SMALL MOLECULE CARBAMATE OR UREA HAIR GROWTH COMPOSITIONS AND USES

COMPOSITIONS POUR LA CROISSANCE DES CHEVEUX A BASE DE PETITES MOLECULES DE CARBAMATES OU D'UREES ET UTILISATION DE CES COMPOSITIONS

English Abstract

This invention relates to pharmaceutical compositions and methods for treating
alopecia and promoting hair growth using small molecule carbamates and ureas.

French Abstract

Cette invention concerne des compositions pharmaceutiques et des procédés qui permettent de traiter l'alopécie et de favoriser la croissance des cheveux à l'aide de petites molécules de carbamates et d'urées.

Claims

43
WE CLAIM:
1. A method for treating alopecia or promoting
hair growth in an animal, which comprises
administering to said animal an effective amount of a
small molecule carbamate or urea.
2. The method of claim 1, wherein the small
molecule carbamate or urea has an affinity for an
FKBP-type immunophilin.
3. The method of claim 2, wherein the FKBP-type
immunophilin is FKBP-12.
4. The method of claim 1, wherein the small
molecule carbamate or urea is immunosuppressive.
5. The method of claim 1, wherein the small
molecule carbamate or urea is non-immunosuppressive.
5. The method of claim 1, wherein the small
molecule carbamate or urea is a compound of formula I
<IMG>

44
or a pharmaceutically acceptable salt, ester, ar
solvate thereof, wherein:
A is CH2, O, NH or N- (C1-C4 alkyl) ;
B and D are independently Ar, hydrogen,C1-C6
straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl or alkynyl, C5-C7 cycloalkyl
substituted C1-C6 straight or branched chain alkyl or
C3-C6 straight ar branched chain alkenyl or alkynyl,
C5-C7 cycloalkenyl substituted C1-C6 straight or
branched chain alkyl or C3-C6 straight or branched
chain alkenyl or alkynyl, Ar substituted C1-C6 straight
or branched chain alkyl, or Ar substituted C3-C6
straight or branched chain alkenyl or alkynyl ; wherein
any carbon atom of said alkyl is optionally replaced
by a heteroatom selected from the group consisting of
O, S, SO, SO2 and NR, wherein R is selected from the
group consisting of hydrogen, C1-C4 straight or
branched chain alkyl, C3-C4 straight or branched chain
alkenyl or alkynyl, and C1-C4 bridging alkyl wherein a
bridge is formed between the nitrogen and a carbon
atom of said heteroatom-containing chain to form a
ring, and wherein said ring is optionally fused to an
Ar group;
J is selected from the group consisting of
hydrogen, C1-C6 straight or branched chain alkyl, C3-C6
straight or branched chain alkenyl , and -CH2Ar; K is
selected from the group consisting of C1-C4 straight or
branched chain alkyl, -CH2Ar, and cyclohexylmethyl; or

45
J and K are taken together to form a 5-7 membered
heterocyclic ring which is substituted with O, S, SO,
or SO2 ;
Z is O or S;
Y is O or N, provided that
when Y is O, then R1 is a lone pair of
electrons and R2 is selected from the group consisting
of Ar, C1-C6 straight or branched chain alkyl, and C3-C6
straight or branched chain alkenyl or alkynyl; and
when Y is N, then R1 and R2 are independently
selected from the group consisting of Ar, C1-C6
straight or branched chain alkyl, and C3-C6 straight or
branched chain alkenyl or alkynyl; or R1 and R2 are
taken together to form a heterocyclic 5-6 membered
ring selected from the group consisting of
pyrrolidine, imidazolidine, pyrazolidine, piperidine,
and piperazine;
Ar is a carbocyclic aromatic group selected from
the group consisting of phenyl, 1-naphthyl,
2-naphthyl, indenyl, azulenyl, fluorenyl, and
anthracenyl; or a heterocyclic aromatic group selected
from the group consisting of 2-furyl, 3-furyl,
2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl,
2-pyrazolinyl, pyrazolidinyl, isoxazolyl,
isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl,
1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl,
pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl,

46
indolizinyl, indolyl, isoindolyl, 3H-indolyl,
indolinyl, benzo[b]furanyl, benzo[b]thio-phenyl,
1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl,
4H-quinolizinyl, quinolinyl,
1,2,3,4-tetrahydroquinolinyl, isoquinolinyl,
1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,
pteridinyl, carbazolyl, acridinyl, phenazinyl,
phenothiazinyl, and phenoxazinyl; wherein Ar is
unsubstituted or substituted with one or more
substituent(s) independently selected from the group
consisting of hydrogen, halogen, hydroxy, nitro, -SO3H,
trifluoromethyl, trifluoromethoxy, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched chain
alkenyl, O- (C1-C6 straight or branched chain alkyl),
O-(C3-C4 straight or branched chain alkenyl), O-benzyl,
O-phenyl, 1, 2-methylenedioxy, -NR3R4, carboxyl, N-(C1-C5
straight or branched chain alkyl or C3-C5 straight or
branched chain alkenyl) carboxamides, N,N-di-(C1-C5
straight or branched chain alkyl or C3-C5 straight or
branched chain alkenyl) carboxamides, morpholinyl,
piperidinyl, O-X, CH2- (CH2) q-X, O- (CH2) q-X, (CH2) q-O-X,
and CH=CH-X;
R3 and R4 are independently selected from the
group consisting of C1-C6 straight or branched chain
alkyl, C3-C6 straight or branched chain alkenyl,
hydrogen, and benzyl; or R3 and R4 are taken together
to form a 5-6 membered heterocyclic ring;

47
X is selected from the group consisting of
4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl,
2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, and
pyrimidyl;
q is 0-2; and
n is 0 or 1.
7. The method of claim 6, wherein J and K are
taken together to form a 5-7 membered ring.
8. The method of claim 7, wherein at least one
of said B and D is/are independently represented by
the formula - (CH2) r- (X) - (CH2) s-Ar, wherein:
r is 1-4;
s is 0-1; and
each X is independently selected from the group
consisting of CH2, O, S, SO, SO2, and NR, wherein R is
selected from the group consisting of hydrogen, C1-C4
straight or branched chain alkyl, C3-C4 straight or
branched chain alkenyl or alkynyl , and C1-C4, bridging
alkyl wherein a bridge is formed between the nitrogen
atom and Ar.
9. The method of claim 6, wherein:
Ar is selected from the group consisting of
phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl,
isoindolyl, quinolinyl, isoquinolinyl, 1,2,3,4-

48
tetrahydroiso-quinolinyl, and
1,2,3,4-tetrahydroquinolinyl, wherein said Ar is unsubstituted
or substituted with one or more substituent(s)
independently selected from the group consisting of
hydrogen, hydroxy, nitro, trifluoromethyl, C1-C6
straight or branched chain alkyl, O-(C1-C6 straight or
branched chain alkyl) , halogen, SO3H, and NR3R4; and
R3 and R4 are independently selected from the
group consisting of C1-C6 straight or branched chain
alkyl, C3-C6 straight or branched chain alkenyl,
hydrogen, and benzyl; or R3 and R4 are taken together
to form a 5-6 membered heterocyclic ring.
10. The method of claim 1, wherein the small
molecule carbamate or urea is a compound of formula II
or III
<IMGS>
or a pharmaceutically acceptable salt, ester, or
solvate thereof, wherein:
Y, R1 and R2 are as defined in claim 6;
Ar is as defined in claim 6;
J is hydrogen, C1-C6 straight or branched chain

49
alkyl , or C3-C6 straight or branched chain alkenyl ; and
w is 1 or 2.
11. The method of claim 1, wherein the small
molecule carbamate or urea is a compound of formula IV
or V
<IMG>
or a pharmaceutically acceptable salt, ester, or
solvate thereof, wherein:
Y, R1 and R2 are as defined in claim 6;
Ar is as defined in claim 6;
J is hydrogen, C1-C6 straight or branched chain
alkyl, or C3-C6 straight or branched chain alkenyl; and
w is 1 or 2.
12. The method of claim 1, wherein the small
molecule carbamate or urea is a compound of formula VI
<IMG>

50
or a pharmaceutically acceptable salt, ester, or
solvate thereof, wherein:
V is C, N, or S;
J and K, taken together with V and the carbon
atom to which they are respectively attached, form a
5-7 membered saturated or unsaturated heterocyclic
ring containing, in addition to V, one or more
heteroatom(s) selected from the group consisting of O,
S, SO, SO2, N, NH, and NR;
R is either C1-C9 straight or branched chain
alkyl , C2-C9 straight or branched chain alkenyl , C3-C9
cycloalkyl, C5-C7 cycloalkenyl, or Ar1, wherein R is
either unsubstituted of substituted with one or more
substituent(s) independently selected from the group
consisting of halo, haloalkyl, carbonyl, carboxy,
hydroxy, nitro, trifluoromethyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched chain
alkenyl , C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy,
benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino,
alkylamino, aminoalkyl, aminocarboxyl, and Ar2;
Ar1 and Ar2 are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or
heterocyclic ring; wherein the individual ring size is
5-8 members; wherein said heterocyclic ring contains
1-6 heteroatom(s) independently selected from the
group consisting of O, N, and S;
A, B, D, R1, R2, Y, Z, and n are as defined in
claim 6 above.

51
13. A pharmaceutical composition which
comprises:
(i) an effective amount of a small molecule
carbamate or urea for treating alopecia or
promoting hair growth in an animal; and
(ii) a pharmaceutically acceptable carrier.
14. The pharmaceutical composition of claim 13,
wherein the small molecule carbamate or urea has an
affinity for an FKBP-type immunophilin.
15. The pharmaceutical composition of claim 14,
wherein the FKBP-type immunophilin is FKBP-12.
16. The pharmaceutical composition of claim 13,
wherein the small molecule carbamate or urea is
immunosuppressive.
17. The pharmaceutical composition of claim 13,
wherein the small molecule carbamate or urea is
non-immunosuppressive.
18. The pharmaceutical composition of claim 13,
wherein the small molecule carbamate or urea is a
compound of formula I

52
<IMG>
or a pharmaceutically acceptable salt, ester, or
solvate thereof, wherein:
A is CH2, O, NH or N- (C1-C4 alkyl) ;
B and D are independently Ar, hydrogen, C1-C6
straight or branched chain alkyl, C2-C6 straight or
branched chain alkenyl or alkynyl, C5-C7 cycloalkyl
substituted C1-C6 straight or branched chain alkyl or
C3-C6 straight or branched chain alkenyl or alkynyl,
C5-C7, cycloalkenyl substituted C1-C6 straight or
branched chain alkyl or C3-C6 straight or branched
chain alkenyl or alkynyl, Ar substituted C1-C6 straight
or branched chain alkyl, or Ar substituted C3-C6
straight or branched chain alkenyl or alkynyl ; wherein
any carbon atom of said alkyl is optionally replaced
by a heteroatom selected from the group consisting of
O, S, SO, SO2 and NR, wherein R is selected from the
group consisting of hydrogen, C1-C4 straight or
branched chain alkyl, C3-C4 straight or branched chain
alkenyl or alkynyl, and C1-C4 bridging alkyl wherein a
bridge is formed between the nitrogen and a carbon
atom of said heteroatom-containing chain to form a

53
ring, and wherein said ring is optionally fused to an
Ar group;
J is selected from the group consisting of
hydrogen, C1-C6 straight or branched chain alkyl, C3-C6
straight or branched chain alkenyl, and -CH2Ar; K is
selected from the group consisting of C1-C4 straight or
branched chain alkyl, -CH2Ar, and cyclohexylmethyl; or
J and K are taken together to form a 5-7 membered
heterocyclic ring which is substituted with O, S, SO,
or SO2;
Z is O or S;
Y is O or N, provided that
when Y is O, then R1 is a lone pair of
electrons and R2 is selected from the group consisting
of Ar, C1-C6 straight or branched chain alkyl, and C3-C6
straight or branched chain alkenyl or alkynyl; and
when Y is N, then R1 and R2 are independently
selected from the group consisting of Ar, C1-C6
straight or branched chain alkyl, and C3-C6 straight or
branched chain alkenyl or alkynyl; or R1 and R2 are
taken together to form a heterocyclic 5-6 membered
ring selected from the group consisting of
pyrrolidine, imidazolidine, pyrazolidine, piperidine,
and piperazine;
Ar is a carbocyclic aromatic group selected from
the group consisting of phenyl, 1-naphthyl,
2-naphthyl, indenyl, azulenyl, fluorenyl, and
anthracenyl; or a heterocyclic aromatic group selected

54
from the group consisting of 2-furyl, 3-furyl,
2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl,
2-pyrazolinyl, pyrazolidinyl, isoxazolyl,
isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl,
1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl,
pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl,
indolizinyl, indolyl, isoindolyl, 3H-indolyl,
indolinyl, benzo[b]furanyl, benzo[b]thio-phenyl,
1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl,
4H-quinolizinyl, quinolinyl, 1,2,3,
4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,
4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,
pteridinyl, carbazolyl, acridinyl, phenazinyl,
phenothiazinyl, and phenoxazinyl; wherein Ar is
unsubstituted or substituted with one or more
substituent(s) independently selected from the group
consisting of hydrogen, halogen, hydroxy, nitro, -SO3H,
trifluoromethyl, trifluoromethoxy, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched chain;
alkenyl , O- (C1-C6; straight or branched chain alkyl ) ,
O-(C3-C4 straight or branched chain alkenyl), O-benzyl,
O-phenyl , 1,2 -methylenedioxy, -NR3R4, carboxyl , N- (C1-C5
straight or branched chain alkyl or C3-C5 straight or
branched chain alkenyl) carboxamides, N,N-di-(C1-C5
straight or branched chain alkyl or C3-C5 straight or
branched chain alkenyl) carboxamides, morpholinyl,

55
piperidinyl , O-X, CH2- (CH2) q-X, O- (CH2) q-X, (CH2) q-O-X,
and CH=CH-X;
R3 and R4 are independently selected from the
group consisting of C1-C6 straight or branched chain
alkyl, C3-C6 straight or branched chain alkenyl,
hydrogen, and benzyl; or R3 and R4 are taken together
to form a 5-6 membered heterocyclic ring;
X is selected from the group consisting of
4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl,
2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, and
pyrimidyl;
q is 0-2; and
n is 0 or 1.
19. The pharmaceutical composition of claim 18,
wherein J and K are taken together to form a 5-7
membered ring.
20. The pharmaceutical composition of claim 19,
wherein at least one of said B and D is/are
independently represented by the formula -(CH2)r-(X)-(CH2)
s-Ar, wherein:
r is 1-4;
s is 0-1; and
each X is independently selected from the group
consisting of CH2, O, S, SO, SO2, and NR, wherein R is
selected from the group consisting of hydrogen, C1-C4

56
straight or branched chain alkyl, C3-C4 straight or
branched chain alkenyl or alkynyl, and C1-C4 bridging
alkyl wherein a bridge is formed between the nitrogen
atom and Ar.
21. The pharmaceutical composition of claim 18,
wherein:
Ar is selected from the group consisting of
phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, indolyl,
isoindolyl, quinolinyl, isoquinolinyl,
1,2,3,4-tetrahydroiso-quinolinyl, and
1,2,3,4-tetrahydroquinolinyl, wherein said Ar is unsubstituted
or substituted with one or more substituent(s)
independently selected from the group consisting of
hydrogen, hydroxy, nitro, trifluoromethyl, C1-C6
straight or branched chain alkyl, O-(C1-C6 straight or
branched chain alkyl), halogen, SO3H, and NR3R4; and
R3 and R4 are independently selected from the
group consisting of C1-C6 straight or branched chain
alkyl, C3-C6 straight or branched chain alkenyl,
hydrogen, and benzyl; or R1 and R4 are taken together
to form a 5-6 membered heterocyclic ring.
22. The pharmaceutical composition of claim 13,
wherein the small molecule carbamate or urea is a
compound of formula II or III

57
<IMGS>
or a pharmaceutically acceptable salt, ester, or
solvate thereof, wherein:
Y, R1 and R2 are as defined in claim 18;
Ar is as defined in claim 18;
J is hydrogen, C1-C6 straight or branched chain
alkyl, or C3-C6 straight or branched chain alkenyl; and
w is 1 or 2.
23. The pharmaceutical composition of claim 13,
wherein the small molecule carbamate or urea is a
compound of formula IV or V
<IMGS>
or a pharmaceutically acceptable salt, ester, or
solvate thereof, wherein:
Y, R1 and R2 are as defined in claim 18;

58
Ar is as defined in claim 18;
J is hydrogen, C1-C6 straight or branched chain
alkyl, or C3-C6 straight or branched chain alkenyl; and
w is 1 or 2.
24. The pharmaceutical composition of claim 13,
wherein the small molecule carbamate or urea is a
compound of formula VI
<IMG>
or a pharmaceutically acceptable salt, ester, or
solvate thereof, wherein:
V is C, N, or S;
J and K, taken together with V and carbon atom to
which they are respectively attached, form a 5-7
membered saturated or unsaturated heterocyclic ring
containing, in addition to V, one or more
heteroatom(s) selected from the group consisting of O,
S, SO, SO2, N, NH, and NR;
R is either C1-C9 straight ar branched chain
alkyl, C2-C9 straight or branched chain alkenyl, C3-C9
cycloalkyl, C5-C7 cycloalkenyl, or Ar1, wherein R is
either unsubstituted of substituted with one or more

59
substituent(s) independently selected from the group
consisting of halo, haloalkyl, carbonyl, carboxy,
hydroxy, nitro, trifluoromethyl, C1-C6 straight or
branched chain alkyl, C2-C6 straight or branched chain
alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy,
benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino,
alkylamino, aminoalkyl, aminocarboxyl, and Ar2;
Ar1 and Ar2 are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or
heterocyclic ring; wherein the individual ring size is
5-8 members; wherein said heterocyclic ring contains
1-6 heteroatom(s) independently selected from the
group consisting of O, N, and S;
A, B, D, R1, R2, Y, Z, and n are as defined in
claim 18 above.

Description

CA 02333679 2000-12-O1
WO 99/62484 PCT/US98/11243
SMALL MOLECULE CARBAMATE OR UREA
HAIR GROWTH COMPOSITIONS AND USES
This application is a continuation-in-part of
U.S. Patent Application No. 08/869,426, filed on June
4, 1997, the entire contents of which are herein
incorporated by reference.
BACKGROUND OF THE INVENTION
1. Field of Invention
This invention relates to pharmaceutical
compositions and methods for treating alopecia and
promoting hair growth using low molecular weight,
small molecule carbamates and ureas.
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 disarders such as nutritional disorders and
internal secretion disorders. The mechanisms causing
hair loss are very complicated, but in some instances
can be attributed to aging, genetic disposition, the
activation of male hormones, the loss of blood supply
to hair follicles, and scalp abnormalities.
The immunosuppressant drugs FK506, rapamycin and
cyclosporin are well known as potent T-cell specific

CA 02333679 2000-12-O1
WO 99/62484 PCT/US98/11243
2 . _
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 of
FK506 and related agents are disclosed in many U.B.
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

CA 02333679 2000-12-O1
WO 99/62484 PCT/US98/11243
3 ._
they do not claim methods of hair revitalization, they
disclose the known use of FK506 for effecting hair
growth. Similar to FK506 (and the claimed variations
in the Honbo et al. patent), the compounds claimed in
these patents are relatively large. Further, the
cited patents 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 ~f
l0 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 for non-immunosuppressant, small molecule
compounds which are useful as hair revitalizing
compounds.
Hamilton and Steiner disclose in U.S. Patent No.
5,614,547 novel pyrrolidine carboxylate compounds
which bind to the immunophilin FKBP12 and stimulate
nerve growth, but which lack immunosuppressive
effects. Unexpectedly, it has been discovered that

CA 02333679 2000-12-O1
WO 99/62484 PCT/US98/11243
.. _
these non-immunosuppressant compounds promote hair
growth with an efficacy similar to FK506. Yet their
novel small molecule structure and non-
immunosuppressive properties differentiate them from
FK506 and related immunosuppressive compounds found in
the prior art.
SUMMARY OF THE INVENTION
The present invention relates to a method for
treating alopecia or promoting hair growth in an
animal, which comprises administering to said animal
an effective amount of a small molecule carbamate or
urea.
The present invention further relates to a
pharmaceutical composition which comprises:
(i) an effective amount of a small molecule
carbamate or urea for treating alopecia or
promoting hair growth in an animal; and
(ii) a pharmaceutically acceptable carrier.
The small molecule carbamates and ureas used in
the inventive methods and aharm.aceutlcc.~. ccr..:positi~~s
may be immunosuppressive, but are preferably non-
immunosuppressive compounds having an affinity for
FKBP-type immunophilins, particularly FKBP12. Non-
immunosuppressive compounds, as their name suggests,
do not exert any significant immunosuppressive
activity.

CA 02333679 2000-12-O1
WO 99162484 PCTlUS98/11243
. _
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 related neuroimmunophilin FKBP ligand, GPI 1044,
after six weeks. FIG. 2 shows that 90% of the shaved
area is covered with new hair growth when GPI 1044 is
administered.
FIG. 3 is a photograph of mice treated with 10 ~.M
of a related neuroimmunophilin FKBP ligand, GPI 1116,
after six weeks. FIG. 3 shows that 90% of the shaved
area is covered with new hair growth when GPI 1116 is
administered.
FIG. 4 is a photograph of mice treated with 3 ~,M
of a related neuroimmunophilin FKBP ligand, GPI 1102,
after six weeks. FIG. 3 shows that 90% of the shaved
area is covered with new hair growth when GPI 1102 is
administered.
FIG. 5 i~ a bar graph plotting the hair arowt'_u
scores of unshaven animals and shaven animals treated
with a vehicle, GPI 1044 ( 1 ~.M, 3 ~,M and 10 ~.M) , GPI
1116 ( 1 uM and 10 ~.M) , and GPI 1102 ( 1 ~.M and 3 ~.M) .
FIG. 6 is a bar graph depicting the relative hair
growth indices for C57 Black 6 mice treated with a
vehicle, FK506, related neuroimmunophilin FKBP ligand
GPI 1116, and GPI 1206 14 days after treatment with

CA 02333679 2000-12-O1
WO 99/62484 PCT/US98/I 1243
6 . _
each identified compound. Figure 6 demonstrates the
remarkable early hair growth promoted by
neuroimmunophilin FKBP ligands.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
"Alopecia" refers to deficient hair growth and
partial or complete loss of hair, including without
limitation androgenic alopecia (male pattern
baldness?, toxic alopecia, alopecia senilis, alopecia
areata, 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. A:Lopecia has a number of etiologies,
including genetic factors, aging, local and systemic
diseases, febrile conditions, mer_tal stresses,
hormonal problems, and secondary effects of drugs.
"GPI 1044" refers to the compound
~ /o s
N
O~O O D
L

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~ .
wherein B is 3-Phenylpropyl, D is 3-Phenylpropyl, and
L .is Phenyl.
"GPI 1102°' refers to 4-phenyl-1-(3-phenylpropyl)
butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2
piperidinecarboxylate.
"GPI 1116" refers to 1-phenethyl-3-phenylpropyl
1 - ( 3 , 3 - d i m a t h y 1 - 2 - o x o p a n t a n o y 1 ) - 2 -
piperidinecarboxylate.
"GPI 1206" refers to a compound of formula
N
O
N-
~ O
HNI 'S
GPI 1206
"Isomers" refer to different compounds that have
the same molecular formula. "Stereoisomers" are
isomers that differ only in the way the atoms are
arranged in space. "Enantiomers" are a pair of
stereoisomers that are non-superimposable mirror
images of each other. "Diatcrec__~orrers" are
stereoisomers which are not mirror images of each
other. "Racemic mixture" means a mixture containing
equal parts of individual enantiomers. "Non-racemic
mixture" is a mixture containing unequal parts of
individual enantiomers or stereoisomers.
"Pharmaceutically acceptable salt, ester, or
solvate" refers to a salt, ester, or solvate of a

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8
subject compound which possesses the desired
pharmacological activity and which is neither
biologically nor otherwise undesirable. A salt,
ester, or solvate can be formed with inorganic acids
such as acetate, adipate, alginate, aspartate,
benzoate, 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. Examples 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 argi_nine, lysir_e, and so forth. Alsc,
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

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9 , _
halides, such as benzyl and phenethyl bromides; and
others. Water or oil-soluble or dispersible products
are thereby obtained.
"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-pigmente~a rcot. 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

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predisposed to alopecia; and/or
(ii) inhibiting, retarding or reducing alopecia;
and/or
(iii) promoting hair growth; and/or
5 (iv) prolonging the anagen phase of the hair
cycle; and/or
(v) converting vellus hair to growth as terminal
hair. Terminal hair is coarse, pigmented, long hair
in which the bulb of the hair follicle is seated deep
10 in the dermis. Vellus hair, on the other hand, is
fine, thin, non-pigmented short hair in which the hair
bulb is located superficially in the dermis. As
alopecia progresses, the hairs change from the
terminal to the vellus type.
Methods of the Present Invention
The present invention relates to a methad for
treating alopecia or promoting hair growth in an
animal, which comprises administering to said animal
an effective amount of a small molecule carbamate or
urea.
The inventive method is particularly useful for
treating male pattern alopecia, alopecia senilis,
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.

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11
Pharmaceutical Compositions of the Present Invention
The present invention also relates to a pharma-
ceutical composition comprising:
(i) an effective amount of a small molecule
carbamate or urea for treating alopecia or
promoting hair growth in an animal; and
(ii) a pharmaceutically acceptable carrier.
SMALL MOLECULE CARHAMATES AND UREAS
The carbamates and ureas used in the methods and
pharmaceutical compositions of the present invention
are low molecular weight, small molecule compounds
having an affinity for FKBP-type immunophilins, such
as FKBP12. When a carbamate or urea binds to an FKBP-
type immunophil.in, it has been found to inhibit the
prolyl-peptidyl cis-trans 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, but preferably are non-
immunosuppressive. uxample~ of useful compounds ~.~=a
set forth below.
FORMULA I
An exemplary small molecule carbamate or urea is
a compound of Formula I

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12
K D
J' A
n B I
Z~ wY R1
1
R2
or a pharmaceutically acceptable salt, ester, or
solvate thereof, wherein:
A is CH2, O, NH or N- (C1-C4 alkyl) ;
B and D are independently Ar, hydrogen, C1-C6
straight or branched chain alkyl, CZ-C6 straight or
branched chain alkenyl or alkynyl, CS-C~ cycloalkyl
substituted C1-C6 straight or branched chain alkyl or
C3-C6 straight ar branched chain alkenyl or alkynyl,
CS-C, cycloalkenyl substituted C1-C6 straight or
branched chain alkyl or C3-C6 straight or branched
chain alkenyl or' alkynyl, Ar substituted C1-C6 straight
or branched chain alkyl, or Ar substituted C,-C
straight or branched chain alkemy or ~l'cynyl; vahereir_
any carbon atom of said alkyl is optionally replaced
by a heteroatom selected from the group consisting of
O, S, SO, SOz, and NR, wherein R is selected from the
group consisting of hydrogen, C1-C9 straight or
branched chain alkyl, C3-C4 straight or branched chain
alkenyl or alkynyl, and C1-CQ bridging alkyl wherein a
bridge is formed between the nitrogen and a carbon

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13
atom of said heteroatom-containing chain to form a
ring, and wherein said ring is optionally fused to an
Ar group;
J is selected from the group consisting of
hydrogen, C1-C6 straight or branched chain alkyl, C3-C6
straight or branched chain alkenyl, and -CHzAr; K is
selected from the group consisting of Cl-C4 straight or
branched chain alkyl, -CHzAr, and cyclohexylmethyl; or
J and K are taken together to form a 5-7 membered
heterocyclic ring which is substituted with O, S, SO,
or SO2;
Z is O or S;
Y is O or N, provided that
when Y is O, then R~ is a lone pair of
electrons and Rz is selected from the group consisting
of Ar, C1-C6 straight or branched chain alkyl, and C3-C6
straight or branched chain alkenyl or alkynyl; and
when Vii.' is N, then R1 and R2 are independently
selected from the group consisting of Ar, C1-C6
straight or branched chain alkyl, and C3-C6 straight or
rranched chain alkenyl or alkynyi.; or F~i arc: ~.~e
taken together to form a heterocyclic 5-6 membered
ring selected from the group consisting of
pyrrolidine, imidazolidine, pyrazolidine, piperidine,
and piperazine;
Ar is a carbocyclic aromatic group selected from
the group consisting of phenyl, 1-naphthyl, 2-
naphthyl, indenyl, azulenyl, fluorenyl, and

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14
anthracenyl; or a heterocyclic aromatic group selected
from the group consisting of 2-furyl, 3-furyl, 2-
thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl,
2-pyrazolinyl, pyrazolidinyl, isoxazolyl,
isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl,
1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl,
pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl,
indolizinyl, indolyl, isoindolyl, 3H-indolyl,
indolinyl, benzo[b]furanyl, benzo[b]thio-phenyl, 1H-
indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-
quinolizinyl, quinolinyl, 1,2,3,4-
tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-
tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,
pteridinyl, c~arbazolyl, acridinyl, phenazinyl,
phenothiazinyl, and phenoxazinyl; wherein Ar is
unsubstituted or substituted with one or more
substituent(s) :independently selected from the group
consisting of hydrogen, halogen, hydroxy, nitro, -S03H,
trifluoromethyl., trifluoromethoxi~, C1-C6 st=aight or
branched chain alkyl, CZ-C6 straight or branched chain
alkenyl, O- (C1-C5 straight or branched chain alkyl) , O-
(C3-C4 straight or branched chain alkenyl), O-benzyl,
O-phenyl, 1, 2-methylenedioxy, -NR3R9, carboxyl, N- (Cl-CS
straight or branched chain alkyl or C3-CS straight or
branched chain alkenyl) carboxamides, N,N-di-(C1-CS
straight or branched chain alkyl or C3-CS straight or

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branched chain. alkenyl) carboxamides, morpholinyl,
piperidinyl, O~-X, CHZ- (CH2) q-X, O- (CHZ) Q-X, (CHz) q-O-X,
and CH=CH-X;
R3 and R4 are independently selected from the
5 group consisting of Cl-C6 straight or branched chain
alkyl, C3-C6 straight or branched chain alkenyl,
hydrogen, and benzyl; or R, and R4 are taken together
to form a 5-6 membered heterocyclic ring;
X is selected from the group consisting of 4-
10 methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl,
2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, and
pyrimidyl;
q is 0-2; and
15 n is 0 or 1.
In a preferred embodiment of Formula I, J and K
are taken together to form a 5-7 membered ring.
In a more preferred embodiment of Formula I, at
least one of said B and D is/are independently
represented by the formula - (CHZ) r- (X) - (CHI,) e-Ar,
wherein:
r is 1-4;
s is 0-1;
Ar is as defined above in Formula I; and
each X is independently selected from the group
consisting of CH2, O, S, SO, 502, and NR, wherein R is
selected from t:he group consisting of hydrogen, C1-C4
straight or branched chain alkyl, C3-C4 straight or

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16
branched chain alkenyl or alkynyl, and C1-C4 bridging
alkyl wherein a bridge is formed between the nitrogen
atom and Ar.
In another preferred embodiment of Formula T, Ar
is selected from the group consisting of phenyl, 2-
pyridyl, 3-pyridyl, 4-pyridyl, indolyl, isoindolyl,
quinolinyl, i.soquinolinyl, 1,2,3,4-tetrahydroiso-
quinolinyl, and 1,2,3,4-tetrahydroquinolinyl, wherein
said Ar is unsubstituted or substituted with one or
more substituent(s) independently selected from the
group consisting of hydrogen, hydroxy, vitro,
trifluoromethyl., C1-C6 straight or branched chain
alkyl, O-(C,-C6 straight or branched chain alkyl),
halogen, S03H, and NR3R4; and
~ R3 and R9 are independently selected from the
group consisting of C1-C6 straight or branched chain
alkyl, C3-C6 straight or branched chain alkenyl,
hydrogen, and benzyl; or R3 and R4 are taken together
to form a 5-6 membered heterocyclic ring.
In another preferred embodiment of the compounds
of formula I, the small molecule carbamate or ureG is
the compound GF~I 1206, of the formula
N
~ ~ /
N
0
~t~s
GPI 1206

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1~ ,.
FORMULAS II AND III
Another exemplary small molecule carbamate or
urea is a compound of Formula iI or III
Ar
S
i
i''~ O
Ar J\N O~~AI
/~ Rl ~\
O-"Y-Rl ) w ~Y~O O/\~Ar
Rz ~r Rz
II III
or a pharmaceutically acceptable salt, ester, or
solvate thereof, wherein:
Y, R1 and R2 are as defined above in Formula I;
Ar is as defined above in Formula I;
J is hydrogen, C1-C6 straight or branched chain
alkyl , or C3-C6 straight or branched chain alkenyl ; and
w is 1 or 2.
FORMULAS IV AND V
A further exemplary small molecule carbamate or
urea is a compound of Formula IV or V
n ,- r _
Ar Ar
R1 R1
IV V

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or a pharmaceutically acceptable salt, ester, or
solvate thereof, wherein:
Y, R1 and Rz are as defined above in Formula I;
Ar is as defined above in Formula I;
J is hydrogen, C1-C6 straight or branched chain
alkyl, or C,-C6 straight or branched chain alkenyl; and
w is 1 or 2.
FORMULA VI
A further exemplary small molecule carbamate or
urea is a compound of Formula VI
K D
JwV 1 A n 2 B
O VI
Y Z
R1 R2
or a pharmaceutically acceptable salt, ester, or
solvate theree:f, wherein:
V is C, N, or S;
J and K, taken together with V and the carbon
atom to which they are respectively attached, form a
5-7 membered saturated or unsaturated heteracyclic
ring containing, in addition to V, one oz. more
heteroatom(s) selected from the group consisting of O,
S, SO, 502, N, NH, and NR;

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19 . _ _
R is either Cl-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, C3-C9
cycloalkyl, CS-C~ cycloalkenyl, or Arl, wherein R is
either unsubstituted of substituted with one or more
substituent(s) independently selected from the group
consisting of halo, haloalkyl, carbonyl, carboxy,
hydroxy, nitro, trifluoromethyl, C1-C6 straight or
branched chain alkyl, CZ-C6 straight or branched chain
alkenyl, C1-C~ alkoxy, Cz-C4 alkenyloxy, phenoxy,
benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino,
alkylamino, aminoalkyl, aminocarboxyl, and Ar2;
Arl and Ar2 are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or
heterocyclic ring; wherein the individual ring size is
5-8 members; wherein said heterocyclic ring contains
1-6 heteroatom(s) independently selected from the
group consisting of O, N, and S;
A, B, D, R1, R2, Y, Z, and n are as defined in
Formula I above.
Representative compounds of Formulas I-VI are
presented in Table I.

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TABLE I
(CH2)m D
O
\N n B
5
O
Z I R1
R2
1 o Compound m Z n D B R1 R2
1 1 O 2 3-pyridylH 2-methylbutyl H
2 1 O 2 3-pyridylH 1,1-dimethylpropyl
H
15 3 1 S 2 3-pyridylH cyclohexyl H
4 1 O 2 3-pyridylH cyclohexyl H
5 1 S 2 3-pyridylH 1-adamantyl H
All the compounds of Formulas I-VI possess
20 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-VI. It is understood that the compounds of
Formulas I-VI encompass individual stereoisomers as

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21
well as mixtures (racemic and non-racemic) of
stereoisomers. Preferably, S-stereoisomers are used
in the pharmaceutical compositions and methods of the
present invention.
Synthesis of Small Molecule Carbainates and Ureas
The compounds of Formulas I-VI may be readily
prepared by standard techniques of organic chemistry,
utilizing the general synthetic pathway depicted
below. As described by Scheme I, cyclic amino acids
1 protected by suitable blocking groups P on the amino
acid nitrogen may be reacted with alcohols ROH to
generate esters 2. After removal of the protecting
group, the free amine 3 may be reacted with a variety
of isocyanates or isothiocyanates to provide the final
ureas or thioureas, respectively. Alternatively,
reaction of 1 with amines provides the corresponding
amide compounds.

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22
SCHEME I
( CHa ) m -( CHZ ) ~
OH , R-OH ~ O-R nepzotect
Coupliag Method ~N
P O ~ O
1 2
~( CHZ ) ~
Ri - 4 C=Z
O-R
CHZC12
O
R1
3 5
Isocyanates (R1NC0) or isothiocyanates (R1NCS) 4
may be conveniently prepared from the corresponding
readily available amines by reaction with phosgene or
thiophosgene, as depicted in Scheme II.
SCHEME II
Z
--,. Rm_~TC;
C1 C1
Affinity for FKBP12
The compounds used in the inventive methods and
pharmaceutical compositions have an affinity fox the
FK506 binding protein, particularly FKBP12. The
inhibition of t:he prolyl peptidyl cis-traps isomerase

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23
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
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 II.
The cis-traps 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 traps 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 rage constant as a functior_ of inhib'tor
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 (SO mg/ml
in 1 mM HCl) and 10 mL of test compound at various
concentrations in dimethyl sulfoxide. The reaction is

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24
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.
TABLE II
In Vitro Test Results - Formulas I-V
Compound Ki ( nM )
1 70
2 742
3 131
4 1482
5 116
Route of Administration
To effectively treat alopecia or promote hair
growth, the compounds used ir: the ~nv~ntive method
and pharmaceutical compositions must readily affect
the targeted areas. For these purposes, the compounds
are preferably administered topically to the skin.
For topical application to the skin, the
compounds can be formulated into suitable ointments
containing the compounds suspended or dissolved in,
for example, mixtures with one or more of the

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following: mineral oil, liquid petrolatum, white
petrolatum, propylene glycol, polyoxyethylene
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the compounds can be formulated into
5 suitable lotions or creams containing the active
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
10 alcohol and wager.
Other routes of administration known in the
pharmaceutical art are also contemplated by this
invention.
15 Do s acre
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 leve:Ls of about 0 . 1 mg to about 1, 000 mg.
20 The specific dose level for any particular patient
will vary depending upon a variety of factc;~-s,
including the activity of the specific compound
employed; the age, body weight, general health, sex
and diet of the patient; the time of administration;
25 the rate of excretion; drug combination; the severity
of the particular disease being treated; and the form
of administration. Typically, in vitro dosage-effect
results provide useful guidance on the proper doses

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26 '
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
other hair revitalizing agents will depend upon the
factors previously stated and the effectiveness of the
drug combination.
EXAMPLES
The following examples are illustrative of the
present invention and are not intended to be
limitations thereon. Unless otherwise indicated, all
percentages are based upon 100% by weight of the final
composition.
Examp 1 a 1
Synthesis of 3-(3-pvridvl)-1-propyl (2S)-1-[(2-
methylbutyl) carbamoyl] pyrrolidine-2-carboxylate (1)
3 - ( 3 -pvridyl ) --1-propel ( 2 S) -N- ( tert-butyloxy-
carbonyl)Qyrrolidine-2-carbaxylate
A mixture of N-(tert-butyloxycarbonyl)-(S)-
proline (3.0 g;; 13.9 mmol), 3-(3-Pyridyl)-1-propanol
(2.90 g; 20.9 mmol) , dicyclohexylcarbodiimide (4.59 g;
22.24 mmol), camphorsulfonic acid (1.08 g; 4.63 mmol),
and 4-dimethylaminopyridine (0.60 g; 4.63 mmol) in dry
methylene chloride (100 mL) was stirred overnight.
The reaction mixture was diluted with methylene

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27
chloride (50 mL) and water (100 mL), and the layers
were separated. The organic phase was washed with
water (3 x 100 mL), dried over magnesium sulfate, and
concentrated, and the crude residue was purified on a
silica gel column eluting with ethyl acetate to obtain
4.60 g (95%) of the ester as a thick oil. 1H NMR (300
MHz, CDC13): b 1.45 (s, 9H); 1.70-2.05 (m, 5H); 2.32
(m, 1H); 2.71 (t, 2H); 3.50 (m, 2H); 4.15 (m, 2H);
4.18 (m, 1H); 7.24 (m, 1H); 7.51 (m, 1H); 8.48 (m,
2H) .
3-(3-pyridyl)-1-taropyl pyrrolidine-2-carboxylate
A solutian of 3- (3-pyridyl) -1-propyl (2S) -N-
(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (3.00
g; 9 mmol) in methylene chloride (50 mL) and
trifluoroacetic acid (5 mL) was stirred at room
temperature for three hours. Saturated potassium
carbonate was added until the pH was basic, and the
reaction mixture was extracted with methylene chloride
(3x) . The combined organic extracts were dried and
concentrated to yield 2.00 g (95%) of the free amine
as a thick oil. 1H NMR (30C MHz, CDC1-..) ~ S ' .8';-2.2~
(m, 6H); 2.79 (m, 2H); 3.03 (m, 2H total); 3.07 (m,
2H); 3.84 (m, 1H); 4.24 (m, 2H); 7.32 (m, 1H),; 7.60
(m, 1H) ; 8.57 (m, 2H) .
2S 3- (3 _pyridyl) --:L-propyl (2S) -1- [ (2-methybutyl) -
carbamoyl)pyrralidine-2-carboxvlate (1)
A solution of 2-methylbutylamine (113 mg; 1.3
mmol) and triethylamine (132 mg; 1.3 mmol) in

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methylene chloride (5 mL) was added to a solution of
triphosgene (128 mg; 0.43 mmol) in methylene chloride
(5 mL). The resulting mixture was refluxed for 1 hour
and then cooled to room temperature . 3 - ( 3 -Pyridyl ) -1-
propyl (2S)-pyrrolidine-2-carboxylate (300 mg; 1.3
mmol} in 5 mL of methylene chloride was added and the
resulting mixture was stirred for 1 hour and then
partitioned between water and a 1:1 mixture of ethyl
acetate and hexane. The organic phase was dried,
concentrated and purified by column chromatography
(50% ethyl acetate/hexane) to obtain 250 mg (55%) of
the compound of Example 1 (Compound 1, Table I) as an
oil. 'H NMR (CDC13, 300 MHz) : 8 0.89-0.93 (m, 6H) ;
1.10-1.20 (m, 1H); 1.27 (s, 1H); 1.36-1.60 (m, 2H);
1.72 (s, 2H); :1.97-2.28 (m, 6H); 2.70-2.75 (m, 2H);
2.92-3.54 (m, 4H); 4.16-4.20 (dt, 2H); 4.45-4.47 (m,
2H); 7.21-7.29 (m, 1H); 7.53-7.56 (dd, 1H); 8.46-8.48
(s, 2H) . Analysis calculated for C19H29N3~3 - 0.5 H20:
C, 64.02; H, 8.48; N, 11.79. Found: C, 63.72; H,
8.42; N, 11.83.
Examine 2
Synthesis of 3-(3-pyridyl)-1-propel (2S)-1-[(1',1'-
dimeth~rlpropyl)carbamoyl]pyrrolidine-2-carboxylate
(2)
Reaction of 3- (3-pyridyl) -1-propyl (2S) -
pyrrolidine-2-carboxylate with the isocyanate
generated from tert-amylamine and triphosgene, as

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described for Example 1, provided the compound of
Example 2 (Compound 2, Table I) in 62% yield. 1H NMR
(CDC13, 300 MHz): b 0.83 (t, 3H); 1.27 (s, 6H); 1.64-
1.71 (m, 2H); 1.91-2.02 (m, 7H); 2.66-2.71 (t, 2H);
3.29-3.42 (m, 2H); 4.11-4.15 (t, 3H); 4.37-4.41 (m,
1H) . Analysis calculated for C19Hz9N3O3 - 0,.5 H20: C,
64.04; H, 8.48; N, 11.79. Found: C, 64.23; H, 8.31;
N, 11.30.
Example 3
Synthesis of 3-(3-pyridyl)-1-propel (2S)-1
f(cyclohexyl)thiocarbamoyll-pyrrolidine-2
carboxylate (3)
A mixture of cyclohexylisothiocyanate (120 mg;
0.9 mmol), 3-(3-pyridyl)-1-propyl (2S)-pyrrolidine-2-
carboxylate {200 mg; 0.9 mmol) triethylamine (90 mg;
0.9 mmol) in 20 mL of methylene chloride was stirred
for 1 hour and then partitioned between water and a
1:1 mixture of ethyl acetate and hexane. The organic
phase was dried, concentrated and purified by column
chromatography (50°~ ethyl acetate/hexane) to obtain
160 mg (470) of the compound of Example 3 (Compound 3,
Table I) . 1H NMR (CDC13, 300 MHz) : 81.16-1.40 (m,
6H) ; 1 .50-1.71 (m, 4H) ; 1. 95-2 . 08 (m, 7H) ; 2 .70-2 .75
(t, 2H); 3.40-3.60 (m, 2H); 4.17-4.26 (m, 2H); 4.95-
4.98 (d, 1H); 5.26-5.29 (d, 1H); 7.17-7.25 (m., 1H).
Analysis calculated for CZOHz9N30zS : C, 63 . 97 ; H, 7 . 78 ;
N, 11.19. Found: C, 63.25; H, 7.80; N, 11.07.

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Example 4
Synthesis of 3-(3-pvridyl)-1-propyl (2S)-1
L(cvclohexyl)carbamovl7-pyrrolidine-2-carboxylate
(4)
5 A mixture of cyclohexylisocyanate (100 mg; 0.9
mmol), 3-(3-pyridyl)-1-propyl (2S)-pyrrolidine-2-
carboxylate (200 mg; 0.9 mmol) and triethylamine (90
mg; 0.9 mmol) in 20 mL of methylene chloride was
stirred for 1 hour and then partitioned between water
10 and a 1 :1 mixture of ethyl acetate and hexane . The
organic phase was dried, concentrated and purified by
column chromatography (50°s ethyl acetate/hexane) to
obtain 120 mg (36°s) of the compound of Example 4
( Compound 4 , Tabl a I ) . 1H NMR ( CDC13 , 3 0 0 MHz ) : b
15 1.20-1.27 (m, 6H); 1.69-1.75 (m, 4H); 1.94-2.03 (m,
4H); 2.67-2.73 (t, 2H); 3.31-3.44 (m, 3H); 4.12-4.16
(m, 2H); 4.39-4.42 (m, 1H); 7.25-7.34 (m, 1H); 7.25-
7.55 (dd, 1H); 8.45 (s, 2H). Analysis calculated for
CzoH29N3O3 - 0 . 6 Hz0 : C, 64 . 88 ; H, 8 . 22 ; N, 11 . 3 5 .
20 Found: C, 64.6'0; H, 8.18; N, 11.21.
Example 5
Synthesis of 3-(3-pyridyl)-1-propyl S2S)-1-[(1-
adamantyl)thiocarbamoyl7-pyrrolidine-2-carboxylate
25 (5)
A mixture of 1-adamantylisocyanate (250 mg; 0.9
mmol), 3-(3-pyridyl)-1-propyl (2S)-pyrrolidine-2-
carboxylate (200 mg; 0.9 mmol) and triethylamine (90

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mg; 0.9 mmol) in 20 mL of methylene chloride was
stirred for 1 hour and then partitioned between water
and a 1:1 mixture of ethyl acetate and hexane . The
organic phase was dried, concentrated and purified by
column chromatography (50% ethyl acetate/hexane) to
obtain 150 mg (38%) of the compound of Example 5
(Compound 5, Table I), 1H NMR (CDC13, 300 MHz): b
1.39-1.44 (d, 2H); 1.65 (s, 4H); 1.95-2.07 (m, 8H);
2.07-2.20 (m, 5H); 2.71-2.76 (m, 2H); 3.37-3.45 (m,
1H); 3.50-3.60 (m, 1H); 4.09-4.18 (m, 2H); 4.99-5.21
(d, 1H); 7.21-7.25 (m, 1H). Analysis calculated for
CZQH33N3OZS - 0 . 4 HzO: C, 66 . 30 ; H, 7 . 84 ; N, 9 . 66 .
Found: C, 66.41; H, 7.79; N, 9.50.
Example 6
In Vivo Hair Generation Tests With C57 Black 6 Mice
Experiment A: C57 black 6 mice were used to
demonstrate the hair revitalizing properties of
related neuro-i.mmunophilin FKBP ligands GPI 1044, GPI
1116 and GPI 1102. C57 black 6 mice, approximately 7
weeks old, had an area of about ?. ~.r~ches by ~ irL:WE~
on their hindquarters shaved to remove all existing
hair. Care was taken not to nick or cause abrasion to
the underlaying dermal layers. The animals were in
anagen growth phase, as indicated by the pinkish color
of the skin . Ref erring now to FIGS . 1, 2 , 3 and 4 ,
four animals were treated by topical administration
with 20% propylene glycol vehicle (FIG. 1), and, for

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32 w
each compound, seven animals were treated by topical
administration with 10 ACM GPI 1044 (FIG. 2) , 10 ACM GPI
1116 (FIG. 3) , or 3 ACM GPI 1102 (FIG. 4) . The animals
were treated with vehicle, GPI 1044, 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, 3 and
4 show that animals treated with the related
neuroimmunophilin ligands, 10 ~M GPI 1044, 10 ACM GPI
1116, and 3 ~M GPI 1102, exhibited dramatic hair
growth, covering as much as 50% of the shaved area in
some animals. FIG. 5 compares the hair growth score
of unshaven animals with the hair growth scores of
shaven animals treated with a vehicle, GPI 1044 (1 ACM,
3 :cM ~a.nd 1 0 yM) , GPI 1116 ( 1 uM and 1 C ~M) , and CFI
1102 ( 1 ~.M and 3 ACM) .
Experiment B: C57 Black 6 mice were used to
demonstrate the hair revitalizing properties of
neuroimmunophilin FKBP ligands, including GPI 1206.
C57 Black 6 mire, 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

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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
topical administration with a vehicle, FK506, or a
neuroimmunophilin FKHP 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 observer, on a scale of
0 (no growth) to five (complete hair regrowth in
shaved area).
Figure 6 shows that after 14 days, the animals
treated with vehicle exhibited the beginning of growth
in small tufts. In contrast, animals treated with one
of the neuroimmunophilin FKBP ligands, GPI 1206,
exhibited dramatic hair growth.

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Exam~~le 7
A lotion comprising the following composition may
be prepared.
(%)
95% Ethanol 80.0
a small molecule carbamate or urea as defined 10.0
above
a-Tocopherol acetate 0.01
Ethylene oxide (40 mole) adducts of hardened 0.5
castor oil
purified water 9.0
perfume and dye q.s.
Into 95% ethanol are added a small molecule
carbamate or urea, 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 8
A lotion comprising the following composition
shown may be prepared.
5 (%)
95% Ethanol 80.0
a small molecule carbamate or urea as defined 0.005
above
Hinokitol 0.01
10 Ethylene oxide (40 mole) adducts of hardened 0.5
castor oil
Purified water 19.0
Perfume arid dye q,s,
15 Into 95% ethanol are added a small molecule
carbamate or urea, 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
20 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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36 . .
Example 9
An emulsion may be prepared from A phase and B
phase having the following compositions.
(A phase) (%)
Whale wax 0.5
Cetanol 2.0
Petrolatum 5.0
Squalane 10.0
Polyoxyethylene (10 mole) monostearate 2.0
Sorbitan monooleate 1.0
a small molecule carbamate or urea as defined 0.01
above
(B phase) (%)
Glycerine 10.0
Purified water 69.0
Perfume, dye, and preservative q,s.
The A phase and the B phase are respectively
heated and melted and maintained at 80°c. Both phases
are then mixed and cooled under stirring to normal
temperature to obtain an emulsion.
The emulsion may k:-a app'.ied by spraying once to
four times per day to a site having marked baldness or
alopecia.

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Example 10
A cream may be prepared from A phase and B phase
having the following compositions.
(A Phase) (%)
Fluid paraf f in 5 . 0
Cetostearyl alcohol 5.5
Petrolatum 5.5
Glycerine monostearate 33.0
Polyoxyethylene (20 mole) 2-octyldodecyl 3.0
ether
Propylparaben 0.3
(B Phase) (%)
a small molecule carbamate or urea as 0.8
defined above
Glycerine 7.0
Dipropylene glycol 20.0
Polyethylene glycol 4000 5.0
Sodium Hexametaphosphate 0.005
Purified water 44.895
The A phase is heated and melted, and maintained
at 70°c . The B phase is added into the A phase and the
mixr_ure is stirred to obtain an emulsion. The
emulsion is then cooled to obtain a cream.
The cream may be applied once to 4 times per day
to a site having marked baldness or alopecia.

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3g
Examine I1
A liquid comprising the following composition may
be prepared.
Polyoxyethylene butyl ether 20.0
Ethanol 50.0
a small molecule carbamate or urea as defined 0.001
above
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 small molecule carbamate or urea, 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 baldr_ess or alopecia.

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39 . _
Example 12
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 small molecule carbamate or urea as defined 5.0
above
Ethanol 2.0
Perfume 0.3
Purified water'
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 small molecule carbamate or urea, 5.0 g of
polyethylene glycol, and 2.0 g of ethylene glycol
distearate to 2.0 g of ethanol, followed by stirr~_:g,
and 0.3 g of perfume are successively added. The
resulting mixture is heated and subsequently cooled to
obtain a shampoo.
The shampoo may be used on the scalp once or
twice per day.

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40 .
Example 13
A patient is suffering from alopecia senilis. A
small molecule carbamate or urea 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 14
A patient is suffering from male pattern
alopecia. A small molecule carbamate or urea 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 15
A.patient is suffering from alopecia areata. A
small molecule carbamate or urea as identified above,
or a pharmaceutical composition comprising the same,
may be administered to the patient. Increased hair
growth is expected to occur following trea~me~a.
Example 16
A patient is suffering from hair loss caused by
skin lesions. A small molecule carbamate or urea as
identified above, or a pharmaceutical composition
comprising the same, may be administered to the

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41
patient. Increased hair growth is expected to occur
following treatment.
Example 17
A patient is suffering from hair loss caused by
tumors. A small molecule carbamate or urea 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 18
A patient is suffering from hair loss caused by
a systematic disorder, such as a nutritional disorder
or an internal secretion disorder. A small molecule
carbamate or urea 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 i3
A patient is suffering from hair loss caused by
chemotherapy. A small molecule carbamate or urea 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 20
A patient is suffering from hair loss caused by
radiation. A small molecule carbamate or urea 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.
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.

Representative Drawing