Note: Descriptions are shown in the official language in which they were submitted.
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PIPECOLIC ACID DERIVATIVE $AIR GROWTH
COMPOSITIONS AND USES
This application is a continuation-in-part of
U.S. Patent Application No. 08/869,426, filed on June
4, 1997, the entire contents of which are herein
incorporated by reference.
HACRGROUND OF THE INVENTION
1. Field of Invention
This invention relates to pharmaceutical
compositions and methods for treating alopecia and
promoting hair growth using pipecolic acid
derivatives.
2. Description of Related Art
Hair loss occurs in a variety of situations.
These situations include male pattern alopecia,
alopecia senilis, alopecia areata, diseases
accompanied by basic skin lesions or tumors, and
systematic disorders such as nur.riti onal disorders and
internal secretion disorders. The mechanisms causing
hair loss are very complicated, but in some instances
can be attributed to aging, genetic disposition, the
activation of male hormones, the loss of blood supply
to hair follicles, and scalp abnormalities.
The immunosuppressant drugs FK506, rapamycin and
cyclosporin are well known as potent T-cell specific
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immunosuppressants, and are effective against graft-
rejection after organ transplantation. It has been
reported that topical, but not oral, application of
FK506 (Yamamoto et al., J. Invest. Dermatol., 1994,
102, 160-164; Jiang et al., J. Invest. Dermatol. 1995,
104, 523-525) and cyclosporin (Iwabuchi et al., J.
Dermatol. Sci. 1995, 9, 64-69) stimulates hair growth
in a dose-dependent manner. One form of hair loss,
alopecia areata, is known to be associated with
autoimmune activities; hence, topically administered
immunomodulatory compounds are expected to demonstrate
efficacy for treating that type of hair loss. The
hair growth stimulating effects of FK506 have been the
subject of an international patent filing covering
FK506 and structures related thereto for hair growth
stimulation (Honbo et al., EP 0 423 714 A2). Honbo et
al. discloses the use of relatively large tricyclic
compounds, known for their immunosuppressive effects,
as hair revitalizing agents.
The hair growth and revitalization effects cf
FK50~ and related agents are disclosed in many U.S_
patents (Goulet et al., U.S. Patent No. 5,258,389;
Luly et al., U.S. Patent No. 5,457,111; Goulet et al.,
U.S. Patent No. 5,532,248; Goulet et al., U.S. Patent
No. 5,189,042; and Ok et al., U.S. Patent No.
5,208,241; Rupprecht et al., U.S. Patent No.
5,284,840; Organ et al., U.S. Patent No. 5,284,877).
These patents claim FK506 related compounds. Although
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they do not claim methods of hair revitalization, they
disclose the known use of FK506 for effecting hair
growth. Similar to FK506 (and the claimed variations
in the Honbo et al. patent), the compounds claimed in
these patents are relatively large. Further, the
cited patents relate to immunomodulatory compounds for
use in autoimmune related diseases, for which FK506's
efficacy is well known.
Other U.S. patents disclose the use of
cyclosporin and related compounds for hair
revitalization (Hauer et al., U.S. Patent No.
5,342,625; Eberle, U.S. Patent No. 5,284,826; Hewitt
et al., U.S. Patent No. 4,996,193). These patents
also relate to compounds useful for treating
autoimmune diseases and cite the known use of
cyclosporin and related immunosuppressive compounds
for hair growth.
However, immunosuppressive compounds by
definition suppress the immune system and also exhibit
other toxic side effects. Accordingly, there is a
need fcr non-immunosuppressant, small molecule
compounds which are useful as hair revitalizing
compounds.
Hamilton and Steiner disclose in U.S. Patent No.
5,614,547 novel pyrrolidine carboxylate compounds
which bind to the immunophilin FKBP12 and stimulate
nerve growth, but which lack immunosuppressive
effects. Unexpectedly, it has been discovered that
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these non-immunosuppressant compounds promote hair
growth with an efficacy similar to FK506. Yet their
novel small molecule structure and non-immuno-
suppressive properties differentiate them from FK506
and related immunosuppressive compounds found in the
prior art.
SUI~iARY OF TFiE INVENTION
The present invention relates to a method for
treating alopecia or promoting hair growth in an
animal, which comprises administering to said animal
an effective amount of a pipecolic acid derivative.
The present invention further relates to a
pharmaceutical composition which comprises:
(i) an effective amount of a pipecolic acid
derivative for treating alopecia or
promoting hair growth in an animal; and
(ii) a pharmaceutically acceptable carrier.
The pipecolic acid derivatives used in the
inventive methods and pharmaceutical compositions
include immunosuppressive and non-immunosuppressive
compounds having an affinity for FKBP-type
immunophilins, particularly FKBP12. Non
immunosuppressive compounds, as their name suggests,
do not exert any significant immunosuppressive
activity.
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BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a photograph of mice treated with a
vehicle after six weeks. FIG. 1 shows that less than
3% of the shaved area is covered with new hair growth
5 when the vehicle (control) is administered.
FIG. 2 is a photograph of mice treated with 10 ~,M
of a pipecolic acid derivative, GPI 1116, after six
weeks. FIG. 2 shows that 90°s of the shaved area is
covered with new hair growth when GPI 1116 is
administered.
FIG. 3 is a photograph of mice treated with 3 uM
of a pipecolic acid derivative, GPI 1102, after six
weeks . FIG. 3 shows that 90% of the shaved area is
covered with new hair growth when GPI 1102 is
administered.
FIG. 4 is a bar graph plotting the hair growth
scores of unshaven animals and shaven animals treated
with a vehicle, GPI 1116 (1 ~,M and 10 ~,M), GPI 1102 (1
~.M and 3 ~,M), and a related pipecolic acid derivative
neuroimmunophilin FKBP ligand, GPI 1044 (1 ~,M, 3 ~.M
and 10 ~.M ) .
FIG. 5 is a bar graph depicting the relative hair
growth indices for C57 Black 6 mice treated with a
vehicle, FK506, related neuroimmunophilin FKBP ligand
GPI 1206, and GPI 1116, 14 days after treatment with
each identified compound. Figure 5 demonstrates the
remarkable early hair growth promoted by neuro-
immunophilin FKBP ligands.
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DETAILED DESCRIPTION OF THE INVENTION
Definitions
"Alopecia" refers to deficient hair growth and
partial or complete loss of hair, including without
limitation androgenic alopecia (male pattern
baldness), toxic alopecia, alopecia senilis, alopecia
areata, alopecia pelada and trichotillomania.
Alopecia results when the pilar cycle is disturbed.
The most frequent phenomenon is a shortening of the
hair growth or anagen phase due to cessation of cell
proliferation. This results in an early onset of the
catagen phase, and consequently a large number of
hairs in the telogen phase during which the follicles
are detached from the dermal papillae, and the hairs
fall out. Alopecia has a number of etiologies,
including genetic factors, aging, local and systemic
diseases, febrile conditions, mental stresses,
hormonal problems, and secondary effects of drugs.
"GPI 1044" refers to a compound of formula
25
O~ ~ O D
O
L
wherein B is 3-Phenylpropyl, D is 3-Phenylpropyl, and
L is Phenyl.
"GPI 1102" refers to Compound 98, 4-phenyl-1-(3-
phenylpropyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
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piperidinecarboxylate.
"GPI 1116" refers to Compound 103, 1-phenethyl-3-
phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarboxylate.
"GPI 1206" refers to a compound of formula
N
O
N
~ O
HNI 'S
GPI 1206
to
"Isomers" refer to different compounds that have
the same molecular formula. "Stereoisomers" are
isomers that differ only in the way the atoms are
arranged in space. "Enantiomers" are a pair of
stereoisomers that are non-superimposable mirror
images of each other. "Diastereoisomers" are
stereoisomers which are not mirror images of each
other. "Racemic mixture" means a mixture containing
2~ equal parts of individual enantiomers . "Non-race~.:ic
r,;:~xture" is a mixture containing unequal parts of
individual enantiomers or stereoisomers.
"Pharmaceutically acceptable salt, ester, or
solvate" refers to a salt, ester, or solvate of a
subject compound which possesses the desired
pharmacological activity and which is neither
biologically nor otherwise undesirable. A salt,
ester, or solvate can be formed with inorganic acids
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such as acetate, adipate, alginate, aspartate,-
benzoate, benzenesulfonate, bisulfate, butyrate,
citrate, camphorate, camphorsulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, glucoheptanoate, gluconate,
glycerophosphate, hemisulfate, heptanoate, hexanoate,
hydrochloride, hydrobromide, hydroiodide, 2-
hydroxyethanesulfonate, lactate, maleate,
methanesulfonate,naphthylate,2-naphthalenesulfonate,
nicotinate, oxalate, sulfate, thiocyanate, tosylate
and undecanoate. Eamples of base salts, esters, or
solvates include ammonium salts; alkali metal salts,
such as sodium and potassium salts; alkaline earth
metal salts, such as calcium and magnesium salts;
salts with organic bases, such as dicyclohexylamine
salts; N-methyl-D-glucamine; and salts with amino
acids, such as arginine, lysine, and so forth. Also,
the basic nitrogen-containing groups can be
quarternized with such agents as lower alkyl halides,
such as methyl, ethyl, propyl, and butyl chlorides,
bromides, and iodides; dialkyl sulfates, such as
dimethyl, diethyl, dibutyl, and diamyl sulfates; long
chain halides, such as decyl, lauryl, myristyl, and
stearyl chlorides, bromides, and iodides; aralkyl
halides, such as benzyl and phenethyl bromides; and
others. Water or oil-soluble or dispersible products
are thereby obtained.
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"Pilar cycle" refers to the life cycle of hair
follicles, and includes three phases:
(1) the anagen phase, the period of active hair
growth which, insofar as scalp hair is
concerned, lasts about three to five years;
(2) the catagen phase, the period when growth
stops and the follicle atrophies which,
insofar as scalp hair is concerned, lasts
about one to two weeks; and
(3) the telogen phase, the rest period when hair
progressively separates and finally falls
out which, insofar as scalp hair is
concerned, lasts about three to four months .
Normally 80 to 90 percent of the follicles are in the
anagen phase, less than 1 percent being in the catagen
phase, and the rest being in the telogen phase. In
the telogen phase, hair is uniform in diameter with a
slightly bulbous, non-pigmented root. By contrast, in
the anagen phase, hair has a large colored bulb at its
root.
"Promoting hair growth" refers to maintaining,
inducing, stimulating, accelerating, or revitalizing
the germination of hair.
"Treating alopecia" refers to:
(i) preventing alopecia in an animal which may be
predisposed to alopecia; and/or
(ii) inhibiting, retarding or reducing alopecia;
and/or
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(iii) promoting hair growth; and/or
(iv) prolonging the anagen phase of the hair
cycle; and/or
(v) converting vellus hair to growth as terminal
5 hair. Terminal hair is coarse, pigmented, long hair
in which the bulb of the hair follicle is seated deep
in the dermis. Vellus hair, on the other hand, is
fine, thin, non-pigmented short hair in which the hair
bulb is located superficially in the dermis. As
10 alopecia progresses, the hairs change from the
terminal to the vellus type.
Methods of the Present Invention
The present invention relates to a method for
15 treating alopecia or promoting hair growth in an
animal, which comprises administering to said animal
an effective amount of a pipecolic acid derivative.
The inventive method is particularly useful for
treating male pattern alopecia, alopecia senilis,
20 alopecia areata, alopecia resulting from skin lesions
or tumors, alopecia resulting from cancer therapy such
as chemotherapy and radiation, and alopecia resulting
from systematic disorders such as nutritional
disorders and internal secretion disorders.
Pharmaceutical Compositions of the Present Invention
The present invention also relates to a pharma-
ceutical composition comprising:
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(i) an effective amount of a pipecolic acid-
derivative for treating alopecia or
promoting hair growth in an animal; and
(ii) a pharmaceutically acceptable carrier.
PIPECOLIC ACID DERIVATIVES
The pipecolic acid derivatives used in the
methods and pharmaceutical compositions of the present
invention have an affinity for FKBP-type
immunophilins, such as FKBP12. When a pipecolic acid
derivative binds to an FKBP-type immunophilin, it has
been found to inhibit the prolyl-peptidyl cis-traps
isomerase, or rotamase, activity of the binding
protein. Unexpectedly, the compounds have also been
found to stimulate hair growth. These rotamase
inhibiting compounds may be immunosuppressive or non-
immunosuppressive. Examples of useful compounds are
set forth below.
COMPOUND 1
Ocain et al., Biochemical arc Biophysical
Research Communications, Vol. 192, No. 3, 1993,
incorporated herein by reference, discloses an
exemplary pipecolic acid derivative represented by
Formula I. The compound was synthesized at Wyeth-
Ayerst by Dr. Phil Hughes by reaction of 4-phenyl-
1,2,4-triazoline-3,5-dione with rapamycin.
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FORMULA I
H
'OMe
I
15
Way-124,466
COMPOUND 2
~:h~kraborty et al., Chemistry and Biology, Vol.
2, pp. 157-161, March 1995, incorporated herein by
reference, discloses an exemplary pipecolic acid
derivative represented by Formula II.
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FORMULA II
7
II
O
1
O
~NH
10
Me H
O
RAP-Pa
COMPOUNDS 3-5
Ikeda et al., J. Am. Chem. Soc., Vol. 116, pp.
4143-4144, 1994, incorporated herein by reference,
discloses exemplary pipecolic acid derivatives
represented by Formula III and Table I.
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FORMULA III
III
N
'N H
H
10
CbzH Me'''~~~~~.
Me
TABLE I
Compound Structure
3 n = 1
4 n = 2
5 n = 3
COMPOTJI~.~L,'~ 6 - 9
Wang et al., Bioorganic and Medicinal Chemistry
Letters, Vol. 4, No. 9, pp. 1161-1166, 1994,
25 incorporated herein by reference, discloses exemplary
pipecolic acid derivatives represented by Formula IV
and Table II.
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FORMULA IV
CH30 / pCH3
IV
5 p \
CH30 p
TABLE II
Compound Structure
6 X = H, H
7 X = CHz
8 X = H, CH3
9 X = O
COMPOUND 10
Birkenshaw et al., Bioorganic & Medicinal
Chemistry Letters, Vol. 4, No. 21, pp. 2501-2506,
1994, incorporated herein by reference, discloses an
exemplary pipecolic acid deri-restive represented by
Formula V.
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- FORMULA V
V
O
15
COMPOUNDS 11-21
Holt et al., J. Am. Chem. Soc., Vol. 115, pp.
9925-9938, 1993, incorporated herein by reference,
discloses exemplary pipecolic acid derivatives
represented by Formula VI and Tables III and IV.
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- FORMULA VI
R2
( VI
TABLE III
Compound .Ra
11
/f
12
OMe
OMe
13
OMe
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TABLE III (continued)
Compound Rz
14
f
15
16
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TABLE III (continued)
Compound R2
17
18
20
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TABLE IV
Compound Structure
19
15 20
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TABLE IV (continued)
Compound Structure
21
15
COMPOUNDS 22-30
Caffery et al., Bioorganic & Medicinal Chemistry
Letters, Vol. 4, No. 21, pp. 2507-2510, 1994,
20 incorporated herein by reference, discloses exemplary
pipecolic acid derivatives represented by Formulas
VII-IX and Tables V-VII.
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FORMULA VII
O
VII
15 TABLE V
Compound Structure
22 y = 1
23 y = 2
24 y = 3
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FORMULA VIII
~o
,
l
VIII
O
1o O O
O
TABLE VI
Compound Structure
25 n = 1
26 n = 2
27 n = 3
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FORMULA IX
0
IX
n
O
~'' 0
O
TABLE VII
Compound Structure
28 n = 1
29 n = 2
30 n = 3
COMPOUND 31
Teague et al., Bioorganic & Medicinal Chemistry
Letters, Vol. 3, No. 10, pp. 1947-1950, 1993,
incorporated herein by reference, discloses an
exemplary pipecolic acid derivative represented by
Formula X.
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FORMULA X
TT/~
5
to
O
N ~ x
O O
~-O
OH
'O
I
OMe OMe
COMPOUNDS 32-34
Yamashita et al., Bioorganic & Medicinal
Chemistry Letters, Vol. 4., No. 2, pp. 325-328, 1994,
incorporated herein by reference, discloses exemplary
pipecolic acid derivatives represented by Formula XI
and Table VIII.
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FORMULA XI
xz
o~ o
to
TABLE VIII
Compound Structure
32 R = phenyl
33 R = N(allyl)2
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TABLE VIII (continued)
Compound Structure
34
0
COMPOUND 35-55
Holt et al., Bioorganic & Medicinal Chemistry
Letters, Vol. 4, No. 2, pp. 315-320, 1994,
incorporated herein by reference, discloses exemp'_.ry
pipecolic acid derivatives represented by Formula XII
and Tables IX-XI.
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FORMULA XII
Et
XII
0
R
TABLE IX
Compound Structure
35 R =
36 R =
2 o Me
37 R =
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29 ..
TABLE IX (continued)
Compound Structure
38 R =
10
39 R =
20
40 R =
41 R =
42 R =
~OAc
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TABLE IX (continued)
Compound Structure
5
43 R = ~ Q
HO
44 R = ~ O
Me0
45 R =
HO
46 R =
Me0
47 R =
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31
TABLE IX (continued)
Compound Structure
48 R =
N
49 R = ~ Q
50 R =
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TABLE X
Compound Structure
51 N""C02Et
0 \S
52
H<
53
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TABLE XI
Compound Structure
54
O
S02 O =
/ \
OMe
55
O
S02 O
COMPOUNDS 56-68
Holt et al., Bioorganic & Medicinal Chemistry
Letters, Vol. 3, No. 10, pp. 1977-1980, 1993,
incorporated herein by reference, discloses exemplary
pipecolic acid derivatives represented by Formulas
XIII and XIV and Tables XII-XIV.
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FORMULA XIII
XIII
TABLE XII
Compound Structure
56 X = OH
57 X = OMe
58 X = Oi Pr
59 X = OBn
60 X = OCH MePh
61 X = OCHzCHCHPh
6 2 X = OCHzCH2CH2 { 3 ,
4 -OMe2 ) Ph
63 X = NHBn
64 X = NHCH2CHzCHzPh
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FORMULA XIV
u~
5
XIV
15
TABLE XIII
Compound Structure
65 R = Me
66 R = Bn
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TABLE XIV
Compound Structure
u~
67
15
68
Me0'
2 0 ... .
0
,,,,
Me0'
25 O OMe
O
""", ~// U
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COMPOUNDS 69-83
Hauske et al., J. Med. Chem., Vol. 35, pp. 4284-
4296, 1992, incorporated herein by reference,
discloses exemplary pipecolic acid derivatives
represented by Formulas XV-XVIII and Tables XV-XVIII.
FORMULA XV
~n O
to N R xv
2
R1
TABLE XV
Compound Structure
69 n = 2
Rl
RZ = Phe-o- tert-butyl
70 n = 2
O
2 5 Rl = ~ / OCH3
R2 = Phe-o-tert-butyl
3
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FORMULA RVI
XVI
,,,. wRl
to H H
TABLE XVI
Compound Structure
71 R1 = m-OCH3Ph
R3 = Val-O-tent-butyl
72 R1 = m-OCH3Ph
R3 = Leu-O-tert-butyl
73 R1 = m-OCH3Ph
R3 = I leu-O- tert-butyl
74 Rl = .m-OCH3Ph
R3 - hexahydro-Phe-O-tert-
butyl
75 R1 = m-OCH3Ph
R3 - allylalanine-O- tert-
butyl
76 R1 = B-naphthyl
R3 = Val-O- tert-butyl
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FORMULA RVII
H O
N
XVII
4
___H
N
to Ri
TABLE XVII
Compound Structure
R1 = CHz (CO) -m-OCH3Ph
RQ = CHZPh
RS = OCH3
78 R1 - CHZ (CO) -B-naphthyl
R, - CH2Pr
RS = OCH3
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FORMULA XVIII
5 C]~Y
XVIII
R4
wRl
10 H H
TABLE XVIII
Compound Structure
79 R1 = m-OCH3Ph
X = trans-CH=CH
R9 = H
Y = OC (O) Ph
80 Rl = m-OCH3Pr.
X = trans-CH=CH
RQ = H
Y = OC (O) CF3
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TAHLE XVIII (coatiaued)
Compound Structure
81 R1 = m-OCH3Ph
X = trans-CH=CHI
R4 = _
y = _
82 R1 = m-OCH3Ph
X = traps-CH=CH
R4 = H
Y = OCH2CH=CHZ
83 Rl = m-OCH3Ph
X = C=O
R4 = H
Y = Ph
COMPOUND 84
Teague et al . , Bioorganic & Med. Chem. T etr:.~r~ ,
Vol. 4, No. 13, pp. 1581-1584, 1994, incorporated
herein by reference, discloses an exemplary pipecolic
acid derivative represented by Formula XIX.
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FORMULA XIX
HO
Me0
XIX
15
SLB506
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COMPOUNDS 85-88
Stocks et al., eioorganic & Med. Chem. Letters,
Vol. 4, No. 12, pp. 1457-1460, 1994, incorporated
herein by reference, discloses exemplary pipecolic
acid derivatives represented by Formula XX and Tables
XIX and XX.
TAHLE XIX
Compound Structure
15
HO
Me0
0
HO o
,,,,,,,
~OMe
H
OMe
O
O
N '~O
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FORMULA XX
M
O
XX
N O
to p
R1
TABLE XX
Compound Structure
20 86 R1 = H
RZ = OMe
R3 = CHZOMe
8 7 Rl = H
25 Rz = H
R3 = H
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TABLE XX (continued)
Compound S truc ture
8 8 Rl =
Me
RZ =
H
R3 =
H
COMPOUNDS 89-110
10 Additional exemplary pipecolic acid derivatives
are represented by Formulas XXI-XXV and Tables XXI-
XXV.
FORMULA XXI
15
R
XXI
TABLE XXI
Compound Structure
89 R = 3,4-dichloro
90 R = 3,4,5-trimethoxy
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46
TABLE XXI (continued)
Compound Structure
91 R = H
92 R = 3-(2,5-Dimethoxy)phenylpropyl
93 R - 3-(3,4-Methylenedioxy)phenyl
propyl
FORMULA XXII
R
( XXII
TABLE XXII
Compound Structure
94 R = 4-(p-Methoxy)butyl
95 R = 3-Phenylpropyl
96 R = 3-(3-Pyridyl)propyl
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FORMULA XXIII
( XXIII
TABLE XXIII
Compound Structure
97 R = 3-(3-Pyridyl)propyl
98 R = 1,7-biphenyl-4-heptyl
99 R = 4-(4-Methoxy)butyl
100 R - 1-Phenyl-6-(4-methoxyphenyl)-4-
hexyl
101 R = 3-(2,5-Dimethoxy)phenylpropyl
102 R = 3-(3,4-Methylenedioxy)phenylpropyl
103 R = 1,5-Diphenylpentyl
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FORMZJLA XXIV
XXIV
TABLE XXIV
Compound Structure
104 R = 4-(4-Methoxy)butyl
105 R = 3-Cyclohexylpropyl
106 R = 3-Phenylpropyl
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FORMULA XXV
XXV
TABLE XXV
Compound Structure
107 R = 3-Cyclohexylpropyl
108 R = 3-Phenylpropyl
109 R = 4-(4-Methoxy)butyl
110 R = 1,7-biphenyl-4-heptyl
The names of Some of the compounds identified
above are provided below in Table XXVI.
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TABLE XXVI
Compound Name of Species
5 6 4- (4-methoxyphenyl) butyl (2S) -1- [2- (3, 4, 5-
trimethoxyphenyl)acetyl]hexahydro-2-
pyridinecarboxylate
7 4- (4-methoxyphenyl) butyl (2S) -1- [2- (3, 4, 5-
10 trimethoxyphenyl)acryloyl]hexahydro-2-
pyridinecarboxylate
8 4- (4-methoxyphenyl)butyl (2S) -1- [2- (3,4, 5-
trimethoxyphenyl)propanoyl]hexahydro-2-
15 pyridinecarboxylate
9 4- (4-methoxyphenyl)butyl (2S) -1- [2-oxo-2-
(3,4,5-trimethoxyphenyl)acetyl]hexahydro-2-
pyridinecarboxylate
11 3-cyclohexylpropyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)hexahydro-2-pyri3inecarboxy:~.at~
12 3-phenylpropyl (2S)-1-(3,3-dimethyl-2-
oxopentanoyl)hexahydro-2-pyridinecarboxylate
13 3-(3,4,5-trimethoxyphenyl)propyl (2S)-1-
(3,3-dimethyl-2-oxopentanoyl)hexahydro-2-
pyridine-carboxylate
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TABLE XXVI (continued)
Compound Name of Species
14 (1R)-2,2-dimethyl-1-phenethyl-3-butenyl
( 2 S ) - 1 - ( 3 , 3 - d i m a t by 1 - 2 -
oxopentanoyl)hexahydro-2-pyridinecarboxylate
(1R)-1,3-diphenylpropyl (2S)-1-(3,3-
10 dimethyl-2-oxopentanoyl)hexahydro-2-
pyridinecarboxylate
16 (1R)-1-cyclohexyl-3-phenylpropyl (2S)-1-
(3,3-dimethyl-2-oxopentanoyl)hexahydro-2-
15 pyridine-carboxylate
17 (1S) -1, 3-diphenylpropyl (2S) -1- (3, 3-
dimethyl-2-oxopentanoyl)hexahydro-2-
pyridinecarboxylate
18 (1S)-1-cyclohexyl-3-phenylpropyl (2S)-1-
(3,3-3imethyl-2-oxopentanoyl)hexahydro-2-
pyridine-carboxylate
19 (22aS)-15,15-dimethylperhydropyrido[2,1-
c][1,9,4]dioxazacyclononadecine-1,12,16,17-
tetraone
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TABLE XXVI (continued)
Compound Name of Species
20 (24aS)-17,17-dimethylperhydropyrido[2,1-
c][1,9,4]dioxazacyclohenicosine-1,14,18,19-
tetraone
35 ethyl 1-(2-oxo-3-phenylpropanoyl)-2-
piperidinecarboxylate
36 ethyl 1-pyruvoyl-2-piperidinecarboxylate
37 ethyl 1-(2-oxobutanoyl)-2-piperidine-
carboxylate
38 ethyl 1-(3-methyl-2-oxobutanoyl)-2-
piperidine-carboxylate
39 ethyl 1-(4-methyl-2-oxopentanoyl)-2-
piperidinecarboxylate
40 ethyl 1-(3,3-dimethyl-2-oxobutanoyl)-2-
piperidinecarboxylate
41 ethyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-
piperidinecarboxylate
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TABLE XXVI (continued)
Compound Name of Species
42 4-[2-(ethyloxycarbonyl)piperidino]-2,2-
dimethyl-3,4-dioxobutyl acetate
43 ethyl 1-[2-(2-hydroxytetrahydro-2H-2-
p y r a n y 1 ) - 2 - o x o a c a t y 1 ] - 2 -
piperidinecarboxylate
44 ethyl 1-[2-(2-methoxytetrahydro-2H-2-
p y r a n y 1 ) - 2 - o x o a c a t y 1 ] - 2 -
piperidinecarboxylate
45 ethyl 1-[2-(1-hydroxycyclohexyl)-2-
oxoacetyl]-2-piperidinecarboxylate
46 ethyl 1-(2-(1-methoxycyclohexyl)-2-
oxoacetyl]-2-piperidinecarboxylate
47 ethyl 1-(2-cyclohexyl-2-oxoacetyl)-2-
piperidinecarboxylate
48 ethyl 1-(2-oxo-2-piperidinoacetyl)-2-
piperidinecarboxylate
49 ethyl 1-[2-(3,4-dihydro-2H-6-pyranyl)-2-
oxoacetyl)-2-piperidinecarboxylate
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TABLE XXVI (continued)
Compound Name of Species
50 ethyl 1-(2-oxo-2-phenylacetyl)-2-
piperidinecarboxylate
51 ethyl 1-(4-methyl-2-oxo-1-thioxopentyl)-2-
piperidinecarboxylate
52 3-phenylpropyl 1-(2-hydroxy-3,3-
dimethylpentanoyl)-2-piperidinecarboxylate
53 ( 1 R ) - 1 - p h a n y 1 - 3 - ( 3 , 4 , 5 -
trimethoxyphenyl)propyl 1-(3,3-
dimethylbutanoyl)-2-piperidine-carboxylate
54 (1R)-1,3-diphenylpropyl 1-(benzylsulfonyl)-
2-piperidinecarboxylate
55 3-(3,4,5-trimethoxyphenyl)propyl 1-
(benzylsulfonyl)-2-piperidinecarboxylate
56 1- (2- [ (2R, 3R, 6S) -6- ( (2S, 3E, 5E, 7E, 9S, 11R) -
2,13-dimethoxy-3,9,11-trimethyl-12-oxo-
3,5,7-tridecatrienyl]-2-hydroxy-3-
methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-
2-piperidine-carboxylic acid
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TABLE XXVI (continued)
Compound Name of Species
5 57 methyl 1- (2- [ (2R, 3R, 6S) -6- [ (2S, 3E, 5E, 7E, 9S,
11R)-2,13-dimethoxy-3,9,11-trimethyl-12-oxo-
3,5,7-tridecatrienyl]-2-hydroxy-3-methyl-
tetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-
piperidinecarboxylate
58 isopropyl 1- (2- [ (2R, 3R, 6S) -&- [ (2S, 3E, 5E, 7E,
9S,11R)-2,13-dimethoxy-3,9,11-trimethyl-12-
oxo-3,5,7-tridecatrienyl]-2-hydroxy-3-
methyl-tetrahydro-2H-2-pyranyl)-2-
oxoacetyl)-2-piperidinecarboxylate
59 benzyl 1- (2- [ (2R, 3R, 6S) -6- [ (2S, 3E, 5E, 7E, 9S,
11R)-2,13-dimethoxy-3,9,11-trimethyl-12-oxo-
3,5,7-tridecatrienyl]-2-hydroxy-3-methyl-
20 tetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-
piperidinecarboxylate
60 1-phenylethyl 1- (2- [ (2R, 3R, 6S) -6- [ (2S, 3E, 5E,
7E,9S,11R)-2,13-dimethoxy-3,9,11-trimethyl-
25 12-oxo-3,5,7-tridecatrienyl]-2-hydroxy-3-
methyl-tetrahydro-2H-2-pyranyl)-2-
oxoacetyl)-2-piperidinecarboxylate
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TABLE XXVI (continued)
Compound Name of Species
61 (Z) -3-phenyl-2-propenyl 1- (2- [ (2R, 3R, 6S) -6-
[ (2S, 3E, SE, 7E, 9S, 11R) -2, 13-dimethoxy-3, 9, 11-
trimethyl-12-oxo-3,5,7-tridecatrienyl]-2-
hydroxy-3-methyltetrahydro-2H-2-pyranyl)-2-
oxoacetyl)-2-piperidinecarboxylate
62 3- (3, 4-dimethoxyphenyl)propyl 1- (2- [ (2R, 3R,
6S) -6- [ (2S, 3E, 5E, 7E, 9S, 11R) -2, 13-dimethoxy-
3,9,11-trimethyl-12-oxo-3,5,7-
tridecatrienyl]-2-hydroxy-3-
methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-
2-piperidine-carboxylate
63 N2 - b a n z y 1 - 1 - ( 2 - [ ( 2 R , 3 R , 6 S ) - 6 -
[ (2S, 3E, 5E, 7E, 9S, 11R) -2, 13-dimethoxy-
3,9,11-trimethyl-12-oxo-3,5,7-
tridecatrienyl]-2-hydroxy-3-methyl-
tetrahydro-2F.-2-pyrar.«1)-2-oxoacetyl)-2-
piperidinecarboxylate
64 N2- (3-phenylpropyl) -1- (2- [ (2R, 3R, 6S) -6-
[ (2S, 3E, 5E, 7E, 9S, 11R) -2, 13-dimethoxy-3, 9, 11-
trimethyl-12-oxo-3,5,7-tridecatrienyl]-2-
hydroxy-3-methyltetrahydro-2H-2-pyranyl)-2-
oxoacetyl)-2-piperidinecarboxylate.
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TABLE XXVI (continued)
Compound Name of Species
89 (E)-3-(3,4-dichlorophenyl)-2-propenyl 1-
(3,3-dimethyl-2-oxopentanoyl)-2-piperidine-
carboxylate
90 (E)-3-(3,4,5-trimethoxyphenyl)-2-propenyl 1
(3,3-dimethyl-2-oxopentanoyl)-2-piperidine
carboxylate
91 (E)-3-phenyl-2-propenyl 1-(3,3-dimethyl-2-
oxo-pentanoyl)-2-piperidinecarboxylate
92 (E)-3-((3-(2,5-dimethoxy)-phenylpropyl)-
phenyl)-2-propenyl 1-(3,3-dimethyl-2-
oxopentanoyl)-2-piperidinecarboxylate
93 (E)-3-(1,3-benzodioxol-5-yl)-2-propenyl 1-
(3,3-dimethyl-2-oxopentanoyl)-2-piperidine-
carbcxylate
94 4-(4-methoxyphenyl)butyl 1-(2-oxo-2-
phenylacetyl)-2-piperidinecarboxylate
95 3-phenylpropyl 1-(2-oxo-2-phenylacetyl)-2-
piperidinecarboxylate
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TABLE XXVI (continued)
Compound Name of Species
96 3-(3-pyridyl)propyl 1-(2-oxo-2-
phenylacetyl)-2-piperidinecarboxylate
97 3-(3-pyridyl)propyl 1-(3,3-dimethyl-2-
oxopentanoyl)-2-piperidinecarboxylate
98 4-phenyl-1-(3-phenylpropyl)butyl 1-(3,3-
dimethyl-2-oxopentanoyl)-2-piperidine-
carboxylate
99 4-(4-methoxyphenyl)butyl 1-(3,3-dimethyl-2-
oxopentanoyl)-2-piperidinecarboxylate
100 1-(4-methoxyphenethyl)-4-phenylbutyl 1-(3,3
dimethyl-2-oxopentanoyl)-2-piperidine
carboxylate
101 3-(2,5-dimetho;{yphenyl)propyl 1-t,3-
d i m a t h y 1 - 2 - o x o p a n t a n o y 1 ) - 2 -
piperidinecarboxylate
102 3-(1,3-benzodioxol-5-yl)propyl 1-(3,3-
dimethyl-2-oxopentanoyl)-2-piperidine-
carboxylate
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TABLE XXVI (continued)
Compound Naane of Species
103 1-phenethyl-3-phenylpropyl 1-(3,3-dimethyl-
2-oxopentanoyl)-2-piperidinecarboxylate
104 4-(4-methoxyphenyl)butyl 1-(2-cyclohexyl-2-
oxoacetyl)-2-piperidinecarboxylate
105 3-cyclohexylpropyl 1-(2-cyclohexyl-2-
oxoacetyl)-2-piperidinecarboxylate
106 3-phenylpropyl 1-(2-cyclohexyl-2-oxoacetyl)-
2-piperidinecarboxylate
107 3-cyclohexylpropyl 1-(3,3-dimethyl-2-
oxobutanoyl)-2-piperidinecarboxylate
108 3-phenylpropyl 1-(3,3-dimethyl-2-
oxobutanoyl)-2-piperidinecarboxylate
109 4-(4-methoxyphenyl)butyl 1-(3,3-dimethyl-2-
oxobutanoyl)-2-piperidinecarboxylate
110 4-phenyl-1-(3-phenylpropyl)butyl 1-(3,3-
dimethyl-2-oxobutanoyl)-2-piperidine-
carboxylate
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All the compounds of Formulas I-XXV possess
asymmetric centers and thus can be produced as
mixtures of stereoisomers or as individual R- and S-
stereoisomers. The individual stereoisomers may be
obtained by using an optically active starting
material, by resolving a racemic or non-racemic
mixture of an intermediate at some appropriate stage
of the synthesis, or by resolving the compounds of
Formulas I-XXV. It is understood that the compounds
of Formulas I-XXV encompass individual stereoisomers
as well as mixtures (racemic and non-racemic) of
stereoisomers. Preferably, S-stereoisomers are used
in the pharmeceutical compositions and methods of the
present invention.
Affinity for FRBP12
The compounds used in the inventive methods and
pharmaceutical compositions have an affinity for the
FK506 binding protein, particularly FKBPI2. The
inhibition of the prolyl peptidyl cis-traps isomerase
activity of FKBP may be measured as an indicator of
this affinity.
Ki Test Procedure
Inhibition of the peptidyl-prolyl isomerase
(rotamase) activity of the compounds used in the
inventive methods and pharmaceutical compositions can
be evaluated by known methods described in the
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literature (Harding et al., Nature, 1989, 341:758-760;
Holt et al. J. Am. Chem. Soc., 115:9923-9938). These
values are obtained as apparent Ki's and are presented
for representative compounds in TABLE XXVII.
The cis-trans isomerization of an alanine-proline
bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-
p-nitroanilide, is monitored spectrophotometrically in
a chymotrypsin-coupled assay, which releases para-
nitroanilide from the trans form of the substrate.
The inhibition of this reaction caused by the addition
of different concentrations of inhibitor is
determined, and the data is analyzed as a change in
first-order rate constant as a function of inhibitor
concentration to yield the apparent Ki values.
In a plastic cuvette are added 950 mL of ice cold
assay buffer (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 mL
of FKBP (2.5 mM in 10 mM Tris-C1 pH 7.5, 100 mM NaCl,
1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/ml
in 1 mM HC1) and 10 mL of test compound at various
concentrations in dimethyl sulfoxide. The reaction is
initiated by the addition of 5 mL of substrate
(succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL
in 2.35 mM LiCl in trifluoroethanol).
The absorbance at 390 nm versus time is monitored
for 90 seconds using a spectrophotometer and the rate
constants are determined from the absorbance versus
time data files.
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TABLE XXVII
In Ditro Test Results - Formulas I-XXV
Compound Ki (~.M)
6 14 0
9 13
11 170
12 250
13 25
15 17
19 12
36 >10,000
41 1300
50 >10,000
89 1800
90 28
91 39
92 75
93 70
94 165
95 740
96 725
97 130
98 30
99 60
100 15
101 12
102 120
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TABLE XXVII (continued)
In Vitro Test Results - Formulas I-XXV
Compound Ri (EcM)
103 20
104 103
105 760
106 210
107 32
108 2
109 24
110 5
Route of Administration
To effectively treat alopecia or promote hair
growth, the compounds used in the inventive methods
and pharmaceutical compositions must readily affect
the targeted areas. For these purposes, the compounds
are preferably administered topically to the skin.
For topical application to the skin, the
compc~inds pan be formulated into suitable ointments
containing the compounds suspended or dissolved in,
for example, mixtures with one or more of the
following: mineral oil, liquid petrolatum, white
petrolatum, propylene glycol, polyoxyethylene
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the compounds can be formulated into
suitable lotions or creams containing the active
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compound suspended or dissolved in, for example, a
mixture of one or more of the following: mineral oil,
sorbitan monostearate, polysorbate 60, cetyl ester
wax, cetearyl alcohol, 2-octyldodecanol, benzyl
alcohol and water.
Other routes of administration known in the
pharmaceutical art are also contemplated by this
invention.
Dosage
Dosage levels on the order of about 0.1 mg to
about 10,000 mg of the active ingredient compound are
useful in the treatment of the above conditions, with
preferred levels of about 0. 1 mg to about 1, 000 mg.
The specific dose level for any particular patient
will vary depending upon a variety of factors,
including the activity of the specific compound
employed; the age, body weight, general health, sex
and diet of the patient; the time of administration;
the rate of excretion; drug combination; the severity
of the particular disease being treated; and the °orm
of administration. Typically, in vitro dosage-effect
results provide useful guidance on the proper doses
for patient administration. Studies in animal models
are also helpful. The considerations for determining
the proper dose levels are well known in the art.
The compounds can be administered with other hair
revitalizing agents. Specific dose levels for the
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other hair revitalizing agents will depend upon the.
factors previously stated and the effectiveness of the
drug combination.
5 EXAMPLES
The following examples are illustrative of the
present invention and are not intended to be
limitations thereon. Unless otherwise indicated, all
percentages are based upon 100°s by weight of the final
10 composition.
Example 1
In Vivo Hair Generation Tests With C57 Black 6 Mice
Experiment A: C57 black 6 mice were used to
15 demonstrate the hair revitalizing properties of
pipecolic acid derivatives GPI 1116 and GPI 1102, as
well as related pipecolic acid derivative
neuroimmunophilin FKBP ligand GPI 1044. C57 black 6
mice, approximately 7 weeks old, had an area of about
20 2 inches by 2 inches on their hindquarters shaved to
remove all existing hair. Care w«s taken not to nick
or cause abrasion to the underlaying dermal layers.
The animals were in anagen growth phase, as indicated
by the pinkish color of the skin. Referring now to
25 FIGS. 1, 2, and 3, four animals were treated by
topical administration with 20a propylene glycol
vehicle (FIG. 1), and seven animals per group were
treated by topical administration with 10 ~M GPI 1116
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(FIG. 2), or 3 ~.M GPI 1102 (FIG. 3). The animals were.
treated with vehicle, GPI 1116, or GPI 1102 every 48
hours (3 applications total over the course of 5 days)
and the hair growth was allowed to proceed for 6
weeks. Hair growth was quantitated by the percent of
shaved area covered by new hair growth during this
time period.
FIG. 1 shows that animals treated with vehicle
exhibited only a small amount of hair growth in
patches or tufts, with less than 3% of the shaved area
covered with new growth. In contrast, FIGS. 2 and 3
show that animals treated with 10 ~,M GPI 1116 and 3 ~.M
GPI 1102 exhibited dramatic hair growth, covering as
much as 500 of the shaved area in some animals. FIG.
4 compares the hair growth score of unshaven animals
with the hair growth scores of shaven animals treated
with a vehicle, GPI 1116 (1 ~.M and 10 ~.M), GPI 1102 (1
~.M and 3 ~:M), and related neuroimmunophilin FKBP
ligand GPI 1044 ( 1 ~,M, 3 ~.M and 10 ~.M) .
Experiment B: C57 Black 6 mice were used to
demonstrate the hair revitalizing pr:~~~er ties of
neuroimmunophilin FKBP ligands, including GPI 1116.
C57 Black 6 mice, 55 to 75 days old, had an area of
about 2 inches by 2 inches on their hindquarters
shaved to remove all existing hair. Care was taken
not to nick or cause abrasion to the underlying dermal
layers. The animals were in a anagen growth phase
when shaved. Five animals per group were treated by
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topical administration with a vehicle, FK506, or a
neuroimmunophilin FKBP ligand (GPI 1116 or 1206) at a
concentration of one micromole per milliliter to the
shaved area. The animals were treated three times per
week, and hair growth was evaluated 14 days after
initiation of treatment. Hair growth was quantitated
by the percent of shaved area covered by new hair
growth, as scored by a blinded cbserver, on a scale of
0 (no growth) to five (complete hair regrowth in
shaved area).
Figure 5 shows that after 14 days, the animals
treated with vehicle exhibited the beginning of growth
in small tufts. In contrast, animals treated with one
of the neuroimmunophilin FKBP ligands exhibited
dramatic hair growth.
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Exaa~p 1 a 2
A lotion comprising the following composition may
be prepared.
(%)
95% Ethanol 80.0
a pipecolic acid derivative as defined above 10.0
a-Tocopherol acetate 0.01
Ethylene oxide (40 mole) adducts of hardened 0.5
castor oil
purified water 9.0
perfume and dye q.s.
Into 95% ethanol are added a pipecolic acid
derivative, a-tocopherol acetate, ethylene oxide (40
mole) adducts of hardened castor oil, perfume and a
dye. The resulting mixture is stirred and dissolved,
and purified water is added to the mixture to obtain
a transparent liquid lotion.
5 ml of the lotion may be applied once or twice
per day to a site having marked baldness or alopecia.
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Example 3
A lotion comprising the following composition
shown may be prepared.
(%)
95% Ethanol 80.0
a pipecolic acid derivative as defined above 0.005
Hinokitol 0.01
Ethylene oxide (40 mole) adducts of hardened 0.5
castor oil
Purified water I9.0
Perfume and dye q.s.
Into 95% ethanol are added a pipecolic acid
derivative, hinokitol, ethylene oxide (40 mole)
adducts of hardened castor oil, perfume, and a dye.
The resulting mixture is stirred, and purified water
is added to the mixture to obtain a transparent liquid
lotion.
The lotion may be applied by spraying once to 4
times per day to a site having marked baldness or
alopecia.
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Example 4
An emulsion may be prepared from A phase and B
phase having the following compositions.
5 (A phase) (~)
Whale wax 0.5
Cetanol 2.0
Petrolatum 5.0
Squalane - 10.0
l0 Polyoxyethylene (10 mole) monostearate 2.0
Sorbitan monooleate 1.0
a pipecolic acid derivative as defined above 0.01
(8 phase) (o)
Glycerine 10.0
15 Purified water 69.0
Perfume, dye, and preservative q,s.
The A phase and the B phase are respectively
heated and melted and maintained at 80°c. Both phases
20 are then mixed and cooled under stirring to normal
temperature to obtain an emulsion.
The emulsion may be applied by spraying once to
four times per day to a site having marked baidnes~ .c-r
alopecia.
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Example 5
A cream may be prepared from A phase and B phase
having the following compositions.
5 (A Phase) (s)
Fluid paraf f in 5 . 0
Cetostearyl alcohol 5.5
Petrolatum 5.5
Glycerine monostearate 33.0
10 Polyoxyethylene (20 mole) 2-octyldodecyl 3.0
ether
Propylparaben 0.3
(B Phase)
a pipecolic acid derivative as defined above 0.8
15 Glycerine 7.0
Dipropylene glycol 20.0
Polyethylene glycol 4000 5.0
Sodium Hexametaphosphate 0.005
Purified water 44.895
20
The A phase is heated and melted, and maintained
at 70°c . The B phase is added into the A phase and the
mixture is stirred to obtain an emulsion. The
~r~alsion is then cooled to obtain a cream.
25 The cream may be applied once to 4 times per day
to a site having marked baldness or alopecia.
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Example 6
A liquid comprising the following composition may
be prepared.
(%)
Polyoxyethylene butyl ether 20.0
Ethanol 50.0
a pipecolic acid derivative as defined above 0.001
Propylene glycol 5.0
Polyoxyethylene hardened castor oil 0.4
derivative (ethylene oxide 80 mole adducts)
Perfume q
.s.
Purified water q.s.
Into ethanol are added polyoxypropylene butyl
ether, propylene glycol, polyoxyethylene hardened
castor oil, a pipecolic acid derivative, and perfume.
The resulting mixture is stirred, and purified water
is added to the mixture to obtain a liquid.
The liquid may be applied once to 4 times per day
to a site having marked baldness or alopecia.
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Example 7
A shampoo comprising the following composition
may be prepared.
Sodium laurylsulfate 5.0
Triethanolamine laurylsulfate 5.0
Betaine lauryldimethylaminoacetate 6.0
Ethylene glycol distearate 2.0
Polyethylene glycol 5.0
a pipecolic acid derivative as defined above 5.0
Ethanol 2.0
Perfume 0.3
Purified water 69.7
Into 69.7 of purified water are added 5.0 g of
sodium laurylsulfate, 5.0 g of triethanolamine
laurylsulfate, 6.0 g of betaine lauryldimethyl-
aminoacetate. Then a mixture obtained by adding 5.0
g of a pipecolic acid derivative, 5.0 g of
polyethylene glycol, and 2.0 g of ethylene glycol
distearate to 2.0 g of ethanol, followed by stirring,
and 0.3 a of perfume are successively added. The
resulting mixture is heated and subsequently cooled to
obtain a shampoo.
The shampoo may be used on the scalp once or
twice per day.
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Exaamle 8
A patient is suffering from alopecia senilis. A
pipecolic acid derivative as identified above, or a
pharmaceutical composition comprising the same, may be
administered to the patient. Increased hair growth is
expected to occur following treatment.
Exams 1 a 9
A patient is suffering from male pattern
alopecia. A pipecolic acid derivative as identified
above, or a pharmaceutical composition comprising the
same, may be administered to the patient. Increased
hair growth is expected to occur following treatment.
Example 10
A patient is suffering from alopecia areata. A
pipecolic acid derivative as identified above, or a
pharmaceutical composition comprising the same, may be
administered to the patient. Increased hair growth is
expected to occur following treatment.
Example 11
A patient is suffering from hair loss caused by
skin lesions. A pipecolic acid derivative as
identified above, or a pharmaceutical composition
comprising the same, may be administered to the
patient. Increased hair growth is expected to occur
following treatment.
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Example 12
A patient is suffering from hair loss caused by
tumors. A pipecolic acid derivative as identified
above, or a pharmaceutical composition comprising the
5 same, may be administered to the patient. Increased
hair growth is expected to occur following treatment.
Example 13
A patient is suffering from hair loss caused by
10 a systematic disorder, such as a nutritional disorder
or an internal secretion disorder. A pipecolic acid
derivative as identified above, or a pharmaceutical
composition comprising the same, may be administered
to the patient. Increased hair growth is expected to
15 occur following treatment.
Example 14
A patient is suffering from hair loss caused by
chemotherapy. A pipecolic acid derivative as
20 identified above, or a pharmaceutical composition
comprising the same, may be administered to tile
patient. Increased hair growth is expected to occur
following treatment.
25 Example 15
A patient is suffering from hair loss caused by
radiation. A pipecolic acid derivative as identified
above, or a pharmaceutical composition comprising the
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same, may be administered to the patient. Increased
hair growth is expected to occur following treatment.
The invention being thus described, it will be
obvious that the same may be varied in many ways.
Such variations are not to be regarded as a departure
from the spirit and scope of the invention and all
such modifications are intended to be included within
the scope of the following claims.
