Hair loss abstract
The present disclosure describes methods for treating hair loss
in mammals, including arresting and/or reversing hair loss and promoting
hair growth. The methods comprise administering a cardiac-sparing
compound having a structure of formula (I) as described herein and
a pharmaceutically-acceptable carrier. 1
Hair loss claims
What is claimed is:
1. A method of treating hair loss comprising administering a composition
comprising a cardiac-sparing compound characterized by the structure:
15and pharmaceutically acceptable salts, hydrates, and biohydrolyzable
amides, esters, and imides thereof, wherein: R is selected from
the group consisting of hydrogen, hydroxy, esterified hydroxy, and
etherified hydroxy; R.sub.1, R.sub.2, and R.sub.4 are each, independently,
selected from the group consisting of hydrogen, halogen, trifluoromethyl
and lower alkyl; R.sub.3 is selected from the group consisting of
halogen, trifluoromethyl, lower alkyl, aryl, aryl-lower alkyl, cycloalkyl,
cycloalkyl-lower alkyl, and: 16R.sub.8 is selected from the group
consisting of hydrogen, lower alkyl, aryl, cycloalkyl, aryl-lower
alkyl, and cycloalkyl-lower alkyl; R.sub.9 is selected from the
group consisting of hydroxy and acyloxy; R.sub.10 is selected from
the group consisting of hydrogen and lower alkyl; with the proviso
that R.sub.9 and R.sub.10 collectively optionally represent oxo;
W is selected from the group consisting of --O-- and --S--; X is
selected from the group consisting of --NR.sub.7, S, and O; R.sub.5
is selected from the group consisting of hydrogen, lower alkyl,
and aryl-lower alkyl and R.sub.6 is hydrogen; with the proviso that
when X is --NR.sub.7, R.sub.5 and R.sub.6 together are optionally
oxo; R.sub.7 is selected from the group consisting of hydrogen and
lower alkyl; and Z is selected from the group consisting of carboxyl
and carboxyl derivatized as a pharmaceutically acceptable ester
or amide.
2. A method according to claim 1 wherein X is --NR.sub.7 and R.sub.5
and R.sub.6 together are oxo.
3. A method according to any of claims 1 and 2 wherein: R substitutes
on the 4' position; R.sub.1 substitutes on the 3 position; R.sub.2
substitutes on the 5 position; R.sub.3 substitutes on the 3' position;
and R.sub.4 substitutes on the 5' position.
4. A method according any of claims 1 and 2 wherein: W is --O--;
R is selected from the group consisting of hydroxy, esterified hydroxy,
and etherified hydroxy; R.sub.4 is hydrogen; R.sub.3 is selected
from the group consisting of lower alkyl, aryl-lower alkyl, cycloalkyl-lower
alkyl and 17 and Z is selected from the group consisting of carboxyl
and carboxyl derivatized as a pharmaceutically acceptable ester.
5. A method according to claim 4 wherein the compound is characterized
by the structure: 18wherein R.sub.1 and R.sub.2 are each, independently,
selected from the group consisting of hydrogen, halogen, trifluoromethyl,
and C.sub.1-C.sub.3 alkyl.
6. A method according claim 5 wherein R.sub.7 is selected from
the group consisting of hydrogen and C.sub.1-C.sub.3 alkyl.
7. A method according to any of claims 5 and 6 wherein R is hydroxy.
8. A method according to any of claims 5, 6, and 7 wherein R.sub.3
is selected from the group consisting of isopropyl, benzyl, benzyl
substituted with halogen, and trifluoromethyl.
9. A method according to any of claims 5, 6, 7, and 8 wherein Z
is carboxyl.
10. A method according to any of the preceding claims wherein the
administration is topical.
Hair loss description
FIELD OF THE INVENTION
[0001] 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
[0002] 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.
[0003] 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.
[0004] 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.RTM. by Pharmacia
& Upjohn), and oral finasteride (marketed as Propecia.RTM. 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.
[0005] 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
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 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.g., Fischer et al., DE 1,617,477,
published Jan. 8, 1970; Mortimer, GB 2,138,286, published Oct. 24,
1984; and Lindenbaum, WO 96/25943, assigned to Life Medical Sciences,
Inc., published Aug. 29, 1996.
[0006] 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.g.,
Walker et al., U.S. Pat. No. 5,284,971, assigned to Syntex, issued
Feb. 8, 1994 and Emmett et al., U.S. Pat. No. 5,061,798, assigned
to Smith Kline & French Laboratories, issued Oct. 29, 1991.
Surprisingly, however, the present inventors have discovered biphenyl
derivatives which promote 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 biphenyl derivatives useful in 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 biphenyl derivatives described for use in the
methods and compositions herein are cardiac-sparing compounds useful
for treating hair loss, including arresting and/or reversing hair
loss and promoting hair growth.
SUMMARY OF THE INVENTION
[0007] The present invention relates to methods for treating hair
loss comprising administering a cardiac-sparing compound which has
been found by the present inventors to be particularly useful for
treating hair loss in mammals, including arresting and/or reversing
hair loss and promoting hair growth. The compounds utilized in the
present method are biphenyl derivatives having the structure: 2
[0008] and pharmaceutically acceptable salts, hydrates, and biohydrolyzable
amides, esters, and imides thereof, wherein R, R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, X, W, and Z are defined
herein.
DETAILED DESCRIPTION OF THE INVENTION
[0009] The present invention relates to methods of using compounds
and compositions which are particularly useful for treating hair
loss in mammals, including arresting and/or reversing hair loss
and promoting hair growth.
[0010] 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 are cardiac-sparing. The
preferred compounds useful in the method of the present invention
are therefore, as defined herein below, cardiac-sparing.
[0011] Publications and patents are referred to throughout this
disclosure. All references cited herein are hereby incorporated
by reference.
[0012] All percentages, ratios, and proportions used herein are
by weight unless otherwise specified.
[0013] 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.
[0014] 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
[0015] The following is a list of definitions for terms used herein:
[0016] 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.
[0017] As used herein, "alkyl" is a saturated, straight
or branched chain monovalent hydrocarbon radical. Unless otherwise
specified, alkyls have from 1 to about 10 carbon atoms (C.sub.1-C.sub.10).
Preferred alkyls include, for example, methyl, ethyl, propyl, iso-propyl,
tert-butyl, n-butyl, sec-butyl, and iso-butyl.
[0018] As used herein, the term "aryl" is a carbocyclic
or heterocyclic aryl. Carbocyclic aryl is optionally substituted
phenyl or optionally substituted naphthyl. Heterocyclic aryl is
optionally substituted phenyl or optionally substituted naphthyl,
having at least one heteroatom (N, O, or S) making up the aryl ring.
[0019] As used herein, the term "aryl-lower alkyl" is
aryl substituted by at least one alkyl, lower alkoxy, lower alkanoyloxy,
or trifluoromethyl.
[0020] As used herein, "biohydrolyzable amides" are amides
of the compounds used in 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.
[0021] As used herein, "biohydrolyzable esters" are esters
of the compounds used in 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.
[0022] As used herein, "biohydrolyzable imides" are imides
of the compounds used in 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.
[0023] As used herein "cycloalkyl" refers to a saturated
cyclic hydrocarbon radical, preferably C.sub.5-C.sub.7 cycloalkyl.
Most preferably, a cycloalkyl is cyclopentyl or cyclohexyl.
[0024] As used herein, the term "cycloalkyl-lower alkyl"
is cycloalkyl substituted by at least one alkyl, lower alkoxy, lower
alkanoyloxy, or trifluoromethyl. Non-limiting examples of cycloalkyl-lower
alkyl include 1- or 2-(cyclopentyl or cyclohexyl)ethyl; 1-, 2-,
or 3-(cyclopentyl) or cyclohexyl)propyl; or 1-, 2-, 3-, or 4-(cyclopentyl
or cyclohexyl)butyl.
[0025] As used herein "halogen", "halo", or
the like refers to chlorine, bromine, iodine, and fluorine, preferably
fluorine and chlorine.
[0026] As used herein, the term "lower" in connection
with organic radicals or compounds defines such with up to and including
7, preferably up to an including 4, and most preferably one or two
carbon atoms. The "lower" radical or compound may be straight
or branched.
[0027] As used herein, "pharmaceutically acceptable"
means suitable for use in a human or other mammal.
[0028] 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 site(s) 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.
[0029] Acyl is preferably lower alkanoyl, carbocyclic aryl-lower
alkanoyl, or carbocyclic aroyl.
[0030] Lower alkanoyl is preferably acetyl, propionyl, butyryl,
or pivaloyl.
[0031] Lower alkyanoyloxy is preferably acetoxy, pivaloyloxy, or
propionyloxy.
Methods of the Present Invention
[0032] The present invention relates to methods of treating hair
loss comprising administering a composition comprising a compound
having the structure: 3
[0033] and pharmaceutically acceptable salts, hydrates, and biohydrolyzable
amides, esters, and imides thereof, wherein:
[0034] (a) R is selected from the group consisting of hydrogen,
hydroxy, esterified hydroxy, and etherified hydroxy;
[0035] (b) R.sub.1, R.sub.2, and R.sub.4 are each, independently,
selected from the group consisting of hydrogen, halogen, trifluoromethyl,
and lower alkyl;
[0036] (c) R.sub.3 is selected from the group consisting of halogen,
trifluoromethyl, lower alkyl, aryl, aryl-lower alkyl, cycloalkyl,
cycloalkyl-lower alkyl, and: 4
[0037] (d) R.sub.8 is selected from the group consisting of hydrogen,
lower alkyl, aryl, cycloalkyl, aryl-lower alkyl, and cycloalkyl-lower
alkyl;
[0038] (e) R.sub.9 is selected from the group consisting of hydroxy
and acyloxy;
[0039] (f) R.sub.10 is selected from the group consisting of hydrogen
and lower alkyl; or wherein R.sub.9 and R.sub.10 together represent
oxo;
[0040] (g) W is selected from the group consisting of --O-- and
--S--;
[0041] (h) X is selected from the group consisting of --NR.sub.7,
S, and O;
[0042] (i) R.sub.5 is selected from the group consisting of hydrogen,
lower alkyl, and aryl-lower alkyl and R.sub.6 is hydrogen; or wherein
R.sub.5 and R.sub.6 are together oxo, provided that X is --NR.sub.7;
[0043] (j) R.sub.7 is selected from the group consisting of hydrogen
and lower alkyl; and
[0044] (k) Z is selected from the group consisting of carboxyl
and carboxyl derivatized as a pharmaceutically acceptable ester
or amide.
[0045] The compounds useful in the method herein are further described
in Yokoyama et al., U.S. Pat. No. 5,401,772, assigned to Ciba-Geigy
Corp., issued Mar. 28, 1995; Yokoyama et al., EP 0,580,550, assigned
to Ciba-Geigy Corp., published Jan. 26, 1994; and Yokoyama et al.,
"Synthesis and Structure-Activity Relationships of Oxamic Acid
and Acetic Acid Derivative Related to L-Thyronine", Journal
of Medicinal Chemistry, Vol. 38, pp. 695-707 (1995). However, for
convenience, the compounds are more fully described herein below:
[0046] The R Moiety
[0047] The R moiety is selected from hydrogen, hydroxy, esterified
hydroxy, and etherified hydroxy. As used herein "esterified
hydroxy" refers to acyloxy, e.g., acyloxy derived from an organic
carboxylic acid. Preferred esterified hydroxy include lower alkanoyloxy,
aroyloxy, and aryl-lower alkanoyloxy. As used herein, "etherified
hydroxy" preferably represents lower alkoxy, lower alkenyloxy,
C.sub.5-C.sub.7 cycloalkyloxy, carbocyclic aryl-lower alkoxy, tetrahydropyranyloxy,
C.sub.5-C.sub.7 cycloalkyl-lower alkoxy, and the like.
[0048] More preferably, the R moiety is selected from hydroxy,
esterified hydroxy, and etherified hydroxy. Even more preferably,
the R moiety is selected from hydroxy, lower alkanoyloxy, lower
alkoxy, and tetrahydropyranyloxy. Most preferably, the R moiety
is hydroxy.
[0049] Preferably, the R moiety substitutes at the 4' position
as shown herein.
[0050] The R.sub.1, R.sub.2, R.sub.4 Moieties
[0051] R.sub.1, R.sub.2, and R.sub.4 are each, independently, selected
from hydrogen, halogen, trifluoromethyl and lower alkyl.
[0052] Preferably, R.sub.1 and R.sub.2 are each, independently,
selected from halogen, trifluoromethyl, and C.sub.1-C.sub.3 alkyl.
More preferably, R.sub.1 and R.sub.2 are each, independently, selected
from halogen and C.sub.1-C.sub.3 alkyl. Still more preferably, R.sub.1
and R.sub.2 are each, independently, selected from chlorine and
methyl. Preferably, R.sub.1 and R.sub.2 are equivalent. Most preferably,
R.sub.1 and R.sub.2 are each methyl.
[0053] R.sub.4 is preferably hydrogen.
[0054] Preferably, R.sub.1 substitutes at the 3 position as shown
herein. Preferably, R.sub.2 substitutes at the 5 position as shown
herein. Preferably, R.sub.4 substitutes at the 5' position as shown
herein.
[0055] The R.sub.3 Moiety
[0056] The R.sub.3 moiety is selected from halogen, trifluoromethyl,
lower alkyl, aryl, aryl-lower alkyl, cycloalkyl-lower alkyl, and:
5
[0057] R.sub.8 is selected from hydrogen, lower alkyl, aryl, cycloalkyl,
aryl-lower alkyl, and cycloalkyl-lower alkyl. R.sub.9 is selected
from hydroxy and acyloxy. As used herein, the term "acyloxy"
is --O-acyl, wherein acyl is preferably selected from lower alkanoyl,
carbocyclic aryl-lower alkanoyl, and carbocyclic aroyl. R.sub.10
is selected from hydrogen and lower alkyl; or wherein R.sub.9 and
R.sub.10 together represent oxo (doubly-bonded oxygen).
[0058] Preferably, the R.sub.3 moiety is selected from lower alkyl,
aryl-lower alkyl, cycloalkyl-lower alkyl and 6
[0059] More preferably, the R.sub.3 moiety is selected from iso-propyl,
benzyl, benzyl substituted with halogen, and trifluoromethyl. Most
preferably, R.sub.3 is iso-propyl.
[0060] The R.sub.3 moiety preferably substitutes at the 3' position
as shown herein.
[0061] The W Moiety
[0062] W is selected from --O-- and --S--. Most preferably, W is
--O--.
[0063] The X Moiety
[0064] X is selected from --NR.sub.7--, --S--, and --O--. Preferably,
X is --NR.sub.7-- or --O--. Most preferably, X is --NR.sub.7--.
[0065] The R.sub.5 and R.sub.6 Moieties
[0066] R.sub.5 is selected from hydrogen, lower alkyl, and aryl-lower
alkyl. R.sub.6 is hydrogen. Alternatively, and most preferably,
R.sub.5 and R.sub.6 are, together, an oxo moiety (.dbd.O).
[0067] The R.sub.7 Moiety
[0068] R.sub.7 is selected from hydrogen and lower alkyl. Most
preferably, R.sub.7 is hydrogen.
[0069] The Z Moiety
[0070] Z is selected from carboxyl (--CO.sub.2H) and carboxyl derivatized
as a pharmaceutically acceptable ester or amide. As used herein,
a "carboxyl derivatized as a pharmaceutically acceptable ester"
represents esterified carboxyl, preferably a prodrug ester which
is convertible by solvolysis or under physiological conditions to
the corresponding free carboxylic acid. Similarly, a "carboxyl
derivatized as a pharmaceutically acceptable amide" represents
carboxyl which has been functionalized as an amide, preferably a
prodrug amide which is convertible by solvolysis or under physiological
conditions to the corresponding free carboxylic acid. The amide
may be a primary amide, i.e., --C(.dbd.O)NH.sub.2.
[0071] Preferably, Z is selected from carboxyl and carboxyl derivatized
as a pharmaceutically acceptable ester. Most preferably, Z is carboxyl.
[0072] Preferred carboxyl derivatized as a pharmaceutically acceptable
ester include lower alkoxycarbonyl; (amino, acylamino, mono- or
di-lower alkylamino)-lower alkoxycarbonyl; carboxy-lower alkoxycarbonyl,
e.g., .alpha.-carboxy-lower alkoxycarbonyl; lower alkoxycarbonyl-lower
alkoxycarbonyl, e.g., .alpha.-lower alkoxycarbonyl-lower alkoxycarbonyl;
.alpha.-(di-lower alkylamino, amino, mono-lower alkylamino, morpholino,
piperidino, pyrrolidino, 1-lower alkyl-piperazino)-carbonyl-lower
alkoxycarbonyl; carbocyclic and heterocyclic aryl-lower alkoxycarbonyl,
preferably optionally (halo, lower alkyl or lower alkoxy)-substituted
benzyloxycarbonyl, or pyridylmethoxycarbonyl; 1-(hydroxy, lower
alkanoyloxy or lower alkoxy)-lower alkoxycarbonyl, e.g., pivaloyloxymethoxycarbonyl;
(hydroxy, lower alkanoyloxy or lower alkoxy)-lower alkoxymethoxycarbonyl;
1-(lower alkoxycarbonyloxy)-lower alkoxycarbonyl; 5-indanyloxycarbonyl;
3-phthalidoxycarbonyl and (lower alkyl, lower alkoxy or halo)-substituted
3-phthalidoxycarbonyl; dibydroxypropyloxycarbonyl wherein hydroxy
groups are free or are protected in the form of ketals, e.g., a
lower alkylidene, a benzylidene or a 5- or 6-membered cycloalkylidene
derivative, preferably (2,2-dimethyl-1,3-dioxolan4-yl)-methoxycarbonyl.
[0073] Carboxyl derivatized as a pharmaceutically acceptable prodrug
ester is most preferably C.sub.1-C.sub.4 alkoxycarbonyl, benzyloxycarbonyl
optionally substituted on phenyl by lower alkyl, lower alkoxy, halo
or trifluoromethyl, 1-(C.sub.2-C.sub.4-alkanoyloxy)-ethoxycarbonyl,
(2,2-dimethyl-1,3-dioxolan4-yl)-methoxycarbonyl, 5-indanyloxycarbonyl,
1-(C.sub.1-C.sub.4-alkoxycarbonyloxy)-ethoxycarbonyl or 3-pyridylmethoxycarbonyl.
[0074] Carboxyl derivatized as a pharmaceutically acceptable amide
is preferably carbamoyl or N-substituted carbamoyl, preferably lower
alkylamino carbamoyl, arylamino carbamoyl, di-lower alkylamino carbamoyl,
morpholino carbamoyl, N-lower alkylpiperazino carbamoyl, pyrrolidino
carbamoyl, piperidino carbamoyl, (amino or acylamino)-lower alkylamino
carbamoyl or aryl-lower alkylamino carbamoyl.
Preferred Compounds of the Present Invention
[0075] Preferred compounds of the present invention include those
wherein X is --NR.sub.7 and R.sub.5 and R.sub.6 are together oxo.
Such compounds are represented as: 7
[0076] An even more preferred compound of this structure is wherein
W is --O--.
[0077] Further preferred compounds include those wherein R substitutes
at the 4' position, R.sub.3 substitutes at the 3' position, R.sub.1
substitutes at the 3 position, R.sub.2 substitutes at the 5 position,
and R.sub.4 is hydrogen. Such compounds are represented as: 8
[0078] An even more preferred compound of this structure is wherein
W is --O--.
[0079] Other preferred compounds useful in the present invention
are described in Yokoyama et al., "Synthesis and Structure--Activity
Relationships of Oxamic Acid and Acetic Derivatives Related to L-Thyronine",
Journal of Medicinal Chemistry, Vol. 38, pp. 695-707 (1995). These
compounds are further described in Table 1 below:
1TABLE 1 9 Example No. R.sub.1 R.sub.2 Y R.sub.7 1 hydrogen hydrogen
hydroxy hydrogen 2 iodine iodine hydroxy hydrogen 3 bromine bromine
hydroxy hydrogen 4 bromine bromine NH.sub.2 hydrogen 5 bromine bromine
NH--CH.sub.3 hydrogen 6 chlorine chlorine hydroxy hydrogen 7 fluorine
fluorine hydroxy hydrogen 8 methyl methyl hydroxy hydrogen 9 methyl
methyl NH.sub.2 hydrogen 10 methyl methyl hydroxy methyl 11 iso-propyl
iso-propyl hydroxy hydrogen 12 methyl methyl O--CH.sub.2--CH.sub.3
hydrogen 13 methyl methyl O--CH.sub.2-phenyl hydrogen
Analytical Methods
[0080] The present invention relates to methods of treating hair
loss by administering a compound having a structure as described
herein. 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).
[0081] Cardiotoxicity Assay:
[0082] 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 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.
[0083] Two groups each of six male Sprague Dawley rats (Harlan
Sprague Dawley, Inc., Indianapolis, Ind.) (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.
[0084] 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.
[0085] The vehicle is 91:9 (v:v) propylene glycol:ethanol. The
test compound is prepared at a concentration of 500 .mu.g/mL in
the vehicle.
[0086] 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 .mu.L of dosing solution per kg of rat. For
rats in the test compound group, this corresponds to a dose of 250
.mu.g of test compound per kg of rat.
[0087] 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.
[0088] 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.
[0089] On day 30 in the morning, the rats of each group are euthanized
with CO.sub.2 from dry ice. Each rat is immediately weighed for
total body weight.
[0090] 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.
[0091] 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).
[0092] 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-sparing.
[0093] Telogen Conversion Assay:
[0094] 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").
[0095] 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, Ind.) 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.
[0096] Three groups of 44 day-old C3H mice are utilized: a vehicle
control group, a positive control group, and a test compound group,
wherein the test compound group is administered a compound used
in the method of 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 1 below, Typical
dosage concentrations are set forth in Table 1, however the skilled
artisan will readily understand that such concentrations may be
modified.
2TABLE 1 Group Animal Concen- Application Length of # # Compound
traton volume Study 1 1-10 Test 0.1% in 400 .mu.L 19 or 24 Compound
vehicle* topical days 2 11-20 Positive 0.01% in 400 .mu.L 19 or
24 Control vehicle* topical days (T3) * 3 21-30 Vehicle** N/A 400
.mu.L 19 or 24 topical days **The vehicle is 60% ethanol, 20% propylene
glycol, and 20% dimethyl isosorbide (commercially available from
Sigma Chemical Co., St. Louis, MO).
[0097] 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 .mu.L to each mouse's back. The 400
.mu.L application is applied slowly while moving hair on the mouse
to allow the application to reach the skin.
[0098] 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 2, the grades 0 to 4 represent the following visual observations
as the skin progresses from white to bluish-black.
3 TABLE 2 Visual Observation Grade Whitish Skin Color 0 Skin is
light gray (indication 1 of initiation of anagen) Appearance of
Blue Spots 2 Blue Spots are aggregating to form 3 one large blue
area Skin is dark blue (almost black) 4 with color covering majority
of treatment area (indication of mouse in full anagen)
Method of Making
[0099] The compounds used in the methods of the present invention
are prepared according to procedures which are well-known to those
ordinarily skilled in the art. The starting materials used in preparing
the compounds are known, made by known methods, or are commercially
available as a starting material.
[0100] 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 Organic Chemistry, John Wiley & Sons (1992).
[0101] 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 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 skilled artisan. Examples of many such manipulations can be
found in, for example, T. Greene, Protecting Groups in Organic Synthesis,
John Wiley & Sons (1981).
[0102] The compounds of the present invention may have one or more
chiral centers. 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, may
be separated using known methods, such as through the use of, for
example, chiral salts and chiral chromatography.
[0103] 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.
[0104] The syntheses of the compounds useful in the present invention
are described in the art. Accordingly, the ordinarily skilled artisan
will be able to prepare the compounds described herein. For further
guidance, the syntheses of the present compounds are described in
Yokoyama et al., U.S. Pat. No. 5,401,772, assigned to Ciba-Geigy
Corp., issued Mar. 28, 1995; Yokoyama et al., EP 0,580,550, assigned
to Ciba-Geigy Corp., published Jan. 26, 1994; and Yokoyama et al.,
"Synthesis and Structure-Activity Relationships of Oxamic Acid
and Acetic Acid Derivative Related to L-Thyronine", Journal
of Medicinal Chemistry, Vol. 38, pp. 695-707 (1995).
[0105] For example, the following describes the synthesis of illustrative
compounds utilized in the present invention.
EXAMPLE 1
[0106] 10
[0107] 1a. 2-isopropyl anisole: Potassium hydroxide (5.6 g) is
added to 13.4 mL acetone followed by 2-isopropylphenol (13.6 g).
After the potassium hydroxide is dissolved, methyl iodide (14.2
g) is added. The reaction is refluxed for about 16 hours. 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 MgSO.sub.4, filtered,
and concentrated under reduced pressure. The material is fractionally
distilled under reduced pressure to afford 1a.
[0108] 1b. Bis(3-isopropyl-4-methoxyphenyl)iodonium Tetrafluoroborate:
Acetic anhydride (7 mL) is cooled to -15.degree. C. in a dry ice
acetone bath. Fuming nitric acid (5.4 mL) is added dropwise. Iodine
(2.5 g) is added in one piece followed by dropwise addition of 4.7
mL trifluoroacetic acid. 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.degree. C.
To this cooled solution is added dropwise a solution of 2-isopropyl
anisole (1a; 7.43 g) in 35 mL acetic anhydride and 5 mL trifluoroacetic
acid. The reaction is allowed to stand in a refrigerator for about
16 hours. 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.
The solid is collected, washed with hexane, and dried under vacuum
to afford 1b.
[0109] 1c. 2',6'-dimethyl-3-isopropyl-4-methoxy-4'-nitrodiphenyl
ether: Bis(3-isopropyl-4-methoxyphenyl)iodonium tetrafluoroborate
(1b; 3 g) is weighed and taken up in 7.7 mL dichloromethane and
0.5 g 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 on silica
gel followed by crystallization from hexane:ethyl acetate affords
1c.
[0110] 1d. Methyl N-[3,5-dimethyl-4-(4'-methoxy-3'-isopropylphenoxy)phenyl-
]oxamate: 2',6'-dimethyl-3-isopropyl-4-methoxy-4'-nitrodiphenyl
ether (1c; 0.51 g) is dissolved in 20 mL ethanol and 60 mg of 10%
palladium on carbon is added. The reaction is hydrogenated for 3
hours, then filtered through celite and concentrated under reduced
pressure. Dimethyl oxamate (3 g), is added to the residue and the
reaction is heated to 120.degree. C. for 4 hours. The reaction mixture
is concentrated under reduced pressure and purified by chromatography
on silica gel to afford 1d.
[0111] 1e. N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)phenyl]oxamat-
e: Methyl N-[3,5-dimethyl-4-(4'-methoxy-3'-isopropylphenoxy)phenyl]oxamate
(1d; 350 mg) is dissolved in 3.5 mL dichloromethane and cooled in
a dry ice acetone bath. To this solution is dropwise added 2 mL
boron tribromide (1 M in dichloromethane). The reaction is stirred
about 16 hours and is allowed to reach ambient temperature. At this
time, the reaction is poured onto 10 mL ice and water. To this mixture
is added 10 mL ethyl acetate. The organic layer is separated and
the aqueous phase is extracted twice with 10 mL ethyl acetate. The
organic layers are combined, dried over magnesium sulfate, and concentrated
under reduced pressure. The material is dissolved in 1:1 acetonitrile:water
and loaded onto a column containing 5 g C.sub.18-derivatized silica
gel and equilibrated with water. The product is eluted using a step
gradient, 2.times.15 mL 25:75 acetonitrile:water, 1.times.15 mL
35:65 acetonitrile:water, 1.times.15 mL 40:60 acetonitrile:water,
2.times.15 mL 45:55 acetonitrile:water, and 1.times.15 mL 50:50
acetonitrile:water to afford 1e.
EXAMPLE 2
[0112] 11
[0113] The compound of Example 2 is synthesized as described in
Yokoyama et al., "Synthesis and Structure-Activity Relationships
of Oxamic Acid and Acetic Acid Derivative Related to L-Thyronine",
Journal of Medicinal Chemistry, Vol. 38, pp. 695-707 (1995).
EXAMPLE 3
[0114] 12
[0115] The compound of Example 3 is synthesized as described in
Yokoyama et al., U.S. Pat. No. 5,401,772, assigned to Ciba-Geigy
Corp., issued Mar. 28, 1995.
EXAMPLE 4
[0116] 13
[0117] 4a. 2',6'-diiodo-3-isopropyl-4-methoxy-4'-nitrodiphenyl
ether: Bis(3-isopropyl-4-methoxyphenyl)iodonium tetrafluoroborate
(prepared as described in Example 1b) (3 g) is weighed is taken
up in 7.7 mL dichloromethane and 0.5 g copper bronze is added. The
mixture is cooled in an ice water bath. A solution of 2,6-diiodo-4-nitrophenol
(1.53 g) and triethyl amine (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, 25 mL methanol is added to the reaction and
is filtered through a plug of silica gel. The silica gel is washed
with an additional 5 mL of methanol and the filtrate is concentrated
under reduced pressure. Purification of the product by chromatography
on silica gel affords 4a.
[0118] 4b. Methyl N-[3,5-diiodo-4-(4'-methoxy-3'-isopropylphenoxy)phenyl]o-
xamate: 2',6'-diiodo-3-isopropyl-4-methoxy-4'-nitrodiphenyl ether
(4a) (0.62 g) is dissolved in 20 mL ethanol and 2 mL N,N-dimethylformamide
and 40 mg of 10% palladium on carbon is added. The reaction is hydrogenated
for 4 hours, then filtered through celite and concentrated under
reduced pressure. Dimethyl oxamate (3 g) is added to the residue
and the reaction is heated to 120.degree. C. for 3 hours. The reaction
mixture is concentrated under reduced pressure and purified by chromatography
on silica gel to afford 4b.
[0119] 4c. N-[3,5-diiodo 4(4'-hydroxy-3'-isopropylphenoxy)phenyl]oxamate:
Methyl N-[3,5-diiodo-4-4'-methoxy-3'-isopropylphenoxy)phenyl]oxamate
(4b) (62 mg) is dissolved in 1 mL dichloromethane and cooled in
a dry ice acetone bath. To this solution is added 0.2 mL boron tribromide
(1 M in dichloromethane). The reaction is stirred for about 16 hours
and allowed to reach room temperature. The reaction is poured onto
10 mL ice and water. To this mixture is added 10 mL ethyl acetate.
The organic layer is separated and the aqueous phase is extracted
a second time with 10 mL ethyl acetate. The organic layers are combined,
washed with brine, dried over magnesium sulfate, and concentrated
under reduced pressure. Purification of the product by chromatography
on silica gel affords 4c.
EXAMPLE 5
[0120] 14
[0121] 5. N-[3,5-dimethyl-4-(4'-methoxy-3'-isopropylphenoxy)phenyl]oxamate-
: Methyl N-[3,5-dimethyl-4-(4'-methoxy-3'-isopropylphenoxy)phenyl]oxamate
(prepared as described in Example 1d) (750 mg) is dissolved in 12
mL methanol and 2.2 ML 1 N sodium hydroxide is added. The sample
is reacted overnight. The mixture is concentrated under reduced
pressure. To the mixture is added 25 mL water and 15 mL ethyl acetate,
followed by 5 mL 1 N HCl. The mixture is transferred to a separatory
funnel and an additional 35 mL ethyl acetate is added. The organic
layer is separated and the aqueous phase is extracted once with
15 mL ethyl acetate and once with 10 mL ethyl acetate. The organic
layers are combined, washed with 25 mL saturated sodium chloride,
and dried over magnesium sulfate. The solution is filtered and concentrated
under reduced pressure to afford 5.
Use of the Present Compounds
[0122] The methods of the present invention are performed by administering
to a mammal (preferably a human) a compound having a structure as
described herein and, preferably, a pharmaceutically-acceptable
or cosmetically-acceptable carrier.
[0123] The compounds herein 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.
[0124] Preferably the compounds of the present invention are, as
defined herein, cardiac-sparing.
[0125] Preferably, in the methods of the present invention, 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).
[0126] 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.
[0127] 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 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.
[0128] 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 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.sup.nd Ed., (1976).
[0129] 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.
[0130] 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.
[0131] 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.
[0132] 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-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.
[0133] 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 skilled
in the art.
[0134] 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.
[0135] 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.
[0136] 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.
[0137] 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.
[0138] 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.
[0139] 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:
[0140] 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, dimethyl sulphoxide, 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.
[0141] 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.RTM.", Liposome Technology,
Vol. 1, pp. 141-156 (1993); Wallach, U.S. Pat. No. 4,911,928, assigned
to Micro-Pak, Inc., issued Mar. 27, 1990; and Weiner et al., U.S.
Pat. No. 5,834,014, assigned to The University of Michigan and Micro-Pak,
Inc., issued Nov. 10, 1998 (with respect to Weiner et al., with
a compound as described herein administered in lieu of, or in addition
to, minoxidil).
[0142] The compounds of the present invention may also be administered
by iontophoresis. See, e.g., internet site www.unipr.it/arpa/dipfarm/erasmus-
/erasm14.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); Ferry, "Theoretical
Model of Iontophoresis Utilized in Transdermal Drug Delivery",
Pharmaceutical Acta Helvetiae, Vol 70, pp. 279-287 (1995); Gangarosa
et al., "Modem 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 lontophoresis", 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 viva in Humans", Pharm. 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 Nude Mouse Skin by Electrorepulsion
and Electroosmosis", Pharm. Res., Vol. 12 (11), pp. 1623-1627
(1995).
[0143] 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.
[0144] 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.
[0145] 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-l-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, dimethyl sulphoxide, N,N-dimethyl acetamide,
N,N-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-m-toluamide,
and, 1-dodecylazacyloheptan-2-one.
[0146] 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.
[0147] The present invention further relates to kits comprising
a compound and/or composition herein 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 herein 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.
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