U.S. patent application number 14/608458 was filed with the patent office on 2015-05-28 for ester pro-drugs of [3-(1-(1h-imidazol-4-yl)ethyl)-2-methylphenyl] methanol for treating skin diseases and conditions.
The applicant listed for this patent is Allergan, Inc.. Invention is credited to Ken Chow, Mohammed I. Dibas, John E. Donnello, Michael E. Garst, Daniel W. Gil, Liming Wang.
Application Number | 20150148394 14/608458 |
Document ID | / |
Family ID | 44675870 |
Filed Date | 2015-05-28 |
United States Patent
Application |
20150148394 |
Kind Code |
A1 |
Dibas; Mohammed I. ; et
al. |
May 28, 2015 |
ESTER PRO-DRUGS OF [3-(1-(1H-IMIDAZOL-4-YL)ETHYL)-2-METHYLPHENYL]
METHANOL FOR TREATING SKIN DISEASES AND CONDITIONS
Abstract
The present invention relates to method for treating skin
diseases and skin conditions in a subject in need of such
treatment, which comprises administering a therapeutically
effective amount of a composition comprising ester pro-drugs of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or
enantiomers thereof, pharmaceutical compositions containing them
and their use as pharmaceuticals.
Inventors: |
Dibas; Mohammed I.; (Laguna
Niguel, CA) ; Gil; Daniel W.; (Corona Del Mar,
CA) ; Donnello; John E.; (Dana Point, CA) ;
Chow; Ken; (Newport Coast, CA) ; Wang; Liming;
(Irvine, CA) ; Garst; Michael E.; (Newport Beach,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc. |
Irvine |
CA |
US |
|
|
Family ID: |
44675870 |
Appl. No.: |
14/608458 |
Filed: |
January 29, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13925502 |
Jun 24, 2013 |
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14608458 |
|
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|
13233665 |
Sep 15, 2011 |
8492422 |
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13925502 |
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Current U.S.
Class: |
514/400 |
Current CPC
Class: |
Y10S 514/912 20130101;
A61K 31/4174 20130101; A61K 9/0014 20130101; A61P 27/06 20180101;
A61K 31/4164 20130101; C07D 233/64 20130101 |
Class at
Publication: |
514/400 |
International
Class: |
A61K 31/4174 20060101
A61K031/4174; A61K 9/00 20060101 A61K009/00 |
Claims
1.-11. (canceled)
12. A method for treating psoriasis comprising administering to a
subject a therapeutically effective amount of a composition
comprising a compound having a structure of Formula II:
##STR00017## wherein: R.sup.1 is H or optionally substituted
C.sub.1-3 alkyl; R.sup.2 is H or optionally substituted C.sub.1-3
alkyl; R.sup.3 is H, optionally substituted C.sub.1-10 alkyl,
optionally substituted heterocycle or optionally substituted aryl;
and R is optionally substituted C.sub.1-10 alkyl, optionally
substituted heterocycle or optionally substituted aryl; or a
pharmaceutically acceptable salt thereof; and one or more selected
from the group consisting of pharmaceutically acceptable carriers,
preservatives, auxiliary agents, stabilizing agents, thickening
agents, coloring agents and perfumes.
13. The method of claim 1, wherein R.sup.1 is C.sub.1-3 alkyl.
14. The method of claim 1, wherein R.sup.2 is C.sub.1-3 alkyl.
15. The method of claim 1, wherein R.sup.1 is methyl.
16. The method of claim 1, wherein R.sup.2 is methyl.
17. The method of claim 1, wherein R.sup.3 is H, phenyl or
C.sub.1-10 alkyl.
18. The method of claim 1, wherein R.sup.3 is H.
19. The method of claim 1, wherein R is selected from the group
consisting of methyl, iso-butyl, tert-butyl, iso-propyl,
ethylphenyl, phenyl, 2-amino-1-phenylethyl,
2-(2-amino-3-methyl-butyrylamino)-2-methyl-prop-1-yl,
1-amino-2-methyl-prop-1-yl,
2-(2-amino-acetylamino)-2-methyl-prop-1-yl. Most preferred R groups
are tert-butyl, iso-propyl.
20. The method of claim 1, wherein R.sup.1 is H or C.sub.1-3 alkyl;
R.sup.2 is H or C.sub.1-3 alkyl; R.sup.3 is H, C.sub.1-10 alkyl,
heterocycle or aryl; and R is C.sub.1-10 alkyl, heterocycle or
aryl.
21. The method of claim 1, wherein the compound having a structure
of Formula II is selected from the group consisting of: iso-Butyric
acid 3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;
2,2-Dimethyl-propionic acid
3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester; Acetic
acid 3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;
Benzoic acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl
ester; 3-Methyl-butyric acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;
3-Phenyl-propionic acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;
2-Amino-3-methyl-butyric acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;
2-(2-Amino-3-methyl-butyrylamino)-3-methyl-butyric acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;
2-(2-Amino-acetylamino)-3-methyl-butyric acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester; and
2-Amino-3-phenyl-propionic acid
3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester.
22. The method according to claim 1, wherein the pharmaceutically
acceptable carriers are selected from the group consisting of
glucose, lactose, gum acacia, gelatin, mannitol, starch paste,
magnesium trisilicate, talc, corn starch, keratin, colloidal
silica, potato starch, urea, medium chain length triglycerides and
dextrans.
23. The method according to claim 1, wherein the composition is
formulated for topical skin application.
24. The method according to claim 23, wherein the composition is
formulated to enhance long duration of action.
25. The method according to claim 24, wherein the composition is
formulated with slow releasing pellets.
26. The method according to claim 1, wherein the composition is
formulated as suspension, gel, solution, lotion, cream, ointment,
foams, emulsions, microemulsions, milks, serums, aerosols, sprays,
dispersions, microcapsules, vesicles, microparticles,
nanoparticles, wet cloths, soaps, cleansing bars, dry cloths,
facial cloths.
27. The method according to claim 23, wherein the pharmaceutical
composition is formulated as suspension, gel, solution, lotion,
cream, ointment, foams, emulsions, microemulsions, milks, serums,
aerosols, sprays, dispersions, microcapsules, vesicles,
microparticles, nanoparticles, wet cloths, soaps, cleansing bars,
dry cloths, facial cloths.
28. The method according to claim 23, wherein the pharmaceutical
compositions is further formulated as a solid, semi-solid or
liquid.
29. The method according to claim 1, wherein the pharmaceutical
compositions is further formulated for oral use, as tablets,
troches, lozenges, aqueous or oily suspensions, dispersible powders
or granules, emulsions, hard or soft capsules, syrups or elixirs.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Non-Provisional
patent application Ser. No. 13/925,502, filed Jun. 24, 2013 which
is a divisional application of U.S. Non-Provisional patent
application Ser. No. 13/233,665, filed Sep. 15, 2011 now U.S. Pat.
No. 8,492,422 issued Jul. 23, 2013, which claims the benefit of
U.S. Provisional Patent Application Ser. No. 61/383,370 filed on
Sep. 16, 2010, all of which are incorporated herein by reference in
their entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a method for treating skin
diseases and skin conditions in a subject in need of such
treatment, which comprises administering a therapeutically
effective amount of a composition comprising ester pro-drugs of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or of its
enantiomers.
[0004] 2. Summary of the Related Art
[0005] Three alpha-1 and three alpha-2 adrenergic receptors have
been characterized by molecular and pharmacological methods.
Activation of these alpha receptors evokes physiological responses
with useful therapeutic applications.
[0006] Compound, 4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole,
generically known as, medetomidine is an alpha 2 adrenergic
agonist, for use in the sedation of animals. The hydrochloride salt
of the (S) enantiomer of medetomidine, generically known as
dexmedetomidine, (S) 4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole,
is also indicated for use as a sedative or analgesic in cats and
dogs.
[0007] The metabolite of dexmedetomidine is (S)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol together
with its racemic mixture, compound
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, are
described in the literature in Journal of Chromatography, (1997),
762(1+2), 281-291 by Hui, Y.-H et al.
[0008] [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol is
described in "Synthesis of detomidine and medetomidine metabolites:
1,2,3-trisubstituted arenes with 4'(5')-imidazolylmethyl groups" in
Journal of Heterocyclic Chemistry (1993), 30(6), (1645-1651) by
Stoilov et al.
[0009] Kavanagh, et al. describe
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol in
"Synthesis of Possible Metabolites of Medetomidine
{1-(2,3-dimethylphenyl)-1-[imidazol-4(5)-yl]ethane" in Journal of
Chemical Research, Synopses (1993), (4), 152-3.
##STR00001##
[0010] [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol] is
described by Salonen, et al. in "Biotransformation of Medetomidine
in the Rat" in Xenobiotica (1990), 20(5), 471-80. PCT Int. Appl. WO
2010093930 A1 discloses
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol and its (S)
and (R) enantiomers.
SUMMARY OF THE RELATED ART
[0011] Three alpha 1 and three alpha 2 adrenergic receptors have
been characterized by molecular and pharmacological methods.
Activation of these alpha 2 receptors evokes physiological
responses and has useful therapeutic actions.
[0012] The present invention relates to a method for treating skin
diseases and skin conditions in a subject in need of such
treatment, which comprises administering a therapeutically
effective amount of a composition comprising ester pro-drugs of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol. Upon
hydrolytic and/or enzymatic cleavage of the ester functionality the
parent compound,
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, is released
to act as a selective modulator of the alpha 2 adrenergic
receptors.
[0013] In another aspect, the present invention relates to a method
for treating skin diseases and skin conditions in a subject in need
of such treatment, which comprises administering a therapeutically
effective amount of a composition comprising ester pro-drugs of (S)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or
pharmaceutical compositions containing them. Upon hydrolytic and/or
enzymatic cleavage of the ester functionality the parent compound,
active metabolite, (S)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, is released
to act as a selective modulator of the alpha 2 adrenergic
receptors.
[0014] In another aspect the present invention provides relates to
a method for treating skin diseases and skin conditions in a
subject in need of such treatment, which comprises administering a
therapeutically effective amount of a composition comprising ester
pro-drugs of (R)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or
pharmaceutical compositions containing them. Upon hydrolytic and/or
enzymatic cleavage of the ester functionality the parent compound
(R) [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, is
released to act as a selective modulator of the alpha 2 adrenergic
receptors.
[0015] The ester pro-drugs of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol will be
useful for the treatment or prevention in mammals, including
humans, of a range of skin diseases and skin conditions which
include, but are not limited to: rosacea, sunburn, chronic sun
damage, discreet erythemas, psoriasis, atopic dermatitis,
menopause-associated hot flashes, hot flashes resulting from
orchiectomyatopic dermatitis, photoaging, seborrheic dermatitis,
acne, allergic dermatitis, irritant dermatitis, telangiectasia
(dilations of previously existing small blood vessels) of the face,
rhinophyma (hypertrophy of the nose with follicular dilation), red
bulbous nose, acne-like skin eruptions (may ooze or crust), burning
or stinging sensation of the face, irritated and bloodshot and
watery eyes, cutaneous hyperactivity with dilation of blood vessels
of the skin, Lyell's syndrome, Stevens-Johnson syndrome, erythema
multiforme minor, erythema multiforme major and other inflammatory
skin diseases. Skin conditions which result in rosacea can be
induced by intake of spicy food, of alcohol, of chocolate, of hot
or alcoholic drinks, temperature variations, heat, exposure to
ultraviolet or infrared radiation, exposure to low relative
humidity, exposure of the skin to strong winds or currents of air,
exposure of the skin to surfactants, irritants, irritant
dermatological topical agents, and cosmetics.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 shows the rate of percutaneous absorption as the flux
of [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, Compound
2, pivalate derivative prodrug and Compound 1, 2-methylpropanoate
derivative prodrug.
[0017] FIG. 2 shows the distribution of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, Compound 2,
pivalate derivative prodrug and Compound 1, 2-methylpropanoate
derivative prodrug in each skin layer.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention relates to a method for treating skin
diseases and skin conditions in a subject in need of such
treatment, which comprises administering a therapeutically
effective amount of a composition comprising ester pro-drugs of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, ester
pro-drugs of (S)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol and ester
pro-drugs of (R)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or the
tautomers thereof, or pharmaceutically acceptable salts
thereof.
[0019] The term "subject", as used herein, refers to a human
patient.
[0020] In a preferred embodiment the present invention relates to a
method for treating skin diseases and skin conditions in a subject
in need of such treatment, which comprises administering a
therapeutically effective amount of a composition comprising esters
pro-drugs of
(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or the
tautomers thereof, or pharmaceutically acceptable salts thereof.
Upon hydrolytic or enzymatic cleavage of the ester functionality
the parent compound, active metabolite,
(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, is
released to act as a selective modulator of the alpha 2 adrenergic
receptors.
[0021] In one aspect of the invention, there is provided a method
for treating skin diseases and skin conditions in a patient in need
thereof which comprises, consists essentially of or consists of
administering a therapeutically effective amount of a
pharmaceutical composition comprising, consisting essentially of or
consisting of a therapeutically effective amount of ester pro-drugs
of [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the
tautomers thereof, or pharmaceutically acceptable salts
thereof.
[0022] In another aspect of the invention, there is provided a
method for treating skin diseases and skin conditions in a patient
in need thereof which comprises, consists essentially of or
consists of administering a therapeutically effective amount of a
pharmaceutical composition comprising, consisting essentially of or
consisting of a therapeutically effective amount of ester pro-drugs
(S) [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the
tautomers thereof, or pharmaceutically acceptable salts
thereof.
[0023] In another aspect of the invention, there is provided a
method for treating skin diseases and skin conditions in a patient
in need thereof which comprises, consists essentially of or
consists of administering a therapeutically effective amount of a
pharmaceutical composition comprising, consisting essentially of or
consisting of a therapeutically effective amount of ester pro-drugs
of (R) [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or
the tautomers thereof, or pharmaceutically acceptable salts
thereof.
[0024] In another aspect of the invention, there is provided a
method for treating or improving skin diseases and skin conditions
including but not limited to: rosacea, sunburn, chronic sun damage,
discreet erythemas, psoriasis, atopic dermatitis,
menopause-associated hot flashes, hot flashes resulting from
orchiectomyatopic dermatitis, photoaging, seborrheic dermatitis,
acne, allergic dermatitis, irritant dermatitis, telangiectasia
(dilations of previously existing small blood vessels) of the face,
rhinophyma (hypertrophy of the nose with follicular dilation), red
bulbous nose, acne-like skin eruptions (may ooze or crust), burning
or stinging sensation of the face, irritated and bloodshot and
watery eyes, cutaneous hyperactivity with dilation of blood vessels
of the skin, Lyell's syndrome, Stevens-Johnson syndrome, erythema
multiforme minor, erythema multiforme major and other inflammatory
skin diseases. Skin conditions which result in rosacea can be
induced by intake of spicy food, of alcohol, of chocolate, of hot
or alcoholic drinks, temperature variations, heat, exposure to
ultraviolet or infrared radiation, exposure to low relative
humidity, exposure of the skin to strong winds or currents of air,
exposure of the skin to surfactants, irritants, irritant
dermatological topical agents, and cosmetics.
[0025] In another aspect of the invention, there is provided a
method for treating or improving skin diseases and skin conditions
including but not limited to: rosacea, sunburn, chronic sun damage,
discreet erythemas, psoriasis, atopic dermatitis,
menopause-associated hot flashes, hot flashes resulting from
orchiectomyatopic dermatitis, photoaging, seborrheic dermatitis,
acne, allergic dermatitis, irritant dermatitis, telangiectasia
(dilations of previously existing small blood vessels) of the face,
rhinophyma (hypertrophy of the nose with follicular dilation), red
bulbous nose, acne-like skin eruptions (may ooze or crust), burning
or stinging sensation of the face, irritated and bloodshot and
watery eyes, cutaneous hyperactivity with dilation of blood vessels
of the skin, Lyell's syndrome, Stevens-Johnson syndrome, erythema
multiforme minor, erythema multiforme major and or other
inflammatory skin diseases, which comprises, consists essentially
of or consists of administering a therapeutically effective amount
of a pharmaceutical composition comprising, consisting essentially
of or consisting of a therapeutically effective amount of ester
pro-drugs of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the
tautomers thereof, or pharmaceutically acceptable salts
thereof.
[0026] In another aspect of the invention, there is provided a
method for treating or improving skin diseases and skin conditions
including but not limited to: rosacea, sunburn, chronic sun damage,
discreet erythemas, psoriasis, atopic dermatitis,
menopause-associated hot flashes, hot flashes resulting from
orchiectomyatopic dermatitis, photoaging, seborrheic dermatitis,
acne, allergic dermatitis, irritant dermatitis, telangiectasia
(dilations of previously existing small blood vessels) of the face,
rhinophyma (hypertrophy of the nose with follicular dilation), red
bulbous nose, acne-like skin eruptions (may ooze or crust), burning
or stinging sensation of the face, irritated and bloodshot and
watery eyes, cutaneous hyperactivity with dilation of blood vessels
of the skin, Lyell's syndrome, Stevens-Johnson syndrome, erythema
multiforme minor, erythema multiforme major and or other
inflammatory skin diseases, which comprises, consists essentially
of or consists of administering a therapeutically effective amount
of a pharmaceutical composition comprising, consisting essentially
of or consisting of a therapeutically effective amount of ester
pro-drugs of (S)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the
tautomers thereof, or pharmaceutically acceptable salts
thereof.
[0027] In another aspect of the invention, there is provided a
method for treating or improving skin diseases and skin conditions
including but not limited to: rosacea, sunburn, chronic sun damage,
discreet erythemas, psoriasis, atopic dermatitis,
menopause-associated hot flashes, hot flashes resulting from
orchiectomyatopic dermatitis, photoaging, seborrheic dermatitis,
acne, allergic dermatitis, irritant dermatitis, telangiectasia
(dilations of previously existing small blood vessels) of the face,
rhinophyma (hypertrophy of the nose with follicular dilation), red
bulbous nose, acne-like skin eruptions (may ooze or crust), burning
or stinging sensation of the face, irritated and bloodshot and
watery eyes, cutaneous hyperactivity with dilation of blood vessels
of the skin, Lyell's syndrome, Stevens-Johnson syndrome, erythema
multiforme minor, erythema multiforme major and or other
inflammatory skin diseases, which comprises, consists essentially
of or consists of administering a therapeutically effective amount
of a pharmaceutical composition comprising, consisting essentially
of or consisting of a therapeutically effective amount of ester
pro-drugs of (R)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the
tautomers thereof, or pharmaceutically acceptable salts
thereof.
[0028] In another aspect of the invention, there is provided a
method for treating skin diseases and conditions including but not
limited to rosacea induced by intake of spicy food, of chocolate,
of alcohol, of hot or alcoholic drinks, temperature variations,
heat, exposure to ultraviolet or infrared radiation, exposure to
low relative humidity, exposure of the skin to strong winds or
currents of air, exposure of the skin to surfactants, irritants,
irritant dermatological topical agents, and cosmetics.
[0029] In another aspect of the invention, there is provided a
method for treating skin diseases and conditions including but not
limited to rosacea induced by intake of spicy food, of chocolate,
of alcohol, of hot or alcoholic drinks, temperature variations,
heat, exposure to ultraviolet or infrared radiation, exposure to
low relative humidity, exposure of the skin to strong winds or
currents of air, exposure of the skin to surfactants, irritants,
irritant dermatological topical agents, and cosmetics, which
comprises, consists essentially of or consists of or consists of
administering a therapeutically effective amount of a
pharmaceutical composition comprising, consisting essentially of or
consisting of a therapeutically effective amount of ester pro-drugs
of [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the
tautomers thereof, or pharmaceutically acceptable salts
thereof.
[0030] In another aspect of the invention, there is provided a
method for treating skin diseases and conditions including but not
limited to rosacea induced by intake of spicy food, of chocolate,
of alcohol, of hot or alcoholic drinks, temperature variations,
heat, exposure to ultraviolet or infrared radiation, exposure to
low relative humidity, exposure of the skin to strong winds or
currents of air, exposure of the skin to surfactants, irritants,
irritant dermatological topical agents, and cosmetics, which
comprises, consists essentially of or consists of or consists of
administering a therapeutically effective amount of a
pharmaceutical composition comprising, consisting essentially of or
consisting of a therapeutically effective amount of ester pro-drugs
of (S) [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or
the tautomers thereof, or pharmaceutically acceptable salts
thereof.
[0031] In another aspect of the invention, there is provided a
method for treating skin diseases and conditions including but not
limited to rosacea induced by intake of spicy food, of chocolate,
of alcohol, of hot or alcoholic drinks, temperature variations,
heat, exposure to ultraviolet or infrared radiation, exposure to
low relative humidity, exposure of the skin to strong winds or
currents of air, exposure of the skin to surfactants, irritants,
irritant dermatological topical agents, and cosmetics, which
comprises, consists essentially of or consists of or consists of
administering a therapeutically effective amount of a
pharmaceutical composition comprising, consisting essentially of or
consisting of a therapeutically effective amount of ester pro-drugs
of (R) [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or
the tautomers thereof, or pharmaceutically acceptable salts
thereof.
[0032] In another aspect of the invention, there is provided a
method for treating skin diseases and skin conditions wherein the
pharmaceutical composition comprising, consisting essentially of or
consisting of a therapeutically effective amount ester pro-drugs of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, is selected
from topical skin application, direct injection, applications and
formulations that may further enhance the long duration of actions
such as a slow releasing pellet, suspension, gel, solution, cream,
lotion, ointment, foams, emulsions, microemulsions, milks, serums,
aerosols, sprays, dispersions, microcapsules, vesicles,
microparticles, nanoparticles, wet cloths, dry cloths, facial
cloths.
[0033] In another aspect of the invention, there is provided a
method for treating skin diseases and skin conditions wherein the
pharmaceutical composition comprising, consisting essentially of or
consisting of a therapeutically effective amount of ester pro-drugs
of (S) [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol is
selected from topical skin application, direct injection,
applications and formulations that may further enhance the long
duration of actions such as a slow releasing pellet, suspension,
gel, solution, cream, lotion, ointment, foams, emulsions,
microemulsions, milks, serums, aerosols, sprays, dispersions,
microcapsules, vesicles, microparticles, nanoparticles, wet cloths,
dry cloths, facial cloths.
[0034] In another aspect of the invention, there is provided a
method for treating skin diseases and skin conditions wherein the
pharmaceutical composition comprising, consisting essentially of or
consisting of a therapeutically effective amount of ester pro-drugs
of (R) [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol is
selected from topical skin application, direct injection,
applications and formulations that may further enhance the long
duration of actions such as a slow releasing pellet, suspension,
gel, solution, lotion, cream, ointment, foams, emulsions,
microemulsions, milks, serums, aerosols, sprays, dispersions,
microcapsules, vesicles, microparticles, nanoparticles, wet cloths,
soaps, cleansing bars, dry cloths, facial cloths.
[0035] In another aspect of the invention, there is provided a
method of decreasing the irritation of skin associated with rosacea
treatment regimen of topically applied a therapeutically effective
amount of ester pro-drugs of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, of (S)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or of (R)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, the method
of treating telangiectasia with a therapeutically effective amount
of ester pro-drugs of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, of (S)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or of (R)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol and
therefore, it also includes the method of reducing redness
associated with the appearance of rosacea.
[0036] The present invention is beneficial when used in conjunction
with topically applied or oral rosacea treatments of such as
retinoids (isotretinoin), metronidazole, tertracyclines
(doxycycline), phytosphingosine, antibacterial agents,
antiparasitic agents, antifungal agents, anti-inflammatory agents,
antihistamines, anti-pruriginous agents, anesthetics, antiviral
agents, keratolytic agents, anti free-radical agents, anti
seborrheic agents, antidandruff agents, anti acne agents,
sunscreens and sun blocking agents, and active agents which modify
at least one of cutaneous differentiation, proliferation, and
pigmentation.
[0037] The present invention is beneficial when used in conjunction
with topically applied or oral rosacea treatments such as retinoids
(isotretinoin), metronidazole, tertracyclines (doxycycline),
phytoshingosine, antibacterial agents, antiparasitic agents,
antifungal agents, anti-inflammatory agents, antihistamines,
anti-pruriginous agents, anesthetics, antiviral agents, keratolytic
agents, anti free-radical agents, anti seborrheic agents,
antidandruff agents, anti acne agents, sunscreens and sun blocking
agents, and active agents which modify at least one of cutaneous
differentiation, proliferation, and pigmentation, which comprises,
consists essentially of or consists of or consists of administering
a therapeutically effective amount of a pharmaceutical composition
comprising, consisting essentially of or consisting of a
therapeutically effective amount of ester pro-drugs of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the
tautomers thereof, or pharmaceutically acceptable salts
thereof.
[0038] The present invention is beneficial when used in conjunction
with topically applied or oral rosacea treatments of such as
retinoids (isotretinoin), metronidazole, tertracyclines
(doxycycline), phytosphingosine, antibacterial agents,
antiparasitic agents, antifungal agents, anti-inflammatory agents,
antihistamines, anti-pruriginous agents, anesthetics, antiviral
agents, keratolytic agents, anti free-radical agents, anti
seborrheic agents, antidandruff agents, anti acne agents,
sunscreens and sun blocking agents, and active agents which modify
at least one of cutaneous differentiation, proliferation, and
pigmentation, which comprises, consists essentially of or consists
of or consists of administering a therapeutically effective amount
of a pharmaceutical composition comprising, consisting essentially
of or consisting of a therapeutically effective amount of ester
pro-drugs of (S)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the
tautomers thereof, or pharmaceutically acceptable salts
thereof.
[0039] The present invention is beneficial when used in conjunction
with topically applied or oral rosacea treatments of such as
retinoids (isotretinoin), metronidazole, tertracyclines
(doxycycline), phytosphingosine, antibacterial agents,
antiparasitic agents, antifungal agents, anti-inflammatory agents,
antihistamines, anti-pruriginous agents, anesthetics, antiviral
agents, keratolytic agents, anti free-radical agents, anti
seborrheic agents, antidandruff agents, anti acne agents,
sunscreens and sun blocking agents, and active agents which modify
at least one of cutaneous differentiation, proliferation, and
pigmentation, which comprises, consists essentially of or consists
of or consists of administering a therapeutically effective amount
of a pharmaceutical composition comprising, consisting essentially
of or consisting of a therapeutically effective amount of ester
pro-drugs of (R)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, or the
tautomers thereof, or pharmaceutically acceptable salts
thereof.
[0040] "Prodrugs" are frequently referred to by the term
"metabolically cleavable derivatives" which refers to compound
forms which are rapidly transformed in vivo to the parent compound
according to the invention, for example, by hydrolysis in blood.
Thus, prodrugs are compounds bearing groups which are removed by
biotransformation prior to exhibiting their pharmacological action.
Such groups include moieties which are readily cleaved in vivo from
the compound bearing it, which compound after cleavage remains or
becomes pharmacologically active. Such metabolically cleavable
groups form a class well known to practitioners of the art. They
include, but are not limited to such groups as alkanoyl (i.e.
acetyl, propionyl, butyryl, and the like), unsubstituted and
substituted carbocyclic aroyl (such as benzoyl, substituted benzoyl
and 1- and 2-naphthoyl), alkoxycarbonyl (such as ethoxycarbonyl),
trialklysilyl (such as trimethyl- and triethylsilyl), monoesters
formed with dicarboxylic acids (such as succinyl), phosphate,
sulfate, sulfonate, sulfonyl, sulfinyl and the like. The compounds
bearing the metabolically cleavable groups have the advantage that
they may exhibit improved bioavailability as a result of enhanced
solubility and/or rate of absorption conferred upon the parent
compound by virtue of the presence of the metabolically cleavable
group. (T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery
System", Vol. 14 of the A.C.S. Symposium Series; "Bioreversible
Carriers in Drug Design", ed. Edward B. Roche, American
Pharmaceutical Association and Pergamon Press, 1987).
[0041] In one aspect, the invention therefore relates to a method
for treating skin diseases and skin conditions in a subject in need
of such treatment, which comprises administering a therapeutically
effective amount of a composition comprising a compound having
Formula I, its individual enantiomers, its individual
diastereoisomers, its individual hydrates, its individual solvates,
its individual crystal forms, its individual isomers, its
individual tautomers or a pharmaceutically acceptable salt
thereof,
##STR00002##
wherein R.sup.1 is H or C.sub.1-3 alkyl; R.sup.2 is H or C.sub.1-3
alkyl; R.sup.3 is H, C.sub.1-10 alkyl, heterocycle or aryl; and R
is C.sub.1-10 alkyl, heterocycle or aryl.
[0042] In a preferred aspect, the invention therefore relates to a
method for treating skin diseases and skin conditions in a subject
in need of such treatment, which comprises administering a
therapeutically effective amount of a composition comprising a
compound having Formula II, its individual diastereoisomers, its
individual hydrates, its individual solvates, its individual
crystal forms, its individual isomers, its individual tautomers or
a pharmaceutically acceptable salt thereof,
##STR00003##
wherein R.sup.1 is H or C.sub.1-3 alkyl; R.sup.2 is H or C.sub.1-3
alkyl; R.sup.3 is H, C.sub.1-10 alkyl, heterocycle or aryl; and R
is C.sub.1-10 alkyl, heterocycle or aryl.
[0043] In another aspect, the invention therefore relates to a
method for treating skin diseases and skin conditions in a subject
in need of such treatment, which comprises administering a
therapeutically effective amount of a composition comprising a
compound having Formula III, its individual diastereoisomers, its
individual hydrates, its individual solvates, its individual
crystal forms, its individual isomers, its individual tautomers or
a pharmaceutically acceptable salt thereof,
##STR00004##
wherein R.sup.1 is H or C.sub.1-3 alkyl; R.sup.2 is H or C.sub.1-3
alkyl; R.sup.3 is H, C.sub.1-10 alkyl, heterocycle or aryl; and R
is C.sub.1-10 alkyl, heterocycle or aryl.
[0044] In another aspect, the present invention relates to
pharmaceutical compositions containing as active ingredient ester
pro-drugs of [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol
for treatment of skin diseases and skin conditions.
[0045] In another aspect, the present invention relates to
pharmaceutical compositions containing as active ingredient ester
pro-drugs (S)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol for
treatment of skin diseases and skin conditions.
[0046] In another aspect, the present invention relates to
pharmaceutical compositions containing as active ingredient ester
pro-drugs of (R)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol for
treatment of skin diseases and skin conditions.
[0047] The following paragraphs provide definitions of the various
chemical moieties that make up the compounds of the invention and
are intended to apply uniformly throughout the specification and
claims unless expressly stated otherwise.
[0048] The term "alkyl" as used herein, is defined as including a
saturated monovalent alkane moiety having straight or branched
alkane moieties or combinations thereof and containing 1-10 carbon
atoms, preferably 1-8 carbon atoms and more preferably 1-4 carbon
atoms. Alkyl moieties can optionally be substituted by, but not
limited to, amino groups, aryl groups, halogens. One methylene
(--CH.sub.2--) of the alkyl chain, can be replaced by carbonyl,
--NH--, carboxyl, amide, sulfur or by oxygen. Examples include, but
are not limited to, methyl, ethyl, propyl, butyl, sec-butyl,
pentyl, iso-pentyl, neo-pentyl, hexyl, iso-hexyl, 3-methyl-butyl,
2-amino-N-isobutyl acetamide, iso-butyl, tert-butyl, iso-propyl,
ethylphenyl, methylphenyl,
2-amino-3-methyl-butanamide-N-2-methyl-1-propyl,
1-amino-2-methyl-prop-1-yl.
[0049] The term "heterocycle" as used herein is defined as an
aromatic or non aromatic 5 to 10 membered monocyclic or bicyclic
ring containing at least one heteroatom selected from O or N or S
or combinations thereof, interrupting the carbocyclic ring
structure. Heterocycles can optionally be substituted by, but not
limited to, C.sub.1-6 alkyl, amino, halogen, --O(C.sub.1-6 alkyl),
--OC(O)(C.sub.1-6 alkyl), --C(O)O(C.sub.1-6 alkyl),
--NHC(O)(C.sub.1-6 alkyl), --C(O)NH(C.sub.1-6 alkyl), --S(C.sub.1-6
alkyl) groups. Examples include, but are not limited to, furyl,
pyrryl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl,
pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl,
isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl,
purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl,
1,2,5-thiadiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, quinazolinyl,
pyridazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl,
hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl,
triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl,
pyrazolopyrimidinyl, pyrrolidinyl, piperidinyl and piperazinyl.
[0050] The term "aryl" as used herein, is defined as including an
organic moiety derived from an aromatic hydrocarbon consisting of a
monocyclic or bicyclic ring containing 6-10 carbon atoms by removal
of one hydrogen atom, such as phenyl or naphtyl. Aryl groups can
optionally be substituted by, but not limited to, C.sub.1-6 alkyl,
amino, halogen, --O(C.sub.1-6 alkyl), --OC(O)(C.sub.1-6 alkyl),
--C(O)O(C.sub.1-6 alkyl), --NHC(O)(C.sub.1-6 alkyl),
--C(O)NH(C.sub.1-6 alkyl), --S(C.sub.1-6 alkyl) groups. Examples
include, but are not limited to, phenyl, naphtyl.
[0051] The term "H" as used herein refers to a hydrogen atom.
[0052] The term "O" as used herein refers to an oxygen atom.
[0053] The term "S" as used herein refers to a sulfur atom.
[0054] The term "N" as used herein refers to a nitrogen atom.
[0055] The term "amino" as used herein refers to a group of formula
--NH.sub.2.
[0056] The term "amide" as used herein refers to a group of formula
--C(O)NH-- or --NHC(O)--.
[0057] The term "halogen", as used herein refers to an atom of
chlorine, bromine, iodine or fluorine.
[0058] The term "carbonyl" as used herein refers to a group of
formula --C.dbd.O.
[0059] The term "carboxyl", as used herein refers to a group of
formula --C(O)O-- or --OC(O)--.
[0060] Generally R.sup.1 is H or C.sub.1-3 alkyl. Preferred R.sup.1
is C.sub.1-3 alkyl. Most preferred R.sup.1 is methyl.
[0061] Generally R.sup.2 is H or C.sub.1-3 alkyl. Preferred R.sup.2
is C.sub.1-3 alkyl. Most preferred R.sup.2 is methyl.
[0062] Generally R.sup.3 is H, C.sub.1-10 alkyl, heterocycle or
aryl. Preferred R.sup.3 is H, phenyl or C.sub.1-10 alkyl. Most
preferred R.sup.3 is H.
[0063] Generally R is C.sub.1-10 alkyl, heterocycle or aryl.
Preferred R is methyl, iso-butyl, tert-butyl, iso-propyl,
ethylphenyl, phenyl, 2-amino-1-phenylethyl,
2-(2-amino-3-methyl-butyrylamino)-2-methyl-prop-1-yl,
1-amino-2-methyl-prop-1-yl,
2-(2-amino-acetylamino)-2-methyl-prop-1-yl. Most preferred R groups
are tert-butyl, iso-propyl.
[0064] As used herein, "tautomer" refers to the migration of
protons between adjacent single and double bonds. The
tautomerization process is reversible. Compounds described herein
can undergo any possible tautomerization that is within the
physical characteristics of the compound. The following is a
tautomerization example that can occur in compounds described
herein:
##STR00005##
Compounds of the Invention are:
[0065] iso-Butyric acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester; [0066]
2,2-Dimethyl-propionic acid
3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester; [0067]
Acetic acid 3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl
ester; [0068] Benzoic acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester; [0069]
3-Methyl-butyric acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester; [0070]
3-Phenyl-propionic acid
3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester; [0071]
2-Amino-3-methyl-butyric acid
3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester; [0072]
2-(2-Amino-3-methyl-butyrylamino)-3-methyl-butyric acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester; [0073]
2-(2-Amino-acetylamino)-3-methyl-butyric acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester; [0074]
2-Amino-3-phenyl-propionic acid
3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester.
Intermediates of the Invention are:
[0074] [0075] iso-Butyric acid
3-[(S)-1-(1-iso-butyryl-1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl
ester; [0076] 2,2-Dimethyl-propionic acid
3-{(S)-1-[1-(2,2-dimethyl-propionyl)-1H-imidazol-4-yl]-ethyl}-2-methyl-be-
nzyl ester; [0077] Acetic acid
3-[(S)-1-(1-acetyl-1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;
[0078] Benzoic acid
3-[(S)-1-(1-benzoyl-1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester;
[0079] 3-Methyl-butyric acid
2-methyl-3-{(S)-1-[1-(3-methyl-butyryl)-1H-imidazol-4-yl]-ethyl}-benzyl
ester; [0080] Phenyl-propionic acid
2-methyl-3-{(S)-1-[1-(3-phenyl-propionyl)-1H-imidazol-4-yl]-ethyl}-benzyl
ester; [0081] 2-tert-Butoxycarbonylamino-3-methyl-butyric acid
3-{(S)-1-[1-(2-tert-butoxy
carbonylamino-3-methyl-butyryl)-1H-imidazol-4-yl]-ethyl}-2-methyl-benzyl
ester; [0082] 2-tert-Butoxycarbonylamino-3-methyl-butyric acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester; [0083]
2-(2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-methyl-butyric
acid
3-{(S)-1-[1-(2-tert-butoxycarbonylamino-3-methyl-butyryl)-1H-imidazo-
l-4-yl]-ethyl}-2-methyl-benzyl ester; [0084]
2-(2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-methyl-butyric
acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;
[0085] 2-(2-tert-Butoxycarbonylamino-acetylamino)-3-methyl-butyric
acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester;
[0086] 2-tert-Butoxycarbonylamino-3-phenyl-propionic acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester.
[0087] Some compounds of Formula I, Formula II and Formula III and
some of their intermediates have at least one stereogenic center in
their structure. This stereogenic center may be present in an (R)
or (S) configuration, said (R) and (S) notation is used in
correspondence with the rules described in Pure Appli. Chem.
(1976), 45, 11-13.
[0088] The term "pharmaceutically acceptable salts" refers to salts
or complexes that retain the desired biological activity of the
above identified compounds and exhibit minimal or no undesired
toxicological effects. The "pharmaceutically acceptable salts"
according to the invention include therapeutically active,
non-toxic base or acid salt forms, which the compounds of Formula
I, Formula II or Formula III are able to form. The acid addition
salt form of a compound of Formula I, Formula II or Formula III
that occurs in its free form as a base can be obtained by treating
the free base with an appropriate acid such as an inorganic acid,
for example but not limited to, hydrochloric acid, hydrobromic
acid, sulfuric acid, phosphoric acid, nitric acid and the like; or
an organic acid such as for example but not limited to, as citric
acid, acetic acid, oxalic acid, tartaric acid, succinic acid, malic
acid, fumaric acid, ascorbic acid, benzoic acid, tannic acid,
palmoic acid, alginic acid, polyglutamic acid, naphthalene-sulfonic
acid, napthalenedisulfonic, and polygalacturonic acid as well as
base addition salts such as those formed with alkali- and alkaline
earth metals such as sodium, potassium and calcium and the like
(Handbook of Pharmaceutical Salts, P. Heinrich Stahal& Camille
G. Wermuth (Eds), Verlag Helvetica Chemica Acta-Zurich, 2002,
329-345).
[0089] The compounds can also be administered as pharmaceutically
acceptable quaternary salts known by those skilled in the art,
which specifically include, but not limiting to the quaternary
ammonium salt of the formula --NY.sup.+Z.sup.-, wherein Y is
hydrogen, alkyl, or benzyl, and Z is a counterion, including but
not limited to, chloride, bromide, iodide, --O-- alkyl,
toluenesulfonate, methylsulfonate, sulfonate, phosphate, or
carboxylate (such as fumarate, benzoate, succinate, acetate,
glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate,
benzoate, cinnamoate, mandeloate, benzyloate, and
diphenylacetate).
[0090] In another embodiment of the invention, there are provided
pharmaceutical compositions including at least one compound of the
invention in a pharmaceutically acceptable carrier thereof. The
phrase "pharmaceutically acceptable" means the carrier, diluent or
excipient must be compatible with the other ingredients of the
formulation and not deleterious to the recipient thereof.
[0091] Pharmaceutical compositions of the present invention can be
used in the form of a solid, a solution, an emulsion, a dispersion,
a patch, a micelle, a liposome, and the like, wherein the resulting
composition contains one or more compounds of the present
invention, as an active ingredient, in admixture with an organic or
inorganic carrier or excipient suitable for enteral or parenteral
applications. Invention compounds may be combined, for example,
with the usual non-toxic, pharmaceutically acceptable carriers for
tablets, pellets, capsules, suppositories, solutions, emulsions,
suspensions, and any other form suitable for use. The carriers
which can be used include but are not limited to, glucose, lactose,
gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate,
talc, corn starch, keratin, colloidal silica, potato starch, urea,
medium chain length triglycerides, dextrans, and other carriers
suitable for use in manufacturing preparations, in solid,
semisolid, or liquid form. In addition auxiliary, stabilizing,
thickening and coloring agents and perfumes may be used. Invention
compounds are included in the pharmaceutical composition in an
amount sufficient to produce the desired effect upon the process or
disease condition.
[0092] Pharmaceutical compositions containing invention compounds
may be in a form suitable for oral use, for example, as tablets,
troches, lozenges, aqueous or oily suspensions, dispersible powders
or granules, emulsions, hard or soft capsules, or syrups or
elixirs. Compositions intended for oral use may be prepared
according to any method known in the art for the manufacture of
pharmaceutical compositions and such compositions may contain one
or more agents selected from the group consisting of a sweetening
agent such as sucrose, lactose, or saccharin, flavoring agents such
as peppermint, oil of wintergreen or cherry, coloring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets containing invention compounds in
admixture with non-toxic pharmaceutically acceptable excipients may
also be manufactured by known methods. The excipients used may be,
for example, (1) inert diluents such as calcium carbonate, lactose,
calcium phosphate or sodium phosphate; (2) granulating and
disintegrating agents such as corn starch, potato starch or alginic
acid; (3) binding agents such as gum tragacanth, corn starch,
gelatin or acacia, and (4) lubricating agents such as magnesium
stearate, stearic acid or talc. The tablets may be uncoated or they
may be coated by known techniques to delay disintegration and
absorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate may
be employed. In some cases, formulations for oral use may be in the
form of hard gelatin capsules wherein the invention compounds are
mixed with an inert solid diluent, for example, calcium carbonate,
calcium phosphate or kaolin. They may also be in the form of soft
gelatin capsules wherein the invention compounds are mixed with
water or an oil medium, for example, peanut oil, liquid paraffin or
olive oil.
[0093] The pharmaceutical compositions may be in the form of a
sterile injectable suspension. This suspension may be formulated
according to known methods using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example,
as a solution in 1,3-butanediol. Sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic
mono- or diglycerides, fatty acids (including oleic acid),
naturally occurring vegetable oils like sesame oil, coconut oil,
peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like
ethyl oleate or the like. Buffers, preservatives, antioxidants, and
the like can be incorporated as required.
[0094] The present invention concerns also the use of a compound of
Formula I, Formula II or Formula III, or a pharmaceutically
acceptable salt thereof, for the manufacture of a medicament for
the therapeutic application. The present invention concerns also
the a method for manufacturing a medicament intended for
therapeutic application wherein a compound having general Formula
I, Formula II or Formula III, or a pharmaceutically active
derivative or salt thereof is used.
[0095] Since individual subjects may present a wide variation in
severity of symptoms and each drug has its unique therapeutic
characteristics, the precise mode of administration and dosage
employed for each subject is left to the discretion of the
practitioner. The patient will be administered the compound orally
in any acceptable form, such as a tablet, liquid, capsule, powder
and the like, or other routes may be desirable or necessary,
particularly if the patient suffers from nausea. Such other routes
may include, without exception, transdermal, parenteral,
subcutaneous, intranasal, via an implant stent, intrathecal,
intravitreal, topical to the eye, back to the eye, intramuscular,
intravenous, and intrarectal modes of delivery. The actual amount
of the compound to be administered in any given case will be
determined by a physician taking into account the relevant
circumstances, such as the severity of the condition, the age and
weight of the patient, the patient's general physical condition,
the cause of the condition, and the route of administration.
Additionally, the formulations may be designed to delay release of
the active compound over a given period of time, or to carefully
control the amount of drug released at a given time during the
course of therapy.
[0096] Ester pro-drugs of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, of (S)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or of (R)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol and their
pharmaceutically-acceptable salts have extended alpha-2 adrenergic
receptor agonist activity in treating skin diseases and skin
conditions and may be administered through different routes,
including but not limited to topical skin patches, direct
injection, formulations that may further enhance the long duration
of actions such as a slow releasing pellet, suspension, gel, or
sustained delivery devices such as any suitable drug delivery
system (DDS) known in the art.
[0097] Skin diseases and skin conditions which may be treated with
pharmaceutical compositions containing as active ingredient ester
pro-drugs of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, of (S)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or of (R)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol include, but
are not limited to: rosacea, sunburn, chronic sun damage, discreet
erythemas, psoriasis, atopic dermatitis, menopause-associated hot
flashes, hot flashes resulting from orchiectomyatopic dermatitis,
photoaging, seborrheic dermatitis, acne, allergic dermatitis,
irritant dermatitis, telangiectasia (dilations of previously
existing small blood vessels) of the face, rhinophyma (hypertrophy
of the nose with follicular dilation), red bulbous nose, acne-like
skin eruptions (may ooze or crust), burning or stinging sensation
of the face, irritated and bloodshot and watery eyes, cutaneous
hyperactivity with dilation of blood vessels of the skin, Lyell's
syndrome, Stevens-Johnson syndrome, erythema multiforme minor,
erythema multiforme major and or other inflammatory skin diseases
and other inflammatory skin diseases. Skin conditions which result
in rosacea can be induced by intake of spicy food, of alcohol, of
chocolate, of hot or alcoholic drinks, temperature variations,
heat, exposure to ultraviolet or infrared radiation, exposure to
low relative humidity, exposure of the skin to strong winds or
currents of air, exposure of the skin to surfactants, irritants,
irritant dermatological topical agents, and cosmetics.
[0098] "Pharmaceutical composition," as used here, means a
composition that is suitable for administering to human patients
for the treatment of disease. In one embodiment, therefore, the
compound of the invention is formulated as pharmaceutically
acceptable salts and further include one or more pharmaceutically
acceptable excipients.
[0099] Ester pro-drugs of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, of (S)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or of (R)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol may be
formulated with efficacy enhancing components as disclosed in U.S.
Pat. No. 7,491,383 B2, which is hereby incorporated by reference in
its entirety.
[0100] The ester pro-drugs of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, of (S)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol or of (R)
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol have
physiochemical and pharmacokinetic properties that are beneficial
for sustained activity, particularly when the drug is delivered
continuously (e.g. to the skin by a dermal patch).
[0101] The compounds may be administered through different routes,
including but not limited to topical dermatological application of
an effective dose, direct injection, or formulations that may
further enhance the long duration of actions such as a slow
releasing pellet, suspension, gel, solution, lotion, cream,
ointment, foams, emulsions, microemulsions, milks, serums,
aerosols, sprays, dispersions, microcapsules, vesicles,
microparticles, nanoparticles, wet cloths, dry cloths, facial
cloths.
[0102] With respect to the present invention reference to a
compound or compounds, is intended to encompass that compound in
each of its possible isomeric forms and mixtures thereof unless the
particular isomeric form is referred to specifically.
[0103] The present invention also concerns a process for preparing
the compounds having general Formula I, Formula II or Formula III.
The synthetic scheme set forth below, illustrates how compounds
according to the invention can be made. Those skilled in the art
will be able to routinely modify and/or adapt the following scheme
to synthesize any compounds of the invention covered by Formula I,
Formula II or Formula III.
General Scheme for Synthesizing Ester Prodrugs of
(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol
##STR00006##
[0105] In a first step
(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol (CAS
189255-79-6) can react with the desired acyl chloride, in the
presence of N,N-dimethyl formamide (DMF), tertahydrofuran (THF),
triethylamine (TEA) and 4-dimethyl aminopyridine (DMAP). After a
typical work-up by extraction, the residue can be purified by
medium pressure liquid chromatography (MPLC) (0% to 40% ethyl
acetate in hexanes) to yield the intermediate compound as amorphous
solid.
[0106] In a second step, the intermediate obtained in the first
reaction, can react with methanol (MeOH). The residue can be
purified by MPLC (50% ethyl acetate in hexanes then 5% 7N
ammonia/methanol/dichloromethane) to yield the desired compound as
a solid.
[0107] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the invention
claimed. As used herein, the use of the singular includes the
plural unless specifically stated otherwise.
[0108] The present invention includes all pharmaceutically
acceptable isotopically enriched compounds. Any compound of the
invention may contain one or more isotopic atoms enriched or
different than the natural ratio such as deuterium .sup.2H (or D)
in place of protium .sup.1H (or H) or use of .sup.13C enriched
material in place of .sup.12C and the like. Similar substitutions
can be employed for N, O and S. The use of isotopes may assist in
analytical as well as therapeutic aspects of the invention. For
example, use of deuterium may increase the in vivo half-life by
altering the metabolism (rate) of the compounds of the invention.
These compounds can be prepared in accord with the preparations
described by use of isotopically enriched reagents.
[0109] The following examples are for illustrative purposes only
and are not intended, nor should they be construed as limiting the
invention in any manner. Those skilled in the art will appreciate
that variations and modifications of the following examples can be
made without exceeding the spirit or scope of the invention.
[0110] The IUPAC names of the compounds mentioned in the examples
were generated with ACD version 8.0.
[0111] Unless specified otherwise in the examples, characterization
of the compounds is performed according to the following
methods:
[0112] NMR spectra are recorded on 300 MHz Varian and acquired at
room temperature. Chemical shifts are given in ppm referenced
either to internal TMS or to the residual solvent signal.
[0113] All the reagents, solvents, catalysts for which the
synthesis is not described are purchased from chemical vendors such
as Sigma Aldrich, Fluka, Lancaster, however some known reaction
intermediates, for which the CAS registry number is mentioned, were
prepared in-house following known procedures.
[0114] Usually the compounds of the invention were purified by
flash column chromatography.
The Following Abbreviations are Used in the Examples
[0115] DCM dichloromethane [0116] MeOH methanol [0117] CD.sub.3OD
deuterated methanol [0118] NH.sub.3 ammonia [0119] Na.sub.2SO.sub.4
sodium sulfate [0120] DMF N,N-dimethylformamide [0121] MgSO.sub.4
magnesium sulfate [0122] EtOAc ethylacetate [0123] i-PrOH
iso-propanol [0124] CDCl.sub.3 deuterated chloroform [0125] MPLC
medium pressure liquid chromatography [0126] DMF dimethylformamide
[0127] TEA triethylamine [0128] THF tertahydrofuran [0129] DMAP
4-dimethylaminopyridine [0130] RT room temperature [0131]
Boc-L-Valine N-(tert-Butoxycarbonyl)-L-valine [0132] Boc-Glycine
N-(tert-Butoxycarbonyl)glycine [0133] Boc-L-Phenylalanine
N-(tert-Butoxycarbonyl)-L-phenylalanine [0134] HCl hydrochloric
acid [0135] H.sub.2O water [0136] EDCl
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide [0137] NaHCO.sub.3
sodium bicarbonate
Example 1
Intermediate 1
iso-Butyric acid
3-[(S)-1-(1-isobutyryl-1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl
ester
[0138] To a solution of
(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol (1.34 g,
6.2 mmol) in DMF (8 ml) and THF (50 ml), were added TEA (3.5 ml,
24.8 mmol), DMAP (780 mg, 6.2 mmol) and iso-butyryl chloride (2.18
g, 20.5 mmol). The resulting mixture was stirred at RT for 16 h,
quenched with H.sub.2O and extracted with ethyl acetate. The
combined organic layers were washed with brine, and dried over
Na.sub.2SO.sub.4, and concentrated under reduced pressure. The
residue was purified by MPLC (0% to 40% ethyl acetate in hexanes)
to yield Intermediate 1 as a solid.
[0139] .sup.1H-NMR (CD.sub.3OD, .delta. ppm): 1.15 (d, J=7.03 Hz,
6H), 1.26 (d, 6H, J=6.74 Hz), 1.56 (d, J=7.03 Hz, 3H), 2.34 (s,
3H), 2.58 (hept, J=7.03 Hz, 1H), 3.34 (hept, J=7.74 Hz, 1H), 4.42
(q, J=7.03 Hz, 1H), 5.15 (s, 2H), 7.07-7.10 (m, 2H), 7.12-7.15 (m,
1H), 7.31 (s, 1H), 8.35 (s, 1H).
[0140] Intermediates 2-6 were prepared in a similar manner to the
method described in Example 1 starting with
(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol. The
acyl chloride used in each case and the results are tabulated below
in Table 1.
TABLE-US-00001 TABLE 1 Intermediate .sup.1 NMR (Solvent; .delta.
number IUPAC name Acyl chloride ppm) 2 2,2-Dimethyl-propionic acid
Pivaloyl chloride (CD.sub.3OD): 1.19 (s, 3-{(S)-1-[1-(2,2-dimethyl-
9H), 1.42 (s, 9H), propionyl)-1H-imidazol-4- 1.56 (d, J = 7.03 Hz,
yl]-ethyl}-2-methyl-benzyl 3H), 2.34 (s, 3H), ester 4.42(q, J =
7.03 Hz, 1H), 5.15(s, 2H), 7.07-7.10 (m, 2H), 7.12-7.15 (m, 1H),
7.33 (s, 1H), 8.40 (s, 1H). 3 Acetic acid 3-[(S)-1-(1- Acetyl
chloride (CD.sub.3OD): 1.55 (d, acetyl-1H-imidazol-4-yl)- J = 7.03
Hz, 3H), 2.05 ethyl]-2-methyl-benzyl ester (s, 3H), 2.33 (s, 3H),
2.58 (s, 3H), 4.39(q, J = 7.03 Hz, 1H), 5.15(s, 2H), 7.07-7.10 (m,
2H), 7.12-7.15 (m, 1H), 7.30 (s, 1H), 8.29 (s, 1H). 4 Benzoic acid
3-[(S)-1-(1- Benzoyl chloride (CD.sub.3OD): 1.58 (d,
benzoyl-1H-imidazol-4-yl)- J = 7.03 Hz, 3H), 2.43
ethyl]-2-methyl-benzyl (s, 3H), 4.46(q, ester: J = 7.03 Hz, 1H),
5.41 (s, 2H), 7.11-7.18 (m, 2H), 7.27-7.35 (m, 2H), 7.42-7.50 (m,
2H), 7.50-7.63 (m, 3H), 7.65-7.71 (m, 1H), 7.79 (d, J = 7.33 Hz,
2H), 8.00 (d, J = 7.33 Hz, 2H), 8/09 (s, 1H). 5 3-Methyl-butyric
acid 2- Methylbutanoyl (CD.sub.3OD): 0.91 (d,
methyl-3-{(S)-1-[1-(3- chloride J = 6.44 Hz, 6H), 1.01
methyl-butyryl)-1H- (d, J = 6.44 Hz, 6H),
imidazol-4-yl]-ethyl}-benzyl 1.54 (d, J = 7.03 Hz, ester 3H), 2.05
(hept, J = 6.44 Hz, 1H), 2.15- 2.25 (m, 3H), 2.33 (s, 3H), 2.81 (d,
J = 7.03 Hz, 3H), 4.42(q, J = 7.03 Hz, 1H), 5.14(s, 2H), 7.07-7.19
(m, 3H), 7.28 (s, 1H), 8.32 (s, 1H). 6 3-Phenyl-propionic acid 2-
Phenylpropanoyl (CD.sub.3OD): 1.52 (d, methyl-3-{(S)-1-[1-(3-
chloride J = 7.03 Hz, 3H), 2.24 phenyl-propionyl)-1H- (s, 3H), 2.64
(t, imidazol-4-yl]-ethyl}-benzyl J = 7.61 Hz, 2H), 2.90 ester (t, J
= 7.61 Hz, 2H), 3.04 (t, J = 7.61 Hz, 2H), 3.24 (t, J = 7.61 Hz,
2H), 4.34 (q, J = 7.03 Hz, 1H), 5.13 (s, 2H), 7.08- 7.248 (m, 14H),
8.25 (s, 1H).
Example 2
Compound 1
iso-Butyric acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl
ester
##STR00007##
[0142] Intermediate 1 was dissolved in MeOH (50 ml) and the mixture
was stirred at RT for 24 h and then concentrated under reduced
pressure. The residue was purified by MPLC (50% ethyl acetate in
hexanes then 5% 7N NH.sub.3/MeOH/DCM) to yield Compound 1 as a
solid.
[0143] .sup.1H-NMR (CD.sub.3OD; .delta. ppm): 1.15 (d, J=7.03 Hz,
6H), 1.54 (d, J=7.03 Hz, 3H), 2.33 (s, 3H), 2.56 (hept, J=7.03 Hz,
1H), 4.42 (q, J=7.03 Hz, 1H), 5.15 (s, 2H), 6.70 (s, 1H), 7.07-7.10
(m, 2H), 7.12-7.15 (m, 1H), 7.55 (s, 1H).
[0144] Compounds 2-6 and of the invention were prepared according
to the procedure described in Example 2, by reacting the
corresponding intermediate with methanol. The results are tabulated
below in Table 2.
TABLE-US-00002 TABLE 2 Comp. Inter. No. IUPAC name No. .sup.1NMR
(Solvent, .delta. ppm) 2 ##STR00008## 2 (CD.sub.3OD): 1.19 (s, 9H),
1.54 (d, J = 7.03 Hz, 3H), 2.33 (s, 3H), 4.42 (q, J = 7.03 Hz, 1H),
5.13 (s, 2H), 6.70 (s, 1H), 7.07-7.10 (m, 2H), 7.12-7.15 (m, 1H),
7.55 (s, 1H). 3 ##STR00009## 3 (CD.sub.3OD): 1.54 (d, J = 7.03 Hz,
3H), 2.04 (s, 3H), 2.33 (s, 3H), 4.42 (q, J = 7.03 Hz, 1H), 5.13
(s, 2H), 6.70 (s, 1H), 7.07-7.10 (m, 2H), 7.12-7.15 (m, 1H), 7.55
(s, 1H). 4 ##STR00010## 4 (CD.sub.3OD): 1.54 (d, J = 7.03 Hz, 3H),
2.31 (s, 3H), 4.42 (q, J = 7.03 Hz, 1H), 5.13 (s, 2H), 6.70 (s,
1H), 7.07-7.15 (m, 2H), 7.25-7.28 (m, 1H), 7.54- 7.47 (m, 2H),
7.55-7.60 (m, 2H), 8.0 (d, J = 7.33 Hz, 2H). 5 ##STR00011## 5
(CD.sub.3OD): 0.93 (d, J = 7.03 Hz, 6H), 1.54 (d, J = 7.03 Hz, 3H),
2.07 (hept, J = 7.03 Hz, 1H), 2.21 (d, J = 7.03 Hz, 2H), 2.33 (s,
3H), 4.42 (q, J = 7.03 Hz, 1H), 5.15 (s, 2H), 6.70 (s, 1H), 7.07-
7.10 (m, 2H), 7.12-7.15 (m, 1H), 7.55 (s, 1H). 6 ##STR00012## 6
(CD.sub.3OD): 1.54 (d, J = 7.03 Hz, 3H), 2.23 (s, 3H), 2.65 (t, J =
7.61 Hz, 2H), 2.91 (t, J = 7.61 Hz, 2H), 4.40 (q, J = 7.03 Hz, 1H),
5.13 (s, 2H), 6.70 (s, 1H), 7.08-7.24 (m, 8H), 7.55 (s, 1H).
Example 3
Intermediate 7
2-tert-Butoxycarbonylamino-3-methyl-butyric acid
3-{(S)-1-[1-(2-tert-butoxy
carbonylamino-3-methyl-butyryl)-1H-imidazol-4-yl]-ethyl}-2-methyl-benzyl
ester
[0145] To a solution of
(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol (216 mg,
1.0 mmol) in DMF (2 ml) and THF (12 ml) were added EDCl (671 mg,
3.5 mmol), DMAP (427 mg, 3.5 mmol) and Boc-L-Valine (651 mg, 3.0
mmol). The mixture was stirred at RT for 16 h, quenched with
H.sub.2O and extracted with ethyl acetate. The combined organic
layers were washed with H.sub.2O, brine, and dried over
Na.sub.2SO.sub.4, and concentrated under reduced pressure. The
residue was purified by a column chromatography (30% ethyl acetate
in hexanes) to yield Intermediate 7 as white solid.
[0146] .sup.1H-NMR (CD.sub.3OD; .delta. ppm): 0.85-1.01 (m, 12H),
1.20-1.48 (m, 18H), 1.56 (d, J=7.03 Hz, 3H), 2.01-2.20 (m, 2H),
2.35 (s, 3H), 4.03 (m, 1H), 4.42 (q, J=7.03 Hz, 1H), 4.60-4.65 (m,
1H), 5.15-5.29 (m, 2H), 7.10-7.20 (m, 2H), 7.20-7.25 (m, 1H), 7.33
(s, 1H), 8.44 (s, 1H).
Example 4
Intermediate 8
2-tert-Butoxycarbonylamino-3-methyl-butyric acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester
[0147] The title compound was prepared from Intermediate 7 (600 mg,
0.98 mmol) in 30 ml of MeOH according to the procedure described in
Example 2.
[0148] .sup.1H-NMR (CD.sub.3OD; .delta. ppm): 0.85-0.95 (m, 6H),
1.42 (m, 9H), 1.54 (d, J=7.03 Hz, 3H), 2.05 (m, 1H), 2.33 (s, 3H),
4.00 (d, J=6.15 Hz, 1H), 4.40 (q, J=7.03 Hz, 1H), 5.15-5.28 (m,
2H), 6.67 (s, 1H), 7.10-7.20 (m, 2H), 7.20-7.25 (m, 1H), 7.55 (s,
1H).
Example 5
Compound 7
2-Amino-3-methyl-butyric acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester
##STR00013##
[0150] To Intermediate 8 (390 mg, 0.94 mmol) was added 4N HCl in
dioxane (8 ml). The resulting solution was stirred at RT for 4 hrs,
then quenched with H.sub.2O, neutralized with aqueous saturated
NaHCO.sub.3 and extracted with 25% isopropyl alcohol in chloroform.
The combined organic layers were dried over Na.sub.2SO.sub.4, and
concentrated under reduced pressure. The residue was purified by a
column chromatography (5% 7N NH.sub.3/MeOH in DCM) to yield
Compound 7 as white solid.
[0151] .sup.1H-NMR (CD.sub.3OD; .delta. ppm): 0.85 (d, J=6.74 Hz,
3H), 0.91 (d, J=6.74 Hz, 3H), 1.54 (d, J=7.03 Hz, 3H), 1.96 (hept,
J=6.74 Hz, 1H), 2.33 (s, 3H), 3.28 (d, J=6.74 Hz, 2H), 4.42 (q,
J=7.03 Hz, 1H), 5.20-5.25 (m, 2H), 6.67 (s, 1H), 7.10-7.12 (m, 2H),
7.13-7.20 (m, 1H), 7.55 (s, 1H).
Example 6
Intermediate 9
2-(2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-methyl-butyric
acid
3-{(S)-1-[1-(2-tert-butoxycarbonylamino-3-methyl-butyryl)-1H-imidazol-4-y-
l]-ethyl}-2-methyl-benzyl ester
[0152] The title compound was prepared from Compound 7 (490 mg,
1.55 mmol), Boc-L-Valine (1.01 g, 4.67 mmol), EDCl (1.04 g, 5.42
mmol) and DMAP (671 mg, 5.5 mmol) according to the procedure
described in Example 3.
[0153] .sup.1H-NMR (CD.sub.3OD; .delta. ppm): 0.85-0.92 (m, 12H),
1.43 (s, 9H), 1.55 (d, J=7.03 Hz, 3H), 1.97 (m, 1H), 2.14 (hept,
J=6.60 Hz, 1H), 2.35 (s, 3H), 3.88 (d, J=7.30 Hz, 1H), 4.35 (d,
J=6.90 Hz, 1H), 4.42 (, d, J=7.03 Hz, 1H), 5.18-5.25 (m, 2H), 6.67
(s, 1H), 7.10-7.15 (m, 2H), 7/17-7.20 (m, 1H), 7.55 (s, 1H).
Example 7
Intermediate 10
2-(2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-methyl-butyric
acid 3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester
[0154] The title compound was prepared from Intermediate 9 (750 mg,
1.05 mmol) in 30 ml of MeOH according to the procedure described in
Example 2.
[0155] .sup.1H-NMR (CD.sub.3OD; .delta. ppm): 0.89 (d,d, J=7.03 Hz,
6H), 1.44 (s, 9H), 1.54 (d, J=7.33 Hz, 3H), 2.14 (hept, J=6.74 Hz,
1H), 2.33 (s, 3H), 3.74 (s, 2H), 4.35-4.55 (m, 2H), 5.20 (s, 2H),
6.67 (s, 1H), 7.10-7.17 (m, 2H), 7.19-7.23 (m, 1H), 7.56 (s,
1H).
Example 8
Compound 8
2-(2-Amino-3-methyl-butyrylamino)-3-methyl-butyric acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester
##STR00014##
[0157] The title compound was prepared from Intermediate 10 (450
mg, 0.87 mmol) in 8 ml of 4N HCl/Dioxane according to the procedure
described in Example 5.
[0158] .sup.1H-NMR (CD.sub.3OD; .delta. ppm): 0.85 (d, J=7.03 Hz,
3H), 0.91 (d, J=6.74 Hz, 3H), 0.92 (d, J=7.3 Hz. 3H), 1.14 (d,
J=6.2 Hz, 3H), 1.54 (d, J=7.03 Hz, 3H), 1.94 (hept, J=5.2 Hz, 1H),
2.14 (hept, J=6.2 Hz, 1H), 2.33 (s, 3H), 3.18 (d, J=5.2 Hz, 1H),
4.34 (d, J=6.2 Hz, 1H), 4.42 (q, J=7.03 Hz, 1H), 5.21-5.26 (m, 2H),
6.67 (s, 1H), 7.10-7.15 (m, 2H), 7.18-7.20 (m, 1H), 7.55 (s,
1H).
Example 9
Intermediate 11
2-(2-tert-Butoxycarbonylamino-acetylamino)-3-methyl-butyric acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester
[0159] The title compound was prepared from Compound 8 (405 mg,
1.28 mmol), Boc-Glycine (675 mg, 3.86 mmol), EDCl (859 mg, 4.48
mmol) and DMAP (547 mg, 4.48 mmol) according to the procedure
described in Example 3. The title compound was purified by column
chromatography using 5% 7N NH.sub.3/MeOH in DCM.
[0160] .sup.1H-NMR (CD.sub.3OD; .delta. ppm): 0.89 (d, J=6.74 Hz,
3H), 0.91 (d, J=6.74 Hz, 3H), 1.55 (d, J=7.30 Hz, 3H), 2.14 (hept,
J=6.74 Hz, 1H), 2.33 (s, 3H), 4.37 (d, J=5.90 Hz, 1H), 4.42 (q,
J=7.03 Hz, 1H), 5.20-5.25 (m, 2H), 6.67 (s, 1H), 7.10-7.12 (m, 2H),
7.13-7.20 (m, 1H), 7.55 (s, 1H).
Example 10
Compound 9
2-(2-Amino-acetylamino)-3-methyl-butyric acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester
##STR00015##
[0162] The title compound was prepared from Intermediate 11 (320
mg, 0.68 mmol) with 10 ml of 4N HCl/Dioxane according the procedure
described in Example 5.
[0163] .sup.1H-NMR (CD.sub.3OD; .delta. ppm): 0.89 (d, J=6.74 Hz,
3H), 0.91 (d, J=6.74 Hz, 3H), 2.14 (hept, J=6.74 Hz, 1H), 2.33 (s,
3H), 4.37 (d, J=5.90 Hz, 1H), 4.42 (q, J=7.03 Hz, 1H), 5.20-5.25
(m, 2H), 6.67 (s, 1H), 7.10-7.12 (m, 2H), 7.13-7.20 (m, 1H), 7.55
(s, 1H).
Example 11
Intermediate 12
2-tert-Butoxycarbonylamino-3-phenyl-propionic acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester
[0164] The title compound was prepared from
(S)-[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol (216 mg,
1.0 mmol), Boc-L-Phenylalanine (795 mg, 3.0 mmol), EDCl (671 mg,
3.5 mmol) and DMAP (427 mg, 3.5 mmol) according to the procedure
described in Example 3. Intermediate 12 was purified by a column
chromatography using 35-100% ethyl acetate in hexane.
[0165] .sup.1H-NMR (CD.sub.3OD; .delta. ppm): 1.36 (s, 9H), 1.55
(d, J=7.03 Hz, 3H), 2.28 (s, 3H), 2.85-2.95 (m, 1H), 3.05-3.11 (m,
1H), 4.38 (m, 1H), 4.40 (q, J=7.03 Hz, 1H), 5.17 (s, 2H), 6.69 (s,
1H), 7.08-7.24 (m, 8H), 7.55 (s, 1H).
Example 12
Compound 10
2-Amino-3-phenyl-propionic acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester
##STR00016##
[0167] The title compound was prepared from Intermediate 12 (240
mg, 0.52 mmol) with 8 ml of 4N HCl/Dioxane according to the
procedure described in Example 5.
[0168] .sup.1H-NMR (CD.sub.3OD; .delta. ppm): 1.54 (d, J=7.03 Hz,
3H), 2.26 (s, 3H), 2.90-3.00 (m, 2H), 3.73 (t, J=6.40 Hz, 1H), 4.40
(q, J=7.03 Hz, 1H), 5.13-5.18 (m, 2H), 6.68 (s, 1H), 7.08-7.12 (m,
5H), 7.13-7.22 (m, 3H), 7.55 (s, 1H).
Example 13
In Vitro Human Skin Permeability Assay
[0169] Human, ex vivo, trunk skin was cut into multiple smaller
sections large enough to fit on nominal 2 cm.sup.2 static Franz
diffusion cells. The dermal receptor compartment was filled to
capacity with receptor solution consisting of 0.1.times. phosphate
buffered solution with 0.1% Oleth-20, and the epidermal chamber
(chimney) is left open to ambient laboratory environment. The cells
were placed in a diffusion apparatus in which the receptor solution
in contact with the underside of the dermis was stirred
magnetically at .about.600 RPM and its temperature maintained to
achieve a skin surface temperature of 32.0.+-.1.0.degree. C.
[0170] To assure the integrity of each skin section, its
permeability to tritiated water was determined before application
of the test products. Skin specimens in which absorption of
.sup.3H.sub.2O was less than 1.56 .mu.L-equ/cm.sup.2 were
considered acceptable.
[0171] [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol,
Compound 2 (2,2-Dimethyl-propionic acid
3-[(S)-1-(1H-imidazol-4-yl)-ethyl]-2-methyl-benzyl ester) and
Compound 1 (iso-Butyric acid
3-[(S)-1-(1H-imidazol-4-yl)ethyl]-2-methyl-benzyl ester) were
applied separately to three (3) replicate sections of the same
donor skin for each donor, evaluating three (3) donors for the
designated dose duration. A dose of 5 mg formulation/cm.sup.2/skin
section was evenly dispersed and rubbed into the skin surface using
a glass rod.
[0172] At designated time points and at the end of the study dose
duration, the receptor solution was removed in its entirety, and a
predetermined volume aliquot saved for subsequent analysis. After
the last receptor sample was collected, the donor compartment
(chimney) was removed, and the surface of the skin was cleansed
twice to collect any un-absorbed formulation from the skin surface.
Following the surface cleanse, the skin was tape stripped to remove
the stratum corneum. The tape strips were extracted overnight in
acetonitrile and analyzed for content of the compound of interest.
The skin was then removed from the diffusion cell, split into
epidermis and dermis, and each skin sample extracted overnight in
50%:50% (v/v) ethanol/water or 50%:50% (v/v) methanol water for
epidermis and dermis, respectively. The skin section samples were
analyzed for content of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, Compound 2
and Compound 1. All samples were stored at .about.-20.degree. C.
(.+-.15.degree. C.) pending analysis. Quantitation of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, Compound 2,
and Compound 1 were analyzed by liquid chromatography with tandem
mass spectrometry (PLC/MS).
[0173] Replicates within donors were averaged and the standard
deviation calculated for each key parameter. Within donor averages
were then collated and the across donor population mean with
standard error of the mean calculated.
[0174] FIG. 1 shows the rate of percutaneous absorption as the flux
of [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol (closed
circles, solid line), Compound 2, pivalate derivative prodrug (open
squares, dotted line includes parent drug), and Compound 1,
2-methylpropanoate derivative prodrug (open triangles and dashed
line includes parent drug) that appears in the receptor solution
under the skin after a 0.18%, 0.65% and 0.55% (w/w) dose,
respectively. The flux of parent drug
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol formed after
dosing Compound 2, pivalate derivative prodrug (closed squares,
dotted line) and Compound 1, 2-methylpropanoate derivative prodrug
(closed triangles and dashed line) on human trunk skin are
plotted.
[0175] FIG. 2 shows the distribution of
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, Compound 2,
pivalate derivative prodrug (open bars represent formed parent),
and Compound 1, 2-methylpropanoate derivative prodrug (open bars
represent formed parent) in each skin layer following a 48 hour
dose exposure of a 0.18%, 0.65% and 0.55% (w/w) dose, respectively
to ex vivo human trunk skin as a mass recovered.
[0176] The data indicate that Compound 2, pivalate derivative and
Compound 1, 2-methylpropanoate derivative, penetrate into and
through ex vivo human trunk skin using the in vitro Franz diffusion
cell.
* * * * *