comprises
one or more linker group, each linker group being independently
selected from the group consisting of alkyl (alkylene) and
cycloalkyl (cycloalkylene), and the alkyl (alkylene) or cycloalkyl
(cycloalkylene) is unsubstituted or substituted (e.g., with one or
more substituent each substituent being independently selected from
the group consisting of --OH, halo, oxo, alkyl, heteroalkyl,
cycloalkyl, and heterocycloalkyl). In some embodiments, the linker
comprises an unsubstituted or substituted
alkylene-cycloalkylene-alkylene. In some embodiments, the linker
comprises one or more linker group, each linker group being
independently selected from the group consisting of a bond, --O--,
--O(C.dbd.O)--, --O(C.dbd.O)--O--, --S--, unsubstituted alkylene,
unsubstituted cycloalkylene,
C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O, C.dbd.O(CHCH).sub.nC.dbd.O,
C.dbd.O(OCH.sub.2CH.sub.2O).sub.nC.dbd.O,
O(CH.sub.2CH.sub.2O).sub.n, and C.dbd.O(CH.sub.2CH.sub.2O).sub.n,
and (CH(CH.sub.3)C(.dbd.O)O).sub.n, wherein n is 1-20. In some
embodiments, the linker is a bond, unsubstituted alkylene,
unsubstituted alkylene-cycloalkylene-alkylene,
C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O, C.dbd.O(CHCH).sub.nC.dbd.O,
C.dbd.O(OCH.sub.2CH.sub.2O).sub.nC.dbd.O,
O(CH.sub.2CH.sub.2O).sub.n, and C.dbd.O(CH.sub.2CH.sub.2O).sub.n,
(CH(CH.sub.3)C(.dbd.O)O).sub.n,
C.dbd.O(CH.sub.2CH.sub.2).sub.nC.dbd.O(CH(CH.sub.3)C(.dbd.O)O).sub.n,
wherein n is 1-20. In some embodiments, n is 1-10. In some
embodiments, n is 6. In some embodiments, n is 5. In some
embodiments, n is 4. In some embodiments, n is 3. In some
embodiments, n is 2. In some embodiments, n is 1.
[0394] In some embodiments, the linker is hydrolyzed in a buffered
solution. In some embodiments, the linker is hydrolyzed by an
enzyme. In some embodiments, the enzyme is a hydrolase (e.g., a
protease or an esterase).
[0395] In some embodiments, the first radical is a (e.g., hydroxyl
or carboxyl) radical of a compound selected from the group
consisting of:
##STR00093## ##STR00094## ##STR00095## ##STR00096##
##STR00097##
[0396] In some embodiments, the second radical is a (e.g., hydroxyl
or carboxyl) radical of a compound selected from the group
consisting of:
##STR00098## ##STR00099## ##STR00100##
[0397] In some embodiments, the second radical is a (e.g., hydroxyl
or carboxyl) radical of a compound selected from the group
consisting of:
##STR00101## ##STR00102##
[0398] In some embodiments, the second radical is a radical of a
drug. In some embodiments, the drug is a prostaglandin. In some
embodiments, the prostaglandin is selected from the group
consisting of latanoprost, latanoprost acid, travoprost, travoprost
acid, tafluprost, tafluprost acid, bimatoprost, bimatoprost acid,
sepetaprost, and sepetaprost acid, or a fragment or radical of any
of the foregoing.
[0399] In some embodiments, the second radical is a (e.g., hydroxyl
or carboxyl) radical of a compound selected from the group
consisting of:
##STR00103## ##STR00104##
[0400] In some embodiments, the disclosure provides a compound for
glaucoma, or pharmaceutically acceptable salt thereof, having a
structure provided in Table 3. In some embodiments, parent
conjugate compounds that form articles (e.g., pellets), using
methods described in the examples herein, are shown in Table 3. In
some embodiments, the compound for glaucoma, or pharmaceutically
acceptable salt thereof, provided in Table 3 is a solid at a
temperature of at least 20.degree. C. In some embodiments, the
compound for glaucoma, or pharmaceutically acceptable salt thereof,
provided in Table 3 is processable at a temperature of at least
20.degree. C. In some embodiments, the compound for glaucoma, or
pharmaceutically acceptable salt thereof, provided in Table 3 is
processable into an article, as described herein, at a temperature
of at least 20.degree. C. In some embodiments, the compound for
glaucoma, or pharmaceutically acceptable salt thereof, provided in
Table 3 comprises a first radical that is processable in its free
form and a second radical that is not processable in its free form.
In some embodiments, the compound for glaucoma in Table 3 is
processable when the first radical that is processable in its free
form and the second radical that is not processable in its free
form are joined by a linker. In some embodiments, the linker is a
bond. In some embodiments, the linker comprises one more linker
group, each linker group being independently selected from the
group consisting of a bond, alkyl or cycloalkyl, wherein the alkyl
or cycloalkyl may optionally be substituted. In some embodiment the
linker forms, together with the first and/or the second radical, an
ether. In some embodiment the linker forms, together with the first
and/or the second radical, an ester. In some embodiment the linker
forms, together with the first and/or second radical, a
carbonate.
TABLE-US-00003 TABLE 3 Compound Number Structure Name 1
##STR00105## 2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13-
dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15,16,17- dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7-
((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3-
(trifluoromethyl)phenoxy) but-1-en-1- yl)cyclopentyl)hept-5- enoate
2 ##STR00106## 2- ((8S,9R,10S,11S,13S,14S, 16R,17R)-9-fluoro-11,17-
dihydroxy-10,13,16- trimethyl-3-oxo-
6,7,8,9,10,11,12,13,14,15,16,17- dodecahydro- 3H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7-
((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3- hydroxy-4-(3-
(trifluoromethyl)phenoxy)but- 1-en-1- yl)cyclopentyl)hept-5- enoate
3 ##STR00107## 2- ((8S,9R,10S,11S,13S,14S,16R,17R)- 9-fluoro-11,7-
dihydroxy-10,13,16- trimethyl-3-oxo-
6,7,8,9,10,11,12,13,14,15,16,17- dodecahydro- 3H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7-
((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5-
phenylpentyl)cyclopentyl) hept-5-enoate 4 ##STR00108##
(8R,9S,13S,14S)-13- methyl-17-oxo- 7,8,9,11,12,13,14,15,16,17-
decahydro-6H- cyclopenta[a]phenanthren- 3-yl(Z)-7-
((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5-
phenylpentyl)cyclopentyl) hept-5-enoate 5 ##STR00109##
2-((8S,10S,13S,14S,17R)- 17-hydroxy-10,13- dimethyl-3-oxo-
2,3,6,7,8,10,12,13,14,15,16,17- dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7-
((1R,2R,3R,5S)-3,5- dihydroxy-2-((S,E)-3- hydroxy-5-phenylpent-1-
en-1-yl)cyclopentyl)hept- 5-enoate 6 ##STR00110##
2-((8S,14S,17R)-17- hydroxy-10,13-dimethyl- 3-oxo-
2,3,6,7,8,10,12,13,14,15,16,17- dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7-
((1R,2R,3R,5S)-3,5- dihydroxy-2-((R)-3- hydroxy-5-
phenylpentyl)cyclopentyl) hept-5-enoate 7 ##STR00111##
2-((8S,14S,17R)-17- hydroxy-10,13-dimethyl- 3-oxo-
2,3,6,7,8,10,12,13,14,15,16,17- dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl(Z)-7-
((1R,2R,3R,5S)-2-((E)-3,3- difluoro-4-phenoxybut-1- en-1-yl)-3,5-
dihydroxycyclopentyl)hept- 5-enoate 8 ##STR00112##
(4-((((2-((8S,14S,17R)-17- hydroxy-10,13-dimethyl- 3-oxo-
2,3,6,7,8,10,12,13,14,15,16,17- dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2- oxoethoxy)carbonyl)oxy)
methyl)cyclohexyl)methyl) (Z)-7-((1R,2R,3R,55)-3,5-
dihydroxy-2-((R,E)-3- hydroxy-4-(3- (trifluoromethyl)phenoxy)
but-1-en-1- yl)cyclopentyl)hept-5- enoate 9 ##STR00113##
(4R,4aS,7aR,12bS)-3- (cyclopropylmethyl)-4a- hydroxy-7-oxo-
2,3,4,4a,5,6,7,7a- octahydro-1H-4,12- methanobenzofuro[3,2-
e]isoquinolin-9-yl(Z)-7- ((1R,2R,3R,5S)-3,5- dihydroxy-2-((R,E)-3-
hydroxy-4-(3- (trifluoromethyl)phenoxy) but-1-en-1-
yl)cyclopentyl)hept-5- enoate 10 ##STR00114##
(S)-1-(tert-butylamino)- 3-((4-morpholino-1,2,5- thiadiazol-3-
yl)oxy)propan-2-yl(R)-4- ((3R,5R,8R,9S,10S,12S,13R,14S,17R)- 3,12-
dihydroxy-10,13- dimethylhexadecahydro- 1H-
cyclopenta[a]phenanthren- 17-yl)pentanoate 11 ##STR00115##
(S,E)-1-((1R,2R,3S,5R)-2- ((Z)-7-(ethylamino)-7-
oxohept-2-en-1-yl)-3,5- dihydroxycyclopentyl)-5-
phenylpent-1-en-3-yl(2- ((8S,10S,13S,14S,17R)- 17-hydroxy-10,13-
dimethyl-3-oxo- 2,3,6,7,8,10,12,13,14,15,16,17- dodecahydro-1H-
cyclopenta[a]phenanthren- 17-yl)-2-oxoethyl) carbonate
Preparation of Compounds
[0401] The compounds used in the reactions described herein are
made according to organic synthesis techniques known to those
skilled in this art, starting from commercially available chemicals
and/or from compounds described in the chemical literature.
"Commercially available chemicals" are obtained from standard
commercial sources including Acros Organics (Pittsburgh, Pa.),
Aldrich Chemical (Milwaukee, Wis., including Sigma Chemical and
Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research
(Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall,
U.K.), Chemservice Inc. (West Chester, Pa.), Crescent Chemical Co.
(Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman Kodak Company
(Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.), Fisons
Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah),
ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics (Cornwall,
U.K.), Lancaster Synthesis (Windham, N.H.), Maybridge Chemical Co.
Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah), Pfaltz
& Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),
Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,
Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCI
America (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville,
Md.), and Wako Chemicals USA, Inc. (Richmond, Va.).
[0402] Suitable reference books and treatise that detail the
synthesis of reactants useful in the preparation of compounds
described herein, or provide references to articles that describe
the preparation, include for example, "Synthetic Organic
Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et
al., "Organic Functional Group Preparations," 2nd Ed., Academic
Press, New York, 1983; H. O. House, "Modern Synthetic Reactions",
2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.
Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley &
Sons, New York, 1992; J. March, "Advanced Organic Chemistry:
Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience,
New York, 1992. Additional suitable reference books and treatise
that detail the synthesis of reactants useful in the preparation of
compounds described herein, or provide references to articles that
describe the preparation, include for example, Fuhrhop, J. and
Penzlin G. "Organic Synthesis: Concepts, Methods, Starting
Materials", Second, Revised and Enlarged Edition (1994) John Wiley
& Sons ISBN: 3-527-29074-5; Hoffman, R. V. "Organic Chemistry,
An Intermediate Text" (1996) Oxford University Press, ISBN
0-19-509618-5; Larock, R. C. "Comprehensive Organic
Transformations: A Guide to Functional Group Preparations" 2nd
Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced
Organic Chemistry: Reactions, Mechanisms, and Structure" 4th
Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera,
J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN:
3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of
Functional Groups" (1992) Interscience ISBN: 0-471-93022-9;
Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John
Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C.,
"Intermediate Organic Chemistry" 2nd Edition (1993)
Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic
Chemicals: Starting Materials and Intermediates: An Ullmann's
Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in
8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons,
in over 55 volumes; and "Chemistry of Functional Groups" John Wiley
& Sons, in 73 volumes.
[0403] Specific and analogous reactants are optionally identified
through the indices of known chemicals prepared by the Chemical
Abstract Service of the American Chemical Society, which are
available in most public and university libraries, as well as
through on-line databases (contact the American Chemical Society,
Washington, D.C. for more details). Chemicals that are known but
not commercially available in catalogs are optionally prepared by
custom chemical synthesis houses, where many of the standard
chemical supply houses (e.g., those listed above) provide custom
synthesis services. A reference for the preparation and selection
of pharmaceutical salts of the dual-acting meibomian gland
dysfunction pharmacological agent described herein is P. H. Stahl
& C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag
Helvetica Chimica Acta, Zurich, 2002.
Pharmaceutical Compositions
[0404] In some embodiments, the compound described herein has a
structure provided in any one of Formula (I), Formula (IA), Formula
(IB'), Formula (IB), Formula (IC), Formula (II), Formula (IIA),
Formula (IIB), Formula (III), Formula (IV), or Formula (V). In
certain embodiments, the compounds as described herein is
administered as a pure chemical. In other embodiments, the compound
described herein is combined with a pharmaceutically suitable or
acceptable carrier (also referred to herein as a pharmaceutically
suitable (or acceptable) excipient, physiologically suitable (or
acceptable) excipient, or physiologically suitable (or acceptable)
carrier selected on the basis of a chosen route of administration
and standard pharmaceutical practice as described, for example, in
Remington: The Science and Practice of Pharmacy (Gennaro, 21.sup.st
Ed. Mack Pub. Co., Easton, Pa. (2005)).
[0405] One embodiment provides a pharmaceutical composition
comprising any compound provided herein, such as a compound that
has the structure of any one of Formula (I), Formula (IA), Formula
(IB'), Formula (IB), Formula (IC), Formula (II), Formula (IIA),
Formula (IIB), Formula (III), Formula (IV), Formula (V), Formula
(VI), Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula
(VII), Formula (VII-A), Formula (VII-B), Formula (VIII), Formula
(VIII-A), Formula (VIII-B), Formula (IX), or Formula (X), or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable excipient. Another embodiment provides
the pharmaceutical composition, wherein the pharmaceutical
composition is suitable for ophthalmic administration. Another
embodiment provides the pharmaceutical composition, wherein the
pharmaceutical composition is suitable for intraocular ophthalmic
administration. In some embodiments, intraocular ophthalmic
administration is intraocular, subretinal, superciliary, forniceal,
into Schlemm's canal, inside a bleb, intracameral, intravitreal,
suprachoroidal, punctal, retrobulbar, or subconjunctival.
[0406] In some embodiments, any composition provided herein, such
as containing a compound as described by any one of Formula (I),
Formula (IA), Formula (IB'), Formula (IB), Formula (IC), Formula
(II), Formula (IIA), Formula (IIB), Formula (III), Formula (IV),
Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula
(VI-C), Formula (VII), Formula (VII-A), Formula (VII-B), Formula
(VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX), or
Formula (X), (or pharmaceutically acceptable salt thereof)
comprises an optional additional component, in that it contains
less than about 5%, or less than about 1%, or less than about 0.1%,
of other molecules, such as, for example, impurities, synthetic
materials (e.g., unreacted starting materials (e.g., a steroid
provided herein in its free form), hydrolyzed materials (e.g., a
steroid provided herein in its free form), unreacted intermediates,
or the like) or byproducts (e.g., synthesis by-products or
processing by-products, such as produced by heat processing,
solvent processing, and/or sterilization).
[0407] In some embodiments, any article or implant provided herein,
such as containing a compound as described by any one of Formula
(I), Formula (IA), Formula (IB'), Formula (IB), Formula (IC),
Formula (II), Formula (IIA), Formula (IIB), Formula (III), Formula
(IV), Formula (V), Formula (VI), Formula (VI-A), Formula (VI-B),
Formula (VI-C), Formula (VII), Formula (VII-A), Formula (VII-B),
Formula (VIII), Formula (VIII-A), Formula (VIII-B), Formula (IX),
or Formula (X), (or pharmaceutically acceptable salt thereof) is
substantially pure, in that it contains less than about 5%, or less
than about 1%, or less than about 0.1%, of other organic small
molecules, such as, for example, impurities, synthetic materials
(e.g., unreacted starting materials (e.g., a steroid provided
herein in its free form), hydrolyzed materials (e.g., a steroid
provided herein in its free form), unreacted intermediates, or the
like) or byproducts (e.g., synthesis by-products or processing
by-products, such as produced by heat processing, solvent
processing, and/or sterilization).
[0408] In certain embodiments, any compound provided herein, such
as the compound as described by any one of Formula (I), Formula
(IA), Formula (IB'), Formula (IB), Formula (IC), Formula (II),
Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula
(V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C),
Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII),
Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X),
(or pharmaceutically acceptable salt thereof) is substantially
pure, in that it contains less than about 5%, or less than about
1%, or less than about 0.1%, of other organic small molecules, such
as impurities, unreacted intermediates or byproducts (e.g.,
synthesis by-products or processing by-products, such as produced
by heat processing, solvent processing, and/or sterilization).
[0409] In certain embodiments, any compound provided herein, such
as the compound as described by any one of Formula (I), Formula
(IA), Formula (IB'), Formula (IB), Formula (IC), Formula (II),
Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula
(V), Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C),
Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII),
Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X),
(or pharmaceutically acceptable salt thereof) is a pharmaceutical
implant or article. In some embodiments, the implant or article
comprises at least 50 wt. % (at least 60 wt. %, at least 70 wt. %,
at least 80 wt. %, at least 90 wt. %, at least 95 wt. %, at least
98 wt. %, or the like) of the compound and/or pharmaceutically
acceptable salt thereof. In some embodiments, the implant or
article releases (such as by surface erosion) the compound, the
first radical, and/or the second radical (and/or other (e.g.,
active) fragment or metabolite of the compound). In some
embodiments, release is at or near zero-order (e.g., in an aqueous
medium, such as in a buffer solution, serum, biological
environment, in vivo, or the like, such as at a physiological
temperature (e.g., 37.degree. C.). In some embodiments, the first
radical and the second radical are released from the pharmaceutical
implant or article at 37.degree. C. in 100% bovine serum or at
37.degree. C. in phosphate buffered saline (PBS) at a rate such
that t.sub.10 is greater than or equal to 1/10 of t.sub.50. In some
embodiments, the first radical and the second radical are released
from the pharmaceutical implant or article at 37.degree. C. in
mixture of fetal bovine serum (FBS) and phosphate buffered saline
(PBS) (e.g., 1% FBS in PBS) at a rate such that t.sub.10 is greater
than or equal to 1/10 of t.sub.50.
[0410] In some embodiments, certain forms of pharmaceutical
compositions described herein (e.g., fibers, fiber meshes, woven
fabrics, non-woven fabrics, pellets, cylinders, rods, hollow tubes,
microparticles (e.g., microbeads), nanoparticles (e.g., nanobeads),
or other shaped articles) provide a controllable surface area. In
some embodiments, the controllable surface area is injected, does
not require removal after completion of drug release, and allows
for tailoring of drug release rates for a given indication. In
certain embodiments, methods provided herein do not require (or
comprise) removal of an article or implant, or residual materials
or components thereof (e.g., because the implant is completely or
almost completely (e.g., bio- or physiologically) degraded or
degradable (e.g., at least 80 wt. %, at least 85 wt. %, at least 90
wt. %, at least 95 wt. %, at least 98 wt. %, at least 99 wt. %, or
the like)).
[0411] In some embodiments, the implants, articles, or compositions
described herein are amorphous. In some embodiments, the implants,
articles, or compositions described herein are formed by heat-based
and solvent based processing methods. Non-limiting examples of heat
processing methods include heat molding, injection molding,
extrusion, 3D printing, melt electrospinning, fiber spinning, fiber
extrusion, and/or blow molding. Non-limiting examples of solvent
processing include coating, micro printing, dot printing,
micropatterning, fiber spinning, solvent blow molding, emulsions,
electrospraying, and electrospinning. In some embodiments,
processing methods to form an intermediate glassy state of any of
the above heat and solvent based methods as well as heat and
solvent based methods that lead to glassy state material with no
defined shape (e.g. spray drying, lyophilization, powder melting,
etc.).
[0412] The term "glassy state," as used herein, generally refers to
an amorphous solid including greater than 70%, 80%, 90%, 95%, 98%,
or 99% (w/w) of compositions, articles, or implants described
herein. In some embodiments, the compositions, articles, or
implants described herein exhibit a glass transition temperature
above 38.degree. C. In the glassy state, as measured by
differential scanning calorimetry (DSC), X-ray powder diffraction
(XRD), or polarized light microscopy (PLM), the level of
crystallinity is, for example, from 0-15% (e.g., less than 1%,
0-1%, 0-3%, 0-5%, 0-7%, 0-9%, 0-10%, or 0-13%). In some
embodiments, glass formulations are formed using heat processing or
solvent processing methods described herein (e.g., in the
examples).
[0413] In some embodiments, the pharmaceutical compositions
described herein are prepared by electrospinning. In some
embodiments, the pharmaceutical compositions of the disclosure are
dissolved in a solvent (e.g., acetone) at concentrations ranging
from, e.g., 10-30% w/v, and are electrosprayed to form micro- and
nanoparticles. In some embodiments, the solution is loaded into a
syringe and injected at a rate (e.g., 0.5 mL/h) onto a stationary
collection plate. In some embodiments, a potential difference
(e.g., 18 kV) is maintained between the needle and collecting
surface. For example, in certain embodiments, a concentration of
10% w/v is used to obtain nanoparticles. In other embodiments, a
concentration of 30% w/v is used to obtain micro particles.
[0414] The pharmaceutical compositions of the disclosure are
dissolved in a solvent (e.g., THF, or 1:1 ratio of DCM/THF). In
some embodiments, the solution is loaded into a syringe and
injected at a rate (e.g., 0.5 mL/h) onto a cylindrical mandrel
rotating at a particular rotational speed, e.g., 1150 rpm, to
obtain aligned fibers, or onto a stationary collector surface to
obtain unaligned fibers. In some embodiments, a potential
difference (e.g., 18 kV or 17 kV) is maintained between the needle
and collecting surface for aligned and random fibers.
[0415] In other embodiments, fibers are prepared from the melt at
elevated temperatures, the glassy state intermediate, or from the
solution by dissolving the pharmaceutical compositions described
herein in a solvent (e.g., DCM, THF, or chloroform). As used
herein, "melt spinning" describes heat processing from the melt
state, "heat spinning" describes heat processing from the glassy
state, and "wet", "dry", and "gel" spinning describe solution
processing.
[0416] In some embodiments, the viscous melt, intermediate, or
solution is fed through a spinneret and fibers are formed upon
cooling (melt or heat spinning) or following solvent evaporation
with warm air as the compound exits the spinneret (dry spinning).
In some embodiments, wet spinning and gel spinning are used to
produce the fibers disclosed herein. "Heat spinning," as used
herein, describes a process that is similar to the melt spinning,
but performed with a glassy state intermediate and heated above the
glass transition temperature (T.sub.g), obtaining the viscous fluid
to extrude/spin instead of the melt. Alternatively, tweezers may be
dipped into melted material or concentrated solutions and retracted
slowly in order to pull fibers. The rate of pulling and distance
pulled may be varied to yield fibers and columnar structures of
different thickness.
[0417] In some embodiments, micro-particles or nano-particles made
from the pharmaceutical composition are formed using an emulsion
process. In some embodiments, the pharmaceutical composition is
dissolved in an organic solvent (e.g. DCM, THF, etc.). In some
embodiments, a surfactant (e.g. SDS, PVA, etc.) is added (e.g. 1%)
to the solution/mixture. In some embodiments, the resulting mixture
is stirred for the appropriate time at room temperature to form an
emulsion. In some embodiments, the emulsion is subsequently added
to Milli-Q water under stirring for an appropriate time (e.g., 1 h)
to remove residual solvent. The resulting micro- or nano-particles
may be collected by centrifugation and dried.
[0418] In some embodiments, injectable cylinders or rods made from
a pharmaceutical composition described herein is formed by heat
extrusion. In some embodiments, the pharmaceutical composition is
loaded into a hot melt extruder, heated to a temperature above the
melting point (e.g., for crystalline compositions) or glass
transition temperature (e.g., for pre-melted or amorphous
compositions), and extruded using (i) a compressive force to push
the material through the nozzle and (ii) a tensile force (or
gravity) to pull the material out of the extruder. The extrudate
may be cut to the desired length for suitable drug dosing for a
medical indication.
[0419] In some embodiments, a milling process is used to reduce the
size of an article described to form sized particles, e.g., beads,
in the micrometer (microbeads) to nanometer size range (nanobeads).
The milling process may be performed using a mill or other suitable
apparatus. In some embodiments, dry and wet milling processes, such
as, for example, jet milling, cryo-milling, ball milling, media
milling, sonication, and homogenization are used in methods
described herein. In some embodiments, heating of the milled
microparticle above the T.sub.g is performed to achieve a spherical
shape. In some embodiments, particles with non-spherical shapes are
used as milled.
[0420] In certain embodiments, a composition described herein has a
limited window (e.g., short timeframe of seconds to minutes) of
thermal stability, whereby the purity of the dimer is affected
(e.g., minimally) at elevated temperatures. In some embodiments, an
intermediate glassy state form (e.g., film, surface coating,
pellet, micro-particles, or other shaped article) is made to avoid
decomposition. In some embodiments, heat or solvent processing is
used to remove or reduce the crystallinity of the material to form
a glassy state composition. In some embodiments, the glassy state
composition is heat processed at a lower temperature (e.g.,
processing just above the glass transition temperature (T.sub.g),
and below the melt temperature (T.sub.m)). In some embodiments, the
lower temperature allows for a longer timeframe for heat processing
the glassy state material into the final shaped article, while
reducing the impact of processing conditions on the purity of the
prodrug dimer in the article.
[0421] Exemplary processing details are provided in the
Examples.
[0422] In some embodiments, the processable compound as described
by any one of Formula (I), Formula (IA), Formula (IB'), Formula
(IB), Formula (IC), Formula (II), Formula (IIA), Formula (IIB),
Formula (III), Formula (IV), Formula (V), Formula (VI), Formula
(VI-A), Formula (VI-B), Formula (VI-C), Formula (VII), Formula
(VII-A), Formula (VII-B), Formula (VIII), Formula (VIII-A), Formula
(VIII-B), Formula (IX), or Formula (X), is formulated for
administration by injection. In some instances, the injection
formulation is an solid formulation. In some instances, the
injection formulation is a non-aqueous formulation.
[0423] In certain aspects, the pharmaceutical compositions
described herein provide an article (e.g., as described herein)
with a controlled release profile (e.g., by surface erosion). In
some embodiments, the surface erosion allows the article to
maintain its physical form, while gradually decreasing in size as
the surface erodes (e.g., at a constant rate), rather than by, for
example, bulk erosion that is characteristic of some polymer-based
drug release vehicles (e.g., polylactic/glycolic acid). In some
embodiments, the surface erosion inhibits burst release and/or
reduces the formation of inflammatory particulates (e.g., no or
minimal crystalline particulates are formed or released from the
articles when drug is released as described herein). In some
embodiments, compositions described herein are delivered over a
period of time. For example, a slower and steadier rate of delivery
(e.g., release of less than 10% of the first radical or the second
radical in their free form (as a percentage of the total drug, the
first radical or the second radical in their free form, present in
the article) at 37.degree. C. in 100% bovine serum over 5 days)
results in a reduction in the frequency with which the
pharmaceutical composition is administered to a subject and/or
improve the safety profile of the drug. In some embodiments, the
drug release is tailored to avoid side effects of slower and longer
release of the drug by engineering the article to provide constant
release over a comparatively shorter period of time. In some
embodiments, the drug release is tailored for dose and duration
suitable for the indication or administration method.
[0424] In some embodiments, the release rate is related to, for
example, the drug configuration of the dimer. In some embodiments,
the drug release rate from an article described herein is modulated
by the cleavage of dimer-linker bond through hydrolysis or
enzymatic degradation. In some embodiments, the linking moiety
(e.g., the linker) affects drug release rate. In some embodiments,
the drug release rate is controlled by a functional group on the
composition described herein to conjugate through to the linker,
for example, a primary vs. a secondary hydroxyl group. In some
embodiments, the release rate from a dimer is related to percentage
of the loaded dimer compared to the final drug dimer formulation
(e.g., by using a pharmaceutical excipient (e.g., bulking
agent/excipient). In some embodiments, the release rate is
controlled by the size of a microbead. In some embodiments, drug
release is tailored based on the solubility of drug dimer (e.g.,
through selection of appropriate drug and/or linker) that will
influence the rate of surface erosion (e.g.,
dissolution/degradation) from the article. In other embodiments,
drug release is affected by changes in surface area of the
formulation, e.g., by changing the diameter of the microbeads. By
adjusting the vide supra factors, dissolution, degradation,
diffusion, and controlled release may be varied over wide ranges.
For example, release may be designed to be initiated over minutes
to hours, and may extend over the course of days, weeks, months, or
years.
[0425] In some instances, provided herein is a heat processed
pellet (e.g., FIGS. 2B, 3B, 5B, 7B, 8B, 9B, 15B, and 19B) or rod
(e.g., FIGS. 10A, 11A, 12A, and 13A) of a heterodimer (e.g., a
steroid-prostaglandin heterodimer) (e.g., FIGS. 2A, 3A, 5A, 6A, 7A,
8A, 9A, 15A, and 19A) exemplified herein. In some instances,
provided herein is a drug release profile of a pellet (e.g., FIGS.
2C, 2D, 3C, 3D, 5C, 5D, 6B, 6C, 7C, 7D, 8C, 8D, 9C, 9D, and 15C) or
a rod (FIGS. 10B, 10C, 11B, 12B, 12C, 13B, and 13C) provided herein
in fetal bovine serum (FBS), phosphate-buffered saline (PBS), or a
combination thereof over a period (e.g., an extended period is
time) of time (e.g., 15 days, 30 days, 60 days, 90 days, 120 days,
365 days, or more). In some instances, the release profile of a
composition provided herein (e.g., a steroid-prostaglandin
heterodimer derived pellet) is measured as the change (e.g.,
increase) in concentration of one or more drug (e.g., a steroid
and/or a prostaglandin) in a solution over a period of time. In
some instances, the release profile of a composition provided
herein (e.g., a steroid-prostaglandin heterodimer derived pellet)
is measured as an increase in concentration of a steroid over a
period of time. FIG. 8C illustrates release of both steroid and
prostaglandin in FBS. As is illustrated, both steroid and
prostaglandin have similar release profiles. It is expected that
because steroid and prostaglandin are directly linked, there should
be an identical release profile. However, the steroid and
prostaglandin appear to have slightly differing release profile at
many time points, e.g., as a function of greater difficulty in
detecting one of the chromophores (e.g., prostaglandin or steroid)
over the other of the chromophores (e.g., steroid or
prostaglandin). Other figures demonstrating drug release illustrate
release of prostaglandins, which may be overestimated or
underestimated as a result of detection methods. However, other
figures demonstrate that the various compounds provided herein and
illustrated therein demonstrate release of prostaglandin (and,
implicitly, steroid). As such this data demonstrates a platform for
providing compounds and implants (e.g., with high drug content, low
excipient content (e.g., that needs to be removed), and other
benefits, such as described herein) that provide long-lasting
release of prostaglandins (and steroid) under desirable conditions.
In some instances, the release profile of a composition provided
herein (e.g., a steroid-prostaglandin heterodimer derived pellet)
is measured as an increase in concentration of a prostaglandin over
a period of time. In some instances, the release profile of a
composition provided herein (e.g., a steroid-prostaglandin
heterodimer derived pellet) is measured as an increase in
concentration of a steroid and a prostaglandin over a period of
time (e.g., FIG. 8B). In some instances, the increase in
concentration of one drug (e.g., a steroid) over a period of time
corresponds with the increase in concentration of another drug
(e.g., a prostaglandin) over a period of time. In some instances,
drug release (e.g., of prostaglandins) is difficult to analyze by
HPLC and UV techniques (e.g., poor chromophores), which may, for
instance, result in over-or under estimation of released amounts
(e.g., in particular for sustained release applications where
released amounts of prostaglandin analogs are present at low
amounts). In some instances, an increase of steroid concentration
in solution over a period of time is used to quantify a drug (e.g.,
prostaglandin) release profile.
[0426] In some embodiments, a pharmaceutical composition containing
a dimer described herein is administered to a subject by the
following non-limiting examples oral, sublingual, nasal,
intradermal, subcutaneous, intramuscular, rectal, vaginal,
intravenous, intraarterial, intracisternal, intraperitoneal,
intravitreal, periocular, topical (as by powders, creams,
ointments, or drops), buccal and inhalational administration. In
certain instances, the articles described herein are administered
parenterally as injections (intravenous, intramuscular, or
subcutaneous), or locally as injections (intraocularly or into a
joint space). In some embodiments, the formulations described
herein are admixed under sterile conditions with a pharmaceutically
acceptable carrier, preservatives and/or buffers.
[0427] In some embodiments, the implant, article, or composition
described herein is suitable for ophthalmic administration,
subcutaneous administration, or intraspinal administration. In some
embodiments, the ophthalmic administration is intraocular,
subretinal, superciliary, forniceal, into Schlemm's canal, inside a
bleb, intracameral, intravitreal, suprachoroidal, punctal,
retrobulbar, or subconjunctival.
[0428] In some instances, the implant, article, or composition
described herein is a coating on a device. In some instances, the
device is a contact lenses, a microshunt device, microinvasive
glaucoma surgery (MIGS) device, an intraocular lenses, or the
like.
[0429] The dose of the composition comprising at least one compound
as described herein differ, depending upon the patient's (e.g.,
human) condition, that is, general health status, age, and other
factors.
[0430] Pharmaceutical compositions are administered in a manner
appropriate to the disease to be treated (or prevented). An
appropriate dose and a suitable duration and frequency of
administration will be determined by such factors as the condition
of the patient, the type and severity of the patient's disease, the
particular form and/or potency of the active ingredient, and the
method of administration. In general, an appropriate dose and
treatment regimen provides the composition(s) in an amount
sufficient to provide therapeutic and/or prophylactic benefit
(e.g., an improved clinical outcome, such as more frequent complete
or partial remissions, or longer disease-free and/or overall
survival, or a lessening of symptom severity). Optimal doses are
generally determined using experimental models and/or clinical
trials. The optimal dose depends upon the body mass, weight, or
blood volume of the patient.
[0431] In other embodiments, the compositions described herein are
combined with a pharmaceutically suitable or acceptable carrier
(e.g., a pharmaceutically suitable (or acceptable) excipient,
physiologically suitable (or acceptable) excipient, or
physiologically suitable (or acceptable) carrier. Exemplary
excipients are described, for example, in Remington: The Science
and Practice of Pharmacy (Gennaro, 21.sup.st Ed. Mack Pub. Co.,
Easton, Pa. (2005)).
[0432] In certain aspects, provided herein is a method of treating
an ophthalmic, neurological, orthopedic, acute or chronic pain, or
post-operative disease or disorder in a patient in need of thereof,
comprising administering to the patient any compound provided
herein, or a pharmaceutically acceptable salt thereof, or a (e.g.,
pharmaceutical) composition comprising any compound provided
herein, or a pharmaceutically acceptable salt thereof, such as a
compound having a structure of any one of Formula (I), Formula
(IA), Formula (IB'), Formula (IB), Formula (IC), Formula (II),
Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula
(V) Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C),
Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII),
Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X).
In certain aspects, provided herein is a method of treating an
ophthalmic disease or disorder in a patient in need of thereof,
comprising administering to the patient any compound provided
herein, or a pharmaceutically acceptable salt thereof, or a (e.g.,
pharmaceutical) composition comprising any compound provided
herein, or a pharmaceutically acceptable salt thereof, such as a
compound having a structure of any one of Formula (I), Formula
(IA), Formula (IB'), Formula (IB), Formula (IC), Formula (II),
Formula (IIA), Formula (IIB), Formula (III), Formula (IV), Formula
(V) Formula (VI), Formula (VI-A), Formula (VI-B), Formula (VI-C),
Formula (VII), Formula (VII-A), Formula (VII-B), Formula (VIII),
Formula (VIII-A), Formula (VIII-B), Formula (IX), or Formula (X).
Another embodiment provides the method wherein the pharmaceutical
composition is in the form of a solid suitable for intraocular
ophthalmic administration (e.g., injection). In some embodiments,
intraocular ophthalmic administration is intraocular, subretinal,
superciliary, forniceal, into Schlemm's canal, inside a bleb,
intracameral, intravitreal, suprachoroidal, punctal, retrobulbar,
or subconjunctival.
[0433] Methods involving treating a subject may include preventing
a disease, disorder or condition from occurring in the subject
which may be predisposed to the disease, disorder and/or condition
but has not yet been diagnosed as having it; inhibiting the
disease, disorder or condition, e.g., impeding its progress; and
relieving the disease, disorder, or condition, e.g., causing
regression of the disease, disorder and/or condition. Treating the
disease or condition includes ameliorating at least one symptom of
the particular disease or condition, even if the underlying
pathophysiology is not affected (e.g., such treating the pain of a
subject by administration of an agent even though such agent does
not treat the cause of the pain).
[0434] Another embodiment provides the method wherein the
ophthalmic disease or disorder is selected from glaucoma, ocular
inflammation, diabetic macular edema, posterior inflammation,
anterior inflammation, macular degeneration (e.g., wet macular
degeneration (AMD) or dry AMD), post-cataract surgery, and retinal
vein occlusion. In some embodiments, the ocular disease or disorder
is glaucoma.
EXAMPLES
Example 1: Analytical Methods
Analytical Example 1: High Performance Liquid Chromatography
(HPLC)
[0435] Samples (20.0 mg) are dissolved in acetonitrile (10.0 mL) to
make 2 mg/mL solution. For the system: solvent A was Water+0.05%
trifluoroacetic acid (TFA); solvent B was Acetonitrile+0.05% TFA;
the flow rate was 1.0 mL/min; and the detection method was UV @242
nm and UV Spectra from 190 to 400 nm. The samples were loaded onto
an Agilent 1100 series HPLC with either (i) a Phenomenex Gemini-NX
C18 Column (5 .mu.m; 110 .ANG.; 250.times.4.6 mm; 00G-4454-E0) or
(ii) Phenomenex SecurityGuard Analytical Guard Column (KJO-4282)
with Gemini C18 4.times.3.0 mm Guard Cartridge (AJO-7597). The
solvent gradient profile is shown in Table 4
TABLE-US-00004 TABLE 4 Time (min) % A Solvent % B Solvent 0 80 20
40 16 84 42 0 100 50 0 100
Analytical Example 2: Nuclear Magnetic Resonance (NMR)
[0436] Compounds (10 mg) were dissolved in 666 uL of either
CDCl.sub.3 or DMSO-d6 and loaded in an 8-inch length, 5 mm diameter
NMR tube. The instrument was a Varian Mercury 400 NMR spectrometer.
Proton NMR spectra were obtained with 16 scans using the default
method. FIDs were processed with MestRe-C software.
Analytical Example 3: Mass Spectrometry (MS)
[0437] Compounds were dissolved in acetonitrile at 1 mg/ml and used
directly for analysis on an Agilent 6538 QTOF, using ESI MS+ as ion
source.
Analytical Example 4: Melting Point
[0438] Compound powder was prepared neat in a glass capillary tube,
and melting temperature was measured manually with standard glass
capillary tube melting point apparatus.
Analytical Example 5: Differential Scanning Calorimetry (DSC)
[0439] 5-10 mg of compounds were weighed in an aluminum pan. Using
a Hitachi Differential Scanning calorimeter DSC7020, samples were
heated from room temperature to 110-150.degree. C. at 10.degree.
C./min, cooled to -30.degree. C. at 10.degree. C./min, and heated
again to 110-150.degree. C. at 10.degree. C./min.
Example 2: Chemical Synthesis
[0440] Solvents, reagents and starting materials were purchased
from commercial vendors and used as received unless otherwise
described. All reactions were performed at room temperature unless
otherwise stated. Starting materials were purchased from commercial
sources or synthesized according to the methods described herein or
using literature procedures.
Chemical Synthesis Example 1
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethy-
l)phenoxy)but-1-en-1-yl)cyclopentyl)hept-5-enoic Acid (Travoprost
Acid)
##STR00116##
[0442] To a stirred solution of travoprost (1 g, 2.00 mmol) in MeOH
(16 mL) was added 1M NaOH.sub.(aq) (16 mL, 16 mmol) and the mixture
stirred for 16 h. The mixture was quenched into 0.5M HCl.sub.(aq)
(32 mL, 16 mmol) and the aqueous extracted with DCM (2.times.100
mL). The DCM layers were combined dried (MgSO.sub.4) and
concentrated to give travoprost acid (916 mg, 100%) as a colorless
oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39 (1H, t, J=8
Hz), 7.22 (1H, d, J=8 Hz), 7.15 (1H, s), 7.08 (1H, d, J=8 Hz), 5.70
(2H, m), 5.40 (2H, m), 4.98 (1H, heptet, J=6.5 Hz), 4.52 (1H, m),
3.97 (3H, m), 3.25 (2H, br s), 2.60 (1H, br s), 2.38 (1H, m),
2.30-1.96 (7H, m), 1.76 (1H, dd, J=16, 4 Hz), 1.65 (2H, quintet,
J=7), 1.55 (1H, m).
Chemical Synthesis Example 2
(8S,10S,13S,14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-1,2,6,-
7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one
(Anecortave Desacetate)
##STR00117##
[0444] To a stirred suspension of anecortave acetate (3.0 g, 7.76
mmol) in methanol (80 mL) was added potassium hydroxide solution
(77.5 mL of a 0.2M solution, 15.52 mmol) and the mixture stirred
overnight. The reaction mixture was quenched into ice water (400
mL), stirred and filtered to collect the precipitate which was
dissolved in DCM (300 mL), washed with water (300 mL) and dried
over sodium sulfate to give anecortave desacetate (1.0 g, 37%).
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 5.66 (s, 1H); 5.52 (d, 1H,
J=5 Hz), 5.28 (s, 1H, OH), 4.60 (t, J=5 Hz, 1H, OH), 4.31 (AB, 2H,
J=19 Hz, .DELTA.v=82.5 Hz, further split (J=5 Hz) by OH), 2.60 (m,
3H), 2.50 (m, 1H), 2.25 (m, 3H), 2.05 (m, 3H), 1.80 (m, 2H), 1.55
(m, 2H), 1.22 (m, 1H), 1.20 (s, 3H), 1.02 (q, 1H, J=12 Hz), 0.49
(s, 3H).
Chemical Synthesis Example 3
2-((8S,10S,13S,14S,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,10,12,13-
,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluorometh-
yl)phenoxy)but-1-en-1-yl)cyclopentyl)hept-5-enoate (Compound 1)
##STR00118##
[0446] To a stirred solution of travoprost acid (180 mg, 0.393
mmol) in dry pyridine (20 mL) under nitrogen was added anecortave
desacetate (406 mg, 1.18 mmol), 4-(dimethylamino)pyridine (96 mg,
0.786 mmol) and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (150 mg, 0.786 mmol) and the mixture was stirred
overnight. The mixture was concentrated and the residue dissolved
in DCM (100 mL), the solution washed with 0.5 M hydrochloric acid
(100 mL), water (100 mL), dried (MgSO.sub.4) and concentrated onto
5 g reverse phase silica. Purification was performed by reverse
phase Biotage automated chromatography (aqueous-MeCN gradient).
Product containing fractions were combined, extracted with DCM,
dried (MgSO.sub.4) and concentrated to give the product as an
off-white solid (102 mg, 33%). Melting point: 78-80.degree. C. HPLC
retention time: 31.7 min, ESI MS+ Found,
C.sub.44H.sub.55F.sub.3NaO.sub.9.sup.+ Exact Mass: 807.3684.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.45 (1H, t, J=8 Hz), 7.20
(3H, m), 5.62 (1H, s), 5.55-5.40 (6H, m), 5.20 (1H, s, OH), 5.11
(1H, br s), 4.95 (1H, d, J=12 Hz), 4.80 (1H, d, J=12 Hz), 4.48 (1H,
br s), 4.31 (2H, m), 3.85 (3H, m), 3.64 (1H, m), 2.60 (2H, m), 2.38
(1H, m), 2.25 (3H, m), 2.20 (3H, m), 2.05 (3H, m), 1.95 (3H, m),
1.80 (6H, m), 1.55 (3H, m), 1.41 (1H, m), 1.22 (1H, m), 1.20 (3H,
s), 1.02 (1H, q, J=12 Hz), 0.49 (3H, s).
Chemical Synthesis Example 4
2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trime-
thyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phe-
nanthren-17-yl)-2-oxoethyl
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluorometh-
yl)phenoxy)but-1-en-1-yl)cyclopentyl)hept-5-enoate (Compound 2)
##STR00119##
[0448] To a stirred solution of travoprost acid (180 mg, 0.393
mmol) and dexamethasone (1.54 g, 3.93 mmol) in dry THF (50 mL)
under nitrogen was added 4-(dimethylamino)pyridine (96 mg, 0.786
mmol) and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (150 mg, 0.786 mmol) and the mixture was stirred
overnight. The mixture was concentrated onto 10 g reverse phase
silica. Purification was performed by reverse phase Biotage
automated chromatography (aqueous-MeCN gradient), product
containing fractions were combined, extracted with DCM, dried
(MgSO.sub.4) and concentrated to give a solid which was further
purified by normal phase Biotage automated chromatography
(hexane-ethyl acetate gradient). Product containing fractions were
combined and concentrated to give the product as an off-white solid
(120 mg, 37%). Melting point: 80.degree. C. HPLC retention time:
30.5 min, ESI MS+ Found, C.sub.45H.sub.56F.sub.4NaO.sub.10.sup.+
Exact Mass: 855.3707. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.45
(1H, t, J=8 Hz), 7.20 (4H, m), 6.20 (1H, d), 5.99 (1H, s),
5.60-5.35 (4H, m), 5.20 (1H, m), 5.11 (1H, d), 4.95 (1H, d, J=12
Hz), 4.76 (1H, d, J=12 Hz), 4.50 (1H, d), 4.31 (2H, m), 4.05 (1H,
m), 3.89 (3H, m), 3.64 (1H, m), 3.59 (1H, m), 2.83 (1H, m), 2.60
(1H, m), 2.38 (1H, m), 2.25 (3H, m), 2.20 (3H, m), 2.05 (3H, m),
1.95 (3H, m), 1.78 (2H, m), 1.60-1.40 (4H, m), 1.30 (1H, m), 1.21
(3H, s), 1.02 (1H, q, J=12 Hz), 0.82 (3H, s), 0.78 (3H, d).
Chemical Synthesis Example 5
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclope-
ntyl)hept-5-enoic Acid (Latanoprost Acid)
##STR00120##
[0450] To a stirred solution of latanoprost (1 g, 2.31 mmol) in
MeOH (16 mL) was added 1M NaOH.sub.(aq) (18.5 mL, 18.5 mmol) and
the mixture stirred for 16 h. The mixture was quenched into 0.5M
HCl.sub.(aq) (37 mL, 18.5 mmol) and the aqueous extracted with DCM
(2.times.100 mL). The DCM layers were combined dried (MgSO.sub.4)
and concentrated to give latanoprost acid (902 mg, 100%) as a
colorless oil. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.98 (1H, br
s), 7.23 (2H, m), 7.12 (3H, m), 5.42 (1H, m), 5.23 (1H, m), 4.39
(2H, m), 4.20 (1H, m), 3.82 (1H, m), 3.60 (1H, m), 3.36 (1H, m),
2.60 (1H, m), 2.52 (1H, m), 2.15 (3H, m), 1.98 (4H, m), 1.60-1.25
(10H, m), 1.20 (1H, m).
Chemical Synthesis Example 6
2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trime-
thyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phe-
nanthren-17-yl)-2-oxoethyl
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclop-
entyl)hept-5-enoate (Compound 3)
##STR00121##
[0452] To a stirred solution of latanoprost acid (153 mg, 0.393
mmol) and dexamethasone (1.54 g, 3.93 mmol) in dry THF (50 mL)
under nitrogen was added 4-(dimethylamino)pyridine (96 mg, 0.786
mmol) and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (150 mg, 0.786 mmol) and the mixture was stirred
overnight. The mixture was concentrated onto 10 g reverse phase
silica. Purification was performed by reverse phase Biotage
automated chromatography (aqueous-MeCN gradient), product
containing fractions were combined, extracted with DCM, dried
(MgSO.sub.4) and concentrated to give a solid which was further
purified by normal phase Biotage automated chromatography
(hexane-ethyl acetate gradient). Product containing fractions were
combined and concentrated to give the product as an off-white solid
(102 mg, 34%). Melting point: 78.degree. C. HPLC retention time:
30.8 min, ESI MS+ Found, C.sub.45H.sub.62FO.sub.9.sup.+ Exact Mass:
765.4378 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.35-7.05 (6H, m),
6.20 (1H, d), 5.99 (1H, s), 5.50-5.25 (3H, m), 5.10 (1H, s), 5.00
(1H, d), 4.80 (1H, d), 4.40 (2H, d), 4.21 (2H, m), 3.85 (1H, m),
3.61 (1H, m), 2.83 (2H, m), 2.60 (4H, m), 2.38 (4H, m), 2.11 (6H,
m), 1.75 (1H, m), 1.60-1.20 (18H, m), 1.02 (1H, q, J=12 Hz), 0.82
(3H, s), 0.78 (3H, d).
Chemical Synthesis Example 7
(8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-c-
yclopenta[a]phenanthren-3-yl
(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclop-
entyl)hept-5-enoate (Compound 4)
##STR00122##
[0454] To a stirred solution of latanoprost acid (153 mg, 0.393
mmol) and estrone (318 mg, 1.179 mmol) in dry THF (50 mL) under
nitrogen was added 4-(dimethylamino)pyridine (96 mg, 0.786 mmol)
and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
(150 mg, 0.786 mmol) and the mixture was stirred overnight. The
mixture was concentrated onto 10 g reverse phase silica.
Purification was performed by reverse phase Biotage automated
chromatography (aqueous-MeCN gradient), product containing
fractions were combined, extracted with DCM, dried (MgSO4) and
concentrated to give a solid which was further purified by normal
phase Biotage automated chromatography (hexane-ethyl acetate
gradient). Product containing fractions were combined and
concentrated to give the product as an off-white solid (28 mg,
11%). Melting point: 65.degree. C. HPLC retention time: 35.9 min,
ESI MS+ Found, C41H54NaO6+ Exact Mass: 665.3818 .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.23 (2H, m), 7.12 (3H, m), 7.04 (1H, d),
6.51 (1H, m), 6.45 (1H, m), 5.42 (1H, m), 5.23 (1H, m), 4.39 (2H,
m), 4.20 (1H, m), 3.82 (1H, m), 3.60 (1H, m), 3.36 (1H, m), 2.75
(2H, m), 2.60 (1H, m), 2.52 (1H, m), 2.42 (1H, m), 2.30 (1H, m),
2.15 (4H, m), 2.05 (1H, m), 1.98 (4H, m), 1.92 (2H, m), 1.74 (1H,
m), 1.60-1.25 (16H, m), 1.20 (1H, m), 0.81 (3H, s).
Chemical Synthesis Example 8
##STR00123##
[0456] Dexamethasone (314 mg, 0.80 mmol, 1.0 equiv) was dissolved
in THF (20 mL) under nitrogen and phosgene solution (2.86 mL of a
1.4 M solution in toluene, 4.0 mmol, 5 equiv) was added dropwise
with stirring. The mixture was stirred at room temperature
overnight. Concentration of the mixture afforded the dexamethasone
chloroformate as a thick oil which was dissolved in DCM (50 mL).
Triethylene glycol (1.07 mL, 1.20 g, 8 mmol, 10 equiv) and pyridine
(130 .mu.L, 126 mg, 1.60 mmol, 2.0 equiv) were added and the
mixture stirred for 2 h. The reaction solution was washed with
water (2.times.50 mL) and the DCM layer concentrated onto normal
phase silica (2 g) and purified by automated normal phase
chromatography (ethyl acetate-hexane). The product containing
fractions were combined and concentrated in vacuo to give the
dexamethasone-triethyleneglycol ester intermediate as an off-white
glassy solid (296 mg, 0.52 mmol, 65%). This was dissolved in DCM
(50 mL) and latanoprost acid (202 mg, 0.52 mmol),
4-(dimethylamino)pyridine (127 mg, 1.04 mmol) and
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (198
mg, 1.04 mmol) were added and the mixture was stirred overnight.
The reaction solution was washed with water (2.times.50 mL) and the
DCM layer concentrated onto reverse phase silica (2 g) and purified
by automated reverse phase chromatography (acetonitrile-water). The
product containing fractions were concentrated in vacuo to give the
dexamethasone-triethyleneglycol-latanoprost as a colourless oil (49
mg, 0.052 mmol, 10%). HPLC retention time: 33.9 min, ESI MS+ Found,
C52H74FO14+ Exact Mass: 941.5063 .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 7.35-7.05 (6H, m), 6.20 (1H, d), 5.99 (1H, s), 5.50-5.25
(3H, m), 5.10 (1H, s), 5.00 (1H, d), 4.80 (1H, d), 4.40 (2H, d),
4.21 (6H, m), 3.85 (1H, m), 3.65 (4H, m), 3.61 (1H, m), 3.57 (4H,
s), 2.83 (2H, m), 2.60 (4H, m), 2.38 (4H, m), 2.11 (6H, m), 1.75
(1H, m), 1.60-1.20 (18H, m), 1.02 (1H, q, J=12 Hz), 0.82 (3H, s),
0.78 (3H, d).
Chemical Synthesis Example 9
##STR00124##
[0458] To a stirred solution of travoprost acid (180 mg, 0.393
mmol) and acetaminophen (297 mg, 1.97 mmol) in dry THF (50 mL)
under nitrogen was added 4-(dimethylamino)pyridine (96 mg, 0.786
mmol) and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (150 mg, 0.786 mmol) and the mixture was stirred
overnight. The mixture was concentrated onto 5 g reverse phase
silica. Purification was performed by reverse phase Biotage
automated chromatography (aqueous-MeCN gradient), product
containing fractions were combined, extracted with DCM, dried
(MgSO.sub.4) and concentrated to give travoprost-acetaminophen
ester (139 mg, 60%) as a colourless oil. HPLC retention time: 22.6
min, ESI MS+ Found, C.sub.31H.sub.37F.sub.3NO.sub.7.sup.+ Exact
Mass: 592.2522. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.97 (1H, s,
NH), 7.57 (2H, d, J=8 Hz), 7.45 (1H, t, J=8 Hz), 7.22 (2H, m), 7.15
(1H, s), 6.98 (2H, d), 5.70 (2H, m), 5.40 (2H, m), 4.98 (1H,
heptet, J=6.5 Hz), 4.52 (1H, m), 3.97 (3H, m), 3.25 (2H, br s),
2.60 (1H, br s), 2.38 (1H, m), 2.30-1.96 (10H, m), 1.76 (1H, dd,
J=16, 4 Hz), 1.65 (2H, quintet, J=7), 1.55 (1H, m).
Chemical Synthesis Example 10
##STR00125##
[0460] To a stirred solution of travoprost acid (180 mg, 0.393
mmol) and 1-Adamantanemethanol (327 mg, 1.97 mmol) in dry THF (50
mL) under nitrogen was added 4-(dimethylamino)pyridine (96 mg,
0.786 mmol) and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (150 mg, 0.786 mmol) and the mixture was stirred
overnight. The mixture was concentrated onto 5 g reverse phase
silica. Purification was performed by reverse phase Biotage
automated chromatography (aqueous-MeCN gradient), product
containing fractions were combined, extracted with DCM, dried
(MgSO.sub.4) and concentrated to give travoprost-acetaminophen
ester (71 mg, 30%) as a colourless oil. HPLC retention time: 40.3
min, ESI MS+ Found, C.sub.34H.sub.46F.sub.3O.sub.6.sup.+ Exact
Mass: 607.3246. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.60 (1H, t,
J=8 Hz), 7.22 (2H, m), 7.15 (1H, s), 5.60-5.40 (3H, m), 5.20 (1H,
m), 5.10 (1H, d J=8.0 Hz), 4.52 (1H, m), 4.30 (2H, m), 3.88 (3H,
m), 3.63 (1H, m), 3.56 (2H, s), 2.93 (1H, m), 2.20-1.80 (10H, m),
1.70-1.40 (15H, m), 1.25 (1H, m).
Chemical Synthesis Example 11
##STR00126##
[0462] To a solution of latanoprost acid (202 mg, 0.52 mmol) and
triethylene glycol (42 uL, 39 mg, 0.26 mmol) in DCM (50 mL) was
added 4-(dimethylamino)pyridine (127 mg, 1.04 mmol) and
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (198
mg, 1.04 mmol) were added and the mixture was stirred overnight.
The reaction solution was washed with water (2.times.50 mL) and the
DCM layer concentrated onto reverse phase silica (2 g) and purified
by automated reverse phase chromatography (acetonitrile-water). The
product containing fractions were concentrated in vacuo to give the
latanoprost-triethyleneglycol-latanoprost as a colourless oil (37
mg, 0.042 mmol, 8%). HPLC retention time: 30.2 min, ESI MS+ Found,
C52H79O12+ Exact Mass: 895.5972 .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 7.23 (4H, m), 7.12 (6H, m), 5.42 (2H, m), 5.23 (2H, m),
4.39 (4H, m), 4.25-4.20 (6H, m), 3.82 (2H, m), 3.65 (4H, m),
3.60-3.55 (6H, m), 3.36 (2H, m), 2.60 (2H, m), 2.52 (2H, m), 2.15
(6H, m), 1.98 (8H, m), 1.60-1.25 (20H, m), 1.20 (2H, m).
Chemical Synthesis Example 12
##STR00127##
[0464] To a stirred solution of latanoprost (222.0 mg, 0.51 mmol)
in dry DCM (20 mL) was added n-butylboronic acid (60.1 mg, 0.59
mmol) and the mixture stirred at reflux for 1 h under nitrogen
atmosphere. The mixture was concentrated and the residue
redissolved in dry DCM, the mixture heated to reflux for 3 h,
concentrated to give the 9, 11-boronate of latanoprost (254 mg,
100%) as a clear colourless oil which was and used directly without
further purification. 1H NMR (400 MHz, CDCl3) .delta. (ppm):
7.28-7.17 (m, 2H), 7.17-7.03 (m, 3H), 5.49-5.27 (m, 2H), 4.93 (ddd,
J=15.2, 7.6, 4.9 Hz, 1H), 4.28-4.13 (m, 1H), 4.07-3.90 (m, 1H),
3.65-3.46 (m, 1H), 2.78-2.67 (m, 1H), 2.67-2.41 (m, 1H), 2.28-2.11
(m, 4H), 2.09-1.98 (m, 2H), 1.91-1.79 (m, 1H), 1.79-1.53 (m, 7H),
1.53-1.38 (m, 3H), 1.38-1.07 (m, 12H), 0.89-0.75 (m, 3H), 0.64-0.52
(m, 2H). To a solution of 9, 11-boronate of latanoprost (254 mg,
0.51 mmol) in dry DCM (25 mL) was added pyridine (164 uL, 162 mg,
2.04 mmol) and triethylene glycol bis(chloroformate) (52 uL, 70 mg,
0.255 mmol, 0.5 equiv) and the mixture stirred for 4 h, methanol (5
mL) was added and the mixture stirred overnight. The mixture was
concentrated onto 1 g reverse phase silica. Purification was
performed by reverse phase Biotage automated chromatography
(aqueous-MeCN gradient), product containing fractions were
combined, extracted with DCM, dried (MgSO.sub.4) and concentrated
to give latanoprost-TEG-latanoprost carbonate dimer (68 mg, 25%) as
a colourless oil. HPLC retention time: 48.2 min, ESI MS+ Found,
C60H91O16+ Exact Mass: 1067.6307 .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 7.23 (4H, m), 7.12 (6H, m), 5.42 (2H, m), 5.23 (2H, m),
4.39 (4H, m), 4.25-4.20 (6H, m), 3.82 (2H, m), 3.65 (4H, m),
3.60-3.55 (6H, m), 3.36 (2H, m), 2.60 (2H, m), 2.52 (2H, m), 2.15
(6H, m), 1.98 (8H, m), 1.60-1.25 (20H, m), 1.20 (2H, m), 1.00 (12H,
d).
Chemical Synthesis Example 13
##STR00128##
[0466] To a solution of 9, 11-boronate of latanoprost (254 mg, 0.51
mmol) in dry DCM (25 mL) was added pyridine (82 uL, 81 mg, 1.02
mmol) and ethylchloroformate (48 uL, 55 mg, 0.51 mmol) and the
mixture stirred for 4 h, methanol (5 mL) was added and the mixture
stirred overnight. The mixture was concentrated onto 1 g reverse
phase silica. Purification was performed by reverse phase Biotage
automated chromatography (aqueous-MeCN gradient), product
containing fractions were combined, extracted with DCM, dried
(MgSO.sub.4) and concentrated to give latanoprost-15-ethyl
carbonate (154 mg, 60%) as a colourless oil. HPLC retention time:
34.8 min, ESI MS+ Found, C29H45O7+ Exact Mass: 505.3165 .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 7.23 (2H, m), 7.12 (3H, m), 5.42 (1H,
m), 5.23 (1H, m), 4.80 (1H, m), 4.60 (1H, m), 4.39 (2H, m), 4.20
(1H, m), 4.03 (2H, m), 3.82 (1H, m), 3.60 (1H, m), 2.60 (1H, m),
2.52 (1H, m), 2.15 (2H, m), 1.98 (4H, m), 1.80-1.25 (10H, m), 1.20
(4H, m), 1.16 (6H, d).
Chemical Synthesis Example 14: (Bimatoprost-Anecortave Ester;
Compound 5)
##STR00129##
[0468] To a stirred solution of bimatoprost acid (1.0 g, 2.57 mmol)
in dry pyridine (120 mL) under nitrogen was added anecortave
desacetate (1.77 g, 5.14 mmol), 4-(dimethylamino)pyridine (0.62 g,
5.14 mmol) and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (0.99 g, 5.14 mmol) and the mixture was stirred for 4
d at 37.degree. C. The mixture was concentrated and the residue
dissolved in DCM (150 mL), the solution washed with 0.5 M
hydrochloric acid (150 mL), water (100 mL), dried (MgSO.sub.4) and
concentrated onto 5 g reverse phase silica. Purification was
performed by reverse phase Biotage automated chromatography
(aqueous-MeCN gradient) followed by normal phase Biotage automated
chromatography (hexanes-ethyl acetate). Product containing
fractions were combined, concentrated, redissolved in MeCN (50 mL)
and concentrated to give the product as an off-white solid (445 mg,
24%). Melting point: 110-115.degree. C. HPLC retention time: 29.7
min, ESI MS+ Calculated for C.sub.44H.sub.58NaO.sub.8.sup.+;
737.4024, Found: 737.4020. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
7.25 (t, J=7.5 Hz, 2H), 7.20-7.10 (m, 3H), 5.66 (d, J=1.5 Hz, 1H),
5.58-5.17 (m, 6H), 4.97 (d, J=17.6 Hz, 1H), 4.84 (d, J=17.6 Hz,
1H), 4.65 (d, J=4.6 Hz, 1H), 4.49 (d, J=5.8 Hz, 1H), 4.34 (d, J=5.0
Hz, 1H), 3.92 (td, J=6.4, 3.5 Hz, 2H), 3.67 (ddd, J=13.6, 6.9, 4.0
Hz, 1H), 2.72-2.42 (m, 4H), 2.37-1.92 (m, 16H), 1.88-1.75 (m, 3H),
1.75-1.62 (m, 2H), 1.62-1.49 (m, 3H), 1.44 (ddd, J=14.1, 5.7, 2.4
Hz, 1H), 1.40-1.21 (m, 5H), 1.07-0.93 (m, 1H), 0.48 (s, 3H).
Chemical Synthesis Example 15: (Latanoprost-Anecortave Ester;
Compound 6)
##STR00130##
[0470] To a stirred solution of latanoprost acid (1.0 g, 2.56 mmol)
in dry pyridine (60 mL) under nitrogen was added anecortave
desacetate (1.76 g, 5.12 mmol), 4-(dimethylamino)pyridine (0.62 g,
5.12 mmol) and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (0.99 g, 5.14 mmol) and the mixture was stirred for 4
d at 37.degree. C. The mixture was concentrated and the residue
dissolved in DCM (150 mL), the solution washed with 0.5 M
hydrochloric acid (150 mL), water (100 mL), dried (MgSO.sub.4) and
concentrated onto 4 g reverse phase silica. Purification was
performed by reverse phase Biotage automated chromatography
(aqueous-MeCN gradient) followed by normal phase Biotage automated
chromatography (hexanes-ethyl acetate). Product containing
fractions were combined, concentrated, redissolved in MeCN (50 mL)
and concentrated to give the product as an off-white solid (415 mg,
23%). Melting point: 122-124.degree. C. HPLC retention time: 31.4
min, ESI MS+ Calculated for C.sub.44H.sub.60NaO.sub.8.sup.+;
739.4180, Found: 737.4183. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
7.25 (t, J=7.5 Hz, 2H), 7.21-7.10 (m, 3H), 5.65 (d, J=1.6 Hz, 1H),
5.55-5.42 (m, 3H), 5.36-5.25 (m, 1H), 4.99 (d, J=17.6 Hz, 1H), 4.85
(d, J=17.6 Hz, 1H), 4.45-4.34 (m, 2H), 4.20 (d, J=5.4 Hz, 1H),
3.94-3.84 (m, 1H), 3.68-3.57 (m, 1H), 3.38 (d, J=9.8 Hz, 1H),
2.75-2.51 (m, 5H), 2.50-2.42 (m, 4H), 2.41-1.91 (m, 10H), 1.83 (dt,
J=11.7, 7.5 Hz, 3H), 1.69-1.31 (m, 12H), 1.30 (s, 3H), 1.23 (tt,
J=9.3, 5.5 Hz, 1H), 1.07-0.93 (m, 1H), 0.48 (s, 3H).
Chemical Synthesis Example 16: (Tafluprost-Anecortave Ester;
Compound 7)
##STR00131##
[0472] To a solution of tafluprost acid (800 mg, 1.95 mmol) and
anecortave desacetate (1.34 g, 3.90 mmol) in dry pyridine (50 mL)
was added DMAP (476 mg, 3.90 mmol) and EDCl (747 mg, 3.90 mmol) at
0.degree. C., then stirred at 20.degree. C. for 10 h. The reaction
mixture was poured into DCM (50 mL), washed with 1M aqueous HCl
(3.times.100 mL), the organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated to give a residue. The
residue was purified by prep-HPLC (column: Phenomenex luna C18
(250*70 mm, 15 um); mobile phase: [water (0.225% FA)-ACN]; B %:
35%-80%, 23 min) to give the product (600 mg, 42%) as an off-white
solid. Melting point: 107-110.degree. C. HPLC retention time: 33.8
min, ESI MS+ Calculated for C.sub.43H.sub.54F.sub.2NaO.sub.8.sup.+;
759.3684, Found: 759.3690. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
7.30 (t, J=7.8 Hz, 2H) 6.92-7.05 (m, 3H) 6.09 (br dd, J=15.7, 8.9
Hz, 1H) 5.77 (dt, J=15.7, 11.2 Hz, 1H) 5.65 (s, 1H) 5.49-5.55 (m,
2H) 5.39-5.48 (m, 1H) 5.22-5.31 (m, 1H) 4.93-5.02 (m, 1H) 4.79-4.89
(m, 1H) 4.73 (d, J=5.9 Hz, 1H) 4.47 (d, J=4.8 Hz, 1H) 4.33 (br t,
J=12.9 Hz, 2H) 3.92 (br d, J=3.8 Hz, 1H) 3.75 (quin, J=6.9 Hz, 1H)
2.53-2.69 (m, 3H) 1.90-2.37 (m, 15H) 1.74-1.87 (m, 3H) 1.55 (quin,
J=7.2 Hz, 3H) 1.39-1.49 (m, 2H) 1.25-1.37 (m, 4H) 0.92-1.07 (m, 1H)
0.48 (s, 3H)
Chemical Synthesis Example 18:
(Travoprost-cyclohexanedimethanol-Anecortave; Compound 8)
##STR00132##
[0474] Anecortave desacetate (640 mg, 1.86 mmol) was dissolved in
dry THF (40 mL) under nitrogen and phosgene solution (6.64 mL of a
1.4 M solution in toluene, 9.29 mmol) was added dropwise with
stirring. The mixture was stirred at room temperature overnight.
Concentration of the mixture afforded anecortave chloroformate as a
pale yellow solid (740 mg, 98%) that was used without further
purification or analysis.
[0475] To a stirred suspension of 1,4-cyclohexanedimethanol (2.48
g, 1.72 mmol) in dry CH.sub.2Cl.sub.2 (30 mL) was added anecortave
chloroformate (700 mg, 1.72 mmol) and dry pyridine (1.08 mL, 13.4
mmol). The solution was stirred at room temperature for 16 h,
concentrated and the yellow residue re-dissolved in
CH.sub.2Cl.sub.2 (50 mL). The solution was washed with 0.5 M
hydrochloric acid (2.times.50 mL), water (50 mL), dried
(MgSO.sub.4) and evaporated to give anecortave-CDM as a pale yellow
solid (701 mg, 79%). HPLC retention time: 27.4 min. ESI MS+
calculated for C.sub.30H.sub.42NaO.sub.2.sup.+; 537.2823, Found:
537.2830. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 5.66 (1H, s),
5.54-5.51 (2H, m), 5.04 (1H, d, J=17.8, Hz), 4.83 (1H, d, J=17.8
Hz), 4.37-4.29 (1H, m), 4.02 (1H, d, J=7.2 Hz), 3.92 (1H, d, J=6.4
Hz), 3.30-3.25 (1H, m), 3.22-3.17 (1H, m), 2.68-2.43 (3H, m),
2.36-2.18 (3H, m), 2.12-1.94 (4H, m), 1.87-1.69 (5H, m), 1.61-1.48
(2H, m), 1.45-1.28 (5H, m), 1.30 (3H, s), 1.06-0.79 (3H, m),
0.52-0.46 (3H, m).
[0476] A stirred solution of travoprost acid (200 mg, 0.436 mmol)
in dry MeCN (10 mL) under nitrogen was stirred at -15.degree. C.
(ice/salt bath). N-Methylmorpholine (96.8 .mu.L, 0.872 mmol) and
isobutyl chloroformate (57.8 .mu.L, 0.436 mmol) were added and the
solution stirred for 10 mins. The solution was then added dropwise
to a suspension of anecortave-CDM (453 mg, 0.872 mmol) in dry MeCN
(20 mL) under nitrogen at -15.degree. C. (ice/salt bath). After 10
mins stirring, the mixture was warmed to room temperature and
stirred for 3 hours. The mixture was concentrated onto reverse
phase silica (3 g) and purified by automated reverse phase
chromatography (aqueous-MeCN). The product containing fractions
were concentrated in vacuo to give the product as a colorless solid
(53 mg, 13%). For thermal property measurements, the solid was
dissolved in DCM and concentrated in vacuo to give a colorless
solid. Melting point: not observed (Tg=.about.43.degree. C.). HPLC
retention time: 37.8 min. ESI MS+ calculated for
C.sub.53H.sub.69F.sub.3NaO.sub.12.sup.+; 977.4633, Found: 977.4640.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.49 (1H, t, J=8.0 Hz),
7.26-7.19 (2H, m), 7.18 (1H, s), 5.65 (1H, s), 5.58-5.38 (5H, m),
5.26-5.18 (1H, m), 5.10 (1H, d, J=4.8 Hz), 5.02 (1H, dd, J=17.8,
1.79 Hz), 4.82 (1H, d, J=17.8 Hz), 4.52 (1H, d, J=5.8 Hz),
4.35-4.26 (2H, m), 4.01 (1H, d, J=7.2 Hz), 3.96-3.86 (5H, m), 3.78
(1H, d, J=6.5 Hz), 3.71-3.63 (1H, m), 2.66-2.42 (3H, m), 2.35-2.25
(2H, m), 2.25-2.10 (6H, m), 2.10-2.03 (2H, m), 2.00-1.92 (5H, m),
1.83-1.65 (5H, m), 1.60-1.26 (12H, m), 1.29 (3H, s), 1.05-0.81 (3H,
m), 0.47 (3H, s).
Chemical Synthesis Example 19: (Travoprost-Naltrexone; Compound
9)
##STR00133##
[0478] To a stirred solution of travoprost acid (122 mg, 0.27 mmol)
and naltrexone.HCl (100 mg, 0.27 mmol) in dry DCM (20 mL) under
nitrogen was added 4-(dimethylamino)pyridine (132 mg, 1.08 mmol)
and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
(104 mg, 0.54 mmol) and the mixture was stirred overnight. The
mixture was concentrated onto 2 g reverse phase silica.
Purification was performed by reverse phase Biotage automated
chromatography (aqueous-MeCN gradient), product containing
fractions were combined and concentrated, the residue dissolved in
MTBE (20 mL) and concentrated to give travoprost-naltrexone ester
(84 mg, 40%) as a glassy white solid. Melting point: 56.degree. C.
HPLC retention time: 17.6 min, ESI MS+ Calculated for
C.sub.43H.sub.51F.sub.3NO.sub.9.sup.+; 782.3516, Found: 782.3512.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.50 (t, J=7.9 Hz, 1H),
7.32-7.15 (m, 3H), 6.80 (d, J=8.2 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H),
5.64-5.39 (m, 3H), 5.34-5.23 (m, 1H), 5.11 (d, J=4.8 Hz, 2H), 4.90
(s, 1H), 4.53 (d, J=5.8 Hz, 1H), 4.36 (d, J=4.9 Hz, 1H), 4.31 (p,
J=5.3 Hz, 1H), 3.93 (dq, J=8.9, 4.8 Hz, 2H), 3.69 (p, J=7.4 Hz,
1H), 3.16 (d, J=5.6 Hz, 1H), 3.09-3.06 (m, 1H), 2.97-2.84 (m, 2H),
2.70-2.53 (m, 2H), 2.43-2.30 (m, 4H), 2.26-1.89 (m, 8H), 1.77 (td,
J=9.7, 5.8 Hz, 1H), 1.62 (p, J=7.3 Hz, 2H), 1.49-1.20 (m, 4H), 1.10
(s, 1H), 0.87 (dtd, J=14.1, 6.9, 4.0 Hz, 1H), 0.58-0.42 (m, 2H),
0.19-0.09 (m, 2H).
Chemical Synthesis Example 20: (Timolol-deoxycholic Acid; Compound
10)
##STR00134##
[0480] To a stirred solution of timolol free base (316 mg, 1.0
mmol) and deoxycholic acid (393 mg, 1.0 mmol) in dry DCM (20 mL)
under nitrogen was added 4-(dimethylamino)pyridine (244 mg, 2.0
mmol) and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (384 mg, 2.0 mmol) and the mixture was stirred for 2
d. The mixture was concentrated onto 1 g reverse phase silica.
Purification was performed by reverse phase Biotage automated
chromatography (aqueous-MeCN gradient), product containing
fractions were combined and concentrated, the residue dissolved in
MTBE (20 mL) and concentrated to give timolol-deoxycholic ester
(242 mg, 35%) as a glassy white solid. Melting point: 73.degree. C.
HPLC retention time: 36.2 min, ESI MS+ Calculated for
C.sub.37H.sub.63N.sub.4O.sub.6.sup.+; 691.4463, Found: 691.4464
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 5.11 (qd, J=6.3, 2.8 Hz,
1H), 4.61 (dd, J=11.4, 2.8 Hz, 1H), 4.51-4.41 (m, 2H), 4.19 (d,
J=4.1 Hz, 1H), 3.77 (d, J=3.8 Hz, 1H), 3.68 (t, J=4.8 Hz, 4H),
3.48-3.34 (m, 5H), 2.70 (d, J=6.3 Hz, 2H), 2.33 (ddd, J=14.4, 9.0,
4.9 Hz, 1H), 2.16 (dq, J=15.5, 8.1 Hz, 1H), 1.86-1.41 (m, 11H),
1.38-1.11 (m, 11H), 1.11 (s, 1H), 1.08-0.93 (m, 11H), 0.90 (d,
J=6.2 Hz, 3H), 0.84 (s, 3H), 0.55 (s, 3H).
Chemical Synthesis Example 21: (Bimatoprost(C.sub.15)-Anecortave
Carbonate; Compound 11)
##STR00135##
[0482] To a stirred solution of bimatoprost amide (100 mg, 0.241
mmol) in dry pyridine (3 mL) under nitrogen was added anecortave
chloroformate (196 mg, 0.482 mmol). The yellow solution was stirred
for 4 days, concentrated and re-dissolved in CH.sub.2Cl.sub.2 (5
mL). The mixture was concentrated onto reverse phase silica (2 g)
and purified by automated reverse phase chromatography
(aqueous-MeCN). The product containing fractions were concentrated
to give a solid that was further purified by normal phase Biotage
automated chromatography (hexane-ethyl acetate gradient). The
product containing fractions were concentrated in vacuo to give the
product as a colorless solid (23 mg, 12%). Melting point: not
observed (Tg=.about.60.degree. C.). HPLC retention time: 30.5 min.
ESI MS+ calculated for C.sub.47H.sub.63NNaO.sub.9.sup.+; 808.4395,
Found: 808.4397. .sup.1H NMR (400 MHz, DMSO-d6) 7.68 (1H, t, J=5.7
Hz, NH), 7.30-7.22 (2H, m), 7.19-7.12 (3H, m), 5.65 (1H, s),
5.55-5.38 (5H, m), 5.33-5.26 (1H, m), 5.03 (1H, d, J=17.8 Hz),
4.82-4.76 (2H, m), 4.70-4.64 (2H, m), 3.98-3.89 (2H, m), 3.07-2.99
(2H, qd, J=7.2, 5.7 Hz), 2.67-2.43 (6H, m), 2.38-2.15 (5H, m),
2.15-1.89 (10H, m), 1.86-1.63 (3H, m), 1.59-1.21 (8H, m), 1.29 (3H,
s), 0.98 (3H, t, J=7.2 Hz), 0.47 (3H, s).
Example 3: Formation and Evaluation of Processable Conjugates
Process Example 1: Heat Processing Pellets
[0483] A compound of the disclosure was formed into a pellet in the
glassy state by heat molding. Crystalline powder of the conjugate
compound was melted between 85.degree. C. to 110.degree. C. and
pressed into a cylindrical mold of .about.1 mm height.times.1 mm
diameter.
Process Example 2: Solvent Processing for Compound 4
[0484] Compound 4 was formed into a thin film coating on a polymer
surface by solvent casting. Compound 4 was dissolved in acetone at
50 mg/ml. 20 .mu.l was cast onto a Dacron coupon and left to air
dry at room temperature overnight followed by 2 h under vacuum at
50.degree. C.
Process Example 3: Heat Processing Rods
[0485] A compound of the disclosure was formed into a rod in the
glassy state by heat extrusion. The conjugate compound was
initially melted at a temperature up to 140.degree. C. The
resulting material was then loaded into a heat extruder with a 30G
die head, heated between 70.degree. C. to 125.degree. C., and
pressure was applied to a piston to form extrudate from the
extruder. The extrudate was cut to different lengths.
Example 4: Drug Release Evaluation from Pellets or Extruded
Rods
[0486] Drug release from heat-molded pellets or extruded rods of
Compounds of the disclosure were assessed in either fetal bovine
serum (FBS), phosphate buffered saline (PBS), or 1% FBS in PBS
(v/v). Heat-molded pellets or extruded rods were placed in 20 ml
glass vials, to which was added 2 ml of release buffer. Samples
were incubated at 37.degree. C. with constant agitation at 115 rpm.
At intervals up to 14 days in length, release buffer was assessed
for released drug and then fully replaced with 2 ml of fresh
buffer. For FBS release conditions, acetonitrile was added to
precipitate proteins and extract drug release products. Samples
were analyzed by high performance liquid chromatography (HPLC) to
quantify drug products.
Example 5. Sterilization of a Heat Processed Rod of Compound 5
[0487] Compound 5 was formed into rods by melt extrusion and cut to
length. The resulting implants were loaded into the lumen of
needles and terminally sterilized by ethylene oxide, gamma
irradiation, and E-beam. Following sterilization, samples were
dissolved in a suitable solvent and assessed for changes in purity
due to sterilization by HPLC.
[0488] For example, FIG. 18 shows purity of compound 5 before
(pre-sterilization) or post sterilization of Compound 5 in ethylene
oxide, or by gamma-radiation or E-beam.
Example 6: In Vivo Evaluation
Biological Example 1: Implantation of Extruded Rod of Compound 5 in
Rabbit Eye
[0489] Compound 5 was formed into rods by melt extrusion and were
cut to 1, 1.5 or 2 mm length. The resulting implants were loaded in
the lumen of needles, terminally sterilized, and injected into the
anterior chamber of rabbits. Implants settled into the inferior
iridocorneal angle and were visualized by anterior chamber optical
coherence tomography.
Biological Example 2: Implantation of Extruded Rod of Compound 6 in
Rabbit Eye
[0490] Compound 6 was formed into rods by melt extrusion and were
cut to 1.5 mm length. The resulting implants were loaded in the
lumen of needles, terminally sterilized, and injected into the
anterior chamber of rabbits. Implants settled into the inferior
iridocorneal angle and were visualized by anterior chamber optical
coherence tomography.
[0491] For example, FIG. 14 shows an extruded rod
steroid-prostaglandin heterodimer (bimatoprost-anecortave, Compound
5) exemplified herein in a rabbit eye.
* * * * *