U.S. patent application number 11/075922 was filed with the patent office on 2005-07-14 for inhibitors of melanocyte tyrosinase as topical skin lighteners.
This patent application is currently assigned to MediQuest Therapeutics, Inc.. Invention is credited to Curto, Ernest V., Dooley, Thomas P..
Application Number | 20050152859 11/075922 |
Document ID | / |
Family ID | 22681701 |
Filed Date | 2005-07-14 |
United States Patent
Application |
20050152859 |
Kind Code |
A1 |
Dooley, Thomas P. ; et
al. |
July 14, 2005 |
Inhibitors of melanocyte tyrosinase as topical skin lighteners
Abstract
Methods and formulations are provided to reduce pigmentation in
skin, using an array of compounds selected from benzimidazoles,
phenylthioureas, phenyltiols, phenylamines, bi- and multicyclic
phenols, thiopheneamines, and benzothiamides. The compounds
preferably inhibit pigment systhesis in melanocytes through the
tyrosinase pathway. The methods can be used for lightening skin,
and for treating uneven skin complexions which result from
hyperpigmentation-related medical conditions such as melasma, age
spots, freckles, ochronosis, and lentigo. The compounds can be used
medically or cosmetically.
Inventors: |
Dooley, Thomas P.; (Vestavia
Hills, AL) ; Curto, Ernest V.; (Huntsville,
AL) |
Correspondence
Address: |
CONNOLLY BOVE LODGE & HUTZ LLP
SUITE 800
1990 M STREET NW
WASHINGTON
DC
20036-3425
US
|
Assignee: |
MediQuest Therapeutics,
Inc.
Bothell
WA
|
Family ID: |
22681701 |
Appl. No.: |
11/075922 |
Filed: |
March 10, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11075922 |
Mar 10, 2005 |
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10427561 |
May 1, 2003 |
|
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|
10427561 |
May 1, 2003 |
|
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09795683 |
Feb 28, 2001 |
|
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60185610 |
Feb 29, 2000 |
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Current U.S.
Class: |
424/59 |
Current CPC
Class: |
A61K 8/4946 20130101;
A61K 8/4913 20130101; A61K 31/145 20130101; A61K 2800/782 20130101;
A61K 31/381 20130101; A61K 31/095 20130101; A61K 8/411 20130101;
A61K 31/24 20130101; A61K 31/167 20130101; A61K 31/17 20130101;
A61K 8/4973 20130101; A61K 31/404 20130101; A61Q 19/02 20130101;
A61K 8/49 20130101; A61K 8/4986 20130101; A61K 31/136 20130101;
A61K 8/46 20130101; A61K 31/428 20130101; A61K 31/4184 20130101;
A61P 17/00 20180101; A61K 31/36 20130101 |
Class at
Publication: |
424/059 |
International
Class: |
A61K 007/42; A61K
007/135 |
Claims
What is claimed is:
1. A method for protecting skin from ultraviolet rays and
photoaging comprising administering to a human in need of
ultraviolet ray absorption for protection from ultraviolet rays or
photoaging, an effective amount of at least one compound defined by
the structure. 28and R10 is methyl, ethyl or propyl, or a
pharmaceutically acceptable salt or ester thereof.
2. The method of claim 1 wherein R.sub.10 is methyl.
3. The method of claim 1 wherein R.sub.10 is ethyl.
4. The method of claim 1 wherein R.sub.10 is propyl.
5. The method of claim 1 wherein the compound has an IC.sub.50
against mammalian tyrosinase activity of less than or equal to 300
uM, and an IC.sub.50 of cytotoxicity in mammalian melanocytic cells
of greater than 500 uM.
6. The method of claim 1 wherein the compound has an IC.sub.50
against melanin production in mammalian melanocytic cells of less
than or equal to 300 uM, and an IC.sub.50 of cytotoxicity in
mammalian melanocytic cells of greater than 500 uM.
7. The method of claim 1 wherein the compound is an
antioxidant.
8. The method of claim 1 wherein the administration is through a
topical formulation.
9. The method of claim 1 wherein the method further lightens skin
pigmentation.
10. A method of inhibiting or preventing pigment production in a
mammal comprising administering to the mammal an effective amount
of a compound defined by the structure below, or a pharmaceutically
acceptable salt or ester thereof: 29and R.sub.10 is methyl, ethyl
or propyl.
11. The method of claim 10 wherein the compound has an IC.sub.50
against mammalian tyrosinase activity of less than or equal to 300
uM, and an IC.sub.50 of cytotoxicity in mammalian melanoctyic cells
of greater than 500 uM.
12. The method of claim 10 wherein the compound has an IC.sub.50
against melanin production in mammalian melanocytic cells of less
than or equal to 300 uM, and an IC.sub.50 of cytotoxicity in
mammalian melanocytic cells of greater than 500 uM.
13. The method of claim 10 wherein the compound absorbs ultraviolet
radiation.
14. The method of claim 10 wherein the compound is an
antioxidant.
15. The method of claim 10 wherein the mammal is a human.
16. The method of claim 10 wherein the administration is through a
topical formulation or an occlusive patch.
17. The method of claim 10 wherein the method is for lightening
skin pigmentation
18. The method of claim 10 wherein the method is for treating
hyperpigmentation-related medical conditions.
19. The method of claim 10 wherein R.sub.10 is methyl.
20. The method of claim 10 wherein R.sub.10 is ethyl.
21. The method of claim 10 wherein R.sub.10 is propyl.
22. A method of inhibiting tyrosine hydroxylase comprising
administering an effective amount of a compound defined by the
structure below or a pharmaceutically acceptable salt or ester
thereof: 30and R.sub.10 is methyl, ethyl or propyl.
23. The method of claim 12 wherein the hyperpigmentation-related
medical condition is melasma, age spots, freckles, ochronosis,
postinflammatory hyperpigmentation, or lentigo.
24. The method of claim 22 wherein R.sub.10 is methyl.
25. The method of claim 23 wherein R.sub.10 is ethyl.
26. The method of claim 24 wherein R.sub.10 is propyl.
Description
CROSS REFERENCE TO PRIOR APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
09/795,683, filed Feb. 28, 2001, now abandoned and further claims
priority to U.S. provisional patent application No. 60/185,610,
filed Feb. 29, 2000. This application incorporates the entire
disclosure of U.S. Ser. No. 09/795,683 and 60/185,610 as if fully
set forth herein.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds and methods for
inhibiting the activity of melanocyte tyrosinase in mammalian skin,
in order to reduce the expression and production of skin
pigmentation, and thereby lighten the color of mammalian skin.
BACKGROUND OF THE INVENTION
[0003] Melanogenesis is the process of production and subsequent
distribution of melanin by melanocytes within the skin and hair
follicles [1, 2]. Melanocytes have specialized lysosome-like
organelles, termed melanosomes, which contain several enzymes that
mediate the production of melanin. The copper-containing enzyme
tyrosinase catalyzes the oxidation of the amino acid tyrosine into
DOPA and subsequently DOPA-quinone. At least two additional
melanosomal enzymes are involved in the eumelanogenesis pathway
that produces brown and black pigments, including TRP-1 (DHICA
oxidase), and TRP-2 (DOPAchrome tautomerase). Depending on the
incorporation of a sulfur-containing reactant (e.g. cysteine or
glutathione) into the products, the melanogenesis pathway diverges
to produce pheomelanins (amber and red pigments).
[0004] The perceived color of skin and hair is determined by the
ratio of eumelanins to pheomelanins, and in part on blood within
the dermis. The balance in skin hue is genetically regulated by
many factors, including but not limited to: (a) the levels of
expression of tyrosinase, TRP-2, and TRP-1; (b) thiol conjugation
(e.g. with glutathione or cysteine) leading to the formation of
pheomelanins; (c) the .alpha.-melanocyte-stim- ulating hormone
(.alpha.-MSH) and melanocortin receptor, which is coupled to the
adenylate cyclase/protein kinase A pathway; [15] (d) the product of
the agouti locus, agouti signal protein, which has been documented
to down-regulate pigmentation of hair melanocytes in rodents; [16]
and (e) yet unknown mechanisms that regulate the uptake and
distribution of melanosomes in recipient epidermal and hair matrix
keratinocytes. [2, 13, 14].
[0005] Abnormalities of human skin pigmentation occur as a result
of both genetic and environmental factors. Exposure of skin
(especially Caucasian) to ultraviolet radiation, particularly in
the UVB (i.e. intermediate) wavelengths, upregulates synthesis of
melanocyte tyrosinase resulting in increased melanogenesis and thus
tanning. However, acute or persistent UVB exposure can result in
the formation of hyperpigmented lesions or regions of skin,
including malignant melanoma skin cancer. [17] Both actinic damage
and constitutional abnormalities can produce affected regions such
as melasma, age spots, liver spots, freckles and other lentigenes.
[3, 18, 19].
[0006] Vitiligo is the converse of hyperpigmentation, in which
cutaneous melanocytes are either ablated or fail to produce
sufficient pigment. [17, 18, 20] Although it would be desirable to
restore lost pigmentation in vitiligo-affected skin with topical
therapies, this has proven to be quite difficult to accomplish in a
high proportion of subjects. As an alternative to PUVA therapy or
cosmetic camouflage with dihydroxyacetone sunless-tanning lotions,
[18] one might reduce the normal pigmentation of the unaffected
skin to reduce contrast. Furthermore, a global market demand has
developed for skin-lightening agents as "vanity" cosmeceutical
products, because lighter skin color is preferred by some
dark-skinned individuals in many countries and races, for
psychological or sociological reasons. [4, 5].
[0007] Some purportedly "active" or "functional" agents for
lightening skin color (e.g. arbutin, kojic acid, niacinamide,
licorice, magnesium ascorbyl phosphate, among others) have not been
demonstrated yet to be clinically efficacious when critically
analyzed in carefully controlled studies [5, 6, 25]. The U.S.
FDA-approved pharmaceutical products containing 24% hydroquinone
("HQ") are minimally to moderately efficacious. However, HQ has
been demonstrated to be cytotoxic to cultured mammalian
melanocytes, and mutagenic in Salmonella and mammalian Chinese
hamster V79 cells [3-6, 10, 11, 25]. HQ appears to be an important
intermediate in the bioactivation of the carcinogen benzene [12].
Although it has been repeatedly asserted in the dermatologic
literature for many years, without substantiation, that HQ is an
inhibitor of tyrosinase, this compound is not an effective
inhibitor of the mammalian enzyme [5, 6, 25]. Hydroquinone's in
vitro mechanism of action appears to be primarily a melanocytic
cytotoxic effect. Its clinical mechanism of action on whole skin
remains uncertain.
[0008] In view of these biochemical disadvantages of the standard
skin bleaching agent, HQ, it is highly desirable to identify other
compounds with improved efficacy and safety characteristics. Methyl
gentisate ("MG"), the methyl ester of gentisic acid (GA;
2,5-dihydroxybenzoic acid), is a moderately potent inhibitor of
melanin accumulation in a murine melanocyte cell culture primary
screen [6, 25]. GA is a natural product from the root of the genus
Gentiana, named after Gentius, an Illyrian (Greco-Roman) king of
the 2.sup.nd century B.C., said to have first discovered the
medicinal properties of the plant [7]. The sodium salt of GA is
thought to be an analgesic and an anti-inflammatory agent. GA is a
ubiquitous metabolite, produced not only by plants, but also by
Penicillium patulum and Polyporus tumulosus, and is excreted into
the urine of mammals following ingestion of salicylates [8, 9]. MG
and GA are simple phenolic compounds structurally similar to HQ,
yet lacking the mutagenic activity of HQ [25]. MG has not been
developed as a commercially available topical skin lightener
product to date.
[0009] Two patent publications of Sansei Seiyaku also disclose a
number of compounds, which allegedly are active as either
tyrosinase inhibitors or as skin lightening agents, JP 5-124925 and
JP 5-124922. The compounds are various benzimidazolethiols, but
have not been developed as commercially available topical skin
lightener products to date. In addition, phenylthiourea (PTU) has
been reported as an inhibitor of tyrosinase, but has not been
developed as a commercially available topical skin lightener
product to date [30-32].
[0010] It is an object of this invention to provide methods and
compositions for reducing pigmentation in skin from mammals,
including humans.
[0011] Another object is to provide methods and compositions for
reducing pigmentation of skin for cosmetic, beauty-enhancing, or
esthetic effects.
[0012] It is another object to provide methods and compositions for
treating hyperpigmentation-related medical conditions such as
melasma, age spots, freckles, ochronosis, postinflammatory
hyperpigmentation, lentigo, and other pigmented skin blemishes.
[0013] Another object of the present invention is to provide
methods and compositions for inhibiting mammalian melanocyte
tyrosinase, the rate-limiting enzyme in the production of melanin
from tyrosine and DOPA.
[0014] Still another object of the invention is to provide methods
and compositions to absorb ultraviolet radiation (UVR), and thus to
protect skin from UVR and photoaging.
[0015] An additional object of the invention is to provide
antioxidant compositions that protect skin from oxidative damage,
and/or to prevent oxidative decomposition of product
formulations.
[0016] Another object is to facilitate discovery of compounds that
inhibit mammalian tyrosinase in cell-free extracts from mammalian
melanocyte or melanoma cells, using either a colorometric DOPA
oxidation or a radiolabeled tyrosine or DOPA substrate assay
(IC.sub.50.ltoreq.300 EM).
[0017] Another object is to facilitate discovery of compounds that
inhibit de novo pigment production (synthesis and/or accumulation)
in cultured mammalian melanocyte or melanoma cells
(IC.sub.50.gtoreq.300 .mu.M).
[0018] Another object is to facilitate evaluation of compounds for
toxicity in mammalian melanocyte, melanoma, or other cell cultures
(IC.sub.50.gtoreq.300 .mu.M).
[0019] Another object is to provide composition of matter and/or
identity of compounds that are efficacious and/or exhibit reduced
toxicity using one or more of the bioassays described in other
objects, with biochemical characteristics equivalent to or superior
to hydroquinone or methyl gentisate.
[0020] Another object is to provide active and/or functional
compounds from diverse structural classes, including but not
limited to the following examples: benzoimidazoles, phenylamines,
phenylthioureas, phenols, and phenylthiols.
[0021] Still another object is to provide synthesis of derivatives
of active and/or functional compounds of the invention, including
by organic synthesis, combinatorial chemistry, medicinal chemistry,
X-ray crystallography, rational drug design, and other methods.
[0022] Another object is to provide the use of formulations of the
present invention for cosmetic, cosmeceutical, over-the-counter
drug, and prescription drug products.
[0023] Another object is to provide formulations of the present
invention for the purpose of reducing or preventing pigmentation in
hair, albeit during the biosynthesis of hair, as a result of
blocking pigment production within the melanocytes of hair
follicles.
[0024] Another object is to provide the active and/or functional
compounds of the present invention for use in inhibiting tyrosinase
or tyrosinase-like enzymes from non-mammalian species, for instance
for use in the food science industry for the inhibition of
enzymatic browning.
[0025] Still another object is to provide the active and/or
functional compounds of the present invention for use in inhibiting
tyrosine hydroxylase enzymes, in order to reduce the biosynthesis
of DOPA and/or catecholamines.
SUMMARY OF THE INVENTION
[0026] Several classes of compounds are provided that reduce or
prevent the production of pigment by mammalian melanocytes. The
compounds preferably inhibit the enzymatic activity of melanocyte
tyrosinase, though some compounds control pigment production in
melanocyte cells without being potent inhibitors of the enzyme.
Therefore, the compounds can be used in applications wherein
controlling or preventing the production of pigments in mammalian
skin is desired. A few examples of such applications include:
[0027] 1. As a vanity product, to lighten the skin of an
individual, especially of dark skinned individuals;
[0028] 2. To lessen the hue of pigmented skin blemishes such as
freckles and age spots;
[0029] 3. To diminish uneven pigmentation marks and surface color
irregularities;
[0030] 4. To treat hyperpigmentation-related medical conditions
such as melasma, ochronosis, and lentigo;
[0031] 5. To lighten hair pigmentation when applied to skin
containing pigmented hair follicles;
[0032] 6. To lessen postinflammatory hyperpigmentation resulting
from trauma or invasive surgery from a face lift, laser treatment,
or cosmetic surgery; and
[0033] 7. To reduce skin pigmentation in normal skin adjacent to
areas affected by vitiligo, thereby diminishing the contrast in
color between normal and vitiligo affected skin.
[0034] Several classes of active skin lightening compounds have
been discovered with which the present invention can be practiced.
These compounds exhibit activity in the mammalian tyrosinase and/or
melanocyte cell culture pigmentation assays, yet with minimal or no
cytotoxicity. These compounds exhibit characteristics that are
equivalent to or superior to the known standard skin-bleaching
agent, hydroquinone, or the known standard tyrosinase inhibitor,
methyl gentisate.
[0035] The compounds are typically applied topically to the skin
wherein tyrosinase activity is sought to be reduced through a
lotion or occlusive patch. The compounds can be spread over a
larger area to produce an even skin tone fade, or they can be
applied locally to skin blemishes and other localized conditions to
minimize skin irregularities. Moreover, because most of the
compounds are selective against melanocyte tyrosinase, the
compounds can also be administered systemically by methods
including oral, intradermal, transdermal, intraveneous, and
parenteral administrations. The product works by inhibiting the
production of melanin in cells beneath the skin surface. Because
the skin naturally renews itself every ca. 28 days, when the
compounds of the present invention are administered old
(differentiated) pigmented keratinocytes cells are gradually
sloughed off and keratinocytes with less melanin are eventually
brought to the surface giving the skin a lighter, more even toned
complexion.
[0036] In a first principal embodiment the compounds of the present
invention are benzimidazole and phenylthiourea related compounds
represented by the following formula (I): 1
[0037] wherein:
[0038] 1) R.sub.1 is H or a valence for bonding;
[0039] 2) R.sub.2 is S, or SH;
[0040] 3) one of the dotted lines (----) represents a bond;
[0041] 4) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
CR.sub.8, or N;
[0042] 5) R.sub.8 is (i) hydrogen, (ii) halogen, (iii) NO.sub.2,
(iv) --CN, (v) --OR.sub.10, (vi) --NHSO.sub.2--C.sub.1-3alkyl,
(vii) --NHCO--C.sub.1-5 alkyl, (viii) oxime, (ix) hydrazine, (x)
--NR.sub.9R.sub.10, (xi) HSO.sub.2, (xii) HSO.sub.3, (xiii)
thio-C.sub.1-5 alkyl, (xiv) C.sub.1-5 acyloxy, (xv)
H.sub.2PO.sub.3, (xvi) thiol, (xvii) --COOR.sub.9, (xviii)
C.sub.1-5 alkynyl, or (xix) --C.sub.1-5 alkyl, --C.sub.1-5 alkenyl,
aryl, heteroaryl, or heterocycle, optionally substituted with one
or more of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy,
halogen, NR.sub.9R.sub.10, C.sub.1-5 thioether, or C.sub.1-5
alkoxy;
[0043] 6) R.sub.9 is hydrogen or C.sub.1-3 alkyl;
[0044] 7) R.sub.10 is hydrogen, or C.sub.1-5 alkyl optionally
substituted with --OH;
[0045] 8) R" is C or CH;
[0046] 9) when R" is C:
[0047] a) R' is CR.sub.8, C(R.sub.8).sub.2, N, or NH, and forms a
bond with R";
[0048] b) 1 or 2 of R.sub.5 and R.sub.6 are NH or COR.sub.10 other
than COH, the remainder of R.sub.4, R.sub.5, R.sub.6, and R.sub.7
being CH; and
[0049] 10) when R" is CH, R' is CH.sub.3 or NH.sub.2.
[0050] In a second principal embodiment the compounds of the
present invention are benzimidazole and phenylthiourea related
compounds represented by the following formula (II): 2
[0051] wherein:
[0052] 1) R.sub.1 is H;
[0053] 2) R.sub.2 is selenium;
[0054] 3) R" is C or CH;
[0055] 4) when R" is C, R' is C(R.sub.8).sub.2 or NR.sub.3, and
forms a bond with R";
[0056] 5) when R" is CH, R' is CH.sub.3 or NH.sub.2;
[0057] 6) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
CR.sub.8, or N;
[0058] 7) R.sub.3 is (i) substituted or unsubstituted alkyl,
alkenyl, aryl, or heterocycle, (ii) --C.sub.1-5 alkoxy, (iii) --OH,
(iv) hydrogen, (v) C(O)--C.sub.1-3 alkyl, or (vi)
--(CH.sub.2).sub.1-5 (O)NR.sub.9R.sub.10;
[0059] 8) R.sub.8 is (i) hydrogen, (ii) halogen, (iii) NO.sub.2,
(iv) --CN, (v) --OR.sub.10, (vi) --NHSO.sub.2--C.sub.1-3alkyl,
(vii) --NHCO--C.sub.1-5 alkyl, (viii) oxime, (ix) hydrazine, (x)
--NR.sub.9R.sub.10, (xi) HSO.sub.2, (xii) HSO.sub.3, (xiii)
thio-C.sub.1-5 alkyl, (xiv) C.sub.1-5 acyloxy, (xv)
H.sub.2PO.sub.3, (xvi) thiol, (xvii) --COOR.sub.9, (xiii) C.sub.1-5
alkynyl, or (xix) --C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl,
heteroaryl, or heterocycle, optionally substituted with one or more
of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen,
NR.sub.9R.sub.10, C.sub.1-5 thioether, or C.sub.1-5 alkoxy;
[0060] 9) R.sub.9 is hydrogen or C.sub.1-3 alkyl; and
[0061] 10) R.sub.10 is hydrogen, or C.sub.1-5 alkyl optionally
substituted with --OH.
[0062] In a third principal embodiment the compounds of the present
invention are phenylthiol, phenylamine, and multicyclic-phenolic
related compounds of the following structure (III): 3
[0063] wherein:
[0064] 1) R.sub.1 is (CH.sub.2).sub.nSR.sub.7,
(CH.sub.2).sub.nNHR.sub.7, or OR.sub.7;
[0065] 2) n is 0, 1, 2, or 3,
[0066] 3) R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are
independently selected from (i) hydrogen, (ii) halogen, (iii)
NO.sub.2, (iv) --CN, (v) --OR.sub.10, (vi)
--NHSO.sub.2--C.sub.1-3alkyl, (vii) --NHCO--C.sub.1-5 alkyl, (viii)
oxime, (ix) hydrazine, (x) --NR.sub.9R.sub.10, (xi) HSO.sub.2,
(xii) HSO.sub.3, (xiii) thio-C.sub.1-5 alkyl, (xiv) C.sub.1-5
acyloxy, (xv) H.sub.2PO.sub.3, (xvi) thiol, (xvii) --COOR.sub.9,
(xviii) C.sub.1-5 alkynyl, or (xix) --C.sub.1-5 alkyl, --C.sub.1-5
alkenyl, aryl, heteroaryl, or heterocycle, optionally substituted
with one or more of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5
acyloxy, halogen, NR.sub.9R.sub.10, C.sub.1-5 thioether, or
C.sub.1-5 alkoxy;
[0067] 4) alternatively, R.sub.3 and R.sub.4, or R.sub.4 and
R.sub.5, combine to form a fused ring-structure which is
cycloalkyl, aryl, or heterocyclic selected from phenyl,
cyclopentyl, cyclohexyl, pyrrole, furan, thiophene, pyrazole,
pyridine, --X--(CH.sub.2).sub.n'--X--wherein n' is 1 and X is
nitrogen, sulfur, or oxygen, and --(CH).sub.n"XH-- wherein n" is 2
and X is as defined above;
[0068] 5) R.sub.7 is (i) substituted or unsubstituted alkyl,
alkenyl, aryl, or heterocycle, (ii) --C.sub.1-5 alkoxy, (iii)
hydrogen, (iv) --NR.sub.9R.sub.10, (v) C(O)--C.sub.1-3 alkyl, or
(vi) --(CH.sub.2).sub.mC(O)NR.sub.9R.sub.10;
[0069] 6) R.sub.9 is hydrogen or C.sub.1-3 alkyl;
[0070] 7) R.sub.10 is hydrogen, or C.sub.1-5 alkyl optionally
substituted with --OH;
[0071] 8) m is 1, 2, 3, 4, or 5; and
[0072] 9) provided that when R.sub.1 is OR.sub.7, R.sub.3 and
R.sub.4, or R.sub.4 and R.sub.5, combine to form a fused
ring-structure which is cycloalkyl, aryl, or heterocyclic selected
from phenyl, cyclopentyl, cyclohexyl, pyrrole, furan, thiophene,
pyrazole, pyridine, --X--(CH.sub.2).sub.n'--X-- wherein n' is 1 and
X is nitrogen, sulfur, or oxygen, and --(CH).sub.n"--XH-- wherein
n" is 2 and X is as defined above.
[0073] In a fourth principal embodiment the compounds of the
present invention are benzothiamide and thiophene amine derivatives
defined by structures (IV) or (V): 4
[0074] wherein:
[0075] 1) R.sub.1, R.sub.2, and R.sub.3 are independently (i)
substituted or unsubstituted alkyl, alkenyl, aryl, or heterocycle,
(ii) hydrogen, (iii) C(O)--C.sub.1-3 alkyl, or (iv)
--(CH.sub.2).sub.1-5C(O)NR.sub.9R.su- b.10;
[0076] 2) R.sub.9 is hydrogen or C.sub.1-3 alkyl;
[0077] 3) R.sub.10 is hydrogen, or C.sub.1-5 alkyl optionally
substituted with --OH;
[0078] 4) Y and Y' are independently oxygen or sulfur,
[0079] 5) X is oxygen, sulfur, or nitrogen; and
[0080] 6) R.sub.4 is C.sub.1-5 alkyl, optionally substituted by
--OH, or NR.sub.9R.sub.9.
DETAILED DESCRIPTION OF THE INVENTION
[0081] Discussion
[0082] As noted above, compounds for inhibiting or preventing
melanin formation in skin have been discovered for the treatment of
various melanin-associated conditions. For example, the compound
can be used as a "vanity" product, to lighten the skin of an
individual, especially of dark skinned individuals. Alternatively,
the compound can be used to reduce uneven pigmentation marks and
surface color irregularities, or to diminish pigmented skin
blemishes such as freckles and age spots and
hyperpigmentation-related medical conditions such as melasma,
ochronosis, and lentigo. The compounds can also be used to lighten
hair when applied to skin containing pigmented hair follicles, and
to lessen postinflammatory hyperpigmentation resulting from trauma
or invasive surgery from a face lift, laser treatment, or cosmetic
surgery. The active or functional compounds can also be used to
reduce skin pigmentation in normal skin adjacent to areas affected
by vitiligo, thereby diminishing the contrast in color between
normal and vitiligo affected skin.
[0083] The invention thus provides a method for lightening
mammalian skin that includes applying or otherwise administering an
effective treatment amount of an active skin-lightening compound
selected from a benzimidazole, a phenylthiourea, a phenylthiol, a
bi- or multicyclic phenol, thiopheneamine, a benzothiamide, a
phenylamine, or a pharmaceutically acceptable salt or ester
thereof, optionally in a pharmaceutically acceptable carrier, to a
mammalian subject in need thereof. The invention also includes a
pharmaceutical composition for topical or general systemic
administration, including oral, intradermal, transdermal, occlusive
patch, intraveneous, and parenteral formulations, that includes an
effective pigment inhibiting amount of the compound. The present
invention is principally concerned with compositions that inhibit
mammalian tyrosinase activity, and which thus have medicinal and/or
cosmetic value. However, the present invention can also extend to
compounds that inhibit melanin formation within melanocytes through
mechanisms other than tyrosinase activity.
[0084] Many of the compounds also possess other activities that are
beneficial when integrated into the compositions of the present
invention. For example, many of the compounds also absorb UV light,
and can thus be used to block the harmful effects of the sun's
rays. Some of the compounds also possess antioxidant properties,
and thus can inhibit oxidative damage to the skin, or contribute to
the stability of the formulation.
[0085] Furthermore, although unrelated to skin pigmentation per se,
some of the compounds of the present invention may also inhibit
tyrosine hydroxylase (TH). This enzyme is structurally dissimilar
from tryosinase, but also catalyzes the formation of DOPA from
tysosine. TH is critical for the formation of catecolamines.
Therefore, some of the compounds of the present invention which
coincidentally inhibit TH activity may have utility in reducing
catecholamine biosynethsis, for instance for use as inhibitor
"probes" in laboratory experiments where reduction in catacholamine
pools is desirable. [30-32].
[0086] Compounds of the Present Invention
[0087] In a first principal embodiment the compounds of the present
invention are benzimidazolethiol and phenylthiourea related
compounds represented by the following formula (I): 5
[0088] wherein:
[0089] a. R.sub.1 is H or a valence for bonding;
[0090] b. R.sub.2 is S, or SH;
[0091] c. one of the dotted lines (----) represents a bond;
[0092] d. R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
CR.sub.8, or N;
[0093] e. R.sub.8 is (i) hydrogen, (ii) halogen, (iii) NO.sub.2,
(iv) --CN, (v) --OR.sub.10, (vi) --NHSO.sub.2--C.sub.1-3alkyl,
(vii) --NHCO--C.sub.1-5 alkyl, (viii) oxime, (ix) hydrazine, (x)
--NR.sub.9R.sub.10, (xi) HSO.sub.2, (xii) HSO.sub.3, (xiii)
thio-C.sub.1-5 alkyl, (xiv) C.sub.1-5 acyloxy, (xv)
H.sub.2PO.sub.3, (xvi) thiol, (xvii) --COOR.sub.9, (xviii)
C.sub.1-5 alkynyl, or (xix) --C.sub.1-5 alkyl, --C.sub.1-5 alkenyl,
aryl, heteroaryl, or heterocycle, optionally substituted with one
or more of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy,
halogen, NR.sub.9R.sub.10, C.sub.1-5 thioether, or C.sub.1-5
alkoxy;
[0094] f. R.sub.9 is hydrogen or C.sub.1-3 alkyl;
[0095] g. R.sub.10 is hydrogen, or C.sub.1-5 alkyl optionally
substituted with --OH;
[0096] h. R" is C or CH;
[0097] i. when R" is C:
[0098] i. R' is CR.sub.8, C(R.sub.8).sub.2, N or NH, and forms a
bond with R";
[0099] ii. 1 or 2 of R.sub.5 and R.sub.6 are N or COR.sub.10 other
than COH, the remainder of R.sub.4, R.sub.5, R.sub.6, and R.sub.7
being CH; and
[0100] j. when R" is CH, R' is CH.sub.3 or NH.sub.2.
[0101] A first series of subembodiments of the first principal
embodiment is defined when R.sub.1, R.sub.2, and R' are as defined
above, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
CR.sub.8, R" is CH, and:
[0102] 1) R.sub.8 is (i) hydrogen, (ii) halogen, (iii) NO.sub.2,
(iv) --CN, (v) --OR.sub.10, (viii) --NR.sub.9R.sub.10, (xi)
C.sub.1-5 acyloxy, (xii) thiol, (xiii) COOR.sub.9, or (xiv)
--C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl, heteroaryl, or
heterocycle, optionally substituted with one or more of --OH, --SH,
C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen, NR.sub.9R.sub.10,
C.sub.1-5 thioether, or C.sub.1-5 alkoxy;
[0103] 2) R.sub.8 is (i) hydrogen, (ii) halogen, (iii) NO.sub.2,
(iv) --CN, (v) --OR.sub.9, (viii) --NR.sub.9R.sub.9, (xi) C.sub.1-3
acyloxy, (xii) thiol, (xiii) COOR.sub.9, or (xiv) --C.sub.1-3
alkyl, --C.sub.1-3 alkenyl, aryl, heteroaryl, or heterocycle,
optionally substituted with one or more of --OH, --SH, C(O)H,
COOR.sub.9, C.sub.1-5 acyloxy, halogen, NR.sub.9R.sub.9, C.sub.1-3
thioether, or C.sub.1-3 alkoxy;
[0104] 3) R.sub.8 is (i) hydrogen, (ii) halogen, (v) --OR.sub.9,
(viii) --NR.sub.9R.sub.9, (xii) thiol, or (xiv) --C.sub.1-3 alkyl
or alkenyl optionally substituted with one or more of --OH, --SH,
halogen, or NH.sub.2;
[0105] 4) R.sub.8 is C.sub.1-3 alkyl;
[0106] 5) R.sub.8 is OR.sub.10 or OR.sub.9; or
[0107] 6) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CH, C(OH), C(SH), CNH.sub.2, C(CH.sub.3),
C(OCH.sub.3), CF, C(CF.sub.3), and C(CHCHBr).
[0108] A second series of subembodiments of the first principal
embodiment is defined when R.sub.1, R.sub.2, and R' are as defined
above, R" is CH, and:
[0109] 1) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, 2 or 3 of R.sub.4, R.sub.5, R.sub.6, and
R.sub.7 are CH, and R.sub.8 is (i) hydrogen, (ii) halogen, (iii)
NO.sub.2, (iv) --CN, (v) --OR.sub.10, (vi) --NR.sub.9R.sub.10,
(vii) C.sub.1-5 acyloxy, (viii) thiol, (ix) COOR.sub.9, or (x)
--C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl, heteroaryl, or
heterocycle, optionally substituted with one or more of --OH, --SH,
C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen, NR.sub.9R.sub.10,
C.sub.1-5 thioether, or C.sub.1-5 alkoxy;
[0110] 2) R.sub.4, R.sub.5, R.sub.5, and R.sub.7 are independently
selected from CR.sub.8, 2 or 3 of R.sub.4, R.sub.5, R.sub.6, and
R.sub.7 are CH, and R.sub.8 is (i) hydrogen, (ii) halogen, (iii)
--OR.sub.9, (iv) --OH, (v) --NR.sub.9R.sub.9, (vi) thiol, or (vii)
--C.sub.1-3 alkyl or alkenyl optionally substituted with one or
more of --OH, --SH, halogen, or NH.sub.2;
[0111] 3) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, 2 or 3 of R.sub.4, R.sub.5, R.sub.6, and
R.sub.7 are CH, and R.sub.8 is C.sub.1-3 alkyl;
[0112] 4) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.9, R.sub.5 is OR.sub.9, and 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH; or
[0113] 5) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CH, C(OH), C(SH), CNH.sub.2, C(CH.sub.3),
C(OCH.sub.3), CF, C(CF.sub.3), and C(CHCHBr), and 2 or 3 of
R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH.
[0114] A third series of subembodiments of the first principal
embodiment is defined when R.sub.1 and R.sub.2 are as defined
above, R" is CH, and:
[0115] 1) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, and R' is NH.sub.2;
[0116] 2) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is (i) hydrogen, (ii) halogen,
(iii) NO.sub.2, (iv) --CN, (v) --OR.sub.10, (viii)
--NR.sub.9R.sub.10, (xi) C.sub.1-5 acyloxy, (xii) thiol, (xiii)
COOR.sub.9, or (xiv) --C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl,
heteroaryl, or heterocycle, optionally substituted with one or more
of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen,
NR.sub.9R.sub.10, C.sub.1-5 thioether, or C.sub.1-5 alkoxy, 2 or 3
of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH, and R' is
NH.sub.2;
[0117] 3) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is (i) hydrogen, (ii) halogen, (v)
--OR.sub.9, (vii) --OH, (viii) --NR.sub.9R.sub.9, (xii) thiol, or
(xiv) --C.sub.1-3 alkyl or alkenyl optionally substituted with one
or more of --OH, --SH, halogen, or NH.sub.2, 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH, and R' is NH.sub.2;
[0118] 4) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is C.sub.1-3 alkyl, OR.sub.10, or
OR.sub.9, 2 or 3 of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH,
and R' is NH.sub.2;
[0119] 5) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CH, C(OH), C(SH), CNH.sub.2, C(CH.sub.3),
C(OCH.sub.3), CF, CCF.sub.3, and C(CHCHBr), 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH; and R' is NH.sub.2;
[0120] 6) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, and R' is CH.sub.3;
[0121] 7) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.9, R.sub.8 is (i) hydrogen, (ii) halogen,
(iii) NO.sub.2, (iv) --CN, (v) --OR.sub.10, (viii)
--NR.sub.9R.sub.10, (xi) C.sub.1-5 acyloxy, (xii) thiol, (xiii)
COOR.sub.9, or (xiv) --C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl,
heteroaryl, or heterocycle, optionally substituted with one or more
of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen,
NR.sub.9R.sub.10, C.sub.1-5 thioether, or C.sub.1-5 alkoxy, 2 or 3
of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH, and R' is
CH.sub.3;
[0122] 8) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is (i) hydrogen, (ii) halogen, (v)
--OR.sub.9, (vii) --OH, (viii) --NR.sub.9R.sub.9, (xii) thiol, or
(xiv) --C.sub.1-3 alkyl or alkenyl optionally substituted with one
or more of --OH, --SH, halogen, or NH.sub.2, 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH, and R' is CH.sub.3;
[0123] 9) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.9, R.sub.9 is R.sub.8 is C.sub.1-3 alkyl or
OR.sub.9, 2 or 3 of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH,
and R' is CH.sub.3;
[0124] 10) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CH, C(OH), C(SH), CNH.sub.2, C(CH.sub.3),
C(OCH.sub.3), CF, CCF.sub.3, and C(CHCHBr), 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH, and R' is CH.sub.3;
[0125] A fourth series of subembodiments of the first principal
embodiment is defined when R.sub.1 and R.sub.2 are as defined
above, R" is C, R' is N or NH, and:
[0126] 1) 1 or 2 of R.sub.5 and R.sub.6 are COR.sub.10 other than
COH, the remainder of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 being
CH;
[0127] 2) 1 or 2 of R.sub.5 and R.sub.6 are COR.sub.9 other than
COH, the remainder of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 being
CH;
[0128] 3) 1 or 2 of R.sub.5 and R.sub.6 are N, the remainder of
R.sub.4, R.sub.5, R.sub.6, and R.sub.7 being CH;
[0129] 4) R.sub.5 is COR.sub.9 other than COH, and R.sub.4,
R.sub.6, and R.sub.7 are CH;
[0130] 5) R.sub.6 is COR.sub.9 other than COH, and R.sub.4,
R.sub.5, and R.sub.7 are CH; or
[0131] 6) R.sub.5 and R.sub.6 are COR.sub.9 other than COH, and
R.sub.4 and R.sub.7 are CH.
[0132] A fifth series of subembodiments of the first principal
embodiment are defined when R.sub.1 and R.sub.2 are as defined
above, R" is C, R' is CH or CH.sub.2, and:
[0133] 1) 1 or 2 of R.sub.5 and R.sub.6 are COR.sub.10 other than
COH, the remainder of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 being
CH;
[0134] 2) 1 or 2 of R.sub.5 and R.sub.6 are COR.sub.9 other than
COH, the remainder of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 being
CH;
[0135] 3) 1 or 2 of R.sub.5 and R.sub.6 are N, the remainder of
R.sub.4, R.sub.5, R.sub.6, and R.sub.7 being CH;
[0136] 4) R.sub.5 is COR.sub.9 other than COH, and R.sub.4,
R.sub.6, and R.sub.7 are CH;
[0137] 5) R.sub.6 is COR.sub.9 other than COH, and R.sub.4,
R.sub.5, and R.sub.7 are CH; or
[0138] 6) R.sub.5 and R.sub.6 are COR.sub.9 other than COH, and
R.sub.4 and R.sub.7 are CH.
[0139] A first series of preferred species of the first principal
embodiment are defined when R.sub.1 and R.sub.2 are as defined
above, R" is C, R' is NH or N, and:
[0140] 1) R.sub.5 is COCH.sub.3, and R.sub.4, R.sub.6, and R.sub.7
are CH;
[0141] 2) R.sub.6 is COCH.sub.3, and R.sub.4, R.sub.5, and R.sub.7
are CH;
[0142] 3) R.sub.5 and R.sub.6 are COCH.sub.3, and R.sub.4 and
R.sub.7 are CH;
[0143] A second series of preferred species of the first principal
embodiment are defined when R.sub.1 and R.sub.2 are as defined
above, R" is CH, R' is NH.sub.2, and:
[0144] 1) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH;
[0145] 2) R.sub.4 is CCH.sub.3, and R.sub.5, R.sub.6, and R.sub.7
are CH;
[0146] 3) R.sub.5 is CCH.sub.3, and R.sub.4, R.sub.6, and R.sub.7
are CH;
[0147] 4) R.sub.6 is CCH.sub.3, and R.sub.4, R.sub.5, and R.sub.7
are CH;
[0148] 5) R.sub.7 is CCH.sub.3, and R.sub.4, R.sub.5, and R.sub.6
are CH;
[0149] 6) R.sub.4 is COCH.sub.3, and R.sub.5, R.sub.6, and R.sub.7
are CH;
[0150] 7) R.sub.5 is COCH.sub.3, and R.sub.4, R.sub.6, and R.sub.7
are CH;
[0151] 8) R.sub.6 is COCH.sub.3, and R.sub.4, R.sub.5, and R.sub.7
are CH;
[0152] 9) R.sub.7 is COCH.sub.3, and R.sub.4, R.sub.5, and R.sub.6
are CH;
[0153] 10) R.sub.4 is CF, and R.sub.5, R.sub.6, and R.sub.7 are
CH;
[0154] 11) R.sub.5 is CF, and R.sub.4, R.sub.6, and R.sub.7 are
CH;
[0155] 12) R.sub.6 is CF, and R.sub.4, R.sub.5, and R.sub.7 are
CH;
[0156] 13) R.sub.7 is CF, and R.sub.4, R.sub.5, and R.sub.6 are
CH;
[0157] 14) R.sub.4 is COH, and R.sub.5, R.sub.6, and R.sub.7 are
CH;
[0158] 15) R.sub.5 is COH, and R.sub.4, R.sub.6, and R.sub.7 are
CH;
[0159] 16) R.sub.6 is COH, and R.sub.4, R.sub.5, and R.sub.7 are
CH;
[0160] 17) R.sub.7 is COH, and R.sub.4, R.sub.5, and R.sub.6 are
CH;
[0161] 18) 2 of R.sub.4, R.sub.5, R.sub.6 are R.sub.7 are
CCH.sub.3, and 2 of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are
CH;
[0162] 19) 2 of R.sub.4, R.sub.5, R.sub.6 are R.sub.7 are
COCH.sub.3, and 2 of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are
CH;
[0163] 20) 2 of R.sub.4, R.sub.5, R.sub.6 are R.sub.7 are CF, and 2
of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH; or
[0164] 21) 2 of R.sub.4, R.sub.5, R.sub.6 are R.sub.7 are COH, and
2 of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH;
[0165] A third series of preferred species of the first principal
embodiment are defined when R" is CH, R' is CH.sub.3, and R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are as defined in any one of the
second series of preferred species.
[0166] In a second principal embodiment the compounds of the
present invention are benzimidazoles and phenylthiourea related
compounds represented by the following formula (II): 6
[0167] wherein:
[0168] 1) R.sub.1 is H;
[0169] 2) R.sub.2 is selenium;
[0170] 3) R" is C or CH;
[0171] 4) when R" is C, R' is C(R.sub.8).sub.2 or NR.sub.3, and
forms a bond with R";
[0172] 5) when R" is CH, R' is CH.sub.3 or NH.sub.2;
[0173] 6) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
CR.sub.8, or N;
[0174] 7) R.sub.3 is (i) substituted or unsubstituted alkyl,
alkenyl, aryl, or heterocycle, (ii) --C.sub.1-5 alkoxy, (iii) --OH,
(iv) hydrogen, (v) C(O)--C.sub.1-3 alkyl, or (vi)
--(CH.sub.2).sub.1-5C(O)NR.sub.9R.sub.- 10;
[0175] 8) R.sub.8 is (i) hydrogen, (ii) halogen, (iii) NO.sub.2,
(iv) --CN, (v) --OR.sub.10, (vi) --NHSO.sub.2--C.sub.1-3alkyl,
(vii) --NHCO--C.sub.1-5 alkyl, (viii) oxime, (ix) hydrazine, (x)
--NR.sub.9R.sub.10, (xi) HSO.sub.2, (xii) HSO.sub.3, (xiii)
thio-C.sub.1-5 alkyl, (xiv) C.sub.1-5 acyloxy, (xv)
H.sub.2PO.sub.3, (xvi) thiol, (xvii) --COOR.sub.9, (xviii)
C.sub.1-5 alkynyl, or (xix) --C.sub.1-5 alkyl, --C.sub.1-5 alkenyl,
aryl, heteroaryl, or heterocycle, optionally substituted with one
or more of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy,
halogen, NR.sub.9R.sub.10, C.sub.1-5 thioether, or C.sub.1-5
alkoxy;
[0176] 9) R.sub.9 is hydrogen or C.sub.1-3 alkyl; and
[0177] 10) R.sub.10 is hydrogen, or C.sub.1-5 alkyl optionally
substituted with --OH.
[0178] A first series of subembodiments of the second principal
embodiment are defined when R.sub.1, R.sub.2, R' and R" are as
defined above, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CR.sub.8,
and:
[0179] 1) R.sub.8 is (i) hydrogen, (ii) halogen, (iii) NO.sub.2,
(iv) --CN, (v) --OR.sub.10, (viii) --NR.sub.9R.sub.10, (xi)
C.sub.1-5 acyloxy, (xii) thiol, (xiii) COOR.sub.9, or (xiv)
--C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl, heteroaryl, or
heterocycle, optionally substituted with one or more of --OH, --SH,
C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen, NR.sub.9R.sub.10,
C.sub.1-5 thioether, or C.sub.1-5 alkoxy;
[0180] 2) R.sub.8 is (i) hydrogen, (ii) halogen, (iii) NO.sub.2,
(iv) --CN, (v) --OR.sub.9, (viii) --NR.sub.9R.sub.9, (xi) C.sub.1-3
acyloxy, (xii) thiol, (xiii) COOR.sub.9, or (xiv) --C.sub.1-3
alkyl, --C.sub.1-3 alkenyl, aryl, heteroaryl, or heterocycle,
optionally substituted with one or more of --OH, --SH, C(O)H,
COOR.sub.9, C.sub.1-5 acyloxy, halogen, NR.sub.9R.sub.9, C.sub.1-3
thioether, or C.sub.1-3 alkoxy;
[0181] 3) R.sub.8 is (i) hydrogen, (ii) halogen, (v) --OR.sub.9,
(viii) --NR.sub.9R.sub.9, (xii) thiol, or (xiv) --C.sub.1-3 alkyl
or alkenyl optionally substituted with one or more of --OH, --SH,
halogen, or NH.sub.2;
[0182] 4) R.sub.8 is C.sub.1-3 alkyl;
[0183] 5) R.sub.9 is OR.sub.10 or OR.sub.9; or
[0184] 6) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CH, C(OH), C(SH), CNH.sub.2, C(CH.sub.3),
C(OCH.sub.3), CF, CCF.sub.3, and C(CHCHBr).
[0185] A second series of subembodiments of the second principal
embodiment is defined when R.sub.1, R.sub.2, R' and R" are as
defined above, and:
[0186] 1) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, 2 or 3 of R.sub.4, R.sub.5, R.sub.6, and
R.sub.7 are CH, and R.sub.8 is (i) hydrogen, (ii) halogen, (iii)
NO.sub.2, (iv) --CN, (v) --OR.sub.10, (vi) --NR.sub.9R.sub.10,
(vii) C.sub.1-5 acyloxy, (viii) thiol, (ix) COOR.sub.9, or (x)
--C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl, heteroaryl, or
heterocycle, optionally substituted with one or more of --OH, --SH,
C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen, NR.sub.9R.sub.10,
C.sub.1-5 thioether, or C.sub.1-5 alkoxy;
[0187] 2) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.9, 2 or 3 of R.sub.4, R.sub.5, R.sub.6, and
R.sub.7 are CH, and R.sub.8 is (i) hydrogen, (ii) halogen, (iii)
--OR.sub.9, (iv) --OH, (v) --NR.sub.9R.sub.9, (vi) thiol, or (vii)
--C.sub.1-3 alkyl or alkenyl optionally substituted with one or
more of --OH, --SH, halogen, or NH.sub.2;
[0188] 3) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, 2 or 3 of R.sub.4, R.sub.5, R.sub.6, and
R.sub.7 are CH, and R.sub.8 is C.sub.1-3 alkyl;
[0189] 4) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is OR.sub.9, and 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH; and
[0190] 5) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CH, C(OH), C(SH), CNH.sub.2, C(CH.sub.3),
C(OCH.sub.3), CF, CCF.sub.3, and C(CHCHBr), and 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH.
[0191] A third series of subembodiments of the second principal
embodiment are defined when R.sub.1 and R.sub.2 are as defined
above, R" is C, and:
[0192] 1) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, and R' is NR.sub.3;
[0193] 2) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is (i) hydrogen, (ii) halogen,
(iii) NO.sub.2, (iv) --CN, (v) --OR.sub.10, (viii)
--NR.sub.9R.sub.10, (xi) C.sub.1-5 acyloxy, (xii) thiol, (xiii)
COOR.sub.9, or (xiv) --C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl,
heteroaryl, or heterocycle, optionally substituted with one or more
of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen,
NR.sub.9R.sub.10, C.sub.1-5 thioether, or C.sub.1-5 alkoxy, 2 or 3
of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH, and R' is
NR.sub.3;
[0194] 3) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is (i) hydrogen, (ii) halogen, (v)
--OR.sub.9, (vii) --OH, (viii) --NR.sub.9R.sub.9, (xii) thiol, or
(xiv) --C.sub.1-3 alkyl or alkenyl optionally substituted with one
or more of --OH, --SH, halogen, or NH.sub.2, 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH, and R' is NR.sub.3;
[0195] 4) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is R.sub.8 is C.sub.1-3 alkyl or
OR.sub.9, 2 or 3 of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH,
and R' is NR.sub.3;
[0196] 5) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CH, C(OH), C(SH), CNH.sub.2, C(CH.sub.3),
C(OCH.sub.3), CF, CCF.sub.3, and C(CHCHBr), 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH; and R' is NR.sub.3;
[0197] 6) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R' is NR.sub.3, and R.sub.3 is hydrogen, or
C.sub.1-5 alkyl optionally substituted with --OH;
[0198] 7) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is (i) hydrogen, (ii) halogen,
(iii) NO.sub.2, (iv) --CN, (v) --OR.sub.10, (viii)
--NR.sub.9R.sub.10, (xi) C.sub.1-5 acyloxy, (xii) thiol, (xiii)
COOR.sub.9, or (xiv) --C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl,
heteroaryl, or heterocycle, optionally substituted with one or more
of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen,
NR.sub.9R.sub.10, C.sub.1-5 thioether, or C.sub.1-5 alkoxy, 2 or 3
of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH, R' is NR.sub.3,
and R.sub.3 is hydrogen, or C.sub.1-5 alkyl optionally substituted
with --OH;
[0199] 8) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is (i) hydrogen, (ii) halogen, (v)
--OR.sub.9, (vii) --OH, (viii) --NR.sub.9R.sub.9, (xii) thiol, or
(xiv) --C.sub.1-3 alkyl or alkenyl optionally substituted with one
or more of --OH, --SH, halogen, or NH.sub.2, 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH, R' is NR.sub.3, and R.sub.3
is hydrogen, or C.sub.1-5 alkyl optionally substituted with
--OH;
[0200] 9) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is R.sub.9 is C.sub.1-3 alkyl or
OR.sub.9, 2 or 3 of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH,
R' is NR.sub.3, and R.sub.3 is hydrogen, or C.sub.1-5 alkyl
optionally substituted with --OH;
[0201] 10) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CH, C(OH), C(SH), CNH.sub.2, C(CH.sub.3),
C(OCH.sub.3), CF, CCF.sub.3, and C(CHCHBr), 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH; R' is NR.sub.3; and R.sub.3
is hydrogen, or C.sub.1-5 alkyl optionally substituted with
--OH;
[0202] 11) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R' is NR.sub.3, and R.sub.3 is hydrogen or
C.sub.1-3 alkyl;
[0203] 12) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is (i) hydrogen, (ii) halogen,
(iii) NO.sub.2, (iv) --CN, (v) --OR.sub.10, (viii)
--NR.sub.9R.sub.10, (xi) C.sub.1-5 acyloxy, (xii) thiol, (xiii)
COOR.sub.9, or (xiv) --C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl,
heteroaryl, or heterocycle, optionally substituted with one or more
of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen,
NR.sub.9R.sub.10, C.sub.1-5 thioether, or C.sub.1-5 alkoxy, 2 or 3
of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH, R' is NR.sub.3,
and R.sub.3 is hydrogen or C.sub.1-3 alkyl;
[0204] 13) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is (i) hydrogen, (ii) halogen, (v)
--OR.sub.9, (vii) --OH, (viii) --NR.sub.9R.sub.9, (xii) thiol, or
(xiv) --C.sub.1-3 alkyl or alkenyl optionally substituted with one
or more of --OH, --SH, halogen, or NH.sub.2, 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH, R' is NR.sub.3, and R.sub.3
is hydrogen or C.sub.1-3 alkyl;
[0205] 14) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is R.sub.8 is C.sub.1-3 alkyl or
OR.sub.9, 2 or 3 of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH,
R' is NR.sub.3, and R.sub.3 is hydrogen or C.sub.1-3 alkyl; or
[0206] 15) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CH, C(OH), C(SH), CNH.sub.2, C(CH.sub.3),
C(OCH.sub.3), CF, CCF.sub.3, and C(CHCHBr), 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH; R' is NR.sub.3, and R.sub.3
is hydrogen or C.sub.1-3 alkyl.
[0207] A fourth series of subembodiments of the second principal
embodiment is defined when R.sub.1 and R.sub.2 are as defined
above, R" is CH, and:
[0208] 1) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, and R' is NH.sub.2;
[0209] 2) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is (i) hydrogen, (ii) halogen,
(iii) NO.sub.2, (iv) --CN, (v) --OR.sub.10, (viii)
--NR.sub.9R.sub.10, (xi) C.sub.1-5 acyloxy, (xii) thiol, (xiii)
COOR.sub.9, or (xiv) --C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl,
heteroaryl, or heterocycle, optionally substituted with one or more
of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen,
NR.sub.9R.sub.10, C.sub.1-5 thioether, or C.sub.1-5 alkoxy, 2 or 3
of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH, and R' is
NH.sub.2;
[0210] 3) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is (i) hydrogen, (ii) halogen, (v)
--OR.sub.9, (vii) --OH, (viii) --NR.sub.9R.sub.9, (xii) thiol, or
(xiv) --C.sub.1-3 alkyl or alkenyl optionally substituted with one
or more of-OH, --SH, halogen, or NH.sub.2, 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH, and R' is NH.sub.2;
[0211] 4) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is R.sub.8 is C.sub.1-3 alkyl or
OR.sub.9, 2 or 3 of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH,
and R' is NH.sub.2;
[0212] 5) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CH, C(OH), C(SH), CNH.sub.2, C(CH.sub.3),
C(OCH.sub.3), CF, CCF.sub.3, and C(CHCHBr), 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH; and R' is NH.sub.2;
[0213] 6) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, and R' is CH.sub.3;
[0214] 7) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is (i) hydrogen, (ii) halogen,
(iii) NO.sub.2, (iv) --CN, (v) --OR.sub.10, (viii)
--NR.sub.9R.sub.10, (xi) C.sub.1-5 acyloxy, (xii) thiol, (xiii)
COOR.sub.9, or (xiv) --C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl,
heteroaryl, or heterocycle, optionally substituted with one or more
of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen,
NR.sub.9R.sub.10, C.sub.1-5 thioether, or C.sub.1-5 alkoxy, 2 or 3
of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH, R' is NR.sub.3,
and R' is CH.sub.3;
[0215] 8) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is (i) hydrogen, (ii) halogen, (v)
--OR.sub.9, (vii) --OH, (viii) --NR.sub.9R.sub.9, (xii) thiol, or
(xiv) --C.sub.1-3 alkyl or alkenyl optionally substituted with one
or more of-OH, --SH, halogen, or NH.sub.2, 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH, and R' is CH.sub.3;
[0216] 9) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CR.sub.8, R.sub.8 is R.sub.9 is C.sub.1-3 alkyl or
OR.sub.9, 2 or 3 of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH,
and R' is CH.sub.3; and
[0217] 10) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are independently
selected from CH, C(OH), C(SH), CNH.sub.2, C(CH.sub.3),
C(OCH.sub.3), CF, CCF.sub.3, and C(CHCHBr), 2 or 3 of R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are CH; and R' is CH.sub.3.
[0218] A first series of preferred species of the second principal
embodiment are defined when R.sub.1 and R.sub.2 are as defined
above, R" is C, R' is NH, and:
[0219] 1) R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH;
[0220] 2) R.sub.4 is CCH.sub.3, and R.sub.5, R.sub.6, and R.sub.7
are CH;
[0221] 3) R.sub.5 is CCH.sub.3, and R.sub.4, R.sub.6, and R.sub.7
are CH;
[0222] 4) R.sub.6 is CCH.sub.3, and R.sub.4, R.sub.5, and R.sub.7
are CH;
[0223] 5) R.sub.7 is CCH.sub.3, and R.sub.4, R.sub.5, and R.sub.6
are CH;
[0224] 6) R.sub.4 is COCH.sub.3, and R.sub.5, R.sub.6, and R.sub.7
are CH;
[0225] 7) R.sub.5 is COCH.sub.3, and R.sub.4, R.sub.6, and R.sub.7
are CH;
[0226] 8) R.sub.6 is COCH.sub.3, and R.sub.4, R.sub.5, and R.sub.7
are CH;
[0227] 9) R.sub.7 is COCH.sub.3, and R.sub.4, R.sub.5, and R.sub.6
are CH;
[0228] 10) R.sub.4 is CF, and R.sub.5, R.sub.6, and R.sub.7 are
CH;
[0229] 11) R.sub.5 is CF, and R.sub.4, R.sub.6, and R.sub.7 are
CH;
[0230] 12) R.sub.6 is CF, and R.sub.4, R.sub.5, and R.sub.7 are
CH;
[0231] 13) R.sub.7 is CF, and R.sub.4, R.sub.5, and R.sub.6 are
CH;
[0232] 14) R.sub.4 is COH, and R.sub.5, R.sub.6, and R.sub.7 are
CH;
[0233] 15) R.sub.5 is COH, and R.sub.4, R.sub.6, and R.sub.7 are
CH;
[0234] 16) R.sub.6 is COH, and R.sub.4, R.sub.5, and R.sub.7 are
CH;
[0235] 17) R.sub.7 is COH, and R.sub.4, R.sub.5, and R.sub.6 are
CH;
[0236] 18) 2 of R.sub.4, R.sub.5, R.sub.6 are R.sub.7 are
CCH.sub.3, and 2 of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are
CH;
[0237] 19) 2 of R.sub.4, R.sub.5, R.sub.6 are R.sub.7 are
COCH.sub.3, and 2 of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are
CH;
[0238] 20) 2 of R.sub.4, R.sub.5, R.sub.6 are R.sub.7 are CF, and 2
of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH; or
[0239] 21) 2 of R.sub.4, R.sub.5, R.sub.6 are R.sub.7 are COH, and
2 of R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are CH;
[0240] A second series of preferred species of the second principal
embodiment are defined when R" is CH, R' is NH.sub.2, and R.sub.4,
R.sub.5, R.sub.6, and R.sub.7 are as defined in any one of the
first series of preferred species.
[0241] A third series of preferred species of the present invention
are defined when R" is CH, R' is CH.sub.3, and R.sub.4, R.sub.5,
R.sub.6, and R.sub.7 are as defined in any one of the first series
of preferred species.
[0242] In a third principal embodiment the compounds of the present
invention are phenylthiol, phenylamine, and multicyclic-phenolic
related compounds of the following structure (III): 7
[0243] wherein:
[0244] 1) R.sub.1 is (CH.sub.2).sub.nSR.sub.7,
(CH.sub.2).sub.nNHR.sub.7, or OR.sub.7;
[0245] 2) n is 0, 1, 2, or 3,
[0246] 3) R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are
independently selected from (i) hydrogen, (ii) halogen, (iii)
NO.sub.2, (iv) --CN, (v) --OR.sub.10, (vi)
--NHSO.sub.2--C.sub.1-3alkyl, (vii) --NHCO--C.sub.1-5 alkyl, (viii)
oxime, (ix) hydrazine, (x) --NR.sub.9R.sub.10, (xi) HSO.sub.2,
(xii) HSO.sub.3, (xiii) thio-C.sub.1-5 alkyl, (xiv) C.sub.1-5
acyloxy, (xv) H.sub.2PO.sub.3, (xvi) thiol, (xvii) --COOR.sub.9,
(xviii) C.sub.1-5 alkynyl, or (xix) --C.sub.1-5 alkyl, --C.sub.1-5
alkenyl, aryl, heteroaryl, or heterocycle, optionally substituted
with one or more of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5
acyloxy, halogen, NR.sub.9R.sub.10, C.sub.1-5 thioether, or
C.sub.1-5 alkoxy;
[0247] 4) alternatively, R.sub.3 and R.sub.4, or R.sub.4 and
R.sub.5, combine to form a fused ring-structure which is
cycloalkyl, aryl, or heterocyclic selected from phenyl,
cyclopentyl, cyclohexyl, pyrrole, furan, thiophene, pyrazole,
pyridine, --X--(CH.sub.2).sub.n'--X--wherein n' is 1 and X is
nitrogen, sulfur, or oxygen, and --(CH).sub.n"XH-- wherein n" is 2
and X is as defined above;
[0248] 5) R.sub.7 is (i) substituted or unsubstituted alkyl,
alkenyl, aryl, or heterocycle, (ii) --C.sub.1-5 alkoxy, (iii)
hydrogen, (iv) C(O)--C.sub.1-3 alkyl, or (v)
--(CH.sub.2).sub.mC(O)NR.sub.9R.sub.10;
[0249] 6) R.sub.9 is hydrogen or C.sub.1-3 alkyl;
[0250] 7) R.sub.10 is hydrogen, or C.sub.1-5 alkyl optionally
substituted with --OH;
[0251] 8) m is 1, 2, 3, 4, or 5; and
[0252] 9) provided that when R.sub.1 is OR.sub.7, R.sub.3 and
R.sub.4, or R.sub.4 and R.sub.5, combine to form a fused
ring-structure which is cycloalkyl, aryl, or heterocyclic selected
from phenyl, cyclopentyl, cyclohexyl, pyrrole, furan, thiophene,
pyrazole, pyridine, --X--(CH.sub.2).sub.n'--X-- wherein n' is 1 and
X is nitrogen, sulfur, or oxygen, and --(CH).sub.n"XH-- wherein n"
is 2 and X is as defined above.
[0253] A first series of subembodiments of the third principal
embodiment are defined when R.sub.1 is (CH.sub.2).sub.nSR.sub.7, n
is 0, 1, 2, or 3 but preferably 0, and:
[0254] 1) R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as
defined above, and R.sub.7 is hydrogen, C.sub.1-5 alkyl optionally
substituted with --OH, or C(O)C.sub.1-3 alkyl;
[0255] 2) R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as
defined above, and R.sub.7 is hydrogen, C.sub.1-3 alkyl, or
C(O)C.sub.1-3 alkyl;
[0256] 3) R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as
defined above, and R.sub.7 is hydrogen;
[0257] 4) R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are
independently selected from (i) hydrogen, (ii) halogen, (iii)
NO.sub.2, (iv) --CN, (v) --OR.sub.10, (viii) --NR.sub.9R.sub.10,
(xi) C.sub.1-5 acyloxy, (xii) thiol, (xiii) COOR.sub.9, or (xiv)
--C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl, heteroaryl, or
heterocycle, optionally substituted with one or more of --OH, --SH,
C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen, NR.sub.9R.sub.10,
C.sub.1-5 thioether, or C.sub.1-5 alkoxy, or (xv) --NHCO--C.sub.1-5
alkyl; and R.sub.7 is as defined above;
[0258] 5) R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are
independently selected from (i) hydrogen, (ii) halogen, (iii)
NO.sub.2, (iv) --CN, (v) --OR.sub.9, (viii) --NR.sub.9R.sub.9, (xi)
C.sub.1-3 acyloxy, (xii) thiol, (xiii) COOR.sub.9, (xiv)
--C.sub.1-3 alkyl, --C.sub.1-3 alkenyl, aryl, heteroaryl, or
heterocycle, optionally substituted with one or more of --OH, --SH,
C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen, NR.sub.9R.sub.9,
C.sub.1-3 thioether, or C.sub.1-3 alkoxy, or (xv) --NHCO--C.sub.1-3
alkyl; and R.sub.7 is as defined above;
[0259] 6) R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are
independently selected from (i) hydrogen, (ii) halogen, (v)
--OR.sub.9, (viii) --NR.sub.9R.sub.9, (xii) thiol, (xiv)
--C.sub.1-3 alkyl or alkenyl optionally substituted with one or
more of --OH, --SH, halogen, or NH.sub.2, or (xv) --NHCO--C.sub.1-3
alkyl; and R.sub.7 is as defined above;
[0260] 7) R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are
independently selected from C.sub.1-3 alkyl, OR.sub.9, or
--NHCO--CH.sub.3 alkyl; and R.sub.7 is as defined above;
[0261] 8) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from phenyl, cyclopentyl, cyclohexyl,
pyrrole, furan, thiophene, pyrazole, pyridine,
--X--(CH.sub.2).sub.n'--X--wherein n' is 1 and X is nitrogen,
sulfur, or oxygen, and --(CH).sub.n"XH--wherein n" is 2 and X is as
defined above; and (b) the remainder of R.sub.2, R.sub.3, R.sub.5
and R.sub.6 are independently selected from (i) hydrogen, (ii)
halogen, (iii) NO.sub.2, (iv) --CN, (v) --OR.sub.10, (vi
--NR.sub.9R.sub.10, (vii) C.sub.1-5 acyloxy, (viii) thiol, (ix)
COOR.sub.9, or (x) --C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl,
heteroaryl, or heterocycle, optionally substituted with one or more
of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen,
NR.sub.9R.sub.10, C.sub.1-5 thioether, or C.sub.1-5 alkoxy; and
R.sub.7 is as defined above;
[0262] 9) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from phenyl, cyclopentyl, cyclohexyl,
pyrrole, furan, thiophene, pyrazole, pyridine,
--X--(CH.sub.2).sub.n', --X--wherein n' is 1 and X is nitrogen,
sulfur, or oxygen, and --(CH).sub.n"--XH-- wherein n" is 2 and X is
as defined above; and (b) the remainder of R.sub.2, R.sub.3,
R.sub.5 and R.sub.6 are independently selected from (i) hydrogen,
(ii) halogen, (iii) NO.sub.2, (iv) --CN, (v) --OR.sub.9, (vi)
--NR.sub.9R.sub.9, (vii) C.sub.1-3 acyloxy, (viii) thiol, (ix)
COOR.sub.9, or (x) --C.sub.1-3 alkyl, --C.sub.1-3 alkenyl, aryl,
heteroaryl, or heterocycle, optionally substituted with one or more
of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen,
NR.sub.9R.sub.9, C.sub.1-3 thioether, or C.sub.1-3 alkoxy; and
R.sub.7 is as defined above;
[0263] 10) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from phenyl, cyclopentyl, cyclohexyl,
pyrrole, furan, thiophene, pyrazole, pyridine,
--X--(CH.sub.2).sub.n'--X--wherein n' is 1 and X is nitrogen,
sulfur, or oxygen, and --(CH).sub.n"XH-- wherein n" is 2 and X is
as defined above; and (b) the remainder of R.sub.2, R.sub.3,
R.sub.5 and R.sub.6 are independently selected from (i) hydrogen,
(ii) halogen, (iii) --OR.sub.9, (iv) --NR.sub.9R.sub.9, (v) thiol,
or (vi) --C.sub.1-13 alkyl or alkenyl optionally substituted with
one or more of --OH, --SH, halogen, or NH.sub.2; and R.sub.7 is as
defined above;
[0264] 11) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from phenyl, cyclopentyl, cyclohexyl,
pyrrole, furan, thiophene, pyrazole, pyridine,
--X--(CH.sub.2).sub.n'--X--wherein n' is 1 and X is nitrogen,
sulfur, or oxygen, and --(CH).sub.n"XH--wherein n" is 2 and X is as
defined above; and (b) the remainder of R.sub.2, R.sub.3, R.sub.5
and R.sub.6 are independently selected from C.sub.1-3 alkyl or
OR.sub.9; and R.sub.7 is as defined above;
[0265] 12) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from phenyl, cyclopentyl, cyclohexyl,
pyrrole, furan, thiophene, pyrazole, and pyridine; and (b) the
remainder of R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are
independently selected from (i) hydrogen, (ii) halogen, (iii)
NO.sub.2, (iv) --CN, (v) --OR.sub.10, (vi) --NR.sub.9R.sub.10,
(vii) C.sub.1-5 acyloxy, (viii) thiol, (ix) COOR.sub.9, or (x)
--C.sub.1-5 alkyl, --C.sub.1-5 alkenyl, aryl, heteroaryl, or
heterocycle, optionally substituted with one or more of --OH, --SH,
C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen, NR.sub.9R.sub.10,
C.sub.1-5 thioether, or C.sub.1-5 alkoxy; and R.sub.7 is as defined
above;
[0266] 13) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from phenyl, cyclopentyl, cyclohexyl,
pyrrole, furan, thiophene, pyrazole, and pyridine; and (1) the
remainder of R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are
independently selected from (i) hydrogen, (ii) halogen, (iii)
NO.sub.2, (iv) --CN, (v) --OR.sub.9, (vi) --NR.sub.9R.sub.9, (vii)
C.sub.1-3 acyloxy, (viii) thiol, (ix) COOR.sub.9, or (x)
--C.sub.1-3 alkyl, --C.sub.1-3 alkenyl, aryl, heteroaryl, or
heterocycle, optionally substituted with one or more of --OH, --SH,
C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen, NR.sub.9R.sub.9,
C.sub.1-3 thioether, or C.sub.1-3 alkoxy; and R.sub.7 is as defined
above;
[0267] 14) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from phenyl, cyclopentyl, cyclohexyl,
pyrrole, furan, thiophene, pyrazole, or pyridine; and (b) the
remainder of R.sub.2, R.sub.3, R.sub.5 and R.sub.4 are
independently selected from (i) hydrogen, (ii) halogen, (iii)
--OR.sub.9, (iv) --NR.sub.9R.sub.9, (v) thiol, or (vi) --C.sub.1-3
alkyl or alkenyl optionally substituted with one or more of --OH,
--SH, halogen, or NH.sub.2; and R.sub.7 is as defined above;
[0268] 15) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from phenyl, cyclopentyl, cyclohexyl,
pyrrole, furan, thiophene, pyrazole, or pyridine; and (b) the
remainder of R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are
independently selected from C.sub.1-3 alkyl or OR.sub.9; and
R.sub.7 is as defined above;
[0269] 16) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from --X--(CH.sub.2).sub.n'--X-- wherein n'
is 1 and X is nitrogen, sulfur, or oxygen; and (b) the remainder of
R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are independently selected
from (i) hydrogen, (ii) halogen, (iii) NO.sub.2, (iv) --CN, (v)
--OR.sub.10, (vi) --NR.sub.9R.sub.10, (vii) C.sub.1-5 acyloxy,
(viii) thiol, (ix) COOR.sub.9, or (x) --C.sub.1-5 alkyl,
--C.sub.1-5 alkenyl, aryl, heteroaryl, or heterocycle, optionally
substituted with one or more of --OH, --SH, C(O)H, COOR.sub.9,
C.sub.1-5 acyloxy, halogen, NR.sub.9R.sub.10, C.sub.1-5 thioether,
or C.sub.1-5 alkoxy; and R.sub.7 is as defined above;
[0270] 17) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from --X--(CH.sub.2).sub.n'--X-- wherein n'
is 1 and X is nitrogen, sulfur, or oxygen; and (b) the remainder of
R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are independently selected
from (i) hydrogen, (ii) halogen, (iii) NO.sub.2, (iv) --CN, (v)
--OR.sub.9, (vi) --NR.sub.9R.sub.9, (vii) C.sub.1-3 acyloxy, (viii)
thiol, (ix) COOR.sub.9, or (x) --C.sub.1-3 alkyl, --C.sub.1-3
alkenyl, aryl, heteroaryl, or heterocycle, optionally substituted
with one or more of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5
acyloxy, halogen, NR.sub.9R.sub.9, C.sub.1-3 thioether, or
C.sub.1-3 alkoxy; and R.sub.7 is as defined above;
[0271] 18) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from --X--(CH.sub.2).sub.n'--X-- wherein n'
is 1 and X is nitrogen, sulfur, or oxygen; and (b) the remainder of
R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are independently selected
from (i) hydrogen, (ii) halogen, (iii) --OR.sub.9, (iv)
--NR.sub.9R.sub.9, (v) thiol, or (vi) --C.sub.1-3 alkyl or alkenyl
optionally substituted with one or more of --OH, --SH, halogen, or
NH.sub.2; and R.sub.7 is as defined above;
[0272] 19) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from --X--(CH.sub.2).sub.n'--X-- wherein n'
is 1 and X is nitrogen, sulfur, or oxygen; and (b) the remainder of
R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are independently selected
from C.sub.1-3 alkyl or OR.sub.9; and R.sub.7 is as defined
above;
[0273] 20) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from --(CH).sub.n"XH-- wherein n" is 2 and X
is nitrogen, sulfur, or oxygen; and (b) the remainder of R.sub.2,
R.sub.3, R.sub.5 and R.sub.6 are independently selected from (i)
hydrogen, (ii) halogen, (iii) NO.sub.2, (iv) --CN, (v) --OR.sub.10,
(vi) --NR.sub.9R.sub.10, (vii) C.sub.1-5 acyloxy, (viii) thiol,
(ix) COOR.sub.9, or (x) --C.sub.1-5 alkyl, --C.sub.1-5 alkenyl,
aryl, heteroaryl, or heterocycle, optionally substituted with one
or more of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy,
halogen, NR.sub.9R.sub.10, C.sub.1-5 thioether, or C.sub.1-5
alkoxy; and R.sub.7 is as defined above;
[0274] 21) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from --(CH).sub.n"XH-- wherein n" is 2 and X
is nitrogen, sulfur, or oxygen; and (b) the remainder of R.sub.2,
R.sub.3, R.sub.5 and R.sub.6 are independently selected from (i)
hydrogen, (ii) halogen, (iii) NO.sub.2, (iv) --CN, (v) --OR.sub.9,
(vi) --NR.sub.9R.sub.9, (vii) C.sub.1-3 acyloxy, (viii) thiol, (ix)
COOR.sub.9, or (x) --C.sub.1-3 alkyl, --C.sub.1-3 alkenyl, aryl,
heteroaryl, or heterocycle, optionally substituted with one or more
of --OH, --SH, C(O)H, COOR.sub.9, C.sub.1-5 acyloxy, halogen,
NR.sub.9R.sub.9, C.sub.1-3 thioether, or C.sub.1-3 alkoxy; and
R.sub.7 is as defined above;
[0275] 22) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from --(CH).sub.n"XH-- wherein n" is 2 and X
is is nitrogen, sulfur, or oxygen; and (b) the remainder of
R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are independently selected
from (i) hydrogen, (ii) halogen, (iii) --OR.sub.9, (iv)
--NR.sub.9R.sub.9, (v) thiol, or (vi) --C.sub.1-3 alkyl or alkenyl
optionally substituted with one or more of --OH, --SH, halogen, or
NH.sub.2; and R.sub.7 is as defined above;
[0276] 23) (a) R.sub.3 and R.sub.4, or R.sub.4 and R.sub.5, combine
to form a fused ring-structure which is cycloalkyl, aryl, or
heterocyclic selected from --(CH).sub.n"XH-- wherein n" is 2 and X
is nitrogen, sulfur, or oxygen; and (b) the remainder of R.sub.2,
R.sub.3, R.sub.5 and R.sub.5 are independently selected from
C.sub.1-3 alkyl or OR.sub.9; and R.sub.7 is as defined above;
[0277] A second series of subembodiments is defined when R.sub.1 is
(CH.sub.2).sub.nSR.sub.7, n is 0, 1, 2, or 3, R.sub.7 is C.sub.1-5
alkyl optionally substituted with --OH, or C(O)C.sub.1-3 alkyl; and
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined in
any one of the 4.sup.th through 23d subembodiments of the first
series of subembodiments. A subset of the second series of
embodiments is defined when R.sub.1 is SR.sub.7, R.sub.7 is
C.sub.1-5 alkyl optionally substituted with --OH, or C(O)C.sub.1-3
alkyl; R.sub.4, is --NHCO--C.sub.1-3 alkyl; and R.sub.2, R.sub.3,
R.sub.5 and R.sub.6 are CH.
[0278] A third series of subembodiments is defined when R.sub.1 is
(CH.sub.2).sub.nSR.sub.7, n is 0, 1, 2, or 3, R.sub.7 is C.sub.1-3
alkyl, or C(O)C.sub.1-3 alkyl; and R.sub.2, R.sub.3, R.sub.4,
R.sub.5 and R.sub.6 are as defined in any one of the 4.sup.th
through 23d subembodiments of the first series of subembodiments.
Preferably, R.sub.4, is --NHCO--C.sub.1-3 alkyl; and R.sub.2,
R.sub.3, R.sub.5 and R.sub.6 are CH.
[0279] A fourth series of subembodiments is defined when R.sub.1 is
(CH.sub.2).sub.nSR.sub.7, n is 0, 1, 2, or 3, R.sub.7 is hydrogen;
and R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined
in any one of the 4.sup.th through 23d subembodiments of the first
series of subembodiments. Preferably, R.sub.4, is --NHCO--C.sub.1-3
alkyl; and R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are CH.
[0280] A fifth series of subembodiments is defined when R.sub.1 is
SR.sub.7, R.sub.7 is C.sub.1-5 alkyl optionally substituted with
--OH; and R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as
defined in any one of the 4.sup.th through 23d subembodiments of
the first series of subembodiments. Preferably, R.sub.4, is
--NHCO--C.sub.1-3 alkyl; and R.sub.2, R.sub.3, R.sub.5 and R.sub.6
are CH.
[0281] A sixth series of subembodiments is defined when R.sub.1 is
SR.sub.7, R.sub.7 is C.sub.1-3 alkyl; and R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and R.sub.4 are as defined in any one of the
4.sup.th through 23d subembodiments of the first series of
subembodiments. Preferably, R.sub.4, is --NHCO--C.sub.1-3 alkyl;
and R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are CH.
[0282] A seventh series of subembodiments is defined when R.sub.1
is SR.sub.7, R.sub.7 is hydrogen; and R.sub.2, R.sub.3, R.sub.4,
R.sub.5 and R.sub.4 are as defined in any one of the 4.sup.th
through 23d subembodiments of the first series of subembodiments.
Preferably, R.sub.4, is --NHCO--C.sub.1-3 alkyl; and R.sub.2,
R.sub.3, R.sub.5 and R.sub.6 are CH.
[0283] An eighth series of subembodiments is defined when R.sub.1
is (CH.sub.2).sub.nNHR.sub.7, n is 0, 1, 2, or 3, R.sub.7 is
C.sub.1-5 alkyl optionally substituted with --OH; and R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined in any one of
the 4.sup.th through 23d subembodiments of the first series of
subembodiments.
[0284] A ninth series of subembodiments is defined when R.sub.1 is
(CH.sub.2).sub.nNHR.sub.7, n is 0, 1, 2, or 3, R.sub.7 is C.sub.1-3
alkyl; and R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as
defined in any one of the 4.sup.th through 23d subembodiments of
the first series of subembodiments.
[0285] An tenth series of subembodiments is defined when R.sub.1 is
(CH.sub.2).sub.nNHR.sub.7, n is 0, 1, 2, or 3, R.sub.7 is hydrogen;
and R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined
in any one of the 4.sup.th through 23d subembodiments of the first
series of subembodiments.
[0286] An eleventh series of subembodiments is defined when R.sub.1
is NHR.sub.7, R.sub.7 is C.sub.1-5 alkyl optionally substituted
with --OH; and R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are
as defined in any one of the 4.sup.th through 23d subembodiments of
the first series of subembodiments.
[0287] A twelfth series of subembodiments is defined when R.sub.1
is NHR.sub.7, R.sub.7 is C.sub.1-3 alkyl; and R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and R.sub.6 are as defined in any one of the
4.sup.th through 23d subembodiments of the first series of
subembodiments.
[0288] A thirteenth series of subembodiments is defined when
R.sub.1 is NHR.sub.7, R.sub.7 is hydrogen; and R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and R.sub.6 are as defined in any one of the
4.sup.th through 23d subembodiments of the first series of
subembodiments.
[0289] An fourteenth series of subembodiments is defined when
R.sub.1 is OR.sub.7, R.sub.7 is C.sub.1-5 alkyl optionally
substituted with --OH; and R.sub.2, R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 are as defined in any one of the 8.sup.th through 23d
subembodiments of the first series of subembodiments.
[0290] A fifteenth series of subembodiments is defined when R.sub.1
is OR.sub.7, R.sub.7 is C.sub.1-3 alkyl; and R.sub.2, R.sub.3,
R.sub.4, R.sub.5 and R.sub.6 are as defined in any one of the
8.sup.th through 23d subembodiments of the first series of
subembodiments.
[0291] A sixteenth series of subembodiments is defined when R.sub.1
is OR.sub.7, R.sub.7 is hydrogen; and R.sub.2, R.sub.3, R.sub.4,
R.sub.5 and R.sub.6 are as defined in any one of the 8.sup.th
through 23d subembodiments of the first series of
subembodiments.
[0292] A first series of species of the second principal embodiment
are defined when R.sub.1 is SH or SC(O)CH.sub.3, and:
[0293] 1) R.sub.2 is OCH.sub.3, and R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 are CH.
[0294] 2) R.sub.3 is OCH.sub.3, and R.sub.2, R.sub.4, R.sub.5 and
R.sub.6 are CH.
[0295] 3) R.sub.4 is OCH.sub.3, and R.sub.2, R.sub.3, R.sub.5 and
R.sub.6 are CH.
[0296] 4) R.sub.5 is OCH.sub.3, and R.sub.2, R.sub.3, R.sub.4 and
R.sub.6 are CH.
[0297] 5) R.sub.6 is OCH.sub.3, and R.sub.2, R.sub.3, R.sub.4 and
R.sub.5 are CH.
[0298] 6) 2 of R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are
OCH.sub.3, and the remainder of R.sub.2, R.sub.3, R.sub.4, R.sub.5,
and R.sub.6 are CH.
[0299] 7) R.sub.2 is SCH.sub.3, and R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 are CH.
[0300] 8) R.sub.3 is SCH.sub.3, and R.sub.2, R.sub.4, R.sub.5 and
R.sub.6 are CH.
[0301] 9) R.sub.4 is SCH.sub.3, and R.sub.2, R.sub.3, R.sub.5 and
R.sub.6 are CH.
[0302] 10) R.sub.5 is SCH.sub.3, and R.sub.2, R.sub.3, R.sub.4 and
R.sub.6 are CH.
[0303] 11) R.sub.6 is SCH.sub.3, and R.sub.2, R.sub.3, R.sub.4 and
R.sub.5 are CH.
[0304] 12) 2 of R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are
SCH.sub.3, and the remainder of R.sub.2, R.sub.3, R.sub.4, R.sub.5,
and R.sub.6 are CH.
[0305] 13) R.sub.2 is NHC(O)CH.sub.3, and R.sub.3, R.sub.4, R.sub.5
and R.sub.6 are CH.
[0306] 14) R.sub.3 is NHC(O)CH.sub.3, and R.sub.2, R.sub.4, R.sub.5
and R.sub.6 are CH.
[0307] 15) R.sub.4 is NHC(O)CH.sub.3, and R.sub.2, R.sub.3, R.sub.5
and R.sub.6 are CH.
[0308] 16) R.sub.5 is NHC(O)CH.sub.3, and R.sub.2, R.sub.3, R.sub.4
and R.sub.6 are CH.
[0309] 17) R.sub.6 is NHC(O)CH.sub.3, and R.sub.2, R.sub.3, R.sub.4
and R.sub.5 are CH.
[0310] A second series of preferred species are defined when
R.sub.1 is NH.sub.2, and R.sub.2, R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 are as defined in any one of species 1-17 of the first
series of preferred embodiments.
[0311] A third series of preferred species are defined when R.sub.1
is NHC(O)CH.sub.3, and R.sub.2, R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 are as defined in any one of species 1-17 of the first
series of preferred embodiments.
[0312] In a fourth principal embodiment the compounds of the
present invention are defined by structures (IV) or (V): 8
[0313] wherein:
[0314] 1) R.sub.1, R.sub.2, and R.sub.3 are independently (i)
substituted or unsubstituted alkyl, alkenyl, aryl, or heterocycle,
(ii) hydrogen, (iii) C(O)--C.sub.1-3 alkyl, or (iv)
--(CH.sub.2).sub.1-5C(O)NR.sub.9R.su- b.10;
[0315] 2) R.sub.9 is hydrogen or C.sub.1-3 alkyl;
[0316] 3) R.sub.10 is hydrogen, or C.sub.1-5 alkyl optionally
substituted with --OH;
[0317] 4) Y and Y' are independently oxygen or sulfur;
[0318] 5) X is oxygen, sulfur, or nitrogen; and
[0319] 6) R.sub.4 is C.sub.1-5 alkyl, optionally substituted by
--OH, or NR.sub.9R.sub.9.
[0320] A first series of subembodiments of the fourth principal
embodiment are defined by structure (IV) when Y and Y' are as
described above, and:
[0321] 1. R.sub.1 is hydrogen, and R.sub.2 and R.sub.3 are
C.sub.1-5 alkyl optionally substituted with --OH; and
[0322] 2. R.sub.1 is hydrogen, and R.sub.2 and R.sub.3 are hydrogen
or C.sub.1-3 alkyl.
[0323] A second series of subembodiments of the fourth principal
embodiment are defined by structure (V) when:
[0324] 1. X is sulfur, R.sub.1 is hydrogen, and R.sub.2 is
C.sub.1-5 alkyl optionally substituted with --OH;
[0325] 2. X is sulfur, R.sub.1 is hydrogen, and R.sub.2 is hydrogen
or C.sub.1-3 alkyl;
[0326] 3. X is sulfur, R.sub.1 is hydrogen, R.sub.2 is C.sub.1-5
alkyl optionally substituted with --OH; and R.sub.4 is
unsubstituted (CH.sub.2).sub.1-5; or
[0327] 4. X is sulfur, R.sub.1 is hydrogen, R.sub.2 is hydrogen or
C.sub.1-3 alkyl, and R.sub.4 is unsubstituted
(CH.sub.2).sub.1-3.
[0328] Preferred species are defined for structure (IV) when Y is
sulfur, Y' is oxygen, R.sub.1 and R.sub.2 are hydrogen, and R.sub.3
is methyl, and for structure (V) when X is sulfur, R.sub.4 is
ethylene and R.sub.1 and R.sub.2 are hydrogen.
[0329] The compounds of this invention can be optionally
substituted with substituents that do not adversely affect the
activity of the compound as a skin lightener. Nonlimiting examples
of substituents include, but are not limited to, alkyl (including
lower alkyl), heteroalkyl, aryl, heterocyclic (including heteroaryl
and heterocycloalkyl), halo, hydroxyl, carboxyl, acyl, acyloxy,
amino, alkylamino, arylamino, alkoxy, aryloxy, alkylthio,
alkylamido, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,
phosphate, or phosphonate, either unprotected, or protected as
necessary, as known to those skilled in the art, for example, as
taught in Greene, et al., Protective Groups in Organic Synthesis,
John Wiley and Sons, Second Edition, 1991. It will be understood
that the present invention also covers "prodrugs" for such
compositions, and pharmaceutically acceptable salts and esters
thereof.
[0330] Properties of the Compounds of the Present Invention
[0331] In the present invention, one or all of three in vitro
bioassays can be utilized to evaluate the efficacy and toxicity of
candidate skin-lightening compounds. The three bioassays
characterize the compounds with regard to mammalian tyrosinase
enzyme inhibition (cell free), pigmentation in melanocyte cultured
cells, and cytotoxicity of mammalian cultured cells. Both
cell-based pigmentation and cell-free enzymatic assays have been
developed [5, 6, 25] using the mammalian melanocyte cell line,
Mel-Ab, a C57BL/6 mouse-derived cell line that produces high levels
of melanin. [21] A distinct advantage of this approach is that
humans share substantial sequence similarities in their genes (DNA)
and proteins (such as tyrosinase) with mice, relative to
non-mammalian species (e.g., mushrooms). So, mouse Mel-Ab
melanocytes can serve as adequate surrogates for human melanocytes
for many pharmacologic purposes.
[0332] These adherent murine melanocytes are grown on tissue
culture plastic in medium supplemented with fetal bovine serum,
12-O-tetradecanoylphorbol-13-acetate (TPA) to stimulate cell
division via down-regulation of protein kinase C, [22, 23] and
cholera toxin to stimulate adenylate cyclase activity in the
absence of .alpha.-MSH. [15, 24] Cellular lysates of Mel-Ab cells
may be used as tyrosinase enzyme preparations. Multi-well plate
assays have been validated [5, 6, 25] for enzyme inhibition (e.g.,
DOPA oxidation by colorimetric measurement or radiolabeled
substrate incorporation into melanin) and for pigmentation assays
on cultured Mel-Ab cells. After 4 days of treatment of cultured
cells, melanin content is determined using a spectrophotometer at
400+ nm. [6, 25] This assay can detect an apparent loss in
pigmentation resulting from either inhibition of de novo synthesis
(e.g. via inhibition of tyrosinase, or the adenylate cyclase
pathway, or another pathway) or a cytostatic/cytotoxic mechanism.
It is therefore a broad primary screen. It is used in parallel with
the tyrosinase enzymatic assay to determine whether an inhibitor of
pigmentation at the cellular level is acting primarily at the
enzyme level.
[0333] To determine cytotoxicity, crystal violet or other staining
methods may be used to quantify adherent cell numbers following a
period of treatment by an agent. HQ is typically used as a positive
control in the assay, since it exhibits an IC.sub.50 in the low
micrograms per milliliter range on Mel-Ab culture using this assay,
albeit owing to cytotoxicity and not inhibition of pigmentation per
se. [6] It should be noted that many inhibitors identified in
cell-free enzymatic assays might have subsequent difficulties with
toxicity or delivery in melanocyte cell-based assays. Therefore,
all three in vitro assays in combination provide an excellent
characterization of candidate skin lightening compounds.
[0334] A distinct advantage of the screening systems (developed by
the inventors of the present invention) is the focus on mammalian
tyrosinase, as opposed to non-mammalian enyzmes often used by other
investigators, such as mushroom tyrosinase. Since the biochemical
and pharmacologic characteristics of an enzyme or isozyme can vary
dramatically between species of organisms (e.g., due to
dissimilarities in primary, secondary, and tertiary structure), it
is highly preferable that candidate topical skin lighteners
intended for human use be discovered based on their biochemical
action against a mammalian source of the enzyme. Mushroom
tyrosinase (and in some instances plant polyphenol oxidases) has
been used in the vast majority of prior inhibitor studies. [28, 29]
Yet fungal tyrosinase exhibits substantial dissimilarities from
mammalian tyrosinase(s), and is viewed as a substantially inferior
strategy for pharmacologic screening. Thus, the methods reported by
the inventors of the present invention for screening against
mammalian tyrosinase or within melanocytes is highly preferred over
other possible screening strategies. [5, 6, 25].
[0335] The substrate kinetic "affinity" of mammalian tyrosinase for
L-tyrosine is approximately K.sub.M=600 .mu.M. A potentially
effective candidate skin lightening agent is considered to be
desirable, active, and/or functional if it renders 50% inhibition
of mammalian tyrosinase enzyme activity, at concentrations below
half the enzyme's "affinity" for tyrosine in cell-free enzyme
extracts (IC.sub.50.ltoreq.300 .mu.M) and pigment production in
melanocyte cell cultures (IC.sub.50.ltoreq.300 .mu.M). In preferred
embodiments the agent has an IC.sub.50 against tyrosinase in
cell-free enzyme extracts of less then 200, 100, 50, or 25 .mu.M,
and/or an IC.sub.50 against pigment production in melanocyte cell
cultures of less than 200, 100, 50, or 25 .mu.M. In addition, it is
desirable for the compounds to exhibit minimal cytotoxicity, e.g.,
thus retaining viability of 50% or more of the cultured cells
(IC.sub.50.gtoreq.300 .mu.M), as evidenced by adherent cell number.
In preferred embodiments the agent exhibits toxicity at greater
than 500, 750, or 1000 .mu.M.
[0336] Curto, E. V., et al. (1999) [25] reports that methyl
gentisate is an "effective" candidate skin-lightening agent based
on in vitro bioassays, because it has an IC.sub.50 of 11.2.+-.4
(ug/mL) against tyrosinase activity in cell-free assays, an
IC.sub.50 of 30.9.+-.5 (ug/mL) in melanocyte cell cultures, and
melanocyte cytotoxicity IC.sub.50 of 118.7.+-.12 (ug/mL). Methyl
gentisate thus poses a standard, against which the efficacy and
cytotoxicity of other tyrosinase inhibiting compounds can be
evaluated. By contrast to MG, hydroquinone is an inferior standard,
exhibiting potent cytotoxicity and minimal enzymatic inhibition.
[5, 6, 25].
[0337] Significantly, many of the particular compounds of this
invention are comparable to or a more effective candidate skin
lightening agents than methyl gentisate. Thus, in another
embodiment the invention provides methods for inhibiting pigment
production that includes administering an effective treatment
amount of a pigment inhibiting compound wherein (i) the compound
inhibits tyrosinase activity equivalent to or greater than methyl
gentisate in cell-free enzyme extracts from mammalian melanocyte or
melanoma cells, when evaluated using either a colorometric DOPA
oxidation or a radiolabeled tyrosine or DOPA substrate assay as
described in Curto, E. V., et al. (1999) [25], or (ii) the compound
inhibits de novo pigment production (synthesis and/or accumulation)
equivalent to or greater than methyl gentisate when evaluated in
cultured mammalian melanocyte or melanoma cells. Curto, E. V., et
al. (1999) [25]. In a preferred embodiment the toxicity of the
compound in mammalian melanocyte, melanoma, or other cell cultures
is equivalent to or less than the toxicity of methyl gentisate.
Curto, E. V., et al. (1999) [25].
[0338] In another embodiment computer-based molecular orbital
predictions can aid in the understanding and predictability of
structure-activity relationships, such that other effective
compounds can be identified and evaluated. See Sakurada, J., et
al., "Kinetic and molecular orbital studies on the rate of
oxidation of monosubstituted phenols and anilines by horseradish
peroxidase compound II." Biochemistry 29: 4093-4098 (1990)
[26].
[0339] Definitions and Use of Terms
[0340] The following definitions and term construction are
intended, unless otherwise indicated:
[0341] Specific and preferred values listed below for radicals,
substituents, and ranges, are for illustration only; they do not
exclude other defined values or other values within defined ranges
for the radicals and substituents.
[0342] Halo is fluoro, chloro, bromo, or iodo.
[0343] Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight
and branched groups; but reference to an individual radical such as
"propyl" embraces only the straight chain radical, a branched chain
isomer such as "isopropyl" being specifically referred to.
[0344] The term alkyl, as used herein, unless otherwise specified,
refers to a saturated straight, branched, or cyclic, primary,
secondary, or tertiary hydrocarbon of C.sub.1 to C.sub.10, and
specifically includes methyl, ethyl, propyl, isopropyl,
cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl,
isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl,
cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and
2,3-dimethylbutyl. When the context of this document allows alkyl
to be substituted, the moieties with which the alkyl group can be
substituted are selected from the group consisting of hydroxyl,
amino, alkylamino, arylamino, alkoxy, aryloxy, aryl, heterocycle,
halo, carboxy, acyl, acyloxy, amido, nitro, cyano, sulfonic acid,
sulfate, phosphonic acid, phosphate, or phosphonate, either
unprotected, or protected as necessary, as known to those skilled
in the art, for example, as taught in Greene, et al., Protective
Groups in Organic Synthesis, John Wiley and Sons, Second Edition,
1991, hereby incorporated by reference.
[0345] The term lower alkyl, as used herein, and unless otherwise
specified, refers to a C.sub.1 to C.sub.4 saturated straight,
branched, or if appropriate, a cyclic (for example, cyclopropyl)
alkyl group, including both substituted and unsubstituted forms.
Unless otherwise specifically stated in this application, when
alkyl is a suitable moiety, lower alkyl is preferred. Similarly,
when alkyl or lower alkyl is a suitable moiety, unsubstituted alkyl
or lower alkyl is preferred.
[0346] The terms alkenyl and alkynyl refer to alkyl moieties,
including both substituted and substituted forms, wherein at least
one saturated C--C bond is replaced by a double or triple bond.
Thus, (C.sub.2-C.sub.6)alkenyl can be vinyl, allyl, 1-propenyl,
2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl,
2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl,
3-hexenyl, 4-hexenyl, or 5-hexenyl. Similarly,
(C.sub.2-C.sub.6)alkynyl can be ethynyl, 1-propynyl, 2-propynyl,
1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,
3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,
or 5-hexynyl.
[0347] The term "alkylene" refers to a saturated, straight chain,
divalent alkyl radical of the formula --(CH.sub.2).sub.n--, wherein
n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
[0348] As used herein, with exceptions as noted, "aryl" is intended
to mean any stable monocyclic, bicyclic or tricyclic carbon ring of
up to 8 members in each ring, wherein at least one ring is aromatic
as defined by the Huckel 4n+2 rule. Examples of aryl ring systems
include phenyl, naphthyl, tetrahydronaphthyl, and biphenyl. The
aryl group can be substituted with one or more moieties selected
from the group consisting of hydroxyl, amino, alkylamino,
arylamino, alkoxy, aryloxy, alkyl, heterocycle, halo, carboxy,
acyl, acyloxy, amido, nitro, cyano, sulfonic acid, sulfate,
phosphonic acid, phosphate, or phosphonate, either unprotected, or
protected as necessary, as known to those skilled in the art, for
example, as taught in Greene, et al., Protective Groups in Organic
Synthesis, John Wiley and Sons, Second Edition, 1991.
[0349] The term heterocycle or heterocyclic, as used herein except
where noted represents a stable 5- to 7-membered monocyclic or
stable 8- to 1-membered bicyclic heterocyclic ring which is either
saturated or unsaturated, including heteroaryl, and which consists
of carbon atoms and from one to three heteroatoms selected from the
group consisting of N, O, S, and P; and wherein the nitrogen and
sulfur heteroatoms may optionally be oxidized, and the nitrogen
heteroatom may optionally be quaternized, and including any
bicyclic group in which any of the above-defined heterocyclic rings
is fused to a benzene ring. The heterocyclic ring may be attached
at any heteroatom or carbon atom which results in the creation of a
stable structure.
[0350] Nonlimiting examples of heteroaryl and heterocyclic groups
include furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl,
imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl,
quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl,
indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl,
thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl,
quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl,
thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole,
1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole,
isothiazole, pyrimidine or pyridazine, and pteridinyl, aziridines,
thiazole, isothiazole, 1,2,3-oxadiazole, thiazine, pyridine,
pyrazine, piperazine, pyrrolidine, oxaziranes, phenazine,
phenothiazine, morpholinyl, pyrazolyl, pyridazinyl, pyrazinyl,
quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl,
5-azauracilyl, triazolopyridinyl, imidazolopyridinyl,
pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine, N6-alkylpurines,
N6-benzylpurine, N6-halopurine, N6-vinypurine, N6-acetylenic
purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl
purine, thymine, cytosine, 6-azapyrimidine, 2-mercaptopyrmidine,
uracil, N5-alkyl-pyrimidines, N5-benzylpyrimidines,
N5-halopyrimidines, N5-vinyl-pyrimidine, N5-acetylenic pyrimidine,
N5-acyl pyrimidine, N5-hydroxyalkyl purine, and N6-thioalkyl
purine, and isoxazolyl. The heteroaromatic and heterocyclic
moieties can be optionally substituted as described above for aryl,
including substituted with one or more substituents selected from
hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, alkyl,
heterocycle, halo, carboxy, acyl, acyloxy, amido, nitro, cyano,
sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate,
either unprotected, or protected as necessary, as known to those
skilled in the art, for example, as taught in Greene, et al.,
Protective Groups in Organic Synthesis, John Wiley and Sons, Second
Edition, 1991.
[0351] The heteroaromatic can be partially or totally hydrogenated
as desired. As a nonlimiting example, dihydropyridine can be used
in place of pyridine. Functional oxygen and nitrogen groups on the
heteroaryl group can be protected as necessary or desired. Suitable
protecting groups are well known to those skilled in the art, and
include trimethylsilyl, dimethylhexylsilyl, 1-butyldi-methylsilyl,
and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl
groups, acyl groups such as acetyl and propionyl, methanesulfonyl,
and p-toluenesulfonyl.
[0352] The term acyl refers to a carboxylic acid ester in which the
non-carbonyl moiety of the ester group is selected from straight,
branched, or cyclic alkyl or lower alkyl, alkoxyalkyl including
methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as
phenoxymethyl, aryl including phenyl optionally substituted with
halogen, C.sub.1 to C.sub.4 alkyl or C.sub.1 to C.sub.4 alkoxy,
sulfonate esters such as alkyl or aralkyl sulphonyl including
methanesulfonyl, the mono, di or triphosphate ester, trityl or
monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g.
dimethyl-t-butylsilyl) or diphenylmethylsilyl. Aryl groups in the
esters optimally comprise a phenyl group. The term "lower acyl"
refers to an acyl group in which the non-carbonyl moiety is lower
alkyl.
[0353] The term alkoxy, as used herein, and unless otherwise
specified, refers to a moiety of the structure --O-alkyl, wherein
alkyl is as defined above.
[0354] Synthetic Methods 9
[0355] Precursor: Mono- or multiple-substituted benzene. Most are
commercially available or can be easily prepared from commercial
compounds. The definition of benzene ring substituents R.sub.1,
R.sub.2, R.sub.3 and R.sub.4 is given in formulas (1) and (II) in
section of Summary of The Invention.
[0356] Reactants: Nitric acid, Zinc, Hydrochloric acid, Carbon
disulfide, Methyl isothiocyanate, Thiourea, Sulfur, Sodium
diethyldithiocarbamate, Selenourea.
[0357] Solvents: 1,4-Dioxane, Toluene, Pyridine, Dichloromethane,
Tetrahydrofuran, Water.
[0358] References: Saxena, D. B.; Khajuria, R. K; Suri, O. P.
Synthesis and Spectral Studies of 2-Mercaptobenzimidazole
Derivatives. J. Heterocycl. Chem., 19, 681-683, (1982).
[0359] The 1,2-phenylenediamine derivatives (V) can be prepared by
twice nitration/reduction reactions on substituted benzene (I),
some substituents may need protection under above reaction
conditions. Cyclization of (V) with CS.sub.2, or CH.sub.3NCS, or
thiourea, or S, or (C.sub.2H.sub.5).sub.2NCS.sub.2Na can give the
desired 2-mercaptobenzimidazole derivatives (VI). Reaction of (VI)
with R.sub.5X (R.sub.5 can be alkyl or acyl group; X is Cl, Br, I)
can produce alkylated products (VIII). 2-Benzimidazoline-selenium
derivatives (VI) and (DC) can be synthesized similarly by reacting
selenourea with (V). 10
[0360] Precursor: Substituted benzene. Most are commercially
available or can be easily prepared from commercial compounds. The
definition of benzene ring substituents R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.5 is given in formulas (I) and (II) in section of
Summary Of The Invention.
[0361] Reactants: Nitric acid, Zinc, Hydrochloric acid, Ammonium
thiocyanate, Potassium thiocyanate, Potassium selenocyanate.
[0362] Solvents: Acetonitrile, Pyridine, Dichloromethane,
Tetrahydrofuran, Water.
[0363] References: Rasmussen, C. R.; Villani, F. J., Jr.; Weaner,
L. E.; Reynolds, B. E.; Hood, A. R.; Hecker, L. R.; Nortey, S. O.;
Hanslin, A.; Costanzo, M. J.; et al. Improved Procedures for the
Preparation of Cycloalkyl-, and Arylalkyl-, and Arylthioureas.
Synthesis, 6,456-459, (1988).
[0364] Various arylthiourea compounds (IV) can be prepared by
reaction of corresponding aniline (III) with NH.sub.4SCN or KSCN in
aqueous HCl solution. Alkylation of (IV) by R.sub.6X (R.sub.6 can
be alkyl or acyl group; X is Cl, Br, I) can yield monoalkylated
product (VI). By replacing KSCN with KSeCN, the selenium analogous
(V) can also be prepared. 11
[0365] Precursor: Substituted benzene. Most are commercially
available or can be easily prepared from commercial compounds. The
definition of benzene ring substituents R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.5 is given in formulas (1) and (II) in section of
Summary Of The Invention.
[0366] Reactants: Chlorosulfonic acid, Dichlorodimethylsilane,
Zinc, Cl(CH.sub.2).sub.nCl (n is 1-3), Aluminum chloride, Thiourea,
Sodium hydroxide.
[0367] Solvents: Tetrahydrofuran, Benzene, Dimethyl sulfoxide,
Water.
[0368] References: Uchiro, H.; Kobayashi, S. Non-aqueous Reduction
of Aromatic Sulfonyl Chlorides to Thios Using a
Dichlorodimethylsilane-zinc-- dimethylacetamide System. Tetrahedron
Lett., 40, 3179-3182, (1999).
[0369] Substituted arylsulfonyl chlorides (II) can be easily
prepared from substituted aromatic compounds (I) by reaction with
excess chlorosulfonic acid. Reduction of (II) with
dichlorodimethylsilane/zinc will give desired phenylthiole
derivatives (E). The substituted phenylalkyl mercaptans (VI) can be
prepared from the corresponding chloro compounds (V) which can be
obtained from alkylation reaction of (1) (Friedel-Crafts reaction).
Both thiole compounds (II) and (VI) can react with alkyl halide
R.sub.6X to form the corresponding sulfides (IV) and (VII). 12
[0370] Precursor: Substituted benzene. Most are commercially
available or can be easily prepared from commercial compounds. The
definition of benzene ring substituents R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.5 is given in formulas (1) and (II) in section of
Summary Of The Invention.
[0371] Reactants: Nitric acid, Zinc, Hydrochloric acid,
Br(CH.sub.2).sub.nBr (n is 1-3), Aluminum chloride.
[0372] Solvents: Benzene, Tetrahydrofuran, Diethyl ether,
Water.
[0373] The preparation of products (II), (IV) and (V) is same as
described previously. Reaction of (V) with alkyl amine
R.sub.6NH.sub.2 (R.sub.6 is hydrogen or alkyl) can give
arylalkylamine derivatives (VI). 13
[0374] Precursor: Substituted thiophene. Most are commercially
available or can be easily prepared from commercial sources. The
definition of ring substituents R.sub.1, R.sub.2 and R.sub.3 is
same as that given in formulas (I) and (II) in section of Summary
of The Invention.
[0375] Reactants: Butyllithium, Cl(CH.sub.2).sub.nNMe.sub.2 (n is
1-3), Ethyl chloroformate.
[0376] Solvents: Diethyl ether, Tetrahydrofuran, Benzene.
[0377] References: Hallberg, A.; Gronowitz, S. On The Reaction of
Some Thienyllithium Derivatives with
1-Chloro-2-dimethylaminoethane. Chem. Scr., 16, 42-46, (1980).
[0378] Reaction of substituted thiophene with butyllithium can
yield 2-thienyllithium salt (II), protection may be necessary for
some substituents. Substituted 2-thiophenealkylamine (III) can be
prepared by reaction of (E) with 1-chloro-2-dimethylaminoalkane.
The products (III), (IV) and (V) can be converted to each other by
alkylation/dealkylation reactions using alkyl halide R.sub.4X and
ClCO.sub.2Et, respectively. 14
[0379] Precursor: Substituted benzene. Most are commercially
available or can be easily prepared from commercial compounds. The
definition of benzene ring substituents R.sub.1, R.sub.2, R.sub.3,
R.sub.4 and R.sub.5 is given in formulas (I) and (M) in section of
Summary Of The Invention.
[0380] Reactants: Potassium thiocyanate, Polyphosphoric acid,
Sulfuric acid.
[0381] Solvents: Benzene, Water.
[0382] References: Sastry, S.; Kudav, N. A. One-step Synthesis of
Aromatic Thio Amides: Reaction of Aromatic Compounds with Potassium
Thiocyanate in Polyphosphoric Acid or Sulfuric Acid. Indian J.
Chem., Sect. B, 18B, 455, (1979).
[0383] Benzothioamide derivatives (II) can be prepared from
substituted benzene (I) in one single step by reaction with KSCN in
polyphosphoric acid or sulfuric acid. The alkylated product (III
can be obtained by using alkyl halide R.sub.6X (X is Cl, Br,
I).
[0384] Pharmaceutical Formulations and Dosing Regimes
[0385] In one embodiment, a compound of this invention is applied
or administered to the skin during an appropriate period and using
a sufficient number of dosages to achieve skin lightening. The
concentration of active compound in the composition will depend on
absorption, inactivation, and excretion rates of the compound as
well as other factors known to those of skill in the art. It is to
be noted that dosage values will also vary with the severity of the
condition to be alleviated. It is to be further understood that for
any particular subject, specific dosage regimens should be adjusted
over time according to the individual need and the professional
judgment of the person administering or supervising the
administration of the compositions, and that the concentration
ranges set forth herein are exemplary only and are not intended to
limit the scope or practice of the claimed composition. The active
ingredient may be administered as a single dose, or may be divided
into a number of smaller doses to be administered at varying
intervals of time.
[0386] Topical and other formulations of these active and/or
functional compounds are of utility in lightening skin pigmentation
in humans and other animals. These formulations may be useful for
pure cosmetic purposes, simply to obtain a lighter skin color for
perceived beautification. The formulations also have medicinal
value and can, for example, decrease hyperpigmentation of melasma,
age spots, freckles, and other skin blemishes. The compounds of
this invention act primarily by inhibiting mammalian melanocyte
tyrosinase, the rate-limiting enzyme in the production of melanin
from tyrosine and DOPA. Some compounds also absorb ultraviolet
radiation (UVR), and may thus protect skin from UVR and photoaging.
In addition, some compounds may be antioxidants that protect skin
from oxidative damage, and/or may prevent oxidative decomposition
of product formulations.
[0387] If desirable these formulations could also be used to reduce
pigmentation in hair, albeit during the biosynthesis of hair, by
blocking pigment production within the melanocytes of hair
follicles. The formulations would likely not affect the already
emerged pigmented portions of hair, unlike a bleaching agent.
[0388] The formulations useful in the present invention contain
biologically effective amounts of the functional and/or active
compound(s). A biologically effective amount of the active compound
is understood by those skilled in the art to mean that a sufficient
amount of the compound in the composition is provided such that
upon administration to the human or animal by, for example, topical
route, sufficient active agent is provided on each application to
give the desired result. However, the biologically effective amount
of the active compound is at a level that it is not toxic to the
human or animal during the term of treatment. By a suitable
biologically compatible carrier, when the compound is topically
applied, it is understood that the carrier may contain any type of
suitable excipient in the form of cosmetic compositions,
pharmaceutical adjuvants, sunscreen lotions, creams, and the like.
In one embodiment the active compound is administered in a
liposomal carrier.
[0389] The active compound is administered for a sufficient time
period to alleviate the undesired symptoms and the clinical signs
associated with the condition being treated, or to achieve the
level of desired skin lightening. The individual dosage, dosage
schedule, and duration of treatment may be determined by clinical
evaluations by those of skill in the art.
[0390] Solutions or suspensions for topical application can include
the following components: a sterile diluent such as water for
injection, saline solution, fixed oils, polyethylene glycols,
glycerin, propylene glycol or other synthetic solvents;
antibacterial agents such as benzyl alcohol or methyl parabens;
antioxidants such as ascorbic acid or sodium bisulfite; chelating
agents such as ethylenediaminetetraacetic acid (EDTA); buffers such
as acetates, citrates or phosphates; and agents for the adjustment
of tonicity such as sodium chloride or dextrose. pH can be adjusted
with acids or bases, such as hydrochloric acid or sodium
hydroxide.
[0391] Suitable vehicles, carriers, or formulations for topical
application are known, and include lotions, suspensions, ointments,
oil-in-water emulsions, water-in-oil emulsions, creams, gels,
tinctures, sprays, powders, pastes, and slow-release transdermal or
occlusive patches. Thickening agents, emollients, and stabilizers
can be used to prepare topical compositions. Examples of thickening
agents include petrolatum, beeswax, xanthan gum, or polyethylene
glycol, humectants such as sorbitol, emollients such as mineral
oil, lanolin and its derivatives, or squalene. A number of
solutions and ointments are commercially available, especially for
dermatologic applications.
[0392] The compounds can be provided in the form of
pharmaceutically-acceptable salts. As used herein, the term
"pharmaceutically-acceptable salts or complexes" refers to salts or
complexes that retain the desired biological activity of the parent
compound and exhibit minimal, if any, undesired toxicological
effects. Examples of such salts are (a) acid addition salts formed
with inorganic acids (for example, hydrochloric acid, hydrobromic
acid, sulfuric acid, phosphoric acid, nitric acid, and the like),
and salts formed with organic acids such as acetic acid, oxalic
acid, tartaric acid, succinic acid, malic acid, ascorbic acid,
benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic
acid, naphthalenesulfonic acids, naphthalenedisulfonic acids, and
polygalacturonic acid; (b) base addition salts formed with
polyvalent metal cations such as zinc, calcium, bismuth, barium,
magnesium, aluminum, copper, cobalt, nickel, cadmium, and the like,
or with an organic cation formed from N,N-dibenzylethylene-diamine
or ethylenediamine; or (c) combinations of (a) and (b); e.g., a
zinc tannate salt or the like.
[0393] The compounds can be modified in order to enhance their
usefulness as pharmaceutical compositions. For example, it is well
know in the art that various modifications of the active molecule,
such as alteration of charge, can affect water and lipid solubility
and thus alter the potential for percutaneous absorption. The
vehicle, or carrier, can also be modified to enhance cutaneous
absorption, enhance the reservoir effect, and minimize potential
irritancy or neuropharmacological effects of the composition. See,
in general, Arndt, et al. [27].
[0394] Thus, the invention provides various formulations as topical
skin lighteners containing the active and/or functional compounds
described above. The invention further provides formulations as
topical anti-oxidants containing the active and/or functional
compounds described above. In still another embodiment the
invention provides formulations as topical sunscreens containing
the active and/or functional compounds described above. Such
formulations can be made in combination with other active and/or
functional ingredients used in skincare products (e.g. organic or
inorganic sunscreen, antioxidant, anti-inflammatory, anti-erythema,
antibiotic, antimicrobial, humectant, or other ingredients). Other
ingredients can be formulated with the compounds to augment their
effect, including but not limited to Vitamin C, Vitamin E,
magnesium ascorbyl phosphate, aloe vera extract, and retinoic
acids. In addition, alpha-hydroxy acids can be included to speed up
the skin lightening process by exfoliating surface colored
skin.
[0395] The compounds of the present invention can also be
formulated for alternative routes of administration other than
topical application, including but not limited to general systemic,
oral, intradermal, transdermal, occlusive patches, intravenous, or
parenteral administration, and pharmaceutical compositions known
generally to those skilled in the art.
[0396] The compounds can also be formulated along with other active
and/or functional ingredients used in skincare products, depending
on the intended use of the formulation. For example, the compounds
can be formulated with organic or inorganic sunscreens, an
antioxidant, an anti-inflammatory, an anti-erythema, an antibiotic,
an antimicrobial, a humectant, or other ingredients.
[0397] The active and/or functional compounds described above may
also be of use in inhibiting tyrosinase-like enzymes from
non-mammalian species, for instance for use in the food science
industry for the inhibition of enzymatic browning. [28, 29]
Inhibition of plant polyphenol oxidases by agents described here
may coincidentally have activity against these non-mammalian
enzymes. Suitable formulations for spraying or treatment of fruits
are known generally to those skilled in the art. Treatment by these
formulations containing the enzyme inhibitors of the present
invention might improve shelf life of plant or fungal foods.
EXAMPLES
Example 1
Benzoimidazolethiols
[0398] A first class of compounds based upon the template compound
benzimidazolethiol (lower left structure) were tested for
tyrosinase inhibition, cell culture pigment inhibition, and
toxicity, by methods described in Curto, E. V., et al. (1999) [25].
Results of the tests are given in Table 1.
1 TABLE 1 15 16 ID # R.sub.1 R.sub.2 R.sub.3 R.sub.5 R.sub.6 R E P
T .epsilon. .lambda..sub.max 138 NH SH N H H C 0.25 -- -- 14300 300
140 NH SH N CH3 H C 0.12 2.4 >1000 6300 305 084 NH SH N
OCH.sub.3 H C 0.07 1.6 >1000 10000 310 040 S SH N H H C 8 -- --
091 S SH N H OCH.sub.2CH.sub.3 C >1000 >1000 >1000 205 NH
.dbd.S N(CO)CH.sub.3 H H C 0.5 8.3 35 098 NH .dbd.Se NH H H C 0.8
14 132 135 NH .dbd.S NH H H N 4 256 >1000 *Inhibition [.mu.M] as
measured in three assays. Here "E" is the concentration of compound
that produces 50% pigment inhibition in the cell-free
mammalian-enzyme assay system. "P" is for the concentration of
compound that produces 50% inhibition in the
mammalian-melanocyte-culture pigment assay system. "T" is the
concentration of compound that kills 50% of cells in the #
mammalian-melanocyte-culture toxicity assay system. The compound
extinction coefficient is .epsilon. [OD/M .times. cm] at the
wavelength of maximum absorbency .lambda..sub.max [nm].
Example 2
Thiophenols
[0399] A second class of compounds based upon the template compound
benzenethiol were tested for tyrosinase inhibition, cell culture
pigment inhibition, and toxicity, by methods described in Curto, E.
V., et al. (1999) [25]. Results of the tests are given in Table
2.
2TABLE 2 17 ID # R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 E P T
.epsilon. .lambda..sub.max 099 H H OCH.sub.3 H H 53 85 202 3000 265
102 H H H SCH.sub.3 H 0.24 115 126 2300 280 083 H H H
NH(CO)CH.sub.3 H 19 82 542 4700 265 103 H H OCH.sub.3 OCH.sub.3 H 8
8 >1000 4300 250 093 H OCH.sub.3 H H OCH.sub.3 500 200 200 2700
305 148 (CO)CH.sub.3 H H NH(CO)CH.sub.3 H 500 30 125 3300 255
*Inhibition [.mu.M] as measured in three assays. Here "E" is the
concentration of compound that produces 50% pigment inhibition in
the cell-free mammalian-enzyme assay system. "P" is for the
concentration of compound that produces 50% inhibition in the
mammalian-melanocyte-culture pigment assay system. "T" is the
concentration of compound that kills 50% of cells # in the
mammalian-melanocyte-culture toxicity assay system. The compound
extinction coefficient is .epsilon. [OD/M .times. cm] at the
wavelength of maximum absorbency .lambda..sub.max [nm].
Example 3
Phenylthioureas
[0400] A third class of compounds based upon the template compound
phenylthiourea (lower left structure) were tested for tyrosinase
inhibition, cell culture pigment inhibition, and toxicity, by
methods described in Curto, E. V., et al. (1999) [25]. Results of
the tests are given in Table 3.
3 TABLE 3 18 19 ID # R.sub.2 R.sub.3 R.sub.4 R.sub.5 R E P T
.epsilon. .lambda..sub.max 033 H H H H NH.sub.2 2 12 >1000 181
OCH.sub.3 H H H NH.sub.2 >1000 >1000 105 H F H H NH.sub.2
1.52 1.78 >1000 11000 255 104 H OH H H NH.sub.2 4 8 >1000 131
H CH.sub.3 H H NH.sub.2 0.82 2.28 >1000 053 H H OCH.sub.3 H
NH.sub.2 8 30 60 049 H H NH(CS)NH.sub.2 H NH.sub.2 4 250 >1000
101 H CH.sub.3 H CH.sub.3 NH.sub.2 250 125 >1000 054 H H H H
CH.sub.3 16 16 >1000 *Inhibition [.mu.M] as measured in three
assays. Here "E" is the concentration of compound that produces 50%
pigment inhibition in the cell-free mammalian-enzyme assay system.
"P" is for the concentration of compound that produces 50%
inhibition in the mammalian-melanocyte-culture pigment assay
system. "T" is the concentration of compound that kills 50% of
cells in the # mammalian-melanocyte-culture toxicity assay system.
The compound extinction coefficient is .epsilon. [OD/M .times. cm]
at the wavelength of maximum absorbency .lambda..sub.max [nm].
Example 4
Miscellaneous
[0401] A fourth group of miscellaneous compounds of diverse
structure were also tested for tyrosinase inhibition, cell culture
pigment inhibition, and toxicity, by methods described in Curto, E.
V., et al. (1999) [25]. Results of the tests are given in Table
4.
4TABLE 4 20 21 22 23 1 2 3 4 24 25 26 27 5 6 7 8 # ID # E P T
.epsilon. .lambda..sub.max 1 081 5 81 500 1000 275 2 100 32 62
>1000 3 073 >1000 100 >1000 4 079 73 71 472 5 006 110 182
>1000 6 092 79 236 >1000 7 009 98 209 775 8 026 54 153 367
*Inhibition [.mu.M] as measured in three assays. Here "E" is the
concentration of compound that produces 50% pigment inhibition in
the cell-free mammalian-enzyme assay system. "P" is for the
concentration of compound that produces 50% inhibition in the
mammalian-melanocyte-culture pigment assay system. "T" is the
concentration of compound that kills 50% of cells in the #
mammalian-melanocyte-culture toxicity assay system. The compound
extinction coefficient is .epsilon.[OD/M .times. cm] at the
wavelength of maximum absorbency .lambda..sub.max [nm].
[0402] Throughout this application, various publications are
referenced. The disclosures of these publications in their
entireties are hereby incorporated by reference into this
application in order to more fully describe the state of the art to
which this invention pertains.
[0403] It will be apparent to those skilled in the art that various
modifications and variations can be made in the present invention
without departing from the scope or spirit of the invention. Other
embodiments of the invention will be apparent to those skilled in
the art from consideration of the specification and practice of the
invention disclosed herein. It is intended that the specification
and examples be considered as exemplary only, with a true scope and
spirit of the invention being indicated by the following
claims.
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* * * * *