U.S. patent application number 14/175356 was filed with the patent office on 2014-06-19 for composition and method for promoting hair growth.
This patent application is currently assigned to R-Tech Ueno, Ltd.. The applicant listed for this patent is R-Tech Ueno, Ltd.. Invention is credited to Tsuyoshi HABE, Takashi SEKIDA, Ryuji UENO.
Application Number | 20140171496 14/175356 |
Document ID | / |
Family ID | 34135320 |
Filed Date | 2014-06-19 |
United States Patent
Application |
20140171496 |
Kind Code |
A1 |
UENO; Ryuji ; et
al. |
June 19, 2014 |
COMPOSITION AND METHOD FOR PROMOTING HAIR GROWTH
Abstract
The present invention provides a method and composition for
promoting hair growth in a mammal which comprises a prostaglandin
compound having two hetero atoms at the 15 position as an active
ingredient thereof.
Inventors: |
UENO; Ryuji; (Potomac,
MD) ; HABE; Tsuyoshi; (Sasayama-shi, JP) ;
SEKIDA; Takashi; (Nishinomiya-shi, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
R-Tech Ueno, Ltd. |
Tokyo-to |
|
JP |
|
|
Assignee: |
R-Tech Ueno, Ltd.
Tokyo-to
JP
|
Family ID: |
34135320 |
Appl. No.: |
14/175356 |
Filed: |
February 7, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10567462 |
Feb 5, 2007 |
8686035 |
|
|
PCT/JP2004/011864 |
Aug 12, 2004 |
|
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14175356 |
|
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60494121 |
Aug 12, 2003 |
|
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Current U.S.
Class: |
514/452 ;
514/530 |
Current CPC
Class: |
A61K 8/37 20130101; A61Q
7/00 20130101; C07D 317/30 20130101; C07C 405/00 20130101; A61P
17/14 20180101; A61P 17/00 20180101; A61K 31/357 20130101; A61K
8/4973 20130101; A61K 31/22 20130101; A61K 8/498 20130101; C07D
319/06 20130101 |
Class at
Publication: |
514/452 ;
514/530 |
International
Class: |
A61K 8/49 20060101
A61K008/49; A61Q 7/00 20060101 A61Q007/00; A61K 8/37 20060101
A61K008/37 |
Claims
1. A method for promoting hair growth in a mammalian subject,
comprising administering an effective amount of a prostaglandin
compound as shown by the following formula (I): ##STR00008##
wherein L, M and N are hydrogen, hydroxy, halogen, lower alkyl,
hydroxy(lower)alkyl, lower alkanoyloxy or oxo, wherein at least one
of L and M is a group other than hydrogen, and the five-membered
ring may have at least one double bond; A is --CH.sub.3, or
--CH.sub.2OH, --COCH.sub.2OH, --COOH or a functional derivative
thereof; B is --CH.sub.2--CH.sub.2--, --CH.ident.CH-- or Z.sub.1
and Z.sub.2 are oxygen, nitrogen or sulfur; R.sub.2 and R.sub.3 are
lower alkyl, which are optionally linked together to form lower
alkylene; R.sub.1 is a saturated or unsaturated bivalent lower or
medium aliphatic hydrocarbon residue, which is unsubstituted or
substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocyclic
group, and at least one of carbon atom in the aliphatic hydrocarbon
is optionally substituted by oxygen, nitrogen or sulfur; and Ra is
a saturated or unsaturated lower or medium aliphatic hydrocarbon,
which is unsubstituted or substituted with halogen, oxo, hydroxy,
lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl,
cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic group or
heterocyclic-oxy group; lower alkoxy; lower alkanoyloxy;
cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl; aryloxy;
heterocyclic group; heterocyclic-oxy group.
2. The method as described in claim 1, wherein the prostaglandin
compound is represented by the formula (II): ##STR00009## wherein
L, M, A, B, Z.sub.1, Z.sub.2, R.sub.1, R.sub.2 and R.sub.3 are the
same as claim 1, X.sub.1 and X.sub.2 are hydrogen, lower alkyl, or
halogen; R.sub.4 is a single bond or lower alkylene; and R.sub.5 is
lower alkyl, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl,
cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic group or
heterocyclic-oxy group.
3. The method as described in claim 1, wherein said prostaglandin
compound is
13,14-dihydro-15,15-ethylenedioxy-20-ethyl-PGF.sub.2.alpha.
isopropyl ester.
4. The method as described in claim 1, wherein said prostaglandin
compound is
13,14-dihydro-15,15-ethylenedioxy-17-phenyl-18,19,20-trinor-PGF.sub.2.alp-
ha. isopropyl ester.
5. The method as described in claim 1, wherein said prostaglandin
compound is
13,14-dihydro-15,15-trimethylenedioxy-20-ethyl-PGF.sub.2.alpha.
isopropyl ester.
6. The method as described in claim 1, wherein said prostaglandin
compound is 13,14-dihydro-15,15-dimethoxy-20-ethyl-PGF.sub.2.alpha.
isopropyl ester.
7. The method as described in claim 1, wherein said prostaglandin
compound is
13,14-dihydro-15,15-ethylenedioxy-20-ethyl-PGF.sub.2.alpha. ethyl
ester.
8. The method as described in claim 1, wherein the hair is selected
from hair on the top of head, hair on armpits, hair on pubic area,
eyelash, eyebrow, hair on eyelid, mustache, beard, hair on chest,
hair on arms and hair on legs.
9. The method as described in claim 8, wherein the hair is selected
from hair on scalp, beard, hair on head, hair on pubic area, hair
on upper lip, eyelash, eyebrow, and hair on eyelid.
10. The method as described in claim 8, wherein the hair is hair on
scalp.
11. The method as described in claim 8, wherein the hair is
eyelash.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is application is a continuation of application Ser.
No. 10/567,462 filed Feb. 7, 2006, which is a National Stage of
PCT/JP2004/011864 filed Aug. 12, 2004, which claims benefit of U.S.
Provisional Application No. 60/494,121 filed Aug. 12, 2003. The
disclosure of application Ser. No. 10/567,462 is incorporated
herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to a composition and method
for promoting hair growth in a mammalian subject.
BACKGROUND ART
[0003] Hair loss or alopecia may result from genetic factors,
aging, local or systemic disease or certain therapeutic drugs
designed to alleviate conditions such as cancer. Various
preparations for preventing or reducing hair loss and/or promoting
hair growth are proposed, for example those containing female
hormones which can promote blood circulation, reinforce hair root
function, moisturize scalp and inhibit male hormone function;
5.alpha.-reductase inhibitors; or minoxdil, trichosaccharides or
the like as main ingredients. However, they cannot show
satisfactory hair growth-promoting effects, and some may raise
side-effect problems such as sexual function disorder.
[0004] It is strongly desired to develop a hair growth-promoting
agent having superior effects without side effect.
[0005] Prostaglandins (hereinafter, referred to as PG(s)) are
members of class of organic carboxylic acids, which are contained
in tissues or organs of human or other mammals, and exhibit a wide
range of physiological activity. PGs found in nature (primary PGs)
generally have a prostanoic acid skeleton as shown in the formula
(Al:
##STR00001##
[0006] On the other hand, some of synthetic analogues of primary
PGs have modified skeletons. The primary PGs are classified to
PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs
according to the structure of the five-membered ring moiety, and
further classified into the following three types by the number and
position of the unsaturated bond at the carbon chain moiety:
[0007] Subscript 1: 13,14-unsaturated.-15-OH
[0008] Subscript 2: 5,6- and 13,14-diunsaturated-15-OH
[0009] Subscript 3: 5,6-, 13,14-, and
17,18-triunsaturated-15-OH.
[0010] Further, the PGFs are classified, according to the
configuration of the hydroxyl group at the 9- and 11-position, into
.alpha. type (the hydroxyl group is of an .alpha.-configuration)
and .beta. type (the hydroxyl group is of a
.beta.-configuration).
[0011] Certain prostaglandin compound having two hetero atoms at
the 15 position are known in the art. U.S. Pat. No. 4,088,775
discloses certain 15-ethylenedioxy-prostanoic acid. In addition,
U.S. Pat. No. 4,870,104 discloses 11 halo prostaglandins which may
have an ethylenedioxymethylene group at 15-position and use thereof
as agents inhibiting gastric acid secretion. Further, U.S. Pat. No.
6,353,014 discloses a certain 15-ketal analogs of F series
prostaglandins useful for treating ocular hypertension and
glaucoma.
[0012] Those prior arts do not disclose nor suggest that
prostaglandin compound having two hetero atoms at the 15 position
may be useful in the stimulation of hair growth.
DISCLOSURE OF THE INVENTION
[0013] An object of the present invention is to provide a
composition for promoting hair growth in a mammalian subject.
[0014] Further object of the present invention is to provide a
method for promoting hair growth in a mammalian subject.
[0015] Still further object of the present invention is to provide
a novel compound useful for promoting hair growth in a mammalian
subject.
[0016] Namely, the present invention relates to a composition for
promoting hair growth in a mammalian subject which comprises a
prostaglandin compound having two hetero atoms at the 15 position
as an active ingredient thereof.
[0017] Further, the present invention relates to a method for
promoting hair growth in a mammalian subject, which comprises
topically administering a prostaglandin compound having two hetero
atoms at the 15 position to the subject in need thereof.
[0018] Furthermore, the present invention relates to use of a
prostaglandin compound having two hetero atoms at the 15 position
for manufacturing a composition for promoting hair growth in a
mammalian subject.
[0019] Still further, the present invention relates to a novel
prostaglandin compound having two hetero atoms at the 15
position.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The nomenclature of the PG compounds used herein is based on
the numbering system of the prostanoic acid represented in the
above formula (A).
[0021] The formula (A) shows a basic skeleton of the C-20 carbon
atoms, but the present invention is not limited to those having the
same number of carbon atoms. In the formula (A), the numbering of
the carbon atoms which constitute the basic skeleton of the PG
compounds starts at the carboxylic acid (numbered 1), and carbon
atoms in the .alpha.-chain are numbered 2 to 7 towards the
five-membered ring, those in the ring are 8 to 12, and those in the
.omega.-chain are 13 to 20. When the number of carbon atoms is
decreased in the .alpha.-chain, the number is deleted in the order
starting from position 2; and when the number of carbon atoms is
increased in the .alpha.-chain, compounds are named as substitution
compounds having respective substituents at position 2 in place of
the carboxy group (C-1). Similarly, when the number of carbon atoms
is decreased in the .omega.-chain, the number is deleted in the
order starting from position 20; and when the number of carbon
atoms is increased in the .omega.-chain, the carbon atoms beyond
position 20 are named as substituents. Stereochemistry of the
compounds is the same as that of the above formula (A) unless
otherwise specified.
[0022] In general, each of the terms PGD, PGE and PGF represents a
PG compound having hydroxy groups at positions 9 and/or 11, but in
the present specification, these terms also include those having
substituents other than the hydroxy group at positions 9 and/or 11.
Such compounds are referred to as 9-dehydroxy- 9-substituted-PG
compounds or 11-dehydroxy-11-substituted-PG compounds. A PG
compound having hydrogen in place of the hydroxy group is simply
named as 9- or 11-dehydroxy-PG compound.
[0023] As stated above, the nomenclature of the PG compounds is
based on the prostanoic acid skeleton. However, in case the
compound has a similar partial structure as a prostaglandin, the
abbreviation of "PG" may be used. Thus, a PG compound of which
.alpha.-chain is extended by two carbon atoms, that is, having 9
carbon atoms in the .alpha.-chain is named as
2-decarboxy-2-(2-carboxyethyl)-PG compound. Similarly, a PG
compound having 11 carbon atoms in the .alpha.-chain is named as
2-decarboxy-2-(4-carboxybutyl)-PG compound. Further, a PG compound
of which .omega.-chain is extended by two carbon atoms, that is,
having 10 carbon atoms in the .omega.-chain is named as 20-ethyl-PG
compound. These compounds; however, may also be named according to
the IUPAC nomenclatures.
[0024] Examples of the analogs (including substituted derivatives)
or derivatives include a PG compound of which carboxyl group at the
end of .alpha.-chain is esterified; a compound of which
.alpha.-chain is extended; physiologically acceptable salt thereof;
a compound having a double bond at 2-3 position or a triple bond at
position 5-6, a compound having substituent(s) at position 3, 5, 6,
16, 17, 18, 19 and/or 20; and a compound having lower alkyl or a
hydroxy (lower) alkyl group at position 9 and/or 11 in place of the
hydroxy group.
[0025] According to the present invention, preferred substituents
at position 3, 17, 18 and/or 19 include alkyl having 1-4 carbon
atoms, especially methyl and ethyl. Preferred substituents at
position 16 include lower alkyl such as methyl and ethyl, hydroxy,
halogen atoms such as trifluoromethylphenoxy. Preferred
substituents at position 17 include lower alkyl such as methyl and
ethyl, hydroxy, halogen atoms such as chlorine and fluorine,
aryloxy such as trifluoromethylphenoxy. Preferred substituents at
position 20 include saturated or unsaturated lower alkyl such as
C1-4 alkyl, lower alkoxy such as C1-4 alkoxy, and lower alkoxy
alkyl such as C1-4 alkoxy-C1-4 alkyl. Preferred substituents at
position 5 include halogen atoms such as chlorine and fluorine.
Preferred substituents at position 6 include an oxo group forming a
carbonyl group. Stereochemistry of PGs having hydroxy, lower alkyl
or hydroxy{lower}alkyl substituent at position 9 and/or 11 may be
.alpha., .beta. or a mixture thereof.
[0026] Further, the above analogs or derivatives may be compounds
having an alkoxy, cycloalkyl, cycloalkyloxy, phenoxy or phenyl
group at the end of the .omega.-chain where the chain is shorter
than the primary PGs.
[0027] A preferred prostaglandin compound used in the present
invention is represented by formula (I):
##STR00002##
[0028] wherein L, M and N are hydrogen, hydroxy, halogen, lower
alkyl, hydroxy(lower)alkyl, lower alkanoyloxy or oxo, wherein at
least one of L and M is a group other than hydrogen, and the
five-membered ring may have at least one double bond;
[0029] A is --CH.sub.3, or --CH.sub.2OH, --COCH.sub.2OH, --COON or
a functional derivative thereof;
[0030] B is --CH.sub.2--CH.sub.2--, --CH.dbd.CH-- or
--.ident.C--;
[0031] Z.sub.1 and Z.sub.2 are oxygen, nitrogen or sulfur,
[0032] R.sub.2 and R.sub.3 are optionally substituted lower alkyl,
which is optionally linked together to form lower alkylene,
[0033] R.sub.1 is a saturated or unsaturated bivalent lower or
medium aliphatic hydrocarbon residue, which is unsubstituted or
substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocyclic
group, and at least one of carbon atom in the aliphatic hydrocarbon
is optionally substituted by oxygen, nitrogen or sulfur; and
[0034] Ra is a saturated or unsaturated lower or medium aliphatic
hydrocarbon residue, which is unsubstituted or substituted with
halogen, oxo, hydroxy, lower alkoxy, lower alkanoyloxy,
cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy,
heterocyclic group or hetrocyclic-oxy group; lower alkoxy; lower
alkanoyloxy; cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl;
aryloxy; heterocyclic group; heterocyclic-oxy group.
[0035] A more preferred prostaglandin compound used in the present
invention is represented by the formula (II):
##STR00003##
[0036] wherein L and M are hydrogen, hydroxy, halogen, lower alkyl,
hydroxy(lower)alkyl, lower alkanoyloxy or oxo, wherein at least one
of L and M is a group other than hydrogen, and the five-membered
ring may have one or more double bonds;
[0037] A is --CH.sub.3, or --CH.sub.2OH, --COCH.sub.2OH, --COOH or
a functional derivative thereof;
[0038] B is --CH.sub.2--CH.sub.2--, --CH.dbd.CH-- or
--C.ident.--;
[0039] Z.sub.1 and Z.sub.2 are oxygen, nitrogen or sulfur,
[0040] R.sub.2 and R.sub.3 are optionally substituted lower alkyl,
which is optionally linked together to form lower alkylene,
[0041] X.sub.1 and X.sub.2 are hydrogen, lower alkyl, or
halogen;
[0042] R.sub.1 is a saturated or unsaturated bivalent lower or
medium aliphatic hydrocarbon residue, which is unsubstituted or
substituted with halogen, alkyl, hydroxy, oxo, aryl or heterocyclic
group, and at least one of carbon atom in the aliphatic hydrocarbon
is optionally substituted by oxygen, nitrogen or sulfur;
[0043] R.sub.4 is a single bond or lower alkylene; and
[0044] R.sub.5 is lower alkyl, lower alkoxy, lower alkanoyloxy,
cyclo(lower)alkyl, cyclo (lower) alkyloxy, aryl, aryloxy,
heterocyclic group or heterocyclic-oxy group.
[0045] In the above formula, the term "unsaturated" in the
definitions for R.sub.1 and Ra is intended to include at least one
or more double bonds and/or triple bonds that are isolatedly,
separately or serially present between carbon atoms of the main
and/or side chains. According to the usual nomenclature, an
unsaturated bond between two serial positions is represented by
denoting the lower number of the two positions, and an unsaturated
bond between two distal positions is represented by denoting both
of the positions.
[0046] The term "lower or medium aliphatic hydrocarbon" refers to a
straight or branched chain hydrocarbon group having 1 to 14 carbon
atoms (for a side chain, 1 to 3 carbon atoms are preferable) and
preferably 1 to 10, especially 1 to 8 carbon atoms.
[0047] The term "halogen atom" covers fluorine, chlorine, bromine
and iodine.
[0048] The term "lower" throughout the specification is intended to
include a group having 1 to 6 carbon atoms unless otherwise
specified.
[0049] The term "lower alkyl" refers to a straight or branched
chain saturated hydrocarbon group containing 1 to 6 carbon atoms
and includes, for example, methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, t-butyl, pentyl and hexyl.
[0050] The term "lower alkylene" refers to a straight or branched
chain bivalent saturated hydrocarbon group containing 1 to 6 carbon
atoms and includes, for example, methylene, ethylene, propylene,
isopropylene, butylene, isobutylene, t-butylene, pentylene and
hexylene.
[0051] The term "lower alkoxy" refers to a group of lower
alkyl-O--, wherein lower alkyl is as defined above.
[0052] The term "hydroxy(lower)alkyl" refers to a lower alkyl as
defined above which is substituted with at least one hydroxy group
such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and
1-methyl-1-hydroxyethyl.
[0053] The term "lower alkanoyloxy" refers to a group represented
by the formula RCO--O--, wherein RCO-- is an acyl group formed by
oxidation of a lower alkyl group as defined above, such as
acetyl.
[0054] The term "cyclo(lower)alkyl" refers to a cyclic group formed
by cyclization of a lower alkyl group as defined above but contains
three or more carbon atoms, and includes, for example, cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl.
[0055] The term "cyclo(lower)alkyloxy" refers to the group of
cyclo(lower)alkyl-O--, wherein cyclo(lower)alkyl is as defined
above.
[0056] The term "aryl" may include unsubstituted or substituted
aromatic hydrocarbon rings (preferably monocyclic groups), for
example, phenyl, tolyl,
[0057] Examples of the substituents are halogen atom and
halo(lower)alkyl, wherein halogen atom and lower alkyl are as
defined above.
[0058] The term "aryloxy" refers to a group represented by the
formula ArO--, wherein Ax is aryl as defined above.
[0059] The term "heterocyclic group" may include mono- to
tri-cyclic, preferably monocyclic heterocyclic group which is 5 to
14, preferably 5 to 10 membered ring having optionally substituted
carbon atom and 1 to 4, preferably 1 to 3 of 1 or 2 type of hetero
atoms selected from nitrogen atom, oxygen atom and sulfur atom.
Examples of the heterocyclic group include furyl, thienyl,
pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl,
pyrimidyl, pyrazinyl, 2-pyrrolinyl, pyrrolidinyl, 2-imidazolinyl,
imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidino,
piperazinyl, morpholino, indolyl, benzothienyl, quinolyl,
isoquinolyl, purinyl, quinazolinyl, carbazolyl, acridinyl,
phenanthridinyl, benzimidazolyl, benzimidazolinyl, benzothiazolyl,
phenothiazinyl. Examples of the substituent in this case include
halogen, and halogen substituted lower alkyl group, wherein halogen
atom and lower alkyl group are as described above.
[0060] The term "heterocyclic-oxy group" means a group represented
by the formula HcO--, wherein Hc is a heterocyclic group as
described above.
[0061] The term "functional derivative" of A includes salts
(preferably pharmaceutically acceptable salts), ethers, esters and
amides.
[0062] Suitable "pharmaceutically acceptable salts" include
conventionally used non-toxic salts, for example a salt with an
inorganic base such as an alkali metal salt (such as sodium salt
and potassium salt), an alkaline earth metal salt (such as calcium
salt and magnesium salt), an ammonium salt; or a salt with an
organic base, for example, an amine salt (such as methylamine salt,
dimethylamine salt, cyclohexylamine salt, benzylamine salt,
piperidine salt, ethylenediamine salt, ethanolamine salt,
diethanolamine salt, triethanolamine salt,
tris(hydroxymethylamino)ethane salt, monomethyl-monoethanolamine
salt, procaine salt and caffeine salt), a basic amino acid salt
(such as arginine salt and lysine salt), tetraalkyl ammonium salt
and the like. These salts may be prepared by a conventional
process, for example from the corresponding acid and base or by
salt interchange.
[0063] Examples of the ethers include alkyl ethers, for example,
lower alkyl ethers such as methyl ether, ethyl ether, propyl ether,
isopropyl ether, butyl ether, isobutyl ether, t-butyl ether,
-pentyl ether and 1-cyclopropyl ethyl ether; and medium or higher
alkyl ethers such as octyl ether, diethylhexyl ether, lauryl ether
and cetyl ether; unsaturated ethers such as oleyl ether and
linolenyl ether; lower alkenyl ethers such as vinyl ether, allyl
ether; lower alkynyl ethers such as ethynyl ether and propynyl
ether; hydroxy(lower)alkyl ethers such as hydroxyethyl ether and
hydroxyisopropyl ether; lower alkoxy (lower)alkyl ethers such as
methoxymethyl ether and 1-methoxyethyl ether; optionally
substituted aryl ethers such as phenyl ether, tosyl ether,
t-butylphenyl ether, salicyl ether, 3,4-di-methoxyphenyl ether and
benzamidophenyl ether; and aryl(lower)alkyl ethers such as benzyl
ether, trityl ether and benzhydryl ether.
[0064] Examples of the esters include aliphatic esters, for
example, lower alkyl esters such as methyl ester, ethyl ester,
propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl
ester, pentyl ester and 1-cyclopropylethyl ester; lower alkenyl
esters such as vinyl ester and allyl ester; lower alkynyl esters
such as ethynyl ester and propynyl ester; hydroxy(lower)alkyl ester
such as hydroxyethyl ester; lower alkoxy (lower) alkyl esters such
as methoxymethyl ester and 1-methoxyethyl ester; and optionally
substituted aryl esters such as, for example, phenyl ester, tolyl
ester, t-butylphenyl ester, salicyl ester, 3,4-di-methoxyphenyl
ester and benzamidophenyl ester; and aryl(lower)alkyl ester such as
benzyl ester, trityl ester and benzhydryl ester.
[0065] The amide of A mean a group represented by the formula
--CONR'R'', wherein each of R' and R'' is hydrogen, lower alkyl,
aryl, alkyl- or aryl-sulfonyl, lower alkenyl and lower alkynyl, and
include for example lower alkyl amides such as methylamide,
ethylamide, dimethylamide and diethylamide; arylamides such as
anilide and toluidide; and alkyl- or aryl-sulfonylamides such as
methylsulfonylamide, ethylsulfonyl-amide and
tolylsulfonylamide.
[0066] Preferred examples of L and M include hydroxy and oxo, and
especially, M and L are hydroxy groups which has a 5-membered ring
structure of, so called, PGF type.
[0067] Preferred example of A is --COON, its pharmaceutically
acceptable salt, ester or amide thereof.
[0068] Preferred B is --CH.sub.2--CH.sub.2--, so called
13,14-dihydro type.
[0069] Preferred example of X.sub.1 and X.sub.2 is fluorine, so
called 16,16-difluoro type.
[0070] Preferred R.sub.1 is a hydrocarbon residue containing 1-10
carbon atoms, preferably 6-10 carbon atoms. Further, at least one
carbon atom in the aliphatic hydrocarbon is optionally substituted
by oxygen, nitrogen or sulfur.
[0071] Examples of R.sub.1 include, for example, the following
groups: [0072]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0073] --CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--,
[0074] --CH.sub.2--CH.sub.3--CH.sub.2--CH.sub.2--CH.dbd.CH--,
[0075] --CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--,
[0076] --CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--O--CH.sub.2--,
[0077] --CH.sub.2--CH.dbd.CH--CH.sub.2--O--CH.sub.2, [0078]
--CH.sub.2--C.ident.C--CH.sub.2--O--CH.sub.2--, [0079]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2,
[0080]
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0081]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.dbd.CH--,
[0082]
--CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
[0083]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH(CH.sub.3)---
CH.sub.2--, [0084]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2CH(CH.sub.3)--CH.sub.2--,
[0085]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--C-
H.sub.2--, [0086]
--CH.sub.2--CH.dbd.CH--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2---
, [0087]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.-
dbd.CH--, [0088]
--CH.sub.2--C.ident.C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2---
, and [0089]
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH(CH.sub.3-
)--CH.sub.2--.
[0090] Preferred Ra is a hydrocarbon containing 1-10 carbon atoms,
more preferably, 1-8 carbon atoms. Ra may have one or two side
chains having one carbon atom.
[0091] Preferred Z.sub.1 and Z.sub.2 are oxygen.
[0092] R.sub.2 and R.sub.3 are preferably linked together to form
C2 or C3 alkylene.
[0093] The configuration of the ring and the .alpha.- and/or
.omega. chains in the above formula (I) and (II) may be the same as
or different from that of the primary PGs. However, the present
invention also includes a mixture of a compound having a primary
type configuration and a compound of a non-primary type
configuration.
[0094] In the present invention, any of isomers such as the
individual tautomeric isomers, the mixture thereof, or optical
isomers, the mixture thereof, a racemic mixture, and other steric
isomers may be used in the same purpose.
[0095] According to the present invention, a composition for
promoting hair growth comprising the prostaglandin compound defined
as above as an active ingredient is applied to a mammalian subject
in need of promotion of hair growth.
[0096] The term "hair" in the present specification and claims
covers any hair on a mammalian subject, especially a human subject,
for example, hairs on the top of the head, on the armpits, on the
pubic area, on the face including eyelash, eyebrow, eyelid,
mustache, beard and whisker, on the chest, arms and legs.
[0097] The term "promoting hair growth" in the present
specification and claims covers not only promoting hair growth but
also promoting hair germination and thickening hairs. As is shown
in the examples below, the composition of the present invention has
the effect of thickening the growing hair in addition to the
promotion of hair growth.
[0098] According to the present invention, the composition may be
provided as, for example, pharmaceuticals, quasi-drugs (i.e.
iyakubugaihin in Japanese) or cosmetics. The composition may
topically be applied for the purpose of promoting hair growth onto
the surface of skin where hair growth is desired, such as scalp,
face, beard, head, pubic area, upper lip, eyelash, eyebrow, and
eyelid.
[0099] The dose of the prostaglandin compound in the composition of
the present invention may vary according to the compound to be
used, the type of subject, age, skin area to be applied the
composition, progress of baldness or desired effect, administration
volume and period for treatment. Although a suitable concentration
may be chosen as desired, in a typical case wherein the composition
is topically administrated to an adult, the formulation containing
0.0000001%-10%, preferably 0.00001%-5%, more preferably 0.0001%-1%
and especially 0.001-0.1% of .the active ingredient can be applied
1-6 times, preferably 1-4 times per day.
[0100] The dosage form of the composition of the .present invention
can be any of known topically applicable forms. For example, but
not limited thereto, lotion, tonic, emulsion, external drug creams
such as liniments and milky lotions, external semi-solid
preparations such as ointments, paste, jelly and sprays. The
composition may also be formulated as hair shampoos or hair
rinses.
[0101] The composition of the present invention may further contain
physiologically acceptable additives. Said additives may include
the ingredients used with the present compounds such as excipient,
diluent, filler, resolvent, lubricant, adjuvant, binder,
disintegrator, emulsifier, dispersing agent, suspending agent,
thickener, tonicity agent, buffering agent, soothing agent,
preservative, antioxidant, corrigent, flavor, colorant, a
functional material such as cyclodextrin and biodegradable polymer,
stabilizer. They may be further dissolved in an appropriate solvent
such as fatty acid or its mono, di or triglyceride. The additives
are well known to the art and may be selected from those described
in general reference books of pharmaceutics or cosmetics.
[0102] The composition of the present invention may further contain
other ingredients as far as they do not contradict the purpose of
the present invention. The composition may be prepared in a
conventional manner for manufacturing the desired formulations by
adding the prostaglandin compound defined as above.
[0103] The further details of the present invention will follow
with reference to test examples, which, however, are not intended
to limit the present invention.
SYNTHESIS EXAMPLE 1
13, 14-dihydro-15,15-trimethylenedioxy-20-ethyl-PGF.sub.2.alpha.
isopropyl ester (5)
##STR00004##
[0105] To the solution of compound 1 (510.0 mg, 1.273 mmol) in
toluene (10.2 ml), 1,3-propanediol (0.92 ml, 12.73 mmol) and a
catalytic amount of p-toluene sulfonic acid were added and the
mixture was heated for 17 hours under reflux. After that, the
reaction was left stood until it was cooled to room temperature,
and washed with saturated aqueous sodium bicarbonate and saturated
aqueous sodium chloride. The organic phase was dried with magnesium
sulfate and evaporated under reduced pressure. The residue was
purified by means of silica gel column chromatography (Merck 7734,
Hexane: ethyl acetate=3:2) to give compound 2 (581.3mg).
[0106] The solution of compound 2 (580.0 mg, 1.265 mmol) in toluene
(11.6 ml) was cooled to -78.degree. C., 1.5M-DIBAH (in toluene,
2.95 ml, 4.427 mmol) was added dropwise thereto and the mixture was
stirred for 1 hour, and then, methanol (1.79 ml) was added dropwise
to the resulting mixture. Saturated aqueous Rochelle salt (100 ml)
was added thereto and the mixture was vigorously stirred for 30
minutes. The resulting mixture was extracted with ethyl acetate,
and the organic layer was washed with saturated salt water, dried
with magnesium sulfate and evaporated under reduced pressure. The
residue was purified by means of silica gel column chromatography
(Merck 7734, Hexane: ethyl acetate=1:9-0:10) to give compound 3
(275.2 mg, yield 61.4% from 1).
[0107] To the dispersion of (4-carboxybuthyl)triphenyl phosphonium
bromide (1.346 g, 3.038 mmol) in THF (6 ml), 1M-potassium
t-butoxide in THF (6.07 ml, 6.07 mmol) at 0.degree. C. was added.
The reaction was stirred for 1 hour at room temperature and then
cooled to -20.degree. C. Compound 3 (269.2 mg, 0.7594 mmol) in THF
(7 ml) was added dropwise thereto and stirred for 2 hours at
-20-0.degree. C. Ice cold water was added to the reaction, THF was
removed by evaporation evaporated under reduced pressure. To the
concentrated residue at 0.degree. C., ice cold 1N aqueous
hydrochloric acid was added dropwise to adjust the solution to pH
4.
[0108] The solution was extracted with ethyl acetate and the
organic layer was washed with saturated aqueous sodium chloride,
dried with magnesium sulfate and evaporated under reduced pressure.
The residue was added with ether and stirred for 17 hours at room
temperature and then, filtrated with celite. The filtrate was
evaporated under reduced pressure to give crude compound 4.
[0109] Compound 4 (0.7594 mmol) in acetonitrile (7.6 ml) was added
with ABU (0.45 ml, 3.038 mmol), isopropyl iodide (0.30 ml, 3.038
mmol) and stirred for 4 hours at 45.degree. C. The reaction mixture
was evaporated under reduced pressure. The residue was added with
water and extracted with ethyl acetate. The organic layer was
washed with saturated aqueous sodium chloride solution, dried with
magnesium sulfate and evaporated under reduced pressure. The
residue was purified by means of silica gel column chromatography
(Merck 9385, hexane:ethyl acetate=2:3) to give 727.2 mg of the
desired product (yield 72.1% from 3). Thus obtained compound 4
(carboxylic acid, 259.0 mg) was further purified by separation HPLC
to give compound 5 (isopropyl ester, 240.3 mg, HPLC purification
yield 92.8%).
[0110] .sup.1H-NMR spectrum (200 MHz, CDCl.sub.3) of compound 5:
.delta.5.57-5.14(2H, m), 5.01(1H, sept, J=6.2 Hz), 4.17(1H, bs),
3.97(1H, bs), 4.00-3.78(4H, m), 2.76(1H, d, J=6.2 Hz), 2.29(2H, t,
J=7.5 Hz), 2.44-2.06 (5H, m,), 1.88(2H, btu), 1.93-1.18(22H, m),
1.23(6H, d, J=6.2 Hz), 0.89(3H, t, J=6.8 Hz)
SYNTHESIS EXAMPLE 2
13,14-dihydro-15,15-dimethoxy-20-ethyl-PGF.sub.2.alpha. isopropyl
ester (10)
##STR00005##
[0112] To the solution of compound 1 (797.8 mg, 2.002 mmol) in
methanol (2.4 ml), a catalytic amount of p-toluene sulfate, methyl
orthoformate(2.19 ml, 20.02 mmol) and anhydrous magnesium sulfate
(1.20 g, 10.01 mmol) were added and heated under reflux for 4
hours. The reaction was cooled and added with sodium hydrogen
carbonate, and filtered with celite. The filtrate was evaporated
under reduced pressure and the residue was purified by means of
silica gel column chromatography (Merck 7734 g, hexane:ethyl
acetate 3:2) to give compound 7 (884.3 mg, yield 98.9%).
[0113] The solution of compound 7 (767.5 mg, 1.719 mmol) in
toluene(15.4 ml) was cooled to -78.degree. C., 1.5M-DIBAH (in
toluene, 4.0 ml, 6.016 mmol) was added dropwise thereto and the
mixture was stirred for 1 hour. Then, methanol was added dropwise
to the reaction and the reaction was heated to room temperature.
Saturated aqueous Rochelle salt (150 ml) was added thereto and the
mixture was vigorously stirred for 30 minutes. The resulting
mixture was extracted with ethyl acetate, and the organic layer was
washed with saturated salt water, dried with magnesium sulfate and
evaporated under reduced pressure. The residue was purified by
means of silica gel column chromatography (Merck 9385, hexane:
ethyl acetate=1:9) to give compound 8 (415.8 mg, yield 70.2%).
[0114] To the dispersion of (4-carboxybuthyl)triphenyl phosphonium
bromide (1.250 g, 2.819 mmol) in THF, 1M-potassium t-butoxide in
THF (5.64 ml, 5.64 mmol) at 0.degree. C. was added. The reaction
was stirred for 1 hour at room temperature and then cooled to
-20.degree. C. Compound 8 (242.8 mg, 0.7048 mmol) in THF (4 ml) was
added dropwise thereto and stirred for 2 hours at -20-0.degree. C.
Ice cold water was added to the reaction, and THF was removed by
evaporation under reduced pressure. To the residue at 0.degree. C.,
ice cold 1N aqueous hydrochloric acid was added dropwise to adjust
the solution to pH 5. The solution was extracted with ethyl acetate
and the organic layer was washed with saturated aqueous sodium
chloride, dried with magnesium sulfate and evaporated under reduced
pressure. The residue was added with ether and stirred for 17 hours
at room temperature and then, filtrated with celite. The filtrate
was evaporated under reduced pressure to give crude compound 9
(carboxylic acid).
[0115] To the solution of compound 9 (0.7048 mmol) in acetonitrile
(7 ml), DBU (0.42 ml, 2.819 mmol), isopropyl iodide (0.28 ml, 2.819
mmol) were added and the mixture was stirred for 16 hours at
45.degree. C. The reaction mixture was evaporated under reduced
pressure. The residue was added with water and extracted with ethyl
acetate. The organic layer was washed with saturated aqueous sodium
chloride, dried with magnesium sulfate and evaporated under reduced
pressure. The residue was purified by means of silica gel column
(Merck 9385, hexane:ethyl acetate=1:2) to give compound 10(268.0
mg, yield 80.8% from 8).
[0116] Compound 10 obtained as above (total 370 mg) was further
purified by separation HPLC to give purified compound 10 (341.9 mg,
HPLC purification yield 92.4%).
[0117] .sup.1H-NMR spectrum (200 MHz, CDCl.sub.3) of compound 10:
.delta.5.54-5.13(2H, m), 5.00(1H, sept, J=6.2 Hz), 4.18(1H, bs),
3.95(1H, bs), 3.16(6H, s), 2.66(1H, d, J=6.4 Hz), 2.29(2H, t, J=7.3
Hz), 2.48-2.06(5H, m), 1.89(2H, bt), 1.79-1.17(20H, m), 1.23(6H, d,
J=6.2 Hz), 0.89(3H, t, J=6.8 Hz)
SYNTHESIS EXAMPLE 3
13,14-dihydro-15,15-ethylenedioxy-17-phenyl-18,19,20-trinor-PGF.sub.2.alph-
a. isopropyl ester (12)
[0118] Compound 12 was prepared from compound 11 in a same manner
as Synthesis example 1.
##STR00006##
[0119] .sup.1H-NMR spectrum (200 MHz, CDCl.sub.3) of compound
11:.delta.8.04-7.93(2H, m), 7.63-7.38(3H, m), 7.35-7.11(5H, m),
5.21-5.03(2H, m), 2.98-2.24(11H, m), 2.12-1.98(1H, m),
1.80-1.50(2H, m) .sup.1H-NMR spectrum (200 MHz, CDCl.sub.3) of
compound 12:57.35-7.12(5H,m), 5.56-5.35(2H, m), 5.00(1H, sept,
J=6.2 Hz), 4.15(1H, bs), 3.96(4H, s), 3.92(1H, bs), 3.18(1H, bd),
2.86(1H, bd), 2.75-2.63(2H, m), 2.28(2H, t, J=7.3 Hz),
2.46-1.15(17H, m), 1.22(6H, d, J=6.2 Hz)
SYNTHESIS EXAMPLE 4
13,14-dihydro-15,15-ethylenedioxy-20-ethyl-PGF2.alpha. ethyl ester
(15)
##STR00007##
[0121] To the solution of compound 13 (9.18 g, 19.59 mmol) in
methanol (91.8 ml), 8N-aqueous sodium hydroxide (24.49 ml) was
added at 0.degree. C. The reaction mixture was stirred for 3 hours
at room temperature, and then acidified with 6N-hydrochloric acid
at 0.degree. C. The mixture was extracted with ethyl acetate (100
ml+50 ml). The organic layer was washed with saturated aqueous
sodium chloride (100 ml .times.2), dried over anhydrous magnesium
sulfate. The extract was evaporated under reduced pressure to
obtain crude acid 14 as oil.
[0122] To the solution of crude acid 14 and
1,8-diazabicyclo[5.4.0]undec-7-ene (11.72 ml) in acetonitrile (60
ml), ethyl iodide (6.27 ml) was added dropwise at 0.degree. C. The
reaction mixture was stirred at 45.degree. C. for 17 hours, then
cooled to room temperature, and evaporated. To the residue, water
(100 ml) was added. The mixture was extracted with ethyl acetate
(100 ml.times.2). The organic layer was washed with
0.1N-hydrochloric acid, saturated aqueous sodium bicarbonate (100
ml) and saturated aqueous sodium chloride (100 ml). The extract was
dried over anhydrous magnesium sulfate and evaporated. The residue
was purified by two times of silica gel column chromatography
(Merck 7734, 220 g, hexane:ethyl acetate=2:3, .fwdarw.BW-300, 210
g, hexane:2-Propanol=6:1) to obtain ethyl ester 15 (8.60 g, 18.92
mmol, 96.6% from 13) as a colorless oil.
[0123] .sup.1H-NMR (200 MHz in CDCl.sub.3, TMS=0 ppm) of the
compound 15: .delta. 5.58-5.29(2H, m), 4.15(1H, brs), 4.13(2H, q,
J=7.1 Hz), 3.97(1H, brs), 3:94(4H, s), 2.80-2.70(1H, br),
2.49-2.36(1H, m), 2.32(2H, t, J=7.4 Hz), 2.36-2.15(4H, m),
1.90-1.83(2H, m), 1,83-1.12(20H, m), 1.26(3H, t, J=7.1 Hz),
0.88(3H, t, J=6.5 Hz)
EXAMPLE 1
[0124] Eight-weeks-old male C3H/HeN mice were used. The hair on the
back was clipped by electric clipper so that the hair in the
clipped area was removed as much as possible. Three days after the
clipping, mice without visible scratches were selected and used in
this study. Each group consisted of 3 animals. After group
assignment, the groups were housed separately in aluminum cages (3
animals/cage, 180 mm W.times.300 mm D.times.130 mm H; Nippon Cage,
Ltd., Japan).
[0125] Each test compound was dissolved in 70% (w/w) aqueous
ethanol. Each dose formulation of test compound was evenly applied
topically once daily (100 .mu.L per mouse) to the clipped dorsal
skin area (approximately 2.times.4 cm), except for Saturday and
Sunday, for 30 days. The control group received an equal amount of
the vehicle in the same manner.
[0126] Macroscopic observations of the hair growth were performed
14, 16, 18, 21, 23, 25, 28 and 30 days after the start of the
treatment. Hair growth was scored according to the scale below:
[0127] - no hair growth observed
[0128] .+-. hair growth .ltoreq.10% of the clipped area
[0129] + hair growth 10-40% of the clipped area
[0130] ++ hair growth 40-80% of the clipped area
[0131] +++ hair growth .gtoreq.80% of the clipped area
The results are shown in Table 1. In the vehicle-treated control
group, no hair growth was observed during, the treatment period. In
the 0.01% and 0.1% compound A.-treated groups, a dose-dependent
hair growth was noted, and all animals treated with 0.1% compound A
showed a hair growth classified to the highest score (+++) at Days
28 and 30 of treatment. In the 0.1% compound B-treated group, hair
growth score for 2 out of 3 animals were +++ and that of the
remaining animal was ++ at the end of the treatment period. In the
0.1% compound C-treated group, hair growth was observed on 1 out of
3 animals. In the 0.1% compound D-treated group, hair growth was
observed on 2 out of 3 animals
TABLE-US-00001 TABLE 1 Effects of Topical Application of Compound
A, B, C and D on Hair Growth in C3H/HeN Mice Hair Growth Score
Animal Days of Treatments Groups No. 14 16 18 21 23 25 28 30
Control 0101 - - - - - - - - (Vehicle) 0102 - - - - - - - - 0103 -
- - - - - - - Compound A 0301 - .+-. .+-. + ++ +++ +++ +++ 0.1%
0302 - - .+-. .+-. ++ ++ +++ +++ 0303 - .+-. .+-. .+-. ++ ++ +++
+++ Compound A 0201 - - - - - - .+-. .+-. 0.01% 0202 - - - - - + +
+ 0203 - - .+-. .+-. .+-. + ++ ++ Compound B 0501 - - .+-. .+-. +
++ ++ ++ 0.1% 0502 - - - .+-. + + ++ +++ 0503 - - - .+-. + ++ ++
+++ Compound C 0701 - - - - - - - - 0.1% 0702 - - .+-. .+-. .+-. +
+ + 0703 - - - - - - - - Compound D 0901 - - - - - - - - 0.1% 0902
- .+-. .+-. + + + ++ ++ 0903 - - - - - - .+-. .+-. Compound A:
13,14-dihydro-15,15-ethylenedioxy-20-ethyl-PGF.sub.2.alpha.
isopropyl ester Compound B:
13,14-dihydro-15,15-ethylenedioxy-17-phenyl-18,19,20-trinor-PGF.sub.2.alp-
ha. isopropyl ester Compound C:
13,14-dihydro-15,15-trimethylenedioxy-20-ethyl-PGF.sub.2.alpha.
isopropyl ester Compound D:
13,14-dihydro-15,15-dimethoxy-20-ethyl-PGF.sub.2.alpha. isopropyl
ester
EXAMPLE 2
[0132] Eight-weeks-old male C3H/HeN mice were used. The hair on the
back was clipped by electric clipper so that the hair in the
clipped area was removed as much as possible. Three days after the
clipping, mice without visible scratches were selected and used in
this study. Each group consisted of 3 animals. After group
assignment, the groups were housed separately in aluminum cages (3
animals/cage, 180 mm W.times.300 mm D.times.130 mm H; Nippon Cage,
Ltd., Japan).
[0133] Test compound was dissolved in 75% aqueous ethanol. The
formulation of test compound (compound E) was evenly applied
topically once daily (100 .mu.L per mouse) to the clipped dorsal
skin area (approximately 2.times.4 cm), except for Saturday and
Sunday, for 23 days. The control group received an equal amount of
the vehicle in the same manner.
[0134] Macroscopic observations of the hair growth were performed
14, 16, 18, 21 and 23 days after the start of the treatment. Hair
growth was scored according to the scale shown as above. Results
are shown in Table 2. In the 0.1% compound E-treated group, hair
growth was observed on 3 out of 3 animals.
TABLE-US-00002 TABLE 2 Effects of Topical Application of Compound E
on Hair Growth in C3H/HeN Mice Hair Growth Score Days of Treatments
Groups Animal No. 14 16 18 21 23 Control 0101 - - - - - (Vehicle)
0102 - - - - - 0103 - - - - - Compound E 0201 - - .+-. .+-. + 0.1%
0202 - - .+-. ++ ++ 0203 - - - + ++ Compound E:
13,14-dihydro-15,15-ethylenedioxy-20-ethyl-PGF.sub.2.alpha. ethyl
ester
EXAMPLE 3
[0135] 31 days after the start of the treatment conducted in
Example 1, grown-up hairs in the treated area and hairs in the
untreated area (i.e. non clipped area) were collected,
respectively. Enlarged photomicrographs of the collected hairs were
taken. Thickness of the randomly selected each ten hairs were
measured and calculated the average.
[0136] Results are shown in Table 3. The results show that the hair
grown-up by treating with the specific prostaglandin of the present
invention was thicker than those in the untreated area.
TABLE-US-00003 TABLE 3 Effects of Topical Application of Compounds
A and B on Thickness of Grown-up Hair in C3H/HeN Mice Hair
thickness, .mu.m Hair group n mean .+-. SE Control area 3 27.8 .+-.
2.6 0.1% Compound A-treated area 3 34.1 .+-. 1.6 Control area 3
29.3 .+-. 1.0 0.1% Compound B-treated area 3 33.3 .+-. 0.7
* * * * *