U.S. patent application number 09/879888 was filed with the patent office on 2001-11-15 for heterocyclic ester and amide hair growth compositions and uses.
This patent application is currently assigned to GPI NIL Holdings, Inc.. Invention is credited to Hamilton, Gregory S., Steiner, Joseph P..
Application Number | 20010041733 09/879888 |
Document ID | / |
Family ID | 22217329 |
Filed Date | 2001-11-15 |
United States Patent
Application |
20010041733 |
Kind Code |
A1 |
Steiner, Joseph P. ; et
al. |
November 15, 2001 |
Heterocyclic ester and amide hair growth compositions and uses
Abstract
This invention relates to pharmaceutical compositions and
methods for treating alopecia and promoting hair growth using
heterocyclic esters or amides.
Inventors: |
Steiner, Joseph P.;
(Finksburg, MD) ; Hamilton, Gregory S.;
(Catonsville, MD) |
Correspondence
Address: |
Gary M. Nath
NATH & ASSOCIATES PLLC
1030 15th Street, N.W. - 6th Floor
Washington
DC
20005
US
|
Assignee: |
GPI NIL Holdings, Inc.
Wilmington
DE
|
Family ID: |
22217329 |
Appl. No.: |
09/879888 |
Filed: |
June 14, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09879888 |
Jun 14, 2001 |
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09089377 |
Jun 3, 1998 |
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6274617 |
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Current U.S.
Class: |
514/423 ;
514/330 |
Current CPC
Class: |
A61K 31/4439 20130101;
A61Q 7/00 20130101; A61K 2800/70 20130101; Y10S 514/88 20130101;
A61K 31/426 20130101; A61P 17/14 20180101; A61K 8/49 20130101 |
Class at
Publication: |
514/423 ;
514/330 |
International
Class: |
A61K 031/445 |
Claims
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 heterocyclic ester or amide.
2. The method of claim 1, wherein the heterocyclic ester or amide
is non-immunosuppressive.
3. The method Of claim 1, wherein the heterocyclic ester or amide
has an affinity for an FKBP-type immunophilin.
4. The method of claim 3, wherein the FKBP-type immunophilin if
FKBP-12.
5. The method of claim 1, wherein the heterocyclic ester or amide
is a compound of formula I 13or a pharmaceutically acceptable salt,
ester, or solvate thereof, wherein: A and B, together with the
nitrogen and carbon atoms to which they are respectively attacked,
form a 5 -7 membered saturated or unsaturated heterocyclic ring
containing, in addition to the nitrogen atom, one or more
additional O, S, SO, SO.sub.1, N, NH, or NR.sub.1heteroatom; X is O
or S; Z is O, NH, or NR.sub.1; W and Y are independently O, S,
CH.sub.2, or H.sub.2; R.sub.1 is C.sub.1-C.sub.6 straight or
branched chain alkyl or C.sub.2-C.sub.6 straight or branched chain
alkenyl, which is substituted with one or more substituent(s)
independently selected from the group consisting of
(Ar.sub.1).sub.n, C.sub.1-C.sub.6 straight or branched chain alkyl
or C.sub.2-C.sub.6 straight or branched chain alkenyl substituted
with (Ar.sub.1).sub.n, C.sub.3-C.sub.9 cycloalkyl, straight or
branched chain alkyl or C.sub.2-C.sub.6 straight or branched chain
alkenyl substituted with C.sub.3-C.sub.8 cycloalkyl, and Ar.sub.2;
n is 1 or 2; R.sub.2 is either C.sub.1-C.sub.9 straight or branched
chain alkyl, C.sub.2-C.sub.9 straight or branched chain alkenyl,
C.sub.3-C.sub.9 cycloalkyl, C.sub.9-C.sub.7 cycloalkenyl or
Ar.sub.1, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl
is either unsubstituted or substituted with one or more
substituent(s) independently selected from the group consisting of
C.sub.1-C.sub.4 straight or branched chain alkyl, C.sub.2-C.sub.4
straight or branched chain alkenyl, and hydroxy; and Ar.sub.1 and
Ar.sub.2 are independently an alicyclic or aromatic, mono-, bi or
tricyclic, carbo- or heterocyclic ring, wherein the ring is either
unsubstituted or substituted with one or more substituent(s)
independently selected from the group consisting of halo, hydroxy,
nitro, trifluoromethyl, C.sub.1-C.sub.6 straight or branched chain
alkyl, C.sub.2-C.sub.6 straight or branched chain alkenyl,
C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.4 alkenyloxy, phenoxy,
benzyloxy, and amino; wherein the individual ring size is 5-6
members; and wherein the heterocyclic ring contains 1-6
heteroatom(s) independently selected from the group consisting of
O, N, and S.
6. The method of claim 5, wherein the mono- or bicyclic, carbo- or
heterocyclic ring is selected from the group consisting of
naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl,
isoquinolinyl, fluorenyl, and phenyl.
7. The method of claim 5, wherein the one or more additional
heteroatom(s) in the 5-7 membered saturated or unsaturated
heterocyclic ring is NH or NR.sub.1.
8. The method of claim 1, wherein the heterocyclic ester or amide
is a compound of formula II 14or a pharmaceutically acceptable
salt, ester, or solvate thereof, wherein: A, B and C are
independently CH.sub.2, O, S, SO, SO.sub.2, NH, or NR.sub.1;
R.sub.1 is C.sub.1-C.sub.5 straight or branched chain alkyl or
C.sub.2-C.sub.5 straight or branched chain alkenyl, which is
substituted with one or more substituent(s) independently selected
from the group consisting of (Ar.sub.1).sub.n and C.sub.1-C.sub.6
straight or branched chain alkyl or C.sub.2-C.sub.6 straight or
branched chain alkenyl substituted with (Ar.sub.1).sub.n; n is 1 or
2; R.sub.2 is either C.sub.1-C.sub.9 straight or branched chain
alkyl, C.sub.2-C.sub.9 straight or branched chain alkenyl,
C.sub.1-C.sub.8 cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl or
Ar.sub.1; and Ar.sub.1 is an alicyclic or aromatic, mono-, bi- or
tricyclic, carbo- or heterocyclic ring, wherein the ring is either
unsubstituted or substituted with one or more substituent(s)
independently selected from the group consisting of halo, hydroxy,
nitro, trifluoromethyl, C.sub.1-C.sub.6 straight or branched chain
alkyl, C.sub.2-C.sub.6 straight or branched chain alkenyl,
C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.4 , alkenyloxy, phenoxy,
benzyloxy, and amino; wherein the individual ring size is 5-6
members; and wherein the heterocyclic ring contains 1-6
heteroatom(s) independently selected from the group consisting of
O, N, and S.
9. The method of claim 8, wherein: A is CH.sub.2; B is CH.sub.2 or
S; C is CH.sub.2 or NH; R.sub.1 is selected from the group
consisting of 3-phenylpropyl and 3-(3-pyridyl)propyl; and R.sub.2
is selected from the group consisting of 1,1-dimethylpropyl,
cyclohexyl, and tert-butyl.
10. The method of claim 9, wherein: S is CH C is NH; and R.sub.1 is
3-phenylpropyl.
11. The method of claim 9, wherein: B is S; and C is CH.sub.2.
12. The method of claim 8, wherein the compound is selected from
the group consisting of: 3-phenyl-1-propyl
(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-- (4-thiazolidine)
carboxylate; 3-(3-pyridyl)-1-propyl
(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)
carboxylate; and pharmaceutically acceptable salts, esters, and
solvates thereof.
13. The method of claim 1, wherein the heterocyclic ester or amide
is a compound of formula III 15or a pharmaceutically acceptable
salt, ester, or solvate thereof, wherein: A, B, C and D are
independently CH.sub.2, O, S, SO, SO.sub.2, NH, or NR.sub.1;
R.sub.1 is C.sub.1-C.sub.5 straight or branched chain alkyl or
C.sub.2-C.sub.5 straight or branched chain alkenyl, which is
substituted with one or more substituent(s) independently selected
from the group consisting of (AR.sub.1).sub.n and C.sub.1-C.sub.6
straight or branched chain alkyl or C.sub.2-C.sub.6 straight or
branched chain alkenyl substituted with (Ar.sub.1).sub.n; n is 1 or
2; R.sub.2 is either C.sub.1-C.sub.9 straight or branched chain
alkyl, C.sub.2-C.sub.9 straight or branched chain alkenyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or
Ar.sub.1; and Ar.sub.1is an alicyclic or aromatic, mono-, bi- or
tricyclic, carbo- or heterocyclic ring, wherein the ring is either
unsubstituted or substituted with one or more substituent(s)
independently selected from the group consisting of halo, hydroxy,
nitro, trifluoromethyl, C.sub.1-C.sub.6 straight or branched chain
alkyl, C.sub.2-C.sub.6 straight or branched chain alkenyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkenyloxy, phenoxy,
benzyloxy, and amino; wherein the individual ring size is 5-6
members; and wherein the heterocyclic ring contains 1-6
heteroatom(s) independently selected from the group consisting of
O, N, and S.
14. The method of claim 13, wherein: A is CH.sub.2; B is CH.sub.2;
C is S, O, or NH; D is CH.sub.2; R.sub.1 is selected from the group
consisting of 3-phenylpropyl and (3,4,5-trimethoxy)phenylpropyl;
and R.sub.2 is selected from the group consisting of
1,1-dimethylpropyl, cyclohexyl, tert-butyl, phenyl, and 3,4,5-
trimethoxyphenyl.
15. The compound of claim 14, wherein: C is NH; and R.sub.2 is
1,1-dimethylpropyl or phenyl.
16. The method of claim 1, wherein the heterocyclic ester or amide
is a compound of formula IV 16or a pharmaceutically acceptable
salt, ester, or solvate thereof, wherein: V is C, N, or S; A and B,
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 V, one or more
heteroatom(s) independently selected from the group consisting of
O, S, SO, SO.sub.2, N, NH, and NR; R is either C.sub.1-C.sub.9
straight or branched chain alkyl, C.sub.2-C.sub.9 straight or
branched chain alkenyl, C.sub.3-C.sub.9 cycloalkyl, C.sub.5-C.sub.7
cycloalkenyl, or Ar.sub.3l wherein R is either unsubstituted or
substituted with one or more substituent(s) independently selected
from the group consisting of halo, haloalkyl, carbonyl, carboxy,
hydroxy, nitro, trifluoromethyl, C.sub.1-C.sub.6 straight or
branched chain alkyl, C.sub.2-C.sub.6 straight or branched chain
alkenyl, C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.4 alkenyloxy;
phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino,
alkylamirnno, aminoalkyl, aminocarboxyl and Ar.sub.4; Ar.sub.3 and
Ar.sub.4 are independenrly 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; and R.sub.1, R.sub.2, W, X, Y, and Z are as defined in
claim 5 above.
17. A pharmaceutical composition which comprises: (i) an effective
amount of a heterocyclic ester or amide for treating alopecia or
promoting hair growth in an animal; and (ii) a pharmaceutically
acceptable carrier.
18. The pharmaceutical composition of claim 17, wherein the
heterocyclic ester or amide is non-immunosuppressive.
19. The pharmaceutical composition of claim 17, wherein the
heterocyclic ester or amide has an affinity for an FKBP-type
immunophilin.
20. The pharmaceutical composition of claim 19, wherein the
FKBP-type immunophilin is FKBP-12.
21. The pharmaceutical composition of claim 17, wherein the
heterocyclic ester or amide is a compound of formula I 17or a
pharmaceutically acceptable salt, ester or solvate thereof,
wherein: A and B, together with the nitrogen and carbon atoms to
which they are respectively attached, form a 5-7 membered saturated
or unsaturated heterocyclic ring containing, in addition to the
nitrogen atom, one or more additional O, S, SO, SO.sub.2, N, NH, or
NR.sub.1 heteroatom; X is O or S; Z is O, NH or NR.sub.1; W and Y
are independently O, S, CH.sub.2, or H.sub.2; R.sub.1 is
C.sub.1-C.sub.6 straight or branched chain alkyl or C.sub.2-C.sub.6
straight or branched chain alkenyl, which is substituted with one
or more substituent(s) independently selected from the group
consisting of (Ar.sub.1).sub.n, C.sub.1-C.sub.6 straight or
branched chain alkyl or C.sub.2-C.sub.6 straight or branched chain
alkenyl substituted with (Ar.sub.1).sub.n, C.sub.1-C.sub.6
cycloalkyl, C.sub.1-C.sub.6 straight or branched chain alkyl or
C.sub.2-C.sub.6 straight or branched chain alkenyl substituted with
C.sub.3-C.sub.8 cycloalkyl, and Ar.sub.2; n is 1 or 2; R.sub.2 is
either C.sub.1C.sub.9 straight or branched chain alkyl,
C.sub.2-C.sub.9 straight or branched chain alkenyl, C.sub.1-C.sub.8
cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl or Ar.sub.1, wherein said
alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted
or substituted with one or more substituent(s) independently
selected from the group consisting of C.sub.1-C.sub.4 straight or
branched chain alkyl, C.sub.1-C.sub.4 straight or branched chain
alkenyl, and hydroxy; and Ar.sub.1 and Ar.sub.2 are independently
an alicyclic or aromatic mono-, bi- or tricyclic, carbo- or
heterocyclic ring, wherein the ring is either unsubstituted or
substituted with one or more substituent(s) independently selected
from the group consisting of halo, hydroxy, nitro, trifluoromethyl,
C.sub.1-C.sub.6 straight or branched chain alkyl, C.sub.2-C.sub.6
straight or branched chain alkenyl, C.sub.1-C.sub.4 alkoxy,
C.sub.2-C.sub.4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein
the individual ring size is 5-6 members; and wherein the
heterocyclic ring contains 1-6 heteroatom(s) independently selected
from the group consisting of O, N, and S.
22. The pharmaceutical composition of claim 21, wherein the mono-
or bicyclic, carbo- or heterocyclic ring is selected from the group
consisting of napthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl,
quinolinyl, isoquinolinyl, fluorenyl, and phenyl.
23. The pharmaceutical composition of claim 21, wherein the one or
more additional heteroatom(s) in the 5-7 membered saturated or
unsaturated heterocyclic ring is NH or NR.sub.1.
24. The pharmaceutical composition of claim 17, wherein the
heterocyclic ester or amide is a compound of formula II 18or a
pharmaceutically acceptable salt, ester, or solvate thereof,
wherein: A, B and C are independently CH.sub.2, O, S, SO, SO.sub.2,
NH, or NR.sub.1; R.sub.1 is C.sub.1-C.sub.6 straight or branched
chain alkyl or C.sub.2-C.sub.6 straight or branched chain alkenyl,
which is substituted with one or more substituent(s) independently
selected from the group consisting of (Ar.sub.1).sub.n and
C.sub.1-C.sub.6 straight or branched chain alkyl or C.sub.2-C.sub.6
straight or branched chain alkenyl substituted with
(Ar.sub.1).sub.n; n is 1 or 2; R.sub.2 is either C.sub.1-C.sub.9
straight or branched chain alkyl, C.sub.2-C.sub.9 straight or
branched chain alkenyl, C.sub.3-C.sub.9 cycloalkyl, C.sub.5-C.sub.7
cycloalkenyl, or Ar.sub.1; and Ar.sub.1 is a an alicyclic or
aromatic, mono, bi- or tricyclic, carbo- or heterocyclic ring,
wherein the ring is either unsubstituted or substituted with one or
more substituent(s) independently selected from the group
consisting or halo, hydroxy, nitro, trifluoromethyl,
C.sub.1-C.sub.6 straight or branched chain alkyl, C.sub.2-C.sub.6
straight or branched chain alkenyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.5 alkenyloxy, phenoxy, benzyloxy, and amino, wherein
the individual ring is 5-6 members; and wherein the heterocyclic
ring contains 1-6 heteroatom(s) independently selected from the
group consisting of O, N, and S.
25. The pharmaceutical composition of claim 24, wherein: A is
OF.sub.2; B is CH.sub.2 or S; C is CH.sub.2 or NH; R.sub.1 is
selected from the group consisting of 3-phenylpropyl and
3-(3-pyridyl)propyl; and R.sub.2 is selected from the group
consisting of 1,1-dimethylpropyl, cyclohexyl, and tert-butyl.
26. The pharmaceutical composition of claim 25, wherein: B is
CH.sub.2; C is NH; and R.sub.1 is 3-phenylpropyl.
27. The pharmaceutical composition of claim 25, wherein: B is S;
and C is CH.sub.2.
28. The pharmaceutical composition of claim 24, wherein the
compound is selected from the group consisting of:
3-phenyl-1-propyl
(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)
carboxylate; and pharmaceutically acceptable salts, esters, and
solvates thereof.
29. The pharmaceutical composition of claim 17, wherein the
heterocyclic ester or amide is a compound of formula III 19or a
pharmaceutically acceptable salt, ester, or solvate thereof,
wherein: A, B, C and D are independently CH.sub.2, O, S, SO,
SO.sub.2, NH, or NR.sub.1; R.sub.1 is C.sub.1-C.sub.5 straight or
branched chain alkyl or C.sub.2-C.sub.5 straight or branched chain
alkenyl, which is substituted with one or more substituent(s)
independently selected from the group consisting of
(Ar.sub.1).sub.n and C.sub.1-C.sub.6 straight or branched chain
alkenyl or C.sub.2-C.sub.6 straight or branched chain alkenyl
substituted with (Ar.sub.1).sub.n; n is 1 or 2; R.sub.2 is either
C.sub.1-C.sub.9 straight or branched chain alkyl, C.sub.2-C.sub.9
straight or branched chain alkenyl, C.sub.3-C.sub.9 cycloalkyl,
C.sub.5-C.sub.7 cycloalkenyl, or Ar.sub.1; and Ar.sub.1is an
alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or
heterocyclic ring, wherein the ring is either unsubstituted or
substituted with one or more substituent(s) independently selected
from the group consisting of halo, hydroxy, nitro, trifluoromethyl,
C.sub.1-C.sub.6 straight or branched chain alkyl, C.sub.2-C.sub.6
straight or branched chain alkenyl, C.sub.1-C.sub.4 alkoxy,
C.sub.2-C.sub.4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein
the individual ring size is 5-6 members; and wherein the
heterocyclic ring contains 1-6 heteroatom(s) independently selected
from the group consisting of O, N, and S.
30. The pharmaceutical composition of claim 29, wherein: A is C; B
is CH.sub.3; C is S, O or NH; D is CH.sub.2; R, is selected the
group consisting of 3-phenylpropyl and
(3,4,5-trimethoxy)phenylpropyl; and R.sub.2 is selected from the
group consisting of 1,1-dimethylpropyl, cyclohexyl, tert-butyl,
phenyl, and 3,4,5-trimethoxyphenyl.
31. The compound of claim 30, wherein: C is NH; and R.sub.2 is
1,1-dimethylpropyl or phenyl.
32. The pharmaceutical composition of claim 17, wherein the
heterocyclic ester or amide is a compound of formula IV 20or a
pharmaceutically acceptable salt, ester, or solvate thereof,
wherein: V is C, N, or S; A and B, 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) independently selected
from the group consisting of O, S, SO, SO.sub.2, N, NH, and NR; R
is either C.sub.1-C.sub.9 straight or branched chain alkyl,
C.sub.1-C.sub.9 straight or branched chain alkenyl, C.sub.1-C.sub.9
cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or Ar.sub.3, wherein R is
substituent(s) independently selected from the group consisting of
halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro,
trifluoromethyl, C.sub.1-C.sub.6 straight or branched chain alkyl,
C.sub.2-C.sub.5 straight or branched chain alkenyl, C.sub.1-C.sub.4
alkoxy, C.sub.2-C.sub.4 alkenyloxy, phenoxy, benzyloxy, thioalkyl,
alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl,
aminocarboxyl, and Ar.sub.4; Ar.sub.3 and Ar.sub.4 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; and R.sub.1, R.sub.2, W, X, Y, and Z are as defined in
claim 21 above.
Description
[0001] This application is a continuation-in-part of U.S. patent
application No. 08/869,426, filed on Jun. 4, 1997, the entire
contents of which are herein incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of Invention
[0003] This invention relates to pharmaceutical compositions and
methods for treating alopecia and promoting hair growth using low
molecular weight, small molecular heterocyclic esters or
amides.
[0004] 2. Description of Related Art
[0005] 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 hair loss are very complicated, but in some instances
can he attributed to aging, genetic disposition, the activation of
male hormones, the loss of blood supply to hair follicles, and
scalp abnormalities.
[0006] The immunosuppressant drugs FK506, rapamycin and cyclosporin
are well known as potent T-cell specific 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
stimulation (Honbo et al., EP 0 423 714 A2). Honbo et al. discloses
the use of relatively large tricyclic compounds, known for the
immunosuppressive effects, as hair revitalizing agents.
[0007] The hair growth and revitalization effects of FK506 and
related agents are disclosed in many U.S. patents (Goulet et al.,
U.S. Pat. No. 5,258,389; Luly et al., U.S. Pat. No. 5,457,111;
Goulet et al., U.S. Pat. No. 5,532,248; Goulet et al., U.S. Pat.
No. 5,189,042; and Ok et a U.S. Pat. No. 5,208,241; Rupprecht et
al. U.S. Pat. No. 5,284,840; Organ et al., U.S. Pat. No.
5,284,877). These patents claim FK506 related compounds. Although
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.
[0008] Other U.S. patents disclose the use of cyclosporin and
related compounds for hair revitalization (Hauer et al., U.S. Pat.
No. 5,342,625; Eberle, U.S. Pat. No. 5,284,826; Hewitt et al., U.S.
Pat. No. 4,996,193). These patents also relate to compounds useful
treating autoimmune diseases and cite the known use of cyclosporin
and related immunosuppressive compounds for hair growth.
[0009] 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.
[0010] Hamilton and Steiner disclose in U.S. Pat. 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 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
[0011] 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 heterocyclic
ester or amide.
[0012] The present invention further relates to a pharmaceutical
composition which comprises:
[0013] (i) an effective amount of a heterocyclic ester or amide for
treating alopecia or promoting hair growth in an animal; and
[0014] (ii) a pharmaceutically acceptable carrier.
[0015] The heterocyclic esters and amides used in the inventive
methods and pharmaceutical compositions have an affinity for
FKBP-type immunophilins and do not exert any significant
immunosuppressive activity.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 is a photogragh of C57 Black 6 mice before being
shaved for the hair regeneration experiment.
[0017] FIG. 2 is a photograph of mice treated with a vehicle a six
weeks. FIG. 2 shows that less than 3% of the shaved area is covered
with new hair growth when the vehicle (control) is
administered.
[0018] FIG. 3 is a photograph of mice treated with 10 .mu.M of GPI
1046, a related non-immunosuppressive neuroimmunophilin FKBP
ligand, after six weeks. FIG. 3 shows the remarkable effects of
neuroimmunophilin FKBP ligands, wherein 90% of the shaved area is
covered with new hair growth.
[0019] FIG. 4 is a photograph of mice treated with 30 .mu.M of GPI
1046, a related non-immunosuppressive neuroimmunophilin FKBP
ligand, after six weeks. FIG. 4 shows the remarkable ability of
neuroimmunophilin FKBP ligands to achieve, essentially, complete
hair regrowth in the shaved area.
[0020] FIG. 5 is a bar graph depicting the relative hair growth
indices for C57 Black 6 mice treated with a vehicle, FK506, and
various non-immunosuppressive neuroimmunophilin FKBP ligands,
including GPI 1572, 14 days after treatment with each identified
compound. FIG. 5 demonstrates the remarkable early hair growth
neuroimmunophilin FKBP ligands.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0021] "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 chase 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.
[0022] "GPI 1605" refers to a compound of formula 1
[0023] "GPI 1046" refers to 3-(3-pyridyl)-1-propyl
(2s-1-(3,3-dimethyl-1,2- -dioxopentyl)-2-pyrrolidine-carboxylate, a
compound of formula 2
[0024] "GPI 1312" refers to a compound of formula 3
[0025] "GPI 1572" refers to a compound of formula 4
[0026] "GPI 1389" refers to a compound of formula 5
[0027] "GPI 1511" refers to a compound of formula 6
[0028] "GPI 1234" refers to a compound of formula 7
[0029] "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
equal parts of individual enantiomers. "Non-racemic mixture" is a
mixture containing unequal parts or individual enantiomers or
stereoisomers.
[0030] "Pharmaceutically acceptable salt, ester, or solvate" refers
to a salt, ester, or solvate or a subject compound which possesses
the desired pharmacolocical 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 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 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.
[0031] "Pilar cycle" refers to the life cycle of hair follicles,
and includes three phases:
[0032] (1) the anagen phase, the period of active hair growth
which, insofar as scalp hair is concerned, lasts about three to
five years;
[0033] (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
[0034] (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.
[0035] 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.
[0036] "Promoting hair growth" refers to maintaining, inducing,
stimulating, accelerating, or revitalizing the germination of
hair.
[0037] "Treating alopecia" refers to:
[0038] (i) preventing alopecia in an animal which may be
predisposed to alopecia; and/or
[0039] (ii) inhibiting, retarding or reducing alopecia; and/or
[0040] (iii) promoting hair growth; and/or
[0041] (iv) prolonging the anagen phase of the hair cycle;
and/or
[0042] (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 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
[0043] 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 heterocyclic
ester or amide.
[0044] 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.
[0045] Pharmaceutical Compositions of the Present Invention
[0046] The present invention also relates to a pharmaceutical
composition comprising:
[0047] (i) an effective amount of a heterocyclic ester or amide for
treating alopecia or promoting hair growth in an animal; and
[0048] (ii) a pharmaceutically acceptable carrier.
HETEROCYCLIC ESTERS AND AMIDES
[0049] The heterocyclic esters and amides used in the methods and
pharmaceutical compositions of the present invention are low
molecular weight, small molecule compounds having an affinity for
an FKBP-type immunophilin, such as FKBP12. When a heterocyclic
ester or amide binds to an FKBP-type immunophilin, 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. The
compounds are devoid of any significant immunosuppressive
activity.
FORMULA I
[0050] The heterocyclic ester or amide may be a compound of formula
I 8
[0051] or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
[0052] A and B, together with the nitrogen and carbon atoms to
which they are respectively attached, form a 5-7 membered saturated
or unsaturated heterocyclic ring containing, in addition to the
nitrogen atom, one or more additional O, S, SO, SO.sub.2, N, NH or
NR.sub.1 heteroatom(s);
[0053] X is O or S;
[0054] Z is O, NH or NR;
[0055] W and Y are independently O, S, CH.sub.2, or H2;
[0056] R.sub.1 is C.sub.1-C.sub.6 straight or branched chain alkyl
or C.sub.2-C.sub.6 straight or branched chain alkyl, which is
substituted with one or more sustituent(s) independently selected
from the group consisting of (Ar.sub.1).sub.n, C.sub.3-C.sub.6
straight or branched chain alkyl or C.sub.2-C.sub.6 straight or
branched chain alkenyl substituted with (Ar.sub.1).sub.n,
C.sub.3-C.sub.9 cycloalkyl, C.sub.1-C.sub.6 straight or branched
chain alkyl or C.sub.2-C.sub.6 , straight or branched chain alkenyl
substituted with C.sub.3-C.sub.8 cycloalkyl, and Ar.sub.2;
[0057] n is 1 or 2;
[0058] R.sub.2 is either C.sub.1-C.sub.9 straight or branched chain
alkyl, C.sub.2-C.sub.9 straight or branched chain or alkenyl,
C.sub.3-C.sub.9 cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or
Ar.sub.1, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl
is either unsubstituted or substituted with one or more
substituent(s) independently selected from the group consisting of
C.sub.1-C.sub.4 straight or branched chain alkyl, C.sub.2-C.sub.4
straight or branched chain alkenyl, and hydroxyl; and
[0059] Ar.sub.1 and Ar.sub.2 are independently an alicyclic or
aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring,
wherein the ring is either unsubstituted or substituted with one or
more substituent(s) independently selected from the group
consisting of halo, hydroxyl, nitro, trifluoromethyl,
C.sub.1-C.sub.6 straight or branched chain alkyl, C.sub.2-C.sub.6
straight or branched chain alkenyl, C.sub.1-C.sub.4 alkoxy,
C.sub.2-C.sub.4 alkenloxy, phenoxy, benzyloxy, and amino; wherein
the individual ring size is 5-6members; and wherein the
heterocyclic ring contains 7-6 heteroatom(s) independently selected
from the group consisting of O, N, and S.
[0060] Suitable carbo- and heterocyclic rings include without
limitation naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl,
quinolinyl, isoquinolinyl, fluorenyl and phenyl.
FORMULA II
[0061] Additionally, the heterocyclic ester or amide may be a
compound of formula II 9
[0062] or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
[0063] A, B and C are independently CH.sub.2, O, S, SO, SO.sub.2,
NH or NR.sub.1;
[0064] R.sub.1 is C.sub.1-C.sub.5 straight or branched chain alkyl
or C.sub.2-C.sub.5 straight or branched chain alkenyl, which is
substituted with one or more substituent(s) independently selected
from the group consisting of (Ar.sub.1).sub.n and C.sub.1-C.sub.6
straight or branched chain alkyl or C.sub.2-C.sub.6 straight or
branched chain alkenyl substituted with (Ar.sub.1).sub.n;
[0065] n is 1 or 2;
[0066] R.sub.2 is either C.sub.1-C.sub.9 straight or branched chain
alkyl, C.sub.2-C.sub.9 straight or branched chain alkenyl,
C.sub.1-C.sub.9 cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or
Ar.sub.1; and
[0067] Ar.sub.1 is an alicyclic or aromatic, mono-, bi- or
tricyclic, carbo- or heterocyclic ring, wherein the ring is either
unsubstituted or substituted with one or more substituent(s)
independently selected from the group consisting of halo, hydroxyl,
nitro, trifluoromethyl, C.sub.1-C.sub.4 straight or branched chain
alkyl, C.sub.2-C.sub.6 straight or branched chain alkenyl,
C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.4 alkenyloxy, phenoxy,
benzyloxy, and amino; wherein the individual ring size is 5-6
members; and wherein the heterocyclic ring contains 1-6
heteroatom(s) independently selected from the group consisting of
O, N, and S.
[0068] In a preferred embodiment of the compounds of formula I, the
heterocyclic ester or amide is the compound GPI 1572, of the
formula 10
[0069] In a particularly preferred embodiment of formula
compounds:
[0070] A is CH.sub.2;
[0071] B is CH.sub.2 or S;
[0072] C is CH.sub.2 or NH;
[0073] R.sub.1 is selected from the group consisting of
3-phenylpropyl and 3-(3-pyridyl)propyl; and
[0074] R.sub.2 is selected from the group consisting of
1,1-dimethylpropyl cyclohexl, and tert-butyl.
[0075] Specific examples of this embodiment are presented in TABLE
I.
1TABLE I No. A B C R.sub.1 R.sub.2 1 CH.sub.2 S CH.sub.2
3-phenylpropyl 1,1-dimethylpropyl 2 CH.sub.2 S CH.sub.2
3-(3-pyridyl)propyl 1,1-dimethylpropyl 3 CH.sub.2 S CH.sub.2
3-phenylpropyl cyclohexyl 4 CH.sub.2 S CH.sub.2 3-phenylpropyl
tert-butyl 5 CH.sub.2 CH.sub.2 NH 3-phenylpropyl 1,1-dimethylpropyl
6 CH.sub.2 CH.sub.2 NH 3-phenylpropyl cyclohexyl 7 CH.sub.2
CH.sub.2 NH 3-phenylpropyl tert-butyl
FORMULA III
[0076] The heterocyclic ester or amide may also be a compound of
formula III 11
[0077] or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
[0078] A, B, C and D are independently CH.sub.2, O, S, SO,
SO.sub.2, NH or NR.sub.1;
[0079] R.sub.1 is C.sub.1-C.sub.5 straight or branched chain alkyl
or C.sub.2-C.sub.5 straight or branched chain alkenyl, which is
substituted with one or more substituent(s) independently selected
from the group consisting of (Ar.sub.1).sub.n and C.sub.1-C.sub.6
straight or branched chain alkyl or C.sub.2-C.sub.6 straight or
branched chain alkenyl substituted with (Ar.sub.1).sub.n;
[0080] n is 1 or 2;
[0081] R.sub.2 is either C.sub.1-C.sub.9 straight or branched chain
alkyl, C.sub.2-C.sub.9 straight or branched chain alkenyl,
C.sub.3-C.sub.9 . cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or
Ar.sub.1; and
[0082] Ar.sub.1 is an alicyclic or aromatic, mono-, bi- or
tricyclic, carbo- or heterocyclic ring, wherein the ring is either
unsubstituted or substituted with one or more substituent(s)
independently selected from the group consisting of halo, hydroxyl,
nitro, trifluoromethyl, C.sub.1-C.sub.6 straight or branched chain
alkyl, C.sub.2-C.sub.6 straight or branched chain alkenyl, C.sub.1
-C.sub.4 alkoxy, C.sub.2-C.sub.4 alkenyloxy, phenoxy, benzyloxy,
and amino; wherein the individual ring size is 5-6 members; and
wherein the heterocyclic ring contains 1-6 heteroatom(s)
independently selected from the group consisting of O, N, and
S.
[0083] In a particularly preferred embodiment of formula III
compounds:
[0084] A is CH.sub.2;
[0085] B is CH.sub.2;
[0086] C is S, O, or NH;
[0087] D is CH.sub.2;
[0088] R.sub.1 is selected from the group consisting of
3-phenylpropyl and (3,4,5-trimethoxy)phenylpropyl; and
[0089] R.sub.2 is selected from the group consisting of
1,1-dimethylpropyl, cyclohexyl, tert-butyl, phenyl, and
3,4,5-trimethoxyphenyl.
[0090] Specific examples of this embodiment are presented in TABLE
II.
2TABLE II No. A B C D R.sub.1 R.sub.2 8 CH.sub.2 CH.sub.2 S
CH.sub.2 3-phenylpropyl 1,1-dimethylpropyl 9 CH.sub.2 CH.sub.2 O
CH.sub.2 3-phenylpropyl 1,1-dimethylpropyl 10 CH.sub.2 CH.sub.2 S
CH.sub.2 3-phenylpropyl cyclohexyl 11 CH.sub.2 CH.sub.2 O CH.sub.2
3-phenylpropyl cyclohexyl 12 CH.sub.2 CH.sub.2 S CH.sub.2
3-phenylpropyl phenyl 13 CH.sub.2 CH.sub.2 O CH.sub.2
3-phenylpropyl phenyl 14 CH.sub.2 CH.sub.2 NH CH.sub.2
3-phenylpropyl 1,1-dimethylpropyl 15 CH.sub.2 CH.sub.2 NH CH.sub.2
3-phenylpropyl phenyl
FORMULA IV
[0091] The heterocyclic ester or amide may also be a compound of
formula IV 12
[0092] or a pharmaceutically acceptable salt, ester, or solvate
thereof, wherein:
[0093] V is C, N, or S;
[0094] A and B, 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) independently selected from the group consisting
of O, S, SO, SO.sub.2, N, NH;, and N;
[0095] R is either C.sub.1-C.sub.9 straight or branched chain
alkyl, C.sub.2-C.sub.9 straight or branched chain alkenyl,
C.sub.1-C.sub.9 cycloalkyl, C.sub.5-C.sub.7 cycloalkenyl, or
Ar.sub.3, wherein R is either unsubstituted or substituted with one
or more substituent(s) independently selected from the group
consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro,
trifluoromethyl, C.sub.1-C.sub.6 straight or branched chain alkyl,
C.sub.2-C.sub.6 straight or branched chain alkenyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 alkenyloxy, phenoxy, benzyloxy, thioalkyl,
alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl,
aminocarboxyl, and Ar.sub.4;
[0096] Ar.sub.3 and Ar.sub.4 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; and
[0097] R.sub.1, R.sub.2, W, X, Y, and Z are as defined in Formula I
above.
[0098] All the compounds of Formulas I-IV posses 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 t he
compounds of Formulas I-IV. It is understood that the compounds of
Formulas I-IV encompass individual stereoisomers as well as
mixtures (racemic and non-racemic) of stereoisomers. Preferably,
S-stereoisomers are used in the pharmaceutical compositions and
methods of the present invention.
Affinity for FKBP12
[0099] The compounds used in the inventive methods and
pharmaceutical compositions have an affinity for the inhibition of
the prolyl peptidyl cis-trans isomerase activity of FKBP may be
measured as an indicator of this affinity.
K.sub.1 Test Procedure
[0100] 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, 1939,
341:758-760; Holt et al. J. Am. Chem. Soc., 115:9923-9938). These
values are obtained as apparent K.sub.1's and are presented for
representative compounds in TABLE III.
[0101] 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 apparerent
K.sub.1, values.
[0102] 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-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 mL
of chymotrypsin (50 mg/ml in 1 mM HCl) and 10 mL of test compound
at various concentrations in dimethyl sulfoxide. The reaction is
initiated by the addition of 5 mL of substrate in 2.35 mM LiCl in
trifluoroethanol).
[0103] 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.
3TABLE III In Vitro Test Results - Formulas I to IV Compound
K.sub.i (nM) 1 215 2 638
Route of Administration
[0104] 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.
[0105] 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 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
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.
[0106] Other routes of administration known in the pharmaceutical
art are also contemplated by this invention.
Dosage
[0107] Dosage levels on the order of about 0.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 form 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.
[0108] 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
[0109] The following example are illustrations 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.
Example 1
Synthesis of 3-phenyl-1-propyl
(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4--
thiazolidine)carboxylate (1)
1-(1,2-dioxo-2-methoxyethyl)2-(4-thiazolidine- )-carboxylate
[0110] A solution of L-thioproline (1.51 g; 11.34 mmol) in 40 mL of
dry methylene chloride was cooled to 0.degree. C. and treated with
3.3 mL (2.41 g; 23,81 mmol) of triethylamine. After stirring this
mixture for 30 minutes, a solution of methyl oxalyl chloride (1.81
g; 14.74 mmol) was added dropwise. The resulting mixture was
stirred at 0.degree. C. for 1.5 hours, filtered through Celite to
remove solids, dried and concentrated. The crude material was
purified on a silic gel column, 2.0 g of this oxamate as ar.
orange-yellow solid.
3-phenyl-1-propyl (2S)
-1-(1,2-dioxo-2-methoxyethyl)2-(4-thiazolidine)carb- oxylate
[0111] 1-(1,2,-dioxo-2-methoxyethyl)2-(4-thiazolidine)-carboxylate
(500 mg; 2.25 mmol) 3-phenyl-1-propanol 3.65 mmol),
4-dimethylaminopyridine (95 mg; 0.75 mmol) and camphorsulfonic:
acid (175 mg; 0.75 mmol) in 30 mL of methylene chloride were
stirred together overnight. The mixture was filtered through Celite
to remove solids and chromatographed (25% ethyl acetate/hexane) to
obtain 690 mg of material. .sup.1H NMR (CDCl.sub.3, 300 MHz);
.delta.1.92-2.01 (m, 2H)); 2.61-2.69 (m, 2H); 3.34 (m, 1H)
4.11-4.25 (m, 2H) ; 4.73 (m, 1H) ; 5.34 (m1H); 7.12 (m, 3H) ; 7.23
(m, 2H).
3-phenyl-1-propyl (2S)-1- (3,3-dimethyl-1,2-dioxopentyl)
-2-(4-thiazolidine) carboxylate (1)
[0112] A solution of
3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-methoxyethyl)2-(-
4-thiazolidine)carboxylate (670 mg; 1.98 mmol) in tetrahydrofuran
(10 mL) was cooled to--78.degree. C. and treated with 2.3 mL of a
1.0 M solution of 1.1-dimethylpropylmagnesium chloride in ether.
After stirring the mixture for 3 hours, it was poured into
saturated ammonium chloride, extracted into ethyl acetate, and the
organic phase was washed with water, dried and concentrated. The
crude material was purified on a silica gel column, eluting with
25% ethyl acetate in hexane, to obtain 380 mg of the compound of
Example 1 as a yellow oil. .sup.1H NMR (CDCl.sub.3, 300 MHz): d
0.86 (t, 3H); 1.21 (s, 3H); 1.26 (s, 3H); 1.62-1.91 (m, 3H); 2.01
(m, 2H); 2.71 (m, 2H); 3.26-3.33 (m, 2H) 4.19 (m 2H); 4.58 (m, 1H);
7.190 (m, 3H); 7.30 (m, 2H). Analysis calculated for
C.sub.20H.sub.27NO.sub.4S:C C, 63.63; H, 7.23 N, 3.71. Found: C,
64.29; H, 7.39; N, 3.46.
Example 2
Synthesis of 3-(3-pyridyl)-1-propyl
(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-- 2-(4-thiazolidine)
carboxylate (2)
[0113] The compound of Example 2 was prepared according to the
procedure of Example 1, using 3-(3-pyridyl)-1-propanol in the final
step, to yield
3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazoli-
dine)carboxylate. .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 0.89
(t, 3H, J=7.3); 1.25 (s, 3H); 1.28 (s, 3H); 1.77 (q, 2H, J=7.3);
2.03 (tt, 2H, J=6.4, 7.5); 2.72 (t, 2H, J=7.5); 3.20 (dd, 1H,
J=4.0, 11.8); 3.23 (dd, 1H, J=7.0, 11.8); 4.23 (t, 2H, J=6.4); 4.55
(d, 2H, J=8.9); 5.08 (dd, 1H, J=4.0, 7.0); 7.24 (m, 1H); 8.48 (m,
2H). Analysis calculated for
C.sub.19H.sub.26N.sub.2O.sub.4S--0.5H.sub.2O: C, 58.89; H, 7.02; N,
7.23. Found: C, 58.83; H, 7.05; N, 7.19.
Example 3
In Vivo Hair Generation Tests With C57 Black 6 Mice
[0114] Experiment A: C57 black 6 mice were used to demonstrate the
hair revitalizing properties of a low molecular weight, small
molecule, non-immunosuppressive neuroimmunophilin FKBP ligand, GPT
1046, which is related to heterocyclic esters and amides. Referring
now to FIGS. 1 and 2 of the drawings, C57 black 6 mice,
approximately 7 weeks 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 underlaying
dermal layers. The animals were in anagen growth phase, as
indicated by the pinkish color of the skin. Referring now to FIGS.
2, 3 and 4, four animals per group were treated by topical
administration with 20% propylene glycol vehicle (FIG. 2), 10 .mu.M
GPI 1046 (FIG. 3) or 30 .mu.M GPI 1046 (FIG. 4) dissolved in the
vehicle. The animals were treated with vehicle or GPI 1046 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.
[0115] FIG. 2 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,
FIG. 3 shows dramatic hair growth, covering greater than 90% of the
shaved area in all animals. Further, FIG. 4 shows that mice treated
with 30 .mu.M GPI 1046 exhibited essentially complete hair regrowth
and their shaved areas were indistinguishable from unshaven C57
black 6 mice.
[0116] Experiment B: C57 black 6 mice were used to demonstrate the
hair revitalizing properties of a variety of low molecular weight,
small molecule, non-immunosuppressive neuroimmunophilin FKBP
ligands, including GPI 1572. CS57 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 topical administration with vehicle, FK506, or one of
the low molecular weight, small molecule, non-immunosuppressive
neuroimmunophilin FK506 ligands (GPI1605, 1046, 1312, 1572, 1389,
1511, and 1234) 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).
[0117] FIG. 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 low molecular weight,
small molecule, non-immunosuppressive neuroimmunophilin FKBP
ligands, including GPI 1572, exhibited dramatic hair growth.
Example 4
[0118] A lotion comprising the following composition may be
prepared.
4 (%) 95% Ethanol 80.0 a heterocyclic ester or amide as defined
10.0 above .alpha.-Tocopherol acetate 0.01 Ethylene oxide (40 mole)
adducts of hardened 0.5 castor oil purified water 9.0 perfume and
dye q.s.
[0119] Into 95% ethanol are added a heterocyclic ester or amide,
.alpha.-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.
[0120] 5 ml of the lotion may be applied once or twice per day to a
site having marked baldness or alopecia.
Example 5
[0121] A lotion comprising the following composition shown may be
prepared.
5 (%) 95% Ethanol 80.0 a heterocyclic ester or amide as defined
0.005 above Hinokitol 0.01 Ethylene oxide (40 mole) adducts of
hardened 0.5 castor oil Purified water 19.0 Perfume and dye
q.s.
[0122] Into 95% ethanol are added a heterocyclic ester or amide,
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.
[0123] The lotion may be applied by spraying once to 4 times per
day to a site having marked baldness or alopecia.
Example 6
[0124] An emulsion may be prepared from A phase and B phase having
the following compositions.
6 (%) (A phase) Whale wax 0.5 Cetanol 2.0 Petrolatum 5.0 Squalane
10.0 Polyoxyethylene (10 mole) monostearate 2.0 Sorbitan monocleate
1.0 a heterocyclic ester or amide as defined 0.01 above (B phase)
Glycerine 10.0 Purified water 69.0 Perfume, dye, and preservative
q.s.
[0125] The A phase and the B phase are respectively heated and
melted and maintained at 80.degree. C. Both phased are then mixed
and cooled under stirring to normal temperature to obtain an
emulsion.
[0126] The emulsion may be applied by spraying once to four times
per day to a site having marked baldness or alopecia.
Example 7
[0127] A cream may be prepared from A phase and B phase having the
following compositions.
7 (%) (A Phase) Fluid paraffin 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
heterocyclic ester or amide as defined 0.8 above Glycerine 7.0
Dipropylene glycol 20.0 Polyethylene glycol 4000 5.0 Sodium
Hexametaphosphate 0.005 Purified water 44.895
[0128] The A phase is heated and melted, and maintained at
70.degree. C. The B phase is added into the A phase and the mixture
is stirred to obtain an emulsion. The emulsion is then cooled to
obtain a cream.
[0129] The cream may be applied once to 4 times per day to a site
having marked baldness or alopecia.
Example 8
[0130] A liquid comprising the following composition may be
prepared.
8 (%) Polyoxyethylene butyl ether 20.0 Ethanol 50.0 a heterocyclic
ester or amide 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.
[0131] Into ethanol are added polyoxypropylene butyl ether,
propylene glycol, polyoxyethylene hardened castor oil, a
heterocyclic ester or amide, and perfume. The resulting mixture is
stirred, and purified water is added to the mixture to obtain a
liquid.
[0132] The liquid may be applied once to 4 times per day to a site
having marked baldness or alopecia.
Example 9
[0133] A shampoo comprising the following composition may be
prepared.
9 (%) Sodium laurylsulfate 5.0 Triethanolamine laurylsulfate 5.0
Betaine lauryldimethylaminoacetate 6.0 Ethylene glycol distearate
2.0 Polyethylene glycol 5.0 a heterocyclic ester or amide as
defined 5.0 above Ethanol 2.0 Perfume 0.3 Purified water 69.7
[0134] Into 69.7 of purified water are added 5.0 g of sodium
laurylsulfate, 5.0 g triethanolamine laurylsulfate, 6.0 g of
betaine lauryldimethyl-aminoacetate. Then a mixture obtained by
adding 5.0 g of a heterocyclic ester or amide, 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 g of perfume are
successively added. The resulting mixture is heated and
subsequently cooled to obtain a shampoo.
[0135] The shampoo may be used on the scalp once or twice per
day.
Example 10
[0136] A patient is suffering from alopecia senilis. A heterocyclic
ester or amide 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
[0137] A patient is suffering from male pattern alopecia. A
heterocyclic ester or amide 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 12
[0138] A patient is suffering from alopecia areata. A heterocyclic
ester or amide 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 13
[0139] A patient is suffering from hair loss caused by skin
lesions. A heterocyclic ester or amide 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
[0140] A patient is suffering from hair loss caused by tumors. A
heterocyclic ester or amide 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
[0141] A patient is suffering from hair loss caused by a systematic
disorder, such as a nutritional disorder or an internal secretion
disorder. A heterocyclic ester or amide 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
[0142] A patient is suffering from hair loss caused by
chemotherapy. A heterocyclic ester or amide 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 17
[0143] A patient is suffering from hair loss caused by radiation. A
heterocyclic ester or amide 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.
[0144] 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.
* * * * *