Hair loss abstract
A method for treating hair loss in mammals uses compositions containing
prostaglandin F analogs. The compositions can be applied topically
to the skin. The compositions can arrest hair loss, reverse hair
loss, and promote hair growth.
Hair loss claims
What is claimed is:
1. A composition for treating hair loss comprising: A) an active
ingredient selected from the group consisting of a prostaglandin
F analog having a structure selected from the group consisting of
111pharmaceutically acceptable salts and hydrates of the structures
above; biohydrolyzable amides, esters, and imides of the structures
above; optical isomers, diastereomers, and enantiomers of the structures
above; and combinations thereof; wherein R.sup.1 is selected from
the group consisting of C(O)OH, C(O)NHOH, C(O)OR.sup.3, CH.sub.2OH,
S(O).sub.2R.sup.3, C(O)NHR.sup.3, C(O)NHS(O).sub.2R.sup.4, tetrazole,
a cationic salt moiety, a pharmaceutically acceptable amine or ester
comprising 2 to 13 carbon atoms, and a biometabolizable amine or
ester comprising 2 to 13 atoms; R.sup.2 is selected from the group
consisting of a hydrogen atom, a lower heterogenous group, and a
lower monovalent hydrocarbon group; R.sup.3 is selected from the
group consisting of a monovalent hydrocarbon group, a heterogeneous
group, a carbocyclic group, a heterocyclic group, an aromatic group,
a heteroaromatic group, a substituted monovalent hydrocarbon group,
a substituted heterogeneous group, a substituted carbocyclic group,
a substituted heterocyclic group, a substituted aromatic group,
and a substituted heteroaromatic group; R.sup.4 is selected from
the group consisting of a monovalent hydrocarbon group, a heterogeneous
group, a carbocyclic group, a heterocyclic group, an aromatic group,
a heteroaromatic group, a substituted monovalent hydrocarbon group,
a substituted heterogeneous group, a substituted carbocyclic group,
a substituted heterocyclic group, a substituted aromatic group,
and a substituted heteroaromatic group; X is selected from the group
consisting of --C.ident.C--, a covalent bond, --CH.dbd.C.dbd.CH--,
--CH.dbd.CH--, --CH.dbd.N--, --C(O)--, --C(O)Y--, --(CH.sub.2).sub.n--,
wherein n is 2 to 4, --CH.sub.2NH--, --CH.sub.2S--, and --CH.sub.2O--;
Y is selected from the group consisting of an oxygen atom, a sulfur
atom, and NH; and Z is selected from the group consisting of a carbocyclic
group, a heterocyclic group, an aromatic group, a heteroaromatic
group, a substituted carbocyclic group, a substituted heterocyclic
group, a substituted aromatic group, and a substituted heteroaromatic
group; and B) a carrier.
2. The composition of claim 1, wherein R.sup.1 is selected from
the group consisting of CO.sub.2H, C(O)NHOH, CO.sub.2R.sup.3, C(O)NHS(O).sub.2R.sup.4,
and tetrazole.
3. The composition of claim 1, wherein R.sup.2 is a hydrogen atom.
4. The composition of claim 1, wherein R.sup.3 is selected from
the group consisting of methyl, ethyl, and isopropyl.
5. The composition of claim 1, wherein R.sup.4 is a phenyl group.
6. The composition of claim 1, wherein X is a covalent bond and
Z is selected from the group consisting of an aromatic ring, a heteroaromatic
ring, a substituted aromatic ring, and a substituted heteroaromatic
ring.
7. The composition of claim 1, wherein X is --C.ident.C--, and
Z is a monocyclic aromatic ring.
8. The composition of claim 1, wherein component A) is added in
an amount ofIC.sub.50.times.10.sup.-2.gtoreq.% of component A).gtoreq.IC.sub.50.tim-
es.10.sup.-3,where IC.sub.50 of component A) is expressed in nanomolar
units.
9. The composition of claim 8, wherein component C) an activity
enhancer is added to the composition in an amount of 1 to 20%, and
a sufficient amount of component B) is added such that the amounts
of components A), B), and C) combined equal 100%.
10. The composition of claim 1, wherein component B) comprises
an ingredient selected from the group consisting of q) an emollient,
r) a propellant, s) a solvent, t) a humectant, u) a thickener, v)
a powder, w) a fragrance, water, alcohols, aloe vera gel, allantoin,
glycerin, vitamin A and E oils, mineral oil, propylene glycol, polypropylene
glycol-2 myristyl propionate, dimethyl isosorbide, and combinations
thereof.
11. The composition of claim 10, wherein ingredient q) is selected
from the group consisting of 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,
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, petrolatum, mineral oil, butyl myristate, isostearic
acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl
lactate, decyl oleate, myristyl myristate, polydimethylsiloxane,
and combinations thereof.
12. The composition of claim 10, wherein ingredient r) is selected
from the group consisting of propane, butane, isobutane, dimethyl
ether, carbon dioxide, nitrous oxide, and combinations thereof.
13. The composition of claim 10, wherein ingredient s) is selected
from the group consisting of water, ethyl alcohol, methylene chloride,
isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene
glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl
sulfoxide, dimethyl formamide, tetrahydrofuran, and combinations
thereof.
14. The composition of claim 10, wherein ingredient t) is selected
from the group consisting of glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate,
soluble collagen, dibutyl phthalate, gelatin, and combinations thereof.
15. The composition of claim 10, wherein ingredient v) is selected
from the group consisting of chalk, talc, fullers earth, kaolin,
starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra
alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically
modified magnesium aluminum silicate, organically modified montmorillonite
clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer,
sodium carboxymethyl cellulose, ethylene glycol monostearate, and
combinations thereof.
16. A method of treating hair loss comprising administering to
a mammal a composition comprising: A) an active ingredient selected
from the group consisting of a prostaglandin F analog having a structure
selected from the group consisting of 112pharmaceutically acceptable
salts and hydrates of the structures above; biohydrolyzable amides,
esters, and imides of the structures above; optical isomers, diastereomers,
and enantiomers of the structures above; and combinations thereof;
wherein R.sup.1 is selected from the group consisting of C(O)OH,
C(O)NHOH, C(O)OR.sup.3, CH.sub.2OH, S(O).sub.2R.sup.3, C(O)NHR.sup.3,
C(O)NHS(O).sub.2R.sup.4, tetrazole, a cationic salt moiety, a pharmaceutically
acceptable amine or ester comprising 2 to 13 carbon atoms, and a
biometabolizable amine or ester comprising 2 to 13 atoms; R.sup.2
is selected from the group consisting of a hydrogen atom, a lower
heterogenous group, and a lower monovalent hydrocarbon group; R.sup.3
is selected from the group consisting of a monovalent hydrocarbon
group, a heterogeneous group, a carbocyclic group, a heterocyclic
group, an aromatic group, a heteroaromatic group, a substituted
monovalent hydrocarbon group, a substituted heterogeneous group,
a substituted carbocyclic group, a substituted heterocyclic group,
a substituted aromatic group, and a substituted heteroaromatic group;
R.sup.4 is selected from the group consisting of a monovalent hydrocarbon
group, a heterogeneous group, a carbocyclic group, a heterocyclic
group, an aromatic group, a heteroaromatic group, a substituted
monovalent hydrocarbon group, a substituted heterogeneous group,
a substituted carbocyclic group, a substituted heterocyclic group,
a substituted aromatic group, and a substituted heteroaromatic group;
X is selected from the group consisting of --C.ident.C--, a covalent
bond, --CH.dbd.C.dbd.CH--, --CH.dbd.CH--, --CH.dbd.N--, --C(O)--,
--C(O)Y--, --(CH.sub.2).sub.n--, wherein n is 2 to 4, --CH.sub.2NH--,
--CH.sub.2S--, and --CH.sub.2O--; Y is selected from the group consisting
of a sulfur atom, an oxygen atom, and NH; and Z is selected from
the group consisting of a carbocyclic group, a heterocyclic group,
an aromatic group, a heteroaromatic group, a substituted carbocyclic
group, a substituted heterocyclic group, a substituted aromatic
group, and a substituted heteroaromatic group.
17. The method of claim 16, wherein R.sup.1 is selected from the
group consisting of CO.sub.2H, C(O)NHOH, CO.sub.2R.sup.3, C(O)NHS(O).sub.2R.sup.4,
and tetrazole.
18. The method of claim 16, wherein R.sup.2 is a hydrogen atom.
19. The method of claim 16, wherein R.sup.3 is selected from the
group consisting of methyl, ethyl, and isopropyl.
20. The method of claim 16, wherein R.sup.4 is a phenyl group.
21. The method of claim 16, wherein X is a covalent bond and Z
is selected from the group consisting of an aromatic ring, a heteroaromatic
ring, a substituted aromatic ring, and a substituted heteroaromatic
ring.
22. The method of claim 16, wherein X is --C.ident.C--, and Z is
a monocyclic aromatic ring.
23. The method of claim 16, wherein the composition is administered
by a route selected from the group consisting of systemic and topical
routes.
24. The method of claim 23, wherein the composition is a topical
composition in a form selected from the group consisting of solutions,
oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out
hair conditioners, milks, cleansers, moisturizers, sprays, and skin
patches.
25. The method of claim 23, wherein the composition is a topical
composition further comprising B) a carrier, wherein the carrier
is selected from the group consisting of water, alcohols, aloe vera
gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene
glycol, dimethyl isosorbide, polypropylene glycol-2 myristyl propionate,
and combinations thereof.
26. The method of claim 23, wherein the composition further comprises
C) an activity enhancer selected from the group consisting of i)
a hair growth stimulant, ii) a penetration enhancer, and combinations
thereof.
27. The method of claim 26, wherein component i) is selected from
the group vasodilator, an antiandrogen, a cyclosporin, a cyclosporin
analog, an antimicrobial, an anti-inflammatory, a thyroid hormone,
a thyroid hormone derivative, and a thyroid hormone analog, a non-selective
prostaglandin agonist, a non-selective prostaglandin antagonist,
a retinoid, a triterpene, and combinations thereof.
28. The method of claim 26, wherein component ii) is selected from
the group consisting of 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate,
hexan-2,5-diol, polyoxyethylene(2) ethyl ether, di(2-hydroxypropyl)
ether, pentan-2,4-diol, acetone, polyoxyethylene(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, polyoxyethylene
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, di-butyl phthalate,
dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate,
dibutyl succinate, didecyl phthalate, decyl oleate, ethyl caproate,
ethyl salicylate, isopropyl palmitate, ethyl laurate, 2-ethyl-hexyl
pelargonate, isopropyl 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,
1-dodecylazacyloheptan-2-one, and combinations thereof.
29. The method of claim 23, wherein the composition is a topical
composition locally administered on the skin once per day.
30. The method of claim 29, wherein the composition is administered
once per day for 6 to 12 weeks.
31. A mascara composition comprising: A) an active ingredient selected
from the group consisting of a prostaglandin F analog having a structure
selected from the group consisting of 113pharmaceutically acceptable
salts and hydrates of the structures above; biohydrolyzable amides,
esters, and imides of the structures above; optical isomers, diastereomers,
and enantiomers of the structures above; and combinations thereof;
wherein R.sup.1 is selected from the group consisting of C(O)OH,
C(O)NHOH, C(O)OR.sup.3, CH.sub.2OH, S(O).sub.2R.sup.3, C(O)NHR.sup.3,
C(O)NHS(O).sub.2R.sup.4, tetrazole, a cationic salt moiety, a pharmaceutically
acceptable amine or ester comprising 2 to 13 carbon atoms, and a
biometabolizable amine or ester comprising 2 to 13 atoms; R.sup.2
is selected from the group consisting of a hydrogen atom, a lower
heterogenous group, and a lower monovalent hydrocarbon group; R.sup.3
is selected from the group consisting of a monovalent hydrocarbon
group, a heterogeneous group, a carbocyclic group, a heterocyclic
group, an aromatic group, a heteroaromatic group, a substituted
monovalent hydrocarbon group, a substituted heterogeneous group,
a substituted carbocyclic group, a substituted heterocyclic group,
a substituted aromatic group, and a substituted heteroaromatic group;
R.sup.4 is selected from the group consisting of a monovalent hydrocarbon
group, a heterogeneous group, a carbocyclic group, a heterocyclic
group, an aromatic group, a heteroaromatic group, a substituted
monovalent hydrocarbon group, a substituted heterogeneous group,
a substituted carbocyclic group, a substituted heterocyclic group,
a substituted aromatic group, and a substituted heteroaromatic group;
X is selected from the group consisting of --C.ident.C--, a covalent
bond, --CH.dbd.C.dbd.CH--, --CH.dbd.CH--, --CH.dbd.N--, --C(O)--,
--C(O)Y--, --(CH.sub.2).sub.n--, wherein n is 2 to 4, --CH.sub.2NH--,
--CH.sub.2S--, and --CH.sub.2O--; Y is selected from the group consisting
of an oxygen atom, a sulfur atom, and NH; and Z is selected from
the group consisting of a carbocyclic group, a heterocyclic group,
an aromatic group, a heteroaromatic group, a substituted carbocyclic
group. a substituted heterocyclic group, a substituted aromatic
group, and a substituted heteroaromatic group; dd) a water-insoluble
material, ee) a water-soluble, film-forming polymer, ff) a wax;
o) a surfactant; gg) pigment; and s) a solvent.
32. A method for darkening and thickening hair comprising applying
to growing hair and skin, a composition comprising: A) an active
ingredient selected from the group consisting of a prostaglandin
F analog having a structure selected from the group consisting of
114pharmaceutically acceptable salts and hydrates of the structures
above; biohydrolyzable amides, esters, and imides of the structures
above; optical isomers, diastereomers, and enantiomers of the structures
above; and combinations thereof; wherein R.sup.1 is selected from
the group consisting of C(O)OH, C(O)NHOH C(O)OR.sup.3, CH.sub.2OH,
S(O).sub.2R.sup.3, C(O)NHR.sup.3, C(O)NHS(O).sub.2R.sup.4, tetrazole,
a cationic salt moiety, a pharmaceutically acceptable amine or ester
comprising 2 to 13 carbon atoms, and a biometabolizable amine or
ester comprising 2 to 13 atoms; R.sup.2 is selected from the group
consisting of a hydrogen atom, a lower heterogenous group, and a
lower monovalent hydrocarbon group; R.sup.3 is selected from the
group consisting of a monovalent hydrocarbon group, a heterogeneous
group, a carbocyclic group, a heterocyclic group, an aromatic group,
a heteroaromatic group, a substituted monovalent hydrocarbon group,
a substituted heterogeneous group, a substituted carbocyclic group,
a substituted heterocyclic group, a substituted aromatic group,
and a substituted heteroaromatic group; R.sup.4 is selected from
the group consisting of a monovalent hydrocarbon group, a heterogeneous
group, a carbocyclic group, a heterocyclic group, an aromatic group,
a heteroaromatic group, a substituted monovalent hydrocarbon group,
a substituted heterogeneous group, a substituted carbocyclic group,
a substituted heterocyclic group, a substituted aromatic group,
and a substituted heteroaromatic group; X is selected from the group
consisting of --C.ident.C--, a covalent bond, --CH.dbd.C.dbd.CH--,
--CH.dbd.CH--, --CH.dbd.N--, --C(O)--, --C(O)Y--, --(CH.sub.2).sub.n--,
wherein n is 2 to 4, --CH.sub.2NH--, --CH.sub.2S--, and--CH.sub.2O--;
Y is selected from the group consisting of an oxygen atom, a sulfur
atom, and NH; and Z is selected from the group consisting of a carbocyclic
group, a heterocyclic group, an aromatic group, a heteroaromatic
group, a substituted carbocyclic group, a substituted heterocyclic
group, a substituted aromatic group, and a substituted heteroaromatic
group; and B) a carrier.
Hair loss description
FIELD OF THE INVENTION
[0001] This invention relates to compositions and methods for treating
hair loss in mammals. More particularly, this invention relates
to compositions and methods for arresting or reversing hair loss,
or both, and promoting hair growth.
BACKGROUND OF THE INVENTION
[0002] Hair loss is a common problem which is, for example, naturally
occurring or 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 re-growth which causes
partial or full baldness.
[0003] Hair growth on the scalp does not occur continuously, but
rather occurs by a cycle of activity involving alternating periods
of growth and rest. This cycle is divided into three main stages;
anagen, catagen, and telogen. Anagen is the growth phase of the
cycle and is 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 ceases.
The next phase, telogen, is 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.
When hair growth ceases, most of the hair follicles reside in telogen
and anagen is not engaged, thus causing the onset of full or partial
baldness.
[0004] Attempts to invoke the re-growth of hair have been made
by, for example, the promotion or prolongation of anagen. Currently,
there are two drugs approved by the United States Food and Drug
Administration for the treatment of male pattern baldness: topical
minoxidil (marketed as ROGAINE.RTM. by Pharmacia & Upjohn),
and oral finasteride (marketed as PROPECIA.RTM. by Merck & Co.,
Inc.). However, the search for efficacious hair growth inducers
is ongoing due to factors including safety concerns and limited
efficacy.
[0005] The thyroid hormone thyroxine ("T4") converts
to thyronine ("T3") in human skin by deiodinase I, a selenoprotein.
Selenium deficiency causes a decrease in T3 levels due to a decrease
in deiodinase I activity; this reduction in T3 levels is strongly
associated with hair loss. Consistent with this observation, hair
growth is a reported side effect of administration of T4. See, e.g.,
Berman, "Peripheral Effects of L-Thyroxine on Hair Growth and
Coloration in Cattle", Journal of Endocrinology, Vol. 20, pp.
282-292 (1960); and Gunaratnam, "The Effects of Thyroxine on
Hair Growth in the Dog", J. Small Anim. Pract., Vol. 27, pp.
17-29 (1986). Furthermore, T3 and T4 have been the subject of several
patent publications relating to treatment of hair loss. See, e.g.,
Fischer et al., DE 1,617,477, published Jan. 8, 1970; Mortimer,
GB 2,138,286, published Oct. 24, 1984; and Lindenbaum, WO 96/25943,
assigned to Life Medical Sciences, Inc., published Aug. 29, 1996.
[0006] Unfortunately, however, administration of T3 or T4, or both,
to treat hair loss is often not practicable because these thyroid
hormones can induce significant cardiotoxicity. See, e.g., Walker
et al., U.S. Pat. No. 5,284,971, assigned to Syntex, issued Feb.
8, 1994 and Emmett et al., U.S. Pat. No. 5,061,798, assigned to
Smith Kline & French Laboratories, issued Oct. 29, 1991.
[0007] In an alternative approach, prostaglandins have been proposed
to promote hair growth because prostaglandins may have a similar
benefit to thyroid hormones, i.e., increasing hair length and changing
pigmentation. Naturally occurring prostaglandins (e.g., PGA.sub.2,
PGB.sub.2, PGE.sub.1, PGF.sub.2.alpha., and PGI.sub.2) are C-20
unsaturated fatty acids. PGF.sub.2.alpha., the naturally occurring
Prostaglandin F analog in humans, is characterized by hydroxyl groups
at the C9 and C11 positions on the alicyclic ring, a cis-double
bond between C5 and C6, and a trans-double bond between C13 and
C14. PGF.sub.2.alpha. has the formula: 1
[0008] Analogs of naturally occurring Prostaglandin F are known
in the art. For example, see U.S. Pat. No. 4,024,179 issued to Bindra
and Johnson on May 17, 1977; German Patent No. DT-002,460,990 issued
to Beck, Lerch, Seeger, and Teufel published on Jul. 1, 1976; U.S.
Pat. Ser. No.4,128,720 issued to Hayashi, Kori, and Miyake on Dec.
5, 1978; U.S. Pat. No. 4,011,262 issued to Hess, Johnson, Bindra,
and Schaaf on Mar. 8, 1977; U.S. Pat. No. 3,776,938 issued to Bergstrom
and Sjovall on Dec. 4, 1973; P. W. Collins and S. W. Djuric, "Synthesis
of Therapeutically Useful Prostaglandin and Prostacyclin Analogs",
Chem. Rev., Vol. 93, pp. 1533-1564 (1993); G. L. Bundy and F. H.
Lincoln, "Synthesis of 17-Phenyl-18,19,20-Trinorprostaglandins:
I. The PG.sub.1 Series", Prostaglandin, Vol, 9 No. 1, pp. 1-4
(1975); W. Bartman, G. Beck, U. Lerch, H. Teufel, and B. Scholkens,
"Luteolytic Prostaglandin: Synthesis and Biological Activity",
Prostaglandin, Vol. 17 No. 2, pp. 301-311 (1979); C. Iiljebris,
G. Selen, B. Resul, J. Sternschantz, and U. Hacksell, "Derivatives
of 17-Phenyl-18, 19,20-trinorprostaglandin F.sub.2.alpha.. Isopropyl
Ester: Potential Antiglaucoma Agents", Journal of Medicinal
Chemistry, Vol. 38, No. 2, pp. 289-304 (1995).
[0009] Prostaglandins in general have a wide range of biological
activities. For example, PGE.sub.2 has the following properties:
a) regulator of cell proliferation, b) regulator of cytokine synthesis,
c) regulator of immune responses and d) inducer of vasodilatation.
Vasodilatation is thought to be one of the mechanisms of how minoxidil
provides a hair growth benefit. In vitro results in the literature
also indicate some anti-inflammatory properties of the prostaglandins.
c. f.; Tanaka, H. Br J. Pharm. 116, 2298, (1995).
[0010] However, previous attempts at using prostaglandins to promote
hair growth have been unsuccessful. Different prostaglandin analogs
can bind to multiple receptors at various concentrations with a
biphasic effect. Furthermore, administration of naturally occurring
prostaglandins can cause side effects such as inflammation, surface
irritation, smooth muscle contraction, pain, and bronchoconstriction.
Therefore, it is an object of this invention to provide methods
for using prostaglandin analogs to grow hair and to provide compositions
that promote hair growth in humans and lower animals. It is a further
object of this invention to provide a selection of appropriate prostaglandin
analogs that will promote hair growth and that do not cause significant
undesirable side effects.
SUMMARY OF THE INVENTION
[0011] This invention relates to compositions and methods for treating
hair loss. The methods comprise administering the compositions comprising
specific prostaglandin analogs that interact strongly with hair-selective
receptors, such as the FP receptor. The choice of prostaglandin
analog is important because the prostaglandin analogs must selectively
activate the FP receptor and not activate any other receptors that
would negate the effect of activating the FP receptor. The compositions
comprise: component A) the prostaglandin analog, component B) a
carrier, and optionally component C) an activity enhancer.
DETAILED DESCRIPTION OF THE INVENTION
[0012] This invention relates to compositions and methods using
prostaglandin F analogs ("PGF's") to treat hair loss in
mammals. "Treating hair loss" includes arresting hair
loss or reversing hair loss, or both, and promoting hair growth.
[0013] Publications and patents are referred to throughout this
disclosure. All U.S. Patents cited herein are hereby incorporated
by reference.
[0014] All percentages, ratios, and proportions used herein are
by weight unless otherwise specified.
Definition and Usage of Terms
[0015] The following is a list of definitions for terms, as used
herein:
[0016] "Activate" means binding and signal transduction
of a receptor.
[0017] "Acyl group" means a monovalent group suitable
for acylating a nitrogen atom to form an amide or carbamate, an
alcohol to form a carbonate, or an oxygen atom to form an ester
group. Preferred acyl groups include benzoyl, acetyl, tert-butyl
acetyl, para-phenyl benzoyl, and trifluoroacetyl. More preferred
acyl groups include acetyl and benzoyl. The most preferred acyl
group is acetyl.
[0018] "Aromatic group" means a monovalent group having
a monocyclic ring structure or fused bicyclic ring structure. Monocyclic
aromatic groups contain 5 to 10 carbon atoms, preferably 5 to 7
carbon atoms, and more preferably 5 to 6 carbon atoms in the ring.
Bicyclic aromatic groups contain 8 to 12 carbon atoms, preferably
9 or 10 carbon atoms in the ring. Aromatic groups are unsubstituted.
The most preferred aromatic group is phenyl. Bicyclic aromatic groups
include ring systems wherein one ring in the system is aromatic.
Preferred bicyclic aromatic groups are ring systems wherein both
rings in the system are aromatic. Preferred aromatic rings include
naphthyl and phenyl. The most preferred aromatic ring is phenyl.
[0019] "Carbocyclic group" means a monovalent saturated
or unsaturated hydrocarbon ring. Carbocyclic groups are monocyclic.
Carbocyclic groups contain 4 to 10 carbon atoms, preferably 4 to
7 carbon atoms, and more preferably 5 to 6 carbon atoms in the ring.
Carbocyclic groups are unsubstituted. Preferred carbocyclic groups
include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and
cyclooctyl. More preferred carbocyclic groups include cyclohexyl,
cycloheptyl, and cyclooctyl. The most preferred carbocyclic group
is cycloheptyl. Carbocyclic groups are not aromatic.
[0020] "FP agonist" means a compound that activates the
FP receptor.
[0021] "FP receptor" means known human FP receptors,
their splice variants, and undescribed receptors that have similar
binding and activation profiles as the known human FP receptors.
"FP" means the receptor is of the class which has the
highest affinity for PGF.sub.2.alpha. of all the naturally occurring
prostaglandins. FP refers to a known protein.
[0022] "Halogen atom" means F, Cl, Br, or I. Preferably,
the halogen atom is F, Cl, or Br; more preferably Cl or F; and most
preferably F.
[0023] "Halogenated heterogenous group" means a substituted
heterogenous group or a substituted heterocyclic group, wherein
at least one substituent is a halogen atom. Halogenated heterogenous
groups can have a straight, branched, or cyclic structure. Preferred
halogenated heterogenous groups have 1 to 12 carbon atoms, more
preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon
atoms. Preferred halogen atom substituents are Cl and F.
[0024] "Halogenated hydrocarbon group" means a substituted
monovalent hydrocarbon group or a substituted carbocyclic group,
wherein at least one substituent is a halogen atom. Halogenated
hydrocarbon groups can have a straight, branched, or cyclic structure.
Preferred halogenated hydrocarbon groups have 1 to 12 carbon atoms,
more preferably 1 to 6 carbon atoms, and most preferably 1 to 3
carbon atoms. Preferred halogen atom substituents are Cl and F.
The most preferred halogenated hydrocarbon group is trifluoromethyl.
[0025] "Heteroaromatic group" means an aromatic ring
containing carbon and 1 to 4 heteroatoms in the ring. Heteroaromatic
groups are monocyclic or fused bicyclic rings. Monocyclic heteroaromatic
groups contain 5 to 10 member atoms (i.e., carbon and heteroatoms),
preferably 5 to 7, and more preferably 5 to 6 in the ring. Bicyclic
heteroaromatic rings contain 8 to 12 member atoms, preferably 9
or 10 in the ring. Heteroaromatic groups are unsubstituted. Bicyclic
heteroaromatic groups include ring systems in which only one ring
is aromatic. Preferred bicyclic heteroaromatic groups are ring systems
in which both rings are aromatic. Preferred monocyclic heteroaromatic
groups include thienyl, thiazolyl, purinyl, pyrimidyl, pyridyl,
and furanyl. More preferred monocyclic heteroaromatic groups include
thienyl, furanyl, and pyridyl. The most preferred monocyclic heteroaromatic
group is thienyl. Preferred bicyclic heteroaromatic rings include
benzothiazolyl, benzothiophenyl, quinolinyl, quinoxalinyl, benzofuranyl,
benzimidazolyl, benzoxazolyl, indolyl, and anthranilyl. More preferred
bicyclic heteroaromatic rings include benzothiazolyl, benzothiophenyl,
and benzoxazolyl.
[0026] "Heteroatom" means an atom other than carbon in
the ring of a heterocyclic group or the chain of a heterogeneous
group. Preferably, heteroatoms are selected from the group consisting
of nitrogen, sulfur, and oxygen atoms. Groups containing more than
one heteroatom may contain different heteroatoms.
[0027] "Heterocyclic group" means a saturated or unsaturated
ring structure containing carbon and 1 to 4 heteroatoms in the ring.
No two heteroatoms are adjacent in the ring, and no carbon in the
ring that has a heteroatom bonded to it also has a hydroxyl, amino,
or thiol group bonded to it. Heterocyclic groups are not aromatic.
Heterocyclic groups are monocyclic. Heterocyclic groups contain
4 to 10 member atoms (i.e., including both carbon atoms and at least
1 heteroatom), preferably 4 to 7, and more preferably 5 to 6 in
the ring. Heterocyclic groups are unsubstituted. Preferred heterocyclic
groups include piperzyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl,
and piperdyl.
[0028] "Heterogeneous group" means a saturated or unsaturated
chain containing 1 to 18 member atoms (i.e., including both carbon
and at least one heteroatom). No two heteroatoms are adjacent. Preferably,
the chain contains 1 to 12 member atoms, more preferably 1 to 6.
"Lower heterogeneous" means a heterogeneous group having
1 to 6, preferably 1 to 3, member atoms. The chain may be straight
or branched. Preferred branched heterogeneous groups have one or
two branches, preferably one branch. Preferred heterogeneous groups
are saturated. Unsaturated heterogeneous groups have one or more
double bonds, one or more triple bonds, or both. Preferred unsaturated
heterogeneous groups have one or two double bonds or one triple
bond. More preferably, the unsaturated heterogeneous group has one
double bond. Heterogeneous groups are unsubstituted.
[0029] "Monovalent hydrocarbon group" means a chain of
1 to 18, preferably 1 to 12, carbon atoms. "Lower monovalent
hydrocarbon group" means a monovalent hydrocarbon group having
1 to 6, preferably 1 to 3, carbon atoms. Monovalent hydrocarbon
groups may have a straight chain or branched chain structure. Preferred
monovalent hydrocarbon groups have one or two branches, preferably
I branch. Preferred monovalent hydrocarbon groups are saturated.
Unsaturated monovalent hydrocarbon groups have one or more double
bonds, one or more triple bonds, or combinations thereof. Preferred
unsaturated monovalent hydrocarbon groups have one or two double
bonds or one triple bond; more preferred unsaturated monovalent
hydrocarbon groups have one double bond.
[0030] "Pharmaceutically acceptable" means suitable for
use in a human or other mammal.
[0031] "Prostaglandin" means a fatty acid derivative
which has a variety of potent biological activities of a hormonal
or regulatory nature.
[0032] "Protecting group" is a group that replaces the
active hydrogen of a hydroxyl moiety thus preventing undesired side
reaction at the hydroxyl moiety. Use of protecting groups in organic
synthesis is well known in the art. Examples of protecting groups
are found in Chapter 2 Protecting Groups in Organic Synthesis by
Greene, T. W. and Wuts, P. G. M., 2.sup.nd ed., Wiley & Sons,
Inc., 1991. Preferred protecting groups include silyl ethers, alkoxymethyl
ethers, tetrahydropyranyl, tetrahydrofuranyl, esters, and substituted
or unsubstituted benzyl ethers.
[0033] "Safe and effective amount" means a quantity of
a prostaglandin high enough to provide a significant positive modification
of the subject's condition to be treated, but low enough to avoid
serious side effects (at a reasonable benefit/risk ratio).
[0034] "Selective" means having a binding or activation
preference for a specific receptor over other receptors which can
be quantitated based upon receptor binding or activation assays.
[0035] "Subject" means a living, vertebrate, hair- or
fur-bearing animal such as a mammal (preferably human) in need of
treatment.
[0036] "Substituted aromatic group" means an aromatic
group wherein 1 to 4 of the hydrogen atoms bonded to carbon atoms
in the ring have been replaced with other substituents. Preferred
substituents include: halogen atoms, cyano groups, monovalent hydrocarbon
groups, substituted monovalent hydrocarbon groups, heterogeneous
groups, substituted heterogeneous groups, aromatic groups, substituted
aromatic groups, or any combination thereof. More preferred substituents
include halogen atoms, halogenated monovalent hydrocarbon groups,
phenyl groups, and phenoxy groups. Preferred substituted aromatic
groups include naphthyl. The substituents may be substituted at
the ortho, meta, or para position on the ring, or any combination
thereof. The preferred substitution pattern on the ring is ortho
or meta. The most preferred substitution pattern is ortho.
[0037] "Substituted carbocyclic group" means a carbocyclic
group wherein 1 to 4 hydrogen atoms bonded to carbon atoms in the
ring have been replaced with other substituents. Preferred substituents
include: halogen atoms, cyano groups, monovalent hydrocarbon groups,
monovalent heterogeneous groups, substituted monovalent hydrocarbon
groups, substituted heterogeneous groups, aromatic groups, substituted
aromatic groups, or any combination thereof. More preferred substituents
include halogen atoms, halogenated monovalent hydrocarbon groups,
phenyl groups, and phenoxy groups.
[0038] "Substituted heteroaromatic group" means a heteroaromatic
group wherein 1 to 4 hydrogen atoms bonded to carbon atoms in the
ring have been replaced with other substituents. The substituents
include halogen atoms, acyl groups, cyano groups, monovalent hydrocarbon
groups, substituted monovalent hydrocarbon groups, heterogeneous
groups, substituted heterogeneous groups, aromatic groups, substituted
aromatic groups, heteroaromatic groups, substituted heteroaromatic
groups, and any combination thereof. Preferred substituents include
halogen atoms, cyano groups, monovalent hydrocarbon groups, substituted
monovalent hydrocarbon groups, heterogeneous groups, substituted
heterogeneous groups, phenyl groups, phenoxy groups, or any combination
thereof. More preferred substituents include halogen atoms, halogenated
hydrocarbon groups, monovalent hydrocarbon groups, halogenated heterogenous
groups, and phenyl groups.
[0039] "Substituted heterocyclic group" means a heterocyclic
group wherein 1 to 4 hydrogen atoms bonded to carbon atoms in the
ring have been replaced with other substituents. Preferred substituents
include: halogen atoms, cyano groups, monovalent hydrocarbon groups,
substituted monovalent hydrocarbon groups, heterogeneous groups,
substituted heterogeneous groups, aromatic groups, substituted aromatic
groups, or any combination thereof. More preferred substituents
include halogen atoms, halogenated hydrocarbon groups, phenyl groups,
phenoxy groups, or any combination thereof. Substituted heterocyclic
groups are not aromatic.
[0040] "Substituted heterogeneous group" means a heterogeneous
group, wherein 1 to 4 of the hydrogen atoms bonded to carbon atoms
in the chain have been replaced with other substituents. Preferably
substituted heterogeneous groups are mono, di, or trisubstituted.
Preferred substituents include halogen atoms, hydroxy groups, carboxy
groups, aryloxy groups (e.g., phenoxy, chlorophenoxy, tolyloxy,
methoxyphenoxy, benzyloxy, alkyloxycarbonylphenoxy, and acyloxyphenoxy),
acyloxy groups (e.g., propionyloxy, benzoyloxy, and acetoxy), aromatic
groups (e.g., phenyl and tolyl), substituted aromatic groups (e.g.,
alkoxyphenyl, alkoxycarbonylphenyl, and halophenyl), heterocyclic
groups, heteroaromatic groups, substituted heterocyclic groups,
and amino groups (e.g., amino, mono- and di- alkylamino having 1
to 3 carbon atoms, methylphenylamino, methylbenzylamino, alkanylamido
groups of 1 to 3 carbon atoms, carbamamido, ureido, and guanidino).
[0041] "Substituted monovalent hydrocarbon group" means
a monovalent hydrocarbon group wherein 1 to 4 of the hydrogen atoms
bonded to carbon atoms in the chain have been replaced with other
substituents. Preferred substituted monovalent hydrocarbon groups
are mono, di, or trisubstituted. Preferred substituents include
halogen atoms; lower monovalent hydrocarbon groups; hydroxy groups;
aryloxy groups (e.g., phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy,
benzyloxy, alkyloxycarbonylphenoxy, and acyloxyphenoxy); acyloxy
groups (e.g., propionyloxy, benzoyloxy, and acetoxy); carboxy groups;
monocyclic aromatic groups; monocyclic heteroaromatic groups; monocyclic
carbocyclic groups, monocyclic heterocyclic groups, and amino groups
(e.g., amino, mono- and di-alkanylamino groups of 1 to 3 carbon
atoms, methylphenylamino, methylbenzylamino, alkanylamido groups
of 1 to 3 carbon atoms, carbamamido, ureido, and guanidino).
Prostaglandins Used in the Invention
[0042] This invention relates to the use of prostaglandin F analogs
(PGF's) to treat hair loss. Suitable PGF's can have a structure
selected from the group consisting of: 2
[0043] The PGF can also be selected from the group consisting of
pharmaceutically acceptable salts and hydrates of the structures
above; biohydrolyzable amides, esters, and imides of the structures
above; and optical isomers, diastereomers, and enantiomers of the
structures above. Thus, at all stereocenters where stereochemistry
is not defined (C.sub.11, C.sub.12, and C.sub.15), both epimers
are envisioned. Preferred stereochemistry at all such stereocenters
of the compounds of the invention mimic that of naturally occurring
PGF.sub.2.alpha.. A combination of two or more PGF's can also be
used.
[0044] R.sup.1 is selected from the group consisting of C(O)OH,
C(O)NHOH, C(O)OR.sup.3, CH.sub.2OH, S(O).sub.2R.sup.3, C(O)NHR.sup.3,
C(O)NHS(O).sub.2R.sup.4, tetrazole, a cationic salt moiety, a pharmaceutically
acceptable amine or ester comprising 2 to 13 carbon atoms, and a
biometabolizable amine or ester comprising 2 to 13 atoms. Preferably,
R.sup.1 is selected from the group consisting of CO.sub.2H, C(O)NHOH,
CO.sub.2R.sup.3, C(O)NHS(O).sub.2R.sup.4, and tetrazole. More preferably,
R.sup.1 is selected from the group consisting of CO.sub.2H and CO.sub.2R.sup.3.
[0045] R.sup.2 is selected from the group consisting of a hydrogen
atom, a lower heterogenous group, and lower monovalent hydrocarbon
groups. Preferably, R.sup.2 is a hydrogen atom.
[0046] R.sup.3 is selected from the group consisting of a monovalent
hydrocarbon group, a heterogeneous group, a carbocyclic group, a
heterocyclic group, an aromatic group, a heteroaromatic group, a
substituted monovalent hydrocarbon group, a substituted heterogeneous
group, a substituted carbocyclic group, a substituted heterocyclic
group, a substituted aromatic group, and a substituted heteroaromatic
group. Preferably, R.sup.3 is selected from the group consisting
of methyl, ethyl, and isopropyl
[0047] R.sup.4 is selected from the group consisting of a monovalent
hydrocarbon group, a heterogeneous group, a carbocyclic group, a
heterocyclic group, an aromatic group, a heteroaromatic group, a
substituted monovalent hydrocarbon group, a substituted heterogeneous
group, a substituted carbocyclic group, a substituted heterocyclic
group, a substituted aromatic group, and a substituted heteroaromatic
group. Preferably, R.sup.4is a phenyl group.
[0048] X is divalent. X is selected from the group consisting of
--C.ident.C--, a covalent bond, --CH.dbd.C.dbd.CH--, --CH.dbd.CH--,
--CH.dbd.N--, --C(O)--, --C(O)Y--, --(CH.sub.2).sub.n--, wherein
n is 2 to 4, --CH.sub.2NH--, --CH.sub.2S--, and --CH.sub.2O--.
[0049] Y is selected from the group consisting of O, S, and NH.
[0050] Z is selected from the group consisting of a carbocyclic
group, a heterocyclic group, an aromatic group, a heteroaromatic
group, a substituted carbocyclic group, a substituted heterocyclic
group, a substituted aromatic group, and a substituted heteroaromatic
group.
[0051] Preferably, when X is a covalent bond, Z is selected from
the group consisting of an aromatic group, a heteroaromatic group,
a substituted aromatic group, and a substituted heteroaromatic group.
More preferably, when X is a covalent bond, Z is a bicyclic heteroaromatic
group.
[0052] Preferably, when X is --C.ident.C--, Z is a monocyclic aromatic
group. More preferably, when X is --C.ident.C--, Z is selected from
the group consisting of furanyl, thienyl, and phenyl.
[0053] Bonds shown as dashed lines in the second structure above
indicate that those bonds may optionally be double or triple bonds.
For example, when R.sup.1 is C(O)OH in the structure: 3
[0054] The bond at the C2-C3 position may be a single bond or a
double bond. The bond at the C5-C6 position may be a single, double,
or triple bond. The bond at the C13-C14 position may be a single,
double, or triple bond.
[0055] Examples of PGF's'having the structure: 4
[0056] which are suitable for component A) are shown below in Tables
1 and 2.
1TABLE 1 Examples of Suitable PGF's for Component A) 13,14-dihydro-16,17-Z-didehydro-17-
13,14-dihydro-16,17-Z-didehydro-17- (2-fluorophenyl)-17-trinor PGF.sub.1.alpha.
(2-fluorophenyl)-17-trinor PGF.sub.1.alpha. 5 6 13,14-dihydro-E-16,17-didehydro-17-
13,14-dihydro-E-16,17-didehydro-17- phenyl-17-trinor PGF.sub.1.alpha.
(2,4-dichlorophenyl)-17-trinor PGF.sub.1.alpha. 7 8 13,14-dihydro-E-16,17-didehydro-17-
13,14-dihydro-E-16,17-didehydro-17- (2-fluoro-4-methylphenyl)-17-t-
rinor (2-fluoro-5-chlorophenyl)-17-trimor PGF.sub.1.alpha. PGF.sub.1.alpha.
9 10 13,14-dihydro-E-16,17-didehydro-17- 13,14-dihydro-E-16,17-didehydro-17-
(2,5-difluorophenyl)-17-trinor PGF.sub.1.alpha. (2-fluoro-3-chlorophenyl)-17-trinor
PGF.sub.1.alpha. 11 12 13,14-dihydro-E-16,17-didehydro-17- 13,-14dihydro-16,17-didehydro-17-
(2-fluoro-3-methoxyphenyl)-17-tr- inor (3-fluorophenyl)-17-trinor
PGF.sub.1.alpha. PGF.sub.1.alpha. 13 14 13,14-dihydro-16,17-didehydro-17-(4-
13,14-dihydro-E-16,17-didehydro-17- fluorophenyl)-17-trinor PGF.sub.1.alpha.
(3-trifluoromethylphenyl)-17-trinor PGF.sub.1.alpha. 15 16 13,14-dihydro-16,17,17,18-dienyl-18-
13,14-dihydro-16,17,17,18-dienyl- phenyl-18-dinor PGF.sub.1.alpha.
18-(2-fluorophenyl)-18-dinor PGF.sub.1.alpha. 17 18 13,14-dihydro-16,17,17,18-dienyl-18-
13,14-dihydro-16,17,17,18-dienyl- (2,4-difluorophenyl)-18-dinor
PGF.sub.1.alpha. 18-(3-trifluoromethylphenyl)-18- dinor PGF.sub.1.alpha.
19 20 13,14-dihydro-16,17,17,18-dienyl-18- 13,14-dihydro-16,17-didehydro-17-
(4-methoxyphenyl)-18-dinor PGF.sub.1.alpha. (2-fluorophenyl)-17-trinor
PGF.sub.1.alpha. 1- hydroxamic acid 21 22 13,14-dihydro-16,17,17,18-dienyl-18-
13,14-dihydro-16,17-didehydro-17- phenyl-18-dinorPGF.sub.2.alpha.
1-hydroxamic 3-fluorophenyl-17-trinor PGF.sub.1.alpha. 1-N- acid
methanesulfonamide 23 24 13,14-dihydro-16-oxo-16-phenyl-16- 13,14-dihydro-16-oxo-16-(3,5-
tetranorPGF.sub.1.alpha. difluorophenyl)-16-tetranor PGF.sub.1.alpha.
25 26 13,14-dihydro-16-oxo-(2-furanyl)- 13,14-dihydro-16-oxo-16-(3-chl-
oro- 16-tetranor PGF.sub.1.alpha. 5-methylphenyl)-16-tetranor PGF.sub.1.alpha.
27 28 13,14-dihydro-16-oxo-16-(6- 13,14-dihydro-16-oxo-16-(2- fluorobenzo-[b]-furanyl-16-(tetranor
benzo[b]thienyl)-16-tetranor PGF.sub.1.alpha. PGF.sub.1.alpha. 29
30 13,14-dihydro-16-oxo16-(2- 13,14-dihydro-16-oxo-16-(3,5- benzothiazolyl)-16-tetranor
PGF.sub.1.alpha. difluorophenyl)-16-tetranor PGF.sub.1.alpha. 1-hydroxamic
acid 31 32 13,14-dihydro-16-oxo-16-(4- 13,14-dihydro-16-oxo-16-(2-
methylphenyl)-16-tetranor PGF.sub.1.alpha.1- benzo[b]thienyl)-16-tetranor
PGF.sub.1.alpha. hydroxamic acid 1-N-methanesulfonamide 33 34 13,14-dihydro-16-oxo-17-aza-17-
13,14-dihydro-16-oxo-17-aza-17- phenyl-17-trinor PGF.sub.1.alpha.
(3,4-difluorophenyl)-17-trimor PGF.sub.1.alpha. 35 36 13,14-dihydro-16-oxo-17-aza-17-(2-
13,14-dihydro-16-oxo-17-aza-17-(2- furnyl)-17-trinor PGF.sub.1.alpha.
fluorophenyl)-17-trinor PGF.sub.1.alpha. 37 38 13,14-dihydro-16-oxo-16-phenoxy-16-
13,14-dihydro-16-oxo-16-(2- tetranor PGF.sub.1.alpha. fluorophenoxy)-16-tetranor
PGF.sub.1.alpha. 39 40 13,14-dihydro-16-oxo-16-(3- 13,14-dihydro-16-oxo-17-aza-17-
trifluoromethylphenoxy)-16-tetranor (3,4-difluorophenyl)-17-trinor
PGF.sub.1.alpha. PGF.sub.1.alpha. 1-hydroxamic acid 41 42 13,14-dihydro-16-oxo-17-amino-17-
13,14-dihydro-16-oxo-17-amino-17- (3-chlorophenyl)-17-trinor PGF.sub.1.alpha.
1- phenyl-17-trinor PGF.sub.1.alpha. 1-methane hydroxamic acid sulfonamide
43 44 13,14-dihydro-16,17-didehydro-17- 13,14-dihydro-16,17-didehydro-17-
aza-17-phenyl-17-trinor PGF.sub.1.alpha. aza-17-(2-fluorophenyl)-17-trin-
or PGF.sub.1.alpha. 45 46 13,14-dihydro-16,17-didehydro-17- 13,14-dihydro-16-oxo-17-aza-17-
aza-17-(2-furanyl)-17-trinor PGF.sub.1.alpha. (4-phenylphenyl)-17-trinor
PGF.sub.1.alpha. 47 48 13,14-dihydro-16,17-didehydro-17- 13,14-dihydro-16,17-didehydro-17-
aza-17-(3-fluorophenyl)-17-trinor aza-17-(2-furanyl)-17-trinor PGF.sub.1.alpha.
PGF.sub.1.alpha. 1-hydroxamic acid 49 50 13,14-dihydro-16,17-didehydro-17-
13,14-dihydro-16,17-didehydro-17- aza-17-(3-chlorophenyl)-17-trino-
r aza-17-(2-thienyl)-17-trinor PGF.sub.1.alpha. PGF.sub.1.alpha.
1-hydroxamic acid 1-methanesulfonamide 51 52
[0057] Where Me in the table above represents a methyl group.
[0058] The PGF's in Table 1 can be prepared using conventional
organic syntheses. Preferred syntheses are carried out using reaction
schemes 1, 2, and 3. Scheme 1 describes a general reaction scheme
for making PGFs wherein X is --CH.dbd.CH-- (Formula I) or --CH.dbd.C.dbd.CH--
(Formula II). Scheme 2 describes a general reaction scheme for making
PGFs wherein X is --C(O)-- (Formula III) or --C(O)Y-- (Formula IV).
Scheme 3 describes a general reaction scheme for making PGFs wherein
X is --CH.dbd.N-- (Formula V). 53
[0059] In Scheme 1, R.sup.1 and Z are as defined above. The methyl
7(3-(R)-hydroxy-5-oxo-1-cyclopent-1-yl) heptanoate (S1a) depicted
as starting material for Scheme 1 is commercially available (such
as from Sumitomo Chemical or Cayman Chemical).
[0060] In Scheme 1, methyl 7-(3-(R)-hydroxy-5-oxo-1-cyclopent-1-yl)
heptanoate (S1a) is reacted with a silylating agent and base in
a solvent that will allow the silylation to proceed. Preferred silylating
agents include tert-butyldimethylsilyl chloride and tert-butyldimethylsilyl
trifluoromethanesulphonate. The most preferred silylating agent
is tert-butyldimethylsilyl trifluoromethanesulphonate. Preferred
bases include triethylamine, trimethylamine, and 2,6-lutidine. More
preferred bases include triethylamine and 2,6-lutidine. The most
preferred base is 2,6-lutidine. Preferred solvents include halogenated
hydrocarbon solvents with dichloromethane being the most preferred
solvent. The reaction is allowed to proceed at a temperature of
preferably -100.degree. C. to 100.degree. C., more preferably -80.degree.
C. to 80.degree. C., and most preferably -70.degree. C. to 23.degree.
C.
[0061] The resulting silylated compound is isolated by methods
known to one of ordinary skill in the art. Such methods include
extraction, solvent evaporation, distillation, and crystallization.
Preferably, the silyl ether is purified after isolation by distillation
under vacuum.
[0062] The silylated compound is then reacted with the cuprate
generated via Grignard formation of the appropriate alkenyl bromide
as disclosed, for example, in the following references: H. O. House
et. al., "The Chemistry of Carbanions: A Convenient Precursor
for the Generation of Lithium Organocuprates", J. Org. Chem.
Vol. 40 (1975) pp. 1460-69; and P. Knochel et. al., "Zinc and
Copper Carbenoids as Efficient and Selective a'/d' Multicoupling
Reagents", J. Amer. Chem. Soc. Vol. 111 (1989) p. 6474-76.
Preferred alkenyl bromides include 4-bromo-1-butene, 4-bromo-1-butyne,
4-bromo-2-methyl-1-butene, and 4-bromo-2-ethyl-1-butene- . The most
preferred alkenyl bromide is 4-bromo-1-butene. Preferred solvents
include ethereal solvents, of which diethyl ether and tetrahydrofuran
are preferred. The most preferred solvent is tetrahydrofuran. The
Grignard reagent is allowed to form at a temperature of 100.degree.
C. to 23.degree. C., more preferably 85.degree. C. to 30.degree.
C., and most preferably 75.degree. C. to 65.degree. C. The reaction
time is preferably 1 to 6 hours, more preferably 2 to 5 hours, and
most preferably 3 to 4 hours.
[0063] Once the Grignard reagent is formed, the cuprate is generated
from the alkenyl magnesium species. The temperature range for cuprate
formation is -100.degree. C. to 0.degree. C. The preferred temperature
range is -80.degree. C. to -20.degree. C. The more preferred temperature
range is -75.degree. C. to -50.degree. C. The preferred reaction
time is 30 minutes to 6 hours, more preferably 45 minutes to 3 hours.
The most preferred reaction time is 1 to 1.5 hours.
[0064] The alkene thus formed is isolated by methods known to one
of ordinary skill in the art. Such methods include extraction, solvent
evaporation, distillation, and crystallization. Preferably, the
alkene is purified by flash chromatography on silica gel (Merck,
230-400 mesh) using 10% EtOAc/hexanes as the eluent. (EtOAc represents
ethyl acetate.)
[0065] The alkene is then reacted with a hydride reducing agent
and a polar, protic solvent to give the C-9 alcohol. Preferred reducing
agents include lithium aluminum hydride, sodium borohydride, and
L-selectride. More preferred reducing agents include sodium borohydride,
and L-selectride. The most preferred reducing agent is sodium borohydride.
Preferred solvents include methanol, ethanol, and butanol. The most
preferred solvent is methanol. The reduction is carried out at a
temperature of -100.degree. C. to 23.degree. C. The preferred temperature
range is -60.degree. C. to 0.degree. C. The most preferred temperature
range is -45.degree. C. to -20.degree. C.
[0066] The resulting alcohol is isolated by methods known to one
of ordinary skill in the art. Such methods include extraction, solvent
evaporation, distillation, and crystallization. Preferably, the
alcohol is purified by flash chromatography on silica gel (Merck,
230-400 mesh) using 20% EtOAc/hexanes as the eluent.
[0067] The resultant alcohol can be protected as described previously
herein. Preferred silylating agents in this case also include tert-butyldimethylsilyl
chloride and tert-butyldimethylsilyl trifluoromethanesulfonate.
The most preferred silylating agent is tert-butyldimethylsilyl trifluoromethanesulfonate.
Preferred bases include triethylamine, trimethylamine, and 2,6-lutidine.
More preferred bases include triethylamine and 2,6-lutidine. The
most preferred base is 2,6-lutidine. Preferred solvents include
halogenated hydrocarbon solvents with dichloromethane being the
most preferred solvent. The reaction is allowed to proceed at a
temperature of preferably -100.degree. C. to 100.degree. C., more
preferably -80.degree. C. to 80.degree. C., and most preferably
-70.degree. C. to 23.degree. C.
[0068] The resulting silylated compound, S1b is isolated by methods
known to one of ordinary skill in the art. Such methods include
extraction, solvent evaporation, distillation, and crystallization.
Preferably, the silyl ether is purified after isolation by distillation
under vacuum, giving compound S1b.
[0069] The protected alcohol is then treated with a form of osmium
and sodium periodate in a solvent in which both are soluble. Preferred
forms of osmium include osmium tetraoxide and potassium osmate.
Preferred solvent systems include 1:1 mixtures of acetic acid and
water and 1:1:2 mixtures of water, acetic acid and THF. (THF represents
tetrahydrofuran.) The result of this treatment is the aldehyde,
S1c.
[0070] The compound S1c is isolated by methods known to one of
ordinary skill in the art. Such methods include extraction, solvent
evaporation, distillation, and crystallization. Preferably, S1c
is purified by flash chromatography on silica gel (Merck, 230-400
mesh) using 20% EtOAc/hexanes as the eluent.
[0071] The key intermediate aldehyde depicted as S1c can be reacted
with a variety of unsaturated alkenyl anion nucleophiles to provide
the C-9 and C-11-protected 13,14-dihydro-prostaglandin F.sub.1.alpha.
derivatives.
[0072] The resulting compounds can be isolated, but are generally
deprotected using techniques known to one of ordinary skill in the
art, and optionally, manipulated at C-1 to provide the desired acid
derivative at R.sup.1. For example, the condensation of a methyl
ester with an amine or a hydroxylamine provides an amide or a hydroxamic
acid compound, respectively. After any such manipulation at C-1,
the compounds are isolated as the final 13,14-dihydro-15-substituted-15-pentanor
prostaglandin F.sub.1.alpha. derivative, Formula I.
[0073] Compounds depicted by Formula II can be made directly from
intermediate S1c in a manner similar to that for compounds depicted
by Formula I substituting the appropriate allene anion. With allene
nucleophiles, the reaction is carried out preferably at -80.degree.
C. to 0.degree. C., more preferably -80.degree. C. to -20.degree.
C, and most preferably -80.degree. C. to -40.degree. C. Preferred
bases for the reaction include n-butyl lithium, s-butyl lithium,
and t-butyl lithium. The most preferred base is n-butyl lithium.
Preferred solvents for the reaction are ether solvents. Preferred
solvents include diethyl ether, and tetrahydrofuran. The most preferred
solvent is tetrahydrofuran. With heterocyclic nucleophiles, preferred
solvents include ethereal solvents. More preferred ethereal solvents
include diethyl ether, dibutyl ether and tetrahydrofuran. The most
preferred ethereal solvent is tetrahydrofuran. After isolation,
similar C-1 manipulations and/or deprotection of the functional
groups ensues using techniques known to one of ordinary skill in
the art. 54
[0074] In Scheme 2, R.sup.1, Y, and Z are as defined above. The
protected alcohol S1b (from Scheme 1) is treated with a hydroborating
reagent in an ethereal solvent, followed by oxidative removal of
the boron reagent with a suitable oxidant to give a compound of
the type S2a. Preferred hydroborating reagents include monochloroborane-dimethylsulfide,
diborane, borane-tetrahydrofuran and borane-dimethylsulfide. The
most preferred hydroborating reagent is borane-dimethylsulfide.
Preferred ethereal solvents include THF and diethyl ether. The most
preferred solvent is THF. The reaction is carried out from about
1 to about 24 hours at a temperature of about -20.degree. C. to
about +30.degree. C. The preferred temperature range is about 0.degree.
C. to about +20.degree. C. The hydroborated product of this reaction
may then be oxidatively removed to the alcohol using alkaline hydrogen
peroxide (See Boranes in Organic Chemistry, H. C. Brown, Cornell
University Press, Ithaca, N.Y. 1972, pp. 321-325), which may then
be oxidized to either the aldehyde (W.dbd.H) or to the acid (W.dbd.OH)
using methods known to one of ordinary skill in the art. Alternatively,
the hydroborated product may be directly oxidized to the aldehyde
or acid by treatment with chromic acid or a Cr(VI) salt. Such salts
include pyridinium chlorochromate (PCC) and dichlorochromate. See
Brown, H. C.; Kulkarni, Rao, and Patil, Tetrahedron, 1986, 45515.
The preferred method is treatment of the hydroborated product with
PCC in dichloromethane at room temperature. The result of these
manipulations is a compound of the type S2a.
[0075] The compound S2a is isolated by methods known to one of
ordinary skill in the art. Such methods include extraction, solvent
evaporation, distillation, and crystallization. Preferably, S2a
is purified by flash chromatography on silica gel (Merck, 230-400
mesh) using 20% EtOAc/hexanes as the eluent with 0.1% acetic acid
added if W.dbd.OH.
[0076] The key intermediate aldehyde depicted as S2a can be reacted
with a variety unsaturated carbon nucleophiles to provide the C-9
and C-11-protected 13,14-dihydro-16-tetranor prostaglandin F.sub.1.alpha.
derivatives of Formula III.
[0077] With aromatic and heteroaromatic nucleophiles, the reaction
is carried out preferably at -80.degree. C. to 0.degree. C., more
preferably -80.degree. C. to -20.degree. C., and most preferably
-80.degree. C. to -40.degree. C. Preferred bases for the reaction
include n-butyl lithium, s-butyl lithium, lithium diisopropylamide,
and t-butyl lithium. The most preferred base is n-butyl lithium.
Preferred solvents for the reaction are ether solvents. Preferred
solvents include diethyl ether, and tetrahydrofuran. The most preferred
solvent is tetrahydrofuran. With heterocyclic nucleophiles, preferred
solvents include ethereal solvents. More preferred ethereal solvents
include diethyl ether, dibutyl ether and tetrahydrofuran. The most
preferred ethereal solvent is tetrahydrofuran.
[0078] The resulting alcohol can be isolated, but is generally
oxidized as a crude isolate. The oxidation of benzylic alcohols
to benzylic ketones is well known in the art. The preferred reagents
to effect this reaction include KMnO.sub.4, MnO.sub.2, chromic acid,
Jones' reagent, Collins' reagent, and PCC. The most preferred method
is oxidation at room temperature in dichloromethane with PCC for
about 4 hours. The ketones are isolated by column chromatography
using 20% hexanes/ethyl acetate as solvent. The ester is then removed
using standard conditions. See Greene and Wuts, Protecting Groups
in Organic Synthesis, Wiley Interscience, NY pp. 224-276. The free
acid is then treated with 2.1 equivalents of a strong nitrogen base
to effect deprotonation both of the acid and adjacent to the benzylic
ketone. Such bases include LDA. This enolate is reacted with a peroxidizing
agent which has the effect of oxidizing the compound to deliver
the alpha-hydroxy ketone. Such reagents include meta-chloroperoxybenzoic
acid, dimethyl dioxirane, Davis' reagent and peracetic acid. The
crude product may be isolated or the remaining protecting groups
may be removed. At this point manipulation of the acid at C-1 may
take place. For example, re-esterifying, making the amide, the hydroxamic
acid or the sulfonamide using methods known to one of ordinary skill
in the art may be performed to yield compounds according to Formula
III.
[0079] Compounds depicted by Formula IV can be made from intermediate
S2b. In this case, condensation of the free acid is readily achieved
with a variety of alcohols and amines, either by the use of coupling
agents such as dicyclohexylcarbodiimide ("DCC"), or by
activating the acid with, for example, oxalyl chloride. Following
this is the selective removal of the methyl esters as described
in Greene and Wuts, Protecting Groups in Organic Synthesis, Wiley
Interscience, NY pp. 224-276, and the oxidation of the ester enolates
using the same technique described above for the ketone intermediates.
Similarly, as described above, the remaining protecting groups are
removed and the desired manipulation of C-1 is effected, yielding
compounds of Formula IV. 55
[0080] In Scheme 3, R.sup.1 and Z are as defined above. The alkene
S1b (from Scheme 1) is treated with an osmium salt and with an optional
catalyst reoxidant, preferably N-methyl morpholine N-oxide ("NMO"),
to give the diol. This diol is isolated by extraction and purified
by silica gel chromatography. The diol is then oxidized selectively
to the alpha hydroxy aldehyde. This may be accomplished in several
ways. For example, a selective oxidant such as DMSO-oxalyl chloride
may be used. ("DMSO" represents dimethylsulfoxide.) Alternatively,
the primary alcohol may be selectively protected, then the secondary
alcohol protected, then the protection on the primary alcohol may
then be removed and the alcohol oxidized as described above in Scheme
II. However, the preferred method is the addition of a o-bromo-benzyl
bromide protecting group, which can be removed with concomitant
oxidation by tributyl tin hydride and like reagents. This technique
yields compounds of the type S3a, wherein Q.dbd.H. From this step
follows the condensation of the aldehyde with an amine to form an
imine of the type S3b. Appropriate removal of protecting groups
and manipulation of C-1L as stated above in Schemes I and II yields
compounds of Formula V.
2TABLE 2 Examples of Suitable PGF's 13,14-dihydro-15-(2-benzothienyl)-15-
13,14-dihydro-15-(2-benzothi- azolyl)- pentanor PGF.sub.1.alpha.
15-pentanor PGF.sub.1.alpha. 56 57 13,14-dihydro-15-(8-fluoro-2-
13,14-dihydro-16,17-ynyl17-(2,5- benzothiazolyl)-15- pentanor PGF.sub.1.alpha.
difluorophenyl)-17-trinor PGF.sub.1.alpha. 58 59 13,14-dihydro-16,17-ynyl-17-(2,3-
13,14-dihydro-16,17-ynyl-17-(3,5- difluorophenyl)-17-trinor difluorophenyl)-17-trinor
PGF.sub.1.alpha. PGF.sub.1.alpha. 60 61 13,14-dihydro-16,17-ynyl-17-(3,4-
13,14-dihydro-15-(6-fluoro-2- difluorophenyl)-17-trinor benzothienyl)-15-pentanor
PGF.sub.1.alpha. PGF.sub.1.alpha. 62 63 3,14-dihydro-16,17-ynyl-17-(2,4-
13,14-dihydro-16,17-ynyl-17-(3- difluorophenyl)-17-trinor PGF.sub.1.alpha.
fluorophenyl)-17-trinor PGF.sub.1.alpha. methyl ester 64 65 13,14-dihydro-16,17-ynyl-17-(-
2- 13,14-dihydro-16,17-ynyl-17-(4- fluoro-4-methylphenyl)-17-trinor
chlorophenyl)-17-trinor PGF.sub.1.alpha. PGF.sub.1.alpha. 66 67
13,14-dihydro-16,17-ynyl-17-phenyl- 13,14-dihydro-16,17-ynyl-17-(4-
17-trinor PGF.sub.1.alpha. isopropyl ester fluorophenyl)-17-trinor
PGF.sub.1.alpha. ethyl ester 68 69 13,14-dihydro-15-(5-fluoro-2-
13,14-dihydro-16,17-ynyl-17-(2- benzothiazolyl)-15-pentanor PGF.sub.1.alpha.
chlorophenyl)-17-trinor isopropyl ester PGF.sub.1.alpha. 70 71 13,14-dihydro-16,17-ynyl-17-(2-
13,14-dihydro-16,17-ynyl-17-(2- fluorophenyl)-17-trinor PGF.sub.1.alpha.
methyl fluorophenyl)-17-trinor ester PGF.sub.1.alpha. 72 73 13,14-dihydro-16,17-ynyl-17-(4-
13,14-dihydro-16,17-ynyl-18-phenyl- phenyl-phenyl)-17-trinor PGF.sub.1.alpha.
18-dinor PGF.sub.1.alpha. 74 75 13,14-dihydro-16,17-ynyl-17-(4-
13,14-dihydro-16,17-ynyl-18-(2- methylphenyl)-17-trinor PGF.sub.1.alpha.
fluorophenyl)-18-dinor PGF.sub.1.alpha. 76 77 13,14-dihydro-15-phenyl-15-pentanor
13,14-dihydro-15-(4-methylphenyl)- PGF.sub.1.alpha. 15-pentanor
PGF.sub.1.alpha. 78 79 13,14-dihydro-15-(4- 13,14-dihydro-15-(3-
trifluoromethylphenyl)-1- 5-pentanor trifluoromethylphenyl)-15-pentanor
PGF.sub.1.alpha. PGF.sub.1.alpha. 80 81 13,14-dihydro-15-(2-fluorophenyl)-15-
13,14-dihydro-15-(3,5 pentanor PGF.sub.1.alpha. difluorophenyl)-15-pentanor
PGF.sub.1.alpha. ethyl ester 82 83 13,14-dihydro-15-(3-chloro-4-fluoro-6-
13,14-dihydro-15-(3-pyridinyl)-15- methylphenyl)-15pentanor PGF.sub.1.alpha.
pentanor PGF.sub.1.alpha. 84 85 13,14-dihydro-15-(2-chlorophenyl)-15-
13,14-dihydro-15-(4-phenylphenyl)- pentanor PGF.sub.1.alpha. 15-pentanor
PGF.sub.1.alpha. methyl ester 86 87 13,14-dihydro-15-S-(2-fluorop-
henyl)- 13,14-dihydro-15-S-(2- 15-pentanor PGF.sub.1.alpha. fluoronaphthyl)-15-pentanor
PGF.sub.1.alpha. 88 89 13,14-dihydro-15-(3-fluoro-4-pyridyl)- 13,14-dihydro-15-(6-methy-
lnaphth- 15-pentanor PGF.sub.1.alpha. isopropyl ester 2-yl)-15-pentanor
PGF.sub.1.alpha. 90 91 13,14-dihydro-15-benzo(b)thiophen- 13,14-dihydro-15-(6-benzothiazol-5-
5-yl)-15-pentanor PGF.sub.1.alpha. yl)-15-pentanor PGF.sub.1.alpha.
92 93 13,14-dihydro-15-(benzofuran-5-yl)- 13,14-dihydro-15-(5-fluoronaphth-1-
15-pentanor PGF.sub.1.alpha. methyl ester yl)-15-pentanor PGF.sub.1.alpha.
94 95 13,14-dihydro-15-(8-fluoro-2- 13,14-dihydro-15-(8-trifluorometh-
yl- naphthyl)-15-pentanor PGF.sub.1.alpha. 2-naphthyl)-15-pentanor
PGF.sub.1.alpha. 96 97 13,14-dihydro-15-(1-fluoro-3- 13,14-dihydro-16,17-ynyl-17-(2-
trifluoromethyl-2-naphthyl)-15- fluorophenyl)-17-trinor PGF.sub.1.alpha.
1- pentanor PGF.sub.1.alpha. isopropyl ester hydroxamic acid 98
99 13,14-dihydro-15-(benzothiazolyl)-15- 13,14-dihydro-15-(4-fluoro-2-
pentanor PGF.sub.1.alpha. 1-hydroxamic acid benzothienyl)-15-pentanor
PGF.sub.1.alpha. 1- hydroxamic acid 100 101 13,14-dihydro-15-(2-benzothienyl)-15-pentanor
PGF.sub.1.alpha. 1-N-methanesulfonamide 102
[0081] The PGR's in Table 2 can be prepared by conventional organic
syntheses. A preferred synthesis is reaction scheme 4. 103
[0082] In Scheme 4, R.sup.1, R.sup.2, X, and Z are as defined above.
The methyl 7(3-(R)-hydroxy-5-oxo-1-cyclopent-1-yl) heptanoate (S4a)
depicted as starting material for Scheme 4 is commercially available
(such as from Sumitomo Chemical or Cayman Chemical).
[0083] The C.sub.11 alcohol of methyl 7-(3-(R)-hydroxy-5-oxo-1-cyclopent-1-
-yl) heptanoate (S4a) is protected with a suitable protecting group.
The most preferred protecting group is a silyl group. In the above
Scheme 4, methyl 7-(3-(R)-hydroxy-5-oxo-1-cyclopent-1-yl) heptanoate
(S4a) is reacted with a silylating agent and base in a solvent that
will allow the silylation to proceed. Preferred silylating agents
include tert-butyldimethylsilyl chloride and tert-butyldimethylsilyl
trifluoromethanesulphonate. The most preferred silylating agent
is tert-butyldimethylsilyl trifluoromethanesulphonate. Preferred
bases include triethylamine, trimethylamine, and 2,6-lutidine. More
preferred bases include triethylamine and 2,6-lutidine. The most
preferred base is 2,6-lutidine. Preferred solvents include halogenated
hydrocarbon solvents with dichloromethane being the most preferred
solvent. The reaction is allowed to proceed at a temperature of
preferably -100.degree. C. to 100.degree. C., more preferably -80.degree.
C. to 80.degree. C., and most preferably -70.degree. C. to 23.degree.
C.
[0084] The resulting silylated compound is isolated by methods
known to those of ordinary skill in the art. Such methods include
extraction, solvent evaporation, distillation, and crystallization.
Preferably, the silyl ether is purified after isolation by distillation
under vacuum.
[0085] The silylated compound is then reacted with the cuprate
generated via Grignard formation of the appropriate alkenyl bromide
as disclosed, for example, in the following references: H.O. House
et. al., "The Chemistry of Carbanions: A Convenient Precursor
for the Generation of Lithium Organocuprates", J. Org. Chem.,
Vol. 40, pp. 1460-69 (1975); and P. Knochel et. al., "Zinc
and Copper Carbenoids as Efficient and Selective a'/d' Multicoupling
Reagents", J. Amer. Chem. Soc., Vol. 111, p. 6474-76 (1989).
Preferred alkenyl bromides include 4-bromo-1-butene, 4-bromo-1-butyne,
4-bromo-2-methyl-1-butene, and 4-bromo-2-ethyl-1-butene- . The most
preferred alkenyl bromide is 4-bromo-1-butene. Preferred solvents
include ethereal solvents, of which diethyl ether and tetrahydrofuran
are preferred. The most preferred solvent is tetrahydrofuran. The
Grignard reagent is allowed to form at a temperature of 100.degree.
C. to 23.degree. C., more preferably 85.degree. C. to 30.degree.
C., and most preferably 75.degree. C. to 65.degree. C. The reaction
time is preferably 1 to 6 hours, more preferably 2 to 5 hours, and
most preferably 3 to 4 hours.
[0086] Once the Grignard reagent is formed, the cuprate is generated
from the alkenyl magnesium species. The temperature range for cuprate
formation is -100.degree. C. and 0.degree. C. The preferred temperature
range is -80.degree. C. to -20.degree. C., more preferably -75.degree.
C. to -50.degree. C. The preferred reaction time is 30 minutes to
6 hours, more preferably 45 minutes to 3 hours, and most preferably
1 to 1.5 hours.
[0087] The alkene thus formed is isolated by methods known to one
of ordinary skill in the art. Such methods include, but are not
limited to, extraction, solvent evaporation, distillation, and crystallization.
Preferably, the alkene is purified by flash chromatography on silica
gel (Merck, 230-400 mesh) using 10% EtOAc/hexanes as the eluent.
The alkene is then reacted with a hydride reducing agent and a polar,
protic solvent to give the C-9 alcohol. Preferred reducing agents
include lithium aluminum hydride, sodium borohydride, and L-selectride.
More preferred reducing agents include sodium borohydride, and L-selectride.
The most preferred reducing agent is sodium borohydride. Preferred
solvents include methanol, ethanol, and butanol. The most preferred
solvent is methanol. The reduction is carried out at a temperature
between -100.degree. C. and 23.degree. C. The preferred temperature
range is -60.degree. C. to 0.degree. C. The most preferred temperature
range is -45.degree. C. to -20.degree. C.
[0088] The resulting alcohol is isolated by methods known to one
of ordinary skill in the art. Such methods include, but are not
limited to, extraction, solvent evaporation, distillation, and crystallization.
Preferably, the alcohol is purified by flash chromatography on silica
gel (Merck, 230-400 mesh) using 20% EtOAc/hexanes as the eluent.
[0089] The resultant alcohol can be protected as described previously
herein. Preferred silylating agents in this case also include tert-butyldimethylsilyl
chloride and tert-butyldimethylsilyl trifluoromethanesulfonate.
The most preferred silylating agent is tert-butyldimethylsilyl trifluoromethanesulfonate.
Preferred bases include triethylamine, trimethylamine, and 2,6-lutidine.
More preferred bases include triethylamine and 2,6-lutidine. The
most preferred base is 2,6-lutidine. Preferred solvents include
halogenated hydrocarbon solvents with dichloromethane being the
most preferred solvent. The reaction is allowed to proceed at a
temperature of preferably -100.degree. C. to 100.degree. C., more
preferably -80.degree. C. to 80.degree. C., and most preferably
-70.degree. C. to 23.degree. C.
[0090] The resulting silylated compound is isolated by methods
known to those of ordinary skill in the art. Such methods include,
but are not limited to, extraction, solvent evaporation, distillation,
and crystallization. Preferably, the silyl ether is purified after
isolation by distillation under vacuum
[0091] The protected or alcohol is then treated with a form of
osmium, and sodium periodate in a solvent where they are both soluble.
Preferred forms of osmium include osmium tetraoxide and potassium
osmate. Preferred solvent systems include 1:1 mixtures of acetic
acid and water and 1:1:2 mixtures of water, acetic acid and THF.
The result of this treatment is the aldehyde, S4b.
[0092] The compound S4b is isolated by methods known to one of
ordinary skill in the art. Such methods include, but are not limited
to, extraction, solvent evaporation, distillation, and crystallization.
Preferably, S4b is purified by flash chromatography on silica gel
(Merck, 230-400 mesh) using 20% EtOAc/hexanes as the eluent.
[0093] The key intermediate aldehyde depicted as S4b can be reacted
with a variety unsaturated carbon nucleophiles to provide the C-9
and C-11-protected 13,14-dihydro-16-tetranor prostaglandin F.sub.1.alpha.
derivatives depicted as S4c.
[0094] With alkyne nucleophiles, the reaction is carried out preferably
at -80.degree. C. to 0.degree. C., more preferably -80.degree. C.
to -20.degree. C., and most preferably -80.degree. C. to -40.degree.
C. Preferred bases for the reaction include n-butyl lithium, s-butyl
lithium, t-butyl lithium, and lithium diisopropyl amide ("LDA").
Preferred solvents for the reaction are ether solvents. Preferred
solvents include diethyl ether, and tetrahydrofuran. The most preferred
solvent is tetrahydrofuran. With heterocyclic nucleophiles, preferred
solvents include ethereal solvents. More preferred ethereal solvents
include diethyl ether, dibutyl ether and tetrahydrofuran. The most
preferred ethereal solvent is tetrahydrofuran.
[0095] The resulting compounds depicted as S4c can then be deprotected
using techniques known to one of ordinary skill in the art, and
isolated yielding the 13,14-dihydro-15-substituted-15-pentanor prostaglandin
F.sub.1.alpha. derivatives depicted by Formula VI.
[0096] Compounds depicted by Formula VII can be made directly from
the C-9 and C-11-protected 13,14-dihydro-16-tetranor prostaglandin
F.sub.1.alpha. derivatives depicted as S4c by methods known to one
of ordinary skill in the art. For example, the condensation of methyl
esters of S4c with amines or hydroxylamine provides compounds depicted
by Formula VII. These compounds are isolated by methods known to
one of ordinary skill in the art. Such methods include extraction,
solvent evaporation, distillation, and crystallization.
[0097] Examples of PGF's having the structure: 104
[0098] which are suitable for component A) include: cloprostenol
(estrumate), fluprostenol (equimate), tiaprost, alfaprostol, delprostenate,
froxiprost, 9-alpha, 11-alpha, 15-alpha-trihydroxy-16-(3-c- hlorophenoxy)-omega-tetranor-prosta-4-cis-13-trans-dienoic
acid, latanoprost and their analogs; and 13,14-dihydro-16-((3-trifluoromethyl)p-
henoxy)-16-tetranor prostaglandin F.sub.1.alpha., 17-((3-trifluoromethyl)p-
henyl)-17-trinor-prostaglandin F.sub.2.alpha. and its analogs, 13,14-dihydro-18-thienyl-18-dinor
prostaglandin F.sub.1.alpha. and their analogs. Additional PGF's
are also disclosed in CRC Handbook of Eicosanoids: Prostaglandins
and Related Lipids, Volume I, Chemical and Biochemical Aspects,
Part B. Ed. by Anthony L. Willis, CRC Press, Boca Raton, Table Four,
pp. 80-97 (1987) and references therein.
[0099] Preferred PGF's of the present invention are further selective
for the FP receptor over an excitatory prostaglandin receptor in
a ratio of 1:10, preferably from 1:20, more preferably from 1:50.
Compositions of the Invention
[0100] This invention further relates to a composition for treating
hair loss. "Treating hair loss" means arresting hair loss,
reversing hair loss, or both, and promoting hair growth. The composition
comprises component A) the PGF described above and component B)
a carrier. The composition may further comprise component C) one
or more optional activity enhancers.
[0101] The composition can be a pharmaceutical or cosmetic composition,
administered for treatment or prophylaxis of hair loss. Standard
pharmaceutical formulation techniques are used, such as those disclosed
in Remington's Pharmaceutical Sciences, Mack Publishing Company,
Easton, Pa (1990).
[0102] The composition further comprises component B) a carrier.
"Carrier" means one or more compatible substances that
are suitable for administration to a mammal. Carrier includes solid
or liquid diluents, hydrotopes, surface-active agents, and encapsulating
substances. "Compatible" means that the components of
the composition are capable of being commingled with the PGF's,
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 be of sufficiently
high purity and sufficiently low toxicity to render them suitable
for administration to the mammal being treated. The carrier can
be inert, or it can possess pharmaceutical benefits, cosmetic benefits,
or both.
[0103] The choice of carrier for component B) depends on the route
by which A) the PGF will be administered and the form of the composition.
The composition may be in a variety of forms, suitable, for example,
for systemic administration (e.g., oral, rectal, nasal, sublingual,
buccal, or parenteral) or topical administration (e.g., local application
on the skin, ocular, liposome delivery systems, or iontophoresis).
Topical administration directly to the locus of desired hair growth
is preferred.
[0104] Carriers for systemic administration typically comprise
one or more ingredients selected from the group consisting of a)
diluents, b) lubricants, c) binders, d) disintegrants, e) colorants,
f) flavors, g) sweeteners, h) antioxidants, j) preservatives, k)
glidants, m) solvents, n) suspending agents, o) surfactants, combinations
thereof, and others.
[0105] Ingredient a) is a diluent. Suitable diluents include sugars
such as glucose, lactose, dextrose, and sucrose; polyols such as
propylene glycol; calcium carbonate; sodium carbonate; glycerin;
mannitol; sorbitol; and maltodextrin.
[0106] Ingredient b) is a lubricant. Suitable lubricants are exemplified
by solid lubricants including silica, talc, stearic acid and its
magnesium salts and calcium salts, calcium sulfate; and liquid lubricants
such as polyethylene glycol and vegetable oils such as peanut oil,
cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma.
[0107] Ingredient c) is a binder. Suitable binders include polyvinylpyrrolidone;
magnesium aluminum silicate; starches such as corn starch and potato
starch; gelatin; tragacanth; and cellulose and its derivatives,
such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose,
microcrystalline cellulose, and hydroxypropylmethylcellu- lose;
carbomer; providone; acacia; guar gum; and xanthan gum.
[0108] Ingredient d) is a disintegrant. Suitable disintegrants
include agar, alginic acid and the sodium salt thereof, effervescent
mixtures, croscarmelose, crospovidone, sodium carboxymethyl starch,
sodium starch glycolate, clays, and ion exchange resins.
[0109] Ingredient e) is a colorant such as an FD&C dye.
[0110] Ingredient f) is a flavor such as menthol, peppermint, and
fruit flavors.
[0111] Ingredient g) is a sweetener such as saccharin and aspartame.
[0112] Ingredient h) is an antioxidant such as butylated hydroxyanisole,
butylated hydroxytoluene, and vitamin E.
[0113] Ingredient j) is a preservative such as phenol, alkyl esters
of parahydroxybenzoic acid, benzoic acid and the salts thereof,
boric acid and the salts thereof, sorbic acid and the salts thereof,
chorbutanol, benzyl alcohol, thimerosal, phenylmercuric acetate
and nitrate, nitromersol, benzalkonium chloride, cetylpyridinium
chloride, methyl paraben, and propyl paraben. Particularly preferred
are the salts of benzoic acid, cetylpyridinium chloride, methyl
paraben and propyl paraben, and sodium benzoate.
[0114] Ingredient k) is a glidant such as silicon dioxide.
[0115] Ingredient m) is a solvent, such as water, isotonic saline,
ethyl oleate, alcohols such as ethanol, glycerin, glycols (e.g.,
polypropylene glycol and polyethylene glycol), and buffer solutions
(e.g., phosphate, potassium acetate, boric carbonic, phosphoric,
succinic, malic, tartaric, citric, acetic, benzoic, lactic, glyceric,
gluconic, glutaric and glutamic).
[0116] Ingredient n) is a suspending agent. Suitable suspending
agents include AVICEL.RTM. RC-591 from FMC Corporation of Philadelphia,
Pa. and sodium alginate.
[0117] Ingredient o) is a surfactant such as lecithin, polysorbate
80, sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters,
polyoxyethylene monoalkyl ethers, sucrose monoesters, lanolin esters,
and lanolin ethers. Suitable surfactants are known in the art and
commercially available, e.g., the TWEENS.RTM. from Atlas Powder
Company of Wilmington, Del.
[0118] Compositions for parenteral administration typically comprise
A) 0.1 to 10% of a PGF and B) 90 to 99.9% of a carrier comprising
a) a diluent, and m) a solvent. Preferably, component a) is propylene
glycol and m) is ethanol Or ethyl oleate.
[0119] Compositions for oral administration can have various dosage
forms. For example, solid forms include tablets, capsules, granules,
and bulk powders. These oral dosage forms comprise a safe and effective
amount, usually at least 5%, and preferably from 25% to 50%, of
A) the PGF. The oral dosage compositions further comprise B) 50
to 95% of a carrier, preferably 50 to 75%.
[0120] Tablets can be compressed, tablet triturates, enteric-coated,
sugar-coated, film-coated, or multiple-compressed. Tablets typically
comprise A) the PGF, and B) a carrier comprising ingredients selected
from the group consisting of a) diluents, b) lubricants, c) binders,
d) disintegrants, e) colorants, f) flavors, g) sweeteners, k) glidants,
and combinations thereof. Preferred diluents include calcium carbonate,
sodium carbonate, mannitol, lactose and cellulose. Preferred binders
include starch, gelatin, and sucrose. Preferred disintegrants include
alginic acid, and croscarmelose. Preferred lubricants include magnesium
stearate, stearic acid, and talc. Preferred colorants are the FD&C
dyes, which can be added for appearance. Chewable tablets preferably
contain g) sweeteners such as aspartame and saccharin, or f) flavors
such as menthol, peppermint, and fruit flavors.
[0121] Capsules (including time release and sustained release formulations)
typically comprise A) the PGF, and B) a carrier comprising one or
more a) diluents disclosed above in a capsule comprising gelatin.
Granules typically comprise A) the PGF, and preferably further comprise
k) glidants such as silicon dioxide to improve flow characteristics.
[0122] The selection of ingredients in the carrier for oral compositions
depends on secondary considerations like taste, cost, and shelf
stability, which are not critical for the purposes of this invention.
One skilled in the art can optimize appropriate ingredients without
undue experimentation.
[0123] The solid compositions may also be coated by conventional
methods, typically with pH or time-dependent coatings, such that
A) the PGF is released in the gastrointestinal tract at various
times to extend the desired action. The coatings typically comprise
one or more components selected from the group consisting of cellulose
acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl
cellulose phthalate, ethyl cellulose, acrylic resins such as EUDRAGIT.RTM.
coatings (available from Rohm & Haas G.M.B.H. of Darmstadt,
Germany), waxes, shellac, polyvinylpyrrolidone, and other commercially
available film-coating preparations such as Dri-Klear, manufactured
by Crompton & Knowles Corp., Mahwah, N.J. or OPADRY.RTM. manufactured
by Colorcon, Inc., of West Point, Pa.
[0124] Compositions for oral administration can also have liquid
forms. For example, suitable liquid forms include aqueous solutions,
emulsions, suspensions, solutions reconstituted from non-effervescent
granules, suspensions reconstituted from non-effervescent granules,
effervescent preparations reconstituted from effervescent granules,
elixirs, tinctures, syrups, and the like. Liquid orally administered
compositions typically comprise A) the PGF and B) a carrier comprising
ingredients selected from the group consisting of a) diluents, e)
colorants, and f) flavors, g) sweeteners, j) preservatives, m) solvents,
n) suspending agents, and o) surfactants. Peroral liquid compositions
preferably comprise one or more ingredients selected from the group
consisting of e) colorants, f) flavors, and g) sweeteners.
[0125] Other compositions useful for attaining systemic delivery
of the subject compounds include sublingual, buccal and nasal dosage
forms. Such compositions typically comprise one or more of soluble
filler substances such as a) diluents including sucrose, sorbitol
and mannitol; and c) binders such as acacia, microcrystalline cellulose,
carboxymethylcellulose, and hydroxypropylmethylcellulose. Such compositions
may further comprise b) lubricants, e) colorants, f) flavors, g)
sweeteners, h) antioxidants, and k) glidants.
[0126] The compositions may further comprise component C) an optional
activity enhancer. Component C) is preferably selected from the
group consisting of i) hair growth stimulants (other than the PGF)
and ii) penetration enhancers.
[0127] Component i) is an optional hair growth stimulant. Component
i) is exemplified by vasodilators, antiandrogens, cyclosporins,
cyclosporin analogs, antimicrobials, anti-inflammatories, thyroid
hormones, thyroid hormone derivatives, and thyroid hormone analogs,
non-selective prostaglandin agonists or antagonists, retinoids,
triterpenes, combinations thereof, and others. "Non-selective
prostaglandin" agonists and antagonists differ from component
A) in that they do not selectively activate the FP receptor, and
they may activate other receptors.
[0128] Vasodilators such as potassium channel agonists including
minoxidil and minoxidil derivatives such as aminexil and those described
in U.S. Pat. Ser. Nos. 3,382,247, 5,756,092, 5,772,990, 5,760,043,
5,466,694, 5,438,058, 4,973,474, and cromakalin and diazoxide can
be used as optional hair growth stimulants in the composition.
[0129] Examples of suitable antiandrogens include 5-.alpha.-reductase
inhibitors such as finasteride and those described in U.S. Pat.
No. 5,516,779, and in Nane et al., Cancer Research 58, "Effects
of Some Novel Inhibitors of C17,20-Lyase and 5.alpha.-Reductase
in vitro and in vivo and Their Potential Role in the Treatment of
Prostate Cancer," as well as cyproterone acetate, azelaic acid
and its derivatives and those compounds described in U.S. Pat. No.
5,480,913, flutamide, and those compounds described in U.S. Pat.
Ser. Nos. 5,411,981, 5,565,467, and 4,910,226.
[0130] Antimicrobials include selenium sulfide, ketoconazole, triclocarbon,
triclosan, zinc pyrithione, itraconazole, asiatic acid, hinokitiol,
mipirocin and those described in EPA 0,680,745, clinacycin hydrochloride,
benzoyl peroxide, benzyl peroxide and minocyclin.
[0131] Examples of suitable anti-inflammatories include glucocorticoids
such as hydrocortisone, mometasone furoate and prednisolone, nonsteroidal
anti-inflammatories including cyclooxygenase or lipoxygenase inhibitors
such as those described in U.S. Pat. Ser. No. 5,756,092, and benzydamine,
salicylic acid, and those compounds described in EPA 0,770,399,
published May 2, 1997, WO 94/06434, published Mar. 31, 1994, and
FR 2,268,523, published Nov. 21, 1975.
[0132] 3,5,3'-Triiodothyronine is an example of a suitable thyroid
hormone.
[0133] Examples of suitable non-selective prostaglandins agonists
and antagonists include compounds such as those described in WO
98/33497, Johnstone, published Aug. 6, 1998, WO 95/11003, Stjernschantz,
published Apr. 27, 1995, JP 97-100091, Ueno and JP 96-134242, Nakamura.
[0134] Suitable retinoids include isotretinoin, acitretin, and
tazarotene.
[0135] Other optional hair growth stimulants for component i) include
benzalkonium chloride, benzethonium chloride, phenol, estradiol,
chlorpheniramine maleate, chlorophyllin derivatives, cholesterol,
salicylic acid, cysteine, methionine, red pepper tincture, benzyl
nicotinate, D,L--menthol, peppermint oil, calcium pantothenate,
panthenol, castor oil, prednisolone, resorcinol, chemical activators
of protein kinase C, glycosaminoglycan chain cellular uptake inhibitors,
inhibitors of glycosidase activity, glycosaminoglycanase inhibitors,
esters of pyroglutarylic acid, hexosaccharic acids or acylated hexosaccharic
acids, aryl-substituted ethylenes, N-acylated amino acids, flavinoids,
ascomycin derivatives and analogs, histamine antagonists such as
diphenhydramine hydrochloride, triterpenes such as oleanolic acid
and ursolic acid and those described in U.S. Pat. Ser. Nos. 5,529,769,
5,468,888, 5,631,282, and 5,679,705, JP 10017431, WO 95/35103, JP
09067253, WO 92/09262, JP 62093215, and JP 08193094; saponins such
as those described in EP 0,558,509 to Bonte et al., published Sep.
8, 1993 and WO 97/01346 to Bonte et al, published Jan. 16, 1997,
proteoglycanase or glycosaminoglycanase inhibitors such as those
described in U.S. Pat. Ser. Nos. 5,015,470, 5,300,284, and 5,185,325,
estrogen agonists and antagonists, pseudoterins, cytokine and growth
factor promoters, analogs or inhibitors such as interleukin1 inhibitors,
interleukin-6 inhibitors, interleukin-10 promoters, and tumor necrosis
factor inhibitors, vitamins such as vitamin D analogs and parathyroid
hormone antagonists, Vitamin B 12 analogs and panthenol, interferon
agonists and antagonists, hydroxyacids such as those described in
U.S. Pat. No. 5,550,158, benzophenones, and hydantoin anticonvulsants
such as phenytoin, and combinations thereof.
[0136] Other additional hair growth stimulants are described in
JP 09-157,139 to Tsuji et al., published Jun. 17, 1997; EP 0277455
A1 to Mirabeau, published Aug. 10, 1988; WO 97/05887 to Cabo Soler
et al., published Feb. 20, 1997; WO 92/16186 to Bonte et al., published
Mar. 13, 1992; JP 62-93215 to Okazaki et al., published Apr. 28,
1987; U.S. Pat. No. 4,987,150 to Kurono et al., issued Jan. 22,
1991; JP 290811 to Ohba et al., published Oct. 15, 1992; JP 05-286,835
to Tanaka et al., published Nov. 2, 1993, FR 2,723,313 to Greff,
published Aug. 2, 1994, U.S. Pat. No. 5,015,470 to Gibson, issued
May 14, 1991, U.S. Pat. No. 5,559,092, issued Sep. 24, 1996, U.S.
Pat. No. 5,536,751, issued Jul. 16, 1996, U.S. Pat. No. 5,714,515,
issued Feb. 3, 1998, EPA 0,319,991, published Jun. 14, 1989, EPA
0,357,630, published Oct. 6, 1988, EPA 0,573,253, published Dec.
8, 1993, JP 61-260010, published Nov. 18, 1986, U.S. Pat. No. 5,772,990,
issued Jun. 30, 1998, U.S. Pat. No. 5,053, 410, issued Oct. 1, 1991,
and U.S. Pat. No. 4,761,401, issued Aug. 2, 1988.
[0137] The most preferred activity enhancers are minoxidil and
finasteride, most preferably minoxidil.
[0138] Component ii) is a penetration enhancer that can be added
to all of the compositions for systemic administration. The amount
of component ii), when present in the composition, is typically
1 to 5%. Examples of penetration enhancers include 2-methyl propan-2-ol,
propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-diol, polyoxyethylene(2)
ethyl ether, di(2-hydroxypropyl) ether, pentan-2,4-diol, acetone,
polyoxyethylene(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, polyoxyethylene 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, isopropyl palmitate,
ethyl laurate, 2-ethyl-hexyl pelargonate, isopropyl 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, 1-dodecylazacyloheptan-2-one, omega three fatty
acids and fish oils, and combinations thereof.
[0139] In a preferred embodiment of the invention, the PGF's are
topically administered. Topical compositions that can be applied
locally to the skin may be in any form including solutions, oils,
creams, ointments, gels, lotions, shampoos, leave-on and rinse-out
hair conditioners, milks, cleansers, moisturizers, sprays, skin
patches, and the like. Topical compositions comprise: component
A) the PGF described above and component B) a carrier. The carrier
of the topical composition preferably aids penetration of the PGF's
into the skin to reach the environment of the hair follicle. Topical
compositions preferably further comprise C) one or more of the optional
activity enhancers described above.
[0140] The exact amounts of each component in the topical composition
depend on various factors. The amount of component A) depends on
the IC.sub.50 of the PGF selected. "IC.sub.50" means inhibitory
concentration 50.sup.th percentile. The amount of component A) added
to the topical composition is:
IC.sub.50.times.10.sup.-2.gtoreq.% of component A).gtoreq.IC.sub.50.times.-
10.sup.-3,
[0141] where IC.sub.50 is expressed in nanomolar units. For example,
if the IC.sub.50 of the PGF is 1 nM, the amount of component A)
will be 0.001 to 0.01%. If the IC.sub.50 of the PGF is 10 nM, the
amount of component A) will be 0.01 to 0.1%. If the IC.sub.50 of
the PGF is 100 nM, the amount of component A) will be 0.1 to 1.0%.
If the IC.sub.50 of the PGF is 1000 nM, the amount of component
A) will be 1.0 to 10%, preferably 1.0 to 5%. If the amount of component
A) is outside the ranges specified above (i.e., either higher or
lower), efficacy of the treatment may be reduced. IC.sub.50 can
be calculated according to the method in Reference Example 1, below.
One skilled in the art can calculate IC.sub.50 without undue experimentation.
[0142] The topical composition preferably further comprises 1 to
20% component C), and a sufficient amount of component B) such that
the amounts of components A), B), and C), combined equal 100%. The
amount of B) the carrier employed in conjunction with the PGF is
sufficient to provide a practical quantity of composition for administration
per unit dose of the compound. Techniques and compositions for making
dosage forms useful in the methods of this invention are described
in the following references: Modern Pharmaceutics, Chapters 9 and
10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical
Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical
Dosage Forms, 2.sup.nd Ed., (1976).
[0143] Component B) the carrier may comprise a single ingredient
or a combination of two or more ingredients. In the topical compositions,
component B) is a topical carrier. Preferred topical carriers comprise
one or more ingredients selected from the group consisting of water,
alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils,
mineral oil, propylene glycol, polypropylene glycol-2 myristyl propionate,
dimethyl isosorbide, combinations thereof, and the like. More preferred
carriers include propylene glycol, dimethyl isosorbide, and water.
[0144] The topical carrier may comprise one or more ingredients
selected from the group consisting of q) emollients, r) propellants,
s) solvents, t) humectants, u) thickeners, v) powders, and w) fragrances
in addition to, or instead of, the preferred topical carrier ingredients
listed above. One skilled in the art would be able to optimize carrier
ingredients for the topical compositions without undue experimentation.
[0145] Ingredient q) is an emollient. The amount of ingredient
q) in the topical composition is typically 5 to 95%. Suitable emollients
include 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, 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, petrolatum,
mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl
linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl
myristate, polydimethylsiloxane, and combinations thereof. Preferred
emollients include stearyl alcohol and polydimethylsiloxane.
[0146] Ingredient r) is a propellant. The amount of ingredient
r) in the topical composition is typically 5 to 95%. Suitable propellants
include propane, butane, isobutane, dimethyl ether, carbon dioxide,
nitrous oxide, and combinations thereof.
[0147] Ingredient s) is a solvent. The amount of ingredient s)
in the topical composition is typically 5 to 95%. Suitable solvents
include water, ethyl alcohol, methylene chloride, isopropanol, castor
oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl
ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl
formamide, tetrahydrofuran, and combinations thereof. Preferred
solvents include ethyl alcohol.
[0148] Ingredient t) is a humectant. The amount of ingredient t)
in the topical composition is typically 5 to 95%. Suitable humectants
include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate,
soluble collagen, dibutyl phthalate, gelatin, and combinations thereof.
Preferred humectants include glycerin.
[0149] Ingredient u) is a thickener. The amount of ingredient u)
in the topical composition is typically 0 to 95%.
[0150] Ingredient v) is a powder. The amount of ingredient v) in
the topical composition is typically 0 to 95%. Suitable powders
include chalk, talc, fullers earth, kaolin, starch, gums, colloidal
silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites,
trialkyl aryl ammonium smectites, chemically modified magnesium
aluminum silicate, organically modified montmorillonite clay, hydrated
aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl
cellulose, ethylene glycol monostearate, and combinations thereof.
[0151] Ingredient w) is a fragrance. The amount of ingredient w)
in the topical composition is typically 0.001 to 0.5%, preferably
0.001 to 0.1%.
[0152] Component C) the optional activity enhancer is as described
above. Any of the i) hair growth stimulants and ii) penetration
enhancers may be added to the topical compositions. Preferably,
the topical composition comprises 0.01 to 15% of component i) the
optional hair growth stimulant. More preferably, the composition
comprises 0.1 to 10%, and most preferably 0.5 to 5% of component
i). Preferably, the topical composition comprises 1 to 5% of component
ii).
[0153] In an alternative embodiment of the invention, topical pharmaceutical
compositions for ocular administration are prepared by conventional
methods. Topical pharmaceutical compositions for ocular administration
typically comprise A) a PGF, B) a carrier, such as purified water,
and one or more ingredients selected from the group consisting of
y) sugars such as dextrans, particularly dextran 70, z) cellulose
or a derivative thereof, aa) a salt, bb) disodium EDTA (Edetate
disodium), and cc) a pH adjusting additive.
[0154] Examples of z) cellulose derivatives suitable for use in
the topical pharmaceutical composition for ocular administration
include sodium carboxymethyl cellulose, ethyl cellulose, methyl
cellulose, and hydroxypropylmethylcellulose. Hydroxypropylmethylcellulose
is preferred.
[0155] Examples of aa) salts suitable for use in the for use in
the topical pharmaceutical composition for ocular administration
include sodium chloride, potassium chloride, and combinations thereof.
[0156] Examples of cc) pH adjusting additives include HCl or NaOH
in amounts sufficient to adjust the pH of the topical pharmaceutical
composition for ocular administration to 7.2-7.5.
[0157] This invention further relates to a method for darkening
hair, thickening hair, and reversing hair graying. The method comprises
applying the topical composition for treating hair loss to hair,
to skin in the locus of hair, or both. For example, the topical
composition may be applied to hair growing on the scalp or eyelashe |