CA 02375674 2001-11-29
WO 00/73292 PCT/US00/05194
BIARYL 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
WO 00/73292 CA 02375674 2001-11-29 pCT/US00/05194
2
side effect of administration of T4. See, e.g., 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
Anirn. 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:
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
3
R3
O
I
RI~ _Rs
R9
R8 ~ ~~Rlo
R~ Y- X R
~ , 12
RI I
and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides,
esters, and imides
thereof, wherein R,, Rz, R3, R4, R;, R6, R6', R~, R8, R9, R,o, Y, X, R,~, and
R,Z 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
WO 00/73292 CA 02375674 2001-11-29 pCT~S00/05194
4
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 olefinic 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 15 carbon atoms; preferably from 1 to about 10
carbon atoms;
more preferably from 1 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.
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
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,
WO 00/73292 CA 02375674 2001-11-29 pCT/US00/05194
6
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.
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
7
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,
irritation, 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
R2 / R4
Ri Rs
Ra v ~~Rio
R~ Y- X R
~ , i2
RI ~
and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides,
esters, and imides
thereof, wherein:
WO 00/73292 CA 02375674 2001-11-29 PCTNS00/05194
8
(a) R~, RZ, R5, R~, and R,o are each, independently, selected from the group
consisting of
hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and
heteroalkynyl;
(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 -CH~CHK,, X is selected
from
the group consisting of -NZ- and -NH-, and Rl, is C~ - C.~ 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) R6 and R6' are each, independently, selected from the group consisting of
hydrogen,
halogen, hydroxy, amino, nitro, cyano, carboxy, thiol, alkyl, alkenyl,
alkynyl,
heteroalkyl, heteroalkenyl, and heteroalkynyl; or wherein R6 and R6' are,
together,
oxo or thioxo;
(f) Y is selected from the group consisting of bond, alkyl, alkenyl, alkynyl,
heteroalkyl,
heteroalkenyl, and heteroalkynyl;
(g) X is selected from the group consisting of -NZ-, -NH- and -O-;
(h) 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)-;
(i) 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~1 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;
wherein
CA 02375674 2001-11-29
WO 00/73292 PCT/US00/05194
9
when R~, is heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, then a
heteroatom of R,, is not directly covalently bonded to R"; and wherein when Y
is
bond, X is -O-, and R" is -C(O)- then R,~ is not alkyl; and
(j) Z is selected from the group consisting of alkyl, alkenyl, alkynyl,
heteroalkyl,
heteroalkenyl, and heteroalkynyl; 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.
The present compounds are biphenyl compounds linked through a carbon atom
which is
substituted with substituents R6 and R6'. The remaining substituents, as well
as R6 and R6' are
described in further detail below.
The Substituents Rl, R, RS R~, and R,o
The substituents R,, R2, R5, R~, and Rio 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
Rio are more
preferably each, independently, selected from hydrogen, halogen, and lower
alkyl. Most
preferably, R~, R~, R5, R-,, and R,o are each hydrogen.
The Substituent RQ
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 RIZ 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.
Rd 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
WO 00/73292 CA 02375674 2001-11-29 pCT/US00/05194
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 tent-butyl, more preferably iso-
propyl or tert-butyl.
Most preferably, R4 is lower alkyl, particularly iso-propyl or tert-butyl.
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 R8 and R9 is not hydrogen. Preferably, each of R$ and R9 are
not hydrogen.
R8 and R9 are preferably each, independently, selected from halogen, alkyl,
alkenyl,
heteroalkyl, and heteroalkenyl. R~ and R9 are more preferably each,
independently, selected
from halogen, alkyl, alkenyl, and heteroalkyl. R$ 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 Rg and R9
are methyl, ethyl, iso-propyl, and tert-butyl, preferably methyl, iso-propyl,
and tert-butyl, more
preferably methyl and iso-propyl. Most preferably, Rg 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 Substituents R6 and R6'
R6 and R6' are each, independently, selected from hydrogen, halogen, hydroxy,
amino,
nitro, cyano, carboxy, thiol, alkyl, alkenyl, alkynyl, heteroalkyl,
heteroalkenyl, and
CA 02375674 2001-11-29
WO 00/73292 PCT/US00/05194
11
heteroalkynyl; or wherein R~ and R6' are, together, oxo or thioxo. Preferably,
R6 and R6' are
each, independently, selected from hydrogen, halogen, hydroxy, amino, thiol,
alkyl, and
heteroalkyl; or wherein R6 and R6' are, together, oxo. More preferably, R6 and
R6' are each,
independently, selected from hydrogen, halogen, hydroxy, amino, and lower
alkyl; or wherein
R6 and R6' are, together, oxo. Still more preferably, R6 and R6' are each,
independently, selected
from hydrogen, halogen, hydroxy, and lower alkyl (most preferably C, - C3
alkyl); or wherein
R6 and R6' are, together, oxo. Even more preferably, R6 and R6' are each,
independently, selected
from hydrogen and hydroxy; or wherein R6 and R6' are, together, oxo. Most
preferably, R6 and
R6' are each hydrogen.
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 R~, 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
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 Rl~ 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,2 and Z are
bonded together to form a cycle selected from cycloalkyl, cycloalkenyl,
heterocycloalkyl,
heterocycloalkenyl, aryl, and heteroaryl. Most preferably, Z is C~ - C3 alkyl,
particularly methyl,
or R~2 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,, and Z are bonded together to form a cycle selected from the
group consisting
of 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
CA 02375674 2001-11-29
WO 00/73292 PCT/US00/05194
12
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)- with the proviso that wherein when Y is
bond and
X is -O- then R" is -C(O)-. Wherein R" is bond, R,~ is directly bonded to X
and the compound
is an amine (wherein X is -NZ- or -NH-) or an ether (wherein X is -O- and Y is
not bond).
While both bond and -C(O)- are both highly preferred for R", most preferably,
R~ ~ is -C(O)-.
The Substituent R,
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~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;
wherein when RIZ is
heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl,
heterocycloalkenyl, heteroaryl,
heteroarylalkyl, or heteroarylalkenyl, then a heteroatom of R" is not directly
covalently bonded
to R». Accordingly, carbamates and ureas at the -Y-X-R"-R,z linkage are not
contemplated
within the present invention. For example, wherein RI~ is heteroalkyl, it is
not, e.g., -O-CHZ-
CH3, but could be, e.g., -CHz-O-CH3.
Additionally, wherein when Y is bond, X is -O-, and R" is -C(O)- then R~2 is
not alkyl.
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, Rlz is lower alkyl, or is bonded to Z to form a cycle selected
from cycloalkyl,
cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. The
most preferred
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
13
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,~ 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:
Table 1 - Preferred Compounds of the Present Invention
In the following preferred compounds, R6 and R6' are each hydrogen:
O O
/ ~ / _
\
/ I O / O
\ N N
I I
H H
O O
/ _ /
\ \
O / I O
\ N \ N
H I
H
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
14
OH
/ ' /
\
\ C1
/ O / O
N C1 \ N'
I
I
H H
O O
/ ~ / I _
\ ~ \
CI CI
/ O / I O
I \ Ij
~~
C H
N
H
/
\ /
O
\ CI
/ ( ~ / ~ O
\ C1 \ N
I
H
/ O
N
I
H
O O-
\ \
/ I / O
\ ~ \
N N
I
I
H H
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
IS
O OH
_ /
/ I \ I
O / I O
\ I \ N
N ~ I \
I H
H
_O
/ ~ \ \
I
\ /
/ I o /
I
\ N / \ \ N
H ~ O
OH
/ /
\ I \
/ I / O
\
N ~'~/~ \ N
I
H
O/ OH
/
/ ~ \
\ N N
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
16
OH Oi
/ /
\I \I
/I /
\ N \I
N
O O
/ ~ / _
I I
\ \ Cl
/ /
I I
\ N' C1 \ N
I I
Table 2 - Preferred Compounds of the Present Invention
In the following preferred compounds, R6 and R6' are, together, oxo:
~,~ i n
O ( O
N ~ N
I I
H H
WO 00/73292 CA 02375674 2001-11-29 pCT/US00/05194
17
O O
/ ~ /
O~ / I O O' / I O
N \ N
I I
H H
OH O
/ /
I ~I
C1
O' / I O
O' / O
N~ ~I ~
Cl N'
I I
H H
O O
/ ~ / _
I I
C1 \ C1
O / I O O / I O
Cl \ N \ N
I I
H H
WO 00/73292 CA 02375674 2001-11-29 pCT/US00/05194
I8
o \ CI
O~ / ~ O
\
C1 ~ N ~~~
o i I o I
\ ,~~ H
N
I
H
O O
/ _ / _
\ \
O~ / I O~ / I O
\ N \ N
I I
H H
OH
/ I ' \ I
O / O O~ / ( O
\ I \ N
N ~ I \
I H
H
WO 00/73292 CA 02375674 2001-11-29 pCT/[JS00/05194
19
Oi _O
/ \ \
I /
O / I O O~ /
\ N / ~ \ N
~O
H
O/ OH
_ /
/ ~ \
/ O' / I O
o ~ \
\ N N
H
/ OH
O
_ / _
/ ) \
O /
/ I \ I
\ N
I
OH Oi
/ /
\ I \
o, /
o' /
\
N \ N
I
<IMG>
WO 00/73292 CA 02375674 2001-11-29 pCT/US00/05194
21
Table 3 - Preferred Compounds of the Present Invention
In the following preferred compounds, R6 is hydrogen and R6' is hydroxy:
O O
/
\ \
HO / I O HO / I O
\ N' \ \ N
I I
H H
O, O,
/ _ / _
\ \
HO / I O HO / I O
\ N \ N
I I
H H
OH Oi
/ /
\ \
C1
HO / I O
HO / I O
N C1 \ N
I I
H H
CA 02375674 2001-11-29
WO 00/73292 PCT/US00/05194
22
O O
/ ~ / _
\ Cl \ Cl
HO / O HO / O
1 I N I N
\ \
C I I
H H
O~
I
/ _
O \ C1
HO / O
~
\
Cl N
HO ~ O H
I ~~
N
I
H
O O
/ _ / _
\ \
HO / HO / O
I N I N
\ I \ I
H H
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
23
O/ OH
_ /
/I \I
HO / I O
HO / O
\ I \ N
N ~ I w
H H
_O
/ \ \
\ I
HO / I O HO
\ N / ~ \ N
I ~O
H
O/ OH
_ /
/I \I
HO / I O
HO /
\ I \ N
N I
H
/ OH
O
_ /
/I \I
HO /
Ho / I \ I
\ N
I
WO X0/73292 CA 02375674 2001-11-29 PCT/US00/05194
24
OH O
/ /
HO / /
HO
N \ N
O/ O/
/ _ /
\ \ C1
HO / I HO /
\ N~ C1 \ N
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
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., Gomberg-Maitland et al., "Thyroid hormone and
Cardiovascular
Disease", American Heart Journal, Vol. 135(2), pp. 187-196 (1998); Klein and
O~a~ maa,
"Thyroid Hormone and the Cardiovascular System", Current Opinion in
Endocrinology and
Diabetes, Vol. 4, pp.341-346 (1997); and Klem~erer et al., "Thyroid Hormone
Therapy and
Cardiovascular Disease", Progress in Cardiovascular Diseases, Vol. 37 (4), pp.
329-336 (1996).
CA 02375674 2001-11-29
WO 00/73292 PCTNS00/05194
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 500 ~L of dosing solution per kg of rat. For rats in the test
compound group,
this corresponds to a dose of 250 ~tg 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.
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 inj ection sites are rotated in this
area.
On day 30 in the morning, the rats of each group are euthanized with COZ 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
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
26
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 1.1. 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
(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 4 below.
Typical dosage concentrations are set forth in Table 4, however the ordinarily
skilled artisan will
readily understand that such concentrations may be modified.
Table 4
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
27
Group Animal Compound ConcentrationApplication Length
# # of
volume Study
1 1 - 10 Test 0.1% in 400 pL topical19 or 24
days
Compound vehicle**
2 11 - Positive 0.01% in 400 pL topical19 or 24
20 days
Control vehicle**
(T3)
3 21 - Vehicle** N/A 400 ~L topical19 or 24
30 days
**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 ~L to each
mouse's back. The 400
~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 5,
the grades 0 to 4 represent the following visual observations as the skin
progresses from white to
bluish-black.
Table 5
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 one 3
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
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
28
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.
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 can be prepared, after removal of temporary
protection
groups, by condensing (e.g., acylating or alkylating) a compound of the
structure:
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
29
R3 R4
O ~ RS R9 Rio
XH
/ ~ ~ Y
RZ (I)
R8 R~
wherein R,, RZ, R3, R4, R;, R6, R6', R~, R8, R9, R,o, Y, and X are defined
herein above and are in
an appropriately protected form if necessary (see~e.~., T. Greene, Protecting
Groups in Organic
Synthesis, John Wiley & Sons, 1981), with a reactive derivative of a
structure:
O
(II)
HO ~ R~ 2
HO ~ R~ 2 (III)
or
Q i R12
(IV)
wherein R,~ is defined herein above and is in an appropriately protected form
if necessary and Q
is a halogen, preferably bromine or iodine, and most preferably iodine.
Reactive derivatives of
structure II include activated esters such as 1-hydroxybenzotriazole esters
and similar active
esters known to those ordinarily skilled in the art and includes mixed
anhydrides with organic or
inorganic acids such as hydrochloric acid, other halo-acids and sulfonic acids
as well as similar
acids known to those ordinarily skilled in the art. Additionally, reactive
derivatives of structure
II include symmetrical anhydrides of the acids of structure II. Activated
derivatives of structure
III include trifluoromethane 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 formulas II, III, or IV are
commercially
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
available and others can be prepared by methods known to those ordinarily
skilled in the art. A
non-limiting example of condensations of this type is given in Example 4,
below.
Additionally, appropriately protected compounds resulting from the
condensation of a
compound of stucture 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 Example 5 to afford a secondary or tertiary amine and alkylation
of an amine as
described in Example 9.
Furthermore, compounds of the present invention wherein R6 and R6' are
together oxo,
may be reduced to afford additional compounds of the invention after removal
of any temporary
protecting groups by reduction of the ketone functionality to an alcohol
functionality affording a
benzhydrol in which, for example, R6 is hydroxy and R6' is hydrogen. A non-
limiting example of
this reaction is given in Example 5. Additional reduction of this type of
compound, in an
appropriately protected form if necessary, is then possible to afford a
compound of the present
invention wherein both R6, and R6' are hydrogen. Non-limiting examples of this
reaction are
provided in Examples 2, 6, and 8. One may also oxidize compounds wherein R6 is
hydroxy and
R6' is hydrogen to compounds of the invention wherein R6 and R6' are together
oxo using an
oxidizing agent, for example pyridinium dichromate in an inert solvent (e.g.,
dichloromethane)
at a reduced temperature, for example 0 °C.
Compounds of the structure I may also be prepared from compounds of structure
V (see
below) wherein P is, for example, nitro or cyano. Compounds of structure V are
prepared by
activation of an aromatic acid of the structure VI by alkylation of an anisole
of structure VII
using Friedel-Crafts conditions familiar to those ordinarily skilled in the
art. Compounds of the
structures V and IV are commercially available or may be prepared by means
well known in the
art. A non-limiting example of this alkylation reaction is set forth in
Example 3.
O_
R3
R2i ~ /\ \i y P (V)
R~~R
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
31
R3
O ~ Rs
(VI)
R2 / H
R1
R9 Rio
HOC ~ ~ P
(VII)
Rg R~
Compounds of the structure V may be converted to compounds of structure I by
further
transformation. For example, wherein P is nitro, the resulting compound of
structure V may be
converted into a compound of structure I by reduction to the amine using
standard chemical
reaction conditions such as hydrogen and palladium on carbon as in Example 3.
Wherein P is
cyano, the compound of structure V may be converted a compound of structure I
by reduction to
an alkylated amine using conditions known to those ordinarily skilled in the
art.
R3
O ~ Rs
(VIII)
RZ / Br
R1
Rio Riz
Y Rll
O~ C X
(IX)
R8 R~
Compounds of the present invention can also be prepared using aromatic halides
of
structure VIII and benzaldehyde derivatives of the structure IX. Compounds of
the structures
VIII and IX are commercially available or may be prepared by means well known
in the art. A
non-limiting of the preparation of a compound of structure VIII is provided in
Example 1.
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
32
Derivatives of the structure IX may be prepared from aromatic halides as
described in Examples
1, 7 and 10. The aromatic halide of the structure VIII is converted to the
aryl lithium using a
lithium-halogen exchange reaction as described in Examples 1, 7 and 10 and
reacted with the
derivative of structure IX to afford a compound of the present invention in
which either R6 is
hydroxy and R6' is hydrogen.
For even further guidance, the following provides non-limiting examples
illustrating
more specifically the methods of making various compounds of the present
invention.
As used herein, the following abbreviations are used:
N,N-dimethylformamide DMF
tetrah drofuran THF
N-tent-butox carbonyl BOC
N,N - diiso ro ylethylamine i-Pr2NEt or i-Pr~EtN
Trifluoroacetic acid TFA
Example 1
CA 02375674 2001-11-29
WO 00/73292 PCT/US00/05194
33
OH Br Br
\ \ \
/ / /
NOZ NOZ NHZ
la 1b
Br O~ CH
\ \ \O
/ /
\ \
N N
lc 1d HO
\ N
1g
OH \O \O
\ \ I \ \ I \ \
i i
Br if
1e
la. 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 2.5 hours at 0 °C. Water (25 mL) is added
to quench the reaction.
The organic layer is extracted twice with 25 mL 1N hydrochloric acid, twice
with 25 mL water,
twice with 25 mL 1N sodium hydroxide, twice with 25 mL water, 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 and the organic layer
is separated and dried
with magnesium sulfate. The organic layer is concentrated under high vacuum
and the
remaining residue presorted to silica gel using dichloromethane. The presorted
residue is then
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
34
purified by chromatography on silica gel (hexane:ethyl acetate) and
crystallization from hexanes
to afford la.
1b. 4-bromo-3,5-dimethylaniline: A solution of 4-bromo-3,5-dimethyl-
nitrobenzene (la; 0.6
g) is dissolved in 10 mL of ethyl acetate and 80 mg of 10% palladium on carbon
is added. The
reaction is hydrogenated and then filtered through Celite and concentrated
under reduced
pressure to afford 1b.
lc. N (4-bromo-3,5-dimethylphenyl]pyrrolidine: 4-bromo-3,5-dimethylanaline
(1b; 0.88 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, it is
purified by
chromatography on silica gel (hexane:ethyl acetate) to afford lc.
1d. N [4-carboxaldehyde-3,5-dimethylphenyl]pyrrolidine: N [4-bromo-3,5-
dimethylphenyl]pyrrolidine (lc; 0.44 g) is dissolved in 10 mL THF and cooled
to -78 °C under a
nitrogen atmosphere. To this solution is added 2.0 mL tert-butyl lithium (1.7
M in pentane) and
the reaction is stirred for 10 minutes. At this time, it is removed from the
cooling bath and
allowed to stir for 10 minutes. It is then cooled to -78 °C and 0.27 mL
DMF is added. After 10
minutes, the cooling bath is removed and the reaction is stirred for an
additional 2 hours. The
reaction is transferred to a separatory funnel with 15 mL ether and 15 mL
water and the aqueous
layer is acidified with 1 N HCI. The organic layer is isolated and extracted 5
times with brine
and the organic layer is dried over sodium sulfate and concentrated under
reduced pressure.
Purification by chromatography on silica gel (hexane:ethyl acetate) affords
1d.
1e. 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
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
magnesium sulfate, filtered and concentrated under reduced pressure. The
material is
fractionally distilled under reduced pressure to afford 1e.
WO X0/73292 CA 02375674 2001-11-29 PCT/US00/05194
1f. 4-bromo-2-iso-propyl anisole: Potassium bromide (6.3 g), is suspended in
80 mL
dichloromethane and the reaction is cooled to 0 °C under nitrogen. To
this mixture is added 18-
crown-6 (0.7 g) dissolved in 20 mL dichloromethane. At this time, 3-
chloroperoxybenzoic acid
(9.2 g) in 100 mL dichloromethane is added. Then, 2-iso-propyl anisole (1e; 4
g) is added
dropwise and the reaction stirs for an additional 3 hours at 0 °C under
nitrogen. At this time, the
reaction is poured into 300 mL of ice water and stirred for 30 minutes. The
organic layer is
isolated and washed with a saturated sodium hydrogen carbonate solution, then
water and the
organic layer is dried over magnesium sulfate and concentrated under reduced
pressure.
Purification by chromatography on silica gel (hexane:ethyl acetate) affords
1f.
1g. N (3,5-dimethyl-4-(3'-iso-propyl-4'-
methoxybenzylhydroxy)phenyl]pyrrolidine: 4-
bromo-2-iso-propyl anisole (1f; 0.6 g) is dissolved in 15 mL THF and cooled to
-78 °C under a
nitrogen atmosphere. To this solution is added 3.4 mL tert-butyl lithium (1.7
M in pentane) and
the reaction is stirred for 10 minutes. At this time, the mixture is removed
from the cooling bath
and allowed to stir for 10 minutes. It is then cooled to -78 °C and N
[4-carboxaldehyde-3,5-
dimethylphenyl]pyrrolidine (1d; 0.53 g) is added. The reaction is stirred for
1 hour then the
cooling bath is removed and stirred for an additional 2 hours. The reaction is
transferred to a
separatory funnel with 15 mL ether and 15 mL water and the aqueous layer is
acidified with 1 N
HCI. The organic layer is isolated and extracted 5 times with brine, then
dried over sodium
sulfate and concentrated under reduced pressure. Purification by
chromatography on silica gel
(hexane:ethyl acetate) affords 1g.
WO 00/73292 CA 02375674 2001-11-29 pCT~JS00/05194
36
Example 2
\n \n
N~ N
l g Ice, I~)2
2. N [3,5-dimethyl-4-(3'-iso-propyl-4'-methoxybenzyl)phenyl]pyrrolidine: N
[3,5-
dimethyl-4-(3'-iso-propyl-4'-methoxybenzylhydroxy)phenyl]pyrrolidine (1g; 0.4
g) is dissolved
in 10 mL of 9% acetic acid in ethanol and 50 mg of 10% palladium on carbon is
added. The
reaction is hydrogenated, then filtered through Celite and concentrated under
reduced pressure to
afford 2.
Example 3
COZH
C1 ~ C1 CI ~ C1
~O ~O
/ /
\ \ \
NOz NOZ I
3a / Cl / C1
Cl NOZ Cl NHZ
3b 3c
I
1e
3a. 2,6-dichloro-4-nitrobenzoic acid: 2,6-dichloro-4-nitrotoluene (3 g) is
dissolved in 12.5
mL pyridine followed by addition of 12.8 mL water. The mixture is warmed to 90
°C and
potassium permanganate (14.1 g) is added over 1 hour. The mixture is then
refluxed for 1 hour
and then filtered hot. The filtrate is extracted once with 50 mL chloroform.
The aqueous layer
is acidified with 6N hydrochloric acid and extracted twice with 50 mL
chloroform. After drying
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
37
over magnesium sulfate, the organic solution is filtered, and concentrated
under reduced
pressure to afford 3a.
3b. 2,6-dichloro-4-nitro-3'-iso-propyl-4'-methoxy-benzophenone: 2,6-dichloro-4-
nitrobenzoic acid (3a; 0.4 g) is dissolved in 5 mL thionyl chloride and
refluxed for 1 hour. The
thionyl chloride is then distilled away under reduced pressure and the
remaining residue
dissolved in 300 ~L dichloromethane. To this solution, 150 ~,L
trifluoromethanesulfonic acid
and 2-iso-propyl anisole (1e; 0.17 g) is added and reacted for 5 hours. The
dichloromethane is
then removed under reduced pressure and the remaining residue dissolved in 20
mL ethyl
acetate. The organic solution is extracted twice with 20 mL brine solution.
The organic layer is
concentrated under reduced pressure and purified by chromatography on silica
gel (hexane:ethyl
acetate) to afford 3b.
3c. 2,6-dichloro-4-amino-3'-iso-propyl-4'-methoxy-benzophenone: 2,6-dichloro-4-
nitro-3'-
iso-propyl-4'-methoxy-benzophenone (3b; 144 mg) is dissolved in a mixture
containing 10 mL
ethanol and 10 mL ethyl acetate. To this mixture, 19.2 mg of 10% palladium on
carbon is
added. The reaction is hydrogenated, then filtered through Celite and
concentrated under
reduced pressure to afford 3c.
Example 4
\n
( O
NH2 ,.. N
H
3c 4
4. 2,6-dichloro-4-butyryl amido-3'-iso-propyl-4'-methoxy-benzophenone:
Pyridine (91 pL)
and butyric anhydride (184 pL) are added to 2,6-dichloro-4-amino-3'-iso-propyl-
4'-methoxy-
benzophenone (3c; 130 mg) and the reaction is stirred overnight. The reaction
mixture is
concentrated under reduced pressure and the residue is taken up in 20 mL ethyl
acetate. The
organic solution is extracted once with 20 mL saturated sodium bicarbonate,
once with 20 mL
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
38
0.1 N hydrochloric acid, concentrated under reduced pressure and purified by
chromatography
on silica gel (9:1 hexane:ethyl acetate) to afford 4.
Example 5
\,, \"
( O HC
N ~.. N
H H
4 5
5. N (3,5-dichloro-4-(3'-iso-propyl-4'-methoxybenzylhydroxy)phenyl]butylamine:
2,6-
dichloro-4-butyryl amido-3'-iso-propyl-4'-methoxy-benzophenone (4; 0.53 g) is
dissolved in
THF (10 mL) and added dropwise to a mixture of lithium aluminum hydride (0.33
g) in THF (20
mL) under nitrogen and allowed to react overnight. The reaction is cooled in
an ice bath and
water (2 mL) is added dropwise followed by 2 mL 15% sodium hydroxide then 15
mL water.
The precipitate that is formed is filtered off and the precipitate is washed
with THF and ethyl
acetate. The filtrate is concentrated under reduced pressure and the product
is purified by
chromatography on silica gel (hexanes:methylene chloride) to afford 5.
WO 00/73292 CA 02375674 2001-11-29 pCT~S00/05194
39
Example 6
~n ~n
H(
N ~,~ N
H H
6
6. N [3,5-dimethyl-4-(3'-iso-propyl-4'-methoxybenzyl)phenyl]butylamine: N [3,5-
dichloro-
4-(3'-iso-propyl-4'-methoxybenzylhydroxy)phenyl]butylamine (5; 0.6 g) is
dissolved in 12 mL
of 9% acetic acid in ethanol and 75 mg of 10% palladium on carbon is added.
The reaction is
hydrogenated. The reaction is filtered through Celite and concentrated under
reduced pressure
and the product is purified by chromatography on silica gel
(hexanes:dichloromethane) to afford
6.
Example 7
~n
Br Br
\ \
/ /
NH2 N H(
N
O
O
1b 7a ~b
7a. N [4-bromo-3,5-dimethylphenyl]morpholine: 4-bromo-3,5-dimethylanaline (1b;
0.72 g)
is dissolved in 2 mL ethanol and 0.95 mL 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 under reduced pressure, the
mixture is purified by
chromatography on silica gel (hexane:ethyl acetate) to afford 7a.
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
7b. N [3,5-dimethyl-4-(3'-iso-propyl-4'-
methoxybenzylhydroxy)phenyl]morpholine: N
[3,5-dimethyl-4-(3'-iso-propyl-4'-methoxybenzylhydroxy)phenyl]morpholine (7b)
is prepared
analogously to the preparation described above for N [3,5-dimethyl-4-(3'-iso-
propyl-4'-
methoxybenzylhydroxy)phenyl]pyrrolidine (1g).
Example 8
\n
H<
N~ N
~O ~O
7b 8
8. N [3,5-dimethyl-4-(3'-iso-propyl-4'-methoxybenzyl)phenyl]morpholine: N [3,5-
dimethyl-4-(3'-iso-propyl-4'-methoxybenzylhydroxy)phenyl]morpholine (7b; 0.3
g) is dissolved
in 10 mL of 9% acetic acid in ethanol and 45 mg of 10% palladium on carbon is
added. The
reaction is hydrogenated (about 16 hours), then filtered through Celite and
concentrated under
reduced pressure to afford 8.
CA 02375674 2001-11-29
WO 00/73292 PCT/US00/05194
41
Example 9
\" \"
,.,. N~ ~~ N~
H
6 9
9. N methyl-N [3,5-dimethyl-4-(3'-iso-propyl-4'-
methoxybenzyl)phenyl]butylamine: N
[3,S-dimethyl-4-(3'-iso-propyl-4'-methoxybenzyl)phenyl]butylamine (6), 0.1 g,
is dissolved in 1
mL THF. To this solution is added 50 mg sodium borohydride. The resulting
slurry is added to
a 0 °C solution of 0.24 mL 3.0 M sulfuric acid, 0.086 mL 37% aqueous
solution of
formaldehyde and 1 mL THF. The reaction is stirred for 2 hours and then poured
into 3 mL 1N
sodium hydroxide. The aqueous layer is extracted twice with diethyl ether and
the organic
layers are combined and washed with brine. The organic layer is filtered and
the filtrate is
concentrated under reduced pressure and the product is purified by
chromatography on silica gel
(hexanes:dichloromethane) to afford 9.
CA 02375674 2001-11-29
WO 00/73292 PCT/US00/05194
42
Example 10
~O \O
OH
\ / \ /
\ / ( ~ / \ I / \
Br
10a lOb
~O
O~ CH
~O
\ / ( + ~ /
/ ~ H(
N
Br
lOb
1d
10c. N [3,5-dimethyl-4-(3'-benzyl-4'-methoxybenzylhydroxy)phenyl]pyrrolidine:
N [3,5-
dimethyl-4-(3'-benzyl-4'-methoxybenzylhydroxy)phenyl]pyrrolidine (10c) is
prepared
analogously to N [3,5-dimethyl-4-(3'-iso-propyl-4'-
methoxybenzylhydroxy)phenyl]pyrrolidine
(1g), by substituting 2-benzylphenol for 2-iso-propylphenol.
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 Garner.
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
WO 00/73292 CA 02375674 2001-11-29 pCT~JS00/05194
43
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.
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 Remin~ton'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. Carriers must, of course, be of
sufEciently 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
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
44
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
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 5%, 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-
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
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
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.
CA 02375674 2001-11-29
WO 00/73292 PCT/US00/05194
46
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.
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, iso-propyl 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, iso-propyl
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
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
47
magnesium aluminium silicate, organically modified montmorillonite clay,
hydrated aluminium
silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose,
and ethylene
glycol monostearate.
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 Philippot, "New Type of Lipid Vesicle: Novasome~", Liposome
Technolo~y, 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.g., Internet site www.unipr.it/area/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_erry, "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); Parr~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", Pharm. Res., Vol. 12 (12), pp. 1869-1873
(1995); Thysman et
CA 02375674 2001-11-29
WO 00/73292 PCT/US00/05194
48
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
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 gro~rth
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 fmasteride. 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-
WO 00/73292 CA 02375674 2001-11-29 pCT/US00/05194
49
dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-
pyrrolidone, 1,5-
dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxides, sugar esters,
tetrahydrofurfural
alcohol, urea, diethyl-rn-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.
ExamQles of Co~osition 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
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.
Example B
WO 00/73292 CA 02375674 2001-11-29 PCT/US00/05194
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 I 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.
WO 00/73292 CA 02375674 2001-11-29 PCTNS00/05194
51
Example C
A shampoo is made, comprising:
Ex. C-1 Ex. Ex. Ex.
C-2 C-3 C-4
Component
Ammonium Lau I Sulfate11.5 11.5 9.5 7.5
% % %
Ammonium Laureth 4 % 3 % 2 % 2
Sulfate
Cocamide MEA 2 % 2 % 2 % 2
Ethylene Glycol 2 % 2 % 2 % 2
Distearate
Ce I Alcohol 2 % 2 % 2 % 2
Stea I Alcohol 1.2 % 1.2 1.2 1.2
% %
Glycerin 1 % 1 % 1 % 1
Pol uaternium 10 0.5 % 0.25 - -
%
Polyquaternium 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 Fatty Acid
Pol dimeth 1 Siloxane- - 3 % 2
Cocamino ro 1 Betaine- 1 % 3 % 3
Lauryl Dimethyl 1.5 % 1.5 1.5 1.5
Amine % %
Oxide
Decyl Pol lucose - - 1 % 1
DMDM H dantoin 0.15 0.15 0.15 0.15
% % %
Com ound of Exam - 3 % 3 % -
1e 1
Compound of Exam 6 % - - 6
1e 4
Minoxidil 3 % 2
Phenox ethanol 0.5 % 0.5 0.5 0.5
% %
Fra ante 0.5% 0.5% 0.5% 0.5%
Water q.s. q.s. q.s. q.s.
A human subject ng from le patternaldnesseated ethod
sufferi ma b is by of this
tr a m
invention. Specifically, for 12 weeks, the above shampoo is used daily by the
subject.
