NOVEL QUINOLINE ESTERS USEFUL FOR TREATING SKIN DISORDERS
FIELD OF THE INVENTION
The present invention relates to quinoline esters that are effective as Liver X
receptors (LXR) modulators. The present invention also relates to compositions
comprising LXR modulators, and to methods for preparing such compounds. The
invention further relates to the use of quinoline esters in the safe treatment of various
skin disorders and conditions.
BACKGROUND OF THE INVENTION
Skin is subject to deterioration through dermatological disorders, environmental
abuse (wind, air conditioning, central heating) or through the normal ageing process
(chronoageing) which may be accelerated by exposure of skin to sun (photoageing). In
recent years the demand for safer and non-toxic drugs for treating skin disorders has
grown enormously.
Liver X receptors (LXRs), originally identified from liver as orphan receptors, are
members of the nuclear hormone receptor super family and are expressed in skin, for
example in keratinocytes, and granulocytes. LXRs are ligand-activated transcription
factors and bind to DNA as obligate heterodimers with retinoid X receptors (RXRs).
LXRs activated by oxysterols (endogenous ligands) display potent anti-inflammatory
properties in vitro and in vivo. Topical application of LXR ligands inhibits inflammation
in murine models of contact (oxazolone-induced) and irritant (TPA-induced) dermatitis.
Recently, LXRa receptor activators have been reported, e.g., WO 98/32444, have a
therapeutic application in the restoration of the skin's barrier function, the induction of
differentiation and the inhibition of proliferation.
Numerous compounds having LXR modulator activity been proposed and
explored as potential pharmaceuticals because of such activity. In practice, however,
they have not been clinically acceptable because of various side effects. According to
our invention, a novel subclass of quinoline esters having LXR modulating activity is
useful in treating various dermatological disorders and conditions without resulting in
unacceptable side effects. Our approach draws upon the known concept of "soft drugs"
(N. S. Bodor, U.S. Patent 6610675). "Soft drugs" are biologically active chemical
compounds (drugs) which might structurally resemble known active drugs (soft
analogues) or could be entirely new types of structures, but which are characterized by
in vivo destruction (metabolism) to nontoxic moieties, after they achieve their
therapeutic role.
SUMMARY OF THE INVENTION
The present invention provides compounds of Formula (I):
(I)
or a pharmaceutically acceptable salt thereof; wherein
Z is halogen or alkyi; wherein each alkyi is optionally substituted with halogen;
Y is H, alkyi, aryl, heteroaryl, cycloalkyi, heterocycloalkyi, CN; wherein each alkyi
or aryl is optionally substituted with alkyi, or aryl;
Q-i , Q2, Q 3 are each independently H, halogen, alkyi, or aryl; wherein each alkyi,
or aryl is optionally substituted with alkyi, or aryl;
L is OC(O), C(0)0, CH2C(0)0, OC(0)CH 2;
W is H, halogen or alkyi;
X is H, alkyi, S(0) nRi, S0 2NR2R3, CONR4R5, C(R6)2OR7, CN; wherein each alkyi,
S(0) nRi, S0 2NR2R3, CONR4R5, or C(R6)2OR is optionally substituted with alkyi,
S0 2alkyl or S0 2aryl, or S0 2heteroaryl; wherein
R is alkyi, aryl, heteroaryl or cycloalkyi;
R2 and R3 are each independently H, alkyi or heteroaryl;
R4 and R 5 are each independently H or alkyi;
¾ and R7 are each independently H or alkyl; and
n is 1 or 2.
The present invention also provides a pharmaceutical composition comprising an
effective amount of one or more compounds of Formula (I) or a pharmaceutically
acceptable salt thereof and a pharmaceutically acceptable carrier.
The present invention also provides a method for treating a skin disorder in a
patient comprising administering to a patient in need thereof an effective amount of a
compound of Formula (I) or a pharmaceutically acceptable salt thereof or a
pharmaceutical composition comprising an effective amount of a compound of Formula
(I)-
In another embodiment, the skin disorder is selected from the group consisting of
psoriasis, atopic dermatitis, skin wounds, skin aging, photoaging and wrinkling.
In other embodiment, the treatment of a skin disorder further comprises
administering an additional therapeutic agent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is related to quinoline esters of Formula (I), which are
effective as Liver X receptors (LXR) modulators. The present invention is also related to
compositions comprising LXR modulators, and to methods for preparing such
compounds. The quinoline esters of the invention and their polymorphs, solvates,
esters, tautomers, diastereomers, enantiomers, pharmaceutically acceptable salts or
prodrugs show utility in the safe treatment of various skin disorders and conditions.
DEFINITIONS
Before describing the present invention in detail, it is to be understood that this
invention is not limited to specific compositions or process steps, as such may vary. It
should be noted that, as used in this specification and the appended claims, the singular
form "a", "an" and "the" include plural references unless the context clearly dictates
otherwise. Thus, for example, reference to "a compound" includes a plurality of
compounds.
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 is related. The following terms are defined for purposes of the invention as
described herein.
As used herein, unless otherwise noted, "alkyi" whether used alone or as part of
a substituent group refers to a saturated straight and branched carbon chain having 1 to
20 carbon atoms or any number within this range, for example, 1 to 6 carbon atoms or 1
to 4 carbon atoms. Designated numbers of carbon atoms (e.g. C -6) shall refer
independently to the number of carbon atoms in an alkyi moiety or to the alkyi portion of
a larger alkyl-containing substituent. Non-limiting examples of alkyi groups include
methyl, ethyl, n-propyl, /'so-propyl, n-butyl, sec-butyl, /'sobutyl, ferf-butyl, and the like.
Where so indicated, alkyi groups can be optionally substituted. In substituent groups
with multiple alkyi groups such as N(Ci -6alkyl) 2, the alkyi groups may be the same or
different.
As used herein, unless otherwise noted, "alkoxy" refers to groups of formula -
Oalkyl. Designated numbers of carbon atoms (e.g. -OC-i-6) shall refer independently to
the number of carbon atoms in the alkoxy group. Non-limiting examples of alkyi groups
include methoxy, ethoxy, n-propoxy, /'so-propoxy, n-butoxy, sec-butoxy, /'so-butoxy, tertbutoxy,
and the like. Where so indicated, alkoxy groups can be optionally substituted.
As used herein, the terms "alkenyl" and "alkynyl" groups, whether used alone or
as part of a substituent group, refer to straight and branched carbon chains having 2 or
more carbon atoms, preferably 2 to 20, having at least one carbon-carbon double bond
("alkenyl") or at least one carbon-carbon triple bond ("alkynyl"). Where so indicated,
alkenyl and alkynyl groups can be optionally substituted. Nonlimiting examples of
alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also 2-methylethenyl),
isopropenyl (also 2-methylethen-2-yl), buten-4-yl, and the like. Nonlimiting examples of
alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methylhex-
4-yn-1-yl.
As used herein, "cycloalkyl" whether used alone or as part of another group,
refers to a non-aromatic hydrocarbon ring including cyclized alkyi, alkenyl, or alkynyl
groups, e.g., having from 3 to 14 ring carbon atoms, for example, from 3 to 7 or 3 to 6
ring carbon atoms, and optionally containing one or more (e.g., 1, 2, or 3) double or
triple bonds. Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g.,
containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are
located inside or outside of the ring system. Any suitable ring position of the cycloalkyl
group can be covalently linked to the defined chemical structure. Where so indicated,
cycloalkyl rings can be optionally substituted. Nonlimiting examples of cycloalkyl groups
include: cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,
cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl,
octahydropentalenyl, octahydro-1 H-indenyl, 3a,4,5,6,7,7a-hexahydro-3/-/-inden-4-yl,
decahydro-azulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-
1H-fluorenyl. The term "cycloalkyl" also includes carbocyclic rings which are bicyclic
hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1 .1]hexanyl,
bicyclo[2.2.1]heptanyl, bicyclo[3.1 .1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl,
bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.
"Haloalkyl" is intended to include both branched and straight-chain saturated
aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted
with 1 or more halogen atoms. As used herein, halogen refers to F, CI, Br and I.
Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group
have been replaced with halogens (e.g., -CF3, -CF2CF3) . The halogens can be the
same (e.g., CHF2, -CF3) or different (e.g., CF2CI). Where so indicated, haloalkyl groups
can optionally be substituted with one or more substituents in addition to halogen.
Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl,
trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.
The term "aryl" wherein used alone or as part of another group, is defined herein
as an aromatic monocyclic ring of 6 carbons or an aromatic polycyclic ring of from 10 to
14 carbons. Aryl groups include but are not limited to, for example, phenyl or naphthyl
(e.g., naphthylen-1-yl or naphthylen-2-yl). Where so indicated, aryl groups may be
optionally substituted with one or more substituents. Aryl groups also include, but are
not limited to for example, phenyl or naphthyl rings fused with one or more saturated or
partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl), which can
be substituted at one or more carbon atoms of the aromatic and/or saturated or partially
saturated rings.
The term "heterocycloalkyl" whether used alone or as part of another group, is
defined herein as a group having one or more rings (e.g., 1, 2 or 3 rings) and having
from 3 to 20 atoms (e.g., 3 to 10 atoms, 3 to 6 atoms) wherein at least one atom in at
least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S),
and wherein the ring that includes the heteroatom is non-aromatic. In heterocyclyl
groups that include 2 or more fused rings, the non-heteroatom bearing ring may be aryl
(e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocycloalkyl groups
have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently
selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a
heterocycloalkyl group can be oxidized (e.g., N®0 , S(O), S0 2) . Where so indicated,
heterocycloalkyl groups can be optionally substituted.
Non-limiting examples of monocyclic heterocycloalkyl groups include, for
example: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl,
oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl
oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl,
morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl
(valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1 /-/-indole, and 1,2,3,4-
tetrahydro-quinoline. Non-limiting examples of heterocyclic groups having 2 or more
rings include, for example: hexahydro-1/-/-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1/-/-
benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1/-/-indolyl, 1,2,3,4-tetrahydroquinolinyl,
chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1/-/-cycloocta[b]pyrrolyl.
The term "heteroaryl" whether used alone or as part of another group, is defined
herein as a single or fused ring system having from 5 to 20 atoms (e.g., 5 to 10 atoms, 5
to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from
nitrogen (N), oxygen (O), and sulfur (S), and wherein further at least one of the rings
that includes a heteroatom is aromatic. In heteroaryl groups that include 2 or more
fused rings, the non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-
5/-/-cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzo-thiophenyl, indolyl).
Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring
heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S). One
or more N or S atoms in a heteroaryl group can be oxidized (e.g., N®0 , S(O), S0 2) .
Where so indicated, heteroaryl groups can be substituted. Non-limiting examples of
monocyclic heteroaryl rings include, for example: 1,2,3,4-tetrazolyl, [1,2,3]triazolyl,
[1,2,4]triazolyl, triazinyl, thiazolyl, 1/-/-imidazolyl, oxazolyl, furanyl, thiopheneyl,
pyrimidinyl, and pyridinyl. Non-limiting examples of heteroaryl rings containing 2 or
more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,
benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7/-/-purinyl, 9/-/-purinyl, 5 -
pyrrolo[3,2-c/]pyrimidinyl, 7H-pyrrolo[2,3-c/]pyrimidinyl, pyrido[2,3-c/]pyrimidinyl, 2-
phenylbenzo[d]thiazolyl, 1 - -indolyl, 4,5,6,7-tetrahydro-1-/-/-indolyl, quinoxalinyl, 5-
methylquinoxalinyl, quinazolinyl, quinolinyl, and isoquinolinyl.
One non-limiting example of a heteroaryl group as described above is C-1-C5
heteroaryl, which is a monocyclic aromatic ring having 1 to 5 carbon ring atoms and at
least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring
atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), and
sulfur (S). Examples of C1-C5 heteroaryl include, but are not limited to for example,
triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl,
isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl,
pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
For the purposes of the present invention, fused ring groups, spirocyclic rings,
bicyclic rings and the like, which comprise a single heteroatom will be considered to
belong to the cyclic family corresponding to the heteroatom containing ring. For
example, 1,2,3,4-tetrahydroquinoline having the formula:
is, for the purposes of the present invention, considered a heterocycloalkyl group. 6,7-
Dihydro-5/-/-cyclopentapyrimidine having the formula:
is, for the purposes of the present invention, considered a heteroaryl group. When a
fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring
will predominate and determine the type of category to which the ring is assigned. For
example, 1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:
is, for the purposes of the present invention, considered a heteroaryl group.
The term "heteroarylene" whether used alone or as part of another group, is
defined herein as a divalent single or fused ring system having from 5 to 20 atoms (e.g.,
5 to 10 atoms, 5 to 6 atoms), wherein at least one atom in at least one ring is a
heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein further
at least one of the rings that includes a heteroatom is aromatic. In heteroarylene groups
that include 2 or more fused rings, the non-heteroatom bearing ring may be a
carbocycle (e.g., 6,7-Dihydro-5H-cyclopentapyrimidinylene) or aryl (e.g.,
benzofuranylene, benzothiophenylene, indolylene). Exemplary heteroarylene groups
have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently
selected from nitrogen (N), oxygen (O), and sulfur (S). One or more N or S atoms in a
heteroarylene group can be oxidized (e.g., N®0 , S(O), S0 2) . Where so indicated,
heteroarylene groups can be substituted. Non-limiting examples of monocyclic
heteroarylene rings include, for example: 1,2,3,4-tetrazolylene, [1,2,3]triazolylene,
[1,2,4]triazolylene, triazinylene, thiazolylene, 1H-imidazolylene, oxazolylene, furanylene,
thiopheneylene, pyrimidinylene, and pyridinylene. Non-limiting examples of
heteroarylene rings containing 2 or more fused rings include: benzofuranylene,
benzothiophenylene, benzoxazolylene, benzthiazolylene, benztriazolylene,
cinnolinylene, naphthyridinylene, phenanthridinylene, 7H-purinylene, 9H-purinylene, 5 -
pyrrolo[3,2-c/]pyrimidinylene, 7H-pyrrolo[2,3-c/]pyrimidinylene, pyrido[2,3-
c/]pyrimidinylene, 2-phenylbenzo[d]thiazolylene, 1H-indolylene, 4,5,6,7-tetrahydro-1-Hindolylene,
quinoxalinylene, 5-methylquinoxalinylene, quinazolinylene, quinolinylene,
and isoquinolinylene.
One non-limiting example of a heteroarylene group as described above is C1-C5
heteroarylene, which is a monocyclic aromatic ring having 1 to 5 carbon ring atoms and
at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring
atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), and
sulfur (S). Examples of C1-C5 heteroarylene include, but are not limited to for example,
triazinylene, thiazol-2-ylene, thiazol-4-ylene, imidazol-1-ylene, 1H-imidazol-2-ylene, 1 -
imidazol-4-ylene, isoxazolin-5-ylene, furan-2-ylene, furan-3-ylene, thiophen-2-ylene,
thiophen-4-ylene, pyrimidin-2-ylene, pyrimidin-4-ylene, pyrimidin-5-ylene, pyridin-2-
ylene, pyridin-3-ylene, and pyridin-4-ylene.
The term "carbocyclic ring" refers to a saturated cyclic, partially saturated cyclic,
or aromatic ring containing from 3 to 14 carbon ring atoms. A carbocyclic ring may be
monocyclic, bicyclic or tricyclic. A carbocyclic ring typically contains from 3 to 10 carbon
ring atoms and is monocyclic or bicyclic.
The term "heterocyclic ring" refers to a saturated cyclic, partially saturated cyclic,
or aromatic ring containing from 3 to 14 ring atoms, in which at least one of the ring
atoms is a heteroatom that is oxygen, nitrogen, or sulfur. A heterocyclic ring may be
monocyclic, bicyclic or tricyclic. A heterocyclic ring typically contains from 3 to 10 ring
atoms and is monocyclic or bicyclic.
The term "amino" refers to -NH 2.
The term "alkylamino" refers to -N(H)alkyl. Examples of alkylamino substituents
include methylamino, ethylamino, and propylamino.
The term "dialkylamino" refers to -N(alkyl) 2 where the two alkyls may be the
same or different. Examples of dialkylamino substituents include dimethylamino,
diethylamino, ethylmethylamino, and dipropylamino.
The term "halogen" refers to fluorine (which may be depicted as -F), chlorine
(which may be depicted as -CI), bromine (which may be depicted as -Br), or iodine
(which may be depicted as -I).
The term "azide" refers to - N3.
The terms "treat" and "treating," as used herein, refer to partially or completely
alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is
suspected to suffer.
As used herein, "therapeutically effective" refers to a substance or an amount
that elicits a desirable biological activity or effect.
Except when noted, the terms "subject" or "patient" are used interchangeably and
refer to mammals such as human patients and non-human primates, as well as
experimental animals such as rabbits, rats, and mice, and other animals. Accordingly,
the term "subject" or "patient" as used herein means any mammalian patient or subject
to which the compounds of the invention can be administered. In an exemplary
embodiment of the present invention, to identify subject patients for treatment according
to the methods of the invention, accepted screening methods are employed to
determine risk factors associated with a targeted or suspected disease or condition or to
determine the status of an existing disease or condition in a subject. These screening
methods include, but are not limited to for example, conventional work-ups to determine
risk factors that may be associated with the targeted or suspected disease or condition.
These and other routine methods allow the clinician to select patients in need of therapy
using the methods and compounds of the present invention.
The term "substituted" is used throughout the specification. The term
"substituted" is defined herein as a moiety, whether acyclic or cyclic, which has one or
more (e.g. 1-10) hydrogen atoms replaced by a substituent as defined herein below.
Substituents include those that are capable of replacing one or two hydrogen atoms of a
single moiety at a time, and also those that can replace two hydrogen atoms on two
adjacent carbons to form said substituent. For example, substituents that replace single
hydrogen atoms includes, for example, halogen, hydroxyl, and the like. A two hydrogen
atom replacement includes carbonyl, oximino, and the like. Substituents that replace
two hydrogen atoms from adjacent carbon atoms include, for example, epoxy, and the
like. When a moiety is described as "substituted" any number of its hydrogen atoms can
be replaced, as described above. For example, difluoromethyl is a substituted C alkyl;
trifluoromethyl is a substituted C alkyl; 4-hydroxyphenyl is a substituted aryl ring; (N,Ndimethyl
-5-amino)octanyl is a substituted C8 alkyl; 3-guanidinopropyl is a substituted C3
alkyl; and 2-carboxypyridinyl is a substituted heteroaryl.
At various places in the present specification, substituents of compounds are
disclosed in groups or in ranges. It is specifically intended that the description include
each and every individual subcombination of the members of such groups and ranges.
For example, the term "C-i -6 alkyl" is specifically intended to individually disclose C-i, C2,
C3, C4, C5, C6, C1-C6, C1-C5, Ci-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-
C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.
Compounds described herein can contain an asymmetric atom (also referred as
a chiral center), and some of the compounds can contain one or more asymmetric
atoms or centers, which can thus give rise to optical isomers (enantiomers) and
diastereomers. The present teachings and compounds disclosed herein include such
enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically
pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers
and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure
form by standard procedures known to those skilled in the art, which include, but are not
limited to for example, chiral chromatography, diastereomeric salt formation, kinetic
resolution, and asymmetric synthesis. The present invention also includes cis and trans
or E/Z isomers of compounds of Formula ( I) containing alkenyl moieties (e.g. , alkenes
and imines). It is also understood that the present teachings encompass all possible
regioisomers, and mixtures thereof, which can be obtained in pure form by standard
separation procedures known to those skilled in the art, and include, but are not limited
to, column chromatography, thin-layer chromatography, and high-performance liquid
chromatography.
The term "Liver X receptor (LXR)" as used herein, refers to both LXRa and
LXR3, and variants, isoforms, and active fragments thereof. LXR3 is ubiquitously
expressed, while LXRa expression is limited to liver, kidney, intestine, spleen, adipose
tissue, macrophages, skeletal muscle, and, as demonstrated herein, skin .
Representative GenBank® accession numbers for LXRa sequences include the
following: human (Homo sapiens, Q13133), mouse (Mus musculus, Q9Z0Y9), rat
(Rattus norvegicus, Q62685), cow (Bos taurus, Q5E9B6), pig (Sus scrofa, AAY43056),
chicken (Gallus gallus, AAM90897). Representative GenBank® accession numbers for
LXR3 include the following: human (Homo sapiens, P55055), mouse (Mus musculus,
Q60644), rat (Rattus norvegicus, Q62755), cow (Bos taurus, Q5BIS6).
The term "mammal" as used herein, refers to a human, a non-human primate,
canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal.
Those skilled in the art recognize that a therapy which reduces the severity of pathology
in one species of mammal is predictive of the effect of the therapy on another species of
mammal.
The term "modulate" as used herein, refers to encompasses either a decrease or
an increase in activity or expression depending on the target molecule. For example, a
TIMP1 modulator is considered to modulate the expression of TIMP1 if the presence of
such TIMP1 modulator results in an increase or decrease in TIMP1 expression. The
term "skin aging" includes conditions derived from intrinsic chronological aging (for
example, deepened expression lines, reduction of skin thickness, inelasticity, and/or
unblemished smooth surface), those derived from photoaging (for example, deep
wrinkles, yellow and leathery surface, hardening of the skin, elastosis, roughness,
dyspigmentations (age spots) and/or blotchy skin), and those derived from steroidinduced
skin thinning.
Preferred compounds will be LXR modulators with LXRa and/or LXR3 modulator
activities. The term "LXR modulator" includes LXRa and/or LXR3 agonists, antagonists
and tissue selective LXR modulators, as well as other agents that induce the expression
and/or protein levels of LXRs in the skin cells. LXR modulators useful in the present
invention include quinoline compounds.
The term "other therapeutic agents" as used herein, refers to any therapeutic
agent that has been used, is currently used or is known to be useful for treating a
disease or a disorder encompassed by the present invention.
The term "prodrug" as used herein, refers to a pharmacologically inactive
derivative of a parent "drug" molecule that requires biotransformation (e.g., either
spontaneous or enzymatic) within the target physiological system to release or convert
the prodrug into the active drug. Prodrugs are designed to overcome problems
associated with stability, toxicity, lack of specificity, or limited bioavailability. Exemplary
prodrugs comprise an active drug molecule itself and a chemical masking group (e.g., a
group that reversibly suppresses the activity of the drug). Some preferred prodrugs are
variations or derivatives of compounds that have groups cleavable under metabolic
conditions. Exemplary prodrugs become pharmaceutically active in vivo or in vitro when
they undergo solvolysis under physiological conditions or undergo enzymatic
degradation or other biochemical transformation (e.g., phosphorylation, hydrogenation,
dehydrogenation, glycosylation). Prodrugs often offer advantages of solubility, tissue
compatibility, or delayed release in the mammalian organism. (See e.g., Bundgard,
Design of Prodrugs, pp. 7-9, 21- 24, Elsevier, Amsterdam (1985); and Silverman, The
Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San
Diego, CA (1992)). Common prodrugs include acid derivatives such as esters prepared
by reaction of parent acids with a suitable alcohol (e.g., a lower alkanol), amides
prepared by reaction of the parent acid compound with an amine, or basic groups
reacted to form an acylated base derivative (e.g., a lower alkylamide).
The term "pharmaceutically acceptable salt" as used herein, refers to any salt
(e.g., obtained by reaction with an acid or a base) of a compound of the present
invention that is physiologically tolerated in the target animal (e.g., a mammal). Salts of
the compounds of the present invention may be derived from inorganic or organic acids
and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic,
sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,
toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic,
benzoic, malonic, sulfonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like.
Examples of bases include, but are not limited to, alkali metal (e.g., sodium)
hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and
compounds of formula NW4
+, wherein W is C -4 alkyl, and the like.
Examples of salts include, but are not limited to: acetate, adipate, alginate,
aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate,
camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, chloride, bromide, iodide, 2- hydroxyethanesulfonate, lactate,
maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate,
pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,
thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions
of the compounds of the present invention compounded with a suitable cation such as
Na+, NH +, and NW + (wherein W is a C -4 alkyl group), and the like. For therapeutic
use, salts of the compounds of the present invention are contemplated as being
pharmaceutically acceptable. However, salts of acids and bases that are nonpharmaceutically
acceptable may also find use, for example, in the preparation or
purification of a pharmaceutically acceptable compound.
The term "therapeutically effective amount" as used herein, refers to that amount
of the therapeutic agent sufficient to result in amelioration of one or more symptoms of a
disorder, or prevent advancement of a disorder, or cause regression of the disorder. For
example, with respect to the treatment of asthma, a therapeutically effective amount
preferably refers to the amount of a therapeutic agent that increases peak air flow by at
least 5%, preferably at least 10%, at least 15%, at least 20%, at least 25%, at least
30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%,
at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at
least 95%, or at least 100%.
The compounds described herein may be administered to humans and other
animals topically in dosage unit formulations containing conventional nontoxic
pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical
administration may also involve the use of transdermal administration such as
transdermal patches or ionophoresis devices.
Methods of formulation are well known in the art and are disclosed, for example,
in Remington: The Science and Practice of Pharmacy, Mack Publishing Company,
Easton, Pa., 21st Edition (2005), incorporated herein by reference.
Pharmaceutical compositions for use in the present invention can be in the form
of sterile, non-pyrogenic liquid solutions or suspensions, coated capsules,
suppositories, lyophilized powders, transdermal patches or other forms known in the art.
The choice of carrier(s) and dosage forms will vary with the particular condition
for which the composition is to be administered. Examples of various types of
preparations for topical/local administration include ointments, lotions, pastes, creams,
gels, powders, drops, sprays, solutions, inhalants, patches, suppositories, retention
enemas, chewable or suckable tablets or pellets and aerosols. Ointments and creams
may, for example, be formulated with an aqueous or oily base with the addition of
suitable thickening and/or gelling agents and/or glycols. Such base may thus, for
example, include water and/or an oil such as liquid paraffin or a vegetable oil such as
arachis oil or castor oil, or a glycolic solvent such as propylene glycol or 1,3-butanediol.
Thickening agents which may be used according to the nature of the base include soft
paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols, woolfat,
hdyrogenated lanolin and beeswax and/or glyceryl monosterate and/or non-ionic
emulsifying agents.
The solubility of the steroid in the ointment or cream may be enhanced by
incorporation of an aromatic alcohol such as benzyl alcohol, phenylethyl alcohol or
phenoxyethyl alcohol.
Lotions may be formulated with an aqueous or oily base and will in general also
include one or more of the following, namely, emulsifying agents, dispersing agents,
suspending agents, thickening agents, solvents, coloring agents and perfumes.
Powders may be formed with the aid of any suitable powder base e.g. talc, lactose or
starch. Drops may be formulated with an aqueous base also comprising one or more
dispersing agents, suspending agents or solubilizing agents, etc. Spray compositions
may, for example, be formulated as aerosols with the use of a suitable propellane, e.g.,
dichlorodifluoromethane or tricholorfluoromethane.
The proportion of active ingredient in the compositions according to the invention
will vary with the precise compound used, the type of formulation prepared and the
particular condition for which the composition is to be administered. The formulation will
generally contain from about 0.0001 to about 5.0% by weight of the compound of
formula (I). Topical preparations will generally contain 0.0001 to 2.5%, preferably 0.01
to 0.5%, and will be administered once daily, or as needed. Also, generally speaking,
the compounds of the invention can be incorporated into topical and other local
compositions formulated substantially as are such presently available types of
compositions containing known glucocorticosteroids, at approximately the same (or in
the case of the most potent compounds of the invention, at proportionately lower)
dosage levels as compared to known highly active agents such as methyl prednisolone
acetate and beclomethasone dipropionate or at considerably lower dosage levels as
compared to less active known agents such as hydrocortisone.
The amount of active ingredient that may be combined with the carrier materials
to produce a single dosage form will vary depending upon the host treated and the
particular mode of administration. It will be understood, however, that the specific dose
level for any particular subject will depend upon a variety of factors including the activity
of the specific compound employed, the age, body weight, general health, sex, diet,
time of administration, route of administration, rate of excretion, drug combination, and
the severity of the particular disease undergoing therapy. The therapeutically effective
amount for a given situation can be readily determined by routine experimentation and
is within the skill and judgment of the ordinary clinician.
In another aspect of the invention, kits that include one or more compounds of
the invention are provided. Representative kits include a compound described herein
(e.g., quinoline esters of Formula I) and a package insert or other labeling including
directions for treating skin disorders by administering an effective amount of a
compound of the present invention.
In another aspect of the invention, kits that include one or more compounds of
the invention are provided. Representative kits include a compound described herein
(e.g., quinoline esters of Formula I) and a package insert or other labeling including
directions for treating skin disorders in a cell by administering an effective amount of a
compound of the present invention.
The phrase "pharmaceutically acceptable carrier" as used herein means a
pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid
filler, diluent, excipient, solvent or encapsulating material, involved in carrying or
transporting the subject agent 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 the formulation and not injurious to the patient.
Some examples of materials which can 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, safflower oil, sesame oil, olive oil,
corn oil and soybean oil; (10) glycols, such as propylene glycol; ( 1 1) 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 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. A
physiologically acceptable carrier should not cause significant irritation to an organism
and does not abrogate the biological activity and properties of the administered
compound.
An "excipient" refers to an inert substance added to a pharmacological
composition to further facilitate administration of a compound. Examples of excipients
include but are not limited to calcium carbonate, calcium phosphate, various sugars and
types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
A "pharmaceutically effective amount" means an amount which is capable of
providing a therapeutic and/or prophylactic effect. The specific dose of compound
administered according to this invention to obtain therapeutic and/or prophylactic effect
will, of course, be determined by the particular circumstances surrounding the case,
including, for example, the specific compound administered, the route of administration,
the condition being treated, and the individual being treated. A typical daily dose
(administered in single or divided doses) will contain a dosage level of from about 0.01
mg/kg to about 50-100 mg/kg of body weight of an active compound of the invention.
Preferred daily doses generally will be from about 0.05 mg/kg to about 20 mg/kg and
ideally from about 0.1 mg/kg to about 10 mg/kg. Factors such as clearance rate, half-life
and maximum tolerated dose (MTD) have yet to be determined but one of ordinary skill
in the art can determine these using standard procedures.
As used herein, the term "IC50" refers to an amount, concentration or dosage of a
particular test compound that achieves a 50% inhibition of a maximal response in an
assay that measures such response. The value depends on the assay used.
As used herein, the term "soft drugs" refer to biologically active chemical
compounds (drugs) which might structurally resemble known active drugs (soft analogs)
or could be entirely new types of structures, but which are all characterized by a
predictable in vivo destruction (metabolism) to nontoxic moieties, after they achieve
their therapeutic role. The metabolic disposition of the soft drugs takes place with a
controllable rate in a predictable manner.
Soft drug design represents a new approach aimed to design safer drugs with an
increased therapeutic index by integrating metabolism considerations into the drug
design process. They are designed to be rapidly metabolized into inactive species and,
hence, to simplify the transformation-distribution-activity profile of the lead.
Consequently, soft drugs are new therapeutic agents obtained by building in the
molecule, in addition to the activity, the most desired way in which the molecule is to be
deactivated and detoxified subsequent to exerting its biological effects. The desired
activity is generally local, and the soft drug is applied or administered near the site of
action. Therefore, in most cases, they produce pharmacological activity locally, but their
distribution away from the site results in a prompt metabolic deactivation that prevents
any kind of undesired pharmacological activity or toxicity.
The major advantages of the soft drug design include:
a) Improvement of the therapeutic index by minimization of undesired systemic
side effects and elimination of reactive toxic intermediates;
b) Avoidance of nonlocalized or long-term toxicity by providing an easily
accessible route of metabolic degradation;
c) Simplification of the activity/distribution profile by avoiding formation of multiple
active
species;
d) Elimination of so-called "drug interactions" by avoiding metabolic routes that
require competition for saturable, highly used enzyme systems.
The soft drugs of the present invention are quinoline esters of formula (I), which
are active upon topical administration and then are hydrolyzed as they pass through the
skin into metabolites which, upon absorption into the blood plasma, do not cause
serious deleterious effects.
In some embodiments, Z is halogen.
In some embodiments, Z is CF3.
In some embodiments, Y is alkyl.
In some embodiments, Y is aryl.
In some embodiments, Y is CN.
In some embodiments, Q i is H.
In some embodiments, Q2 is H.
In some embodiments, Q3 is H.
In some embodiments, Q3 is halogen.
In some embodiments, L is OC(O).
In some embodiments, L is C(0)0.
In some embodiments, W is H.
In some embodiments, W is halogen.
In some embodiments, W is alkyl.
In some embodiments, X is S0 2Me.
In some embodiments, X is S0 2Et.
In some embodiments, X is S0 2NMe2
In some embodiments, X is S0 2NHMe.
In some embodiments, X is alkyl optionally substituted with alkyl, S0 2alkyl or
S0 2aryl, or S0 2heteroaryl.
In some embodiments, X is S0 2heteroaryl.
In some embodiments, the compound include:
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 3-(ethylsulfonyl)benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 2-methyl-5-(methylsulfonyl)-benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 4-(methylsulfonyl)benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 2-(methylsulfonyl)benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 2-methyl-5-(methylsulfonyl)-benzoate;
3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenyl-3-(ethylsulfonyl)-benzoate;
3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenyl-2-methyl-5-
(methylsulfonyl)benzoate;
3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 4-(methylsulfonyl)-benzoate;
3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 2-(methylsulfonyl)-benzoate;
3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenyl-5-(dimethylsulfamoyl)-2-
methylbenzoate;
3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-(methylsulfonyl)phenyl 3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]-benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 2-chloro-5-(methylsulfonyl)-benzoate;
3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenyl-2-chloro-5-(methylsulfonyl)-
benzoate;
3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-[8-chloro-3-(1-methylethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-(8-chloro-3-methylquinolin-4-yl)phenyl 3-(methylsulfonyl)benzoate;
4-chloro-3-[8-(trifluoromethyl)quinolin-4-yl]phenyl-3-(methylsulfonyl)-benzoate;
3-[3-ethyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-[3-propyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-[8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)benzoate;
3-[3-phenyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-[3-cyano-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(dimethylsulfamoyl)
benzoate;
3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(ethylsulfonyl)-benzoate;
3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 2-methyl-5-
(methylsulfonyl)benzoate;
3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 2-chloro-5-
(methylsulfonyl)benzoate;
3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 4-(methylsulfonyl)-benzoate;
3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 5-(dimethylsulfamoyl)-2-
methylbenzoate;
3-(8-chloro-3-phenylquinolin-4-yl)phenyl 3-(methylsulfonyl)benzoate;
3-(8-chloro-3-phenylquinolin-4-yl)phenyl 3-(ethylsulfonyl)benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 3-(dimethylsulfamoyl)-benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 4-(dimethylsulfamoyl)-benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 3-[(methylsulfonyl)methyl]-benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 3-(methylsulfamoyl)-benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 3-(morpholin-4-ylsulfonyl)-benzoate;
and
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 2-methyl-5-(morpholin-4-
ylsulfonyl)benzoate; or
a pharmaceutically accetable salt thereof.
In another embodiments, a pharmaceutical composition comprising a compound
of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier.
In yet another embodiments, a method of treating a skin disorder in a patient,
comprising administering to a patient in need thereof a compound of Formula (I) or a
pharmaceutically acceptable salt thereof or a pharmaceutical composition.
In some embodiments, the skin disorder is selected from the group consisting of
psoriasis, atopic dermatitis, skin wounds, skin aging, photoaging and wrinkling.
In other embodiments, the treatment of a skin disorder further comprises
administering an additional therapeutic agent.
The Liver X receptors (LXR) modulators of the present invention are quinoline
esters, and include all enantiomeric and diasteriomeric forms and salts of compounds
having the formula (I).
(I)
Compounds of the present invention can be prepared in accordance with the
procedures outlined herein, from commercially available starting materials, compounds
known in the literature, or readily prepared intermediates, by employing standard
synthetic methods and procedures known to those skilled in the art. Standard synthetic
methods and procedures for the preparation of organic molecules and functional group
transformations and manipulations can be readily obtained from the relevant scientific
literature or from standard textbooks in the field. It will be appreciated that where typical
or preferred process conditions (i.e., reaction temperatures, times, mole ratios of
reactants, solvents, pressures, etc.) are given; other process conditions can also be
used unless otherwise stated. Optimum reaction conditions can vary with the particular
reactants or solvent used. Those skilled in the art will recognize that the nature and
order of the synthetic steps presented can be varied for the purpose of optimizing the
formation of the compounds described herein.
The processes described herein can be monitored according to any suitable
method known in the art. For example, product formation can be monitored by
spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., H or
3C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or
by chromatography such as high-performance liquid chromatograpy (HPLC), gas
chromatography (GC), gel-permeation chromatography (GPC), or thin layer
chromatography (TLC).
Preparation of the compounds can involve protection and deprotection of various
chemical groups. The chemistry of protecting groups can be found, for example, in
Greene et al., Protective Groups in Organic Synthesis, 4th. Ed. (John Wiley & Sons,
2007), the entire disclosure of which is incorporated by reference herein for all
purposes.
The reactions or the processes described herein can be carried out in suitable
solvents, which can be readily selected by one skilled in the art. Suitable solvents
typically are substantially nonreactive with the reactants, intermediates, and/or products
at the temperatures at which the reactions are carried out, i.e., temperatures that can
range from the solvent's freezing temperature to the solvent's boiling temperature. A
given reaction can be carried out in one solvent or a mixture of more than one solvent.
Depending on the particular reaction step, suitable solvents for a particular reaction step
can be selected.
The compounds of these teachings can be prepared by methods known in the
art. The reagents used in the preparation of the compounds of these teachings can be
either commercially obtained or can be prepared by standard procedures described in
the literature. For example, compounds of the present invention can be prepared
according to the methods illustrated in the following Synthetic Schemes.
The description of this invention utilizes a variety of abbreviations well known to
those skilled in the art, including the following:
aq.: aqueous
CH3CN: Acetonitrile
DDC : Dicyclohexylcarbodimide
DCM: Dichloromethane
DMF: N,N-Dimethylformamide
DMAP: 4-Dimethylyaminopyridine
DMSO: Dimethylsulfoxide
EDC : 1-ethyl-3-(3'-dimethylaminopropyl)-carbodimide
EtOAc: Ethyl acetate
EtOH: Ethanol
GC: Gas Chromatography
HCI: Hydrochloric acid
HOAc: Acetic acid
HPLC: High performance Liquid Chromatography
K2CO3: Potassium carbonate
MeOH: Methanol
MgS0 4: Magnesium sulfate
Nal: Sodium iodide
TEA: Triethylamine
TFA: Trifluoroacetic acid
THF: Tetrahydrofuran
TLC: Thin Layer Chromatography
TMS: Trimethylsilyl
SYNTHETIC PROCEDURES
The reagents used in the preparation of the compounds of this invention can be
either commercially obtained or can be prepared by standard procedures described in
the literature. In accordance with this invention, compounds in the genus were
prepared by following the general schemes.
General Synthetic Scheme(s) for the Preparation of Intermediates and
Compounds of the Invention
According to Scheme 1, the compounds of formula (I) can be prepared be
prepared by reacting compounds of formula (1) with benzoic acids of formula (2) under
a standard coupling (ester formation) conditions. For example, activation of the acid
using dicyclohexylcarbodimide (DCC) or 1-ethyl-3-(3'-dimethylaminopropyl)-
carbodimide (EDC), the latter typically in the presence of 4-dimethylaminopyridine (see
for example: Dhaon, M. K.; Olsen, R. K.; Ramasamy, K.; Journal of Organic Chemistry,
47, 1962 (1982)).
Scheme 1.
Alternatively, as in Scheme 2, compounds of formula I can be prepared by
reaction of an acid chloride of formula 3 with a phenol of formula 1 in the presence of a
base, typically triethylamine or diisopropylethylamine, in a solvent such as
dichloromethane.
Scheme 2.
According to Scheme 3, certain compounds of formula (I) in which the carbonyl
group of the ester is attached to the 4-phenylquinoline can be prepared by coupling
compounds of formula 1 with compounds of formula 4 in essentially the same manner
as used in Scheme 1.
Scheme 3.
Compounds of formula 1 can be prepared by methods known to one skilled in the
art. For example, several preparations of compounds 1 are described in US. and US...
One approach involves application of the Friedlander reaction to a mixture of an
aminophenone compound of formula 5 and an aldehyde or ketone of formula 6 by
heating at an appropriate temperature, typically 80 to 120 °C, in an appropriate
combination of solvent and strong acid. Examples of such combinations of acid and
solvent are benzenesulfonic acid in toluene, sulfuric acid in acetic acid, and the like. If a
sensitive or reactive group on compounds of formula 1 was protect during the reaction,
for example a phenol may be protected as the methyl ether (methoxy) group, a
deprotection step may be performed to remove the protecting group for reaction as in
the Schemes above.
Scheme 4.
Compounds of formula 2 may be commercially available (e.g., 3-
methylsulfonylbenzoic acid) or can be prepared by a variety of methods known to one
skilled in the art. For example, as in Scheme 5, reaction of a compound of formula 7
with an amine of formula 8 in a solvent such as dichloromethane, tetrahydrofuran (THF),
and the like in the presence of a tertiary organic amine such as triethylamine affords
compounds of formula 2 in which D = a bond and X = SO2NR2R3.
Scheme 5.
7 8 2
As in Scheme 6, compounds of formula 2 where D = a bond and X = SO2R1 can
be prepared from compounds of formula 7 by reduction of the sulfonyl chloride to the
sulfinic acid salt, typically by heating a mixture of sodium bicarbonate and sodium sulfite
in water at 90 - 100 °C. The sulfinic acid salt is alkylated in situ by compounds of
formula 9 (Ri-LG) where LG is a leaving group such as a bromide, an iodide, or a
sulfonate. Typical alkylating agents include methyliodide, ethyliodide, benzylbromide,
and the like. These alkylations are generally performed in the presence of a phase
transfer catalyst such as tetrabutylammonium bromide at elevated temperature, up to
100 °C, but limited by the boiling point of the alkylating agent.
Scheme 6.
Compounds of formula 7 can be made by sulfonylation of a benzoic acid using
chlorosulfonic acid as in Scheme 7 and as described in WO2007/091 140 A1, Examples
102 to 105.
EXAMPLES
The following non-limiting examples are presented merely to illustrate the present
invention. The skilled person will understand that there are numerous equivalents and
variations not exemplified but which still form part of the present teachings.
The following describes the preparation of representative compounds of this
invention. Compounds described as homogeneous were determined to be of 90% or
greater purity (exclusive of enantiomers) by analytical reverse phase chromatographic
analysis with 254 nM UV detection. Melting points are reported as uncorrected in
degrees centigrade. Mass spectral data is reported as the mass-to-charge ratio, m/z
and for high resolution mass spectral data, the calculated and experimentally found
masses, [M+H] +, for the neutral formulae M are reported.
Example 1
Step 1: 3-(ethylsulfonyl)benzoic acid
A stirred mixture of 3-(chlorosulfonyl)benzoic acid (2.20 g, 10.0 mmol), Na2SC>3 (2.34 g,
18.5 mmol), and NaHC0 3 (2.52 g, 30.0 mmol) in water (40 ml.) was heated at 90 °C for
1 h. The reaction was cooled, treated with ethyliodide (3.45 ml_, 50 mmol) and
tetrabutylammonium bromide (100 mg), and heated at 80 °C overnight. The reaction
was then cooled, extracted with DCM (2 x 10 ml.) to remove excess ethyliodide, and
then treated with 2 M aqueous hydrochloric acid until the pH ~2 was obtained. The
resulting solid was suction filtered, washed with water, and vacuum-dried to afford the
title compound as an off-white solid (0.99 g). MS (ESI) m/z 213.0.
Step 2: 3-(8-chloro-3-isoDroDylauinolin-4-yl)Dhenol
A stirred mixture of (2-amino-3-chlorophenyl)(3-hydroxyphenyl)methanone (2.48 g, 10.0
mmol), hydrocinnamaldehyde (2.58 g, 30.0 mmol), and concentrated sulfuric acid (20
mg) in glacial acetic acid (20 mL) was heated at 90 °C for 48 h. The cooled reaction was
poured slowly into a stirred mixture of NaHC0 3 (36 g) and water (50 mL). The mixture
was extracted with ethyl acetate (2 x 100 mL) and the dried extracts (MgS0 4) were
concentrated in vacuo. The residue was purified by chromatography, eluting with a
0:100 to 35:65 E:H gradient to afford an oil which solidified. Trituration with 10:90 E:H
and vacuum drying afforded the title compound as a slightly yellow solid (2.00 g, 67%).
Step 3: 3-(8-chloro-3-isopropylauinolin-4-yl)phenyl 3-(ethylsulfonyl)benzoate
A stirred mixture of 3-(ethylsulfonyl)benzoic acid (75 mg, 0.35 mmol), 3-(2-propyl)-8-
chloro-4-(3-hydroxyphenyl)quinoline (89 mg, 0.30 mmol), and DMAP (20 mg) in DCM
(3.0 mL) at 0 °C was treated with 1.0M dicyclohexyldiimide in DCM (0.35 mL, 0.35
mmol). The reaction was allowed to warm to ambient temperature. After 18 h, the
reaction was treated with water (5 mL), extracted with DCM, and the combined extracts
filtered through a pad of Celite®. The filtrate was dried (MgS0 4) , concentrated in vacuo,
and then purified by chromatography, eluting with a 30:70 to 70:30 E:H gradient. The
product was further purified by reverse phase chromatography eluting with 0:100 to
100:0 CH3CN:H20 to remove traces of dicyclohexylurea affording the title compound as
a very pale yellow solid ( 104 mg). MS (ESI) m/z 494.1 ; HRMS: calcd for C27H24CIN0 4S
+ H+, 494.1 187; found (ESI, [M+H]+ Obs'd), 494.1 194.
Example 2
Step 1: 2-methyl-5-(methylsulfon l)benzoic acid
The title compound was prepared as in Example 1, step 1, except using 5-
(chlorosulfonyl)-2-methylbenzoic acid and methyliodide as the reactants and alkylating
at 35 °C. Chromatography eluting with 0:100 to 10:90 ethanohethyl acetate gave the
title compound as a white solid. MS (ESI) m/z 2 13.0.
Step 2: 3-(8-chloro-3-isopropylauinolin-4-yl)phenyl 2-methyl-5-(methylsulfonyl)-benzoate
The title compound was prepared as in Example 1, step 3, except using 2-methyl-5-
(methylsulfonyl)-benzoic acid to afford the title compound an off-white solid (105 mg).
MS (ESI) m/z 494.1; HRMS: calcd for C27H24CIN0 4S + H+, 494.1 187; found (ESI,
[M+H]+ Obs'd), 494.1 190.
Example 3
3-(8-chloro-3-isopropylguinolin-4-yl)phenyl 4-(methylsulfonyl)benzoate
Prepared as in Example 1, step 3, except using 4-(methylsulfonyl)-benzoic acid to afford
the title compound as light yellow solid solid (70 mg). MS (ESI) m/z 480.1; HRMS: calcd
for C26H22CIN0 4S + H+, 480.1031; found (ESI, [M+H]+ Obs'd), 480.1035.
Example 4
3-(8-chloro-3-isopropylguinolin-4-yl)phenyl 2-(methylsulfonyl)benzoate
Prepared as in Example 1, step 3, except using 2-(methylsulfonyl)-benzoic acid to afford
the title compound as light yellow solid (10 mg). MS (ESI) m/z 480.1; HRMS: calcd for
C26H22CIN0 4S + H+, 480.10318; found (ESI, [M+H]+ Obs'd), 480.1037.
Step 1: 5-(dimethylsulfamoyl)-2-methylbenzoic acid
A vigorously stirred mixture of 5-(chlorosulfonyl)-2-methylbenzoic acid ( 1 .17 g, 5.00
mmol) in DCM (10 ml.) was slowly treated with 40% aqueous diethylamine (2.0 ml_).
After 18 h at ambient temperature, brine (5 ml.) was added and the layers separated.
The aqueous was further extracted with DCM (20 ml.) and the combined extracts dried
(MgS0 4) and concentrated in vacuo. The resulting solid was purified by
chromatography eluting with a 50:50 to 100:0 E: gradient to afford the title compound as
an off-white solid (0.67 g). MS (ESI) m/z 213.0. MS (ESI) m/z 244.1; HRMS: calcd for
CioH13N0 4S + H+, 244.06380; found (ESI, [M+H]+ Obs'd), 244.0638.
Step 2: 3-(8-chloro-3-isoDroDylauinolin-4-yl)Dhenyl 2-methyl-5-(methylsulfonyl)-benzoate
The title compound was prepared as in Example 1, step 3, except using 5-
(dimethylsulfamoyl)-2-methylbenzoic acid to afford the title compound as a white solid
(128 mg). MS (ESI) m/z 523.2; HRMS: calcd for C28H27CIN20 4S + H+, 523.1453; found
(ESI, [M+H]+ Obs'd), 523.1462.
Example 6
3-i3-isoDroDyl-8-(trifluoromethyl)guinolin-4-yllDhenyl-3-(ethylsulfonyl)b
The title compound was prepared as in Example 1, step 3, except using 3-[3-isopropyl-
8-(trifluoromethyl)quinolin-4-yl]phenol (prepared as in WO 2008049047 A2 ) as the
substrate to give a white solid from a foam (131 mg). MS (ESI ) m/z 528.1; HRMS: calcd
for C28H24F3N0 4S + H+, 528.1451; found (ESI , [M+H]+ Obs'd), 528.1451 .
Example 7
3-!3-isoDroDyl-8-(trifluoromethyl)guinolin-4-yllDh
benzoate
The title compound was prepared as in Example 2, step 2, except using 3-[3-isopropyl-
8-(trifluoromethyl)quinolin-4-yl]phenol as the substrate to give a white solid from a foam
(109 mg). MS (ESI ) m/z 528.1 ; HRMS: calcd for C28H24F3N0 4S + H+, 528.1451; found
(ESI, [M+H]+ Obs'd), 528.1454.
Example 8
3-i3-isoDroDyl-8-(trifluoromethyl)guinolin-4-yllDhenyl 4-(methylsulfonyl)-benzoate
The title compound was prepared as in Example 3 except using 3-[3-isopropyl-8-
(trifluoromethyl)quinolin-4-yl]phenol as the substrate to give a white solid from a foam
(98 mg). MS (ESI) m/z 514.1; HRMS: calcd for C27H22F3N0 4S + H+, 514.1294; found
(ESI, [M+H]+ Obs'd), 514.1297.
Example 9
3-[3-isopropyl-8-(trifluoromethyl)auinolin-4-yllphenyl 2-(methylsulfonyl)-benzoate
The title compound was prepared as in Example 4 except using 3-[3-isopropyl-8-
(trifluoromethyl)quinolin-4-yl]phenol as the substrate to give a white solid from a foam
(99 mg). MS (ESI) m/z 514.2; HRMS: calcd for C27H22F3N0 4S + H+, 514.1294; found
(ESI, [M+H]+ Obs'd), 514.1308.
3-f3-isoDroDyl-8-(trifluoromethyl)guinolin-4-yllDhenyl-5-(di
benzoate
The title compound was prepared as in Example 5 except using 3-[3-isopropyl-8-
(trifluoromethyl)quinolin-4-yl]phenol as the substrate to afford the title compound as a
white solid from a foam (139 mg). MS (ESI) m/z 557.2; HRMS: calcd for C29H27F3N20 4S
+ H+, 557.1716; found (ESI, [M+H]+ Obs'd), 557.1717.
Example 11
3-i3-methyl-8-(trifluoromethyl)guinolin-4-yllDhenyl 3-(methylsulfonyl)benzoate
A stirred mixture of 3-(methylsulfonyl)benzoic acid (200 mg, 1.00 mmol) in 1,2-
dichloroethane (5.0 mL) under nitrogen was treated with thionyl chloride (0.40 mL) and
then heated at 80 °C for 2 h. The reaction was cooled slightly and concentrated under a
nitrogen stream to remove solvent and excess thionyl chloride to give a white solid.
Dichloromethane (10 mL) was added followed by 4-(3-hydroxyphenyl)-3-methyl-8-
(trifluoromethyl)quinoline (303 mg, 1.00 mmol). After stirring overnight, the reaction was
washed with aqueous saturated NaHC0 3 (5 mL), dried (MgS0 4) , and concentrated in
vacuo. Chromatography eluting with 0:100 to 40:60 E:H afforded the title compound as
a white solid from a foam (372 mg). MS (ESI) m/z 486.1 ; HRMS: calcd for
C25H 8F3N0 4S + H+, 486.0981; found (ESI, [M+H]+ Obs'd), 486.0982.
Example 12
Step 1: 3-[3-methyl-8-(trifluoromethyl)auinolin-4-yllbenzoic acid
A mixture of 4-bromo-3-methyl-8-(trifluoromethyl)quinoline ( 1 .00 g, 3.45 mmol), 3-
boronobenzoic acid (0.686 g, 4.14 mmol), tetrakis(triphenyl-phosphine)-palladium
(0.199 g, 0.172 mmol) and sodium carbonate ( 1.096 g, 10.34 mmol) in dioxane (15 ml)
and water (5 ml) was refluxed overnight. The reaction was cooled and neutralized with
2N HCI. The mixture was then extracted with ethyl acetate. The combined organics
were dried over MgSC^ and concentrated. Chromatography eluting with 0:100 to 5:95
MeOH:DCM gradient afforded the title compound as a yellow solid (0.818 g, 72%). MS
(ESI) m/z 332.1; HRMS: calcd for C 8H12F3N02 + H+, 332.08929; found (ESI, [M+H]+
Obs'd), 332.0894
Step 2: 3-(methylsulfonyl)Dhenyl 3-f3-methyl-8-(trifluoromethyl)guinolin-4-yll-benzoate
The title compound was prepared essentially as in Example 11 except using 3-[3-
methyl-8-(trifluoromethyl)quinolin-4-yl]benzoic acid as the substrate for conversion to
the acid chloride and 3-(methylsulfonyl)phenol as the other reactant, affording a white
solid. MS (ESI) m/z 486.1; HRMS: calcd for C25H 8F3N0 4S + H+, 486.0981; found (ESI,
[M+H]+ Obs'd), 486.0984.
Example 13
3-(8-chloro-3-isopropylguinolin-4-yl)phenyl 2-chloro-5-(methylsulfonyl)-benzoate
A stirred mixture of 2-chloro-5-(methylsulfonyl)benzoic acid (75.5 mg, 0.33 mmol), 3-(2-
propyl)-8-chloro-4-(3-hydroxyphenyl)quinoline (89 mg, 0.30 mmol), and DMAP (3.6 mg,
0.03 mmol) in DMF ( 1 .5 ml.) at 20 °C was treated with 1-ethyl-3-(3'-
dimethylaminopropyl)-carbodiimide hydrochoride (80 mg, 0.45 mmol). After stirring
overnight, the reaction was treated with water (10 ml_), extracted with ethyl acetate (2 x
10 ml_), and the extracts dried (MgS0 4) and concentrated in vacuo. Purification by
chromatography, eluting with a 0:100 to 50:50 E:H gradient gave the title compound as
a very pale yellow solid from a foam (67 mg). MS (ESI) m/z 514.1; HRMS: calcd for
C26H2iCI 2N0 4S + H+, 514.0641; found (ESI, [M+H]+ Obs'd), 514.0640.
Example 14
3-[3-isopropyl-8-(trifluoromethyl)auinolin-4-yllphenyl-2-ch
benzoate
The title compound was prepared as in Example 13 except using 3-[3-isopropyl-8-
(trifluoromethyl)quinolin-4-yl]phenol as the substrate to give a white solid from a foam
(76 mg). MS (ESI) m/z 548.1 ; HRMS: calcd for C27H2iCIF3N0 4S + H+, 548.0905; found
(ESI, [M+H]+ Obs'd), 548.0899.
Example 15
3-[3-isopropyl-8-(trifluoromethyl)auinolin-4-yllphenyl 3-(methylsulfonyl)-benzoate
A stirred mixture of 3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenol (99 mg, 0.30
mmol) and 4-methylmorpholine (91 mg, 0.90 mmol) in DCM (3.0 ml.) under nitrogen
was treated with 3-(methylsulfonyl)benzoic acid chloride (131 mg, 0.60 mmol) and then
heated at 35 °C for 2 1 h. The reaction was cooled, treated with saturated aqueous
NaHC0 3 (5 ml.) and extracted with DCM (2 x 3 ml_). The combined extracts were dried
(MgS0 4) , concentrated in vacuo, and the residue purified by chromatography eluting
with a 0:100 to 50:50 E:H gradient. The title compound was obtained as a white solid
from a foam (84 mg). MS (ESI) m/z 514.1; HRMS: calcd for C27H2 2F 3N0 4S + H+,
514.1294; found (ESI, [M+H]+ Obs'd), 514.1297.
Example 16
3-[8-chloro-3-(1-methylethyl)guinolin-4-yllphenyl 3-(methylsulfonyl)benzoate
A stirred mixture of 3-(2-propyl)-8-chloro-4-(3-hydroxyphenyl)quinoline (89 mg, 0.30
mmol) and triethylamine (0.20 ml.) in DCM (2.0 ml.) at 20 °C was treated with 3-
(methylsulfonyl)benzoic acid chloride (60 mg, 0.30 mmol). After stirring overnight, the
reaction was treated with aqueous NaHC0 3 (3 ml.) and extracted with DCM (2 x 5 ml_).
The extracts were dried (MgS0 4) and concentrated in vacuo. Purification by
chromatography, eluting with a 0:100 to 50:50 E:H gradient gave the title compound as
an off-white solid from a foam (50 mg). MS (ESI) m/z 480.1; HRMS: calcd for
C26H22CIN0 4S + H+, 480.1031; found (ESI, [M+H]+Obs'd), 480.1036.
Example 17
3-(8-chloro-3-methylguinolin-4-yl)phenyl 3-(methylsulfonyl)benzoate
The title compound was prepared in essentially as in Example 16 except using 8-chloro-
4-(3-hydroxyphenyl)-3-methylquinoline as substrate to afford a light yellow solid. MS
(ESI) m/z 452.1; HRMS: calcd for C24H18CIN0 4S + H+, 452.0718; found (ESI, [M+H]+
Obs'd), 452.0724.
Example 18
4-chloro-3-i8-(trifluoromethyl)auinolin-4-yllDhenyl-3-(methylsulfonyl)benzoate
The title compound was prepared in essentially as in Example 16 except using 4-chloro-
3-[(8-(trifluoromethyl)quinolin-4-yl]phenol as substrate to afford a tacky white solid.
MS (ESI) m/z 506.1; HRMS: calcd for C24H15CIF3N0 4S + H+, 506.0435; found (ESI,
[M+H]+ Obs'd), 506.0443.
Example 19
Step 1: 3-i3-ethyl-8-(trifluoromethyl)auinolin-4-yllDhenol
A mixture of [2-amino-3-(trifluoromethyl)phenyl](3-hydroxyphenyl)methanone (0.200 g,
0.71 1 mmol), butyraldehyde (0.191 mL, 2.133 mmol), and benzenesulfonic acid (0.337
g, 2.133 mmol) in toluene (3 mL) was refluxed overnight. The reaction was concentrated
under a nitrogen stream and taken into ethyl acetate and washed with saturated
NaHC03, then water. After concentrating in vacuo, the residue was purified by
chromatography eluting with a 0:100 to 25:75 E:H gradient to afford the title compound
as a brown solid (0.166 g, 74%). MS (ESI) m/z 318.1 ; HRMS: calcd for C 8H14F3NO +
H+, 318.1 100; found (ESI, [M+H]+ Obs'd), 318.1 107.
Step 2: 3-i3-ethyl-8-(trifluoromethyl)auinolin-4-yllDhenyl 3-(methylsulfonyl)-benzoate
The title compound was prepared in essentially as in Example 13 except using 3-[3-
ethyl-8-(trifluoromethyl)quinolin-4-yl]phenol as substrate to afford a light yellow solid.
MS (ESI) m/z 500.1; HRMS: calcd for C26H2oF3N0 4S + H+, 500.1 1379; found (ESI,
[M+H]+ Obs'd), 500.1 139.
Example 20
Step 1: 3-i3-DroDyl-8-(trifluoromethyl)guinolin-4-yllDhenol
The title compound was prepared as in Example 19, step 1, except using pentanal as
the aldehyde substrate to afford a brown solid. MS (ESI) m/z 332.1; HRMS: calcd for
C 9H16F3NO + H+, 332.1257; found (ESI, [M+H]+ Obs'd), 332.1260.
Step 2: 3-[3-propyl-8-(trifluoromethyl)auinolin-4-yllphenyl 3-(methylsulfonyl)-benzoate
Prepared as in Example 19, step 2, except using 3-[(8-(trifluoromethyl)quinolin-4-
yl]phenol as the substrate to give a white solid. MS (ESI) m/z 514.1; HRMS: calcd for
C27H22F3N0 4S + H+, 514.12944; found (ESI, [M+H]+ Obs'd), 514.1292.
Example 2 1
3-i8-(trifluoromethyl)guinolin-4-yllDhenyl 3-(methylsulfonyl)benzoate
Prepared as in Example 19, step 2, except using 3-[(8-(trifluoromethyl)quinolin-4-
yl]phenol as the substrate, to give a yellow solid. MS (ESI) m/z 472.1 ; HRMS: calcd for
C24H16F3N0 4S + H+, 472.08249; found (ESI, [M+H]+ Obs'd), 472.0826.
Example 22
3-i3-Dhenyl-8-(trifluoromethyl)guinolin-4-yllDhenyl 3-(methylsulfonyl)benzoate
Prepared as in Example 19, step 2, except using 3-[3-phenyl-8-(trifluoromethyl)quinolin-
4-yl]phenol as the substrate, to give a light yellow solid. MS (ESI) m/z 548.1; HRMS:
calcd for C3oH2oF3N0 4S + H+, 548.1 138; found (ESI, [M+H]+ Obs'd), 548.1 139.
Example 23
3-[3-benzyl-8-(trifluoromethyl)guinolin-4-yllphenyl 3-(methylsulfonyl)benzoate
Prepared as in Example 19, step 2, except using 3-[3-benzyl-8-(trifluoromethyl)quinolin-
4-yl]phenol as the substrate, to give a tan solid. MS (ESI) m/z 562.1; HRMS: calcd for
C3 H22F3N0 4S + H+, 562.1294; found (ESI, [M+H]+ Obs'd), 562.1293.
Example 24
3-[3-cvano-8-(trifluoromethyl)guinolin-4-yllphenyl 3-(methylsulfonyl)benzoate
Prepared as in Example 19, step 2, except using 3-[3-cyano-8-(trifluoromethyl)quinolin-
4-yl]phenol as the substrate, to give an off-white solid. MS (ESI) m/z 497.1; HRMS:
calcd for C25H15F3N20 4S + H+, 497.0777; found (ESI, [M+H]+ Obs'd), 497.0775.
Example 25
3-[3-methyl-8-(trifluoromethyl)guinolin-4-yllphenyl 3-(dimethylsulfamoyl)-benzoate
Prepared as in Example 13, except using 3-[3-methy-8-(trifluoromethyl)quinolin-4-
yl]phenol and 3-(dimethylsulfamoyl)-benzoic acid as substrates to give a white solid. MS
(ESI) m/z 515.1;
Example 26
3-i3-methyl-8-(trifluoromethyl)auinolin-4-yllDhenyl 3-(ethylsulfonyl)benzoate
Prepared as in Example 13, except using 3-[3-methy-8-(trifluoromethyl)quinolin-4-
yl]phenol and 3-(ethylsulfonyl)benzoic acid as substrates to give a white solid. MS (ESI)
m/z 500.1;
Example 27
3-[3-methyl-8-(trifluoromethyl)guinolin-4-yllphenyl 2-methyl-5-(methylsulfonyl)-benzoate
Prepared as in Example 13, except using 3-[3-methy-8-(trifluoromethyl)quinolin-4-
yl]phenol and 2-methyl-5-(methylsulfonyl)benzoic acid as substrates to give a white
solid. MS (ESI) m/z 500.1;
Example 28
3-[3-methyl-8-(trifluoromethyl)guinolin-4-yllphenyl 2-chloro-5-(methylsulfonyl)-benzoate
Prepared as in Example 13, except using 3-[3-methy-8-(trifluoromethyl)quinolin-4-
yl]phenol and 2-chloro-5-(methylsulfonyl)benzoic acid as substrates to give a white
solid. MS (ESI) m/z 520.1;
Example 29
3-[3-methyl-8-(trifluoromethyl)guinolin-4-yllphenyl 4-(methylsulfonyl)benzoate
Prepared as in Example 13, except using 3-[3-methy-8-(trifluoromethyl)quinolin-4-
yl]phenol and 4-(methylsulfonyl)benzoic acid as substrates to give a white solid. MS
(ESI) m/z 486.1;
Example 30
3-[3-methyl-8-(trifluoromethyl)guinolin-4-yllphenyl 5-(dimethylsulfamoyl)-2-
methylbenzoate
Prepared as in Example 13, except using 3-[3-methy-8-(trifluoromethyl)quinolin-4-
yl]phenol and 2- (methylsulfonyl)benzoic acid as substrates to give a white solid from a
glass. MS (ESI) m/z 529.1 ;
Example 3 1
3-(8-chloro-3-Dhenylauinolin-4-yl)Dhenyl 3-(methylsulfonyl)benzoate
Prepared as in Example 13, except using 3-[8-chloro-3-phenylquinolin-4-yl]phenol and
2-(methylsulfonyl)benzoic acid as substrates to give a very pale yellow solid. MS (ESI)
m/z 514.1;
Example 32
3-(8-chloro-3-Dhenylguinolin-4-yl)phenyl 3-(ethylsulfonyl)benzoate
Prepared as in Example 13, except using 3-[8-chloro-3-phenylquinolin-4-yl]phenol and
3-(ethylsulfonyl)benzoic acid as substrates to give a very pale yellow solid. MS (ESI)
m/z 528.1;
Example 33
Step 1: 3-(dimethyIsulfamoyl)benzoic acid
The title compound was prepared essentially as in Example 5, step 1, except using 3-
(chlorosulfonyl)benzoic acid chloride and dimethylamine as the substrates to afford an
off-white solid. MS (ESI) m/z 252.0; HRMS: calcd for C9HnN0 4S + Na+, 252.03010;
found (ESI, [M+Na]+ Obs'd), 252.0297.
CL-131210-2, L42142-37-1
Step 2: 3-(8-chloro-3-isopropylguinolin-4-yl)phenyl 3-(dimethylsulfamoyl)-benzoate
Prepared as in Example 13, except using 3-(2-propyl)-8-chloro-4-(3-
hydroxyphenyl)quinoline and 3-(dimethylsulfamoyl)benzoic acid as the substrates, to
give an off-white solid. MS (ESI) m/z 509.1;
Example 34
step 1: 4-(dimethylsulfamoyl)benzoic acid
The title compound was prepared essentially as in Example 5, step 1, except using 4-
(chlorosulfonyl)benzoic acid chloride and dimethylamine as the substrates to afford an
off-white solid. MS (ESI) m/z 228.0; HRMS: calcd for C9HnN0 4S + H+, 230.04815;
found (ESI, [M+H]+ Obs'd), 230.0484.
CL- 3 2 -2, L421 42-37-2
step 2: 3-(8-chloro-3-isopropylguinolin-4-yl)phenyl 4-(dimethylsulfamoyl)-benzoate
Prepared as in Example 13, except using 3-(2-propyl)-8-chloro-4-(3-
hydroxyphenyl)quinoline and 4-(dimethylsulfamoyl)benzoic acid as the substrates, to
give an off-white solid. MS (ESI) m/z 509. 1;
Example 35
step 1: methyl 3-[(methylsulfonyl)methyllbenzoate
A mixture of methyl 3-(bromomethyl)benzoate (2.29 g, 10.0 mmol) and sodium
methylsulfinate (1.25 g, 85% purity, 10.0 mmol based on 85%) in dimethylformamide
( 10 mL) and water (5 mL) was stirred at 20 °C for 18 h. The reaction was diluted with
water (30 mL) and the resulting solid suction filtered, with water washes, and dried
under vacuum to afford the title compound as a white solid (2.06 g).
MS (ESI ) m/z 246. 1; HRMS: calcd for C 0H12O4S + Na+, 251.03485; found (ESI ,
[M+Na]+) , 251.0350.
step 2: 3-[(methylsulfonyl)methyllbenzoic acid
A mixture of methyl 3-[(methylsulfonyl)methyl]benzoate ( 1 .79 g, 8.00 mmol) and 1.0 M
aqueous lithium hydroxide ( 10 mL, 10.0 mmol) in dioxane (10 mL) was stirred at 20 °C
for 21 h, then treated with 2.0 M aqueous hydrochloric acid until the pH ca. 2. Additional
water was added (10 mL) and the white precipitate was suction filtered, washed with
water, and dried under vacuum to afford the title compound as a white solid ( 1 .5 1 g).
step 3: 3-(8-chloro-3-isopropylguinolin-4-yl)phenyl 3-[(methylsulfonyl)methyll-benzoate
Prepared as in Example 13, using 3-(2-propyl )-8-chloro-4-(3-hydroxyphenyl)quinoline
and 3-[(methylsulfonyl)methyl]benzoic acid as the substrates, to give an off-white solid.
Example 36
step 1: 3-(methylsulfamoyl)benzoic acid
The title compound was prepared as in Example 5, step 1, except using 3-
(chlorosulfonyl)benzoic acid chloride and methylamine (40% aqueous solution) as the
substrates to afford an off-white solid.
step 2: 3-(8-chloro-3-isopropylguinolin-4-yl)phenyl 3-(methylsulfamoyl)-benzoate
Prepared as in Example 13, using 3-(2-propyl )-8-chloro-4-(3-hydroxyphenyl)quinoline
and 3-(methylsulfamoyl)benzoic acid as the substrates, to give an off-white solid.
Example 37
step 1: 3-(morpholin-4-ylsulfonyl)benzoic acid
The title compound was prepared as in Example 5, step 1, except using 3-
(chlorosulfonyl)benzoic acid and morpholine as the substrates to afford an off-white
solid.
MS (ESI ) m/z 272. 1; HRMS: calcd for Cn H 3N0 5S + H+, 272.05872; found (ESI ,
[M+H]+ Obs'd), 272.0592.
step 2: 3-(8-chloro-3-isopropylguinolin-4-yl)phenyl 3-(morpholin-4-ylsulfonyl)-benzoate
Prepared as in Example 13, using 3-(2-propyl )-8-chloro-4-(3-hydroxyphenyl)quinoline
and 3-(morpholin-4-ylsulfonyl)benzoic acid as the substrates, to give an off-white solid.
Example 38
step 1: 2-methyl-5-(morpholin-4-ylsulfonyl)benzoic acid
The title compound was prepared as in Example 5, step 1, except using 5-
(chlorosulfonyl)-2-methylbenzoic acid and morpholine as the substrates to afford an offwhite
solid. MS (ESI ) m/z 286. 1; HRMS: calcd for C 2H15N0 5S + H+, 286.07437; found
(ESI, [M+H]+ Obs'd), 286.0744.
step 2: 3-(8-chloro-3-isopropylguinolin-4-yl)phenyl 2-methyl-5-(morpholin-4-ylsulfon yl)-
benzoate
Prepared as in Example 13, using 3-(2-propyl )-8-chloro-4-(3-hydroxyphenyl)quinoline
and 2-methyl-5-(morpholin-4-ylsulfonyl)benzoic acid as the substrates, to give an offwhite
solid.
Brief Description of Biological Test Prodcedure(s) and Text Summary of Results.
L IGAND-BI NDI NG TEST PROCEDU RE FOR HUMAN LXRp .
Ligand-binding to the human LXRp was demonstrated for representative compounds of
this invention by the following procedure.
Materials and Methods:
Buffer : 100 mM KCI, 100mM TRIS (pH 7.4 at +4 °C), 8.6% glycerol, 0.1 mM PMSF*, 2
mM MTG*, 0.2% CHAPS (* not used in wash buffer)
Tracer: 3H T0901317
Receptor source : E. coli extracted from cells expressing biotinylated hLXRp. Extract
was made in a similar buffer as above, but with 50 mM TRIS.
Day 1
Washed streptavidin and coated flash plates with wash buffer.
Diluted receptor extract to give Bmax ~ 4000 cpm and add to the wells.
Wrapped the plates in aluminum foil and stored them at +4 °C overnight.
Day 2
Made a dilution series in DMSO of the test ligands.
Made a 5 nM solution of the radioactive tracer in buffer.
Mixed 250 m I_ diluted tracer with 5 m I_ of the test ligand from each concentration of the
dilution series.
Washed the receptor-coated flash plates.
Added 200 m I_ per well of the ligand/radiolabel mixture to the receptor-coated flash
plates.
Wrapped the plates in aluminum foil and incubate at +4 °C over night.
Day 3
Aspirated wells, and washed the flashed plates. Sealed the plate.
Measured the remaining radioactivity in the plate.
Results :
Representative compounds of this invention had activity (IC50 values) in the LXR3
ligand binding assay in the range between 0.001 to 20 uM.
Summary of Biological Data:
8 0.0125 0.054 38 1.9
9 0.1 12 0.256
10 0.024 0.064 58 0.53
1 1 0.0035 0.0133 105 73
12 0.154 0.544
13 0.0034 0.0090
14 0.0041 0.017
15 0.0017 0.0035 4 1 5.2
16 0.0022 0.0044
17 0.0037 0.017
18 0.0138 0.122
19 0.0022 0.0040 36 12.5
20 0.0020 0.0029 11 4.49
2 1 0.020 0.120 634 384
22 0.0023 0.0039 9.9 9.15
23 0.0027 0.0058 16 25
24 0.033 0.090
25 0.014 0.058 250 42
26 0.0086 0.052 250 250
27 0.035 0.140 25 99
28 0.019 0.105 67 214
29 0.034 0.154 250 167
30 0.235 0.445 162 137
3 1 0.0026 0.0030 0.98 2.76
32 0.0030 0.0079 6.8 2.86
33 0.0047 0.0150 55 8.3
34 0.064 0.188 78 1.38
35 0.0056 0.0087 11 0.53
36 0.0042 0.0092 8.0 0.4
37 0.069 0.202 60 2.42
38 0.506 0.664 44 0.62
Variations, modifications, and other implementations of what is described herein
will occur to those skilled in the art without departing from the spirit and the essential
characteristics of the present teachings. Accordingly, the scope of the present
teachings is to be defined not by the preceding illustrative description but instead by the
following claims, and all changes that come within the meaning and range of
equivalency of the claims are intended to be embraced therein.
Each of the printed publications, including but not limited to patents, patent
applications, books, technical papers, trade publications and journal articles described
or referenced in this specification are herein incorporated by reference in their entirety
and for all purposes.
WHAT IS CLAIMED IS:
1. A compound of Formula (I):
(I)
or a pharmaceutically acceptable salt thereof; wherein
Z is halogen or alkyi; wherein each alkyi is optionally substituted with halogen;
Y is H, alkyi, aryl, heteroaryl, cycloalkyi, heterocycloalkyi, CN; wherein each alkyi
or aryl is optionally substituted with alkyi, or aryl;
Q-i, Q2, Q 3 are each independently H, halogen, alkyi, or aryl; wherein each alkyi,
or aryl is optionally substituted with alkyi, or aryl;
L is OC(O), C(0)0, CH2C(0)0, OC(0)CH2;
W is H, halogen or alkyi;
X is H, alkyi, S(0) n i , S0 2NR2R3, CONR4R5, C(R6)2OR7, CN; wherein each alkyi,
S(0) nRi, S0 2NR2R3, CONR4R5, or C(R6)2OR is optionally substituted with alkyi,
S0 2alkyl or S0 2aryl, or S0 2heteroaryl; wherein
R is alkyi, aryl, heteroaryl or cycloalkyi;
R2 and R 3 are each independently H, alkyi or heteroaryl;
R4 and R 5 are each independently H or alkyi;
R6 and R are each independently H or alkyi; and
n is 1 or 2.
2. The compound of claim 1, wherein Z is halogen.
3. The compound of claim 1 or 2, wherein Z is CF3.
4. The compound of any one of claims o 3, wherein Y is alkyl.
5. The compound of any one of claims o 3, wherein Y is aryl.
6. The compound of any one of claims o 3, wherein Y is CN.
7. The compound of any one of claims o 6, wherein Q is H.
8. The compound of any one of claims o 7, wherein Q2 is H.
9. The compound of any one of claims o 8, wherein Q3 is H.
10. The compound of any one of claims o 8, wherein Q3 is halogen.
11. The compound of any one of claims o 10, wherein L is OC(O).
12. The compound of any one of claims o 10, wherein L is C(0)0.
13. The compound of any one of claims o 12, wherein W is H.
14. The compound of any one of claims o 12, wherein W is halogen.
15. The compound of any one of claims o 12, wherein W is alkyl.
16. The compound of any one of claims o 15, wherein X is S0 2Me.
17. The compound of any one of claims o 15, wherein X is S0 2Et.
18. The compound of any one of claims 1 to 15, wherein X is S0 2NMe2
19. The compound of any one of claims 1 to 15, wherein X is S0 2NHMe.
20. The compound of any one of claims 1 to 15, wherein X is alkyl optionally
substituted with alkyl, S0 2alkyl or S0 2aryl, or S0 2heteroaryl.
2 1. The compound of any one of claims 1 to 15, wherein X is S0 2heteroaryl.
22. The compound of claim 1, wherein the compound is selected from the
group consisting of:
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 3-(ethylsulfonyl)benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 2-methyl-5-(methylsulfonyl)-benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 4-(methylsulfonyl)benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 2-(methylsulfonyl)benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 2-methyl-5-(methylsulfonyl)benzoate;
3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenyl-3-(ethylsulfonyl)-benzoate;
3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenyl-2-methyl-5-(methylsulfonyl)-
benzoate;
3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 4-(methylsulfonyl)-benzoate;
3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 2-(methylsulfonyl)-benzoate;
3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenyl-5-(dimethyl-sulfamoyl)-2-
methylbenzoate;
3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-(methylsulfonyl)phenyl 3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]-benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 2-chloro-5-(methylsulfonyl)-benzoate;
3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenyl-2-chloro-5-(methylsulfonyl)-
benzoate;
3-[3-isopropyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-[8-chloro-3-(1-methylethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-(8-chloro-3-methylquinolin-4-yl)phenyl 3-(methylsulfonyl)benzoate;
4-chloro-3-[8-(trifluoromethyl)quinolin-4-yl]phenyl-3-(methylsulfonyl)-benzoate;
3-[3-ethyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-[3-propyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-[8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)benzoate;
3-[3-phenyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-[3-cyano-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(methylsulfonyl)-benzoate;
3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(dimethylsulfamoyl)-
benzoate;
3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 3-(ethylsulfonyl)-benzoate;
3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 2-methyl-5-(methylsulfonyl)-
benzoate;
3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 2-chloro-5-(methylsulfonyl)-
benzoate;
3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 4-(methylsulfonyl)-benzoate;
3-[3-methyl-8-(trifluoromethyl)quinolin-4-yl]phenyl 5-(dimethyl-sulfamoyl)-2-
methylbenzoate;
3-(8-chloro-3-phenylquinolin-4-yl)phenyl 3-(methylsulfonyl)benzoate;
3-(8-chloro-3-phenylquinolin-4-yl)phenyl 3-(ethylsulfonyl)benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 3-(dimethylsulfamoyl)-benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 4-(dimethylsulfamoyl)-benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 3-[(methylsulfonyl)methyl]-benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 3-(methylsulfamoyl)-benzoate;
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 3-(morpholin-4-ylsulfonyl)-benzoate;
and
3-(8-chloro-3-isopropylquinolin-4-yl)phenyl 2-methyl-5-(morpholin-4-yl-sulfonyl)-
benzoate; or
a pharmaceutically accetable salt thereof.
23. A pharmaceutical composition comprising a compound of any one of
claims 1 to 22 or a pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier.
24. A method of treating a skin disorder in a patient, comprising administering
to a patient in need thereof a compound of any one of claims 1 to 22 or a
pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 23.
25. The method of claim 24, wherein the skin disorder is selected from the
group consisting of psoriasis, atopic dermatitis, skin wounds, skin aging, photoaging
and wrinkling.
26. The method of claim 24, wherein the treatment of a skin disorder further
comprises administering an additional therapeutic agent.