FIELD OF THE INVENTION
[0001] This application relates to compositions and methods for treating macular
degeneration and other forms of retinal disease whose etiology involves the accumulation of
A2E and/or lipofuscin in retinal tissue, more specifically, for preventing the accumulation of A2E.
BACKGROUND OF THE INVENTION
[0002] Two forms of retinal disease include Stargardt disease, which afflicts young adults,
and age related macular degeneration (AMD), which afflicts adults in midlife and later. Both
forms are characterized by the progressive degeneration of cone photoreceptors located in the
foveal region of the macula, which degeneration leads to loss of high acuity vision in the central
visual field. The disease has been associated with the accumulation of toxic biochemicals,
including lipofuscin, inside retinal pigment epithelium (RPE) cells and extracellular drusen
where the RPE cells are in contact with Bruch's membrane. The accumulation of these
retinotoxic mixtures is one of the most important known risk factors in the etiology of AMD.
[0003] AMD begins as a "dry form" without vascular complications. Currently there are
no known treatments for dry form AMD. One patient in ten progresses to a late-stage form of the
disease known as "wet form" AMD which is characterized by choroidal neovascularization that
invades the macula and disrupts retinal and RPE tissue. Most current wet form AMD treatments
suppress vascular growth or inflammatory processes.
[0004] During the normal visual cycle (summarized in Figure 1), most trans- RAL is
sequestered by opsin proteins in photoreceptor outer segment disc membranes. This
sequestering mechanism protects the trans-RAL group from reacting with
phosphatidylemanolamine (PE) before trans-RAL dehydrogenase (RDH) converts trans-RAL to
the alcohol frczns-retinol. Some trans-RAL molecules escape sequestering, however, and react
with phosphatidylemanolamine to form first //-retmyhdene-phosphatidylemanolamine (APE)
and then A^-retmylidene-N-retmyl-phosphatidylemanolamine (A2PE) in the discs of

photoreceptor outer segments. Both A2PE and trans-RAL that has escaped sequestering are
transported out of photoreceptor disc membranes by an ATP-binding cassette transporter called
Rim protein (RmP) or ABCA4 (formerly ABCR). Following this transportation, trans-RAL is
reduced to trans-retinol by RDH and crosses the outer-segment (OS) plasma membrane, into the
extracellular space where it is taken up by cells of the retinal pigment epithelium (RPE).
[0005] A2PE is taken up by RPE cell lysosomes when RPE cells ingest photoreceptor
outer segments that are shed routinely. Once inside the lysosomes, A2PE is converted
irreversibly to A2E, which causes lysosomal failure. Lysosomal failure poisons the RPE cells and
compromises their ability to provide biochemical support to retinal photoreceptors, leading to the
progressive degeneration of both cell types.
[00.06]. Multiple factors affect the rates of A2E accumulation, both genetic and
environmental. For example, a hereditary mutation in both copies of the ABCA4 transporter gene
increases the accumulation of A2E and leads to Stargardt disease in children and young adults. A
later onset form of Stargardt disease is associated with ABCA4 mutations that are more benign.
Stargardt disease is thought by many to be an early onset form of AMD, where the normal age-
related accumulation of A2E is accelerated by the ABCA4 mutation to a sufficient extent that the
disease is triggered decades before AMD normally appears.
[0007] With respect to environmental factors, it is well established in animal-models that
the rate of A2E formation varies with light exposure. It has been shown that a fatty acid
(phosphatidylglycerol) can protect RPE cells from A2E induced cell death, and that other dietary
factors can influence disease progression, including zinc (which affects retinol oxidoreductase
activity).
[0008] There is a need for effective treatments of dry form AMD and Stargardt disease
which arrest disease progression and preserve or restore vision.

SUMMARY OF THE INVENTION
[0009] The invention relates to compositions and methods for treating macular degeneration and
other forms of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin
in retinal tissue.
[00010] In one embodiment, the present invention provides compositions and methods for
treating macular degeneration and other retinal disease with an etiology involving the
accumulation of A2E and/or lipofuscin by limiting the formation of cytotoxic A2E. For example,
A2E formation is prevented or reduced by limiting the amount of unsequestered trans-RAL
available for reaction with phosphatidyl ethanolarnine (PE) in photoreceptor outer segments. In
one approach, a therapeutic compound i.e. an "RAL-trap" is administered to a patient, whereby the drug competes with PE for trans-RAL by forming a Schiff base adduct. "Free RAL" is
defined as RAL that is not bound to a visual cycle protein.
[00011] In another embodiment, the invention relates to a method of identifying a drug to
treat macular degeneration and other forms of retinal disease whose etiology involves the
accumulation of A2E and/or lipofuscin may include administering a candidate agent to a subject
having, or at risk for developing, macular degeneration and retinal disease, and measuring A2E
formation in the presence of the candidate agent, relative to A2E formation in the absence of the
candidate agent.
[00012] A wide variety of drugs are contemplated for use in the methods of the invention.
In some embodiments, inhibitors of A2E formation include RAL-traps. For example, the
pharmacological target of such RAL-trap compounds is trans-'RAL which has escaped
sequestering by opsins in photoreceptor outer segments. RAL-traps include, for example, cyclic
amines and five- and six-membered heterocyclic amines which may have one or more pairs of
conjugated double bonds, and, for example, may be aromatic. In some embodiments, the RAL
trap is administered to a subject as a topical formulation for delivery by eye drops or via skin
patch.
[00013] The invention relates to a method of treating or preventing macular degeneration
and other forms of retinal disease whose etiology involves the accumulation of A2E and/or
lipofuscin in a subject, the method by administering a composition that reduces the level of A2E

accumulation relative to the level of A2E accumulation in the subject without administration of
the composition. The invention also relates to a method of treating or preventing macular
degeneration and other forms of retinal disease whose etiology involves the accumulation of
A2E and/or lipofuscin in a subject by administering to the subject a composition that reduces the
level of A2E formation relative to the level of A2E formation in the subject without
administration of the composition.
[00014] In some embodiments, the methods of the invention further include diagnosing
macular degeneration and other forms of retinal disease whose etiology involves the
accumulation of A2E and/or lipofuscin in the subject. In other embodiments, the methods further
include monitoring the macular degeneration and other forms of retinal disease whose etiology
involves the accumulation of A2E and/or lipofuscin in the subject.
[00015] In one aspect, the invention relates to administering a composition that includes a
compound selected from benzocaine, procaine, orthocaine, tricaine (MS222, compound 6), and
methyl anthranilate.
[00016] In one aspect, the methods of the invention include administering a composition
that includes a compound of the formula TV: IV, where X is O, N(H), or Si
het is a 5 or 6- membered heterocycle, n is 0, 1,2, or 3, and each D is an unbranched lower alkyl
group. Each D can be the same or different. In one embodiment, the Ds are the same.
[00017] U is a substituent selected from halogen atom; cyano; lower alkyl wherein one or
more hydrogen atoms on the lower alkyl group are optionally substituted by groups selected
from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic
heterocyclic group containing one or more hetero-atoms selected from nitrogen, oxygen, and
sulfur atoms; lower alkylthio wherein one or more hydrogen atoms on the alkyl group are
optionally substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and
aryl; lower alkylsulfonyl wherein one or more hydrogen atoms on the alkyl group are optionally
substituted by groups selected from a Halogen atom, hydroxyl, carbamoyl, amino, and aryl;

hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower
alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N,N-di-lower alkylaminocarbonyl; amino;
N-lower alkylamino; N,N-di-lower alkylamino; fonnylamino; lower alkylcarbonylarnino; .
arxiinosulfonylamino; (N-lower alkylammo)sulfonylamino; (N,N-di-lower
alkylamino)sulfonylamino; aryl, optionally substituted by groups selected from a halogen atom,
hydroxyl, carbamoyl, aryl and amino; and a monocyclic or bicyclic heterocyclic group
containing one or more hetero-atoms selected from nitrogen, oxygen, and sulfur atoms.
[00018] In one embodiment each D is methyl.
[00019] In some embodiments, the substituents (U) are selected such that the first pKa of
the ring NH2 is approximately 3.5.
[00020] In oneaspect, the methods of the invention include administering a composition
that includes a compound of formula I:


where, W, X, Y, and Z are each, independently, N, S, O, CU or CH, and at
least one of W, X, Y, and Z is N; n is 0, 1", 2, 3, or 4,- A is


D is unbranched lower alkyl; R is substituted or
unsubstituted C1, C2, C3, C4, C5, C6, C7, or C8, straight chain alkyl, or substituted or
unsubstituted C3, C4, C5, C6, C7, or C8, branched chain alkyl.
[00021] U is a substituent selected from a halogen atom; cyano; lower alkyl wherein one
or more hydrogen atoms on the lower alkyl group are optionally substituted by groups selected
from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic
heterocyclic group containing one or more hetero-atoms selected from nitrogen, oxygen, and
sulfur atoms; lower alkylthio wherein one or more hydrogen atoms on the alkyl group are
optionally substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and
aryl; lower alkylsulfonyl wherein one or more hydrogen atoms on the alkyl group are optionally
substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and aryl;

hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower
alkoxycarbonyl; carbamoyl; N-lower allcylcarbamoyl; N,N-di-lower alkylaminocarbonyl; amino;
N-lower alkylamino; N,N-di-lower alkylamino; formylamino; lower alkylcarbonylamino;
aminosulfonylamiiio; (N-lower alkylammo)sulfonylamino; (N,N-di-lower
alkylamino)siilfonylamino; aryl, optionally substituted by groups selected from a halogen atom,
. hydroxyl, carbamoyl, aryl and amino; and a monocyclic or bicyclic heterocyclic group
containing one or more hetero-atoms selected from nitrogen, oxygen, and sulfur atoms.
[00022] In one embodiment, the identity of W, X, Y, and Z are such that the compound
comprises a pyridine, pyridazine, pyrazine, or pyrimidine ring.
[00023] . In some embodiments, U is aryl. For example, U can be benzene. U can also be a
halo-substituted benzene.
[00024] In some embodiments, A is . . In some embodiments, A is and
D is methyl.
[00025] In some embodiments, two adjacent U substituents are connected to form a 5- or
6- membered optionally substituted ring. For example, the substituents can be connected to form
a benzene ring, forming a compound having the structure according to formula Ia:


la,, where X, Y, and Z are each, independently, N, O, S, CH, or
absent, such that at least one of X, Y, and Z is N; p is 0,1,2, or 3, B is a halogen atom, hydroxyl,
• carbamoyl, substituted or unsubstituted aryl or amino, A is


D is unbranched lower alkyl, and R is
substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, or C8 straight chain alkyl, or substituted
or unsubstituted C3, C4, C5, C6, C7 or C8 branched chain alkyl.
[00026] Compounds of Formula 1 can include:


[00027] In one embodiment, the composition used in the methods of the invention includes
the compound , or a pharmaceutically acceptable salt thereof.
. [00028] In one aspect, the methods of the invention include administering a composition
that includes a compound of formula II or Ha:
[00029] Ea, where Q, T, and V are each,
independently, N or NH, S, O, CU or CH, such that at least one of Q, T and V is not CU or CH;
the dashed ring represents two double bonds within the ring, which comply with the valency
requirements of the atoms and heteroatoms present in the ring; m is 0,1, or 2; A is
; D is unbranched lower alkyl; R is substituted or
unsubstituted C1, C2, C3, C4, C5, C6, C7 or C8 straight chain alkyl, or substituted or
unsubstituted C3, C4, C5, C6, C7 or C8 branched chain alkyl.
[00030] U is a substituent selected from a halogen atom; cyano; lower alkyl wherein one
or more hydrogen atoms on the lower alkyl group are optionally substituted by groups selected
from a halogen atom, hydroxyl, carbamoyl, amino, aryL and a monocyclic orbicyclic

heterocyclic group containing one or more hetero-atoms selected from nitrogen, oxygen, and
sulfur atoms; lower alkylthio wherein one or more hydrogen atoms on the alkyl group are
optionally substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and
aryl; lower alkylsulfonyl wherein one or more hydrogen atoms on the alkyl group are optionally
substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and aryl;
hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower
alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N,N-di-lower alkylaminocarbonyl; amino;
N-lower alkylamino; N,N-di-lower aUcylamino; formylamino; lower alkylcarbonylarnino;
. aminosdfonylaniino; (N-lower aIkylammo)sulfonylamino; (N,N-di-lower
alkylamino)sulfonylamino; aryl, optionally substituted by groups selected from a halogen atom,
hydroxyl, carbamoyl, aryl and amino; and a monocyclic or bicyclic heterocyclic group
containing oneor.more heterb-atorris selectedfrom nifrogen.oxygen, and sulfur atoms; and'-.
[00031] In one embodiment, in compounds of formula II or Ha, U is aryl. For example, U
can be benzene. U can also be a halo-substituted benzene ring.
[00032] In some embodiments, in compounds of formula II or Ha, A is In
some compounds, each D is methyl.
[00033] In one embodiment, in compounds of formula II or Ha, Q, T, and V are selected
such that the composition includes a furan or thiophene ring.
[00034] In one embodiment, in compounds of formula II or Ha, U is lower alkyl: For
example, U can be methyl.
[00035] In one embodiment, in compounds of formula II or Ha, U is a halogen atom. For
example, U can be fluoro or chloro.
[00036] One example, of a composition useful in the methods of the invention includes the
compound , or a pharmaceutically acceptable salt thereof.

[00037] In one aspect, the methods of the invention include administering a composition
that includes a compound of formula til:
, where, L is a bond or CH2; A is
; D is uribranched lower alkyl; R is substituted or
unsubstituted C1, C2, C3, C4, C5, C6, C7 or C8 straight chain alkyl, or substituted or
unsubstituted C3, C4, C5, C6, C7 or C8 branched chain alkyl, and k is 0,1,2, 3, or 4.
[00038] U is a substituent selected from a halogen "atom; "cyario; lower alkyl' wherein' one'
or more hydrogen atoms on the lower alkyl group are optionally substituted by groups selected
from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic of bicyclic
heterocyclic group containing one or more hetero-atoms selected .from nitrogen, oxygen, and
sulfur atoms; lower alkylthio wherein one or more hydrogen atoms on the alkyl group are
optionally substituted by.groups selected from a halogen atom, hydroxyl; carbamoyl, amino, and
aryl; lower alkylsulfonyl wherein one or more hydrogen atoms on the alkyl group are optionally
substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and aryl;
hydroxyl; lower alkoxy; fofmyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower
alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; NJST-di-lower alkylaminocarbonyl; amino;
N-lower alkylamino; N,N-di-lower alkylamino; formylamino; lower alkylcarbonylamino;
aminosulfonylamino; (N-lower alkylamino)sulfonylamino; (N,N-di-lower
alkylamrno)sulfonylamino; aryl, optionally substituted by groups selected from a halogen atom, '
hydroxyl, carbamoyl, aryl and amino; and a monocyclic or bicyclic heterocyclic group
containing one or more hetero-atoms selected from nitrogen, oxygen, and sulfur atoms.
[00039] In some embodiments, in compounds of formula m, A is In some
compounds, each D is methyl.

[00040] In some embodiments, in compounds of formula HI, U is aryl. For example, U
can be benzene. In some embodiments, U is a halo-substituted benzene ring.
[00041] In one aspect, the methods of the invention include administering a composition
i that includes a compound of formula HI, wherein two adjacent U substituents are connected to
form a 5- or 6- membered, optionally substituted ring.
[00042] For example, methods of the invention include administering a composition that
includes a compound of formula HI, where adjacent U substituents are connected as a heterocyclic
ring, forming a compound having the structure according to formula Ela:
Dla , wherein L is a single bond or CH2,
X, Y, and Z are each, independently, N, NH, O, S, CB, CH, or absent, such that at least one of X,
Y, and Z is N or NH; p is 0,1, 2, or 3; B is a halogen atom, hydroxyl, carbamoyl, aryl or amino;
A is ; D is unbranched lower alkyl; and R is
substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, or C8 straight chain alkyl, or substituted
or unsubstituted C3, C4, C5, C6, C7 or C8 branched chain alkyl.
[00043] In one embodiment, in the compound of formula nia, the fused heterocyclic ring is .
a 6-membered ring. For example, the ring can be a pyridine ring.
[00044] - In one embodiment, in the compound of formula Dla, the fused heterocyclic ring is
a 5-membered ring. For example, the ring can be thiazole, oxazole, or imidazole.
[00045] In one embodiment, in the compound of formula Dla, B is aryl. For example, B is
benzene.
[00046] In one embodiment, methods of the invention include administering a composition


that includes a compound selected from

, or pharmaceutically acceptable salts thereof.
[00047] In one aspect, methods of the invention include adrninistering a composition
chronically to treat or prevent macular degeneration and other forms of retinal disease whose
, etiology involves the accumulation of A2E and/or lipofuscin.
[00048] In one aspect, the invention also relates to a method of identifying a drug for
treating or preventing macular degeneration and other forms of retinal disease whose etiology
involves the accumulation of A2E and/or lipofuscin, by administering a candidate drug to a
subject having, or who is at risk for developing, macular degeneration or other forms of retinal
disease whose etiology involves the accumulation of A2E and/or lipofuscin; and measuring
.accumulation of A2E in the subject; where reduced accumulation of A2E in the presence of the
candidate drug relative to accumulation of A2E in the absence of the candidate drug indicates
that the candidate drug is a drug for treating or preventing.macular degeneration and other forms
of retinal disease whose etiology involves the accumulation of A2E and/or lipofuscin.
[00049] In another aspect, the invention relates to a method of identifying a drug for treating
or preventing macular degeneration and other forms of retinal disease whose etiology involves
the accumulation of A2E and/or lipofuscin, by: contacting an in-vitro model of the visual cycle
with the candidate drug; and measuring accumulation of A2E; wherein reduced accumulation of
A2E in the presence of the candidate drug relative to accumulation of A2E in the absence of the
candidate drug indicates that the candidate drug is a drug for treating or preventing macular
degeneration and other forms of retinal disease whose etiology involves the accumulation of
A2E and/or lipofuscin.
[00050] The present invention relates to compounds and their use to treat macular
degeneration, including dry form AMD and Stargardt disease, and other forms of retinal disease
whose etiology involves the accumulation of A2E and/or lipofuscin. One aspect of the invention

includes a compound of formula I, Ia, II, Ha, IE, IHa, or IV wherein a Schiff Base adduct of said
compound and 1 l-cis-RAL possesses an extinction coefficient equal to or less than that of free
11-cw-RAL. In one embodiment, the absorbahce peak of the Schiff Base adduct is at a
wavelength equal to or lower than that of free 1 l-cis-RAL.
[00051] Another aspect of the invention includes a compound having the formula
IV: (TV), wherein X is 0, N(H), or S and het is a 5 or 6-membered heterocycle. n
represents 0,1, 2, or 3, and each D is an unbranched lower alkyl group. U is a substituent •-
selected from halogen atom; cyano; lower alkyl wherein one or more hydrogen atoms on the
lower alkyl group are.pptionally substituted by. groups, selected from a halogen atom, hydroxyl,
carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic group containing one or more
■ .hetero-atoms selected from nitrogen, oxygen, and sulfur atoms; lower alkylthio wherein one or
more hydrogen atoms on the alkyl group are optionally substituted by groups selected from a
halogen atom, hydroxyl, carbamoyl, amino, and aryl; lower alkylsulfonyl wherein one or more
hydrogen atoms on the alkyl group are optionally substituted by groups selected from a halogen
atom, hydroxyl, carbamoyl, amino, and aryl; hydroxyl; lower alkoxy; formyl; lower
. alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbonyl; carbamoyl; NJlower ':
alkylcarbamoyl; N,N-di-lower alkylaminocarbonyl; amino; N-lower alkylamino; N,N-di-lower
alkylamino; formylamino; lower alkylcarbonylamino; arnmosulfonylamino; (N-lower
alkylarmno)sulfonylamino; (N,N-di-lower alkylammo)sulfonylamino; aryl, optionally substituted
by groups selected from a halogen atom, hydroxyl, carbamoyl, aryl and amino; and a monocyclic
or bicyclic heterocyclic group containing one or more hetero-atoms selected from nitrogen,
oxygen, and sulfur atoms. In another embodiment, each D is methyl. In another embodiment,
the pKa of the ring NH2 (NH2 -»• NH) is approximately 3.5.
[00052] Another aspect of the invention includes a compound represented by general
formula I: (I). W, X, Y, and Z are each, independently, N, S, O, CU or CH, such

that at least one ofW,X,Y, and Z is N. A is D is
unbranched lower alkyl. R is substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, or C8,
straight chain alkyl, or substituted or unsubstituted C3, C4, C5, C6, C7, or C8, branched chain
alkyl. U is a substituent selected from a halogen atom; cyano; lower alkyl wherein one or more
hydrogen atoms on the lower alkyl group are optionally substituted by groups selected from a
halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic heterocyclic
group containing one or more hetero-atoms selected from nitrogen, oxygen, and sulfur atoms;
lower alkylthio wherein one or more hydrogen atoms on the alkyl group are optionally
substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and aryl; lower
alkylsulfonyl wherein one. or more, hydrogen atoms on the alkyl.group are optionally-substituted- -
by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and aryl; hydroxyl; lower
alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower alkoxycarbpnyl; carbamoyl;
N-lower alkylcarbamoyl; N,N-di-lower alkylaminocarbonyl; amino; N-lower alkylamino; N,N-
di-lower alkylamino; formylamino; lower alkylcarbonylamino; aminosulfonylamino; (N-lower
alkylammo)sulfonylamino; (N,N-di-lower alkylamino)sulfonylamino; aryl, optionally substituted
by groups selected from a halogen atom, hydroxyl, carbamoyl, aryl and amino; and a monocyclic
or bicyclic heterocyclic group containing one or more hetero-atoms selected from nitrogen,
oxygen, and sulfur atoms, n represents 0, 1, 2,3, or 4. In one embodiment, the compound
comprises a pyridine, pyridazine, pyrazine, or pyrimidine ring. In another embodiment, U is an
aryl. In another embodiment, U is a benzene. In another embodiment, U is a halo-substituted
benzene. In one embodiment, A is and D is methyl. In another embodiment, two
adjacent U substituents are connected to form a 5- or 6- membered optionally substituted ring. In
another embodiment, two adjacent U substituents are connected as a benzene ring, forming a
compound having the structure, according to formula Ia:
(Ia). X, Y, and Z are each, independently, N, O, S, C(H), or absent,

such that at least one of X, Y, and Z is N. p is 0,1,2, or 3. B is a halogen atom, hydroxyl,
carbamoyl, aryl or amino. A is D is uribranched
lower alkyl, and R is substituted or unsubstituted C1, C2, C3, C4, 05, C6, C7, or C8 straight
chain alkyl, or substituted or unsubstituted C3, C4, C5, C6, C7, or C8 branched chain alkyl.
[00053] In one embodiment, the composition comprises a compound selected from:
. In a further embodiment, the compound
is selected from and pharmaceutically acceptable salts thereof.
[00054] Another aspect of the invention includes a compound represented by formula II or
Ha: (Tla). Q, T, and V are each, independently, N(H),
S, O, CU or CH, such that at least one of Q, T and V is not CU or CH. The dashed ring represents
two double bonds within the ring, which comply with the valency requirements of the atoms and
heteroatoms present in the ring, m is 0,1, or 2. A is
. D is unbranched lower alkyl. R is substituted or
unsubstituted C1, C2, C3, C4, C5, C6, C7 or C8 straight chain alkyl, or substituted or

unsubstituted C3, C4, C5, C6, C7, or C8 branched chain alkyl. U is a substituent selected from a
halogen atom; cyano; lower alkyl wherein one or more hydrogen atoms on the lower alkyl group
are optionally substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino,
aryl, and a monocyclic or bicyclic heterocyclic group containing one or more hetero-atoms
selected from nitrogen, oxygen, and sulfur atoms; lower alkylthio wherein one or more hydrogen
atoms on the alkyl group are optionally substituted by groups selected from a halogen atom,
hydroxyl, carbamoyl, amino, and aryl; lower alkylsulfonyi wherein one or more hydrogen atoms
on the alkyl group are optionally substituted by groups selected from a halogen atom, hydroxyl,
carbamoyl, amino, and aryl; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl;
carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N,N-di-lower
alkylarninocarbonyl; amino; N-lower alkylamino; N,N-di-lower alkylamino; formylamino; lower
alkylcarbbhylarhino; amihosulfdnylarnin'o;' (N-lower a]kylammo)sulfonylamino; (N,N-di-lower
allcylarmno)sulfonylamino; aryl, optionally substituted by groups selected from a halogen atom,
hydroxyl, carbamoyl; aryl and amino; and a monocyclic or bicyclic heterocyclic group
containing one or more hetero-atoms selected from nitrogen, oxygen, and sulfur atoms. In one
embodiment, U is an aryl. In another embodiment, U is a benzene. In another embodiment, U is
a halo-substituted benzene. In one embodiment, A is . In another embodiment, eachD-a'
is methyl. In another embodiment, Q, T, and V are selected such that the composition comprises
a furan or thiophene ring. In another embodiment, U is lower alkyl. In another embodiment, U is
methyl. 'In another embodiment, U is halogen atom. In another embodiment, U is fluoro. In a
further embodiment, the compound is selected from and pharmaceutically
acceptable salts thereof.
[0005 5] Another aspect of the invention includes a compound represented by general
formula HI: . L is a single bond or CH2. A is


D is unbranched lower alkyl. R is substituted or
unsubstituted C1, C2, C3, C4, C5, C6, C7, or C8 straight chain alkyl, or substituted or
unsubstituted C3, C4, C5, C6, C7, or C8 branched chain alkyl. U is a substituent selected from a
halogen atom; cyano; lower alkyl wherein one or more hydrogen atoms on the lower alkyl group
are optionally substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino,
aryl, and a monocyclic or bicyclic heterocyclic group containing one. or more hetero-atoms
selected from nitrogen, oxygen, and sulfur atoms; lower alkylthio wherein one or more hydrogen
atoms on the alkyl group are optionally substituted by groups selected from a halogen atom,
hydroxyl, carbamoyl, amino, and aryl; lower alkylsulfonyl wherein one or more hydrogen atoms
on the alkyl group are optionally substituted by.grpups selected from a halogen atom, hydroxyl,
carbamoyl, amino, and aryl; hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl;
carboxyl; lower alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N,N-di-lower
- alkylaminocarbonyl; amino; N-lower alkylamino; N,N-di-lower alkylamino; formylamino; lower
alkylcarbonylamino; aininosulfonylaniino; (N-lower a]kylamino)sulfonylamino; (N,N-di-lower
alkylammo)smfonylamino; aryl, optionally substituted by groups selected from a halogen atom,
hydroxyl, carbamoyl, aryl and amino; and a monocyclic or bicyclic heterocyclic group
containing one or more hetero-atoms selected from nitrogen, oxygen, and sulfur atoms, k is 0,1,
2, 3, or 4. In one embodiment, A is In another embodiment, each D is methyl. In
another embodiment, U is an aryl. In another embodiment, U is a benzene. In another
embodiment, U is a halo-substituted benzene. In another embodiment, two adjacent U
substituents are connected to form a 5- or 6- membered optionally substituted ring. In another
embodiment, two adjacent U substituents are connected as a heterocyclic ring, forming a
compound having the structure according to formula.ma: . X, Y,
and Z are each, independently, N, O, S, CB, CH, or absent, such that at least one of X, Y, and Z is
N. p is 0,1,2, or 3. B is a halogen atom, hydroxyl, carbamoyl, aryl or amino. A is


D is unbranched lower alkyl. R is substituted or
unsubstituted C1, C2, C3, C4, C5, C6, C7, or C8 straight chain alkyl, or substituted or
unsubstituted C3, C4, C5, C6, C7, or C8 branched chain alkyl. In one embodiment, the fused
heterocyclic ring is a 6-membered ring. In another embodiment, the fused heterocyclic ring is a
pyridine ring. In another embodiment, the fused heterocyclic ring is a 5-membered ring. In
another embodiment, the fused heterocyclic ring is selected from thiazole, oxazole, and imidazole.
In another embodiment, B is aryl. In another embodiment, B is a benzene. In another embodiment,
the compound is selected from , .. . , and
pharmaceutically acceptable salts thereof.
[00056] . Pharmaceutical compositions that include a compound of Formula I, Ia, II, Ha, HI,
ma, or W or a pharmaceutically acceptable salt thereof are used in the methods of the invention.
In one embodiment, the compound of Formula I, Ia, II, Ha, HI, Lla, or TV or a pharmaceutically
acceptable salt thereof is co-administered with one or more additional therapies.
[00057] The above description sets forth rather broadly the more important features of the
present invention in order that the detailed description thereof that follows maybe understood,
and in order that the present contributions to the art may be better appreciated. Other objects and
features of the present invention will become apparent from the following detailed description
considered in conjunction with the examples.
BRIEF DESCRIPTION OF THE^IGURES 1 ^ V>
[00058] Figure 1 is a schematic of the visual cycle.
[00059] Figure 2 is a schematic of the reaction pathway of A2E formation.
[00060] Figure 3 is a schematic of Schiff base formation.

[00061] Figure 4a is a UV-vis spectrum of compound 6 and RAL; Figure 4b is a graph of
the formation of the Scbiff base adduct.
[00062] Figure 5 is a graph of standard curve for ERG measurement of retinal responses to
experimental stimuli of varying light intensity.
[00063] Figure 6a is a graph of ERG measurement of the dark adaptation rate of a photo-
bleached rat during anesthesia, and Figure 6b is a graph of EGR measurement of the dark
adaptation of a photo-bleached rat without anesthesia.
[00064] Figure 7 is a graph of the effect of compound 6 on ERG light sensitivity of a dark-
adapted rat.
[00065] Figure 8 is a graph showing RAL-compound 8 reaction kinetics by NMR.
DETAILED DESCRIPTION OF THE INVENTION
[00066] The present application provides compositions and methods for treating macular
degeneration and other forms, of retinal disease whose etiology involves the accumulation of A2E
and/or lipofuscin, for example, by limiting the formation of cytotoxic A2E. A2E formation can
be prevented or reduced by limiting the amount of trans RAL available for reaction with
phosphatidyl ethanolamine (PE). Progressive A2E accumulation in RPE cells causes dry AMD.
By reducing the amount of A2E accumulation, the present invention prevents the onset and/or
progression of dry AMD. In one approach, a small molecule drug is administered that competes
with PE for reaction with trans-RAL which has escaped sequestering by opsins in photoreceptor
outer segments.
[00067] As shown in Figure 2, RAL contains an aldehyde group. The aldehyde group
stabilizes the binding of 11-czs-RAL to a photoreceptor membrane protein called opsin, by
forming a Scbiff base (Figure 3) with an amino acid sidechain in the opsin binding site. Opsin
releases trans-RAL from this binding site after transducing the photo-isomerization of bound 11-
cis-RAL through a second messenger pathway.
[00068] While the aldehyde group on RAL is a useful molecular anchor for opsin binding,
it is otherwise hazardous because of its Scbiff base reactivity with other biological amines. To

mitigate this risk, visual cycle proteins have evolved molecular mechanisms to continuously
sequester RAL molecules, and thereby shield the aldehyde group from chemical side reactions.
However, these protein sequestering mechanisms are not completely reliable. Over time, as
much as one trans-RAL molecule in three escapes protein sequestering, where it is free to initiate
a reaction cascade which begins with the formation of A2PE in photoreceptor outer segments
and culminates in the formation.of A2E in RPE cell lysosymes.
[00069] Once it is formed inside RPE cell lysosomes, A2E inhibits the ATP-driven proton
pump in lysosome membranes and causes lysosomal pH to increase. The pH increase deactivates
acid hydrolases and thereby causes lysosomal failure. Lysosomal failure is also caused the
detergent action of A2E, which solubilizes lysosomal membranes. Lysosomal failure poisons the
RPE cells and compromises their ability to provide biochemical support to retinal photoreceptors,
leading to the progressive degeneration of both cell types and visual deterioration.
[00070] Hydroxyl amine and aromatic amine compounds were described as aldehyde
nucleophiles in Schiff base reactions with RAL by Hubbard in 1956. Hubbard, J. Am. Chem.
Soc. 78:4662, 1956; see also Rapp and Basinger, Vision Res. 22:1097, 1982, and Fowler et al., J,
Photochem. PhotobiplB8:183,1991. Two such compounds which have a history of safe human
use for other purposes include methyl anthranilate, a natural product found in grapes, and MS-
222, a fish anesthetic used by fish breeders who are exposed to it occupationally during fish
handling. However, MS-222 is pharmacologically active in the human retina and has no
anesthetic activity in mammals.
[00071] In 1963, Dowling showed that anesthetics slow rhodopsin regeneration and dark
adaptation in rats. This was the first report that such small molecules could modulate.retinal
visual performance. Dowling, J. Gen. Physiol. 46:1287,1963. In 1982, Rapp & Basinger
showed that certain local anesthetics form Schiff bases with RAL and slow dark adaptation in
frogs. This was the first elucidation of the chemical reaction mechanism by which these
compounds modulate retinal visual performance. Rapp and Basinger, Vision Res. 22:1097,
1982. In 1997, Bernstein et al. showed that MS222 (6) attenuates night vision reversibly in
human occupational exposure. This was the first report that one such compound can be absorbed
by the skin and modulate human retinal vision reversibly with no known side effects. Bernstein
et al., Am. J. Opthalmol., 124:843,1997.

Definitions
[00072] For convenience, before further description of exemplary embodiments, certain
terms employed in the specification, examples, and appended claims are collected here.
[00073] These definitions should be read in light of the remainder of the disclosure and as
understood by a person of skill in the art.
[00074] The articles "a" and "an" are used herein to refer to one or to more than one (i. e.,
to at least one) of the grammatical object of the article. By way of example, "an element" means
one element or more than one element.
[00075] The terms "comprise," "comprising," "include," "including," "have," and
"having" are used in the inclusive, open sense, meaning that additional elements may be included.
The terms "such as", "e.g.", as used herein are non-limiting and are for illustrative purposes
only. "Including" and "including but not limited to" are used interchangeably.
[00076] The term "or" as used herein should be understood to mean "and/or", unless the
context clearly indicates otherwise.
[00077] In the present specification, the structural formula of the compound represents a
certain isomer for convenience in some cases, but the present invention includes all isomers such
as geometrical isomer, optical isomer.based oh ah asymmetrical carbon, stereoisomer, tautomer
and the like which occur structurally and an isomer mixture and is not limited to the description
of the formula for convenience, and may be any oneof isomer or a mixture. Therefore, an
asymmetrical carbon atom may be present in the molecule and an optically active compound and
a racemic compound may be present in the present compound, but the present invention is not
limited to them and includes any one. In addition, a crystal polymorphism may be present but is
not limiting, but any crystal form may be single or a crystal form mixture, or an anhydride or
hydrate. Further, so-called metabolite which is produced by degradation of the present compound
in vivo is included in the scope of the present invention.
[00078] It will be noted that the structure of some of the compounds of the invention
include asymmetric (chiral) carbon atoms. It is to be understood accordingly that the isomers
arising from such asymmetry are included within the scope of the invention, unless indicated
otherwise. Such isomers can be obtained in substantially pure form by classical separation

techniques and by stereochemically controlled synthesis. The compounds of this invention may
exist in stereoisomers form, therefore can be produced as individual stereoisomers or as
mixtures.
[00079] "Isomerism" means compounds that have identical molecular formulae but that
differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms
in space. Isomers that differ in the arrangement of their atoms in space are termed
"stereoisomers". Stereoisomers that are not mirror images of one another are termed
"diastereoisomers", and stereoisomers that are non-superimposable mirror images are termed
"enantiomers", or sometimes optical isomers. A carbon atom bonded to four nonidentical
substituents is termed a "chiral center".
,[00080] "Chiral isomer" means a compound with at least one chiral center. It has two
enantiomeric forms of opposite chirality and may exist either as an individual enantiomerorjas. a .
mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of
opposite chirality is termed a "racemic mixture". A compound that has more than one chiral
center has 2""1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more
than one chiral center may exist as either an individual diastereomer or as a mixture of
diastereomers, termed a "diastereomeric mixture". When one chiral center is present, a
stereoisomer may be characterized by the-absolute configuration (R or S) of that chiral center.
Absolute configuration refers to the arrangement in space of the substituents attached to the
chiral center. The substituents attached to the chiral center under consideration are ranked in
accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al, Angew. Chem. Inter.
Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78,413; Cahn and Ingold, J.
Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956,12, 81; Cahn, J., Chem. Educ.
1964,41,116).
[00081] "Geometric Isomers" means the diastereomers that owe their existence to
hindered rotation about double bonds. These configurations are differentiated in their names by
the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite
side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
[00082] Further, the structures and other compounds discussed in this application include
all atropic isomers thereof. "Atropic isomers" are a type of stereoisomer in which the atoms of
two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted

rotation caused by hindrance of rotation of large groups about a central bond. Such atropic
isomers typically exist as a mixture, however as a result of recent advances in chromatography
techniques, it has been possible to separate mixtures of two atropic isomers in select cases.
[00083] The terms "crystal polymorphs" or "polymorphs" or "crystal forms" means
crystal structures in which a compound (or salt or solvate thereof) can crystallize in different
crystal packing arrangements, all of which have the same elemental composition. Different
crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points,
density hardness, crystal shape, optical and electrical properties, stability and solubility.
Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause
one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by
crystallization under different conditions.
[00084] Additionally, the compounds of the present invention, for example, the salts of the
compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with
other solvent molecules. Nonlirniting examples of hydrates include monohydrates, dihydrates,
etc. Nonlirniting examples of solvates include ethanol solvates, acetone solvates, etc.
[00085] "Solvates" means solvent addition forms that contain either stoichiometric or non
stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio
of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water
the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate.
Hydrates are formed by the combination of one or more molecules of water with one of the
substances in which the water retains its molecular state as H2O, such combination being able to
form one or more hydrate.
[00086] "Tautomers" refers to compounds whose structures differ markedly in
arrangement of atoms, but which exist in easy and rapid equilibrium. It is to be understood that
compounds of Formula I may be depicted1 as different tautomers. It should also be understood
that when compounds have tautomeric forms, all tautomeric forms are intended to be within the
scope of the invention, and the naming of the compounds does not exclude any tautomer form.
[00087] Some compounds of the present invention can exist in a tautomeric form which
are also intended to be encompassed within the scope of the present invention.
[00088] The compounds, salts and prodrugs of the present invention can exist in several
tautomeric forms, including the enol and imine form, and the keto and enamine form and

geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope
of the present invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid
form, usually one tautomer predominates. Even though one tautomer may be described, the
present invention includes all tautomers of the present compounds
[00089] A tautomer is one of two or more structural isomers that exist in equilibrium and
are readily converted from one isomeric form to another. This reaction results in the formal
migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. In
solutions, where tautomerization is possible, a chemical equilibrium of the tautomers will.be
reached. The exact ratio of the tautomers depends on several factors, including temperature,
solvent, and pH. The concept of tautomers that are interconvertable by tautomerizations is called
tautomerism.
[00090] Of the various types of tautomerism that are possible, two are commonly
observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom
occurs. Ring-chain tautomerism, is exhibited by glucose. It arises- as a result of the aldehyde
group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the
same molecule to give it a cyclic (ring-shaped) form.
[00091] Tautomerizations are catalyzed by: Base: 1. deprotonation; 2. formation of a
delocalized anion (e.g. an enolate); 3. protonation at a different position of the anion; Acid: 1.
protonation; 2. formation of a delocalized cation; 3. deprotonation at a different position adjacent
to the cation.
[00092] Common tautomeric pairs are: ketone - enol, amide - nitrile, lactam - lactirn,
amide - imidic acid tautomerism in heterocyclic rings (e.g. in the nucleobases guanine, mymine,
and cytosine), amine - enamine and enamine - enamine. Examples include:


[00093] As used herein, the term "analog" refers to a chemical compound that is
structurally similar to another but differs slightly in composition (as in the replacement of one
atom by an atom of a different element or in the presence of a particular functional group, or the
replacement of one functional group by another functional group). Thus, an analog is a
compound that is similar or comparable in function and appearance, but not in structure or origin
to. the reference compound.
. [00094] As defined herein, the term "derivative", refers to compounds that have a
common core structure, and are substituted with various groups as described herein. For
. example, all of the compounds represented by formula I are indole derivatives, and have formula
I as a common core.
[00095] The term "bioisostere" refers to.a compound resulting from the exchange of an
atom or of a group of atoms with another, broadly similar, atom or group of atoms. The
objective of a bioisosteric replacement is to create a new compound with similar biological
properties to the parent compound. The bioisosteric replacement may be physicochemically or
topologically based. Examples of carboxylic acid bioisosteres include acyl sulfonimides,
tetrazoles, sulfonates, and phosphonates. See, e.g., Patani andLaVoie, Chem. Rev. 96, 3147-
3176 (1996).
[00096] The phrases "parenteral administration" and "administered parenterally" are art-
recognized terms, and include modes of administration other than enteral and topical
administration, such as injections, and include, without limitation, intravenous, intramuscular,
intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-
articular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
[00097] The term "treating" is art-recognized and includes inhibiting a disease, disorder or
condition in a subject, 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.
[00098] The term "preventing" is art-recognized and includes stopping a disease, disorder
or condition from occurring in a subject which may be predisposed to the disease, disorder and/or
condition but has not yet been diagnosed as having it. Preventing a condition related to a disease

includes stopping the condition from occurring after the disease has been diagnosed but before
the condition has been diagnosed.
[00099] A "pharmaceutical composition" is a formulation containing the disclosed
compounds in a form suitable for administration to a subject. In a preferred embodiment, the
pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is. any of a
variety of forms, including, for example, a capsule, an TV bag, a tablet, a single pump on an
aerosol inhaler, or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed
compound or salts thereof) in a unit dose of composition is an effective amount and is varied
according to the particular treatment involved. One skilled in the art will appreciate that it is
sometimes necessary to make routine variations to the dosage depending on the age and
condition of the patient. The dosage will also depend on the route of administration. A variety
of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal,
subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, and the like. Dosage forms
for the topical or transdermal administration of a compound of this invention include powders,
sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In a preferred
embodiment, the active compound is mixed under sterile conditions with a pharmaceutically
acceptable carrier, and with any preservatives, buffers, or propellants that are required..
[000100] The term 'flash dose" refers to compound formulations that are rapidly dispersing
dosage forms.
[000101] The term "immediate release" is defined as a release of compound from a dosage
form in a relatively brief period of time, generally up to about 60 minutes. The term "modified
. release" is defined to include delayed release, extended release, and pulsed release. The term
"pulsed release" is.defined as a series of releases of drug from a dosage form. The term
"sustained release" or "extended release" is defined as continuous release of a compound from a
dosage form over a prolonged period.
[000102] The phrase "pharmaceutically acceptable" is art-recognized. In certain
embodiments, the term includes compositions, polymers and other materials and/or dosage forms
which are, within the scope of sound medical judgment, suitable for use in contact with the
tissues of human beings and animals without excessive toxicity, irritation, allergic response, or
other problem or complication, commensurate with a reasonable benefit/risk ratio.
[000103] The phrase "pharmaceutically acceptable carrier" is art-recognized, and includes,

for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or
solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or
transporting any subject composition from one organ, or portion of the body, to another organ, or
portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the
other ingredients of a subject composition and not injurious to the patient. In certain
embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of
materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as
lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and
its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)
powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and
suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive
oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as
glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl
laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum r
hydroxide; (15) alginic acid; (16) pyrogen-free water; (17).isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible
substances employed in pharmaceutical formulations.
[000104] The compounds of the invention are capable of further forming salts. All of these
forms are also contemplated within the scope of the claimed invention.
[000105] "Pharmaceutically acceptable salt" of a compound means a salt that is
pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent
compound.
[000106] For example, the salt can be an acid addition salt. One embodiment of an acid
addition salt is a hydrochloride salt
[000107] The pharmaceutically acceptable salts of the present invention can be synthesized
from a parent compound that contains a basic or acidic moiety by conventional chemical
methods. Generally, such salts can be prepared by reacting the free acid or base forms of these
compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic
solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, .
ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in
Remington's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990). For

example, salts can include, but are not limited to, the hydrochloride and acetate salts of the
aliphatic amine-containing, hydroxyl arjodne-containing, and inline-containing compounds of the
present invention.
[000108] It should be understood that all references to pharmaceutically acceptable salts
include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the
same salt.
[000109] The compounds of the present invention can also be prepared as esters, for
example pharmaceutically acceptable esters. For example a carboxylic acid function group in a
compound can be converted to its corresponding ester, e.g., a methyl, ethyl, or other ester. Also,
an alcohol group in a compound can be converted to its corresponding ester, e.g., an acetate,
propionate, or other ester.
[000110] The compounds of the present invention can also be prepared-as prodrugs, for
example pharmaceutically acceptable prodrugs. The terms "pro-drug" and "prodrug" are used
interchangeably herein and refer to any compound which releases an active parent drug in vivo.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g.,
solubility, bioavailability, manufacturing, etc.) the compounds of the present invention can be
' delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the
presently claimed compounds, methods of delivering the same and compositions containing the
same. "Prodrugs" are intended to include any covalently bonded carriers that release an active
parent drug of the present invention in vivo when such prodrug is administered to a subject.
Prodrugs the present invention are prepared by modifying functional groups present in the
compound in such a way that the modifications are cleaved, either in routine manipulation or in
vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a
hydroxy, amino, sulfhydryl, carboxy, or carbonyl group is bonded to any group that, may be
cleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl, free carboxy or free carbonyl
group, respectively.
[000111] Examples of prodrugs include, but are not Umited to, esters (e.g., acetate,
dialkylarninoacetates, formates, phosphates, sulfates, and benzoate derivatives) and carbamates
(e.g., N,N-dimemylaminocarbonyl) of hydroxy functional groups, ester groups (e.g. ethyl esters,
morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (e.g. N-acetyl) N-
Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals

and enol esters of ketone and aldehyde functional groups in compounds of Formula I, and the
like, See Bundegaard, H. "Design of Prodrugs" pi-92, Elesevier, New York-Oxford (1985).
[000112] "Protecting group" refers to a grouping of atoms that when attached to a reactive
group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups
can be found in Green and Wuts, Protective Groups in Organic Chemistry, (Wiley, 2nd ed.
1991); Harrison and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8 (John
Wiley and Sons, 1971-1996); and Kocienski, Protecting Groups, (Verlag, 3rd ed. 2003).
[000113] The term "amine protecting group" is intended to mean a functional group that
converts an amine, amide, or other nitrogen-containing moiety into a different chemical group
that is substantially inert to the conditions of a particular chemical reaction. Amine protecting
groups are preferably removed easily and selectively in good yield under conditions that do not
affect other functional groups of the molecule.. Examples of amine protecting groups include,
but are not limited to, formyl, acetyl, benzyl, f-butyldimethylsilyl, f-butdyldiphenylsilyl, t-
butyloxycarbonyl (Boc),/j-methoxybenzyl, methoxymethyl, tosyl, trifluoroacetyl, trimethylsiiyl
(TMS), fluorenyl-methyloxycarbonyl, 2-trimethylsilyl-ethyoxycarbonyl, 1-methyl-1-(4-
biphenylyl) ethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl (CBZ), 2-trimethylsilyl-
ethanesulfonyl (SES), trityl and substituted trityl groups, 9-fluorenylmethyloxycarbonyl
(FMOC), nitro-veratryloxycarbonyl (NVOC), and the like. Other suitable amine protecting
groups are straightforwardly identified by those of skill in the art.
[000114] Representative hydroxy protecting groups include those where the hydroxy group
is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers,
tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
[000115] The term "pharmaceutically acceptable salts" is art-recognized, and includes
relatively non-toxic, inorganic and organic acid addition salts of compositions, including without
limitation, therapeutic agents, excipients, other materials and the like. Examples of
pharmaceutically acceptable salts include those derived from mineral acids, such as hydrochloric
acid and sulfuric acid, and those derived from organic acids, such as ethanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, and the like. Examples of suitable inorganic bases
for the formation of salts include the hydroxides, carbonates, and bicarbonates of ammonia,
sodium, lithium, potassium, calcium, magnesium, aluminum, zinc and the like. Salts may also be
formed with suitable organic bases, including those that are non-toxic and strong enough to form

such salts. For purposes of illustration, the class of such organic bases may include mono-, di-,
and trialkylamines, such as methylamine, olmethylarnine, and triethylamine; mono-, di- or
trmydroxyalkylarnines such as mono-, di-, and triethanolamme; amino acids, such as arginine
and lysine; guanidine; N-memylglucosamine; N-methylglucamine; Lr-glutarnine; N-
methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; „
(trmydioxymemyl)aminoethane; and the like. See, for example, J. Pharm. Sci.'66:l-19 T1977.
[000116] A "patient," "subject," or "host" to be treated by the subj ect method may mean
either a human or non-human animal, such as primates, mammals, and vertebrates.
[000117] The term "prophylactic or therapeutic" treatment is art-recognized and includes
administration to the host of one or more of the subject compositions. If it is administered prior
to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the
host animal) then the treatment is prophylactic, i.e., it protects the host against developing the
unwanted condition, whereas if it is administered after manifestation of the unwanted condition,
the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing
unwanted condition or side effects thereof).
[000118] The terms "therapeutic agent", "drug", "medicament" and "bioactive substance"
are art-recognized and include molecules and other agents that are biologically, physiologically,
or pharmacologically active substances that act locally or systemically in a patient or subject to
treat a disease or condition, such as macular degeneration or other forms of retinal disease whose
etiology involves the accumulation of A2E and/or lipofuscin. The terms include without
limitation pharmaceutically acceptable salts thereof and prodrugs. Such agents may be acidic,
basic, or salts; they may be neutral molecules, polar molecules, or molecular complexes capable
of hydrogen bonding; they may be prodrugs in the form of ethers, esters, amides and the like that
are biologically activated when administered into a patient or subject.
[000119] The phrase "therapeutically effective amount" is an art-recognized term. In
certain embodiments, the term refers to an amount of a therapeutic agent that, when incorporated
into a polymer, produces some desired effect at a reasonable benefit/risk ratio applicable to any
medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient
to eliminate, reduce or maintain (e.g., prevent the spread of) a tumor or other target of a particular
therapeutic regimen. The effective amount may vary depending on such factors as the disease or

t
condition being treated, the particular targeted constructs being administered, the size of the
subject or the severity of the disease or condition. One of ordinary skill in the art may
empirically determine the effective amount of a particular compound without necessitating undue
experimentation. In certain embodiments, a therapeutically effective amount of a therapeutic
agent for in vivo use will likely depend on a number of factors, including: the rate of release of
an agent from a polymer matrix, which will depend in part on the chemical and physical
. characteristics of the polymer; the identity of the agent; the mode and method of administration;
and any other materials incorporated in the polymer matrix in addition to the agent.
[000120] The term "ED50" is art-recognized. In certain embodiments, ED50 means the dose
of a drug which produces 50% of its maximum response or effect, or alternatively, the dose which
produces apre-determined response in 50% of test subjects or preparations. The term "LD50" is
art-recognized. In certain embodiments, LD50 means the dose of a drug which is lethal in 50% of
test subjects. The term "therapeutic index" is an art-recognized term which refers to the
therapeutic index of a drug, defined as IDs/EDa.
[000121] The term "substituted," as used herein, means that any one or more hydrogens on
the designated atom is replaced with a selection from the indicated group, provided that the
designated atom's normal valency is not exceeded, and that the substitution results in a stable
compound. When the substituent is keto (i.e., =0), then 2 hydrogens on the atom are replaced.
Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring
atoms (e.g., C=C, C=N, orN=N).
[000122] With respect to any chemical compounds, the present invention is intended to
include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms
having the same atomic number but different mass numbers. By way of general example and
without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon
.include C-13 and C-14.
[000123] The chemical compounds described herein can have asymmetric centers.
Compounds of the present invention containing an asymmetrically substituted atom can be
isolated in optically active or racemic forms. It is well known in the art how to prepare optically
active forms, such as by resolution of racemic forms or by synthesis from optically active
starting materials. Many geometric isomers of olefins, C=N double bonds, and the like can also

be present in the compounds described herein, and all such stable isomers are contemplated in
the present invention. Cis and trans geometric isomers of the compounds of the present
invention are described and can be isolated as a mixture of isomers or as separated isomeric
forms. All chiral, diastereomeric, racemic, and geometric isomeric forms of a structure are
intended, unless the specific stereochemistry or isomeric form is specifically indicated. All
processes used to prepare compounds of the present invention and intermediates made therein
are, where appropriate, considered to be part of the present invention. All tautomers of shown or
described compounds are also, where appropriate, considered to be part of the present invention.
[000124] When a bond to a substituent is shown to cross a bond connecting two atoms in a
ring, then such substituent can be bonded to any atom in the ring. When a substituent is listed
without indicating the atom via which such substituent is bonded to the rest of the compound of a
given formula, then such substituent can be bonded via any atom in such substituent.
Combinations of substituents and/or variables are permissible, but only if such combinations
result in stable compounds.
[000125] When an atom or a chemical moiety is followed by a subscripted numeric range
(e.g., Ci-6), the invention is meant to encompass each number within the range as well as all
. intermediate ranges. For example, "Ci-6 alkyl" is meant to include alkyl groups with 1, 2,3, 4, 5,
6,1-6, 1-5,1-4, 1-3,1-2, 2-6,2-5, 2-4, 2-3, 3-6, 3-5, 3-4,4-6,4-5, and 5-6 carbons.
[000126] As used herein, "alkyl" is intended to include both branched (e.g., isopropyl, tert-
butyl, isobutyl), straight-chain e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,
nonyl, decyl), and cycloalkyl (e.g, alicyclic) groups (e.g., cyclopropyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl
groups. Such aliphatic hydrocarbon groups have a specified number of carbon atoms. For
example, Ci-6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. As used
herein, "lower alkyl" refers to alkyl groups having from 1 to 6 carbon atoms in the backbone of.
the carbon chain. "Alkyl" further includes alkyl groups that have oxygen, nitrogen, sulfur or
phosphorous atoms replacing one or more hydrocarbon backbone carbon atoms. In certain
embodiments, a straight chain or branched chain alkyl has six or fewer carbon atoms in its
backbone (e.g., C1-C6 for straight chain, C3-C6 for branched chain), for example four or fewer.

Likewise, certain cycloalkyls have from three to eight carbon atoms in their ring structure, such
as five or six carbons in the ring structure.
[000127] The term "substituted alkyls" refers to alkyl moieties having substituents
replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents
can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,
alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including
alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,
alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonato, sulfamoyl, sulfonamido,
nitro, trifluoromethyl, cyano, azido.heterocyclyl, alkylaryl, or an aromatic or heteroaromatic....
moiety. Cycloalkyls can be further substituted, e.g., with the substituents described above. An
"alkylaryl" or an "aialkyl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl
(benzyl)).
[000128] As used herein, "alkenyl" is intended to include hydrocarbon chains of either
straight or branched configuration having one or more carbon-carbon double bonds occurring at
any stable point along the chain. For example, C2-6 alkenyl is intended to include C2, C3, C4, Gs,';? ...
and C6 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl and
propenyl.
[000129] As used herein, "alkynyl" is intended to include hydrocarbon chains of either
straight or branched configuration having one or more carbon-carbon triple bonds occurring.at
any stable point along the chain. For example, C2-6 alkynyl is intended to include C2, C3, C4, C5,
and C6 alkynyl groups. Examples of alkynyl include, but are not limited to, ethynyl and
propynyl.
[000130] Furthermore, "alkyl", "alkenyl", and "alkynyl" are intended to include moieties
which are diradicals, i.e., having two points of attachment. A nonlimiting example of such an
alkyl moiety that is a diradical is -CH2CH2-, i.e., a C2 alkyl group that is covalently bonded via
each terminal carbon atom to the remainder of the molecule.

[000131] "Aryl" includes groups with aromaticity, including 5- and 6-membered
"unconjugated", or single-ring, aromatic groups that may include from zero to four heteroatoms,
as well as "conjugated", or multicyclic, systems with at least one aromatic ring. Examples of
aryl groups include benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole,
triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine,
and the like. Furthermore, the term "aryl" includes multicyclic aryl. groups, e.g., tricyclic,
bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole,
benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole,
benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups having
heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heterocycles,"
"heteroaryls" or "heteroaromatics". The aromatic ring can be substituted at one or more ring
positions with such substituents as described above, as for example,-halogen, hydroxyl, alkox-y,
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,
alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylarninocarbonyl, alkylcarbonyl,
arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl,
alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino,
dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino. arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,
alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido,
nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic
moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are
not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl).
[000132] The terms "heterocyclyl" or "heterocyclic group" include closed ring structures,
e.g., 3- to 10-, or 4- to 7-membered rings, which include one or more heteroatoms.
"Heteroatom" includes atoms of any. element other than carbon or hydrogen. Examples of
heteroatoms include nitrogen, oxygen, sulfur and phosphorus.
[000133] Heterocyclyl groups can be saturated or unsaturated and include pyrrolidine,
oxolane, thiolane, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and
pyrrolidinones, sultams, and sultones. Heterocyclic groups such as pyrrole and furan can have
aromatic character. They include fused ring structures such as quinoline and isoquinoline. Other
examples of heterocyclic groups include pyridine and purine. The heterocyclic ring can be

Substituted at one or more positions with such substituents as described above, as for example,
halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl,
phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino,
arylamino, diarylarnino, and alkylarylamino), acylamino (including alkylcarbonylamino,
arylcarbpnylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,
thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyanp, azido,
heterocyclyl, or an aromatic or heteroaromatic moiety. Heterocyclic groups can also be
substituted at one or more constituent atoms with, for example, a lower alkyl, a lower alkenyl, a
lower alkoxy, a lower alkylthio, a lower alkylamino, a lower alkylcarboxyl, a nitro, a hydroxyl, -
CF3, or -CN, or the like.
[000134] As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodd.
"Counterion" is used to represent a small, negatively charged species such as fluoride, chloride,
bromide, iodide, hydroxide, acetate, and sulfate.
[000135] "Stable compound" and "stable structure" are meant to indicate a compound that
is.sufficiently robust to survive isolation, and as appropriate, purification from a reaction
mixture, and formulation into an efficacious therapeutic agent.
[000136] "Free compound" is used herein to describe a compound in the unbound state.
[000137] "Extinction coefficient" is a constant used in the Beer-Lambert Law which relates
the concentration of the substance being measured (in moles) to the.absorbance of the substance
in solution (how well the substance in solution blocks light beamed through it from getting out
on the other side). It is an indicator of how much light a compound absorbs at a particular
wavelength.
[000138] In the specification, the singular forms also include the plural, unless the context
clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used
herein have the same meaning as commonly understood by one of ordinary skill in the art to
which this invention belongs. In the case of conflict, the present specification will control.
[000139] Throughout the description, where compositions are described as having,
including, or comprising specific components, it is contemplated that compositions also consist

essentially of, or consist of, the recited components. Similarly, where methods or processes are
described as having, including, or comprising specific process steps, the processes also consist
• essentially of, or consist of, the recited processing steps. Further, it should be understood that the
order of steps or order for performing certain actions is immaterial so long as the invention
remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
[000140] "Small molecule" is an art-recognized term. In certain embodiments, this term
refers to a molecule which has a molecular weight of less than about 2000 amu, or less than about
1000 amu, and even less than about 500 amu.
. [000141] All percentages and ratios used herein, unless otherwise indicated, are by weight.
[000142] The "retina" is a region of the central nervous system with approximately 150
million neurons.' It is located at the back of the eye where it rests upon a specialized .epithelial . .
tissue called retinal pigment epithelium or RPE. The retina initiates the first stage of visual
processing by transducing visual stimuli in specialized neurons called "photoreceptors". Their
synaptic outputs are processed by elaborate neural networks in the retina and then transmitted to
the brain. The retina has evolved two specialized classes of photoreceptors to operate under a wide
range of light conditions. "Rod" photoreceptors transduce visual images under low light conditions
and mediate achromatic vision. "Cone" photoreceptors transduce visual images in dim to bright
light conditions and mediate both color vision and high acuity vision.
[000143] Every photoreceptor is compartmentalized into two regions called the "outer" and
"inner" segment The inner segment is the neuronal cell body containing the cell nucleus. The
inner segment survives for a lifetime in the absence of retinal disease. The outer segment is the
region where the light sensitive visual pigment molecules are concentrated in a dense array of
stacked membrane structures. Part of the outer segment is routinely shed and regrown in a diurnal
process called outer segment renewal. Shed outer segments are ingested and metabolized by RPE
cells.
[000144] The "macula" is the central region of the retina which contains the fovea where
visual images are processed by long slender cones in high spatial detail ("visual acuity").
"Macular degeneration" is a form of retinal neurodegeneration which attacks the macula and
destroys high acuity vision in the center of the visual field. AMD begins in a "dry form"
characterized by residual lysosomal granules called lipofuscin in RPE cells, and by extracellular

deposits called "drusen". Drusen contain cellular waste products excreted by RPE cells.
"Lipofuscin" and drusen can be detected clinically by ophthalmologists and quantified using
fluorescence techniques. They can be the first clinical signs of macular degeneration.
[000145] Lipfuscin contains aggregations of A2E. Lipofuscin accumulates in RPE cells and
poisons them by multiple known mechanisms. As RPE cells become poisoned, their biochemical
activities decline and photoreceptors begin to degenerate. Extracellular drusen may further
compromise RPE cells by interfering with their supply of vascular nutrients. Drusen also trigger
inflammatory processes, which leads to choroidal neovascular invasions of the macula in one
patient in ten who progresses to wet form AMD. Both the dry form and wet form progress to
blindness.
[000146] "ERG" is an acronym for electroretinogram, which is the measurement of the
electric field potential emitted by retinal neurons during their response to an experimentally
defined light stimulus. ERG is a non-invasive measurement which can be performed on either
living subjects (human or animal) or a hemisected eye in solution that has been removed
surgically from a living animal.
[000147] As used herein, the term "RAL" means retinaldehyde. The term "RAL-trap"
means a therapeutic compound that binds free RAL and thereby prevents the RAL from Schiff
base condensation with membrane phosphatidylethanolamine (PE). "Free RAL" is defined as
RAL that is not bound to a visual cycle protein. The terms "trans-RAL" and "all-trans-RAL" are
used interchangeably and mean all trans retinaldehyde.
[000148] A2E is a reaction by-product of a complex biochemical pathway called the "visual
cycle" which operates collaboratively in both RPE cells and photoreceptor outer segments. The
visual cycle recycles a photoreactive aldehyde chromophore called "retinaldehyde" which is
derived from vitamin A and is essential for vision. In simplified terms, the visual cycle has four
principal steps: 1) It converts vitamin A in the RPE into an aldehyde chromophore with one
photoreactive strained double bond (1 l-cis-RAL); 2) It transports 11-a's-RAL to the retina
where the it binds to a specialized photoreceptor protein called opsin; 3) Light photoisomerizes
bound 11-cis-RAL to trans-RAL, which initiates the release of bound RAL from the opsin
binding site; 4) It converts trans-RAL (an aldehyde) to vitamin A (an alcohol) and transports
vitamin A back to the RPE where the cycle begins again. The pathway is illustrated in Figure 1

1
which shows RPE cells on top and photoreceptor outer segments below (labeled "OS").
[000149] The aldehyde group of RAL helps bind the molecule to opsin by forming a
reversible chemical bond to an amino acid sidechain in the opsin binding site. While the
aldehyde group on RAL is essential for anchoring the molecule to the opsin binding site, it is
otherwise hazardous because of its propensity to form Schiff bases with other biological amines.
The reaction cascade for A2E formation is shown in Figure 2. The first three reactions take
place in photoreceptor outer segments and produce an intermediary product called A2PE. Once
formed, A2PE partitions into lipid phase and accumulates in photoreceptor outer segment
membranes. When RPE cells ingest discarded outer segments, their accumulated A2PE is routed
to their lysosomes. The final reaction of Figure 2 takes place inside RPE lysosomes and
completes the formation of A2E.
[000150] As described above, macular degeneration and other forms of retinal disease
whose etiology involves the accumulation of A2E and/or lipofuscin may be treated or prevented
by lowering the amount of A2E formed. Compounds useful for doing so include RAI>traps.
RAL-traps lower the amount of A2E formed, for example by forming a covalent bond with RAL
that has escaped sequestering. RAL that has reacted with an RAL-trap compound is thereby
unavailable to react with phosphatidyl ethanolamine.
[000151] Without wishing to be bound by theory, it is thought that treatment of a patient
having AMD with an RAL-trap compound will reduce the rate of A2E formation without rate
limiting the visual cycle, thereby avoiding the visual deficit of night blindness. In contrast,
therapeutic agents for AMD treatment that reduce A2E synthesis are thought to rate-limit the
visual cycle by competitive inhibition of retinoid binding sites of visual cycle proteins, whereby
reduction in the turn-over rate of the visual cycle, causes a reduction in the formation rate of
A2E. The present invention reduces A2E accumulation without competitive inhibition of
retinoid binding sites on visual cycle proteins which is known to cause night blindness.
[000152] In certain embodiments, an RAL-trap is a compound known to form a reversible
Schiff base adduct with RAL (Figure 3).
[000153] RAL-traps of the invention include cyclic amines as well as 5- and 6- membered
cyclic- and heterocyclic amines which may have one or more pairs of conjugated double bonds. In
one example, the cyclic amines are aromatic.


[000154] Such compounds include, for example, aromatic amines, such as benzocaine:
. [000155] Useful controls for testing the effectiveness of RAL-traps are lidocaine, a local
anesthetic that.does not form a Schiff base, thus acting as a negative control; and darkness which
slows or shuts down the visual cycle, as a positive control.
[000156] In one embodiment, the RAL-trap compound reacts with free RAL in a two-step
fashion to form a stabilized adduct. For example, RAL and a primary amine of an RAL-trap
compound condense to form a Schiff base adduct,. and an internal cyclization reaction forms an
uncharged ring which contains the amine nitrogen. This ring formation serves to stabilize the RAL
adduct by making dissociation more unfavorable energetically. This prevents free RAL (i.e. RAL
not bound to opsins or other proteins in the visual cycle) from being available to form Schiff base
condensation products with phosphatidylethanolamine and thence prevents A2E formation.
Further, once the ring closes, it prevents the amine nitrogen, now part of the ring, from condensing

with a second RAL molecule. Reaction of the RAL-trap with a second RAL molecule is thought
to be unfavorable, as such reaction would result in formation of an adduct having a structure
similar to A2E, having dual RAL groups, with spayed tails which could cause lipid packing
. problems in biological membranes and therefore membrane detergency. Further, a reaction of the
amine nitrogen with a second RAL would cause the nitrogen to become charged, which could
cause unfavorable activity, including toxicity, such as poisoning the lysomal proton pump in RPE
cells.
[000157] Compounds useful as RAL-traps include those according to formula IV:
[000158] IV, where X is O, N, N(H), or S, het is an optionally
substituted 5 or 6- membered heterocycle, n is 0,1, 2, or 3, and each D is an uribranched lower
alkyl group. Each D can be the same or different.
[000159] U is a substituent selected from halogen atom; cyano; lower alkyl wherein one or
more hydrogen atoms on the lower alkyl group are optionally substituted by groups selected
from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic
heterocyclic group containing one or more hetero-atoms selected from nitrogen, oxygen, and
sulfur atoms; lower alkylthio wherein one or more hydrogen atoms on the alkyl group are
optionally substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and
aryl; lower alkylsulfonyl wherein one or more hydrogen atoms on the alkyl group are optionally
substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and aryl;
hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower
alkoxycarbonyl; carbamoyl; N-lower allcylcarbamoyl; N,N-di-lower alkylaminocarbonyl; amino;
N-lower alkylamino; N,N-di-lower alkylamino; formylamino; lower alkylcarbonylamino;
ammosulfonylamino; (N-lower alkylammo)sulfonylammo; (N,N-di-lower
alkylarnmo)sulfonylamino; aryl, optionally substituted by groups selected from a halogen atom,
hydroxyl, carbamoyl, .aryl and amino; and a monocyclic or bicyclic heterocyclic group
containing one or more hetero-atoms selected from nitrogen, oxygen, and sulfur atoms.

[000160] In one embodiment, each D is methyl.
[000161] In one embodiment, the ring substituent(s) (U) is chosen such that the pKa of the
first ring NH2 is approximately 3.5. Examples include the following ring systems with the pKa
in parentheses:

[000162] In one embodiment, such compounds react with RAL according to the mechanism
depicted in Scheme 1:

, can be synthesized from the
[000163] Compounds of formula IV,
corresriondine ester:



[000164] A depiction of the reaction between the compound
presented in Scheme 2:

andRALis


[000165] Compounds of the invention include RAL-traps having a 5- or 6- member ring.
For example, the compounds of the invention preserve the absorption properties of 11-cz's-RAL
when the two compounds form a Schiff base adduct, i.e. that forrning the adduct will not increase
the extinction coefficient above that of free ll-cis-RAL nor shift its peak absorbance to a longer
wavelength-. Without being bound by theory, it is thought that this preservation of absorption
properties will rmnimize treatment side effects on vision by protecting 1l-czs-RAL from
photoisbmerization in the adduct state thereby preserving its chromophore activity should it
subsequently dissociate from the adduct and re-enter the visual cycle where it will be available to

" bind to opsin in its photoactive state.
[000166] In certain embodiments, the RAL-trap of the invention is a compound having a
structure represented by general formula I:

[000167] wherein, W, X, Y, and Z are each, independently, N, O, S, CU or CH, such that at
least one ofW, X, Y, and Z is N; n is 0,1,2, 3, or 4, A is
, D is uribranched lower alkyl, and R is substituted
or unsubstituted C1, C2, C3, C4, C5, C6, C7, or C8 straight chain alkyl, or substituted or
unsubstituted C3, C4, C5, C6, C7 or C8 branched chain alkyl. Each D can be the same or
different.
[000168] Substituents on the alkyl chain of R include a halogen atom; C1-C6 alkyl
optionally substituted by a halogen atom, cyano, hydroxyl, carbamoyl, amino, formylamino,
lower alkylcarbonylamino, aminosulfonylamino, or lower alkylthio; lower alkylcarbonyl wherein
the alkyl portion of lower alkylcarbonyl is optionally substituted by a halogen atom, cyano,
hydroxyl, carbamoyl, amino, formylamino, lower alkylcarbonylamino, ammosulfonylamino, or
lower alkylthio; carbamoyl; or lower alkylthio wherein the alkyl portion of lower alkylthio is
optionally substituted by a halogen atom, cyano, hydroxyl, carbamoyl, amino, formylamino,
lower alkylcarbonylamino, aminosulfonylamino, or lower alkylthio.
[000169] U is a substituent selected from halogen atom; cyano; lower alkyl wherein one or
more hydrogen atoms on the lower alkyl group are optionally substituted by groups selected
from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic orbicyclic
heterocyclic group containing one or more hetero-atoms selected from nitrogen, oxygen, and
sulfur atoms; lower alkylthio wherein one or more hydrogen atoms on the alkyl group are
optionally substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and
aryl; lower alkylsulfonyl wherein one or more hydrogen atoms on the alkyl group are optionally

substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and aryl;
hydroxyl; lower alkoxy, formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower
alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N,N-di-lower alkylaminocarbonyl; amino;
N-lower alkylamino; N,N-di-lower alkylamino; formylamino; lower alkylcarbonylamino;
arnmosulfonylamino; (N-lower alkylammo)sulfonylamino; (N,N-di-lower
alkylamino)sulfonylamino; aryl, optionally substituted by groups selected from a halogen atom,
hydroxyl, carbamoyl, aryl and amino; and a monocyclic or bicyclic heterocyclic group
. containing one or more hetero-atoms selected from nitrogen, oxygen, and sulfur atoms.
[000170] In one example, U is aryl, for example benzene.
[000171] In certain compounds, A is , and D is methyl.
[000172] In certain compounds, U is a halo-substituted benzene.
[000173] In other compounds, two U substituents on adjacent carbon atoms are attached to
form a 5 or 6 membered fused ring. Such rings are optionally substituted by groups selected
from a halogen atom, hydroxyl, carbamoyl, aryl and amino. In certain compounds two adjacent
U substituents can form a benzene. For example, such fused compounds have the structure Ia:
la wherein X, Y, and Z are each, independently, N, O, S, CH, or
absent, such that at least one of X, Y, and Z is N; p is 0,1,2, or 3, B is a halogen atom, hydroxyl,
carbamoyl, aryl or amino, A is , D is unbranched
lower alkyl, and R is substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, or C8 straight
chain alkyl, or substituted or unsubstituted C3, C4, C5, C6, C7 or C8 branched chain alkyl.
[000174] Examples of compounds of formula I include pyridine, pyridazine, pyrazine, and
pyrirnidine compounds.


[000175] Compounds of formula I or la include:

[000176] In certain embodiments, the RAL-trap of the invention is a compound having a
structure represented by general formula II or Ha:

wherein, Q, T, and V are each, independently, N, NH, S, O, CU, or CH, such that at least one of
Q, T and V is not CU or CH; the dashed ring represents two double bonds within the ring, which
comply with the valency requirements of the atoms and heteroatoms present in the ring, m is 0,1^

or 2, A is , where D is unbranched lower alkyl, R
is substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7 or C8 straight chain alkyl, or
substituted or unsubstituted C3, C4, C5, C6, C7 or C8 branched chain alkyl. For example, R is
C2. alkyl (ethyl).
[000177] Substituents on the alkyl chain include a halogen atom; C1-C6 alkyl optionally
substituted by a halogen atom, cyano, hydroxyl, carbamoyl, amino, formylamino, lower .
alkylcarbonylamino, aminosulfonylamino, or lower alkylthio; lower alkylcarbonyl wherein the
alkyl portion of lower alkylcarbonyl is optionally substituted by a halogen atom, cyano,
hydroxyl, carbamoyl, amino, formylamino, lower alkylcarbonylamino, annnosulfonylarnino, or
lower alkylthio; carbamoyl; or lower alkylthio wherein the. alkyl portion of lower alkylthio is
optionally substituted by a halogen atom, cyano, hydroxyl, carbamoyl, amino, formylamino,
lower alkylcarbonylamino, aminosulfonylamino, or lower, alkylthio.
[000178] U is a substiruent selected from a halogen atom; cyano; lower alkyl wherein one
or more hydrogen atoms on the lower alkyl group are optionally substituted by groups selected
from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic or bicyclic
heterocyclic group containing one or more hetero-atoms selected from nitrogen, oxygen, and
sulfur atoms; lower alkylthio wherein one or more hydrogen atoms on the alkyl group are
optionally substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and
aryl; lower alkylsulfonyl wherein one or more hydrogen atoms on the alkyl group are optionally
substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino, and aryl;
hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower
alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N,N-di-lower alkylaminocarbonyl; amino;
N-lower alkylamino; N,N-di-lower alkylamino; formylamino; lower alkylcarbonylamino;
aminosulfonylamino; (N-lower alkylanimo)sulfonylamino; (N,N-dirlower
alkylammo)sulfonylamino; aryl, optionally substituted by groups selected from a halogen atom,
hydroxyl, carbamoyl, aryl and amino; and a monocyclic of bicyclic heterocyclic group
containing one or more hetero-atoms selected from nitrogen, oxygen, and sulfur atoms. In one
embodiment, example, U is alkyl. For example, U is methyl, ethyl, or propyl, hi one

' embodiment, U is a halogen, For example, U is chloro, fluoro, or bromo. In certain compounds,
two U substituents on adjacent carbon atoms are attached to form a 5 or 6 membered fused ring.
Such rings are optionally substituted by groups selected from a halogen atom, hydroxyl,
carbamoyl, aryl and amino.
[000179] In one example, U is aryl, for example benzene.
[000180] In certain compounds, A is , and D is methyl.
[000182] . Examples include furan and thiophene compounds, such as
[000181] In certain compounds, U is a halo-substituted benzene.

[000183] In certain embodiments, the RAL-trap of the invention is a compound having a


structure represented by general formula HI:


where D is unbranched lower alkyl, R is
substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, or C8, straight chain alkyl, or substituted
or unsubstituted C3, C4, C5, C6, C7, or C8, branched chain alkyl, k is 0,1,2, 3, or 4.
[000184] Substituents on the alkyl chain include a halogen atom; C1-C6 alkyl optionally
substituted by a halogen atom, cyano, hydroxyl, carbamoyl, amino, formylamino, lower
alkylcarbonylamino, arninosulfonylamino, or lower alkylthio; lower alkylcarbonyl wherein the
alkyl portion of lower alkylcarbonyl is optionally substituted by a halogen atom, cyano,
hydroxyl, carbamoyl, amino, formylamino, lower alkylcarbonylamino, ammosulfonylarninb, or
lower alkylthio; carbamoyl; or lower alkylthio wherein the alkyl portion of lower alkylthio is
optionally substituted by a halogen atom, cyano, hydroxyl, carbamoyl, amino, formylamino,
lower alkylcarbonylamino, arninosulfonylamino, or lower alkylthio.
[000185] U is a substituent selected from halogen atom; cyano; lower alkyl wherein one or
more hydrogen atoms on the lower alkyl group are optionally substituted by groups selected
from a halogen atom, hydroxyl, carbamoyl, amino, aryl, and a monocyclic orbicyclic
heterocyclic group containing one or more hetero-atoms selected from nitrogen, oxygen, and
sulfur atoms; lower alkylthio wherein one or more hydrogen atoms on the alkyl group are
optionally substituted by groups selected from a halogen atom, hydroxyl, carbamoyl, amino,.and
aryl; lower alkylsulfonyl wherein one or more hydrogen atoms on the alkyl group are optionally
substituted by groups selected from-a halogen atom, hydroxyl, carbamoyl, amino, and aryl;
hydroxyl; lower alkoxy; formyl; lower alkylcarbonyl; arylcarbonyl; carboxyl; lower
alkoxycarbonyl; carbamoyl; N-lower alkylcarbamoyl; N,N-di-lower alkylaminocarbonyl; amino;
N-lower alkylamino; N,N-di-lower alkylamino; formylarnino; lower alkylcarbonylamino;
arninosulfonylamino; (N-lower alkylarrrino)sulfonylarnino; (N,N-di-lower
alkylamino)sulfonylamino; aryl, optionally substituted by groups selected from a halogen atom,
hydroxyl, carbamoyl, aryl and amino; and a monocyclic or bicyclic heterocyclic group
containing one or more hetero-atoms selected from nitrogen, oxygen, and sulfur atoms.
Examples include hydroxylarnines and alkyl amine compounds.

1
[000186] In certain compounds, A is and D is methyl.
[000187] In certain compounds, U is a halo-substituted benzene.
[000188] In other compounds, two U substituents on adjacent carbon atoms are attached to
form a 5 or 6 membered fused ring. Such rings are. optionally substituted by groups selected
from a halogen atom, hydroxyl, carbamoyl, aryl and amino. For example, such fused
compounds have the structure Etta:
, wherein X, Y, and Z are each, independently, N, O, S, CH CB,
or absent, such that at least one of X, Y, and Z is N; p is 0,1,2, or 3, B is a halogen atom,
hydroxyl, carbamoyl, aryl or amino, A is D is
unbranched lower alkyl, R is substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, or C8
straight chain alkyl, or substituted or unsubstituted C3, C4, C5, C6, C7 or C8 branched chain
alkyl, and L is a single bond or CH2.
[000189] In some embodiments, two adjacent U substituents form a 6-membered fused
heterocycle, for example, a pyridine ring. In other embodiments, two adjacent U substituents ^
form 5-membered fused heterocycle. For example, two adjacent U substituents form a tbiazole
ring. In other embodiments, two adjacent U substituents form an oxazole ring. In other
embodiments, two adjacent U substituents form an imidazole ring.
[000190] Examples of compounds of formula HI or Hla include:


[000191] Reaction of the compound with RAL produces the following
conjugate:

[000192] Also included are pharmaceutically acceptable addition salts and complexes of the
compounds of the formulas given above. In cases wherein the compounds may have one or
more chiral centers, unless specified, the compounds contemplated herein may be a single
stereoisomer or racemic mixtures of stereoisomers. Further included are prodrugs, analogs, and
derivatives thereof.
Methods
[000193] As discussed above, a disclosed composition may be administered to a subject in
order to treat or prevent macular degeneration and other forms of retinal disease whose etiology
involves the accumulation of A2E and/or lipofuscin. Other diseases, disorders, or conditions
characterized by the accumulation A2E may be similarly treated.
[000194] In one embodiment, a compound is administered to a subject that reduces the
formation of A2E. For example, the compound may compete with PE for reaction vnfhtrans
RAL, thereby reducing the amount of A2E formed. In another embodiment, a compound is
administered to a subject that prevents the accumulation of A2E. For example, the compound
competes so successfully with PE for reaction with trans RAL, no A2E is formed.
[000195] Individuals to be treated fall into three groups: (1) those who are clinically
diagnosed with macular degeneration or other forms of retinal disease whose etiology involves
the accumulation of A2E and/or lipofuscin on the basis of visual deficits (including but not
limited to dark adaptation, contrast sensitivity and acuity) as determined by visual examination
and/or electroretinography, and/or retinal health as indicated by fundoscopic examination of
retinal and RPE tissue for drusen accumulations, tissue atrophy and/or lipofuscin fluorescence;
(2) those who are pre-symptomatic for macular degenerative disease but thought to be at risk
. based on abnormal results in any or all of the same measures; and (3) those who are pre-
symptomatic but thought to be at risk genetically based on family history of macular
degenerative disease and/or genotyping results showing one or more alleles or polymorphisms
associated with the disease. The compositions are adrninistered topically or systemically at one
or more times per month, week or day. Dosages may be selected to avoid side effects if any on
visual performance in dark adaptation. Treatment is continued for a period of at least one, three,
six, twelve or more months. Patients maybe tested at one, three, six, twelve months or longer
intervals to assess safety and efficacy. Efficacy is measured by examination of visual

■ performance and retinal health as described above.
[000196] In one embodiment, a subject is diagnosed as having symptoms of macular
degeneration, and then a disclosed compound is administered. In another embodiment, a subject
may be identified as being at risk for developing macular degeneration (risk factors include a
history of smoking, age, female gender, and family history), and then a disclosed compound is
administered. Li another embodiment, a subject may have dry AMD in both eye, and then a
disclosed compound is administered. In another embodiment, a subject may have wet AMD in
one eye but dry AMD in the other eye, and then a disclosed compound is administered. In yet
another embodiment, a subject may be diagnosed as having Stargardt disease and then a
disclosed compound is administered. In another embodiment, a subject is diagnosed as having
symptoms of other forms of retinal disease whose etiology involves the accumulation of A2E
and/or lipofuscin, and then the compound is administered. In another embodiment a subject may
be identified as being at risk for developing other forms of retinal disease whose etiology
involves the accumulation of A2E and/or lipofuscin, and then the disclosed compound is
administered. In some embodiments, a compound is administered prophylactically. In some
embodiments, a subject has been diagnosed as having the disease before retinal damage is
apparent. For example, a subject is found to carry a gene mutation for ABCA4 and is diagnosed
as being at risk for Stargardt disease before any ophthalmologic signs are manifest, or a subject
is found to have early macular changes indicative of macular degeneration before the subject is
aware of any effect on vision. In some embodiments, a human subject may know that he or she
is in need of the macular generation treatment or prevention.
[000197] In some embodiments, asubject may be monitored for the extent of macular
degeneration. A subject may be monitored in a variety of ways, such as by eye examination,
dilated eye examination, fundoscopic examination, visual acuity test, and/or biopsy. Monitoring
can be performed at a variety of times. For example, a subject may be monitored after a
compound is administered. The monitoring can occur, for example, one day, one week, two
weeks, one month, two months, six months, one year, two years, five years, or any other time
period after the first administration of a compound. A subject can be repeatedly monitored. In
some embodiments, the dose of a compound may be altered in response to monitoring.
[000198] In some embodiments, the disclosed methods may be combined with other

methods for treating or preventing macular degeneration or other forms of retinal disease whose
etiology involves the accumulation of A2E and/or lipofuscin, such as photodynamic therapy.
For example, a patient may be treated with more than one therapy for one or more diseases or
disorders. For example, a patient may have one eye afflicted with dry form AMD, which is treated
with a compound of the invention, and the other eye afflicted with wet form AMD which is treated
with, e.g., photodynamic therapy.
[000199] In some embodiments, a compound for treating or preventing macular
degeneration or other forms of retinal disease whose etiology involves the accumulation of A2E
and/or lipofuscin may be administered chronically. The compound may be administered daily,
more than once daily, twice a week, three times a week, weekly, biweekly, monthly, bimonthly,
semiannually, annually, and/or biannually.
[000200] The therapeutics may be administered by a wide variety of routes, as described
above. In some embodiments, a compound may be administered orally, in the form of a tablet, a
capsule, a liquid, a paste, and/or a powder. In some embodiments, a compound may be
administered locally, as by intraocular injection. In some embodiments, a compound may be
administered systemically in a caged, masked, or otherwise inactive form and activated in the eye
(such as by'photodynamic therapy). In some embodiments, a compound may be administered in
a depot form, so sustained release of the compound is provided over a period of time, such as
hours, days, weeks, and/or months. Preferably the compound is administered topically, as an eye'
drop formulation. Typical dose ranges include 0.5 to 5 mg/lOOg for oral formulations and 0.5%
to 5% solutions for eye drop formulations.
[000201] The compounds of the invention are provided in therapeutic compositions. The
compound is present in an amount that is therapeutically effective, which varies widely
depending largely on the particular compound being used. The preparation of pharmaceutical or
pharmacological compositions will be known to those of skill in the art in light of the present
disclosure. Typically, such compositions maybe prepared as injectables, either as liquid
' solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to
injection; as tablets or other solids for oral administration; as time release capsules; or in any
other form currently used, including eye drops, creams, lotions, salves, inhalants and the like.
Compositions may also be delivered via microdevice, microparticle or sponge.

[000202] Upon formulation, therapeutics will be administered in a manner compatible with
the dosage formulation, and in such amount as is pharmacologically effective. The formulations
are easily administered in a variety of dosage forms, such as the type of injectable solutions
described above, but drug release capsules and the like can also be employed.
[000203] In this context, the quantity of active ingredient and volume of composition to be
administered depends on the host animal to be treated. Precise amounts of active compound
required for administration depend on the judgment of the practitioner and are peculiar to each
individual.
[000204] A niinimal volume of a composition required to disperse the active compounds is
typically utilized. Suitable regimes for administration are also variable, but would be typified by
initially administering the compound and monitoring the results and then giving further
controlled doses at further intervals. The amount of compound incorporated into the
composition also depends upon the desired release profile, the concentration of the compound
required for a biological effect, and the length of time that the biologically active substance has
to be released for treatment. In certain embodiments, the biologically active substance may be
blended with a polymer matrix at different loading levels, in one embodiment at room
temperature and without the need for an organic solvent. In other embodiments, the
compositions may be formulated as microspheres. In some embodiments, the compound may be
formulated for sustained release.
[000205] For oral administration in the form of a tablet or capsule (e.g., a gelatin capsule),
the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable
inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary,
suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated
into the mixture. Suitable binders include starch, magnesium aluminum silicate, starch paste,
gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, natural
sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as
acacia, tragacanth or sodium alginate, polyethylene glycol, waxes and the like. Lubricants used
in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride, silica, talcum, stearic acid, its magnesium or calcium
salt and/or polyethyleneglycol and the like. ..Disintegrators include, without limitation, starch,
methyl cellulose, agar, bentonite, xanthan gum starches, agar, alginic acid or its sodium salt, or

effervescent mixtures, and the like. Diluents, include, e.g., lactose, dextrose, sucrose, mannitol,
sorbitol, cellulose and/or glycine.
[000206] Injectable compositions are preferably aqueous isotonic solutions or suspensions,
and suppositories are advantageously prepared from fatty emulsions or suspensions. The
compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting
or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or
buffers. In addition, they may also contain other therapeutically valuable substances. The
compositions are prepared according to conventional mixing, granulating or coating methods,
respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.
[000207] The compounds of the invention can also be administered in such oral dosage
forms as timed release and sustained release tablets or capsules, pills, powders, granules, elixers,
tinctures, suspensions, syrups and emulsions.
[000208] The compounds of the invention can also be adrninistered topically, such as
directly to the eye, e.g., as an eye-drop or ophthalmic ointment. Eye drops typically comprise an
effective amount of at least one compound of the invention and a carrier capable of being safely
applied to an eye. For example, the eye drops are in the form of an isotonic solution, and the pH
of the solution is adjusted so that there is no irritation of the eye. In many instances, the
epithelial barrier interferes with penetration of molecules into the eye. Thus, most currently used
ophthalmic drugs are supplemented with some form of penetration enhancer. These penetration
enhancers work by loosening the tight junctions of the most superior epithelial cells (Burstein,
1985, Trans Ophthalmol Soc U K 104(Pt 4): 402-9; Ashton et al, 1991, J Pharmacol Exp Ther
259(2): 719-24; Green et al, 1971,.Am J Ophthalmol 72(5): 897-905). The most commonly
used penetration enhancer is benzalkonium chloride (Tang et al., 1994, J Pharm Sci 83(1): 85-
90; Burstein et al, 1980, Invest Ophthalmol Vis Sci 19(3): 308-13), which also works as
preservative against microbial contamination. It is typically added to a final concentration of
0.01-0.05%.
Screening methods
[000209] Suitable compounds may be identified by a variety of screening methods. For
example, a candidate compound may be administered to a subject that has or is at risk of
developing macular degeneration or other forms of retinal disease whose etiology involves the

' accumulation of A2E and/or lipofuscin, and the accumulation of a retinotoxic compound, such as
A2E, can be measured. A drug that results in reduced accumulation of a retinotoxic compound
compared to a control (absence of the drug) would thus be identified as a suitable drug.
[000210] Alternatively, RAL and RPE tissue may be analyzed for the presence of A2E
and/or its precursors.
EXAMPLES
EXAMPLE 1: Synthesis of Compounds
[000211] The compounds of the invention, and related derivatives, can be synthesized by
methods known to one skilled in the art. For example, a detailed method for the synthesis of
compound 7 is described below in Scheme 3.
Scheme 3

[000212] • A mixture of acetonitrile (60 mL) and ethyl 2-amino-l,3, thiazole-4-carboxilate
(0.54g, 3 mmol) and N-fluorobenzenesulfonimide (3.3g, 9 mmol) was heated at reflux
temperature for 18 hours. The color changed from yellow to reddish. The reaction mixture was
concentrated and purified using chromatographic methods: column chromatography (2-5%
methanol-chloroform), prep-TLC (2% methanol-chloroform), prep HPLC (column: Phenomenex
Luna Phenyl-hexyl (150x4.6 mm ID, 3 fim packing), Xi=215 nm, flow rate: 0.8 mL/min,
injection volume: 5 mL, run time: 31 min, mobile phase gradient: A: water w 0.1% v/v TFA; B
MeCN w 0.1% v/v TFA), and prep-TLC (10% meOH-chloroform) to afford a brown solid (380
mg). LCMS m/z: 145,173,191, 381, and.399. !H1SIMR (300 MHz, CDC13) 5:1.3 ppm (m, 3H
Me) and 4.8 ppm (m, 2H, CH2).
EXAMPLE 2: In Vitro SchiffBase Confirmation
[000213] UV/VTS spectroscopy was used to monitor Schiff base condensation of RAL with

the primary amine of a compound of the invention. The in vitro analysis of the Schiff base
condensation product with RAL was performed for the disclosed compounds 1, 2, 3, 4, 5, and 6
and the results are shown in Table 1.
[000214] In the solution phase analysis, the Xmax value of both the free compound and the
RAL Schiff base condensation product (RAL-SBC) are measured along with the value for tau of
the RAL-SBC. As used herein, "RAL-SBC" means the Schiff base condensation product of
RAL and a RAL-compound. Solution phase analysis is performed using a 100:1 mixture of
compound and RAL using protocols known in the art. Several solvent systems were tested
including aqueous, ethanol, octanol, and chloroform:methanol (various e.g., 2:1). The solutipn
kinetics are measured and found to be highly dependent on solvent conditions. Figures 4a and
4b show the results of Schiff base condensation of compound 6 and RAL (100:1) in
chloroform:methanol (2:1).
[000215] Solid phase analysis of the Schiff base condensation is also performed using a 1:1
mixture of compound to RAL. The solid phase analysis is performed using protocols known in
the art. The mixture is dried under nitrogen and condensation reaction occurs to completion.
[000216] Lipid phase analysis is performed using protocols known in the art and ^max, tau
(RAL-SBC vs. APE/A2PB), and competitive inhibition are measured. Liposome conditions are
closer to in situ conditions.
EXAMPLE 3: Log P and pKa values
[000217] Log P values are shown in Table 1 for compounds 1, 2, 3,4, 5, and 6. The
partition coefficient (log P) is the log of the ratio [Xorgamc]/[Xaqueous] for a compound X at a pH
where X at a pH where X is neutral, not ionized. Values above zero denote increasing lipophilic
properties, and below zero, increasing hydrophilic properties. Octanol is commonly used as the
organic solvent. Examples are as follows:
[000218] Log P = 2 X is 102 more soluble in organic solvent than aqueous
[000219] LogP = 0 X is equally soluble in both
[000220] Log P = -2 X is 102 more soluble in aqueous solvent then organic
[000221] Log P values are typically calculated algorithmically (not measured

' experimentally) by software programs such as Pallas and ACDlabs. Calculation results vary by
software product and are regarded as order of magnitude approximations.
[000222] pKa values are shown in Table 1 for compounds 1, 2,3,4,5, 6, and 7. pKa values
are measured using known methods in the art. The acidity of a general acid, HA, is expressed by
the chemical equation:
HA + H20 ^=^= H30+ + A-
which is described by the equiUbrium constant K. According to the general definition of an
equilibrium constant, K is expressed as

Because, in aqueous solution, [H2O] will be constant at 55 moles l"1, that number may be
incorporated into a new constant Ka, defined as the acidity constant:

This measurement when put in logarithmic scale is " a a. An acid with a pKa lower
than 1 is defined as strong, one with a pKa higher than 4 is weak. The volume of distribution (V)
of a drug may widely vary depending on the pKa of the compound. The volume of distribution
relates to the amount of compound in the body to the concentration of compound in the blood or
plasma.


EXAMPLE 4: ERG Analysis of Dark Adaptation
[000223] Dark adaptation is the recovery of visual sensitivity following exposure to light.
Dark adaptation has multiple components including both fast (neuronal) processes and slow
(photochemical) process. Regeneration'of visual pigment is related to the slow photochemical
process. Dark adaptation rates are measured for several reasons. Night blindness results from a
failure to dark adapt (loss of visual light sensitivity). It is possible to find a safe dose for night
vision by measuring drug effects on dark adapted visual light sensitivity.
[000224] An electroretinogram (ERG) is used measure dark adaptation under normal vs.
drug conditions. ERG is the measurement of the electric field potential emitted by retinal
neurons during their response to an experimentally defined light stimulus. More specifically,
ERG measures retinal field potentials at the cornea after a flash of light (e.g., 50 ms). Field
strengths are 102 to 103 microvolts, originating in retinal cells.
[000225] ERG is a non-invasive measurement which can be performed on either living .
subjects (human or animal) or a hemisected eye in solution that has been removed surgically
from a living animal. ERG requires general anesthesia which slows dark adaptation and must be
factored into experimental design.

' [000226] In a typical ERG analysis of dark adaptation experiment, every rat is dark adapted
for hours to reach a consistent state of light sensitivity. The rat is then "photo-bleached" i.e.
exposed briefly to light strong enough to transiently deplete the retina of free 11-cis-RAL (e.g., 2
min at 300 lux). The rat is then returned to dark immediately to initiate dark adaptation, i.e.,
recovery of light sensitivity due to regeneration of visual pigment. ERG is used to measure how
quickly the rat adapts to dark and recovers light sensitivity. Specifically, a criterion response
variable is defined for light sensitivity (see Figure 5).
[000227] The ERG measurement is taken after a specific duration of post-bleach dark
recovery (e.g., 30 min) determined previously by kinetic analysis (see Figures 6a and 6b). A
curve fit is used to calculate value for the sensitivity variable. Figure 6a shows recovery with
anesthesia in the same rat including dark adaptation kinetics for Y50 and a. Slower adaptation is
observed with less light sensitivity where Y50 reaches -4.0. and tau = 22.6 min. Figure 6b shows
recovery without anesthesia (5 different rats) including dark adaptation kinetics for Y50. Faster
adaptation is observed with more light sensitivity where Y50 reaches -5.5 and tau = 9.2 min.
[000228] The same paradigm as described above is followed for dose ranging. As shown
below in Figure 7, in the ERG dose ranging protocol, compound 6 i.p. lowers light sensitivity of
dark, adapted rats in a dose dependent manner. The'effect on vision decreases after 3 hours.
EXAMPLE 5: NMR Analysis of RAL Reactions
[000229] NMR spectroscopy was used to monitor Schiff base condensation and ring
formation of RAL with the primary amine of a compound of the invention. The NMR analysis
of the RAL reactions was performed for the disclosed compounds 6, 8 and 9 as shown in Figure
8 and Table 2. Condensation rates in pure chloroform are as follows: compound 6 > 8 > 9.


EXAMPLE 6: Inhibition of A2E Formation
[000230] This experiment is designed to establish proof of concept that chronic i.p.
injection of a RAL-trap compound lowers the accumulation rate of A2E in wild type Sprague
Dawley rats. These experiments compare the treatment efficacy of RAL-trap compounds to that
of control compounds and lack of treatment.
Materials and Methods:
[000231] The study is performed with wild type Sprague Dawley rats. Rat treatment
groups include for example, 8 rats of mixed gender per treatment condition. Each animal is
treated with one of the following conditions:
o Controls: (1) 13-cis retinoic acid to inhibit retinoid binding sites of visual cycle
proteins as a protocol control, in that such treatment reduces the amount of free trans-
RAL that is released and thereby available to form A2E, but with undesirable side
effects of night blindness, and (2) a commercially available compound known clinically
to modulate retinal function in humans and known experimentally to form a Schiff base
adduct with free RAL, both in vitro and in vivo in animal models.

• Vehicle
• Compound
• Untreated
[000232] ' A number of compounds are tested e.g., 4 compounds. The compounds are tested
across a dose range including 1, 5,15, and 50 mg/kg. Treatment is administered daily for 8
weeks by i.p: injection.
Chemistry:
[000233] The experiments use a variety of chemistry services. For example, these
experiments use commercially available compounds with analytical specification sheets to
characterize the impurities. Compounds are also synthesized. Compounds are prepared in
quantities sufficient for the required dosing. Formulations of the compound are suitable for use
in initial animal safety studies involving intraperitoneal (i.p.) injection. The following three
attributes of the Schiff base reaction product of trans-RAL with compounds of the invention are
determined:
• stability with respect to reaction rates
o absorption properties, specifically uv-vis absorption maxima and extinction
coefficients (see e.g., Figure 5 in Rapp and Basinger, Vision Res. 22:1097, 1982) .
or NMR spectral analysis of reaction kinetics
• log P and log D solubility values e.g. calculated
Biology and Biochemistry:
[000234] The experiments described herein use a variety of biology and biochemistry
services. A "no effect level" (NOEL) dose of compounds of the invention for daily treatment
with an eye drop formation is established, e.g., in the rabbit with an ocular irritation protocol and
in the rodent with ERG measurement of dark adaptation in visual responses to light stimulation.
After treatment and before eye enucleation, the following non-invasive assays are performed in
animals e.g., rabbits:
« RPE and photoreceptor cell degeneration, as evident by fundus photography
(Karan, et al. 2005, PNAS 102:4164)
• Extracellular drusen and intracellular lipofuscin as measured by fundus

fluorescent photography (Karan et al 2005)
[000235] Light responses are characterized by ERG (Weng, et al, Cell 98:13,1999).
Intracellular A2E concentration of retinal RPE cell extracts is measured in all treated animals
upon the conclusion of the treatment protocol using an analytical method such as those described
by Karan et al, 2005; Radu et al, 2003; and Parish et al, PNAS 95:14609,1998. For example,
in a sample of treated animals, one eye is assayed, and the other eye is saved for histology
analysis (as described below). In the remaining animals, both eyes are assayed separately for
A2E formation.
[000236] In the post-treatment eyes set aside for histology (as described above), the
morphology of retinal and RPE tissue is assessed with light microscopy histology techniques
(Karan et al 2005, with the exception that electron microscopy is not used in the experiments
described herein).
[000237] The safety of the treatment regimen is assessed for example using a combination
of:
» Daily documented observation of animal behavior and feeding habits throughout
the treatment period
• Visual performance as measured by ERG at the end of the treatment period
• Ocular histology at the end of the treatment period.
Incorporation By Reference
[000238] The entire disclosure of each of the patent documents, including certificates of
correction, patent application documents, scientific articles, governmental reports, websites, and
other references referred to herein is incorporated by reference in its entirety for all purposes. In
case of a conflict in terminology, the present specification controls.
Other Embodiments
While the invention has been described in conjunction with the detailed description thereof, the
foregoing description is intended to illustrate and not limit the scope of the invention, which is
defined by the scope of the appended claims. Other aspects, advantages, and modifications are
within the scope of the following claims. It will be understood by those skilled in the art that
various changes in form and details may be made therein without departing from the scope of the
invention encompassed by the appended claims.

WE CLAIM :
1. A compound represented by formula Ia:
(Ia) or a pharmaceutically acceptable salt of Ia, wherein
X is CH;
Z is N;
Y is C with the -NH2 attached to Y;
p is 0, 1, 2, or 3;
B is halogen, hydroxyl, carbamoyl, amino, unsubstituted aryl or substituted aryl
wherein substituted aryl has one or more substituents selected from halogen, hydroxyl,
alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl,
alkenylaminocarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino
(including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido),
amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, alkylsulfinyl, sulfamoyl,
sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, and an aromatic or
heteroaromatic moiety;
A is ; and
D is unbranched lower alkyl.
2. The compound as claimed in claim 1, wherein p is 1.

3. The compound as claimed in claim 2, wherein B is halogen.
4. The compound as claimed in claim 3, wherein B is chlorine.
5. The compound as claimed in claim 4, wherein D is CH3.
6. The compound as claimed in claim 5, which isor a
pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a compound represented by formula Ia:
(Ia) or a pharmaceutically acceptable salt of Ia, wherein
X is CH;
Z is N;
Y is C with the -NH2 attached to Y;
p is 0, 1, 2, or 3;
B is halogen, hydroxyl, carbamoyl, amino, unsubstituted aryl or substituted aryl
wherein substituted aryl has one or more substituents selected from halogen, hydroxyl,
alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl,
alkenylaminocarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino
(including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido),
amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, alkylsulfinyl, sulfamoyl,

sulfonamide, nitro, trifiuoromethyl, cyano, azido, heterocyclyl, alkylaryl, and an aromatic or
heteroaromatic moiety;
A is ; and
D is unbranched lower alkyl; and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition comprising the compound as claimed in claim 6 or a
pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
9. A compound, which isor a pharmaceutically acceptable salt
thereof.
10. A compound as claimed in any one of claims 1-6 or 9 in the manufacture of a
medicament for treating or preventing macular degeneration or another form of retinal disease
having an etiology that involves the accumulation of A2E and/or lipofuscin in retinal tissue in a
subject, wherein said medicament reduces the level of A2E accumulation in said subject relative
to the level of A2E accumulation in said subject in the absence of the medicament.
11. A compound as claimed in claim 10, wherein the medicament comprises the compound
or a pharmaceutically acceptable salt thereof.

(54) Title: COMPOSITIONS AND METHODS OF TREATING RETINAL DISEASE
(57) Abstract: Compositions and methods for
treating macular degeneration and other forms
of retinal disease whose etiology involves the
accumulation of A2E and/or lipofuscin, and, more
specifically, for preventing the formation and/or
accumulation of A2E are disclosed.