Hair loss abstract
The present invention provides methods and compositions for treating
hair loss, including arresting and/or reversing hair loss and/or
promoting hair growth, in mammals, such as humans, companion animals
and livestock, using certain thyromimetic compounds.
Hair loss claims
54. A composition of claim 53 wherein the topical composition is
in the form of a lotion, cream, ointment, shampoo, paste, gel, spray,
aerosol or kit; and the effective amount of the compound is about
0.0001% to about 10% (w/v) of the compound per day.
55. A composition of claim 54 which further comprises an effective
amount of finasteride, minoxidil or cyproterone acetate.
56. A kit for treating hair loss in a mammal, the kit comprising:
a) a first pharmaceutical composition comprising a compound of claim
52; b) a second pharmaceutical composition comprising an additional
compound useful for treating hair loss; and c) a container.
57. A kit of claim 56 wherein the additional compound is finasteride,
minoxidil or cyproterone acetate.
Hair loss description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/294,962, filed May 31, 2001.
FIELD OF THE INVENTION
[0002] The present invention provides methods and compositions
for treating hair loss, including arresting and/or reversing hair
loss and promoting hair growth, in mammals, such as humans, companion
animals and livestock, using certain thyromimetic compounds, as
described below.
BACKGROUND OF THE INVENTION
[0003] 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.
[0004] 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.
[0005] There have been many attempts in the literature to prevent
the loss of hair or 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) and oral finasteride (marketed as
PROPECIA.RTM. by Merck & Co., Inc.). For several reasons, however,
including safety concerns and/or limited efficacy, the search for
efficacious hair growth inducers is ongoing.
[0006] Two naturally occurring thyroid hormones, namely, thyroxine
or 3,5,3',5'-tetraiodo-L-thyronine (commonly referred to as "T.sub.4"),
and thyronine or 3,5,3'-triiodo-L-thyronine (commonly referred to
as "T.sub.3"), are shown below: 1
[0007] T.sub.3 is the more biologically active of the two and,
as will be appreciated from the structural formulae provided above,
differs from T.sub.4 by the absence of the 5' iodine. T.sub.3 may
be produced directly from the thyroid gland or, in peripheral tissues,
by the removal of the 5' iodine by deiodinase enzymes. Thyromimetic
analogs are often designed to be structurally similar to T.sub.3.
In addition, naturally occurring metabolites of T.sub.3 are known.
[0008] Interestingly, it is known that the thyroid hormone, thyroxine
("T.sub.4"), converts to triiodo-thyronine ("T.sub.3")
in human skin by deiodinase I, a selenoprotein. Selenium deficiency
causes a decrease in T.sub.3 levels due to a decrease in deiodinase
I activity; this reduction in T.sub.3 levels is strongly associated
with hair loss. Consistent with this observation, hair growth is
a reported side effect of administration of T.sub.4. See, for example,
Berman, "Periperal 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, T.sub.3 and T.sub.4 have been the subject
of several patent publications relating to treatment of hair loss.
See, e.g., German patent 1,617,477; British patent 2,138,286; and
WO 96/25943.
[0009] Thus, it is known that thyroid hormone can exert positive
effects on hair growth; however, administration of T.sub.3 and/or
T.sub.4 to treat hair loss is not practicable because these thyroid
hormones are known to cause adverse side effects, such as inducing
significant cardiotoxicity or adversely affecting bone mineral density
and lean body mass. See, e.g., U.S. Pat. No. 5,284,971; and U.S.
Pat. No. 5,061,798.
[0010] According to the present invention, it has been found that
administration of certain thyromimetic compounds, as described below,
which activate thyroid hormone receptors in certain tissues, including
those in the hair follicle which control growth and hair production,
but spare other tissues, such as the heart, could be used to increase
hair growth in patients suffering from hair loss, or may be used
to prevent or delay hair loss in patients just beginning to lose
their hair.
[0011] Published International patent application WO 00/72810 discloses
methods of treating hair loss using certain sulfonyl thyromimetic
compounds. Published International patent application WO 00/72811
discloses methods of treating hair loss using certain compounds,
such as substituted phenoxy-benzoic acid compounds, described therein.
Published International patent application WO 00/72812 discloses
methods of treating hair loss using certain diphenylether derivatives.
Published International patent application WO 00/72813 discloses
methods of treating hair loss using certain diphenylmethane derivatives.
Published International patent application WO 00/72920 discloses
certain substituted biaryl ether compounds and compositions for
treating hair loss. Published International patent application WO
00/73292 discloses certain biaryl compounds and compositions for
treating hair loss.
[0012] Commonly assigned, published International patent application
WO 00/51971 and commonly assigned, published European patent application
EP 1 033 364 disclose certain oxamic acids and derivatives thereof
as thyroid receptor ligands. Commonly assigned, published European
Patent Application EP 1 088 819 discloses certain 6-azauracil derivatives
as thyroid receptor ligands. Commonly assigned, published European
Patent Application EP 1 127 882 discloses certain tetrazole compounds
as thyroid receptor ligands. Commonly assigned, published European
Patent Application EP 1 148 054 discloses certain thiazolidinedione,
oxadiazolidinedione and triazolone compounds, which are thyroid
receptor ligands.
[0013] The following are recent articles on thyroid hormone receptors
(TRs): M. K. Ahsan et al., J. Med. Invest. 44: 179-184, 1998, studied
the immunohistochemical localization of thyroid hormone receptors
(TRs) in human scalp skin and concluded that the results demonstrated
the presence of thyroid hormone nuclear receptors in human hair
follicles. N. Billoni et al., British Journal of Dermatology 2000:
142: 645-652, established that TR.beta.1 was the predominant form
of TR expressed in the human hair follicle. C. C. Thompson and M.
C. Bottcher, Proc. Natl. Acad. Sci. USA, Vol. 94, pp. 8527-8532,
August 1997, found that the product of a thyroid hormone-responsive
gene, the lack of which confers a hairless phenotype, interacts
with thyroid hormone receptors. A. G. Messenger, British Journal
of Dermatology, 142, 631-635, 2000, discussed the relationship between
thyroid hormone and hair growth.
[0014] J. D. Safer, L. M. Fraser, M. Hoa and M. F. Holick, "Intraperitoneal
and Topical Triiodothyronine Have Opposing Effects on Mouse Skin,"
Abstract P1-530 for The Endocrine Society 83.sup.rd Annual Meeting,
which is scheduled to take place on Jun. 20-23, 2001, in Denver,
Colo.), discusses the differential effects of triiodothyronine on
skin of mouse, depending on route of administration.
[0015] J. D. Safer, et al., Thyroid 11 (8): 717-24 (August 2001),
found topical triiodothyronine stimulates epidermal proloferation,
dermal thickening and hair growth in mice and rats.
[0016] V. L. Malloy, et al., Abstract titled "Effect of Topically
Applied Thyroid Hormone on Androgen Dependent Models of the Pilo-Sebaceous
Apparatus," Clinical Research, Vol. 36, No. 5, page 814A (1998),
observed an inhibitory effect on testosterone induced alopecia after
treatment with topical T.sub.3 in the AGA mouse, a model for androgen
dependent hair loss.
SUMMARY OF THE INVENTION
[0017] The present invention relates to methods for treating hair
loss in mammals comprising administering certain compounds, as described
below.
[0018] The present invention also relates to the use of certain
compounds, as described below, for the manufacture or preparation
of a medicament for the treatment of hair loss in mammals.
[0019] More particularly, the present invention provides such methods
wherein the compounds are cardiac-sparing.
[0020] More particularly, the present invention provides such methods
wherein the treatment is the arresting or reversing of hair loss.
[0021] More particularly, the present invention provides such methods
wherein the treatment is the promotion of hair growth.
[0022] More particularly, the present invention provides such methods
wherein the treatment is the acceleration of hair regrowth following
chemotherapy-induced hair loss.
[0023] More particularly, the present invention provides such methods
wherein the mammal is a human being.
[0024] More particularly, the present invention provides such methods
wherein the compounds are administered topically.
[0025] More particularly, the present invention provides such methods
which further comprise the administration of an effective amount
of an agent for treating hair loss, e.g., finasteride, minoxidil
or cyproterone acetate.
[0026] In addition, the present invention provides topical compositions
for promoting hair growth which comprise an effective amount of
certain compounds, as described below, and pharmaceutically acceptable
carriers.
[0027] More particularly, the present invention provides such compositions
wherein the topical composition is in the form of a lotion, cream,
ointment, shampoo, paste, gel, spray, aerosol or kit. The present
invention also provides such compositions which further comprise
an effective amount of an agent for treating hair loss, e.g., finasteride,
minoxidil or cyproterone acetate.
[0028] In addition, the present invention provides kits for treating
hair loss in a mammal, the kit comprising:
[0029] a) a first pharmaceutical composition comprising a compound
as described below;
[0030] b) a second pharmaceutical composition comprising an additional
compound useful for treating hair loss; and
[0031] c) a container.
[0032] More particularly, the present invention provides such kits
wherein the additional compound is finasteride, minoxidil or cyproterone
acetate
DETAILED DESCRIPTION OF THE INVENTION
[0033] The present invention relates to methods for treating hair
loss in mammals, including arresting and/or reversing hair loss
and promoting hair growth, comprising administering certain thyromimetic
compounds, as described below.
[0034] Preferred mammals include humans, companion animals such
as dogs, cats and horses, and livestock such as cattle, swine and
sheep. Particularly preferred mammals include humans.
[0035] Preferably, in the methods of the present invention, the
compounds are administered topically.
[0036] The preferred compounds useful in the methods of the present
invention are cardiac-sparing. The term "cardiac-sparing"
as used herein means that, at the dosages required for hair growth,
the compounds useful in the methods of the present invention do
not produce any observable cardiotoxicity in the mammal being treated.
[0037] All percentages, ratios and proportions used herein are
by weight unless otherwise specified.
[0038] As used herein, "effective amount of a compound"
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
undue toxicity, irritation or allergic response), commensurate with
a reasonable benefit/risk ratio when used in the manner of the present
invention.
[0039] The phrase "compound(s) useful in the methods of the
present invention," and the like, shall at all times be understood
to include all active forms of such compounds, including, for example,
the free form thereof, e.g., the free acid or base form, and also,
all prodrugs, polymorphs, hydrates, solvates, tautomers, stereoisomers,
e.g., diastereomers and enantiomers, and the like, and all pharmaceutically
acceptable salts as described above, unless specifically stated
otherwise. It will also be appreciated that suitable active metabolites
of such compounds, in any suitable form, are also included herein.
[0040] Following are listed particular examples of thyromimetic
compounds which may be used in practicing the present invention.
It is understood that in the generic formulae employed below, the
variables employed, e.g., "A", "B", "R.sup.1",
"R.sup.2", etc. have the meanings attributed to them only
in the particular Roman numeral section in which they are found.
Thus, the meaning attributed, for example, to "R.sup.1"
is different for the structures in section I than the meaning attributed
to it in the other sections.
[0041] I. For example, the thyromimetic compounds useful in the
methods of the present invention have the following formula, also
described in commonly assigned, published International patent application
WO 00/51971: 2
[0042] a prodrug thereof, a geometric or optical isomer thereof,
or a pharmaceutically acceptable salt of said compound, said prodrug,
or said isomer, wherein:
[0043] R.sup.1, R.sup.2 and R.sup.3 are each independently hydrogen,
halogen, C.sub.1-6 alkyl, trifluoromethyl, 13 CN, --OCF.sub.3 or
--OC.sub.1-6 alkyl;
[0044] R.sup.4 is hydrogen, C.sub.1-12 alkyl optionally substituted
with one to three substitutents independently selected from Group
Z, C.sub.212 alkenyl, halogen, --CN, aryl, heteroaryl, C.sub.3-10
cycloalkyl, heterocycloalkyl, --S(O).sub.2NR.sup.9R.sup.10, --C(O)NR.sup.9R.sup.10,
--(C.sub.1-6 alkyl)-NR.sup.9R.sup.10, --NR.sup.9C(O)R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10,
--NR.sup.9S(O).sub.2R.sup.10, --(C.sub.1-16 alkyl)-OR.sup.11, --OR.sup.11
or --S(O).sub.aR.sup.12, provided that, where R.sup.5 is not fluoro,
R.sup.4 is --S(O).sub.2NR.sup.9R.sup.10, --C(O)NR.sup.9R.sup.10,
--(C.sub.1-6 alkyl)-NR.sup.9R.sup.10, --NR.sup.9C(O)R.sup.10, --NR.sup.9C(O)NR.sup.9R.-
sup.10, --NR.sup.9S(O).sub.2R.sup.10, --(C.sub.1-6 alkyl)-OR.sup.11,
--OR.sup.11 or --S(O).sub.aR.sup.12;
[0045] or R.sup.3 and R.sup.4 may be taken together to form a carbocyclic
ring A of the formula --(CH.sub.2).sub.b-- or a heterocyclic ring
A selected from the group consisting of --Q--(CH.sub.2).sub.c--
and --(CH.sub.2).sub.j--Q--(CH.sub.2).sub.k-- wherein Q is O, S
or NR.sup.17, wherein said carbocyclic ring A and said heterocyclic
ring A are each independently optionally substituted with one or
more substituents independently selected from C.sub.1-4 alkyl, halide
or oxo;
[0046] R.sup.5 is fluoro, hydroxy, C.sub.1-4 alkoxy or OC(O)R.sup.9;
[0047] or R.sup.4 and R.sup.5 may be taken together to form a heterocyclic
ring B selected from the group consisting of --CR.sup.9.dbd.CR.sup.10--NH-
--, --N.dbd.CR.sup.9--NH--, --CR.sup.9.dbd.CH--O-- and --CR.sup.9.dbd.CH--S--;
[0048] R.sup.6 is hydrogen, halogen, C.sub.1-4 alkyl or trifluoromethyl;
[0049] R.sup.7 is hydrogen or C.sub.1-6 alkyl;
[0050] R.sup.8 is --OR.sup.9 or --NR.sup.19R.sup.20;
[0051] R.sup.9 and R.sup.10 for each occurrence are independently
(A) hydrogen, (B) C.sub.1-12 alkyl optionally substituted with one
or more substituents independently selected from Group V, (C) C.sub.2-12
alkenyl, (D) C.sub.3-10 cycloalkyl optionally substituted with one
or more substituents independently selected from C.sub.1-6 alkyl,
C.sub.2-5 alkynyl, C.sub.3-10 cycloalkyl, --CN, --NR.sup.13R.sup.14,
oxo, --OR.sup.18, --COOR.sup.18 or aryl optionally substituted with
X and Y, (E) aryl optionally substituted with X and Y, or (F) het
optionally substituted with X and Y;
[0052] or R.sup.9 and R.sup.10 for any occurrence may be taken
together to form a heterocyclic ring C optionally further containing
a second heterogroup selected from the group consisting of --O--,
--NR.sup.13-- and --S--, and optionally further substituted with
one or more substituents independently selected from C.sub.1-5 alkyl,
oxo, --NR.sup.13R.sup.14, --OR.sup.18, --C(O).sub.2R.sup.18, --CN,
--C(O) R.sup.9, aryl optionally substituted with X and Y, het optionally
substituted with X and Y, C.sub.5-6 spirocycloalkyl, and a carbocyclic
ring B selected from the group consisting of 5-, 6-, 7- and 8-membered
partially and fully saturated, and unsaturated carbocyclic rings,
and including any bicyclic group in which said carbocyclic ring
B is fused to a carbocyclic ring C selected from the group consisting
of 5-, 6-, 7-and 8-membered partially and fully saturated, and unsaturated
carbocyclic rings;
[0053] R.sup.11 is C.sub.1-12 alkyl optionally substituted with
one or more substituents independently selected from Group V, C.sub.2-12
alkenyl, C.sub.3-10 cycloalkyl, trifluoromethyl, difluoromethyl,
monofluoromethyl, aryl optionally substituted with X and Y, het
optionally substituted with X and Y, --C(O)NR.sup.9R.sup.10 or --C(O)R.sup.9;
[0054] R.sup.12 is C.sub.1-12 alkyl optionally substituted with
one or more substituents independently selected from Group V, C.sub.2-12
alkenyl, C.sub.3-10 cycloalkyl, aryl optionally substituted with
X and Y, or het optionally substituted with X and Y;
[0055] R.sup.13 and R.sup.14 for each occurrence are independently
hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, --(C.sub.1-6 alkyl)-C.sub.1-6
alkoxy, aryl optionally substituted with X and Y, het optionally
substituted with X and Y, --(C.sub.1-4 alkyl)-aryl optionally substituted
with X and Y, --(C.sub.1-4 alkyl)-heterocycle optionally substituted
with X and Y, --(C.sub.1-4 alkyl)-hydroxy, --(C.sub.1-4 alkyl)-halo,
--(C.sub.1-4 alkyl)-poly-halo, --(C.sub.1-4 alkyl)-CONR.sup.15R.sup.16
or C.sub.3-10 cycloalkyl;
[0056] R.sup.15 and R.sup.16 for each occurrence are independently
hydrogen, C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl or aryl optionally
substituted with X and Y;
[0057] R.sup.17 is hydrogen, C.sub.1-6 alkyl, --COR.sup.9 or --SO.sub.2R.sup.9;
[0058] R.sup.18 is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
--(C.sub.1-6 alkyl)-C.sub.1-6 alkoxy, aryl optionally substituted
with X and Y, het optionally substituted with X and Y, --(C.sub.1-4
alkyl)-aryl optionally substituted with X and Y, --(C.sub.1-4 alkyl)-heterocycle
optionally substituted with X and Y, --(C.sub.1-4 alkyl)-hydroxy,
--(C.sub.1-4 alkyl)-halo, --(C.sub.1-4 alkyl)-poly-halo, --(C.sub.1-4
alkyl)-CONR.sup.15R.sup.16, --(C.sub.1-4 alkyl)-(C.sub.1-4 alkoxy)
or C.sub.3-10 cycloalkyl;
[0059] R.sup.19 is hydrogen or C.sub.1-6 alkyl;
[0060] R.sup.20 is hydrogen or C.sub.1-6 alkyl;
[0061] W is O, S(O).sub.d, CH.sub.2 or NR.sup.9;
[0062] Group Z is C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen,
--CF.sub.3, --OCF.sub.3, hydroxy, oxo, --CN, aryl, heteroaryl, C.sub.3-10
cycloalkyl, heterocycloalkyl, --S(O).sub.aR.sup.12, --S(O).sub.2NR.sup.9R.sup.10,
--C(O)R.sup.9R.sup.10, and --NR.sup.9R.sup.10;
[0063] Group V is halogen, --NR.sup.13R.sup.14, --OCF.sub.3, --OR.sup.9,
oxo, trifluoromethyl, --CN, C.sub.3-10 , cycloalkyl, aryl optionally
substituted with X and Y, and het optionally substituted with X
and Y;
[0064] het for each occurrence is a heterocyclic ring D selected
from the group consisting of 4-, 5-, 6-, 7- and 8-membered partially
and fully saturated, and unsaturated, heterocyclic rings containing
from one to four heteroatoms independently selected from the group
consisting of N, O and S, and including any bicyclic group in which
said heterocyclic ring D is fused to a benzene ring or a heterocyclic
ring E selected from the group consisting of 4-, 5-, 6-, 7- and
8-membered partially and fully saturated, and unsaturated, heterocyclic
rings containing from one to four heteroatoms independently selected
from the group consisting of N, O and S;
[0065] X and Y for each occurrence are independently (A) hydrogen,
(B) halogen, (C) trifluoromethyl, (D) --OCF.sub.3, (E) --CN, (F)
C.sub.1-6 alkyl optionally substituted with one or more substituents
independently selected from the group consisting of halogen, --OCF.sub.3,
--CF.sub.3 and phenyl, (G) C.sub.1-6 alkoxy, (H) aryl optionally
substituted with one or more substituents independently selected
from the group consisting of halogen, --OCF.sub.3, --CF.sub.3, C.sub.1-4
alkyl and C.sub.1-4 alkoxy, (I) --C(O).sub.2R .sup.13, (J) --C(O)NR.sup.13R.sup.14,
(K) --C(O)R.sup.13(L) --NR.sup.13C(O)NR.sup.13R.sup.14 and (M) --NR.sup.13C(O)R.sup.14;
[0066] or X and Y for any occurrence in the same variable may be
taken together to form (a) a carbocyclic ring D of the formula --(CH.sub.2).sub.e--
or (b) a heterocyclic ring F selected from the group consisting
of --O(CH.sub.2).sub.fO--, (CH.sub.2).sub.gNH-- and --CH.dbd.CHNH--;
[0067] a and d are each independently 0, 1 or 2;
[0068] b is 3, 4, 5, 6 or 7;
[0069] c, f, g, j and k are each independently 2, 3, 4, 5 or 6;
and
[0070] e is 3, 4, 5, 6 or 7.
[0071] Specific thyromimetic compounds which may be used in the
methods of the present invention include the following:
[0072] N-[3-chloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-p-
henyl]-oxamic acid;
[0073] N-[4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl-
]-oxamic acid;
[0074] N-{4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-3,5-dimeth-
yl-phenyl}-oxamic acid;
[0075] N-{3-chloro-4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-5-
-methyl-phenyl}-oxamic acid;
[0076] N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamic
acid;
[0077] N-{3,5-dichloro-4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenox-
y]-phenyl}-oxamic acid;
[0078] N-[3,5-dichloro-4-(3-cyclopentanesulfonyl-4-hydroxy-phenoxy)-phenyl-
]-oxamic acid;
[0079] N-[3,5-dichloro-4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)--
phenyl]-oxamic acid;
[0080] N-[3,5-dichloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-p-
henyl]-oxamic acid;
[0081] N-[4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl--
phenyl]-oxamic acid;
[0082] N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-met-
hyl-phenyl]-oxamic acid;
[0083] N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-p-
henyl]-oxamic acid;
[0084] N-[4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl--
phenyl]-oxamic acid;
[0085] N-[3-chloro-4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-5-me-
thyl-phenyl]-oxamic acid;
[0086] N-[3,5-dichloro-4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)--
phenyl]-oxamic acid;
[0087] N-[4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-p-
henyl]-oxamic acid;
[0088] N-[3-chloro-4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-5-met-
hyl-phenyl]-oxamic acid;
[0089] N-[3,5-dichloro-4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-p-
henyl]-oxamic acid;
[0090] N-[3,5-dichloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy)--
phenyl]-oxamic acid;
[0091] N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethyl--
phenyl}-oxamic acid; and
[0092] N-{3-chloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-me-
thyl-phenyl}-oxamic acid.
[0093] II. The present invention also includes the use of the thyromimetic
compounds of the following formula, also described in commonly assigned,
published European patent application EP 1 033 364: 3
[0094] a prodrug thereof, a geometric or optical isomer thereof,
or a pharmaceutically acceptable salt of said compound, said prodrug,
or said isomer, wherein:
[0095] R.sup.1 and R.sup.2 are independently halogen, C.sub.1-8
alkyl, --CN or C.sub.1-8 perfluoroalkyl; provided that at least
one of R.sup.1 and R.sup.2 is --CN;
[0096] R.sup.3 is hydrogen or C.sub.1-8 alkyl;
[0097] R.sup.4 is halogen, C.sub.1-8 perfluoroalkyl, C.sub.1-8
alkyl, C.sub.1-8 alkanoyl, hydroxy-(C.sub.1-8 alkyl), aryl optionally
substituted with Y and Z, aryl-(C.sub.1-8 alkyl), carbocyclic aroyl
optionally substituted with Y and Z, C.sub.3-10 cycloalkyl optionally
substituted with Y and Z, or C.sub.3-10 cycloalkyl-(C.sub.1-8 alkyl);
[0098] or R.sup.4 is the radical 4
[0099] wherein: R.sup.9 is hydrogen, C.sub.1-8 alkyl, aryl optionally
substituted with Y and Z, aryl-(C.sub.1-8 alkyl), C.sub.3-10 cycloalkyl
optionally substituted with Y and Z, or C.sub.3-10 cycloalkyl-(C.sub.1-8
alkyl); R.sup.10 is --OR.sup.14; R.sup.11 is hydrogen or C.sub.1-8
alkyl; or R.sup.10 and R.sup.11 may be taken together with the carbon
atom to which they are attached to form a carbonyl group;
[0100] R.sup.5 is hydroxy, esterified hydroxy or etherified hydroxy;
[0101] R.sup.6 is hydrogen, halogen, C.sub.1-8 alkyl or C.sub.1-8
perfluoroalkyl;
[0102] R.sup.7 is hydrogen, C.sub.1-8 alkyl or C.sub.1-8 perfluoroalkyl;
[0103] R.sup.8 is --OR.sup.12 or --NR.sup.12R.sup.13;
[0104] R.sup.12 and R.sup.13 are each independently hydrogen or
C.sub.1-8 alkyl;
[0105] R.sup.14 is hydrogen, C.sub.1-8 alkyl or C.sub.1-8 acyl;
[0106] X is O, S(O).sub.a, C.dbd.O or NR.sup.15;
[0107] a is 0, 1 or 2;
[0108] R.sup.15 is hydrogen or C.sub.1-8 alkyl;
[0109] Y and Z for each occurrence are independently (a) hydrogen,
(b) halogen, (c) trifluoromethyl, (d) --OCF.sub.3, (e) --CN, (f)
C.sub.1-6 alkyl optionally substituted with one or more substituents
independently selected from the group consisting of halogen, --OCF.sub.3,
--CF.sub.3 and phenyl, (g) C.sub.1-6 alkoxy, (h) aryl optionally
substituted with one or more substituents independently selected
from the group consisting of halogen, --OCF.sub.3, --CF.sub.3, C.sub.1-4
alkyl and C.sub.1-4 alkoxy, (i) --C(O).sub.2R.sup.16, (j) --C(O)NR.sup.16R.sup.17,
(k) --C(O)R.sup.16, (I) --NR.sup.16C(O)NR.sup.16R.sup.17 or (m)
--NR.sup.16C(O)R.sup.17; or Y and Z for any occurrence may be taken
together to form (a) a carbocycle of the formula --(CH.sub.2).sub.b,
or (b) a heterocycle selected from the group consisting of --O(CH.sub.2).sub.cO--,
--(CH.sub.2).sub.dNH-- and --CH.dbd.CHNH--;
[0110] b is 3, 4, 5, 6 or 7;
[0111] c and d are each independently 2, 3, 4, 5 or 6;
[0112] R.sup.16 and R.sup.17 for each occurrence are independently
hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, --(C.sub.1-6 alkyl)-C.sub.1-6
alkoxy, aryl optionally substituted with X and Y, het optionally
substituted with X and Y, --(C.sub.1-4 alkyl)-aryl optionally substituted
with X and Y, --(C.sub.1-4 alkyl)-heterocycle optionally substituted
with X and Y, --(C.sub.1-4 alkyl)-hydroxy, --(C.sub.1-4 alkyl)-halo,
--(C.sub.1-4 alkyl)-poly-halo, --(C.sub.1-4 alkyl)-CONR.sup.18R.sup.19
or C.sub.3-10 cycloalkyl;
[0113] het for each occurrence is a heterocyclic ring selected
from the group consisting of 4-, 5-, 6-, 7- and 8-membered partially
and fully saturated, and unsaturated, heterocyclic rings containing
from one to four heteroatoms independently selected from the group
consisting of N, O and S, and including any bicyclic group in which
said heterocyclic ring is fused to a benzene ring or a heterocyclic
ring selected from the group consisting of 4-, 5-, 6-, 7- and 8-membered
partially and fully saturated, and unsaturated, heterocyclic rings
containing from one to four heteroatoms independently selected from
the group consisting of N, O and S; and
[0114] R.sup.18 and R.sup.19 for each occurrence are independently
hydrogen, C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl or aryl optionally
substituted with Y and Z.
[0115] III. More preferably, the present invention includes the
use of the thyromimetic compounds of the following formula, also
described in commonly assigned, published European patent application
EP 1 088 819: 5
[0116] an isomer thereof, a prodrug of said compound or isomer,
or a pharmaceutically acceptable salt of said compound, isomer or
prodrug;
[0117] wherein W is (a) --O--, (b) --S(O).sub.m--, (c) --NR.sup.30--,
(d) --C(O)--, (e) --HC.dbd.CH--, (f) --CH.sub.2--, (g) --CHF--,
(h) --CF.sub.2-- or (i) --CH(OH)--;
[0118] R.sup.1 and R.sup.2 are independently (a) hydrogen, (b)
halogen, (c) --(C.sub.1-C.sub.6)alkyl, (d) --CN, (e) --OR.sup.12
or (f) -trifluoromethyl;
[0119] R.sup.3 is (a) hydrogen, (b) halogen, (c) --(C.sub.1-C.sub.6)alkyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, --OCF.sub.3 and --CF.sub.3,
(d) --CN, (e) --OR.sup.12, (f) -trifluoromethyl, (g) --NO.sub.2,
(h) --SO.sub.2--R.sup.13, (i) --C(O).sub.2R.sup.9, (j) --C(O)NR.sup.19R.sup.20,
(k) --C(O)R.sup.16, (I) --NR.sup.21C(O)--NR.sup.- 21R.sup.22, (m)
--NR.sup.19--C(O)R.sup.20 or (n) -NR.sup.17R.sup.18;
[0120] R.sup.4 is (a) --C(R.sup.14)(R.sup.15)(R.sup.16), (b) --(C.sub.0-C.sub.3)alkyl-NR.sup.17R.sup.18,
(c) --C(O)NR.sup.19R.sup.20, (d) --NR.sup.19--C(O)-R.sup.20, (e)
--(C.sub.0-C.sub.3)alkyl-NR.sup.21--C- (O)--NR.sup.21R.sup.22, (f)
--S(O).sub.m--R.sup.22, (g) --S(O).sub.2--NR.sup.21R.sup.22, (h)
--NR.sup.21--S(O).sub.2-R.sup.22, (i) -aryl, (j) -het, (k) --OR.sup.33
or (I) halogen; provided that in substituents (f) and (h), R.sup.22
is other than -OR.sup.34; and provided that when substituent (b)
is --(C.sub.0)alkyl-NR.sup.17R.sup.18, R.sup.18 is other than --C(O)--R.sup.28
or --S(O).sub.2--R.sup.29;
[0121] or R.sup.3 and R.sup.4 may be taken together to form a carbocyclic
ring of Formula --(CH.sub.2).sub.b-- or a heterocyclic ring selected
from the group consisting of --Q--(CH.sub.2).sub.c-- and --(CH.sub.2).sub.j--Q--(CH.sub.2).sub.k--
wherein Q is O, S or NR.sup.25; wherein said carbocyclic ring is
optionally substituted with one or more substituents independently
selected from Group V; and wherein said heterocyclic ring is optionally
substituted with one or more substituents independently selected
from Group Z;
[0122] R.sup.5 is --OR.sup.23;
[0123] or R.sup.4 and R.sup.5 may be taken together to form a heterocyclic
ring selected from the group consisting of --CR.sup.31.dbd.CR.sup.32--NH--
-, --N.dbd.CR.sup.31--NH--, --CR.sup.31.dbd.CR.sup.32--O-- and --CR.sup.31.dbd.CR.sup.32--S--;
[0124] R.sup.6 is (a) hydrogen, (b) halogen, (c) --(C.sub.1-C.sub.6)alkyl
optionally substituted with one to three substituents independently
selected from the group consisting of halogen, --OCF.sub.3 and --CF.sub.3,
(d) --CN, (e) --OR.sup.12, (f) -trifluoromethyl, (g) --NO.sub.2,
(h) --SO.sub.2--R.sup.13, (i) --C(O).sub.2R.sup.9, (j) --C(O)NR.sup.19R.sup.20,
(k) --C(O)R.sup.16, (I) --NR.sup.21C(O)NR.sup.21- R.sup.22, (m)
--NR.sup.19--C(O)R.sup.20 or (n) --NR.sup.17R.sup.18;
[0125] R.sup.7 is (a) hydrogen, (b) --(C.sub.1-C.sub.4)alkyl wherein
each carbon atom is optionally substituted with 1 to 3 halo atoms
or (c) --(CH.sub.2).sub.nCOOR.sup.9;
[0126] R.sup.8 is (a) hydrogen, (b) --(C.sub.1-C.sub.6)alkyl, (c)
--C(O)-OR.sup.9, (d) --C(O)NR.sup.10R.sup.11 or (e) --CN; provided
that in substituent (c), R.sup.9 is other than methyl or ethyl;
and provided that in substitutent (d), R.sup.10 and R.sup.11 are
not both hydrogen;
[0127] R.sup.9 is (a) --(C.sub.1-C.sub.12)alkyl optionally substituted
with one or more substitutents independently selected from Group
V, (b) --(C.sub.2-C.sub.12)alkenyl optionally substituted with phenyl,
(c) --(C.sub.2-C.sub.12)dialkenyl, (d) --(C.sub.3-C.sub.10)cycloalkyl,
(e) -aryl or (f)) -het;
[0128] R.sup.10 and R.sup.11 are independently (a) hydrogen, (b)
--(C.sub.1-C.sub.12)alkyl optionally substituted with one or more
substituents independently selected from Group V, (c) --(C.sub.3-C.sub.10)cycloalkyl
optionally substituted with one or more substituents independently
selected from Group V, (d) --(C.sub.2-C.sub.12)alkenyl or (e) -het;
[0129] or R.sup.10 and R.sup.11 for any occurrence may be taken
together with the nitrogen atom to which are they attached to form
het;
[0130] R.sup.12 is (a) hydrogen or (b) --(C.sub.1-C.sub.6)alkyl
wherein each carbon atom is optionally substituted with 1 to 3 fluoro
atoms;
[0131] R.sup.13 is (a) --(C.sub.1-C.sub.12)alkyl optionally substituted
with one or more substituents independently selected from Group
V, (b) --(C.sub.2-C.sub.12)alkenyl, (c) --(C.sub.3-C.sub.10)cycloalkyl,
(d) --NR.sup.17R.sup.18, (e) -aryl or (f)) -het;
[0132] R.sup.14 is (a) hydrogen, (b) --(C.sub.1-C.sub.6)alkyl or
(c)--O--R.sup.34;
[0133] R.sup.15 is (a) hydrogen or (b) --(C.sub.1-C.sub.6)alkyl;
[0134] or R.sup.14 and R.sup.15 are taken together with the carbon
atom to which they are attached to form a carbonyl group;
[0135] R.sup.16 is (a) hydrogen, (b) --(C.sub.1-C.sub.6)alkyl wherein
each carbon atom is optionally substituted with 1 to 3 fluoro atoms,
(c) --(C.sub.0-C.sub.6)alkyl-(C.sub.3-C.sub.10)cycloalkyl, (d) --(C.sub.0-C.sub.6)alkyl-aryl
or (e) --(C.sub.0-C.sub.6)alkyl-het;
[0136] R.sup.17 is (a) hydrogen, (b) --(C.sub.1-C.sub.12)alkyl
optionally substituted with one or more substituents independently
selected from Group V, (c) -aryl, (d) -het, (e) --OR.sup.34 or (f)
--(C.sub.3-C.sub.10)cycloalkyl;
[0137] R.sup.18 is (a) hydrogen, (b) --(C.sub.1-C.sub.12)alkyl
optionally substituted with one or more substituents independently
selected from Group V, (c) -aryl, (d) -het, (e) --C(O)--R.sup.28,
(f) --S(O).sub.2-R.sup.29, (g) --OR.sup.34 or (h) --(C.sub.3-C.sub.10)cycloal-
kyl;
[0138] or R.sup.17 and R.sup.18 for any occurrence are taken together
with the nitrogen atom to which they are attached to form het;
[0139] R.sup.19 and R.sup.20 for each occurrence are independently
(a) hydrogen, (b) --(C.sub.1-C.sub.12)alkyl optionally substituted
with one or more substituents independently selected from Group
V, (c) --(C.sub.0-C.sub.6)alkyl-aryl, (d) --(C.sub.0-C.sub.6)alkyl-het,
(e) --C(O)--NR.sup.26R.sup.27, (f) --C(O)--R.sup.28, (g) --S(O)R.sub.2--R.sup.29,
(h) --OR.sup.34 or (i) --(C.sub.3-C.sub.10)cyclo- alkyl;
[0140] or R.sup.19 and R.sup.20 for any occurrence are taken together
with the nitrogen atom to which they are attached to form het;
[0141] R.sup.21 and R.sup.22 for each occurrence are independently
(a) hydrogen, (b) --(C.sub.1-C.sub.12)alkyl optionally substituted
with one to three substituents independently selected from Group
V, (c)-aryl, (d) -het, (e) --(C.sub.3-C.sub.10)cycloalkyl or (f)
--OR.sup.34;
[0142] or R.sup.21 and R.sup.22 are taken together with the nitrogen
atom to which they are attached to form het;
[0143] R.sup.23 is (a) hydrogen, (b) --(C.sub.1-C.sub.4)alkyl optionally
substituted with one or more substituents independently selected
from Group V or (c) --C(O)--R.sup.24;
[0144] R.sup.24 is (a) hydrogen, (b) --(C.sub.1-C.sub.12)alkyl
optionally substituted with one or more substituents independently
selected from Group V, (c) --(C.sub.2-C.sub.12)alkenyl, (d) --(C.sub.3-C.sub.10)cycloal-
kyl, (e) -aryl or (f) -het;
[0145] R.sup.25 for each occurrence is independently (a) hydrogen,
(b) --(C.sub.1-C.sub.6)alkyl, (c) --COR.sup.29 or (d) --SO.sub.2R.sup.29;
[0146] R.sup.26 and R.sup.27 for each occurrence are independently
(a) hydrogen, (b) --(C.sub.1-C.sub.6)alkyl, (c) --(C.sub.3-C.sub.10)cycloalky-
l, (d) --(C.sub.0-C.sub.6)alkyl-aryl, or (e) --(C.sub.0-C.sub.6)alky-het,
[0147] R.sup.28 is (a) hydrogen, (b) --(C.sub.1-C.sub.12)alkyl
optionally substituted with one or more substituents independently
selected from Group V, (c) --(C.sub.2-C.sub.12)alkenyl, (d) --(C.sub.3-C.sub.10)cycloal-
kyl, (e) -aryl or (f) -het;
[0148] R.sup.29 is (a) --(C.sub.1-C.sub.12)alkyl optionally substituted
with one or more substituents independently selected from Group
V, (b) --(C.sub.2-C.sub.12)alkenyl, (c) --(C.sub.3-C.sub.10)cycloalkyl,
(d) -aryl or (e) -het;
[0149] R.sup.30 is (a) hydrogen, (b) --(C.sub.1-C.sub.12)alkyl
optionally substituted with one or more substituents independently
selected from Group V, (c) --(C.sub.1-C.sub.12)alkenyl, (d) --(C.sub.3-C.sub.10)cycloal-
kyl, (e) --C(O)--R.sup.31 or (f) --S(O).sub.m--R.sup.32;
[0150] R.sup.31 is (a) hydrogen, (b) --(C.sub.1-C.sub.12)alkyl
optionally substituted with one or more substituents independently
selected from Group V, (c) --(C.sub.2-C.sub.12)alkenyl, (d) --(C.sub.3-C.sub.10)cycloal-
kyl, (e) -aryl, (f) -het or (g) --OR.sup.34;
[0151] R.sup.32 is (a) hydrogen, (b) --(C.sub.1-C.sub.12)alkyl
optionally substituted with one or more substituents independently
selected from Group V, (c) --(C.sub.2-C.sub.12)alkenyl, (d) --(C.sub.3-C.sub.10)cycloal-
kyl, (e) -aryl or (f) -het;
[0152] R.sup.33 is (a) --(C.sub.0-C.sub.6)alkyl-aryl, (b) --(C.sub.0-C.sub.6)alkyl-het,
(c) --(C.sub.7-C.sub.12)alkyl optionally substituted with one or
more substituents independently selected from Group V, (d) --(C.sub.1-C.sub.6)alkyl
wherein at least one carbon atom is substituted with 1 to 3 fluoro
atoms, (e) --(C.sub.2-C.sub.12)alkenyl or (f) --(C.sub.3-C.sub.10)cycloalkyl;
[0153] R.sup.34 is (a) -aryl, (b) -het, (c) --(C.sub.1-C.sub.12)alkyl
optionally substituted with one or more substituents independently
selected from Group V, (d) --(C.sub.2-C.sub.12)alkenyl or (e) --(C.sub.3-C.sub.10)cycloalkyl;
[0154] --(C.sub.3-C.sub.10)cycloalkyl for each occurrence is a
fully or partially saturated mono-, bi- or tricyclic ring containing
three to ten carbon atoms; wherein in the bicyclic ring, a monocyclic
cycloalkyl ring is spiro fused to another cycloalkyl ring or is
fused via two carbon atoms to a benzene ring or another cycloalkyl
ring; and wherein in the tricyclic ring, a bicyclic ring is spiro
fused to a cycloalkyl ring or is fused via two atoms to a benzene
ring or another cycloalkyl ring;
[0155] said --(C.sub.3-C.sub.10)cycloalkyl optionally contains
one to three bridging atoms independently selected from carbon,
oxygen, sulfur and nitrogen; said bridging atoms are attached to
two carbon atoms in the ring; and said bridging atoms are optionally
substituted with one to three groups independently selected from
--(C.sub.1-C.sub.6)alkyl and hydroxy;
[0156] said cycloalkyl ring is optionally substituted on one ring
if the moiety is monocyclic, on one or both rings if the moiety
is bicyclic, or on one, two or three rings if the moiety is tricyclic,
with one or more substitutents independently selected from Group
V;
[0157] Group V is (a) --(C.sub.1-C.sub.6)alkyl optionally substituted
with one or two hydroxy, (b) --(C.sub.2-C.sub.5)alkynyl, (c) -halogen,
(d) --NR.sup.35R.sup.36, (e) --NO.sub.2, (f) --OCF.sub.3, (g) --OR.sup.37,
(h) --SR.sup.37, (i)-oxo, (j) -trifluoromethyl, (k) --CN, (I) --C(O)NR.sup.35--OH,
(m) --COOR.sup.35, (n) --O--C(O)--(C.sub.1-C.sub.6)a- lkyl, (o)
--(C.sub.3-C.sub.10)cycloalkyl optionally substituted with CN, (p)
--(C.sub.0-C.sub.6)alkyl-aryl, (q) --(C.sub.0-C.sub.6)alkyl-het,
(r) --C(O)--(C.sub.1-C.sub.6)alkyl or (s) --C(O)-aryl;
[0158] R.sup.35 and R.sup.36 for each occurrence are independently
(a) hydrogen, (b) --(C.sub.1-C.sub.6)alkyl or (c) --(C.sub.0-C.sub.6)alkyl-ar-
yl;
[0159] R.sup.37 is (a) hydrogen, (b) --(C.sub.1-C.sub.6)alkyl optionally
substituted with one or more halo, hydroxy or methoxy, (c) --(C.sub.0-C.sub.6)alkyl-aryl
or (d) --(C.sub.0-C.sub.6)alkyl-het;
[0160] aryl is (a) phenyl optionally substituted with one or more
substituents independently selected from Group Z; (b) naphthyl optionally
substituted with one or more substituents independently selected
from Group Z or (c) biphenyl optionally substituted with one or
more substituents independently selected from Group Z;
[0161] het for each occurrence is a 4-, 5-, 6-, 7- and 8-membered
fully saturated, partially saturated or fully unsaturated mono-,
bi- or tricyclic heterocyclic ring containing from one to four heteroatoms
independently selected from the group consisting of oxygen, sulfur
and nitrogen; wherein in the bicyclic ring, a monocyclic heterocyclic
ring is spiro fused to a --(C.sub.3-C.sub.8)cycloalkyl ring or to
another heterocyclic ring which is fully or partially saturated;
or is fused via two atoms to a benzene ring, a --(C.sub.3-C.sub.8)cycloalkyl
ring or another heterocyclic ring; and wherein in the tricyclic
ring, a bicyclic ring is spiro fused to a --(C.sub.3-C.sub.8)cycloalkyl
ring or to another heterocyclic ring which is fully or partially
saturated; or is fused via two atoms to a benzene ring, a (C.sub.3-C.sub.6)cycloalkyl
ring, or another heterocyclic ring;
[0162] said het optionally contains one to three bridging atoms
independently selected from oxygen, sulfur and nitrogen; said bridging
atoms are attached to two other atoms in the ring; and said bridging
atoms are optionally substituted with one to three groups independently
selected from --(C.sub.1-C.sub.6)alkyl and hydroxy;
[0163] said het optionally has one or two oxo groups substituted
on carbon or one or two oxo groups substituted on sulfur;
[0164] said het is optionally substituted on carbon or nitrogen,
on one ring if the moiety is monocyclic, on one or both rings if
the moiety is bicyclic, or on one, two or three rings if the moiety
is tricyclic, with one or more substituents independently selected
from Group Z;
[0165] Group Z for each occurrence is independently (a) hydrogen,
(b) halogen, (c) trifluoromethyl, (d) hydroxy, (e) --OCF.sub.3,
(f) --CN, (g) --NO.sub.2, (h) --(C.sub.1-C.sub.6)alkyl optionally
substituted with one or more substituents independently selected
from the group consisting of hydroxy, halogen, --OCF.sub.3 and --CF.sub.3,
(i) --(C.sub.2-C.sub.6)alke- nyl optionally substituted with phenyl,
(j) --(C.sub.2-C.sub.5)alkynyl, (k) --(C.sub.1-C.sub.6)alkoxy, (I)
--(C.sub.0-C.sub.6)alkyl-phenyl optionally substituted with one
or more substituents independently selected from the group consisting
of halogen, --OCF.sub.3, --CF.sub.3, --(C.sub.1-C.sub.4)alkyl, --(C.sub.1-C.sub.4)alkoxy
and --C(O)CH.sub.3, (m) --(C.sub.0-C.sub.6)alkyl-naphthyl optionally
substituted with one or more substituents independently selected
from the group consisting of halogen, --OCF.sub.3, --CF.sub.3, --(C.sub.1-C.sub.4)alkyl,
--(C.sub.1-C.sub.4)alkoxy and --C(O)CH.sub.3, (n) --C(O).sub.2R.sup.35,
(o) --(C.sub.0-C.sub.6)alkyl-C(O)NR.sup.35R.sup.36, (p) --(C.sub.0-C.sub.6)alkyl-C(O)R.sup.38,
(q) --NR.sup.35R.sup.36, (r) --NR.sup.35--C(O)NR.sup.35R.sup.36,
(s) --NR.sup.35--C(O)R.sup.36, (t) --OR.sup.37, (u) --SR.sup.37,
(v) --(C.sub.3-C.sub.10)cycloalkyl, (w) --(C.sub.0-C.sub.6)alkyl-pyridinyl
optionally substituted with one or more --(C.sub.1-C.sub.6)alkyl
which is optionally substituted with one or more substituents independently
selected from the group consisting of hydroxy and halo, (x) --(C.sub.0-C.sub.6)alkyl-piperidinyl
optionally substituted with one or more --(C.sub.1-C.sub.6)alkyl
which is optionally substituted with one or more substituents independently
selected from hydroxy and halo, (y) --SO.sub.2--R.sup.37, (z) --SO.sub.2--NR.sup.35R.su-
p.36 or (a1) --S-phenyl-CH.sub.2OH;
[0166] R.sup.38 is (a) --(C.sub.1-C.sub.6)alkyl, (b) --(C.sub.0-C.sub.6)alkyl-phenyl,
(c) --(C.sub.0-C.sub.6)alkyl-phenanthren- yl optionally substituted
with one to three CF.sub.3, (d) --(C.sub.0-C.sub.6)alkyl-pyrrolidinyl
or (e) --(C.sub.0-C.sub.6)alkyl-mor- pholinyl;
[0167] or any two Z Groups for any occurrence in the same variable
may be taken together to form (a) a carbocyclic ring of the formula
--(CH.sub.2).sub.e-- or (b) a heterocyclic ring selected from the
group consisting of --O(CH.sub.2).sub.fO--, --(CH.sub.2).sub.gNH--
and --CH.dbd.CHNH--;
[0168] m is 0, 1 or 2;
[0169] n is 0, 1, 2 or 3;
[0170] b is 3, 4, 5, 6 or 7;
[0171] c, f, g, j and k are each independently 2, 3, 4, 5 or 6;
and
[0172] e is 3, 4, 5, 6 or 7;
[0173] provided that in a compound of the above formula: 1) the
substituent --C(R.sup.14)(R.sup.15)(R.sup.16) in R.sup.4 is other
than (C.sub.1-C.sub.4)alkyl; and 2) R.sup.4 is halo only when R.sup.8
is --C(O)--OR.sup.9 or --C(O)NR.sup.10R.sup.11.
[0174] More particularly, the following compounds are useful in
the methods of the present invention:
[0175] 8-[[5-[2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazine-2(3H)-y-
l)phenoxyl]-2-hydroxyphenyl]sulfonyl]-spiro[8-azabicyclo[3.2.1]octane-3,2'-
-(3'H)-dihydro-furan];
[0176] 2-{3,5-dichloro-4-[3-(3,3-dimethyl-piperidine-1-sulfonyl)-4-hydroxy-
-phenoxy]-phenyl}-2H-[1,2,4]triazine-3,5-dione;
[0177] 2-{3,5-dichloro-4-[4-hydroxy-3-(3-methyl-3-phenyl-piperidine-1-sulf-
onyl)-phenoxy]-phenyl}-2H-[1,2,4]triazine-3,5-dione;
[0178] N-cyclohexyl-5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]tri-
azin-2-yl)-phenoxy]-2-hydroxy-benzenesulfonamide;
[0179] N-bicyclo[2.2.1]hept-2-yl-5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro--
3H-[1,2,4]triazin-2-yl)-phenoxy]-2-hydroxy-benzamide;
[0180] 2-{3,5-dichloro-4-[3-(3,3-dimethyl-piperidine-1-carbonyl)-4-hydroxy-
-phenoxyl]-phenyl}-2H-[1,2,4]triazine-3,5-dione;
[0181] N-bicyclo[2.2.1]hept-2-yl-5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro--
3H-[1,2,4]triazin-2-yl)-phenoxy]-2-hydroxy-benzamide;
[0182] 2-{3,5-dichloro-4-[4-hydroxy-3-(3-methyl-3-phenyl-piperidine-1-carb-
onyl)-phenoxy]-phenyl}-2H-[1,2,4]triazine-3,5-dione;
[0183] 5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-ph-
enoxy]-N-(6,6-dimethyl-bicyclo[3.1.1]hept-2-yl)-2-hydroxy-benzamide;
[0184] 2-{3,5-dichloro-4-[3-(3,5-dimethyl-piperidine-1-carbonyl)-4-hydroxy-
-phenoxy]-phenyl}-2H-[1,2,4]triazine-3,5-dione;
[0185] 2-{3,5-dichloro-4-[4-hydroxy-3-(piperidine-1-carbonyl)-phenoxy]-phe-
nyl}-2H-[1,2,4]triazine-3,5-dione;
[0186] N-cyclohexyl-5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]tri-
azin-2-yl)-phenoxy]-2-hydroxy-benzamide;
[0187] 2-{3,5-dichloro-4-[3-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-4-hyd-
roxy-phenoxy]-phenyl}-2H-[1,2,4]triazine-3,5-dione;
[0188] 2-{4-[3-(4-fluoro-benzyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-2-
H-[1,2,4]triazine-3,5-dione; and
[0189] 2-{3,5-dichloro-4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-phenyl}--
2H-[1,2,4]triazine-3,5-dione.
[0190] IV. Also, the thyromimetic compounds useful in the methods
of the present invention have the following formula, also described
in commonly assigned published European Patent Application 1 127
882: 6
[0191] or a stereoisomer, pharmaceutically acceptable salt or prodrug
thereof, or a pharmaceutically acceptable salt of the prodrug, wherein:
[0192] W is O, S, SO, SO.sub.2, CH.sub.2, CF.sub.2, CHF, C(.dbd.O),
CH(OH), NR.sup.a, or 7
[0193] X is O, CH.sub.2, CH.sub.2CH.sub.2, S, SO, SO.sub.2, CH.sub.2NR.sup.a,
NR.sup.a, or a bond;
[0194] each R.sup.a is independently hydrogen, C.sub.1-C.sub.6alkyl,
or C.sub.1-C.sub.6alkyl substituted with one substituent selected
from C.sub.3-C.sub.6cycloalkyl or methoxy;
[0195] R.sup.1, R.sup.2, R.sup.3 and R.sup.6 are independently
hydrogen, halogen, C.sub.1-C.sub.8alkyl, --CF.sub.3, --OCF.sub.3,
--OC.sub.1-C.sub.8alkyl, or --CN;
[0196] R.sup.4 is hydrogen, C.sub.1-C.sub.12alkyl, [C.sub.1-C.sub.12alkyl
that is substituted with from one to three substituents independently
selected from Group V], C.sub.2-C.sub.12 alkenyl, C.sub.2-C.sub.12
alkynyl, halogen, --CN, --OR.sup.b, --SR.sup.c, --S(.dbd.O)R.sup.c,
--S(.dbd.O).sub.2R.sup.c, aryl, heteroaryl, C.sub.3-C.sub.10 cycloalkyl,
heterocycloalkyl, --S(.dbd.O).sub.2NR.sup.cR.sup.d, --C(.dbd.O)NR.sup.cR.sup.d,
--C(.dbd.O)OR.sup.c, --NR.sup.aC(.dbd.O)R.sup- .d, --NR.sup.aC(.dbd.O)NR.sup.cR.sup.d,
--NR.sup.aS(.dbd.O).sub.2R.sup.d, --NR.sup.aR.sup.d, --C(.dbd.O)R.sup.c,
[0197] or R.sup.3 and R.sup.4 may be taken together with the carbon
atoms to which they are attached to form an unsubstituted or substituted
carbocyclic ring of formula --(CH.sub.2).sub.i-- or an unsubstituted
or substituted heterocyclic ring selected from the group consisting
of --Q--(CH.sub.2).sub.j-- and --(CH.sub.2).sub.k--Q--(CH.sub.2).sub.l--
wherein Q is O, S or NR.sup.a; i is 3, 4, 5, 6 or 7; j is 2, 3,
4, 5, or 6; k and l are each independently 1, 2, 3, 4, or 5, and
any substituents up to four are selected from C.sub.1-C.sub.4alkyl,
--OR.sup.b, oxo, --CN, phenyl, or --NR.sup.aR.sup.g;
[0198] R.sup.b is hydrogen, C.sub.1-C.sub.12alkyl, [C.sub.1-C.sub.12alkyl
substituted with one to three substituents independently selected
from Group V], aryl, heteroaryl, C.sub.3-C.sub.10 cycloalkyl, heterocycloalkyl,
--C(.dbd.O)NR.sup.cR.sup.d, or --C(.dbd.O)R.sup.f;
[0199] R.sup.c and R.sup.d are each independently selected from
hydrogen, C.sub.1-C.sub.12alkyl, [C.sub.1-C.sub.12alkyl substituted
with one to three substituents independently selected from Group
VI], C.sub.2-C.sub.12alkenyl, C.sub.2-C.sub.12alkynyl, aryl, heteroaryl,
C.sub.3-C.sub.10 cycloalkyl, heterocycloalkyl,
[0200] or R.sup.c and R.sup.d may together along with the atom(s)
to which they are attached form a 3-10 membered unsubstituted or
substituted heterocyclic ring, which may contain a second heterogroup
selected from O, NR.sup.e, or S, wherein any substitutents up to
four are selected from C.sub.1-C.sub.4alkyl, --OR.sup.b, oxo, --CN,
phenyl, or --NR.sup.aR.sup.g;
[0201] R.sup.5 is --OH, --OC.sub.1-C.sub.6alkyl, --OC(.dbd.O)R.sup.f,
--F, --C(.dbd.O)OR.sup.c,
[0202] or R.sup.4 and R.sup.5 may together with the atom(s) to
which they are attached form a heterocyclic ring selected from the
group consisting of --CR.sup.c.dbd.CR.sup.a--NH--, --N.dbd.CR.sup.a--NH--,
--CR.sup.c.dbd.CR.sup.a--O--, --CR.sup.c.dbd.CR.sup.a--S--, --CR.sup.c.dbd.N--NH--,
or --CR.sup.a.dbd.CR.sup.a--CR.sup.a.dbd.N--;
[0203] Group V is halogen, --CF.sub.3, --OCF.sub.3, hydroxy, oxo,
C.sub.1-C.sub.6alkoxy, --CN, aryl, heteroaryl, C.sub.3-C.sub.10cycloalkyl-
, heterocycloalkyl, --SR.sup.f, --S(.dbd.O)R.sup.f, --S(.dbd.O).sub.2R.sup.f,
[--S(.dbd.O).sub.2NR.sup.aR.sup.f, wherein R.sup.a and R.sup.f may
together along with the atom(s) to which they are attached form
a 3-8 membered heterocyclic ring, which may contain a second heterogroup
selected from O, NR.sup.e or S], --NR.sup.aR.sup.g, or [--C(.dbd.O)NR.sup.aR.sup.f,
wherein R.sup.a and R.sup.f may together along with the atom(s)
to which they are attached form a 3-8 membered heterocyclic ring,
which may contain a second heterogroup selected from O, NR.sup.e
or S];
[0204] Group VI is halogen, hydroxy, oxo, C.sub.1-C.sub.6alkoxy,
aryl, heteroaryl, C.sub.3-C.sub.8cycloalkyl, heterocycloalkyl, --CN,
or --OCF.sub.3;
[0205] R.sup.e is hydrogen, --CN, C.sub.1-C.sub.10alkyl, [C.sub.1-C.sub.10alkyl
substituted with one to three substitutents independently selected
from Group V], C.sub.2-C.sub.10alkenyl, C.sub.2-C.sub.10alkoxy,
C.sub.3-C.sub.10cycloalkyl, aryl, heteroaryl, --C(.dbd.O)R.sup.f,
--C(.dbd.O)OR.sup.f, --C(.dbd.O)NR.sup.aR.sup.f, --S(.dbd.O).sub.2NR.sup.aR.sup.f,
or --S(.dbd.O).sub.2R.sup.f;
[0206] R.sup.f is hydrogen, C.sub.1-C.sub.10alkyl, [C.sub.1-C.sub.10alkyl
substituted with from one to three substituents selected from Group
VI], C.sub.2-C.sub.10alkenyl, C.sub.2-C.sub.10alkoxy, C.sub.3-C.sub.10cycloalk-
yl, heterocycloalkyl, aryl, or heteroaryl; and
[0207] R.sup.g is hydrogen, C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.8cycloalky-
l, C.sub.2-C.sub.6 alkenyl, aryl, --C(.dbd.O)R.sup.f, --C(.dbd.O)OR.sup.f,
--C(.dbd.O)NR.sup.aR.sup.f, or --S(.dbd.O).sub.2R.sup.f, provided
that R.sup.1 and R.sup.2 are not both hydrogen, further provided
that when X is CH.sub.2, W is NR.sup.a, R.sup.3 is hydrogen and
R.sup.5 is --OH, then R.sup.6 and R.sup.4 are not both --C(CH.sub.3).sub.3,
further provided that when X is CH.sub.2 or CH.sub.2CH.sub.2, W
is O, and R.sup.3 and R.sup.6 are hydrogen, then R.sup.4 is not
halogen, --CF.sub.3, C.sub.1-C.sub.6alkyl or C.sub.3-C.sub.7cycloalkyl,
and further provided that when R.sup.3 and R.sup.4 are hydrogen
and W is O then R.sup.6 is not halogen, --CF.sub.3, C.sub.1-C.sub.6alkyl
or C.sub.3-C.sub.7cycloalkyl.
[0208] V. In another embodiment, the present invention includes
the use of the thyromimetic compounds of the following formula,
also described in commonly assigned, published European Patent Application
1 148 054: 8
[0209] the stereoisomer and prodrug thereof, and the pharmaceutically
acceptable salt of said compound, stereoisomer, and prodrug, wherein:
[0210] W is oxygen, sulfur, --SO--, --S(O).sub.2, --CH.sub.2--,
--CF.sub.2--, --CHF--, --C(O)--, --CH(OH)--, --NR.sup.a, or --C(.dbd.CH.sub.2)--;
[0211] R.sup.1, R.sup.2, R.sup.3, and R.sup.6 are each independently
hydrogen, halogen, --(C.sub.1-C.sub.8)alkyl, --CF.sub.3, --OCF.sub.3,
--O(C.sub.1-C.sub.8)alkyl, or --CN;
[0212] R.sup.4 is hydrogen, --(C.sub.1-C.sub.12)alkyl substituted
with zero to three substituents independently selected from Group
V, --(C.sub.2-C.sub.12)alkenyl, --(C.sub.2-C.sub.12)alkynyl, halogen,
--CN, --OR.sup.b, --SR.sup.c, --S(O)R.sup.c, --S(O).sub.2R.sup.c,
aryl, heteroaryl, --(C.sub.3-C.sub.10)cycloalkyl, heterocycloalkyl,
--S(O).sub.2NR.sup.cR.sup.d, --C(O)NR.sup.cR.sup.d, --C(O)OR.sup.c,
--NR.sup.aC(O)R.sup.d, --NR.sup.aC(O)NR.sup.cR.sup.d, --NR.sup.aS(O).sub.2R.sup.d,
or --C(O)R.sup.c; or
[0213] R.sup.3 and R.sup.4 are taken together along with the carbon
atoms to which they are attached to form a carbocyclic ring of formula
--(CH.sub.2).sub.l-- or a heterocyclic ring of formula --(CH.sub.2).sub.k--Q--(CH.sub.2).sub.l--
wherein Q is oxygen, sulfur, or --NR.sup.e--; i is 3, 4, 5, or 6;
k is 0, 1, 2, 3, 4, or 5; and l is 0, 1, 2, 3, 4, or 5; and wherein
said carbocyclic ring and said heterocyclic ring are each substituted
with zero to four substituents independently selected from --(C.sub.1-C.sub.4)alkyl,
--OR.sup.b, oxo, --CN, phenyl, or --NR.sup.aR.sup.g;
[0214] R.sup.5 is hydroxy, --O(C.sub.1-C.sub.6)alkyl, --OC(O)R.sup.f,
fluorine, or --C(O)OR.sup.c; or
[0215] R.sup.4 and R.sup.5 are taken together along with the carbon
atoms to which they are attached to form a heterocyclic ring selected
from the group consisting of --CR.sup.c.dbd.CR.sup.a--NH--, --N.dbd.CR.sup.a--NH,
--CR.sup.c.dbd.CR.sup.a--O--, --CR.sup.c.dbd.CR.sup.a--S--, --CR.sup.c.dbd.N--NH--,
and --CR.sup.a.dbd.CR.sup.a--CR.sup.a.dbd.N--;
[0216] R.sup.a for each occurence is independently hydrogen, or
--(C.sub.1-C.sub.6)alkyl substituted with zero or one --(C.sub.3-C.sub.6)cycloalkyl
or methoxy;
[0217] R.sup.b for each occurence is independently hydrogen, --(C.sub.1-C.sub.12)alkyl
substituted with zero to three substituents independently selected
from Group V, aryl, heteroaryl, --(C.sub.3-C.sub.10)cycloalkyl,
heterocycloalkyl, --C(O)NR.sup.cR.sup.d, or --C(O)R.sup.f;
[0218] R.sup.c and R.sup.d for each occurence are each independently
hydrogen, --(C.sub.1-C.sub.12)alkyl substituted with zero to three
substituents independently selected from Group VI, --(C.sub.2-C.sub.12)alkenyl,
--(C.sub.2-C.sub.12)alkynyl, aryl, heteroaryl, --(C.sub.3-C.sub.10)cycloalkyl,
or heterocycloalkyl;
[0219] provided that when R.sup.4 is the moiety --SR.sup.c, --S(O)R.sup.c,
or --S(O).sub.2R.sup.c, R.sup.c is other than hydrogen; or
[0220] R.sup.c and R.sup.d are taken together along with the atom(s)
to which they are attached to form a 3-10 membered heterocylic ring
which may optionally contain a second heterogroup selected from
oxygen, --NR.sup.e--, or sulfur; and wherein said heterocyclic ring
is substituted with zero to four substituents independently selected
from --(C.sub.1-C.sub.4)alkyl, --OR.sup.b, oxo, --CN, phenyl, or
--NR.sup.aR.sup.g;
[0221] R.sup.e for each occurence is hydrogen, --CN, --(C.sub.1-C.sub.10)alkyl
substituted with zero to three substituents independently selected
from Group V, --(C.sub.2-C.sub.10)alkenyl, --(C.sub.2-C.sub.10)alkoxy,
--(C.sub.3-C.sub.10)cycloalkyl, aryl, heteroaryl, --C(O)R.sup.f,
--C(O)OR.sup.f, --C(O)NR.sup.aR.sup.f, or --S(O).sub.2R.sup.f;
[0222] R.sup.f for each occurence is independently --(C.sub.1-C.sub.10)alk-
yl substituted with zero to three substituents independently selected
from Group VI, --(C.sub.2-C.sub.12)alkenyl, --(C.sub.2-C.sub.10)alkynyl,
--(C.sub.3-C.sub.10)cycloalkyl, aryl, heteroaryl, or heterocycloalkyl;
[0223] R.sup.g for each occurence is independently hydrogen, --(C.sub.1-C.sub.6)alkyl,
--(C.sub.2-C.sub.6)alkenyl, aryl, --C(O)R.sup.f, --C(O)OR.sup.f,
--C(O)NR.sup.aR.sup.f, --S(O).sub.2R.sup.f, or --(C.sub.3-C.sub.8)cycloalkyl;
[0224] Group V is halogen, --CF.sub.3, --OCF.sub.3, --OH, oxo,
--(C.sub.1-C.sub.6)alkoxy, --CN, aryl, heteroaryl, --(C.sub.3-C.sub.10)cycloalkyl,
heterocycloalkyl, --SR.sup.f, --S(O)R.sup.f, --S(O).sub.2R.sup.f,
--S(O).sub.2NR.sup.aR.sup.f, --NR.sup.aR.sup.g, or --C(O)NR.sup.aR.sup.f;
[0225] Group VI is halogen, hydroxy, oxo, --(C.sub.1-C.sub.6)alkoxy,
aryl, heteroaryl, --(C.sub.3-C.sub.8)cycloalkyl, heterocycloalkyl,
--CN, or --OCF.sub.3;
[0226] provided that when R.sup.4 is --(C.sub.1-C.sub.12)alkyl
substituted with zero to three substituents independently selected
from Group V, wherein said Group V substituent is oxo, said oxo
group is substituted on a carbon atom other than the C.sub.1 carbon
atom in --(C.sub.1-C.sub.12)alkyl;
[0227] aryl for each occurence is independently phenyl or naphthyl
substituted with zero to four substituents independently selected
from halogen, --(C.sub.1-C.sub.6)alkyl, --CN, --SR.sup.f, --S(O)R.sup.f,
--S(O).sub.2R.sup.f, --(C.sub.3-C.sub.6)cycloalkyl, --S(O).sub.2NR.sup.aR.sup.f,
--NR.sup.aR.sup.g, --C(O)NR.sup.aR.sup.f, --OR.sup.b, -perfluoro-(C.sub.1-C.sub.4)alkyl,
or --COOR.sup.f;
[0228] provided that when said substituent(s) on aryl are --SR.sup.f,
--S(O)R.sup.f, --S(O).sub.2R.sup.f, --S(O).sub.2NR.sup.aR.sup.f,
--NR.sup.aR.sup.g, --C(O)NR.sup.aR.sup.f, --OR.sup.b, or --COOR.sup.f,
said substituents R.sup.b, R.sup.f, and R.sup.g, are other than
aryl or heteroaryl;
[0229] heteroaryl for each occurence is independently a 5-, 6-,
7-, 8-, or 9-membered monocyclic or bicyclic ring having from one
to three heteroatoms selected from O, N, or S;
[0230] wherein in said bicyclic ring, a monocyclic heteroaryl ring
is fused to a benzene ring or to another heteroaryl ring, and having
zero to three substituents independently selected from halogen,
--(C.sub.1-C.sub.4)alkyl, --CF.sub.3, --OR.sup.b, --NR.sup.aR.sup.g,
or --COOR.sup.f;
[0231] provided that when said substituent(s) on heteroaryl are
--NR.sup.aR.sup.g, --OR.sup.b, or --COOR.sup.f, said substituents
R.sup.b, R.sup.f, and R.sup.g, are other than aryl or heteroaryl;
[0232] heterocycloalkyl for each occurence is independently a 5-,
6-, 7-, 8-, or 9-membered monocyclic or bicyclic cycloalkyl ring
having from one to three heteroatoms selected from oxygen, --NR.sup.e,
or sulfur, and having zero to four substituents independently selected
from --(C.sub.1-C.sub.4)alkyl, --OR.sup.b, oxo, --CN, phenyl, or
--NR.sup.aR.sup.g; and
[0233] X is 9
[0234] Methods for making the thyromimetic compounds described
above are disclosed in the above cited patent applications. All
of the hereinabove and below cited references, U.S. patent applications,
published European patent applications and published PCT International
patent applications are hereby incorporated by reference herein
in their entireties.
[0235] The ability of a thyromimetic compound to bind thyroid hormone
receptors may be demonstrated in standard assays known in the art,
such as the Thyroid Hormone Receptor Binding Assay, described at
page 53 of published European application EP 1 088 819. Preferably,
the thyromimetic compounds useful in the methods of the present
invention are TR.beta.1-selective in the Binding Assay and, therefore,
are more selective for the predominant form of the receptor present
in human hair follicles, as recently stated in the art. As such,
these compounds are expected to have a preferential effect on hair
growth relative to cardiac endpoints and other undesirable endpoints.
[0236] Also, as noted above, preferably, the compounds useful in
the present invention are cardiac-sparing. Compounds may be tested
for their cardiac-sparing properties using the following assay:
Cardiotoxicity Assay
[0237] As is well known by those skilled in the art, thyroid hormones
affect cardiac functioning, for example, by causing an increase
in the heart rate as well as an increase in tissue mass, or hypertrophy.
The ability of the compounds useful in the methods of the present
invention to cause the thyroid hormone-like, cardiotoxic effects
may be demonstrated according to the following protocol:
[0238] A. Experimental Summary
[0239] This in vivo screen is designed to evaluate the cardiac
effects of compounds that are thyromimetic. The cardiac endpoints
that are measured are heart weight and heart mitochondrial alpha-glycerophosphate
dehydrogenase ("mGPDH") activity. The protocol involves:
(a) dosing rodents for about 6 days, (b) harvesting tissue and weighing
it, (c) preparing a subcellular fraction of the tissue, enriched
in mitochondria, and (d) subsequent assaying of enzyme activity
thereby.
[0240] B. Preparation of Animals
[0241] A compound useful in the methods of the present invention,
and a vehicle, or T.sub.3 sodium salt, is administered topically
or orally as a single daily dose given between about 3 p.m. to about
6 p.m. for about 6 days.
[0242] Animals are sacrificed by decapitation, tissues are dissected
and weighed (for example, heart), then placed into 10 ml of cold
homogenization buffer (0.25 M sucrose, 25 mM HEPES, pH 7.4, 0.5
mM EDTA, 0.5 mM AEBSF, 1 .mu.g/ml leupeptin), stored on ice. Tissue
homogenates are prepared using a Polytron.RTM. homogenizer (Kinematica
AG, Switzerland), and then centrifuged at 15,000.times.g (11000
rpm, 10 minutes, at 4.degree. C. using a Sorvall.RTM. SM-24 rotor
(Dupont)), after which the supernatant is discarded. The pellet
is resuspended in homogenization buffer containing 0.1% Triton-x
100 (6 mL), followed by sonication for 30 seconds (Branson Sonifier
(Branson, Eagle Rd., Danbury, Conn. 06810), setting #2). Aliquots
(1 ml in duplicate) are stored at -80.degree. C., and 20 .mu.l is
placed in a separate tube for determination of the total protein
concentration in the homogenate, using the BCA Protein Assay Kit
(Pierce, 3747 No. Meridian Rd., Rockford, Ill. 61105).
[0243] The mGPDH enzyme assay is carried out by incubating a sample
of the tissue homogenate (containing a range of protein amounts,
from 10-100 ug) prepared as described above, in a buffer of the
following composition: 225 mM mannitol, 75 mM sucrose, 20 mM HEPES,
pH 7.4, 50 mM KH.sub.2PO.sub.4, 1 mM KCN, 0.0025 mM rotenone, 0.025
mM menadione, 0.06 mM 2,6 dichlororindophenol. The assay is carried
out at 37.degree. C. in a Molecular Devices SpectraMax 96-well plate
spectrophotometer (1311 Orleans Drive, Sunnyvale, Calif. 94089),
by addition of substrate (.alpha.-glycerophosphate) to a final concentration
of 50 mM. The decline in absorbance at 600 nm wavelength is measured
frequently over the next 30-60 minutes. The enzyme activity is calculated
from the change in absorbance at 600 nM versus time. Finally, the
change in absorbance at 600 nm per unit of time is divided by the
amount of protein used in the assay. By comparing the mGPDH enzyme
activity in cardiac tissue from control animals dosed with a vehicle
solution to the mGPDH enzyme activity in cardiac tissue from animals
treated with a thyromimetic compound, the cardiac effect of the
thyromimetic compound can be assessed. Another effect of a thyromimetic
compound on the heart is hypertrophy. Cardiac hypertrophy in response
to a thyromimetic compound can be assessed by comparing the heart
weight in control animals dosed with a vehicle solution to the heart
weight in animals dosed with a thyromimetic compound.
Telogen Conversion Assay
[0244] The Telogen Conversion Assay measures the potential of a
compound (hereinafter referred to as the "test compound")
to convert mice in the resting stage of the hair growth cycle ("telogen")
to the growth stage of the hair growth cycle ("anagen").
Without intending to be limited by theory, there are three principal
phases of the hair growth cycle: anagen, catagen and telogen. The
telogen period in C3H/HeN mice lasts 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. For example, about 40 day-old mice with dark fur (brown
or black) may be used in hair growth experiments; melanogenesis
occurs in these animals along with hair (fur) growth and the topical
application of hair growth inducers may be evaluated in these animals.
[0245] The Telogen Conversion Assay described below is used to
screen test compounds for potential hair growth by measuring melanogenesis:
[0246] Objectives: To evaluate and compare the effect of test compounds
applied topically on C3H/HeN mice for hair growth.
[0247] Animals: Female C3H/HeN mice, six and a half weeks of age.
[0248] Experimental Procedures:
[0249] Route and Duration of Treatment: Topical dosing with test
compounds on mice is scheduled once or twice daily for five (5)
consecutive days for one week to four weeks. Topical dosing begins
on Day 0 by applying test compound or vehicle in volumes of 20 .mu.l
which keeps the solubilized test compound to a prescribed area of
approximately one (1) square centimeter (1 cm.sup.2) in the center
of the clipped lower back of each mouse.
[0250] Study Design: Only mice with pink skin or in the telogen
phase of the hair growth cycle are selected for inclusion in the
study. On Friday, before the experiment starts, the mice are weighed
and then anesthetized with isoflurane in a mouse chamber. The hair
over the lower dorsal area is clipped with a Wahl clipper using
a #40 blade. Care is taken to avoid abrading the skin surface. On
the Monday (Day 0) following hair clipping, the mice are again anesthetized
with isoflurane and photographed with a digital camera. After digital
photographs are taken, the mice receive 20 .mu.l of the respective
test compounds applied with an automated pipette to the clipped
area between the hind legs. The test compound for each treatment
group is evenly spread with the pipette tip to an area approximately
1 square centimeter (1 cm.sup.2), and applied to the same site on
subsequent dosing days. All topical treatments are administered
as described in the Route and Duration of Treatment Section.
[0251] Observations of the test sites are made three (3) times
a week on Monday, Wednesday, and Friday, with observations beginning
immediately after the first week of treatment and looking for changes
in skin pigment, hair growth, and signs of irritation such as scaling,
peeling, scabbing and erythema. Digital photographs are taken on
Days 0, 10, 15, 31 and 35 (end of the study) for the dosing groups.
Body weights of mice are taken on the first and last days of observation
for each test group.
[0252] The scoring system for hair growth is described below:
[0253] 0=No hair growth/pigment change (pink skin);
[0254] 1=Gray/dark skin color (no visible hair growth);
[0255] 2=Sparse/diffuse terminal hair growth;
[0256] 3=dense, normal hair growth.
[0257] ph 2=peripheral hair growth with a score of 2
[0258] ph 3=peripheral hair growth with a score of 3
[0259] ldsh=long, diffuse/scattered hair growth in the dosing site
[0260] Scaling, peeling, scabbing, or erythema are scored as present
(+) and absent (-). Any other local (e.g. test compound precipitation)
or systemic abnormalities and aberrant hair growth are described
on raw data scoring sheet.
[0261] Table 1 is a summary table of the results of the evaluation
of five different test compounds in the Telogen Conversion Assay
described above. Animals were observed and scored for hair growth
using the scoring system for hair growth described above.
1 TABLE 1 Hair Growth Hair in 50% Experi- Growth at of ment LDO
(% Animals Treatment Group Number LDO.sup.1 Animals).sup.2 n.sup.3
(Day).sup.4 PG:EtOH (30:70) 1 wk 1 30 22 9 >30 Cpd #1 (0.001%)
1 wk 1 30 22 9 >30 Cpd #1 (0.01%) 1 wk 1 30 75 8 14 Cpd #1 (0.1%)
1 wk 1 30 100 9 7 Cpd #1 (0.3%) 1 wk 1 30 100 9 9 PG:EtOH (30:70)
2 wks 2 63 0 9 56 Cpd #1 (0.001%) 1 wk 2 35 50 10 18 Cpd #1 (0.01%)
1 wk 2 35 100 10 14 Cpd #1 (0.1%) 1 wk 2 35 100 10 7 Cpd #1 (0.3%)
1 wk 2 35 100 10 9 PG:EtOH (30:70) 2 wks 3 35 30 10 >35 Cpd #2
(0.1%) 2 wks 3 35 100 10 11 Cpd #3 (0.1%) 2 wks 3 35 20 10 >35
Cpd #4 (0.1%) 2 wks 3 35 100 10 9 Cpd #5 (0.1%) 2 wks 3 35 100 10
9 Cpd #1 (0.1%) 2 wks 3 35 100 10 7 Cpd #1 (0.1%) 1 wk 3 35 100
10 7 PG:EtOH (30:70) 1 wk 3 35 20 10 >35 .sup.1LDO is the last
day of observation. .sup.2Percentage (%) of study animals that had
a hair growth score of 1 or greater on the last day of observation
(LDO). .sup.3n is the total number of animals in a group. .sup.4Day
of observation when 50% or greater of the study animals had a hair
growth score of 1 or greater.
[0262] The following are the test compounds (Cpd#) for which results
are summarized in the above Table 1:
[0263] Compound #1: N-Cyclohexyl-5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro--
3H-[1,2,4]triazin-2-yl)-phenoxy]-2-hydroxy-benzamide;
[0264] Compound #2: 2-{3,5-Dichloro-4-[3-(3,4-dihydro-1H-isoquinoline-2-ca-
rbonyl)-4-hydroxy-phenoxy]-phenyl}-2H-[1,2,4]triazine-3,5-dione;
[0265] Compound #3: N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-ox-
amic acid;
[0266] Compound #4: 2-{4-[3-(4-Fluoro-benzyl)-4-hydroxy-phenoxy]-3,5-dimet-
hyl-phenyl}-2H-[1,2,4]triazine-3,5-dione;
[0267] Compound #5: 2-{3,5-Dichloro-4-[3-(4-fluoro-benzoyl)-4-hydroxy-phen-
oxy]-phenyl}-2H-[1,2,4]triazine-3,5-dione.
[0268] There are known in the art other in vitro and in vivo assays
models for understanding the biology of hair growth and for identifying
the mechanisms that control hair growth and the hair growth cycle.
These models are amenable to determining the effect of a compound
useful in the methods of the present invention on hair growth.
[0269] For example, M. P. Philpott, D. A. Sanders and T. Kealey,
Dermatologic Clinics, 14(4):595-607, October 1996, describes an
in vitro culture of whole hair follicles for studying the biology
of hair growth. M. P. Philpott and T. Kealey, Journal of Investigative
Dermatology, 115(6):1152-5, December 2000, describes the rat vibrissa
follicle which is an in vitro model system to investigate hair growth
cycle control. M. Philpott, Experimental Dermatology, 8(4):317-9,
August 1999, describes and references the current status and future
development of in vitro models for the maintenance of isolated hair
follicles which are useful for investigating the biology of hair
growth. D. Van Neste, in H. I. Maibach (Ed.), "Dermatologic
Research Techniques," pp. 37-49, CRC, Press, Boca Raton (1996),
reviews the techniques for the use of scalp grafts onto nude mice
as a model for human hair growth. H. Uno, B. Schroder, T. Fors and
O. Mori, Journal of Cutaneous Aging & Cosmetic Dermatology,
Vol. 1, No. 3, 1990, pp 193-204 describes and references the stumptailed
macaque, Sprague-Dawley rat and C3H mice as models for the study
of hair growth in vivo.
[0270] The methods of the present invention are performed by administering
to a mammal (preferably a human) a compound as described herein
and preferably, a pharmaceutically acceptable or cosmetically acceptable
carrier.
[0271] The compounds described 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 areata, including
male pattern baldness and female pattern baldness. The compounds
described herein may also be used to accelerate the regrowth of
hair following chemotherapy-induced hair loss.
[0272] 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).
[0273] Typically, from about 0.01 mg to about 3000 mg, more preferably
from about 0.05 mg to about 1000 mg, more preferably from about
0.10 mg to about 100 mg, of a compound as described herein is administered
per day for systemic administration. For topical administration,
typically, from about 0.0001% to about 10% (w/v), more preferably
from about 0.0001% to about 1% (w/v), more preferably from about
0.0001 % to about 0.1% (w/v), of a compound as described herein
is administered per day.
[0274] However, it is understood that daily administration of a
compound as described herein 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.
[0275] According to the present invention, the compounds as described
herein are co-administered with a pharmaceutically acceptable or
cosmetically acceptable carrier (herein collectively described as
a "carrier"). The term "carrier," as used herein,
means one or more compatible solid or liquid filler diluents, vehicles
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 as described herein, 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 mammal
(preferably the human being) being treated. The carrier can itself
be inert or it can possess pharmaceutical and/or cosmetic benefits
of its own.
[0276] The compounds useful in the methods of the present invention
may be formulated in any of a variety of forms suitable, for example,
for oral, topical or parenteral administration. Of these, topical
administration is preferred.
[0277] 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 compounds used in the methods
of the present invention. The amount of carrier employed in conjunction
with the compounds used in the methods of the present invention
is sufficient to provide a practical quantity of material for administration
per unit dose of the compounds. Techniques and compositions for
making dosage forms useful in the methods of the present 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, 2nd Ed., (1976).
[0278] 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, e.g., Tween-20;
wetting agents, such sodium lauryl sulfate; coloring agents; flavoring
agents; tableting agents; stabilizers; antioxidants; preservatives;
pyrogen-free water; isotonic saline; and phosphate buffer solutions.
The choice of a carrier to be used in conjunction with the compounds
useful in the methods of the present invention is typically determined
by the way the compound is to be administered.
[0279] Preferably, the compounds useful in the methods of the present
invention are administered topically. The carrier of the topical
composition preferably aids penetration of the compounds as described
herein into the skin to reach the environment of the hair follicle.
Such topical compositions may be in any form including, for example,
solutions, oils, creams, ointments, gels, lotions, pastes, shampoos,
leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers,
sprays, aerosols, skin patches and the like.
[0280] In topical compositions of the present invention, the compound
as described herein may be in a form (e.g., a prodrug) which would
more readily penetrate into the skin and then be converted to the
active form upon reaching the desired skin layer. Also, the topical
compositions containing a compound as described herein 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.
[0281] 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:
[0282] Emollients include, for example, stearyl alcohol, glyceryl
monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol,
mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl
palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate,
hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl
palmitate, dimethylpolysiloxane, di-n-butyl sebacate, isopropyl
myristate, isopropyl palmitate, isopropyl 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 include, for example, propane, butane, isobutane,
dimethyl ether, carbon dioxide and nitrous oxide. Solvents include,
for example, ethyl alcohol, methylene chloride, isopropanol, castor
oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl
ether, diethylene glycol monoethyl ether, dimethyl sulphoxide, dimethyl
formamide and tetrahydrofuran. Humectants include, for example,
glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble
collagen, dibutyl phthalate and gelatin. Powders include, for example,
chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon
dioxide, sodium polyacrylate, tetraalkyl 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.
[0283] The compounds used in the methods of the present invention
may also be administered topically 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 compounds used
in the methods of the present invention 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); U.S. Pat. No. 4,911,928; and U.S. Pat. No. 5,834,014.
[0284] The compounds of the present invention may also be topically
administered by iontophoresis. See, e.g., www.unipr.it/arpa/dipfarm/erasm-
uslerasml4.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. 22 I-8 (1995);
O'Brien et al., "An Updated Review of its Antiviral Activity,
Pharmacokinetic Properties and Therapeutic Efficacy", Drugs,
Vol. 37, pp. 233-309 (1989); Parry et al., "Acyclovir Biovailability
in Human Skin", J. Invest. Dermatol., Vol. 98 (6), pp. 856-63
(1992); Santi et al., "Drug Reservoir Composition and Transport
of Salmon Calcitonin in Transdermal Iontophoresis", Pharm.
Res., Vol 14 (1), pp. 63-66 (1997); Santi et al., "Reverse
Iontophoresis--Parameters Determining Electroosmotic Flow: I. pH
and Ionic Strength", J. Control. Release, Vol. 38, pp. 159-165
(1996); Santi et al., "Reverse Iontophoresis--Parameters Determining
Electroosmotic Flow: II. Electrode Chamber Formulation", J.
Control. Release, Vol. 42, pp. 29-36 (1996); Rao et al., "Reverse
Iontophoresis: Noninvasive Glucose Monitoring in vivo in Humans",
Pharm. Res., Vol. 12 (12), pp. 1869-1873 (1995); Thvsman 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).
[0285] Carriers for systemic administration include, for example,
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, for example, 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.
[0286] Various oral dosage forms can be used, including such solid
forms as tablets, capsules, granules and bulk powders. These oral
forms comprise an effective amount, usually at least about 5%, and
preferably from about 25% to about 50%, of a compound used in the
methods of 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.
[0287] 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 or cellulose; binders such as starch, gelatin
or sucrose; disintegrants such as starch, alginic acid or croscarmelose;
lubricants such as magnesium stearate, stearic acid or 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 or fruit flavors, are
useful adjuvants for chewable tablets. Capsules (including time
release and sustained release formulations) typically comprise one
or more solid diluents as disclosed above. The selection of carrier
components depends on secondary considerations like taste, cost
and shelf stability, which are not critical for the methods per
se of the present invention, and can readily be made by a person
skilled in the art.
[0288] 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 or colorants as
described above.
[0289] Such compositions may also be coated by conventional methods,
typically with pH or time-dependent coatings, such that the compound
as described herein is released in the gastrointestinal tract in
the desired vicinity or is released 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.
[0290] Other compositions useful for attaining systemic delivery
of the compounds useful in the methods of the present invention
include sublingual, buccal and nasal dosage forms. Such compositions
typically comprise one or more 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 described above may also be included.
[0291] The above described compositions containing a compound as
described herein 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 used in the methods of the present invention (see,
for example, www.regrowth.com. for a listing of hair growth treatments).
Particular classes of activity enhancers include hair growth stimulants
and penetration enhancers.
[0292] Non-limiting examples of agents that stimulate hair growth
and/or arrest hair loss which may additionally be used in the compositions
described 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, cyclosporins, such as cyclosporin A, potassium
channel blockers, such as minoxidil, 5-.alpha.-reductase inhibitors,
such as finasteride, and androgen receptor antagonists, such as
cyproterone acetate.
[0293] Preferred hair growth stimulants to be added to the compositions
of the present invention are, for example, minoxidil and finasteride,
with minoxidil being most preferred.
[0294] Non-limiting examples of penetration enhancers which may
additionally be used in the compositions described herein include,
for example, 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate,
hexan-2,5-diol, POE(2) ethyl ether, di(2-hydroxypropyl) ether, pentan-2,4-diol,
acetone, POE(2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic
acid, propan-1-ol, 1,4-dioxane, tetrahydrofuran, butan-1,4-diol,
propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether,
octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl
alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl adipate,
di-isopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl
sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate, dibenzyl
sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate, dimethyl
azelate, butyl myristate, dibutyl succinate, didecyl phthalate,
decyl oleate, ethyl caproate, ethyl salicylate, iso-propyl palmitate,
ethyl laurate, 2-ethyl-hexyl pelargonate, iso-propyl isostearate,
butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl
caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 2-hydroxypropanoic
acid, 2-hydroxyoctanoic 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.
[0295] In all of the foregoing, the compounds used in the methods
of the present invention can be administered alone or as mixtures;
and the compositions may further include additional drugs or excipients
as appropriate for the indication, such as described above.
[0296] The present invention further relates to kits comprising
a compound and/or composition as described 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 as described
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. |