Note: Descriptions are shown in the official language in which they were submitted.
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SUBSTITUTED BIARYL ETHER COMPOUNDS
FIELD OF THE INVENTION
The present invention relates to methods for treating hair loss in mammals,
including
arresting and / or reversing hair loss and promoting hair growth.
BACKGROUND OF THE INVENTION
Hair loss is a common problem which occurs, for example, through natural
processes or
is often chemically promoted through the use of certain therapeutic drugs
designed to alleviate
conditions such as cancer. Often such hair loss is accompanied by lack of hair
regrowth which
causes partial or full baldness.
As is well-known in the art, hair growth occurs by a cycle of activity which
involves
alternating periods of growth and rest. This cycle is often divided into three
main stages which
are known as anagen, catagen, and telogen. Anagen is the growth phase of the
cycle and may be
characterized by penetration of the hair follicle deep into the dermis with
rapid proliferation of
cells which are differentiating to form hair. The next phase is catagen, which
is a transitional
stage marked by the cessation of cell division, and during which the hair
follicle regresses
through the dermis and hair growth is ceased. The next phase, telogen, is
often characterized as
the resting stage during which the regressed follicle contains a germ with
tightly packed dermal
papilla cells. At telogen, the initiation of a new anagen phase is caused by
rapid cell
proliferation in the germ, expansion of the dermal papilla, and elaboration of
basement
membrane components. Wherein hair growth ceases, most of the hair follicles
reside in telogen
and anagen is not engaged, thus causing the onset of full or partial baldness.
There have been many attempts in the literature to invoke the regrowth of hair
by, for
example, the promotion or prolongation of anagen. Currently, there are two
drugs approved by
the United States Food and Drug Administration for the treatment of male
pattern baldness:
topical minoxidil (marketed as Rogaine~ by Pharmacia & Upjohn), and oral
fmasteride
(marketed as Propecia by Merck & Co., Inc.). For several reasons, however,
including safety
concerns and / or lack of efficacy, the search for efficacious hair growth
inducers is ongoing.
Interestingly, it is known that the thyroid hormone known as thyroxine ("T4")
converts
to thyronine ("T3") in human skin by deiodinase I, a selenoprotein. Selenium
deficiency causes
a decrease in T3 levels due to a decrease in deiodinase I activity; this
reduction in T3 levels is
strongly associated with hair loss. Consistent with this observation, hair
growth is a reported
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side effect of administration of T4. See, e.~., Berman, "Peripheral Effects of
L-Thyroxine on
Hair Growth and Coloration in Cattle", Journal of Endocrinology, Vol. 20, pp.
282 - 292 (1960);
and Gunaratnam, "The Effects of Thyroxine on Hair Growth in the Dog", J. Small
Anim. Pract.,
Vol. 27, pp. 17 - 29 (1986). Furthermore, T3 and T4 have been the subject of
several patent
publications relating to treatment of hair loss. See e. ., Fischer et al., DE
1,617,477, published
January 8, 1970; Mortimer, GB 2,138,286, published October 24, 1984; and
Lindenbaum, WO
96/25943, assigned to Life Medical Sciences, Inc., published August 29, 1996.
Unfortunately, however, administration of T3 and / or T4 to treat hair loss is
not
practicable because these thyroid hormones are also known to induce
significant cardiotoxicity.
See, e.~., Walker et al., U.S. Patent No. 5,284,971, assigned to Syntex,
issued February 8, 1994
and Emmett et al., U.S. Patent No. 5,061,798, assigned to Smith Kline & French
Laboratories,
issued October 29, 1991. Surprisingly, the present inventors have discovered
compounds which
strongly initiate hair growth without inducing cardiotoxicity. Consistent with
this discovery, but
without intending to be limited by theory, the present inventors have
surprisingly discovered that
the preferred compounds of the present invention interact strongly with hair-
selective thyroid
hormone receptors but interact less strongly, or not at all, with heart-
selective hormone
receptors. These unique properties are, of course, not shared with T3 and / or
T4. Accordingly,
the compounds and compositions herein are useful for treating hair loss,
including arresting and
/ or reversing hair loss and promoting hair growth.
SUMMARY OF THE INVENTION
The present invention relates to compounds and compositions which are
particularly
useful for treating hair loss in mammals, including arresting and / or
reversing hair loss and
promoting hair growth.
The compounds of the present invention have the structure:
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R3
O
R2 / Ra
Rt \ Rs
O
Rs ~ ~ Rto
R~ Y-X, ~Rt2
Rt t
and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides,
esters, and imides
thereof, wherein R~, R2, R3, R4, R5, R~, R8, R9, R,o, Y, X, R", and R~2 are
defined herein.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds and compositions which are
particularly
useful for treating hair loss in mammals, including arresting and / or
reversing hair loss and
promoting hair growth.
In addition to discovering that the present compounds are useful for treating
hair loss,
the present inventors have also surprisingly discovered that the preferred
compounds of the
present invention are cardiac-sparing.
Publications and patents are referred to throughout this disclosure. All
references cited
herein are hereby incorporated by reference.
All percentages, ratios, and proportions used herein are by weight unless
otherwise
specified.
In the description of the invention various embodiments and/or individual
features are
disclosed. As will be apparent to the ordinarily skilled practitioner all
combinations of such
embodiments and features are possible and can result in preferred executions
of the invention.
As used herein, wherein any variable, moiety, group, or the like occurs more
than one
time in any variable or structure, its definition at each occurrence is
independent of its definition
at every other occurrence.
Definition and Usage of Terms
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The following is a list of definitions for terms used herein:
As used herein "salt" is a cationic salt formed at any acidic (e.g., carboxyl)
group, or an
anionic salt formed at any basic (e.g., amino) group. Many such salts are
known in the art.
Preferred cationic salts include the alkali metal salts (such as, for example,
sodium and
potassium), alkaline earth metal salts (such as, for example, magnesium and
calcium), and
organic salts. Preferred anionic salts include the halides (such as, for
example, chloride salts).
Such acceptable salts must, when administered, be appropriate for mammalian
use.
As used herein, "alkenyl" is an unsubstituted or substituted hydrocarbon chain
radical
having from 2 to about 15 carbon atoms; preferably from 2 to about 10 carbon
atoms; more
preferably from 2 to about 8 carbon atoms, and most preferably from about 2 to
about 6 carbon
atoms. Alkenyls have at least one olefmic double bond. Non-limiting examples
of alkenyls
include vinyl, allyl, and butenyl.
As used herein, "alkoxy" is an oxygen radical having an alkyl, alkenyl, or
alkynyl,
preferably an alkyl or alkenyl, and most preferably an alkyl substituent.
Examples of alkoxy
radicals include -O-alkyl and -O-alkenyl. An alkoxy radical may be substituted
or unsubstituted.
As used herein, "aryloxy" is an oxygen radical having an aryl substituent. An
aryloxy
radical may be substituted or unsubstituted.
As used herein, "alkyl" is an unsubstituted or substituted saturated
hydrocarbon chain
radical having from 1 to about I S carbon atoms; preferably from 1 to about 10
carbon atoms;
more preferably from I to about 6 carbon atoms; and most preferably from 1 to
about 4 carbon
atoms. Preferred alkyls include, for example, methyl, ethyl, propyl, iso-
propyl, and butyl.
As used herein, "alkylene" refers to an alkyl, alkenyl, or alkynyl which is a
diradical.
For example, "methylene" is -CH2-. Alkylenes may be substituted or
unsubstituted.
As used herein, "alkynyl" is an unsubstituted or substituted hydrocarbon chain
radical
having from 2 to about 15 carbon atoms; preferably from 2 to about 10 carbon
atoms; more
preferably from 2 to about 8 carbon atoms, and most preferably from about 2 to
about 6 carbon
atoms. Alkynyls have at least one triple bond.
As used herein, "aryl" is an aromatic ring radical which is either carbocyclic
or
heterocyclic. Preferred aryl groups include, for example, phenyl, benzyl,
tolyl, xylyl, cumenyl,
napthyl, biphenyl, thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl,
pyrimidinyl,
quinolinyl, triazolyl, tetrazolyl, benzothiazolyl, benzofuryl, indolyl,
indenyl, azulenyl, fluorenyl,
anthracenyl, oxazolyl, isoxazolyl, isotriazolyl, imidazolyl, pyraxolyl,
oxadiazolyl, indolizinyl,
indolyl, isoindolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,
cinnolinyl, and the like.
Aryls may be substituted or unsubstituted.
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As used herein, "arylalkenyl" is an alkenyl radical substituted with an aryl
group or an
aryl radical substituted with an alkenyl group. Arylalkenyls may be
substituted or unsubstituted.
As used herein, "arylalkyl" is an alkyl radical substituted with an aryl group
or an aryl
radical substituted with an alkyl group. Preferred arylalkyl groups include
benzyl, phenylethyl,
and phenylpropyl. Arylalkyls may be substituted or unsubstituted.
As used herein, "biohydrolyzable amides" are amides of the compounds of the
present
invention which do not interfere with the activity of the compound, or that
are readily converted
in vivo by a mammalian subject to yield an active compound.
As used herein, "biohydrolyzable esters" are esters of the compounds of the
present
invention which do not interfere with the activity of the compound, or that
are readily converted
in vivo by a mammalian subject to yield an active compound.
As used herein, "biohydrolyzable imides" are imides of the compounds of the
present
invention which do not interfere with the activity of the compound, or that
are readily converted
in vivo by a mammalian subject to yield an active compound.
As used herein, "carbocyclic ring", "carbocycle", or the like is a hydrocarbon
ring
radical. Carbocyclic rings are monocyclic or are fused, bridged, or spiro
polycyclic rings.
Unless otherwise specified, monocyclic rings contain from 3 to about 9 atoms,
preferably from
about 4 to about 7 atoms, and most preferably 5 or 6 atoms. Polycyclic rings
contain from about
7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most
preferably 9 or 10
atoms. Carbocyclic rings (carbocycles) may be substituted or unsubstituted.
As used herein, "cycloalkyl" is a saturated carbocyclic or heterocyclic ring
radical.
Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopentyl, and
cyclohexyl.
Cycloalkyls may be substituted or unsubstituted.
As used herein, "cycloalkenyl" is an unsaturated carbocyclic or heterocyclic
ring radical
having at least one double bond. Cycloalkenyls may be substituted or
unsubstituted.
As used herein, preferred "halogens" (or "halos" or the like) are bromine,
chlorine,
iodine, and fluorine, more preferably, bromine, chlorine, and iodine, even
more preferably
bromine and chlorine, and most preferably chlorine.
As used herein, "heteroalkenyl" is an alkenyl radical comprised of carbon
atoms and one
or more heteroatoms wherein the heteroatoms are selected from the group
consisting of oxygen,
sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and
nitrogen.
Heteroalkenyls may be substituted or unsubstituted.
As used herein, "heteroalkyl" is an alkyl radical comprised of carbon atoms
and one or
more heteroatoms wherein the heteroatoms are selected from the group
consisting of oxygen,
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sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and
nitrogen. Heteroalkyls
may be substituted or unsubstituted.
As used herein, "heteroalkynyl" is an alkynyl radical comprised of carbon
atoms and one
or more heteroatoms wherein the heteroatoms are selected from the group
consisting of oxygen,
sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and
nitrogen.
Heteroalkynyls may be substituted or unsubstituted.
As used herein, "heteroaryl" is an aryl radical comprised of carbon atoms and
one or
more heteroatoms wherein the heteroatoms are selected from the group
consisting of oxygen,
sulfur, nitrogen, and phosphorous, more preferably, oxygen, sulfur, and
nitrogen. Heteroaryls
may be substituted or unsubstituted.
As used herein, "heteroarylalkenyl" is an arylalkenyl radical wherein the aryl
group and
/ or the alkenyl group is comprised of carbon atoms and one or more
heteroatoms wherein the
heteroatoms are selected from the group consisting of oxygen, sulfur,
nitrogen, and phosphorous,
more preferably, oxygen, sulfur, and nitrogen. Heteroarylalkenyls may be
substituted or
unsubstituted.
As used herein, "heteroarylalkyl" is an arylalkyl radical wherein the aryl
group and / or
the alkyl group is comprised of carbon atoms and one or more heteroatoms
wherein the
heteroatoms are selected from the group consisting of oxygen, sulfur,
nitrogen, and phosphorous,
more preferably, oxygen, sulfur, and nitrogen. Heteroarylalkyls may be
substituted or
unsubstituted.
As used herein, "heterocyclic ring", "heterocycle", or the like is a ring
radical comprised
of carbon atoms and one or more heteroatoms in the ring wherein the
heteroatoms are selected
from the group consisting of oxygen, sulfur, nitrogen, and phosphorous, more
preferably,
oxygen, sulfur, and nitrogen. Heterocycles are monocyclic or are fused,
bridged, or spiro
polycyclic rings. Unless otherwise specified, monocycles contain from 3 to
about 9 atoms,
preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms.
Polycycles contain
from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and
most preferably
9 or 10 atoms. Heterocyclic rings (heterocycles) may be substituted or
unsubstituted.
As used herein, "heterocycloalkyl" is a cycloalkyl having at least one
heteroatom in the
ring. Heterocycloalkyls may be substituted or unsubstituted.
As used herein, "heterocycloalkenyl" is a cycloalkenyl having at least one
heteroatom in
the ring. Heterocycloalkyls may be substituted or unsubstituted.
As used herein, a "lower" moiety (e.g., "lower" alkyl) is moiety having 1 to
about 6,
preferably 1 to about 4, carbon atoms.
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As used herein, "pharmaceutically acceptable" means suitable for use in a
human or
other mammal.
As used herein, "safe and effective amount of a compound" (or composition, or
the like)
means an amount that is effective to exhibit biological activity, preferably
wherein the biological
activity is arresting and / or reversing hair loss or promoting hair growth,
at the sites) of activity
in a mammalian subject, without undue adverse side effects (such as toxicity,
irntation, or
allergic response), commensurate with a reasonable benefit / risk ratio when
used in the manner
of this invention.
As used herein unless otherwise specified, the term "substituted" in reference
to a group,
moiety, or the like, means having one or more substituent groups each
independently selected
from hydrogen, alkyl, alkenyl, alkoxy, hydroxy, nitro, amino, alkylamino,
cyano, halo, thiol,
aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl,
morpholinyl, pyrrolidinyl),
imino, hydroxyalkyl, aryloxy, and arylalkyl, preferably hydrogen, alkyl,
alkenyl, alkoxy,
hydroxy, nitro, amino, alkylamino, halo, thiol, and aryloxy, more preferably
hydrogen, alkyl,
alkenyl, alkoxy, hydroxy, nitro, amino, alkylamino, and halo, even more
preferably hydrogen,
alkyl, and alkoxy, and most preferably alkoxy.
Compounds of the Present Invention
The compounds of the present invention have the structure:
R3
O
Rz / R4
Rt RS
O
Ra ~ ~ Rto
R7 Y-X ~Rtz
' Rt t
and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides,
esters, and imides
thereof, wherein:
(a) R,, RZ, R5, R,, and Rio are each, independently, selected from the group
consisting of
hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and
heteroalkynyl;
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(b) R4 is selected from the group consisting of halogen, alkyl, alkenyl,
alkynyl,
cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl,
heteroalkynyl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and
heteroarylalkenyl; wherein when R~ is hydrogen, Y is -CHZCHK,, X is selected
from
the group consisting of -NZ- and -NH-, and R~2 is C~ - C4 alkyl, wherein K~ is
selected from hydrogen and C~ - C4 alkyl and Z is C~ - C4 alkyl, then R4 is
not
arylalkyl;
(c) Rg and R9 are each, independently, selected from the group consisting of
hydrogen,
halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,
heterocycloalkenyl,
heteroaryl, heteroarylalkyl, and heteroarylalkenyl; wherein at least one of Rg
and R9
is not hydrogen;
(d) R3 is selected from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl,
cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl,
heteroalkynyl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl and
heteroarylalkenyl;
(e) Y is selected from the group consisting of bond, alkyl, alkenyl, alkynyl,
heteroalkyl,
heteroalkenyl, and heteroalkynyl;
(f) X is selected from the group consisting of -NZ-, -NH-, and -O-;
(g) R" is selected from the group consisting of bond and -C(O)-; wherein when
Y is
bond and X is -O- then R" is -C(O)-; and wherein when Y is alkyl and X is -O-
then
R, ~ is not -C(O)-;
(h) R,2 is selected from the group consisting of alkyl, alkenyl, alkynyl,
heteroalkyl,
heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,
heterocycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and
heteroarylalkenyl; or wherein when R" is bond, then R,~ and Z may be
optionally
bonded together to form a cycle selected from the group consisting of
cycloalkyl,
cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl;
wherein
when R,Z is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, then a
heteroatom of RIB is not directly covalently bonded to R"; wherein when Y is
bond
or hydroxy-substituted ethyl, X is -NH-, and R,~ is bond, then R,~ is not
methyl; and
wherein when Y is bond, X is -O-, and R" is -C(O)- then R,~ is not aryl; and
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(i) Z is selected from the group consisting of alkyl, alkenyl, alkynyl,
heteroalkyl,
heteroalkenyl, and heteroalkynyl; or wherein when R" is bond, then R~2 and Z
may
be optionally bonded together to form a cycle selected from the group
consisting of
cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and
heteroaryl.
The present compounds are substituted biphenyl ether compounds. The
substituents are
described in further detail below.
The Substituents R~, R, RS R~, and R,o
The substituents R~, Rz, R5, R7, and R,o each substitute on one of the phenyl
rings of the
structure shown herein. R,, RZ, R5, R~, and R,o are each, independently,
selected from hydrogen,
halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and
heteroalkynyl.
R,, RZ, R5, R,, and R,o are preferably each, independently, selected from
hydrogen,
halogen, alkyl, alkenyl, heteroalkyl, and heteroalkenyl. R,, Rz, R5, R~, and
R,o are more
preferably each, independently, selected from hydrogen, halogen, and lower
alkyl. Most
preferably, R~, R2, R5, R~, and R,o are each hydrogen.
The Substituent R4
The substituent R4 is selected from halogen, alkyl, alkenyl, alkynyl,
cycloalkyl,
cycloalkenyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl,
heterocycloalkyl,
heterocycloalkenyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl;
wherein when RZ is
hydrogen, Y is -CHZCHK,, X is selected from the group consisting of -NZ- and -
NH-, and R,~ is
C, - C4 alkyl, wherein K, is selected from hydrogen and C, - C4 alkyl and Z is
C, - C4 alkyl, then
R4 is not arylalkyl.
R4 is preferably selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl,
aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl,
heteroarylalkyl, and heteroarylalkenyl. R4 is more preferably selected from
halogen, alkyl,
alkenyl, heteroalkyl, and heteroalkenyl. R4 is even more preferably selected
from halogen, alkyl,
alkenyl, and heteroalkyl. R4 is most preferably selected from halogen and
lower alkyl. The most
preferred halogens for R4 are chlorine, bromine, and iodine, preferably
chlorine and iodine, and
most preferably iodine. The most preferred lower alkyls for R4 are methyl,
ethyl, iso-propyl, and
tert-butyl, preferably methyl, iso-propyl, and tert-butyl, more preferably iso-
propyl or tent-butyl.
Most preferably, R4 is lower alkyl, particularly iso-propyl or tert-butyl.
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The Substituents R8 and R9
R8 and R9 are each, independently, selected from hydrogen, halogen, alkyl,
alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroalkyl,
heteroalkenyl, heteroalkynyl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, heteroarylalkyl, and
heteroarylalkenyl; wherein
at least one of Rg and R9 is not hydrogen. Preferably, each of R8 and R9 are
not hydrogen.
R8 and R9 are preferably each, independently, selected from halogen, alkyl,
alkenyl,
heteroalkyl, and heteroalkenyl. R8 and R9 are more preferably each,
independently, selected
from halogen, alkyl, alkenyl, and heteroalkyl. R8 and R9 are even more
preferably each,
independently, selected from halogen and lower alkyl. The most preferred
halogens for Rg and
R9 are chlorine and bromine, preferably chlorine. The most preferred lower
alkyls for R8 and R9
are methyl, ethyl, iso-propyl, and tent-butyl, preferably methyl, iso-propyl,
and tert-butyl, more
preferably methyl and iso-propyl. Most preferably, R8 and R9 are each,
independently, selected
from lower alkyl and halogen, particularly methyl and chlorine, respectively.
The Substituent R
R3 substitutes on the oxygen moiety of the biphenyl structure as shown above.
R3 is
selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
aryl, arylalkyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl,
heteroarylalkyl and heteroarylalkenyl. Preferably, R3 is selected from
hydrogen, alkyl, alkenyl,
cycloalkyl, aryl, arylalkyl, heteroalkyl, heteroalkenyl, heterocycloalkyl,
heteroaryl, and
heteroarylalkyl. More preferably, R3 is selected from hydrogen, alkyl,
alkenyl, aryl, arylalkyl,
heteroalkyl, heteroaryl, and heteroarylalkyl. Still more preferably, R3 is
selected from hydrogen,
alkyl, alkenyl, arylalkyl (preferably benzyl), heteroalkyl, and
heteroarylalkyl. Even more
preferably, R3 is selected from hydrogen, lower alkyl, and lower alkenyl. Most
preferably, R3 is
selected from hydrogen and lower alkyl. The most preferred lower alkyl for R3
is methyl.
The Substituent Y
Y is selected from bond, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
and
heteroalkynyl. Wherein Y is bond, X is directly bonded to the phenyl ring
bearing R7, R8, R9,
and R,o. Y is preferably selected from bond, alkyl, alkenyl, heteroalkyl, and
heteroalkenyl.
More preferably, Y is selected from bond and lower alkyl. Most preferably, Y
is bond.
The Substituent X
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X is selected from -NZ-, -NH-, and -O-. Z substitutes on the nitrogen of -NZ-
and is
selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and
heteroalkynyl; or wherein
when R" is bond, then R~2 and Z may be optionally bonded together to form a
cycle selected
from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and
heteroaryl.
Preferably, Z is selected from alkyl, alkenyl, heteroalkyl, and heteroalkenyl,
or R,2 and Z are
bonded together to form a cycle selected from cycloalkyl, cycloalkenyl,
heterocycloalkyl,
heterocycloalkenyl, aryl, and heteroaryl. More preferably, Z is lower alkyl,
or R,z and Z are
bonded together to form a cycle selected cycloalkyl, cycloalkenyl,
heterocycloalkyl,
heterocycloalkenyl, aryl, and heteroaryl. Most preferably, Z is C, - C3 alkyl,
particularly methyl,
or R,z and Z are bonded together to form a cycle selected from cycloalkyl,
cycloalkenyl,
heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.
Preferably, X is selected from -NH- and -NZ-. Most preferably, X is -NH-, -
N(CH3)-, or
-NZ- wherein R,2 and Z are bonded together to form a cycle selected from
cycloalkyl,
cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.
Wherein R,z is bonded to Z to form a cycle, the cycle is preferably selected
from
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, more preferably from
cycloalkyl,
heterocycloalkyl, and aryl, even more preferably from cycloalkyl and
heterocycloalkyl, and most
preferably heterocycloalkyl. In addition to the optional substituents
described herein above, the
cycle may also optionally bear one or more oxo (i.e., doubly bonded oxygen)
substituents. Non-
limiting examples of these cycles include piperidinyl, morpholinyl,
piperazinyl, pyrrolidinyl,
indolinyl, succinimidyl, and hydantoinyl.
The Substituent R"
R" is selected from bond and -C(O)-. However, wherein when Y is bond and X is -
O-
then R" is -C(O)-; and wherein Y is alkyl and X is -O- then R" is not -C(O)-
(but rather is
bond).
Wherein X is selected from -NZ- and -NH-, then both bond and -C(O)- are highly
preferred for R", but most preferably, R" is -C(O)-. Wherein X is -O-, R" is
most preferably -
C(O)-.
The Substituent R,Z
R,, is selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl,
cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl,
arylalkyl, heteroaryl,
heteroarylalkyl, and heteroarylalkenyl; or wherein when R" is bond, then R,Z
and Z may be
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optionally bonded together to form a cycle selected from the group consisting
of cycloalkyl,
cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl;
wherein when R~2 is
heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl,
heteroarylalkyl, or heteroarylalkenyl, then a heteroatom of R,Z is not
directly covalently bonded
to R". Accordingly, carbamates and ureas at the -Y-X-R»-R,2 linkage are not
contemplated
within the present invention. For example, wherein R,z is heteroalkyl, it is
not, e.g., -O-CHZ-
CH3, but could be, e.g., -CHz-O-CH3.
Furthermore, wherein Y is bond or hydroxy-substituted ethyl (i.e., -CHOHCHZ-),
X is
NH-, and R" is bond, then R,2 is not methyl. More preferably, wherein Y is
bond or alkyl, X is -
NH-, and R" is bond, then R,2 is not methyl. Also, wherein Y is bond, X is -O-
, and R~, is
C(O)- then R,~ is not aryl.
Preferably, R,~ is selected from alkyl, alkenyl, heteroalkyl, heteroalkenyl,
cycloalkyl,
cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl,
and heteroarylalkenyl, or is bonded to Z to form a cycle selected from
cycloalkyl, cycloalkenyl,
heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. More preferably,
R~z is selected from
alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, and
heteroarylalkenyl, or is bonded to Z to form a cycle selected from cycloalkyl,
cycloalkenyl,
heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. Even more
preferably, R~z is selected
from alkyl, heteroalkyl, arylalkyl, and heteroarylalkyl, or is bonded to Z to
form a cycle selected
from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and
heteroaryl. Most
preferably, R,2 is lower alkyl, or is bonded to Z to form a cycle selected
from cycloalkyl,
cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. The
most preferred
lower alkyls for R,~ are methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-
butyl, and n-pentyl,
particularly methyl, n-propyl, iso-propyl, n-butyl, and tert-butyl.
Wherein R,z is bonded to Z to form a cycle, the cycle is preferably selected
from
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, more preferably from
cycloalkyl,
heterocycloalkyl, and aryl, even more preferably from cycloalkyl and
heterocycloalkyl, and most
preferably heterocycloalkyl. In addition to the optional substituents
described herein above, the
cycle may also optionally bear one or more oxo (i.e., doubly bonded oxygen)
substituents. Non-
limiting examples of these cycles include piperidinyl, morpholinyl,
piperazinyl, pyrrolidinyl,
indolinyl, succinimidyl, and hydantoinyl.
Preferred compounds of the present invention are set forth in the following
tables:
W~ 00/72920 CA 02375822 2001-11-29 pCT~S00/05251
13
Table 1 - Preferred Compounds of the Present Invention
O O
/ ~ / _
\ \
O / p O / ( O
\ ~ N~ \ N
I I
H H
O O
/
\ \
O / I O O
/ O
N ~ N
I I
H H
OH O/
C1
O
/ I O O
N II / I O
I Cl \ N'
H I
H
O O
/ _ /
C1 \ Cl
O / I O O
/ I O
Cl \ N' v \ \ N
H H
WO 00/72920 CA 02375822 2001-11-29 pCT/US00/05251
14
O~
0
C1
i
O / O
0 ~ ~
o C1 \ N~
I
H
H
_O
\ \ /
/
O / O
/ O
\ N~ \I
N
V p H
O/ OH
/ /
I \I
p O / I O
/ I O
\ \ N
N ~ I
I H
H
O
/ w /
I \I
O O /
/ p I
\ I N ~ \ N~
H ~~ H
WU 00/72920 CA 02375822 2001-11-29 pCT/[JS00/0$2$1
/ OH
O
/ _
/ ~ I
I \
O
O / I O
I \ N
\ N~ I
H
O/ OH
_ /
/ I
I \
O / O /
N~ \ N~
I
OH Oi
/
\I I
O / O
I /
\ N~ \ I N
I
O O
/ _ /
I
\ \
C1
O / O /
I I
\ N~ C1 \ N
I
Analytical Methods
The present invention relates to compounds and methods for treating hair loss.
Preferably, the compound utilized in the present invention will be cardiac-
sparing. Compounds
(test compounds) may be tested for their ability to induce anagen and their
lack of cardiotoxicity
(cardiac-sparing) using the following methods. Alternatively, other methods
well-known in the
WO 00/72920 CA 02375822 2001-11-29 PCT/US00/05251
16
art may be used (but with the term "cardiac-sparing" being defined according
to the method
disclosed herein below).
Cardiotoxicity Assay:
The cardiotoxicity assay measures the potential of a test compound to
adversely affect
the cardiovascular system. As thyroid hormone (T3) damages the cardiovascular
system, the
heart enlarges. See, e.g., Gomber~-Maitland et al., "Thyroid hormone and
Cardiovascular
Disease", American Heart Journal, Vol. 135(2), pp. 187-196 (1998); Klein and
Ojamaa,
"Thyroid Hormone and the Cardiovascular System", Current Opinion in
Endocrinology and
Diabetes, Vol. 4, pp.341-346 (1997); and Klemperer et al., "Thyroid Hormone
Therapy and
Cardiovascular Disease", Progress in Cardiovascular Diseases, Vol. 37 (4), pp.
329-336 (1996).
This increases the weight of the heart relative to whole body weight. The
cardiotoxicity assay
herein below is used to test compounds for potentially adverse cardiac effects
by measuring their
effect on the heart-to-body weight ratio.
Two groups each of six male Sprague Dawley rats (Harlan Sprague Dawley, Inc.,
Indianapolis, IN) (each weighing from approximately 220 grams to 235 grams)
are utilized. The
first group is a vehicle control group and the second group is a test compound
group. The length
of the assay is 30 days, with treatment of vehicle or test compound in vehicle
daily for 28 of
those days as described below.
Prior to initiation of the assay, each rat is allowed to acclimate to standard
environmental conditions for 5 days. Each rat receives food (standard rat chow
diet) and water
ad libitum 5 days prior to initiation of the assay as well as to termination
of the study.
The vehicle is 91:9 (v:v) propylene glycol:ethanol. The test compound is
prepared at a
concentration of 500 ~g/mL in the vehicle.
Each rat is weighed on day 1 of the assay. Dosage calculations are then
performed: each
rat will be administered daily a dosing solution of vehicle or test compound
in vehicle
(depending on whether the rat is in the vehicle control group or the test
compound group,
respectively) at S00 ~,L of dosing solution per kg of rat. For rats in the
test compound group,
this corresponds to a dose of 250 ~g of test compound per kg of rat.
Day 2 is the first day of treatment with dosing solution for both groups. Body
weights
are taken for each rat on days 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, and 29
prior to dosing for
that day; for each rat, the dosing solutions are recalculated and administered
accordingly upon
change in body weight.
WO 00/72920 CA 02375822 2001-11-29 pCT/[JS00/05251
17
Treatment occurs once daily in the morning on days 2 through 29, inclusive,
for each rat
in each group. For each treatment, the dosing solution is administered
subcutaneously between
the shoulders of the rat such that the injection sites are rotated in this
area.
On day 30 in the morning, the rats of each group are euthanized with CO~ from
dry ice.
Each rat is immediately weighed for total body weight.
The hearts of each rat are then excised as follows. An incision is made to
expose the
abdominal cavity. The rib cage is carefully cut at the sternum with small
scissors, such that the
heart and lungs are exposed. With small scissors and forceps, the vessels
connected to the heart
are cut away from the heart. These vessels include the caudal vena cava, left
cranial vena cava
(pulmonary trunk), right cranial vena cava, thoracic aorta, right subclavian
artery, internal
thoracic artery and vein, and any other small attachments. The heart is then
immediately taken
out intact, including the left and right auricles and left and right
ventricles. Immediately
thereafter, any excess tissue is trimmed away, the heart is lightly blotted on
a paper towel until
no more blood is visibly left behind on the paper towel, and the heart is
weighed.
The heart weight is divided by the body weight after euthanization for each
rat to give
the heart/body ratio. The heart/body ratios for each rat in the vehicle
control group are added
together and divided by 6 (i.e., the total number of rats in the group) to
give RV (ratio for
vehicle control group). Similarly, the heart/body ratios for each rat in the
test compound group
are added together and divided by 6 to give RT (ratio for test compound
group).
The index C is then calculated by dividing RT by RV. As defined herein, where
C is
less than 1.3, the test compound is cardiac-sparing. Preferably, C is less
than 1.2, more
preferably less than 1.15, and most preferably less than 1.l. In accordance
with this method, T3
and T4 are not cardiac-sparine.
Telo~en Conversion Assay:
The Telogen Conversion Assay measures the potential of a test compound to
convert
mice in the resting stage of the hair growth cycle ("telogen"), to the growth
stage of the hair
growth cycle ("anagen").
Without intending to be limited by theory, there are three principal phases of
the hair
growth cycle: anagen, catagen, and telogen. It is believed that there is a
longer telogen period in
C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, IN) from approximately 40
days of age
until about 75 days of age, when hair growth is synchronized. It is believed
that after 75 days of
age, hair growth is no longer synchronized. Wherein about 40 day-old mice with
dark fur
(brown or black) are used in hair growth experiments, melanogenesis occurs
along with hair
WO 00/72920 CA 02375822 2001-11-29 PCT/US00/0$251
)g
(fur) growth wherein the topical application of hair growth inducers are
evaluated. The Telogen
Conversion Assay herein below is used to screen compounds for potential hair
growth by
measuring melanogenesis.
Three groups of 44 day-old C3H mice are utilized: a vehicle control group and
a test
compound group, wherein the test compound group is administered a compound
according to the
present invention. The length of the assay is at least 19 days with 15
treatment days (wherein
the treatment days occur Mondays through Fridays). Day 1 is the first day of
treatment. Most
studies will end on Day 19, but a few may be carried out to Day 24 if the
melanogenesis
response looks positive, but occurs slowly. A typical study design is shown in
Table 2 below.
Typical dosage concentrations are set forth in Table 2, however the ordinarily
skilled artisan will
readily understand that such concentrations may be modified.
Table 2
Group Animal Compound Concentration ApplicationLength of
# #
volume Study
1 1 - 10 Test 0.1% in vehicle**400 ~L 19 or 24
days
Compound topical
2 11 - Positive 0.01% in vehicle**400 pL 19 or 24
20 days
Control topical
(T3)
3 21 - Vehicle** N/A 400 pL 19 or 24
30 days
topical
**The vehicle is 60% ethanol, 20% propylene glycol, and 20% dimethyl
isosorbide
(commercially available from Sigma Chemical Co., St. Louis, MO).
The mice are treated topically Monday through Friday on their lower back (base
of tail
to the lower rib). A pipettor and tip are used to deliver 400 p.L to each
mouse's back. The 400
p,L application is applied slowly while moving hair on the mouse to allow the
application to
reach the skin.
While each treatment is being applied to the mouse topically, a visual grade
of from 0 to
4 will be given to the skin color in the application area of each animal. As a
mouse converts
from telogen to anagen, its skin color will become more bluish-black. As
indicated in Table 3,
the grades 0 to 4 represent the following visual observations as the skin
progresses from white to
bluish-black.
Table 3
WO 00/72920 CA 02375822 2001-11-29 pCT/USOU/U5251
19
Visual Observation Grade
Whitish Skin Color 0
Skin is light gray (indication of initiation 1
of anagen)
Appearance of Blue Spots 2
Blue Spots are aggregating to form 3
one large blue area
Skin is dark blue (almost black) with 4
color covering
majority of treatment area (indication
of mouse in full
anagen)
Methods of Making
The compounds of the present invention are prepared according to methods which
are
well-known to those ordinarily skilled in the art. The starting materials used
in preparing the
compounds of the invention are known, made by known methods, or are
commercially available
as a starting material.
It is recognized that the ordinarily skilled artisan in the art of organic
chemistry can
readily carry out standard manipulations of organic compounds without further
direction.
Examples of such manipulations are discussed in standard texts such as J.
March, Advanced
panic Chemistry, John Wiley & Sons, 1992.
The ordinarily skilled artisan will readily appreciate that certain reactions
are best
carried out when other functionalities are masked or protected in the
compound, thus increasing
the yield of the reaction and / or avoiding any undesirable side reactions.
Often, the ordinarily
skilled artisan utilizes protecting groups to accomplish such increased yields
or to avoid the
undesired reactions. These reactions are found in the literature and are also
well within the
scope of the ordinarily skilled artisan. Examples of many such manipulations
can be found in,
for example, T. Greene, Protecting~Groups in Organic Synthesis, John Wiley &
Sons, 1981.
The compounds of the present invention may have one or more chiral center. As
a
result, one may selectively prepare one optical isomer, including
diastereomers and enantiomers,
over another, for example by chiral starting materials, catalysts or solvents,
or may prepare both
stereoisomers or both optical isomers, including diastereomers and enantiomers
at once (a
racemic mixture). Since the compounds of the invention may exist as racemic
mixtures,
mixtures of optical isomers, including diastereomers and enantiomers, or
stereoisomers may be
separated using known methods, such as through the use of, for example, chiral
salts and chiral
chromatography.
WO 00/72920 CA 02375822 2001-11-29 pCT~S00/05251
In addition, it is recognized that one optical isomer, including a
diastereomer and
enantiomer, or a stereoisomer, may have favorable properties over the other.
Thus, when
disclosing and claiming the invention, when one racemic mixture is disclosed,
it is clearly
contemplated that both optical isomers, including diastereomers and
enantiomers, or
stereoisomers substantially free of the other are disclosed and claimed as
well.
The compounds of the present invention may be prepared using a variety of
procedures
known to those ordinarily skilled in the art. Non-limiting general
preparations include the
following.
The compounds of the invention may be prepared, after removal of temporary
protection
groups (see~e.~., T. Greene, Protecting Groins in Or aQ nic Synthesis, John
Wiley & Sons, 1981),
by condensing (e.g., acylating or alkylating) a compound of the structure:
R3 R4
O ~ Rs Rg Rlo
XH
y
R2 ~ _ O (I)
RI
Rg R~
wherein R~, RZ, R3, R4, R5, R,, R8, R9, R,o, Y and X are defined herein above
and are in an
appropriately protected form if necessary, with a reactive derivative of the
structure:
O
~ (II)
HO' _ R
12
HO' R12 (III)
or
Q~ R12 (IV)
wherein R,~ is defined herein above and is in an appropriately protected form
if necessary and Q
is halogen, preferably bromine or iodine, and most preferably iodine. Reactive
derivatives of
structure II include activated esters such as, for example, 1-
hydroxybenzotriazole esters, mixed
WO 00/72920 CA 02375822 2001-11-29 pCT~S00/05251
21
anhydrides with organic or inorganic acids such as hydrochloric acid and
sulfonic acids, and
symmetrical anhydrides of the acids of structure II. Activated derivatives of
structure III include
trifluromethane sulfonyl esters and other activated derivatives known to those
ordinarily skilled
in the art. Compounds of structure IV are generally appropriately reactive
without further
modification; however, it may be necessary to convert a less reactive halogen
to a more reactive
halogen such as bromine or iodine as is known by those ordinarily skilled in
the art. Many
appropriately activated derivatives of structures II, III, or IV are
commercially available and
others may be prepared by methods known to those ordinarily skilled in the
art. Non-limiting
examples of condensations of this type are provided in Examples 2, 3, 4, 8, 9,
10, 12, 13, 14, 16,
18, 19 herein and an example of the removal of a temporary protecting group is
provided in
Example 17.
Additionally, appropriately protected compounds resulting from the
condensation of a
compound of structure I with a compound of structure II, III, or IV may be
further modified to
afford additional compounds of the invention after removal of temporary
protection groups.
These modifications include, but are not limited to, reduction of an amide to
an amine as
described in Examples 7b and 15 to afford a secondary or tertiary amine,
alkylation of an amide
as described in Example 7a and alkylation of the aromatic rings using Friedel-
Crafts conditions
similar to those described in Example 10b.
Compounds of structure I may be prepared from a biaryl ether intermediate of
structure
V wherein P is an electron-withdrawing functionality, for example, a nitro,
cyano or acyl group.
Rz
(V)
Compounds of structure V can be prepared by conversion of an anisole of
structure VI
to a symmetrical bis-aryl iodonium salt as in Example 1b herein followed by
condensation in a
copper catalyzed reaction with a phenol of structure VI. Appropriately
substituted anisoles of
structure VI are commercially available or may be prepared from their
corresponding phenols as
described, for example, in Example 1 a herein, or may be synthesized using
methods known to
those ordinarily skilled in the art. Appropriately substituted phenols of
structure VII are
n8 ~7
W~ 00/72920 CA 02375822 2001-11-29
PCT/US00/05251
22
commercially available or may be prepared using methods known to those
ordinarily skilled in
the art
R3 R4
O ~ Rs
(VI)
R2 ~ H
R1
Ri o
Ho
(VII)
Rg R~
Alternatively, compounds of structure V may be prepared by condensing a 4-
halonitrobenzene of structure IX with an appropriately substituted phenol of
structure VIII in a
base catalyzed reaction as described in Examples 2a, 10a, and 11 a herein.
R3 R4
O ~ Rs
(VIII)
RZ ~ OH
R~
R9 R~ o
Q ~ ~ N02
(IX)
R8 R~
Compounds of structure V may be further modified wherein RZ and / or R4 is
hydrogen
by acylation under Friedel-Crafts conditions as described in Example 10c.
Compounds of the structure V can be converted to compounds of the structure I
by
further transformation. For example, wherein P is nitro, the resulting
compound of structure V
WO 00/72920 CA 02375822 2001-11-29 pCT/IJS00/05251
23
can be converted into a compound of structure I by reduction to the amine
using standard
chemical reactions utilizing, for example, palladium on carbon or tin
chloride. Wherein P is
acyl, such compounds may be converted to compounds of structure I using, for
example,
peracetic acid to convert the acetophenone to an acetyl ester. Alternatively,
the compounds of
structure I may be prepared by reductive alkylation of the ketone using a
primary or secondary
amine and a borohydride reducing reagent. Wherein P is cyano, such compounds
may be
converted a compound of structure I by reduction to an alkylamino compound
using conditions
known to those ordinarily skilled in the art.
For even further guidance, the following non-limiting examples illustrate more
specifically the methods of making various compounds of the present invention.
As used herein, the following abbreviations are used:
Trifluoroacetic acid TFA
Tetrah drofuran THF
N,N-dimeth lformamide DMF
N,N - diiso ro leth lamine i-Pr2NEt or i-Pr2EtN
N-tert-butoxycarbonyl ~ BOC
Example 1
OH ~O
\ \ \
/ /
la
\O
O
\ HO / \ \
/ ---~ /
/ ~ \ NOz
I+ 2 O / O /
1b \
\ NOZ NH2
lc 1d
la. 2-iso-propyl anisole: Potassium hydroxide (5.6 g) is added to 13.4 mL
acetone followed by
2-iso-propylphenol (13.6 g). After the potassium hydroxide is dissolved,
methyl iodide (14.2 g)
is added. The reaction is refluxed overnight. 150 mL of water is added. This
reaction is
extracted 3 times with 100 mL diethyl ether. The organic layer is extracted
twice with 100 mL
W~ 00/72920 CA 02375822 2001-11-29 pCT/US00/05251
24
10% sodium hydroxide in water, once with 100 mL water, and once with 100 mL
saturated
ammonium chloride. After drying over magnesium sulfate, the organic solution
is dried over
MgS04, filtered, and concentrated under reduced pressure. The material is
fractionally distilled
under reduced pressure to afford la.
1b. Bis(3-iso-propyl-4-methoxyphenyl)iodonium Tetrafluoroborate: Acetic
Anhydride, 7
mL, is cooled to -15 °C in a dry ice acetone bath. Fuming nitric (5.4
mL) is added dropwise.
Iodine (2.5 g) is added in one piece followed by dropwise addition of TFA (4.7
mL). After 20
minutes, the reaction is removed from the bath and stirred at room temperature
for 30 minutes.
After the iodine has dissolved, the reaction is sparged to remove nitrogen
oxides and then
concentrated under vacuum. The material is then taken up in 15 mL acetic
anhydride and cooled
to -10 °C. To this cooled solution is added dropwise a solution of 2-
iso-propyl anisole (la; 7.43
g) in 35 mL acetic anhydride and 5 mL TFA. The reaction is allowed to stand in
the refrigerator
overnight. After allowing the reaction to return to room temperature for 3
hours, the reaction is
concentrated under high vacuum. The residue is taken up in 25 mL methanol, 25
mL 10%
sodium bisulfite, and 188 mL 2M sodium tetrafluoroborate. The mixture is
stirred vigorously
for 30 minutes and the supernatant is decanted off. To the residue is added
200 mL hexane and
it is stirred for an additional 30 minutes. At that time, the solid is
collected, washed with
hexane, and dried under vacuum to afford 1b.
lc. 2',6'-dimethyl-3-iso-propyl-4-methoxy-4'-nitrodiphenyl ether: Bis(3-iso-
propyl-4-
methoxyphenyl)iodonium tetrafluoroborate (1b, 3 g), is weighed is taken up in
7.7 mL
dichloromethane and 0.5g copper bronze is added. The mixture is cooled in an
ice water bath.
A solution of 2,6-dimethyl-4-nitrophenol (0.65 g) and triethylamine (0.44 g),
in 5.2 mL
dichloromethane is added dropwise. The reaction is placed in the dark and
stirred for 5 days. At
this time, the reaction is filtered through celite and concentrated under
reduced pressure.
Purification of the product by chromatography over silica gel followed by
crystallization from
hexane:ethyl acetate affords lc.
1d. 2',6'-dimethyl-3-iso-propyl-4-methoxy-4'-aminodiphenyl ether: 2',6'-
dimethyl-3-iso-
propyl-4-methoxy-4'-nitrodiphenyl ether (lc, 5.25 g), is dissolved in 50 mL
ethanol and 7.5 mL
ethyl acetate and 0.75 mg of 10% palladium on carbon is added. The reaction is
hydrogenated
for 3 hours, then filtered through Celite and concentrated under reduced
pressure to provide the
desire amine 1d.
WO 00/72920 CA 02375822 2001-11-29 PCT/US00/05251
Example 2
Cl
\ + CI
C1 \ NOZ
OH
~O \O \O
\ \ \ \ \ \
C1 ~ ~ CI ---~ ~ Cl
O O O
O
Cl \ NOZ Cl \ NHZ Cl \ N ~~
2a 2b 2c H
2a. 2', 6'-dichloro-3-tert-butyl-4-methoxy-4'-nitrodiphenyl ether: Potassium
carbonate (67.5
g) is suspended in 1 liter of methylsulfoxide. 1,2,3-trichloro-5-nitrobenzene
(99 g), is added
followed by 2-tert-butyl-4-hydroxyanisole (80 g). The reaction is heated via a
heating mantle set
at 80 °C and stirred with a mechanical stirrer for 20 hours. The
reaction is allowed to cool to 40
°C and 2 liters of cold water is added while stirring. After stirring
for 2 hours the reaction
mixture is filtered through a medium porosity frit and the filter cake is
allowed to air dry for 17
hours followed drying by vacuum pump for 4 hours to afford 2a.
2b. 3,5-dichloro-4-(4'-methoxy-3'-tert-butylphenoxy)benzylamine: 2',6'-
dichloro-3-tert-
butyl-4-methoxy-4'-nitrodiphenyl ether (2a, 0.35 g), is dissolved in 5 mL of
49:1 ethanol:ethyl
acetate by heating on a water bath (40 °C) and to this solution, tin
chloride dihydrate (1.1 g) is
added. The reaction is heated to 70 °C and stirred for 1.5 hours. The
reaction is allowed to cool
to room temperature, then poured onto ice. The pH is made slightly basic (pH
about 7 - 8) by
addition of 5% aqueous sodium bicarbonate (50 mL) and then extracted with
ethyl acetate (50
mL). The organic phase is washed with brine (50 mL), treated with charcoal and
dried over
MgS04 and filtered. The filtrate is evaporated to provide 2b.
2c. N [3,5-dichloro-4-(4'-methoxy-3'-tert-butylphenoxy)phenyl]butyramide: 3,5-
dichloro
4-(4'-methoxy-3'-tert-butylphenoxy)benzylamine (2b, 0.24 g), is suspended in
pyridine (0.12
WO 00/72920 CA 02375822 2001-11-29 pCT~S00/05251
26
mL), and butyric anhydride (0.23 mL) is added. The reaction is allowed to
proceed for two
hours and then it is concentrated under reduced pressure. The resulting
residue is presorbed
onto silica gel using acetone and purified by chromatography on silica gel.
The product is
crystallized from hexanes to afford 2c.
Example 3
C1
\ HO
\ NOZ
1 b I+ 2
~O ~O ~O
\ \ \ \ \ \
C1 ~ C1 ~ C1
O ~ O ~ ~ O ~ ( O
\ N02 \ NH2 \ N ~~
3a 3b H
3a. 2'-chloro-4'-nitro-6'-methyl-3-iso-propyl-4-methoxydiphenyl ether: Bis(3-
iso-propyl-4-
methoxyphenyl)iodonium tetrafluoroborate (1b, 1.5 g), is taken up in 5 mL
dichloromethane.
Copper bronze (0.26 g) is added. The mixture is cooled in an ice water bath. A
solution of 2-
chloro-4-nitro-6 methylphenol (0.37 g) and triethylamine (0.43 g), in 5 mL
dichloromethane is
added dropwise. The reaction is placed in the dark and stirred for 5 days. At
this time, the
reaction is filtered through celite and concentrated under reduced pressure.
Purification of the
product by chromatography on silica gel affords 3a.
3b. N [3-chloro-5-methyl-4-(4'-methoxy-3'-iso-propylphenoxy)phenyl]butyramide:
2'-
chloro-4'-nitro-6'-methyl-3-iso-propyl-4-methoxydiphenyl ether (3a, 200 mg) is
dissolved in 15
mL ethanol and 30 mg of 10% palladium on carbon is added. The reaction is
hydrogenated for 3
hours, then filtered through Celite and concentrated under reduced pressure.
Butyric anhydride
(4 mL), is added to the residue and the reaction is stirred overnight. At this
time, 20 mL water
and 20 mL ethyl acetate are added and the reaction mixture is extracted with 1
N NaOH until the
pH of the aqueous layer is above 10. After extracting once with brine, drying
over magnesium
W~ 00/72920 CA 02375822 2001-11-29 pCT/US00/05251
27
sulfate and filtering, the organic layer is concentrated under reduced
pressure and purified by
chromatography on silica gel to afford 3b.
Example 4
\O \O
\ \ \ \
/ /
O / O / O
\ NHZ \ N
1d 4 H
4. N [3,5-dimethyl-4-(4'-methoxy-3'-iso-propylphenoxy)phenyl]butyramide:
Pyridine (4.3
mL) is added and 2',6'-dimethyl-3-iso-propyl-4-methoxy-4'-aminodiphenyl ether
(1d, 4.3 g) is
suspended therein. To this solution is added butyric anhydride (2.5 mL) and
the reaction is
stirred overnight. The sample is concentrated under reduced pressure and
dissolved in ethyl
acetate. This is extracted with 120 mL 0.15 N sodium hydroxide twice, washed
with water,
extracted twice with 150 mL 0.35 N hydrochloric acid, once with water and once
with brine.
The sample is dried over sodium sulfate and concentrated under reduced
pressure. The residue
is recrystallized from ethyl acetate:hexanes to afford amide 4.
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28
Example 5
\O OH
\ \ \
/ /
O / O O / O
\ N ~~ \ N ~~
4 H 5 H
5. N [3,5-dimethyl-4-(4'-hydroxy-3'-iso-propylphenoxy)phenyl]butyramide: N
[3,5-
dimethyl-4-(4'-methoxy-3'-iso-propylphenoxy)phenyl]butyramide) (Example 4, 0.5
g) is
dissolved in 5 mL dichloromethane and cooled in a dry ice/iso-propanol bath.
To this solution is
added dropwise 1 M boron tribromide (4.6 mL) in dichloromethane. After 30
minutes, the
reaction is poured over ice (10 g) and is stirred an additional 30 minutes. At
this time, 20 mL
brine is added and stirred 20 minutes. The organic phase is separated and
washed with brine.
The aqueous phase is extracted once with ethyl acetate (10 mL) then the ethyl
acetate layer is
extracted with brine. The organic phases are combined and dried over sodium
sulfate and
concentrated under reduced pressure. The product is purified by chromatography
on silica gel to
afford 5.
Example 6
OH ~ I ~O
\ ~ ~ \
/ /
O / O
O / ~ O
\ N~ ~ N
H 6 H
6. N [3,5-dimethyl-4-(4'-benzyloxy-3'-iso-propylphenoxy)phenyl]butyramide: N
[3,5-
dimethyl-4-(4'-hydroxy-3'-iso-propylphenoxy)phenyl]butyramide) (Example 5, 173
mg) is
dissolved in 5 mL acetone. To this solution is added 96 mg potassium carbonate
and 51
microliters benzyl bromide. The reaction is refluxed overnight. At this time,
it is filtered
W~ 00/72920 CA 02375822 2001-11-29 pCT~S00/05251
29
through celite and concentrated under reduced pressure. The product is
crystallized from
hexanes to afford 6.
Example 7
\O ~O ~O
\ \ \ \ \
/ -s / --s /
O
O / O / I O O /
\ ~ ~~ \ N ~ \
g 7a ~ 7b
7a. N methyl-N [3,5-dimethyl-4-(4'-methoxy-3'-iso-
propylphenoxy)phenyl]butyramide: In a dry flask under nitrogen, 0.34 g sodium
hydride is
suspended in 5 mL THF and stirred 10 minutes. To this solution is added
dropwise N [3,5-
dimethyl-4-(4'-methoxy-3'-iso-propylphenoxy)phenyl]butyramide) (Example 4, 1
g) in 5 mL
THF. The reaction is stirred for 15 minutes and methyl iodide, 0.3 mL is added
dropwise. After
2 hours, the reaction is poured into ice water and extracted with chloroform.
The organic layer
is washed once with water, once with brine then dried over magnesium sulfate
and concentrated
under reduced pressure. The product is purified by chromatography on silica
gel to afford 7a.
7b. N methyl-N [3,5-dimethyl-4-(4'-methoxy-3'-iso-
propylphenoxy)phenyl]butylamine:
In a dry flask under nitrogen is placed lithium aluminum hydride (1.1 g). To
this solid is added
30 mL THF dropwise. After stirring 10 minutes, a solution of N methyl-N [3,5-
dimethyl-4-(4'-
methoxy-3'-iso-propylphenoxy)phenyl]butyramide (7b; 1.37 g) in 6 mL THF is
added dropwise
and the reaction is refluxed overnight. At this time, the reaction is cooled
in an ice bath and 12
mL water is added dropwise followed by dropwise addition of 12 mL 15% sodium
hydroxide
then 60 mL water. The reaction is stirred for 90 minutes. At this time, it is
filtered through
celite and washed with THF and ethyl acetate. The filtrate is concentrated
under reduced
pressure and the product is purified by chromatography on silica gel to afford
7b.
Example 8
WO 00/72920 CA 02375822 2001-11-29 PCT/US00/~52$1
O
\ \ \ w
/ /
O / O /
\ NHZ \ N
1d 8
8. N [3,5-dimethyl-4-(4'-methoxy-3'-iso-propylphenoxy)phenyl]pyrrolidine:
2',6'-
Dimethyl-3-iso-propyl-4-methoxy-4'-aminodiphenyl ether (1d, 1.5 g) is
dissolved in 2 mL
ethanol and 0.75 mL 1,4-diiodobutane is added. The sample is refluxed
overnight. At this time,
it is concentrated under reduced pressure. The sample is taken up in ethyl
acetate and extracted
with 0.1 N sodium hydroxide, water, and brine. After drying over sodium
sulfate, filtering, and
concentration under reduced pressure, the tertiary amine is purified by
chromatography on silica
gelto afford 8.
Example 9
~O ~O
\ \ \
/ /
O / O / O
\ NH2 \ N /
1d g H
9. N [3,5-dimethyl-4-(4'-methoxy-3'-iso-propylphenoxy)phenyl]benzamide:
Pyridine (1
mL) is added and 2',6'-dimethyl-3-iso-propyl-4-methoxy-4'-aminodiphenyl ether
(Example 1d,
0.23 g) is suspended therein. To this solution is added 0.24 mL benzoyl
chloride and the
reaction is stirred for about 1 hour. The sample is concentrated under reduced
pressure and
dissolved in ethyl acetate. This is washed with water and brine then dried
over magnesium
sulfate and concentrated under reduced pressure. The residue is recrystallized
to afford 9.
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31
Example 10
~O
Br / ~ /
--r --a
/ ~ O /
NOZ
OH 10a
NOZ
lOb
~O O ~O ~O
/ / / '\~ F
F ~ F _
O / ~ O / ~ O / ~ ~O
NOZ ~ NOZ ~ N-
H
10c 10d 10e
10a. 4-bromo-3,5-dimethyl-nitrobenzene: 2',6'-dimethyl-4-nitrophenol (3 g) is
added to 50
mL dichloromethane followed by addition of 3.6 mL pyridine. The solution is
cooled to 0 °C
and 3.6 mL trifluoromethanesulfonic anhydride is added dropwise over 20
minutes. The
reaction is mixed for about 3 hours at 0 °C. Water (25 mL) is added to
quench the reaction. The
organic layer is extracted twice with 1N hydrochloric acid (25 mL), twice with
water (25 mL),
twice with 1N sodium hydroxide (25 mL), twice with water (25 mL), dried with
magnesium
sulfate, and concentrated under reduced pressure. The remaining residue is
dissolved in 40 mL
of DMF followed by addition of lithium bromide (4.7 g). The mixture is
refluxed for 17 hours at
150°C. The mixture is concentrated under high vacuum. To this residue,
60 mL water and 60
mL ethyl acetate is added and stirred. This mixture is filtered, the organic
layer separated and
dried with magnesium sulfate. The organic layer is concentrated under high
vacuum and the
remaining residue presorbed to silica gel using dichloromethane. The presorbed
residue is then
purified by chromatography on silica gel and subsequently crystallized from
hexanes to afford
10a.
10b. 3,5-dimethyl-4-(4'-methoxyphenoxy)-nitrobenzene: 4-bromo-3,5-dimethyl-
nitrobenzene (10a, 175 mg) and 4-methoxyphenol (94 mg) are dissolved into 7.5
mL
dimethylsulfoxide. To this solution, anhydrous potassium carbonate (153 mg) is
added and the
WO 00/72920 CA 02375822 2001-11-29 pCT/US00/05251
32
reaction mixed for 23 hours at about 130 °C. After 23 hours the
reaction is precipitated by the
addition of SO mL ice water. The mixture is then extracted with 75 mL ethyl
acetate. The
organic layer is extracted once with 50 mL brine solution, dried with
magnesium sulfate, and
concentrated under high vacuum to afford 10b.
10c. [5-(2,6-dimethyl-4-nitrophenoxy)-2-methoxyphenyl](4-
fluorophenyl)methanone: 4-
fluorobenzoyl chloride (137 mg) is dissolved in 2.5 mL dichloromethane
followed by the
addition of 77 microliters trifluoromethanesulfonic acid. After 5 minutes of
mixing 3,5-
dimethyl-4-(4'-methoxyphenoxy)-nitrobenzene (10b, 182 mg), is added and mixed
for 15 hours.
The reaction is concentrated under high vacuum and the remaining residue is
presorted to silica
gel using dichloromethane. The presorted residue is then purified by
chromatography on silica
gel to afford 10c.
10d. 4-[3-(4-fluorobenzyl)-4-methoxyphenoxy]-3,5-dimethylnitrobenzene: [5-(2,6-
dimethyl-4-nitrophenoxy)-2-methoxyphenyl](4-fluorophenyl)methanone (10c, 138
mg) is
dissolved in 380 microliters of dichloromethane followed by the addition of
230 microliters TFA
and 192 microliters triethylsilane. The reaction is mixed for 15 hours
followed by an extraction
with 20 mL diethyl ether and 10 mL water. The organic layer is extracted once
with 20 mL of
5% sodium carbonate, once with 20 mL water, dried with magnesium sulfate, and
concentrated
under reduced pressure to afford 10d.
10e. 4-[3-(4-fluorobenzyl)-4-methoxyphenoxy]-3,5-dimethyl-butyrylamidobenzene:
4-[3-
(4-fluorobenzyl)-4-methoxyphenoxy]-3,5-dimethylnitrobenzene (10d, 138 mg) is
dissolved in 5
mL ethanol. To this mixture, 18.4 mg of 10% palladium on carbon is added. The
reaction is
hydrogenated for 3 hours, then filtered through Celite and concentrated under
reduced pressure.
Pyridine (91 microliters) and butyric anhydride (184 microliters) are added to
the residue and the
reaction is stirred overnight. The reaction mixture is concentrated under high
vacuum and
purified by chromatography on silica gel to afford 10e.
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33
Example 11
~O \O
~O
C1
+ --~ -
~ N02 O / O
OH ~ NOZ ~ NH2
lla llb llc
11a. 4-chloro-3,5-dimethyl-nitrobenzene: 2',6'-Dimethyl-4-nitrophenol (10 g)
is added to
100 mL dichloromethane followed by the addition of 5.8 mL of pyridine. The
solution is cooled
to -2 °C and 12.1 mL trifluoromethanesulfonic anhydride is added
dropwise over 1 hour. The
reaction is stirred for about 3.5 hours at -2 °C. At this time, SO mL
ice water is added. The
organic layer is extracted twice with 50 mL 1N hydrochloric acid, twice with
50 mL water, twice
with SO mL 1N sodium hydroxide, twice with 50 mL water, dried with magnesium
sulfate,
filtered, and concentrated under reduced pressure. The residue is dissolved in
160 mL of 1-
methyl-2-pyrrolidinone followed by addition of lithium chloride (3.6 g). The
mixture is refluxed
for 17 hours at 120 °C. The mixture is concentrated under reduced
pressure. To this residue,
100 mL water and 100 mL ethyl acetate is added and stirred. This mixture is
filtered, the
organic layer separated, and dried with magnesium sulfate. The organic layer
is concentrated
under high vacuum to afford 11a.
l 1b. 3,5-dimethyl-4-(4'-methoxy-3'-tent-butylphenoxy)-nitrobenzene: 4-Chloro-
3,5-
dimethyl-nitrobenzene (11a, 1.83 g) and 2-tert-butyl-4-hydroxyanisole (1.8 g)
are dissolved in
15 mL dimethylsulfoxide. To this solution, anhydrous potassium carbonate (1.51
g) is added
and the reaction stirred for 17 hours at 120 °C. The reaction is then
cooled to 40 °C and poured
into ethyl acetate (50 mL). The organic layer is then washed with ice water
(50 mL), dried over
magnesium sulfate and concentrated under reduced pressure. The residue is
presorted to silica
gel using acetone. The presorted residue is purified by chromatography on
silica gel to afford
11b.
11c. 3,5-dimethyl-4-(4'-methoxy-3'-tert-butylphenoxy)amino benzene: 3,5-
Dimethyl-4-(4'-
methoxy-3'-tert-butylphenoxy)-nitrobenzene (11b), 1.13 g, is dissolved in 25
mL, ethanol and
WO 00/72920 CA 02375822 2001-11-29 pCT~S00/05251
34
130 mg of 10% palladium on carbon is added. The reaction is hydrogenated for 1
hour, then
filtered through a plug of silica gel and concentrated under reduced pressure
to afford 11c.
Example 12
~O ~O
\ \ \ \
/ /
O / O / O
\ NH2 \ N
1d 12 H
12. N [3,5-dimethyl-4-(4'-methoxy-3'-iso-propylphenoxy)phenyl]-2-
methylpropionamide: Isobutyric anhydride (4 mL) is added to 2',6'-dimethyl-3-
iso-propyl-4-
methoxy-4'-aminodiphenyl ether (1d, 0.21 g) and the reaction is stirred
overnight. At this time,
20 mL water and 20 mL ethyl acetate are added and the reaction mixture is
extracted with 1 N
NaOH until the aqueous layer has a pH above 10. After extracting once with
brine, drying over
magnesium sulfate and filtering, the organic layer is concentrated under
reduced pressure and
purified by chromatography on silica gel to afford 12.
Example 13
~O ~O
\ \
/ /
O / ~ O / ~ O
\ NH2 \ N
H
llc 13
13. N [3,5-dimethyl-4-(4'-methoxy-3'-tert-butylphenoxy)phenyl]butyramide: 3,5-
dimethyl-
4-(4'-methoxy-3'-tert-butylphenoxy)amino benzene (11c, 1.1 g) is suspended in
pyridine (0.6
mL) and butyric anhydride (1.2 mL) is added and the reaction is stirred for 30
minutes under
nitrogen. The mixture is concentrated under reduced pressure and the residue
is taken up in
WO 00/72920 CA 02375822 2001-11-29 pCT~S00/05251
ethyl acetate (30 mL). This material is then washed twice with O.1N HC1 (30
mL), water (30
mL), twice with O.1N NaOH (30 mL), water (30 mL), and brine (30 xnL). The
organic layer is
dried over magnesium sulfate, filtered, and the filtrate is concentrated under
reduced pressure.
The material is crystallized from hexanes to afford 13.
Example 14
~O ~O
\ \
/ /
O / ~ O / ~ O
\ NH2 \ N
H
llc 14
14. N [3,5-dimethyl-4-(4'-methoxy-3'-tert-
butylphenoxy)phenyl]trimethylacetamide: 3,5-
Dimethyl-4-(4'-methoxy-3'-tert-butyl phenoxy)amino benzene (11c, 1.12 g) is
suspended in
pyridine (0.6 mL). To this solution is added trimethylacetyl chloride (0.9 mL)
and the reaction
is stirred overnight. The sample is concentrated under reduced pressure and
dissolved in ethyl
acetate (100 mL). This is washed with 100 mL 0.1 N sodium hydroxide twice,
water (100 mL),
100 mL 0.1 N hydrochloric acid twice, water (100 mL) and brine (100 mL). The
organic layer is
dried over magnesium sulfate, filtered, and concentrated under reduced
pressure. The residue is
presorted to silica gel using acetone and purified by chromatography on silica
gel to afford 14.
Example 1 S
~O \O
\ \
/ /
O / O O /
\ N~~ \ N~
H H
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36
15. N [3,5-dimethyl-4-(4'-methoxy-3'-tert-butylphenoxy)phenyl] butylamine: N
[3,5-
dimethyl-4-(4'-methoxy-3'-tert-butylphenoxy)phenyl]butyramide (13, 0.43 g) is
dissolved in
THF (10 mL) and added dropwise to a solution of lithium aluminum hydride (0.3
g) in THF (30
mL) under nitrogen and allowed to react for two hours. The reaction is cooled
in an ice bath and
water (10 mL) is added dropwise. The precipitate which forms is filtered off
and the filtrate is
concentrated under reduced pressure. The filtrate is purified by
chromatography on silica gel to
afford 15.
Example 16
~O
O
\ \
/ /
O O / O
H O
\ \ N~N
NH2 H
1d 16 O
16. (N [3,5-dimethyl-4-(4'-methoxy-3'-iso-propylphenoxy)phenyl])-N BOC-
glycinamide:
2',6'-dimethyl-3-iso-propyl-4-methoxy-4'-aminodiphenyl ether (1d, 0.44 g) and
N BOC-glycine
(0.27 g) is suspended in 3 mL dichloromethane. To this is added 0.4 mL i-
PrzEtN. After
mixing, O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate
(0.58 g) is
added and the reaction is stirred overnight. The reaction is diluted with 75
mL diethyl ether and
the organic layer is washed with 2M potassium hydrogen sulfate (25 mL x 3),
once with water, 1
N sodium hydroxide (50 mL x 2), and once with 50 mL brine. The organic layer
is dried over
sodium sulfate, filtered and the filtrate is concentrated under reduced
pressure and purified by
chromatography on silica gel to afford 16.
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37
Example 17
~O
O / ~ O O / ~ O
\ N~N O \ N~NHz
H ~ H
16 17
17. (N [3,5-dimethyl-4-(4'-methoxy-3'-iso-propylphenoxy)phenyl])glycinamide:
(N [3,5-
dimethyl-4-(4'-methoxy-3'-iso-propylphenoxy)phenyl])glycinamide (16, 0.175 g)
is dissolved in
1 mL dichloromethane and 0.31 mL TFA. The reaction stirred for 1 hour. At this
time, the
sample is diluted with 25 mL diethyl ether and washed twice with 10 mL 1N
sodium hydroxide
and once with 25 mL brine. The organic layer is dried over sodium sulfate,
filtered, and the
filtrate is concentrated under reduced pressure to afford 17.
Example 18
~O \O
\ \ \ \
/ /
O / O /
\ NHZ \ N 18
1d
18. N [3,5-dimethyl-4-(4'-methoxy-3'-iso-propylphenoxy)phenyl]piperidine:
2',6'-
Dimethyl-3-iso-propyl-4-methoxy-4'-aminodiphenyl ether (1d, 0.275 g) is
dissolved in 1 mL
ethanol and 0.142 mL 1,5-diiodopentane is added. The sample is refluxed for 4
hours. At this
time, it is concentrated under reduced pressure. The sample is taken up in
ethyl acetate and
extracted with 0.1 N sodium hydroxide, water and brine. After drying over
sodium sulfate,
filtering, and concentrating the filtrate under reduced pressure, it is
purified by chromatography
on silica gel to afford 18.
WO 00/72920 CA 02375822 2001-11-29 PCT/[JS00/~$251
38
Example 19
~O ~O
\ W \ W
/ /
O / O /
\ NHZ \ N
1d 19 ~O
19. N [3,5-dimethyl-4-(4'-methoxy-3'-iso-propylphenoxy)phenyl]morpholine:
2',6'-
Dimethyl-3-iso-propyl-4-methoxy-4'-aminodiphenyl ether (1d, 0.25 g) is
dissolved in 2 mL
ethanol and 0.1 SO g di(2-iodoethyl)ether is added. The sample is refluxed
overnight. At this
time, it is concentrated under reduced pressure. The sample is taken up in
ethyl acetate and
extracted with 0.1 N sodium hydroxide, water, and brine. After drying over
sodium sulfate,
filtering, and concentrating the filtrate under reduced pressure, it is
purified by chromatography
on silica gel to afford 19.
Use of the Present Compounds
According to the methods of the present invention, a compound having a
structure as
described herein is administered, most preferably with a pharmaceutically-
acceptable or
cosmetically-acceptable carrier.
The compounds of the present invention may be used for the treatment of such
conditions as treating hair loss in mammals, including arresting and / or
reversing hair loss and
promoting hair growth. Such conditions may manifest themselves in, for
example, alopecia,
including male pattern baldness and female pattern baldness.
In addition, the compounds of the present invention may be useful for weight
control,
including the treatment and / or prevention of obesity. Other uses for the
compounds of the
present invention include stimulation of nail growth, treatment of skin
conditions, prevention of
hair discoloration, obesity, cholesterol lowering, treatment of thyroid
disorders, and treatment of
osteoporosis.
Preferably the compounds of the present invention are, as defined herein,
cardiac-
sparing.
WO 00/72920 CA 02375822 2001-11-29 pCT~S00/0$251
39
Preferably, the compounds are formulated into pharmaceutical or cosmetic
compositions
for use in treatment or prophylaxis of conditions such as the foregoing.
Standard pharmaceutical
formulation techniques are used, such as those disclosed in Remington's
Pharmaceutical
Sciences, Mack Publishing Company, Easton, PA. (1990).
Typically, from about 5 mg to about 3000 mg, more preferably from about 5 mg
to
about 1000 mg, more preferably from about 10 mg to about 100 mg, of a compound
having
a structure as described herein is administered per day for systemic
administration. It is
understood that these dosage ranges are by way of example only, and that daily
administration can be adjusted depending on various factors. The specific
dosage of the
compound to be administered, as well as the duration of treatment, and whether
the
treatment is topical or systemic are interdependent. The dosage and treatment
regimen will
also depend upon such factors as the specific compound used, the treatment
indication, the
efficacy of the compound, the personal attributes of the subject (such as, for
example,
weight, age, sex, and medical condition of the subject), compliance with the
treatment
regimen, and the presence and severity of any side effects of the treatment.
According to the present invention, the subject compounds are co-administered
with a
pharmaceutically-acceptable or cosmetically-acceptable carrier (herein
collectively described as
"carrier"). The term "carrier", as used herein, means one or more compatible
solid or liquid
filler diluents or encapsulating substances which are suitable for
administration to a mammal.
The term "compatible", as used herein, means that the components of the
composition are
capable of being commingled with a compound of the present invention, and with
each other, in
a manner such that there is no interaction which would substantially reduce
the efficacy of the
composition under ordinary use situations. Garners must, of course, be of
sufficiently high
purity and sufficiently low toxicity to render them suitable for
administration to the animal,
preferably mammal (most preferably human), being treated. The carrier can
itself be inert or it
can possess pharmaceutical and / or cosmetic benefits of its own.
The compositions of this invention may be in any of a variety of forms,
suitable (for
example) for oral, rectal, topical, nasal, ocular or parenteral
administration. Of these,
topical and / or oral administration are especially preferred with topical
being most
preferred. Depending upon the particular route of administration desired, a
variety of
carriers well-known in the art may be used. These include solid or liquid
fillers, diluents,
hydrotropes, surface-active agents, and encapsulating substances. Optional
pharmaceutically-active or cosmetically-active materials may be included which
do not
substantially interfere with the activity of the compound of the present
invention. The
WD 00/72920 CA 02375822 2001-11-29 pCT~S00/05251
amount of carrier employed in conjunction with the compound is sufficient to
provide a
practical quantity of material for administration per unit dose of the
compound. Techniques
and compositions for making dosage forms useful in the methods of this
invention are
described in the following references: Modern Pharmaceutics, Chapters 9 and
10, Banker
& Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets
(1981);
and Ansel, Introduction to Pharmaceutical Dosage Forms, 2°d Ed.,
(1976).
Some examples of substances which can serve as carriers or components thereof
are
sugars, such as lactose, glucose and sucrose; starches, such as corn starch
and potato starch;
cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl
cellulose, and
methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants,
such as stearic acid
and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil,
cottonseed oil,
sesame oil, olive oil, corn oil and oil of theobroma; polyols such as
propylene glycol, glycerine,
sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such
as the TWEENS;
wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents;
tableting agents,
stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline;
and phosphate buffer
solutions.
The choice of a carrier to be used in conjunction with the subject compound is
typically
determined by the way the compound is to be administered.
In particular, carriers for systemic administration include sugars, starches,
cellulose
and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils,
synthetic oils,
polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic
saline, and pyrogen-
free water. Preferred carriers for parenteral administration include propylene
glycol, ethyl
oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the carrier, in
compositions for
parenteral administration, comprises at least about 90% by weight of the total
composition.
Various oral dosage forms can be used, including such solid forms as tablets,
capsules, granules and bulk powders. These oral forms comprise a safe and
effective
amount, usually at least about S%, and preferably from about 25% to about 50%,
of a
compound used in the present invention. Tablets can be compressed, tablet
triturates,
enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing
suitable
binders, lubricants, diluents, disintegrating agents, coloring agents,
flavoring agents, flow-
inducing agents, and melting agents. Liquid oral dosage forms include aqueous
solutions,
emulsions, suspensions, solutions and/or suspensions reconstituted from non-
effervescent
granules, and effervescent preparations reconstituted from effervescent
granules, containing
WO 00/72920 CA 02375822 2001-11-29 pCT/US00/05251
41
suitable solvents, preservatives, emulsifying agents, suspending agents,
diluents,
sweeteners, melting agents, coloring agents and flavoring agents.
The carriers suitable for the preparation of unit dosage forms for oral
administration are
well-known in the art. Tablets typically comprise conventional
pharmaceutically-compatible
adjuvants as inert diluents, such as calcium carbonate, sodium carbonate,
mannitol, lactose and
cellulose; binders such as starch, gelatin and sucrose; disintegrants such as
starch, alginic acid
and croscarmelose; lubricants such as magnesium stearate, stearic acid and
talc. Glidants such
as silicon dioxide can be used to improve flow characteristics of the powder
mixture. Coloring
agents, such as the FD&C dyes, can be added for appearance. Sweeteners and
flavoring agents,
such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are
useful adjuvants for
chewable tablets. Capsules (including time release and sustained release
formulations) typically
comprise one or more solid diluents disclosed above. The selection of carrier
components
depends on secondary considerations like taste, cost, and shelf stability,
which are not critical for
the purposes of the subject invention, and can be readily made by a person
ordinarily skilled in
the art.
Orally administered compositions also include liquid solutions, emulsions,
suspensions,
powders, granules, elixirs, tinctures, syrups, and the like. The carriers
suitable for preparation of
such compositions are well known in the art. Typical components of carriers
for syrups, elixirs,
emulsions and suspensions include ethanol, glycerol, propylene glycol,
polyethylene glycol,
liquid sucrose, sorbitol and water. For a suspension, typical suspending
agents include methyl
cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and
sodium alginate;
typical wetting agents include lecithin and polysorbate 80; and typical
preservatives include
methyl paraben and sodium benzoate. Peroral liquid compositions may also
contain one or more
components such as sweeteners, flavoring agents and colorants disclosed above.
Such compositions may also be coated by conventional methods, typically with
pH or
time-dependent coatings, such that the subject compound is released in the
gastrointestinal tract
in the vicinity of the desired topical application, or at various times to
extend the desired action.
Such dosage forms typically include, but are not limited to, one or more of
cellulose acetate
phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose
phthalate, ethyl cellulose,
Eudragit coatings, waxes and shellac.
Other compositions useful for attaining systemic delivery of the subject
compounds
include sublingual, buccal and nasal dosage forms. Such compositions typically
comprise one or
more of soluble filler substances such as sucrose, sorbitol and mannitol; and
binders such as
acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl
methyl cellulose.
WO 00/72920 CA 02375822 2001-11-29 pCT/US00/05251
42
Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents
disclosed above
may also be included.
The compounds of the present invention may also be topically administered. The
carrier
of the topical composition preferably aids penetration of the present
compounds into the skin to
reach the environment of the hair follicle. Topical compositions of the
present invention may be
in any form including, for example, solutions, oils, creams, ointments, gels,
lotions, shampoos,
leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers,
sprays, skin patches, and
the like.
Topical compositions containing the active compound can be admixed with a
variety of
carrier materials well known in the art, such as, for example, water,
alcohols, aloe vera gel,
allantoin, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-
2 myristyl
propionate, and the like.
Other materials suitable for use in topical carriers include, for example,
emollients,
solvents, humectants, thickeners and powders. Examples of each of these types
of materials,
which can be used singly or as mixtures of one or more materials, are as
follows:
Emollients, such as stearyl alcohol, glyceryl monoricinoleate, glyceryl
monostearate,
propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, iso-propyl
isostearate, stearic acid, iso-
butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl
laurate, decyl oleate,
octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-
butyl sebacate, iso-
propyl myristate, iso-propyl palmitate, iso-propyl stearate, butyl stearate,
polyethylene glycol,
triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil,
acetylated lanolin
alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic
acid, isopropyl
linoleate, lauryl lactate, myristyl lactate, decyl oleate, and myristyl
myristate; propellants, such
as propane, butane, iso-butane, dimethyl ether, carbon dioxide, and nitrous
oxide; solvents, such
as ethyl alcohol, methylene chloride, iso-propanol, castor oil, ethylene
glycol monoethyl ether,
diethylene glycol monobutyl ether, diethylene glycol monoethyl ether,
methylsulfoxide,
dimethyl formamide, tetrahydrofuran; humectants, such as glycerin, sorbitol,
sodium 2-
pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin;
and powders, such as
chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide,
sodium polyacrylate,
tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically
modified
magnesium aluminium silicate, organically modified montmorillonite clay,
hydrated aluminium
silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose,
and ethylene
glycol monostearate.
W~ 00/72920 CA 02375822 2001-11-29 pCT~S00/05251
43
The compounds used in the present invention may also be administered in the
form of
liposome delivery systems, such as small unilamellar vesicles, large
unilamellar vesicles, and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as
cholesterol, stearylamine or phosphatidylcholines. A preferred formulation for
topical delivery
of the present compounds utilizes liposomes such as described in Dowton et
al., "Influence of
Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An
in vitro
Study Using Hairless Mouse Skin", S.T.P. Pharma Sciences, Vol. 3, pp. 404 -
407 (1993);
Wallach and Philipgot, "New Type of Lipid Vesicle: Novasome ", Liposome
Technology, Vol.
1, pp. 141 - 156 (1993); Wallach, U.S. Patent No. 4,911,928, assigned to Micro-
Pak, Inc., issued
March 27, 1990; and Weiner et al., U.S. Patent No. 5,834,014, assigned to The
University of
Michigan and Micro-Pak, Inc., issued November 10, 1998 (with respect to Weiner
et al., with a
compound as described herein administered in lieu of, or in addition to,
minoxidil).
The compounds of the present invention may also be administered by
iontophoresis.
See, e.~., Internet site www.unipr.it/arpa/dipfarm/erasmus/erasml4.html; Banga
et al.,
"Hydrogel-based Iontotherapeutic Delivery Devices for Transdermal Delivery of
Peptide/Protein
Drugs", Pharm. Res., Vol. 10 (5), pp. 697-702 (1993); F~, "Theoretical Model
of
Iontophoresis Utilized in Transdermal Drug Delivery", Pharmaceutical Acta
Helvetiae, Vol 70,
pp. 279-287 (1995); Gangarosa et al., "Modern Iontophoresis for Local Drug
Delivery", Int. J.
Pharm, Vol. 123, pp. 159-171 (1995); Green et al., "Iontophoretic Delivery of
a Series of
Tripeptides Across the Skin in vitro", Pharm. Res., Vol 8, pp. 1121-1127
(1991); Jadoul et al.,
"Quantification and Localization of Fentanyl and TRH Delivered by
Iontophoresis in the Skin",
Int. J. Pharm., Vol. 120, pp. 221-8 (1995); O'Brien et al., "An Updated Review
of its Antiviral
Activity, Pharmacokinetic Properties and Therapeutic Efficacy", Drugs, Vol.
37, pp. 233-309
(1989); Parry et al., "Acyclovir Biovailability in Human Skin", J. Invest.
Dermatol., Vol. 98 (6),
pp. 856-63 (1992); Santi et al., "Drug Reservoir Composition and Transport of
Salmon
Calcitonin in Transdermal Iontophoresis", Pharm. Res., Vol 14 (1), pp. 63-66
(1997); Santi et
al., "Reverse Iontophoresis - Parameters Determining Electroosmotic Flow: I.
pH and Ionic
Strength", J. Control. Release, Vol. 38, pp. 159-165 (1996); Santi et al.,
"Reverse Iontophoresis
- Parameters Determining Electroosmotic Flow: II. Electrode Chamber
Formulation", J. Control.
Release, Vol. 42, pp. 29-36 (1996); Rao et al., "Reverse Iontophoresis:
Noninvasive Glucose
Monitoring in vivo in Humans", Phann. Res., Vol. 12 (12), pp. 1869-1873
(1995); Thysman et
al., "Human Calcitonin Delivery in Rats by Iontophoresis", J. Pharm.
Pharmacol., Vol. 46, pp.
725-730 (1994); and Volpato et al., "Iontophoresis Enhances the Transport of
Acyclovir through
WO 00/72920 CA 02375822 2001-11-29 PCT/US00/05251
44
Nude Mouse Skin by Electrorepulsion and Electroosmosis", Pharm. Res., Vol. 12
(11), pp.
1623-1627 (1995).
The compositions used in the present invention may also optionally comprise an
activity
enhancer. The activity enhancer can be chosen from a wide variety of molecules
which can
function in different ways to enhance hair growth effects of a compound of the
present
invention. Particular classes of activity enhancers include other hair growth
stimulants and
penetration enhancers.
Non-limiting examples of other hair growth stimulants which may be used in the
compositions herein, including both systemic and topical compositions,
include, for example,
benzalkonium chloride, benzethonium chloride, phenol, estradiol,
diphenhydramine
hydrochloride, chlorpheniramine maleate, chlorophyllin derivatives,
cholesterol, salicylic acid,
cysteine, methionine, red pepper tincture, benzyl nicotinate, D,L - menthol,
peppermint oil,
calcium pantothenate, panthenol, castor oil, hinokitiol, prednisolone,
resorcinol,
monosaccharides and esterified monosaccharides, chemical activators of protein
kinase C
enzymes, glycosaminoglycan chain cellular uptake inhibitors, inhibitors of
glycosidase activity,
glycosaminoglycanase inhibitors, esters of pyroglutamic acid, hexosaccharic
acids or acylated
hexosaccharic acids, aryl-substituted ethylenes, N-acylated amino acids, and,
of course,
minoxidil or finasteride. The most preferred activity enhancers are minoxidil
and finasteride,
most preferably minoxidil.
Non-limiting examples of penetration enhancers which may be used in the
compositions
herein include, for example, 2-methyl propan-2-ol, propan-2-ol, ethyl-2-
hydroxypropanoate,
hexan-2,5-diol, POE(2) ethyl ether, di(2-hydroxypropyl) ether, pentan-2,4-
diol, acetone, POE(2)
methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol,
1,4-dioxane,
tetrahydrofuran, butan-1,4-diol, propylene glycol dipelargonate,
polyoxypropylene 15 stearyl
ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl
alcohol, dioctyl adipate,
dicapryl adipate, di-isopropyl adipate, di-isopropyl sebacate, dibutyl
sebacate, diethyl sebacate,
dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate,
dibenzyl sebacate, dibutyl
phthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butyl
myristate, dibutyl succinate,
didecyl phthalate, decyl oleate, ethyl caproate, ethyl salicylate, iso-propyl
palmitate, ethyl
laurate, 2-ethyl-hexyl pelargonate, iso-propyl isostearate, butyl laurate,
benzyl benzoate, butyl
benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate,
benzyl salicylate, 2-
hydroxypropanoic acid, 2-hyroxyoctanoic acid, methylsulfoxide, N,N-dimethyl
acetamide, N,N-
dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-
pyrrolidone, 1,5-
WO 00/72920 CA 02375822 2001-11-29 PCT/[JS00/0$251
dimethyl-2-pyrrolidone, I-ethyl-2-pyrrolidone, phosphine oxides, sugar esters,
tetrahydrofurfural
alcohol, urea, diethyl-m-toluamide, and, 1-dodecylazacyloheptan-2-one.
In all of the foregoing, of course, the compounds used in the present methods
can be
administered alone or as mixtures, and the compositions may further include
additional drugs or
excipients as appropriate for the indication.
The present invention further relates to kits comprising a compound and / or
composition of the present invention and information and / or instructions by
words, pictures,
and / or the like, that use of the kit will provide treatment for hair loss in
mammals (particularly
humans) including, for example, arresting and / or reversing hair loss and /
or promoting hair
growth. In addition or in the alternative, the kit may comprise a compound and
/ or composition
of the present invention and information and / or instructions regarding
methods of application
of the compound and / or composition, preferably with the benefit of treating
hair loss in
mammals.
Examples of Composition Administration
The following examples do not limit the invention, but provide guidance to the
ordinarily skilled artisan to perform the methods of the present invention. In
each example, a
compound other than the one mentioned may be substituted in the example by
another having a
structure as described herein with similar results.
Example A
A composition for topical administration is made, comprising:
Component Amount
Compound of Example 3 5
Ethanol 57
Propylene Glycol 19
Dimethyl Isosorbide 19
A human male subject suffering from male pattern baldness is treated by a
method of
this invention. Specifically, for 6 weeks, the above composition is daily
administered topically
to the subject.
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PCT/US00/05251
46
Example B
A composition for topical administration is made according to the method of
Dowton et
al., "Influence of Liposomal Composition on Topical Delivery of Encapsulated
Cyclosporin A:
I. An in vitro Study Using Hairless Mouse Skin", S.T.P. Pharma Sciences, Vol.
3, pp. 404 - 407
(1993), using the compound of Example 2 in lieu of cyclosporin A and using the
Novasome 1 for
the non-ionic liposomal formulation.
A human male subject suffering from male pattern baldness is treated each day
with the
above composition. Specifically, for 6 weeks, the above composition is
administered topically
to the subject.
Example C
A shampoo is made, comprising:
Ex. Ex. Ex. Ex.
C-1 C-2 C-3 C-4
Com onent
Ammonium Lau 1 Sulfate11.5 11.5 9.5 7.5
% % %
Ammonium Laureth 4 % 3 % 2 % 2
Sulfate
Cocamide MEA 2 % 2 % 2 % 2
Eth lene GI col Distearate2 % 2 % 2 % 2
Ce 1 Alcohol 2 % 2 % 2 % 2
Stea 1 Alcohol 1.2 1.2 1.2 1.2
% % %
Gl cerin 1 % 1 % 1 % 1
Pol uaternium 10 0.5 0.25 - -
% %
Pol uaternium 24 - - 0.5 0.25
%
Sodium Chloride 0.1 0.1 0.1 0.1
% % %
Sucrose Polyesters 3 % 3 % - -
of
Cottonate Fa Acid
Sucrose Polyesters 2 % 3 % -
of
Behenate Fa Acid
Pol dimeth 1 Siloxane- - 3 % 2
Cocamino ro 1 Betaine- 1 % 3 % 3
Lauryl Dimethyl Amine1.5 1.5 1.5 1.5
Oxide % % %
Dec 1 Pol lucose - - 1 % 1
DMDM H dantoin 0.15 0.15 0.15 0.15
% % %
Com ound of Exam - 3 % 3 % -
1e 1
Com ound of Exam 6 % - - 6
1e 4
Minoxidil 3 % 2
Phenox ethanol 0.5 0.5 0.5 0.5
% % %
Fra ance 0.5 0.5 0.5 0.5
% % %
Water .s. .s. .s. q.s.
A human subject suffering from male pattern baldness is treated by a method of
this
invention. Specifically, for 12 weeks, the above shampoo is used daily by the
subject.
