Note: Descriptions are shown in the official language in which they were submitted.
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SMALL MOLECULE SULFONAMIDE
HAIR GROWTH COMPOSITIONS AND USES
This application is a continuation-in-part of
U.S. Patent Application No. 08/869,426, filed on June
4, 1997, the entire contents of which are herein
incorporated by reference.
BACKGROUND OF THE INVENTION
1. Field of In.veation
This invention relates to pharmaceutical
compositions and methods for treating alopecia and
promoting hair growth using low molecular weight,
small molecule ~;ulfonamides.
2. Descriptior.~ of Related Art
Hair loss occurs in a variety of situations.
These situations include male pattern alopecia,
alopecia senilis, alopecia areata, diseases
accompanied by basic skin lesions or tumors, and
systematic disorders such as nutritional disorders and
internal secretion disorders. The mechanisms causing
hair loss are very complicated, but in some instances
can be attributed to aging, genetic disposition, the
activation of male hormones, the loss of blood supply
to hair folliclE~s, and scalp abnormalities.
The immunosuppressant drugs FK506, rapamycin and
cyclosporin are well known as potent T-cell specific
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2
_ immunosuppressan.ts, and are effective against graft _
rejection after organ transplantation. It has been
reported that topical, but not oral, application of
FK506 (Yamamoto et al., J. Invest. Dermatol., :L994,
102, 160-164; Jiang et al., J. Invest. Dermatol. 1995,
104, 523-525) and cyclosporin (Iwabuchi et al., J.
Dermatol. Sci. 1995, 9, 64-69) stimulates hair growth
in a dose-dependent manner. One form of hair loss,
alopecia areata, is known to be associated with
autoimmune activities; hence, topically administered
immunomodulatory compounds are expected to demonstrate
efficacy for treating that type of hair loss. The
hair growth stimulating effects of FK506 have been the
subject of an :international patent filing covering
FK506 and struci~ures related thereto for hair growth
stimulation (Honbo et al., EP 0 423 714 A2). Honbo et
al. discloses the use of relatively large tricyclic
compounds, known for their immunosuppressive effer_ts,
as hair revitalizing agents.
The hair growth and revitalization effects of
FK506 and related agents are disclosed in many 11. S.
patents (Goulet et al., U.S. Patent No. 5,258,:389;
Luly et al . , U. f.. Patent No. 5, 457, 111; Goulet et <~1 . ,
U.S. Patent No. 5,532,248; Goulet et al., U.S. Patent
No. 5,189,042; and Ok et al., U.S. Patent No.
5,208,241; Rupprecht et al., U.S. Patent No.
5,284,840; Organ et al., U.S. Patent No. 5,284,877).
These patents claim FK506 related compounds. Although
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3
_ they do not claim methods of hair revitalization, they
disclose the known use of FK506 for effecting hair
growth. Similar to FK506 (and the claimed variations
in the Honbo et al. patent), the compounds claimed in
these patents are relatively large. Further, the
cited patents re:Late to immunomodulatory compounds for
use in autoimmune related diseases, for which FK506's
efficacy is well known.
Other U.S. patents disclose the use of
cyclosporin and related compounds for hair
revitalization (Hauer et al., U.S. Patent No.
5,342,625; Eberle, U.S. Patent No. 5,284,826; Hewitt
et al., U.S. Patent No. 4,996,193). These patents
also relate t.o compounds useful for treating
autoimmune diseases and cite the known use of
cyclosporin and related immunosuppressive compounds
for hair growth..
However, immunosuppressive compounds by
definition suppress the immune system and also exhibit
other toxic side effects. Accordingly, there i.s a
need for non-immunosuppressant, small molecule
compounds which are useful as hair revitalizing
compounds.
Hamilton and Steiner disclose in U.S. Patent No.
5,614,547 novel pyrrolidine carboxylate compounds
which bind to the immunophilin FKBP12 and stimulate
nerve growth, but which lack immunosuppressive
effects. Unexpectedly, it ha.s been discovered that
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4
_ these non-immunosuppressant compounds promote hair
growth with an efficacy similar to FK506. Yet their
novel small molecule structure and non-immuno-
suppressive pro~rerties differentiate them from FK506
and related immunosuppressive compounds found in the
prior art.
S'(TMMARY OF THE INVENTION
The present, invention relates to a method for
treating alopecia or promoting hair growth in an
animal, which comprises administering to said animal
an effective amount of a small molecule sulfonamide.
The present invention further relates to a
pharmaceutical composition which comprises:
(i) an effective amount of a small molecule
sulfonamide for treating alopecia or
promoting hair growth in an animal; and
(ii) a pharmaceutically acceptable carrier.
The small molecule sulfonamides used in the
inventive methods and pharmaceutical compositions may
be immunosuppressive, but are preferably non
immunosuppressive compounds having an affinity for
FKBP-type immunophilins, particularly FKBP12. Non
immunosuppressive compounds, as their name suggests,
do not exert any significant immunosuppressive
activity.
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BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is .a photograph of mice treated with a
vehicle after si:x weeks. FIG. 1 shows that less than
3% of the shaved area is covered with new hair growth
5 when the vehicle (control) is administered.
FIG. 2 is a photograph of mice treated with 10 ~M
of a related neuroimmunophilin FKBP ligand, GPI 1044,
after six weeks. FIG. 2 shows that 90% of the shaved
area is covered with new hair growth when GPI 1044 is
administered.
FIG. 3 is a photograph of mice treated with 10 ~M
of another related neuroimmunophilin FKBP ligand, GPI
1116, after six weeks. FIG. 3 shows that 90% of the
shaved area is covered with new hair growth when GPI
1116 is administered.
FIG. 4 is a photograph of mice treated with 3 ~.M
of a third related neuroimmunophilin FKBP ligand, GPI
1102, after six weeks. FIG. 3 shows that 90% of the
shaved area is covered with new hair growth when GPI
1102 is administered.
FIG. 5 is a bar graph plotting the hair growth
scores of unshaven animals and shaven animals treated
with a vehicle, GPI 1044 (1 ~.M, 3 ~,M and 10 ~.M) , GPI
1116 ( 1 ~M and 1~_0 ~.M) , and GPI 1102 ( 1 ~M and 3 ~,M) .
FIG. 6 is a bar graph depicting the relative hair
growth indices for C57 Black 6 mice treated with a
vehicle, FK506, and related neuroimmunophilin 1~KBP
ligands 14 days after treatment with each identified
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compound. Figure 6 demonstrates the remarkable early
hair growth promoted by neuroimmunophilin FKBP
ligands.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
"Alopecia" refers to deficient hair growth and
partial or complete loss of hair, including without
limitation androgenic alopecia (male pattern
baldness), toxic; alopecia, alopecia senilis, alopecia
areata, alopec;ia pelada and trichotillomania.
Alopecia result; when the pilar cycle is disturbed.
The most frequent phenomenon is a shortening of the
hair growth or anagen phase due to cessation of cell
proliferation. This results in an early onset of the
catagen phase, and consequently a large number of
hairs in the te7_ogen phase during which the follicles
are detached from the dermal papillae, and the hairs
fall out . Alopecia has a number of etiologies,
including genetic factors, aging, local and systemic
diseases, febrile conditions, mental stresses,
hormonal problems, and secondary effects of drugs.
"GPI 1044" refers to the compound
N~O~ ~B
O~ O D
O
L
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wherein B is 3-Phenylpropyl, D is 3-Phenylpropyl, and
L is Phenyl.
"GPI 1102" refers to 4-phenyl-1-(3-phenylpropyl)
butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2
piperidinecarboxylate.
"GPI 1116" refers to 1-phenethyl-3-phenylpropyl
1-(3,3-dimethyl-2-oxopentanoyl)-~2-
piperidinecarboxylate.
"GPI 1206" refers to a compound of formula
N
O ~ /
N
~ O
HN' ' S
GPI 1206
"Isomers" refer to different compounds that have
the same molecular formula. "Stereoisomers" are
isomers that differ only in the way the atoms are
arranged in space. "Enantiomers" are a pair of
stereoisomers that are non-superimposable mirror
images of each other. "Diastereoisomers" are
stereoisomers which are not mirror images of each
other. "Racemic mixture" means a mixture containing
equal parts of individual enantiomers. "Non-racemic
mixture" is a mixture containing unequal part: of
individual enantiomers or stereoisomers.
"Pharmaceutically acceptable salt, ester, or
solvate" refer: to a salt, ester, or solvate of a
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_ subject compound which possesses the desired
pharmacological activity and which is neither
biologically nor otherwise undesirable. A salt,
ester, or solvate can be formed with inorganic acids
such as acetate, adipate, alginate, aspartate,
benzoate, benz~enesulfonate, bisulfate, butyrate,
citrate, camphorate, camphorsulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, glucoheptanoate, gluconate,
glycerophosphate~, hemisulfate, heptanoate, hexanoate,
hydrochloride, hydrobromide, hydroiodide, 2-
hydroxyethanesulfonate, lactate, maleate,
methanesulfonate~,naphthylate,2-naphthalenesulfonate,
nicotinate, oxalate, sulfate, thiocyanate, tosyl.ate
and undecanoate" Examples of base salts, esters, or
solvates includes ammonium salts; alkali metal salts,
such as sodium and potassium salts; alkaline earth
metal salts, such as calcium and magnesium salts;
salts with organic bases, such as dicyclohexylamine
salts; N-methyl.-D-glucamine; and salts with arnino
acids, such as arginine, lysine, and so forth. Also,
the basic n~_trogen-containing groups can be
quarternized with such agents as lower alkyl halides,
such as methyl, ethyl, propyl, and butyl chlorides,
bromides, and iodides; dialkyl sulfates, such as
dimethyl, dieth~Tl, dibutyl, and diamyl sulfates; .Long
chain halides, such as decyl, lauryl, myristyl, and
stearyl chlorides, bromides, and iodides; ara:lkyl
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_ halides, such a;~ benzyl and phenethyl bromides and
others. Water or oil-soluble or dispersible products
are thereby obtained.
"Pilar cyc3_e" refers to the life cycle of hair
follicles, and includes three phases:
(1) the anagen phase, the period of active hair
growtr~ which, insofar as scalp hair is
concerned, lasts about three to five years;
(2 ) the catagen phase, the period when growth
stops and the follicle atrophies which,
insofar as scalp hair is concerned, lasts
about one to two weeks; and
(3) the te:logen phase, the rest period when hair
progrEasively separates and finally falls
out ~nrhich, insofar as scalp hair is
concerned, lasts about three to four months .
Normally 80 to 90 percent of the follicles are in the
anagen phase, less than 1 percent being in the catagen
phase, and the rest being in the telogen phase. In
the telogen pha;3e, hair is uniform in diameter wii~h a
slightly bulbous>, non-pigmented root. By contrast, in
the anagen phase', hair has a large colored bulb at its
root.
"Promoting hair growth" refers to maintaining,
inducing, stimulating, accelerating, or revitalizing
the germination of hair.
"Treating alopecia" refers to:
(i) preveni~ing alopecia in an animal which may be
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predisposed to a~lopecia; and/or
(ii) inhibiting, retarding or reducing alopecia;
and/or
(iii) promoting hair growth; and/or
5 (iv) prolonging the anagen phase of the hair
cycle; and/or
(v) converting vellus hair to growth as terminal
hair. Terminal hair is coarse, pigmented, long hair
in which the bulb of the hair follicle is seated deep
10 in the dermis. Vellus hair, on the other hand, is
fine, thin, non-pigmented short hair in which the hair
bulb is located superficially in the dermis. As
alopecia progresses, the hairs change from the
terminal to the vellus type.
Metho~3s of the Present Invention
The present invention relates to a method for
treating alopecia or promoting hair growth i.n an
animal, which comprises administering to said animal
an effective amount of a small molecule sulfonamide.
The inventive method is particularly useful for
treating male pattern alopecia, alopecia seni:Lis,
alopecia areata,, alopecia resulting from skin lesions
or tumors, alope:cia resulting from cancer therapy such
as chemotherapy and radiation, and alopecia resulting
from systematic disorders such as nutritional
disorders and internal secretion disorders.
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Pharmaceutical Compositions of the Present Invention
The present: invention also relates to a pharma-
ceutical composition comprising:
(i) an effective amount of a small molecule
sul forsamide ; and
(ii) a phax-maceutically acceptable carrier.
SMALL MOLECULE SULFONAMIDES
The sulfonamides used in the methods and
pharmaceutical compositions of the present invent: ion
are low molecular weight, small molecule compounds
having an affinity for FKBP-type immunophilins, such
as FKBP12. When a sulfonamide binds to an FKBP-type
immunophilin, it; has been found to inhibit the prolyl-
peptidyl cis-t.r~ins isomerase, or rotamase, activity of
the binding protein. Unexpectedly, the compounds have
also been found to stimulate hair growth. These
rotamase inhibiting compounds are non-immuno-
suppressive. Examples of useful compounds are set
forth below.
FORMULA I
An exemplary small molecule sulfonamide is a
compound of Formula I
B
J
2
I
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_ or a pharmaceutically acceptable salt thereof,
wherein:
A is CH2, 0, NH, or N- (C1-C4 alkyl) ;
B and D are independently Ar, hydrogen, C1-C6
straight or branched chain alkyl, or Cz-C6 straight or
branched chain alkenyl, wherein said alkyl or alke~nyl
is unsubstituted or substituted with CS-C., cycloalkyl,
CS-C., cycloalken~,rl or Ar, and wherein one or two carbon
atoms) of said alkyl or alkenyl may be substituted
with one or two heteroatom(s) independently selected
from the group consisting of O, S, SO, and SO;, in
chemically reasonable substitution patterns, or
Q
wherein Q is hydrogen, C1-C6 straight or
branched chain alkyl, or Cz-C6 straight or
branched chain alkenyl; and
T is Ar or CS-C, cycloalkyl substituted
at positions 3 and 4 with one or more
. substituent(s) independently selected from
the group consisting of hydrogen, hydroxy,
O- (C1-C4 alkyl) , O- (C2-C4 alkenyl) , and
carbonyl;
provided that both B and D are not hydrogen;
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Ar is selected from the group consisting of
phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-
thi enyl , 3 - thienyl , 2 -pyridyl , 3 -pyridyl , 4 -pyri<iyl ,
monocyclic and bicyclic heterocyclic ring systems with
individual ring sizes being 5 or 6 which contain in
either or both rings a total of 1-4 heteroatoms
independently selected from the group consisting o:E O,
N, and S; wherein Ar contains 1-3 substituent:(s)
independently selected from the group consisting of
hydrogen, halo, hydroxy, nitro, trifluoromethyl,
trifluoromethox~r, C1-C6 straight or branched chain
alkyl, CZ-C6 straight or branched chain alkenyl, O- (C1-
C4 straight or branched chain alkyl) , O- (C2-C~ straight
or branched chain alkenyl), O-benzyl, O-phenyl, :L,2-
methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C Z-C6
straight or branched chain alkenyl, CS-C, cycloalkyl,
cycloalken.yl substituted with C1-C4 straight. or
branched chain alkyl or Cz-C4 straight or branched
chain alkenyl, (,Cz-C4 alkyl or Cz-C4 alkenyl) -Ar, or Ar;
J is hydrogen, C1 or CZ alkyl, or benzyl; K is C1
CQ straight or' branched chain alkyl, benzyl, or
cyclohexylmethyl; or J and K are taken together to
form a 5-7 membered heterocyclic ring which is
substituted with O, S, SO, or SOZ;
n is 0 to 3; and
the stereochemistry at carbon positions 1 a:nd 2
is R or S.
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FORMULA II
In a preferred embodiment of Formula I, J and K
are taken together and the small molecule sulfonamide
is a compound of: Formula II
B
m wD
n O II
~ ,
. ~ O
H
~2
E
or a pharmaceutically acceptable salt thereof,
wherein:
n is 1 or 2; and
m is 0 or 7_.
In a more preferred embodiment, B is seler_ted
from the group consisting of hydrogen, benzyl, 2-
phenylethyl, anti 3-phenylpropyl;
D is selected from the group consisting of
phenyl, 3-phenylpropyl, 3-phenoxyphenyl, and 4-
phenoxyphenyl; and
E is selected from the group consisting of
phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-thienyl,
2,4,6-triisopropylphenyl, 4-fluorophenyl, 3-
methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl,
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3,4,5-trimethox;rphenyl, methyl, 1-naphthyl, 8
quinolyl, 1-(5-N,N-dimethylamino)-naphthyl, 4
iodophenyl, 2,4,6-trimethylphenyl, benzyl, 4
nitrophenyl, 2-nitrophenyl, 4-chlorophenyl, and E
5 styrenyl.
FORMLThA III
Another exemplary small molecule sulfonamides is
a compound of Formula III
B
IIz
C;
E
or a pharmaceutically acceptable salt thereof,
wherein:
B and D a.re independently Ar, hydrogen, C1-C6
straight or branched chain alkyl, or Cz-C6 straight or
branched chain alkenyl, wherein said alkyl or alkenyl
is unsubstituted or substituted with CS-C, cycloalkyl,
CS-C., cycloalkenyl or Ar, and wherein one or two carbon
atoms) of said alkyl or alkenyl may be substituted
with one or two heteroatom(s) independently selected
from the group consisting of O, S, SO, and SO2 in
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chemically reasonable substitution patterns, or
T
s Q
wherein Q is hydrogen, C1-C6 straight or
branched chain alkyl, or CZ-C6 straight or
branched chain alkenyl; and
T is Ar or CS-C~ cycloalkyl substituted
at positions 3 and 4 with one or more
substituent(s) independently selected from
the group consisting of hydrogen, hydroxy,
O- (C1-C4 alkyl) , O- (CZ-C4 alkenyl) , and
carbonyl;
provided that both B and D are not hydrogen;
Ar is selected from the group consisting of
phenyl, Z-napth.yl, 2-naphthyl, 2-furyl, 3-furyl, 2-
thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
monocyclic and bicyclic heterocyclic ring systems with
individual ring sizes being 5 or 6 which contain in
either or both rings a total of 1-4 heteroatoms
independently selected from the group consisting of O,
N, and S; wherein Ar contains 1-3 substituent(s)
independently ~~elected from the group consistinc3 of
hydrogen, halo, hydroxy, n:itro, trifluoromethyl,
trifluoromethoxy, C1-C6 straight or branched chain
alkyl, CZ-C6 straight or branched chain alkenyl, O-~(C1-
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C4 straight or branched chain alkyl) , O- (Cz-C4 straight
or branched chain alkenyl), O-benzyl, O-phenyl, L,2-
methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C'2-C6
straight or branched chain alkenyl, CS-C~ cycloalkyl,
CS-C, cycloalken.yl substituted with C1-C4 straight. or
branched chain alkyl or CZ-C4 straight or branched
chain alkenyl, (Cz-C4 alkyl or Cz-C4 alkenyl) -Ar, or Ar;
and
m is 0 to
FORMULA IV
A further exemplary small molecule sulfonamidE~ is
a compound of Formula IV
B
m
O IV
G ~ O O
E
or a pharmaceutically acceptable salt thereof,
wherein:
B and D are independently Ar, hydrogen, C1-C6
straight or branched chain alkyl, or Cz-C6 straight or
branched chain ~ilkenyl, wherein said alkyl or alkenyl
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is unsubstituted or substituted with CS-C, cycloalkyl,
cycloalkenyl, or Ar, and wherein one or two
carbon atoms) of said alkyl or alkenyl may be
substituted with one or two heteroatom(s)
independently selected from the group consisting of O,
S, SO, and S02 in chemically reasonable substitution
patterns, or
T
to
Q
wherein Q is hydrogen, C1-C6 straight or
branched chain alkyl , or CZ-C6 straight or
branched chain alkenyl; and
T is Ar or CS-C, cycloalkyl substituted
at positic>ns 3 and 4 with one or more
substitueni~(s) independently selected from
the group consisting of hydrogen, hydroxy,
O- (C1-C4 alkyl) , O- (CZ-C4 alkenyl) , and
carbonyl;
provided that both B and D are not hydrogen;
Ar is selected from the group consisting of
phenyl, l-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2
thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
monocyclic and bicyclic heterocyclic ring systems with
individual ring sizes being 5 or 6 which contain in
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either or both rings a total of 1-4 heteroatoms _
independently selected from the group consisting of O,
N, and S; wherein Ar contains 1-3 substituent.(s)
independently selected from the group consisting of
hydrogen, halo, hydroxy, nitro, trifluoromethyl,
trifluoromethoxy, C1-C6 straight or branched cYaain
alkyl, Cz-C6 straight or branched chain alkenyl, O- (C1-
C4 straight or branched chain alkyl) , O- (C2-C4 straight
or branched chain alkenyl), O-benzyl, O-phenyl, 1.,2-
methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, Cz-C6
straight or branched chain alkenyl, CS-C~ cycloalkyl,
CS-C~ cycloalkenyl substituted with C,-C9 straight or
branched chain alkyl or CZ-C4 straight or branched
chain alkenyl, (CZ-C4 alkyl or C2-C4 alkenyl) -Ar, or Ar;
and
m is 0 to 3.
FORMULA V
A further exemplary small molecule sulfonamide' is
a compound of Fc>rmula V
B
t'~ ' D
V
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or a pharmaceutically acceptable salt, ester, or
solvate thereof, wherein:
V is C, N, or S;
J and K, taken together with V and the carbon
5 atom to which they are respectively attached, form a
5-7 membered saturated or unsaturated heterocyclic
ring containing, in addition to V, one or more
heteroatom(s) selected from the group consisting of O,
S, SO, SO2, N, NfH, and NR;
10 R is either Cl-C9 straight or branched chain
alkyl, Cz-C9 straight or branched chain alkenyl, C 3-C9
cycloakyl, CS-C;, cycloalkenyl, or Arl, wherein R: is
either unsubstil~uted.of substituted with one or more
substituent(s) independently selected from the group
15 consisting of halo, haloalkyl, carbonyl, carboxy,
hydroxy, nitro, trifluoromethyl, C1-C6 straight or
branched chain alkyl, CZ-C6 straight or branched chain
alkenyl, C1-C4 alkoxy, CZ-C4 alkenyloxy, phenoxy,
benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino,
20 alkylamino, aminoalkyl, aminocarboxyl, and Ar2;
Arl and Ar~z are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or
heterocyclic ring; wherein the individual ring size is
5-8 members; wherein said heterocyclic ring contains
1-6 heteroatoml;s) independently selected from the
group consisting of O, N, and S;
A, B, D, E:, and n are as defined in Formula I
above.
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Representative species of Formulas I-V are
presented in Table I.
TABLE I
Compound Structure
1
~Ni~~O
O
f/ t
4 - p h a n y 1 - 1 - b a t y 1 - 1 -
(benzylsulfonyl) - (2R, S) -2-
pipecolinate
2
O /
N
i
O=S=O O
1,5-diphenyl-3-pentyl-N-(a-
toluene-sulfonyl)pipecolate
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TABLE I (continued)
Compound Structure
3 0
N
0=S=O O
CH3
1,7-diphenyl-4-heptyl-N-(para-
toluene-sulfonyl)pipecolate
N
4
O
N
I
O=S=O O
3- (3-pyridyl) -1-propyl- (2S) -N~- (a-
toluenesulfonyl)pyrrolidine-2-
carboxylate
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_ TABLE I (continued)
Compound Structure
5
N 0 /
0=S=O O \
to ( /
CH3
4-phenyl-1-butyl-N-(para-toluene-
sulfonyl) p:ipecolate
6
N ~ /
0=S=O O \
4-phenyl-1-butyl-N-(benzene-
sulfonyl)pipecolate
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TAHLE I (continued)
Compound Structure
7
O
N
0
to
4-phenyl-1-butyl-N-(a-toluene-
sulfonyl)pipecolate
All the compounds of Formulas I-V possess
asymmetric ceni~ers and thus can be produced as
mixtures of stereoisomers or as individual R- and S-
stereoisomers. The individual stereoisomers may be
obtained by using an optically active starting
material, by resolving a racemic or non-racemic
mixture of an intermediate at some appropriate stage
of the synthesis, or by resolving the compounds of
Formulas I-V. It is understood that the compounds of
Formulas I-V encompass individual stereoisomers as
well as mixtures (racemic and non-racemic) of
stereoisomers. Preferably, S-stereoisomers are used
in the pharmeceutical compositions and methods of the
present invention.
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_ Synthesis of Small Molecule Sulfonamides
The compounds of Formulas I-V may be readily
prepared by standard techniques of organic chemistry,
utilizing the general synthetic pathway depicaed
5 below. As described by Scheme I, amino acids 1
protected by suitable blocking groups P on the amino
acid nitrogen may be reacted with alcohols ROH to
generate esters 2. After removal of the protect:inq
group, the free amine 3 may be reacted with various
10 sulfonyl chlorides 4 to provide final products 5 in
good to excellent yield.
SCHEME I
( CHZ ) n ( CHZ ) n
15 OH - R-OH~ O-R Deprotect;
Coupling Method
P 0 P O
1 2
C
(CHZ) n O=S=0
2 0 O-R. 4
Et3N,CHzClz
H O
3 5
25 Affini~ for FKHP12
The compounds used in the inventive methods and
pharmaceutical compositions have an affinity fox the
FK506 binding protein, particularly FKBP12. The
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26
inhibition of the prolyl peptidyl cis-trans isomerase _.
activity of FKBP may be measured as an indicatox- of
this affinity.
Ki Test Procedure
Inhibition of the peptidyl-prolyl isomer_ase
(rotamase) activity of the compounds used in the
inventive methods and pharmaceutical compositions can
be evaluated by known methods described in the
literature (Hard.ing et al., Nature, 1989, 341:758-760;
Holt et al . J. porn. Chem. Soc. , 115:9923-9938) . These
values are obtained as apparent K;'s and are presented
for representative compounds in TABLE II.
The cis-tra.ns isomerization of an alanine-proline
bond in a model ~~ubstrate, N-succinyl-Ala-Ala-Pro-Phe-
p-nitroanilide, is monitored spectrophotometricall:y in
a chymotrypsin-coupled assay, which releases para-
nitroanilide from the trans form of the substrate.
The inhibition of this reaction caused by the addition
of different concentrations of inhibitor is
determined, and the data is analyzed as a change in
first-order ratE: constant as a function of inhibitor
concentration to yield the apparent K; values.
In a plastic cuvette are added 950 mL of ice cold
assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 mL
of FKBP (2.5 mM in 10 mM Tris-C1 pH 7.5, 100 mM NaCl,
1 mM dithiothrei.tol), 25 mL of chymotrypsin (50 mg/ml
in 1 mM HC1) and 10 mL of test compound at various
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concentrations in dimethyl sulfoxide. The reaction is
initiated by the addition of 5 mL of substrate
(succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL
in 2.35 mM LiCl in trifluoroethanol).
The absorbance at 390 nm versus time is monitored
for 90 seconds using a spectrophotometer and the rate
constants are determined from the absorbance versus
time data files.
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.. TABLE II
In Vitro Test Results - Formulas I-V
Compound Ki (nM)
\N~ ~1~~ ~ ~ 2
o=s=o 0
i
4-phenyl-1-butyl.-1-(benzylsulfonyl)-
(2R, S) -2-pipecol.inate (1)
34
N
I
O =S=O O
I
I
\
1,5-diphenyl-3-pentyl-N-(a-toluenesulfonyl)-
pipecolate (2)
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TABLE II (continued) _.
In Vitro Test Results - Formulas I-V
Compound Ki (nM)
107
1,7-diphenyl-4-heptyl-N-(para-toluene-
sulfonyl)pipecolate (3)
N
332
O /
N
2o O=S=O O
3- (3-pyridyl) -1--propyl- (2S) -N- (a-toluene-
sulfonyl)pyrrolidine-2-carboxyl.ate (4)
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.. TABLE II (continued)
In Vitro Test Results - Formulas I-V
Compound Ki (nM)
5
(] 504
N
o=s=o o \ I
10 \
/
CHI
15 4-phenyl-1-butyl.-N-(para-toluenesulfonyl)-
pipecolate (5)
470
2 0 ('
N ~ ~ /
O=S=O O I
I
4-phenyl-1-butyl-N-(benzenesulfonyl)pipecolate
(6)
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TABLE II (continued)
Ia Vitro Test Results - Formulas I-V
Compound Ki (nM)
12 ;~
~1V/\ v /
O=S=O O
io /
I
4-phenyl-1-buty:L-N-(a-toluenesulfonyl)
pipecolate (7)
Route of Administration
To effectively treat alopecia or promote hair
growth, the compounds used in the inventive methods
and pharmaceutical compositions must readily affect
the targeted areas. For these purposes, the compounds
are preferably administered topically to the skin.
For topical application to the skin, the
compounds can b~e formulated into suitable ointments
containing the compounds suspended or dissolved in,
for example, nnixtures with one or more of the
following: mineral oil, liquid petrolatum, white
petrolatum, propylene glycol, polyoxyethy:Lene
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the compounds can be formulated into
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suitable lotions or creams containing the active
compound suspended or dissolved in, for example, a
mixture of one or more of the following: mineral ail,
sorbitan monostearate, polysorbate 60, cetyl ester
wax, cetearyl alcohol, 2-octyldodecanol, benzyl
alcohol and water.
Other routes of administration known in the
pharmaceutical art are also contemplated by this
invention.
Dosaae
Dosage levels on the order of about 0.1 mg to
about 10,000 mg of the active ingredient compound are
useful in the treatment of the above conditions, with
preferred level, of about 0 . 1 mg to about 1, 000 mg.
The specific dose level for any particular patient
will vary depending upon a variety of factors,
including the activity of the specific compound
employed; the age, body weight, general healthy sex
and diet of the patient; the time of administration;
the rate of excretion; drug combination; the severity
of the particular disease being treated; and the form
of administration. Typically, in vitro dosage-effect
results provide useful guidance on the proper loses
for patient administration. Studies in animal models
axe also helpful.. The considerations for determining
the proper dose levels are well known in the art.
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The compounds can be administered with other hair
revitalizing agents. Specific dose levels for the
other hair revitalizing agents will depend upon the
factors previously stated and the effectiveness of the
drug combination.
EXAMPLES
The following examples are illustrative of the
present invention and are not intended to be
limitations thereon. Unless otherwise indicated, all
percentages are based upon 100% by weight of the :fi.nal
composition.
Example I
Synthesis of 3-(3-Pyridyl)-1-propyl (2S)-N-(a-
toluenesulfonyl)pyrrolidine-2-carboxylate (4)
3 - ( 3 - P~rid~l ) - 1 =propyl N- ( tert-butylo:xy-
carbonyl)pyrroli.dine-2-carboxylate
A mixture of N-(tert-butyloxycarbonyl)-(S)-
proline (6.0 g; 28 mmol), 3-(3-pyridyl)-1-propanol
(5.80 g; 41.8 mmol), dicyclohexylcarbodiimide (9.20 g;
44.48 mmol), camphorsulfonic acid (21.60 g; ~~.26
mmol), and 4-dimethylaminopyridine (1.12 g; 9.26 mmol)
in dry methylene chloride (200 mL) was stirred
overnight. The reaction mixture was filtered through
Celite, concentrated, and purified on a silica gel
column eluting with 40% ethyl acetate in hexane to
obtain 5.0 g of the product as a clear oil (53%). 1H
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34
NMR (300 MHz,CI7C13) : b 1.42(s, 9H) 1.43-1.95 (m,
;
6H); 2.68 (m, 2:H); 3.46-3.52 (m, 2H); 4.11-4.22 (m,
2H) ; 4.33 (m, l:Ei) ; 7. 17-7.24{m, 1H) 7.47 (m, 1H) ;
;
8.43 (s, 2H) .
3-(3-PVridyl)-1-propel pyrrolidine-2-carboxvlate
A solution of 3-(3-pyridyl)-1-propyl N-(tert-
butyloxycarbonyl)pyrrolidine-2-carboxylate (3.0 g; 8.9
mmol) in methylene chloride (40 mL) and
trifluoroacetic acid (8 mL) was stirred at room
temperature for three hours. Saturated potassium
carbonate was added until the pH was basic, and the
reaction mixture was extracted with methylene chloride
(3x). The combined organic extracts were dried and
concentrated to yield 1.60 g (77%) of the free amine
as a thick oil. 1H NMR (300 MHz, CDC13): b 1.71-2.09
(m, 6H); 2.63 (m, 2H); 2.86 (m, 1H); 2.94 (m, 1H);
3.71 (m, 1H); 4.11 (m, 2H); 7.18 {m, 1H); 7.45 (m,
1H) ; 8 .41 (m, 2Hf) .
3-(3-Pyridvl)-1-propyl (2S)-N-(a-toluene-
sulfonvl)pyrrolidine-2-carboxylate (4)
A solution of 3-(3-Pyridyl)-1-propyl pyrrolidine-
2-carboxylate (200 mg; 0.9 mmol) and a-toluenesulfonyl
chloride (160 mg~; 0.9 mmol) in methylene chloride (20
mL) was treated with triethylamine (90 mg; 0.9 mmol)
and stirred for 2 hours at room temperature. The
reaction mixture= was filtered to remove solids and
applied directly to a silica gel column, eluting with
50% ethyl acetate in hexane, to obtain 150 mg (43%) of
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Compound 4 (Table I) as a clear oil. 1H NMR (300 MHz,
CDC13) : b 1.81-1..85 (m, 2H) ; 1.95-2.02 (m, 3H) ; 2.10-
2.25 (m, 1H); 2.69-2.74 (t, 2H); 2.85-2.97 (m, LH);
3.24-3.27 (m, 1H); 4.16-4.20 (m, 2H); 4.29 (d, :LH);
5 4.34 (m, 1H); 4.45 (d, 1H); 7.20-7.25 (m, 1H); '7.35
(m, 3H); 7.49-7.52 (m, 3H); 8.46 (s, 2H). Analysis
calculated for C ZoH24NzO3S : C, 61 . 83 ; H, 6 . 23 ; N, 7 . 21 .
Found: C, 61.5.'3; H, 6.24; N, 7.17.
10 Example 2
Synthesis of 4-Phenyl-1-butyl 1-(a-tolvlsulfonvl)
2-uipecolinate (7)
Methyl 1-(a-tolvlsulfonvl)-2-pipecolinate
To a solution of methyl pipecolinate
15 hydrochloride (1.79 g; 10 mmol) and triethylamine
(1.01 g; 10 mmol) in dry methylene chloride (20 mL)
was added a-toluenesulfonyl chloride (1.9 g; 10 mmol).
The resulting mixture was stirred at room temperature
overnight and then concentrated in vacuo. The crude
20 residue was purified on a silica gel column, eluting
with ethyl acetate, to provide 2.20 g (74~) of the
product was an oil which solidified upon standing. 1H
NMR {CDC13, 300 MHz) : b 1.26-1.71 (m, 5H) ; 2.15 (d,
1H, ~ - 14.4); 3.17 (dt, 1H); 3.45 (d, 1H, ~ - 12.6);
25 3.78 (s, 3H); 9:.28 (s, 2H); 4.58 (m, 1H); 7.26-'7.48
(m, 5H) .
N-(a-tolylsulfo~~l)-2-pipecolic acid
Methyl 1- (cr-tolylsulfonyl) -2-pipecolinate (2.0 g;
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6.72 mmol) was dissolved in ethanol (25 mL) and
treated with 20 mL of 1 N lithium hydroxide. The
mixture was stirred for 2 hours at room temperature,
and then diluted with ethyl acetate (200 mL) and made
acidic (pH 2) with 1 N HCL. The organic layer was
washed with brine, dried over magnesium sulfate, and
concentrated to obtain 1.90 g (100%) of the acid as a
white solid.
4-Phenyl-1-butyl 1- (a-toivlsulfon~rl) -2-pipecolinate
~7 ,_
A solution of N-(a-tolylsulfonyl)-2-pipecolic
acid (400 mg; 1.41 mmol), dicyclohexylcarbodiirnide
(312 mg; 1.5 mmol) , dimethylaminopyridine (7 mg) and
4-phenyl-1-butanol (240 mg; 1.60 mmol) in 100 mL of
methylene chloride was stirred overnight at room
temperature. The mixture was filtered through Celite,
concentrated, a:nd purified on a silica gel column,
eluting with 25% ethyl acetate in hexane, to obtain
380 mg (48%) of Compound 7 (Table I) as a clear oil.
1H NMR (CDC13, 300 MHz) : b 1.10-1 . 69 (m, 5H) ; .l .70
(tt, 4H, ~ - 6.:1, 6.6) ; 2.15 (m, 1H) ; 2.66 (t, 2Fi,
- 6.6); 3.16 (m, 1H); 3.45 (m, 1H); 4.19 (t, 2H,
6.1); 4.28 (s, ~:H); 4.58 (m, 1H); 7.18-7.47 (m, 1UH).
Analysis calculated for Cz3H29NO4S : C, 66 . 48 ; H, 7 ,. 03 ;
N, 3.37. Found.. C, 66.34; H, 7.06; N, 3.41.
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_ Exaau~le 3
Synthesis of 1,5-biphenyl-3-pentyl (N-(a-
toluenesulfonvl)pipecolate (2)
3-Phenyl-1-pro~~nal
Oxalyl chloride (2.90 g; 2.29 mmol) in methylene
chloride (50 mL), cooled to -78°C, was treated with
dimethylsulfoxide (3.4 mL) in 10 mL of methy:Lene
chloride. After stirring for 5 minutes, 3-pheny:L-1-
propanol (2.72 g; 20 mmol) in 20 mL of methy:Lene
chloride was added, and the resulting mixture was
stirred at -78°C'for 15 minutes, treated with 14 mL of
triethylamine, ;stirred an additional 15 minutes, and
poured into 100 mL of water. The layers were
separated, the: organic phase was dried and
concentrated, and the crude residue was purified on a
silica gel column, eluting with 10% ethyl acetate in
hexane, to obtain 1.27 g (47%) of the aldehyde as a
clear oil. 'H TfMR (300 MHz, CDC13) : b 2.80 (m, 2H) ;
2.98 (m, 2H) ; 7.,27 (m, 5H) ; 9.81 (s, 1H} .
1,5-biphenyl-3-x~entanol
A solution of 2-(bromoethyl)benzene (1.73 g; 9.33
mmol) in diethy:lether (10 mL) was added to a stirred
slurry of magne:aium turnings (250 mg; 10. Z8 mmol) in
5 mL of ether. 'The reaction was initiated with a heat
gun, and after the addition was complete the mixture
was heated on an oil bath for 30 minutes. 3-Phenyl-1-
propanal (1.25 g; 9.33 mmol) was added in 10 mL of
ether, and refT~ux was continued for 1 hour. The
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reaction was cooled and quenched with saturated
ammonium chloride, extracted into 2x ethyl acetate,
and the combined organic portions were dried and
concentrated. Chromatographic purification on a
silica gel column (10~ ethyl acetate in hexane)
delivered 1.42 g~ (63~) of the diphenyl alcohol. ~H NMR
(300 MHz, CDC13) : b I . 84 (m, 4H) ; 2 . 61-2 . 76 (m, 4H) ;
3.65 (m, 1H); 7.19-7.29 (m, 10H).
1, 5-Diyhenyl-3-t~entyl N- (a-toluenesulfonyl)pipeco:L ate
A mixture of N-(a-tolylsulfonyl)-2-pipecolic acid
(380 mg; 1.34 mmol), 1,5-diphenyl-3-pentanol (485 mg;
2.01 mmol), dicyclohexylcarbodiimide (445 mg; ;Z.15
mmol), camphorsulfonic acid (105 mg; 0.45 mmol) and
dimethylaminopyridine (55 mg; 0.45 mmol) in 20 mL of
methylene chloride was stirred overnight at :room
temperature. The mixture was filtered through Cel:ite,
concentrated, and purified on a silica gel column,
eluting with 155 ethyl acetate in hexane, to obtain
270 mg (40~) of Compound 2 (Table I) as a clear oil.
'H NMR (CDC13, 300 MHz) : b 0.80 (m, 4H) ; 1.23-1.97 (m,
5H) ; 2.15 (d, 1.H) ; 2 .61-2.69 (m, 4H) ; 3 .23 (m, 1H) ;
3.44 (dm, IH); 4.27 (s, 2H); 4.53 (d, 1H, , - 4.5);
5.06 (m, 1H); 7.16-7.34 (m, 15H). Analysis calculated
for C3oH35NO4S: C, 71.26; H, 6.98; N, 2.77. Found: C,
72.82; H, 7.17; N, 2.53.
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Example 4
In Vivo Hair Generation Tests With C57 Black 6 Mice
Experiment A: C57 black 6 mice were used to
demonstrate the hair revitalizing properties of
related neuroimmunophilin FKBP ligands, GPI 1044, GPI
1116, and GPI 1102. C57 black 6 mice, approximately
7 weeks old, had an area of about 2 inches by 2 inches
on their hindquarters shaved to remove all existing
hair. Care was taken not to nick or cause abrasion to
the underlaying dermal layers. The animals weres in
anagen growth phase, as indicated by the pinkish color
of the skin . F;eferring now to FIGS . 1, 2 , 3 and 4 ,
four animals were treated by topical administration
with 20% propylene glycol vehicle (FTG. 1), and, for
each compound, seven animals were treated by topical
administration with, respectively, 10 ~,M GPI 1044
(FIG. 2) , 10 ~N! GPI 1116 (FIG. 3) , or 3 ACM GPI 1102
(FIG. 4). The animals were treated with vehicle, GPI
1044, GPI 111E>, or GPI 1102 every 48 hours (3
applications total over the course of 5 days) and the
hair growth was allowed to proceed for 6 weeks. Flair
growth was quantitated by the percent of shaved area
covered by new ;hair growth during this time period.
FIG. 1 shows that animals treated with vehicle
exhibited only a small amount of hair growth. in
patches or tufts, with less than 3% of the shaved area
covered with ne~N growth. In contrast, FIGS. 2, 3 and
4 show that animals treated with the related
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. neuroimmunophilin FKBP ligands, 10 ~M GPI 1044, 10 ~.M
GPI 1116, and 3 ~M GPI 1102, exhibited dramatic hair
growth, covering as much as 50~ of the shaved area in
some animals. FIG. 5 compares the hair growth score
5 of unshaven animals with the hair growth scores of
shaven animals treated with a vehicle and with the
related neuroimmunophilin FKBP ligands GPI 1044 (1 ~M,
3 ACM and 10 ACM) , GPI 1116 (1 ~M and 10 ACM) , and GPI
1102 (1 ~.M and 3 ~M).
10 Experiment B: C57 Black 6 mice were used to
demonstrate the hair revitalizing properties of
neuroimmunophilin FKBP ligands. C57 Black 6 mice, 55
to 75 days old,, had an area of about 2 inches by 2
inches on their hindquarters shaved to remove all
15 existing hair. Care was taken not to nick or cause
abrasion to the underlying dermal layers. The animals
were in a anac~en growth phase when shaved. Five
animals per group were treated by topical
administration with a vehicle, FK506, or a
20 neuroimmunophilin FKBP ligand (GPI 1116 or 1206) at a
concentration of one micromole per milliliter to the
shaved area. The animals were treated three times per
week, and hair growth was evaluated 14 days after
initiation of treatment. Hair growth was quantitated
25 by the percent of shaved area covered by new hair
growth, as scorE_d by a blinded observer, on a scale of
0 (no growth) to five (complete hair regrowth in
shaved area) .
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Figure 6 shows that after 14 days, the animals -
treated with vehicle exhibited the beginning of growth
in small tufts. In contrast, animals treated with a
neuroimmunophilin FKBP ligand exhibited dramatic hair
growth.
Example 5
A lotion comprising the following composition may
be prepared.
(%)
95% Ethanol X30.0
a small molecule sulfonamide as defined above :L0.0
a-Tocopherol acetate 0.01
Ethylene oxide (40 mole) adducts of hardened 0.5
castor oil
purified water 9.0
perfume and dye q.s.
Into 95% ethanol are added a small molecule
sulfonamide, a-tocopherol acetate, ethylene oxide (40
mole) adducts of hardened castor oil, perfume and a
dye. The resuli~ing mixture is stirred and dissolved,
and purified water is added to the mixture to obtain
a transparent liquid lotion.
5 ml of th.e lotion may be applied once or twice
per day to a site having marked baldness or alopecia.
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Examt~le 6
A lotion comprising the following composition
shown may be prepared.
{%)
95% Ethanol 80.0
a small molecule sulfonamide as defined above 0.005
Hinokitol 0.01
Ethylene oxides (40 mole) adducts of hardened 0.5
castor oil
Purif ied water 19 ,
0
Perfume and d;te q, s
.
Into 95% ethanol are added a small molecule
sulfonamide, hinokitol, ethylene oxide {40 mole)
adducts of hardened castor oil, perfume, and a dye.
The resulting rnixture is stirred, and purified water
is added to the mixture to obtain a transparent liquid
lotion.
The lotion may be applied by spraying once to 4
times per day to a site having marked baldness or
alopecia.
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Example 7
An emulsion may be prepared from A phase and B
phase having the following compositions.
(A phase) (%)
Whale wax 0.5
Cetanol 2.0
Petrolatum 5.0
Squalane 10.0
Polyoxyethylene (10 mole) monostearate 2.0
Sorbitan monooleate 1.0
a small molecule sulfonamide as defined above 0.01
(B phase) (%)
Glycerine 10.0
Purified water- 69.0
Perfume, dye, and preservative q.s.
The A phase and the B phase are respectively
heated and melted and maintained at 80°c. Both phases
are then mixed and cooled under stirring to normal
temperature to obtain an emulsion.
The emulsion may be applied by spraying once to
four times per day to a site having marked baldness or
alopecia.
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- Example 8 _.
A cream ma.y be prepared from A phase and B phase
having the following compositions.
(A Phase)
Fluid paraf f in 5 . 0
Cetostearyl alcohol 5.5
Petrolatum 5.5
Glycerine monostearate 33.0
Polyoxyethylene (20 mole) 2-octyldodecyl 3.0
ether
Propylparaben 0.3
(B Phase)
a small molecule sulfonamide as defined 0.8
above
Glycerine 7.0
Dipropylene glycol 20.0
Polyethylene glycol 4000 5.0
Sodium Hexametaphosphate 0.005
Purified water' 44.895
The A phase is heated and melted, and maintained
at 70°c . The B phase is added into the A phase and. the
mixture is stirred to obtain an emulsion. The
emulsion is then cooled to obtain a cream.
The cream may be applied once to 4 times per day
to a site having marked baldness or alopecia.
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Example 9 _
A liquid comprising the following composition may
be prepared.
5
Polyoxyethylene butyl ether 20.0
Ethanol 50.0
a small molecule sulfonamide as defined above 0.001
Propylene glycol 5.0
10 Polyoxyethylene hardened castor oil 0.4
derivative (et:hylene oxide 80 mole adducts)
Perfume q,s,
Purified water: q,s,
15 Into ethanol are added polyoxypropylene butyl
ether, propylene glycol, polyoxyethylene hardened
castor oil, a small molecule sulfonamide, and perfume.
The resulting mixture is stirred, and purified water
is added to the mixture to obtain a liquid.
20 The liquid may be applied once to 4 times per. day
to a site having marked baldness or alopecia.
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_ Example 10
A shampoo comprising the following composition
may be preparedl.
(%)
Sodium lauryl:~ulfate 5.0
Triethanolamine laurylsulfate 5.0
Betaine laury7_dimethylaminoacetate 6.0
Ethylene glycol distearate 2.0
Polyethylene c;lycol 5.0
a small molecule sulfonamide as defined above 5.0
Ethanol 2.0
Perfume 0 . 3
Purified water 69.7
Into 69.7 of purified water are added 5.0 g of
sodium lauryl:~ulfate, 5.0 g of triethanolamine
laurylsulfate, 6.0 g of betaine lauryldimethyl-
aminoacetate. Then a mixture obtained by adding 5.0
g of a small molecule sulfonamide, 5.0 g of
polyethylene glycol, and 2.0 g of ethylene glycol
distearate to 2.0 g of ethanol, followed by stirring,
and 0.3 g of perfume are successively added. The
resulting mixture is heated and subsequently cooled to
obtain a shampoo.
The shampoo may be used on the scalp once or
twice per day.
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.. Examvle 11
A patient is suffering from alopecia senilis. A
small moleculE: sulfonamide, or a pharmaceutical
composition comprising the same, may be administered
to the patient. Increased hair growth is expected to
occur following treatment.
Example 12
A patient is suffering from male pataern
alopecia. A small molecule sulfonamide, or a
pharmaceutical composition comprising the same, may be
administered to the patient . :Increased hair growth is
expected to occur following treatment.
Exam»le 13
A patient is suffering from alopecia areata. A
small molecules sulfonamide, or a pharmaceutical
composition comprising the same, may be administered
to the patient. Increased hair growth is expected to
occur following treatment.
Example 14
A patient is suffering from hair loss caused by
skin lesions. A small molecule sulfonamide, or a
pharmaceutical composition comprising the same, may be
administered to the patient. Increased hair growth is
expected to occur following treatment.
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_ Example 15
A patient is suffering from hair loss caused by
tumors. A small molecule sulfonamide, or a
pharmaceutical composition comprising the same, may be
administered to the patient. Increased hair growth is
expected to occur following treatment.
Example 16
A patient is suffering from hair loss caused by
a systematic disorder, such as a nutritional disorder
or an internal secretion disorder. A small molecule
sulfonamide, or a pharmaceutical composition
comprising the same, may be administered to the
patient. Increased hair growth is expected to occur
following treatment.
Example 17
A patient is suffering from hair loss caused by
chemotherapy. A small molecule sulfonamide, or a
pharmaceutical composition comprising the same, may be
administered to the patient. Increased hair growth is
expected to occur following treatment.
Examm~le 18
A patient is suffering from hair loss caused by
radiation. A small molecule sulfonamide, or a
pharmaceutical composition comprising the same, may be
administered to the patient. Increased hair growth is
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expected to occur following treatment.
The invent: ion being thus described, it will be
obvious that the same may be varied in many ways.
Such variations are not to be regarded as a departure
from the spirit and scope of the invention and all
such modifications are intended to be included within
the scope of th.e following claims.