Note: Descriptions are shown in the official language in which they were submitted.
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TOPICAL COMPOSITIONS COMPRISING
PROTECTED FUNCTIONAL THIOLS
TECHNICAL FIELD
The present invention relates to topical compositions for treating amino acid
based
substrates. The topical compositions comprise cosmetic or therapeutic actives
that have been
bound to a protectcd thiol which acts as a molecular 'hook' to impart
"permancnt" benefits to the
amino acid based substrates. The amino acid based substrates can include, for
example,
proteinaceous materials such as keratin, as found in human hair, animal fur,
velus hair on skin,
finger and toe nails; various animal body parts, such as horns, hooves and
feathers; other
naturally occurring protein containing materials, such as wool; and synthetic
polymers. Of
particular interest are compositions which deliver and attach cosmetic actives
to human hair.
BACKGROUND OF THE I1WENTION
It is well known in the art that amino-acid based fibers, particularly hair,
can be treated
with agents that deliver one or more cosmetic benefits, such as conditioning,
styling or setting.
The conventional cosmetic products which have been known and used commercially
have relied
upon two key factors: deposition and retention. The cosmetic actives must
first be physically
deposited onto the hair fiber where the active imparts a benefit to a
sufficient degree. Secondly,
it is essential that the cosmetic actives be retained on the hair beyond the
completion of the
treatment. For example, when hair is rinsed to remove unwanted excess
composition (e.g., a
conditioner) a sufficient amount of the cosmeric active (humectant,
moisturizer, etc.) remains
bonded to the hair so as to maintain the desired cosmetic benefits.
The bonding of the cosmetic active material to the hair is generally of the
nature of
physico-chenucal intermolecular forces, e.g., physisorption. Such physical
forces comprise, for
example, hydrogen bonding, electrostatic interactions, van der Waals
interactions and the like.
As an example, cationic cosmetic agents, generally of the quaternary ammonium
type, are known
CA 02519205 2000-O1-07
2
to bond to hair by virtue of the interaction of their cations with anionic
amino acid residues
within keratin, e.g., glutamic acid, aspartic acid, cysteic acid etc. A major
problem, however,
with physisorption is the inevitable short lived retention of the cosmetic
agent on hair. This is
due to the relatively weak physical forces which bind the cosmetic to hair and
which are easily
disrupted by other treatments, e.g. washing. And, given the frequent need for
treating hair,
performance retention is difficult to achieve and generally does not last in
excess of the period
between washes.
One approach that has been disclosed in the art to overcome the above problem
to provide
truly durable or "permanent" cosmetic benefits to hair that are retained
through multiple washes
is to utilize molecular "hooks" to chemically bond cosmetic actives to hair
keratin, e.g.,
chemisorption. Chemisorption results in a permanent juncture that is
essentially resistant to
physical wear from subsequent washings or physical abrasion. Two conventional
approaches to
achieve chemisorption comprise the use of either electrophilic reactive
moieties or thiol reactive
moieties attached to the cosmetic active. Electrophilic reactive moieties are
designed to react
with thiol functional groups present in hair and thiol reactive moieties are
designed to react with
electrophilic functional groups within the hair to create a covalent bond.
U.S. Patent 5,523,080 issued to Gough et al. on June 4, 1996, U.S. Patent
5,211,942 issued
to Deppert et al. on May 18, 1993, and UK Patent Application GB2197887
published on June 2,
1988, all disclose the use of electrophilic moieties. These electrophilic
chemistries include the
use of azlactone, (haloalkyl)trialkylammonium salts, and acyl halides. All of
these molecular
hooks have potential to react with hair via an electrophilic mechanism which
necessitates
sufficient nucleophilic functional groups present within the keratin structure
with which to react
to a sufficient degree to achieve the desired durable benefits. For hair, this
poses a dilemma in
that it is generally known that hair does not naturally possess a sufficient
concentration of
nucleophilic functional groups under consumer mild conditions to drive the
reaction. However, it
is also generally known that by chemically reducing the disulfide bonds
present within the
cystine amino acid residues of hair, in a manner analogous to cold waving,
sufficient quantities of
nucleophilic cystine residues can be produced. Pre-reduction of hair, to
enable the chemical
reaction with suitable electrophilic cosmetic actives, is illustrated below in
reactions (a) and (b).
Ker represents keratin protein, R-X represents an alkyl halide electrophilic
cosmetic active, R
represents a cosmetic agent and X' is a halide anion such as bromide or
chloride.
Reduction
Ker S S Ker ~- 2 Ker SH
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3
Ker SH + R X ---~ Ker S R + X'
(b)
While electrophilic cosmetic actives have been demonstrated effective at
providing durable
cosmetic benefits to hair, the approach has disadvantages that arise from the
required pre-
reduction step. First, the reduction step is known to be a very harsh chemical
process that
imparts considerable damage to hair. Second, the effective reducing agents are
typically
mercaptans of low molecular weight and are odiferous. The pre-reduction
process generates
unpleasant malodor that remains on the hair for greater than a week time in
most instances.
Thirdly, in addition to unpleasant malodor and resulting hair damage, the
required pre-reduction
imparts an additional step to the process with attendant added inconvenience
to the user.
U.S. Patent 5,087,733 and U.S. Patent 5,206,013 both issued to Deppert et al.
on February
11, 1992 and April 27, 1993 respectively, as well as U.S. Patent 4,973,475
issued to Schnetzinger
and Ciaudelli on November 27, 1990, describe the use of quaternary ammonium
thiols which fall
under the general class of nucleophiIic reactive actives. Such nucleophilic
actives are generally
intended to react with cystine amino acid residues present within hair via
formation of a mixed
disulfide covalent linkage as is demonstrated in the chemical equation (c).
R-SH + Ker- S- S-Ker -'~" Ker- S- S'R + Ker-SH (c)
Ker represents keratin and R-S~-1 represents a suitable nucleophilic active
where R is a cosmetic
agent and -SH representing a nucleophilic moiety. It is generally known that
thiols are the
preferred nucleophilic reactive moieties that possess enough reactive strength
to chemically bond
with the disulfide bond of eystine, Ker-S-S-Ker, under safe and mild consumer
conditions (e.g.,
relatively non toxic, less than 120°F, pH 2 to 11). Most other
prospective nucleophilic molecular
handles are either highly toxic (e.g., selenols), or are unreactive under mild
conditions (e.g.,
alkoxides with pKa -- ZS).
There are two major drawbacks to the use of nucleophilic thiols as reactive
moieties to
form covalent bonds with keratin. First, thiol nucleophilic moieties are known
to be unstable in
the presence of air. Atmosphere induced oxidation of the thiols to the
corresponding, and
unreactive, disulfide as is shown in the following equation (d) where R-SH
represents a suitable
nucleophilic cosmetic active R being an alkyl cosmetic agent and -SH
representing the
nucleophilic moiety:
R-SH + R-SH ~°~ R- S- S-R (~
Such oxidative deactivation of the nucleophilic thiol moieties severely limits
their mode of usage.
Thus, nucleophiIic thiols are generally not stable enough to be utilized as
such in a large majority
CA 02519205 2000-O1-07
4
of current product forms, i.e., re-sealable hair care packages widely used for
shampoos, rinse-off
conditioners etc. Second, the nucleophilic thiol moiety has very little
affinity for hair keratin and
has very low aqueous solubility, both of which hinder its performance in
generating durable
cosmetic benefits, especially when attached to hydrophobic, insoluble cosmetic
actives, i.e.,
hydrocarbon conditioners, in-soluble polymers etc.
Despite major efforts, however, the art has not yet provided molecular "hooks"
that provide
durable cosmetic benefits to hair that last beyond twenty shampoos and which
do not necessitate
the damaging cold waving of hair, i.e. hair reduction, while being oxidatively
stable in solution
for long term storage in a variety of currently used product forms,. e.g.,
rinse of conditioners, two-
in-one shampoos, etc.
The present invention is concerned with topical compositions comprising
classes of
compounds containing at least one thiol in a protected form, which can be
released to provide a -
SH or -S- group prior or simultaneous to use. These protected thiols are
referred to herein as
"hooks". It is understood that within the scope of this invention that
functional thiols as
represented herein include both the protonated thiol, R-SH, and unprotonated
thiolate, R-S-.
It has now been discovered that, surprisingly, such "hooks", R-(S-Pr)m,
provide durable
cosmetic benefits, when applied to amino-acid based substrates without a
damaging cold-waving
process, that last beyond twenty shampoos. It has also been discovered that
the molecular
"hooks" of the present invention provide improved oxidative stability versus
conventional thiols
by virtue of the appended protecting moiety to the thiol group that reduces
the oxidative-
susceptibility of the sulfur atom(s). Furthermore, it has been found that
these molecular "hooks"
significantly outperform conventional nucleophilic thiol hooks in providing
durable cosmetic
benefits. While not being bound by theory, the latter observed effect is
believed to be due to the
unexpected high affinity for keratin provided by certain polarizable
electrophilic groups which
offer improved solubility and possibly even electrostatic interaction with the
charged
keratinaceous substrate. Presumably, such greater affinity affords enhanced
diffusion and
adsorption to the fiber by the cosmetic active enabling greater opportunity
far binding.
The 'hooks' of the present invention enable the achievement of durable
cosmetic benefits
that are resistant to cleansing or shampooing from essentially a non-damaging
process that is void
of cold waving. The binding of the cosmetic actives provided by these
molecular 'hooks' is to
such a degree of durability that the measured cosmetic benefits will remain in
hair for multiple
shampoo cycles, e.g. eight to twenty or more. While not being restricted by
theory, it is believed
that such a high degree of durability is due to the formation of covalent
bonds between the
cosmetic active and the keratinaceous substrate.
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This bond formation may occur in either of two ways. First, the protected
thiol compound
can be mixed with a activating release agent to form the free functional
thiol, reaction (e). The
free thiol will then react with the substrate thereby attaching the functional
group, reaction (f).
R-S-Pr + Release Agent-=~ R-'S (e)
2 R- S- + Ker- S - S-Ker ---~ 2 Ker- S - S -R T Ker-SH
R represents the cosmetic active, Ker represents the keratin protein, S
represents sulfw, -SH
represents the thiol and Pr represents the protecting group. Based on theory,
the above thiol-
protecting group bond is broken via some form of activation yielding the
reactive unprotected
Lhiol which would then be capable of forming a mixed disulfide with keratin
disulfides via
nucleophilic displacement. Such activation could be accomplished via
hydrolysis or by the
action of a nucleophile other than water, either in the substrate itself or in
a separate composition.
Such hydrolysis or nucleophilic attack can itself be enhanced in several way
such as by
application of a source of energy or catalysis. This mixing may be done prior
to use or
simultaneously, during application to the substrate. Where the mixing occws
simultaneously to
application, the release of the protecting group occurs in-situ on the
substrate.
Surprisingly, it has been found that, alternatively, the formation of the
covalent bonds may
occur without mixing with a release agent. Direct reaction of certain
protected thiol compounds
with the hair occurs via the formation of a mixed disulfide with the existing
disulfide bonds
within keratin as is illustrated below, reaction (g):
R-S- Pr + Ker-S-S- Ker ~ R-S-S-Ker + Ker- SH + Pr - OH
While not being bound to theory, it is believed that the keratin itself could
be activating the thiol
protecting group bond to enable the observed durable benefits. The resulting
free protecting
group may or may not undergo decomposition reactions. The byproducts of the
activation of the
sulfur-heterocyclic bond will usually be removed from the substrate by
washing.
The cosmetic agent, R, of the present invention may be monofunctionalized,
i.e. the
cosmetic active moiety, R, carries a single molecular "hook" connected to the
cosmetic agent via
a sulfw-spa carbon bond, or it may be bis- or multi- functionalized, i.e. the
cosmetic active, R,
may cant' two or more spa electrophiles connected to the cosmetic agent via
separate sulfur-spa
carbon bonds. The latter may be useful for example in achieving a greater
degree of chemical
bonding of the cosmetic agent to the substrate or for generating bonds between
adjacent features
of the substrate, e.g. producing a cross-linking effect. The latter may be
employed to improve the
strength or tensile properties of keratinaceous fibers or for enhancing the
degree of hair setting
compared with prior art hair methods.
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6
It is understood that within the scope of this invention, numerous potentially
and actually
tautomeric compounds are involved. Thus, for example, 2-mercaptopyridine (I)
exists under
known conditions in the pyridine-2-thione tautomer form (II). It is to be
understood that when
this development refers to a particular structure, all of the reasonable
additional tautomeric
structures are included. In the art, tautomeric structures are frequently
represented by one single
structure and the present invention follows this general practice.
N ASH N ~S
H
O)
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7
Preferred embodiments of the present invention are related to functional
silicone
compositions. More specifically, these embodiments are related to functional
silicone
compositions which are used in the cosmetics industry.
Silicones are widely used in hair care products due to the conditioning
benefit that they
impart to hair. By modern day technology, the silicone is deposited on hair
during the
application process but is held only by weak physical forces, such as hydrogen
bonding or van
der Waals interactions. Because the forces are weak, the benefits of silicone
by deposition are
short lived. Beneficial conditioning effect can also be caused by treating
hair with silanol capped
amino-functionalized silicones. These can undergo condensation cure reactions
on hair to form
somewhat durable films. Generally, conditioning benefits are attributed to the
deposition of high
molecular weight, high viscosity fluids and gums which can weight down the
hair.
It is widely known by those skilled in the art that covalent bonding is the
key to
"permanent" hair treatment. Processes which alter the structure of the hair,
such as permanent
wave and color treatment methods, do provide longer lasting effects. These
processes include
glycolate reduction and peroxide reoxidation. However, the processes are very
damaging to hair
and can only be carried out every eight to ten weeks.
Gough et al. in U.S. Patent Nos. 5,523,080 and 5,525,332 describe the
synthesis of silicone-
azlactone polymers which exhibit covalent bonding and "permanent" conditioning
bcncfit.
Gough et al. discuss incorporating an azlactone-functionalized copolymer which
consists of
vinylazlactone and methacryloyl polydimethylsiloxane monomers into a silicone-
active group-
hair structure. The hair treatment using the silicone-azlactone polymers did
not consist of the
steps of reduction with a glycolate or reoxidation with peroxide.
New compositions are constantly being sought which impart improved hair care
benefits
without a harsh, damaging chemical treatment.
SUMMARY OF TAE INVENTION
This invention relates to a topical composition for treating amino acid based
substrates
comprising a protected thiol compound having the formula
R--(S-Pr)m
where R is a mono or multivalent cosmetically active functional group, S is
sulfur, and Pr is a
protecting group, and m is an integer between 1 and 100. The invention further
relates to systems
which comprise this protected thiol compound and an activating mechanism. The
protected thiol
compounds of the present invention may be used in hair care compositions,
textile care
CA 02519205 2000-O1-07
8
compositions, cosmetic compositions, oral care compositions, skin care, nail
care, laundry care,
acne care and animal care. compositions.
A preferred embodiment of the present invention provides a silicone
composition and
method for making. The composition comprises a polysiloxane or silicone resin,
at least one
linker, and at least one molecular hook.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to topical compositions which provide attachment
of
functional groups to amino acid based substrates.
As used herein, "cystine containing, amino acid based substrates" are
proteinaceous
materials which contain the amino acid cystine in its amino acid sequence. The
phrase "amino
acid sequence" refers to a specific configuration of the amino acids
comprising a protein.
Cystine amino acid units are represented by Ker-S-S-Ker and cysteine amino
acid units by Ker-
SH. The compositions of the present invention can be used to attach functional
groups to
materials such as keratin, as found in human and animal hair, skin and nails;
various animal body
parts such as horns, hooves and feathers; and other naturally occurring
protein containing
materials, such as wool.
The topical compositions of the present invention can comprise, consist of, or
consist
essentially of the essential dements and limitations of the invention
described herein, as well as
any of the additional or optional ingredients, components, or limitations
described herein.
All percentages, parts and ratios are by weight of the total composition,
unless otherwise
specified. All such weights as they pertain to listed ingredients are based on
the specifec
ingredient level and, therefore, do not. include solvents, carriers, by-
products, filler or other minor
ingredients that may be included in commercially available materials, unless
otherwise specified.
PROTECTED THIOL COMPOUND
The compositions of the present invention comprise a protected thiol compound
having the
formula
R--(S-Pr)m
where R is a mono or multivalent cosmetically active functional group, S is
sulfur, Pr is a
protecting group, and m is an integer ranging from about 1 to about I00,
preferably from about 1
to about 50, more preferably equal to 1 to about 20, and most preferably equal
to I to about 5.
Typically, the protected thiol compounds of the present invention are present
in the
compositions of the invention in an amount from about 0.000001 % to about 30%,
preferably
CA 02519205 2000-O1-07
9
from about 0.0001% to about 25%, more preferably from 0.01 to about 20%, even
more
preferably from about 0.1 % to about 10%, and most preferably from about 1 %
to about 5%, by
weight of the composition. Suitable ranges of amounts will generally depend
upon the functional
group in question. For example, hair conditioners that are modified with the
molecular 'hooks'
of the present invention will normally be present from about 0.01 % to I O% by
weight of the
composition, and hair styling agents that are modified such as cationic
conditioning polymers or
polyisobutylene will normally be present from about 0.01 to 10% by weight of
the composition,
perfluoropolyether materials that are modified may be present from about
0.000001 to 0.1% by
weight of the composition, hair dye chromophoric materials maybe present from
0.1% to 10%
and other film forming polymers that are modified may be present from about
0.01 to 2% of the
composition.
The protected thiol compound comprises from about 1 to about 100, preferably
from about
1 to about 50, more preferably from about I to 20, and most preferably equal
from I to about 5
sulfur atoms, each linked to one protective group.
Protecting Group
The protected thiol compounds of the present invention comprise 1 to about
100, preferably
1 to 50, more preferably I to 20 and most preferably 1 to 5 protecting groups.
The protecting
group may be selected from the range consisting of heterocyclic protecting
groups, sp2 aliphatic
trigonal, carbon protecting groups, sp' carbon protecting groups, metal based
protecting groups,
non-metal and metalloid based protecting groups, energy-sensitive protecting
groups and
mixtures thereof. The protecting group is preferably selected from the range
consisting of
heterocyclic protecting groups, sp'' aliphatic trigonal carbon protecting
groups, spa carbon
protecting groups and non-metal protecting groups. The protecting group is
more preferably
selected from heterocyclic protecting groups, spy aliphatic trigonal carbon
protecting groups and
non-metal protecting groups.
Heteroe~clic Protecting Groups - The cosmetic composition of the present
invention comprises a
protected thiol compound wherein the thiol protective group may be a
heterocyelie ring or ring
system. Heterocyclic groups that are suitable for use in the present invention
include mono- or
polyunsaturated or saturated heterocyclic rings, heterocyclic ring systems,
fused heterocyclic ring
systems, substituted heterocycIic rings, substituted heterocyclic ring systems
or substituted fused
heterocyclic ring systems. The heterocyclic rings contain from about three to
about thirty
members, and may contain electronegative heteroatoms including N, O, S, or P.
The heterocyciic
rings or ring systems also may contain exocyclic double bonds of the C=M type
wherein M is O,
S, NA' or CA'AZ. A' and A' used here, and A' and A'' used hereinafter, each
represent,
CA 02519205 2000-O1-07
independently from one another, a monovalent group which can be the cosmetic
active ,group, R,
or H or any of the following: a straight. branched or mono- or polycyclic
aliphatic, mono or
polyunsaturated alkyl, aryl, heteroalkyl, heteroaliphatic or heteroolefinic
system including 1 to 30
carbon atoms together with 0-15 heteroatoms, especially O, N, S, P, Si, and
can incorporate one
or more substituents including, but not limited to, poly or perfluoro
substitution.
Optional substituents on the heterocyclic ring or ring system, X', X', X',
X'', XS..., can be
selected from electron withdrawing, electron neutral, or electron donating
groups with Hammett
sigma para values between -1.0 and +1.5 which can be non-ionic, zwitterionic,
cationic or anionic
comprising for example C-linked groups of the classes defined above as A',
A'', A', and A°; S-
linked groups including SA', SCN, SO~A', S03A', SSA', SOA', SO~NA'A'', SNA'AZ,
S(NA')A',
S(O)(NA')Az, SA'(NA''), SONA'A2; O-linked groups including OA', OOA', OCN,
ONA'A2; N-
linked groups including NA'A2, NA'AZA'', NC, NA'OA2, NA'SA'', NCO, NCS, NO2,
N=NA',
N=NOA', NA'CN, N=C=NA', NA'NA~A3, NA'NA''NA'A°, NA'N=NA'; other
miscellaneous
groups including COHaI, CONS, CONA'~, CONA'COA2, C(=NA')NA'AZ, CHO, CHS, CN,
NC,
Hal, and derived groups that connect one or more of X', XZ, X', X'°, XS
via a ring system;
Ak is A', Az, A3, and A° or X', Xz, X3, X°, Xs...
Hal is F, CI, Br, or I.
H is hydrogen, O is oxygen, N is nitrogen, C is carbon, S is sulfur, CI is
chlorine, Br is
bromine, I is iodine, F is fluorine, R is any cosmetically active, functional
group or benefit agent
as described herein below.
The invention includes the following preferred non-limiting heterocyclic
exemplary classes
and their X', X~, X3, X4, XS.. . substituted derivatives [Herein referred to
as Class I]:
- Six membered heterocycles with a single heteroatom such as pyridine:
~S--R
N
- Six membered heterocycles with two heteroatoms such as pyrimidines,
pyrazines and
pyridazines:
N
N
S- R S- R N S- R
N N ~N
- Six membered heterocycles with three and four heteroatoms such as triazines
and tetrazines:
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11
.N .N n n
N S-R N S-R N NS-R NUNS-R
N ~ ~~-
N N
- Six membered O, N, and/or S containing heterocycles with C=O, C=S or C=C
exocyclic groups:
O -R -R
~N
O_/ 'N
X S-R X O
X = O, S, or NX
- Cationic six membered heterocycles with one heteroatom such as pyridinium,
pyrylium, and
thiopyrylium salt derivatives:
~~S_.R S-R S-R
N O S
I
Ak
- Cationic six membered heterocyclics with two heteroatoms such as
pyrimidinium and
pyrazinium salt derivatives:
N
N
S-R S-R
N N
f f
Ak Ak
- Five membered heterocycles with one heteroatom such as furans, pyrroles, and
thiophenes:
~~S-R ~~S-R ~~S-R
O \N~' ~ ~S
I
Ak
- Five membered heterocycles with two heteroatoms such as pyrazoles,
isoxazoles, and
isothiazoles:
Nl S-R N~ S-R / S-R
N O
Ak
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12
- Five membered heterocyclics with three heteroatoms such as 1,2,4-triazoles,
1,2,3-triazoles,
1,2,4-oxadiazoles, and 1,2,4-thiadiazoles:
NON S-R Nli Ns-R NON S-R N~~ S-R
.N. .O .S
N
I I
Ak Ak
- Five mernbered cationic heterocycles with two or more heteroatoms such as
pyrazotium and
triazolium:
.~S-R ~S-R
~_N~N ~_N~N,N
I
Ak Ak
- Seven membered heterocycles such as azepines, oxepins and thiepins:
S-R ' / S-R I / S-R
N.r O s
- Seven membered cationic heterocycles such as thiepinium salts:
S-R
S+
I
Ak
and related variations including combinations of the above heterocycles in a
ring system and
fused systems both of which rnay include carbocyclic rings without
heteroatoms. The cationic
heterocycles W 11 also incorporate a CI', Bi, I' or other suitable negatively
charged eounterion.
The invention may also include heterocyclic compounds comprising the cosmetic
active, R,
that are capable of generating a thiol via a ring-opening mechanism. Such
compounds are
represented by the following structures:
X' Q1
t
X~ ~S~ X~ ~~S
X C 2/C, t~C-N( X2iCQ2.-C'.
X Q (~~ M(N),
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13
X~ Qs X' Q~ S
\ , S ~ X~ \C C_X3
X?iC~c C x~C~s'C~ Xzi ~ ., n
.x3 2~ Q~C
X Q~-C~ i
(V), w (~, w (~u),
2
X~ 2
X~
X _ i
Xt=C~~ ~ C~ X'-C C Q~S
vC,- S X y C~~ S , z
Qt,C''M Q C
(.X),
z z
X C-Q~ X C S
X~-C ~ 'S Xt-C ~ C-X3
C=C Q1 C
!~ 3 1
W X (~~ VV
Xz
.,
i /C \ $
x -C i
Q2 C~CwX3
1
W~ ~
(- ---'-/ 7
1
X~_N+~~S j W
vC~ X -N\ ~S
~2
X (XN), and 2/Cv 1
X L (XV),
wherein at least one cosmetic group, R, comprises or is attached to any of the
X', X~, X'
groups.
Q' and QZ represent, independently from one another, a divalent group
comparable to A'
but with the open valencies separated by 0 to 4 atoms.
W' represents an electron withdrawing group with a Hammett sigma para value
more
positive than 0.10 comprising C-linked groups of the classes defined above as
A', A2, A3; S-
linked groups including SA', SCN, SOiA', SO,A', SSA', SOA', SONA'Az, SO~NA'A',
SNA'A',
S(NA')A'', S(O)(NA')A2, SA'(NAZ); O-linked groups including OA', OOA', OCN,
ONA'A2; N-
linked groups including NA'A2, NA'AZA'', NC, NA'OA2, NA'SAz, NCO, NCS, NOZ,
N=NA',
N=NOA', NA'CN, N=C=NA', NA'NAZA3, NA'NAZNA3A4, NA'N=NAz; other miscellaneous
CA 02519205 2000-O1-07
14
groups including COHaI, CONS, CONA'~. CONA'COA'', C(=NA')NA'A'-, CHO, CHS, CN,
NC,
Hal, and derived groups that connect one or more of X', X~, X', X'', X' via a
ring system;
L' is a suitable leaving group including but not limited to SA', OA', or
NA'A''.
Below are some non-limiting representative examples for each of the above
heterocyclic
structures (II through XV) that are capable of generating a thiol via a ring-
opening mechanism:
A thiolactone, thiophthalide, and thiazolidinone (classes II, III and IV),
S O
R
R S
l ~
O ,-- NH' \ O
A dihydrothiophene, dihydrothiopyran, and dihydro-1,4-thiazine (classes V, VI
and VII),
S S
R ..- S R
N
CH3CHZOOC R SO~Ph CH3 COPh
Unsaturated thiolactones and a dihydrothiapyrone (classes VDI, IX and X),
R ~ S . / S R I \S
R
O O O
A dihydrothiepin, thiopyran and thiepinone (classes XI, XII and XIIT),
_ S
S
R ~ / S R ~ I
2
COZEt R \ CO Et
A dihydrothiazoline and 2-methoxythiazolidine (classes XIV and XV),
R-N
R-N ~ CH30
~.. S H
and other related derivatives.
Preferred protected thiol compounds of the heterocyclic thiol protective type
include the
following non-limiting examples:
CA 02519205 2000-O1-07
IS
N
R-S 'N+ Hal'
R-
Hal'
+ Hal-
N
R S
S
+ Hal-
N
R S
N
Hal-
l \
S
0
CA 02519205 2000-O1-07
16
Hal
N
R-S
N
S
I_+ SI
Ha
S
+Hal'
N~
N
R- S
N
S
R S + Hal
N
\0
~~ + Hal-
R S N
CA 02519205 2000-O1-07
17
R S ~ + Hal'
N
R S
O
and mixtures thereof, wherein Hal- is C1-, Br , I' or any suitable negatively
charged counterion.
sp'' Aliphatic Trigonal Carbon Protectine Groups - The protecting groups of
the present invention
may comprise a sp? carbon moiety v~herein the divalent sulfur atom is bonded
on one side to the
cosmetic active and on the other side to a sp'' carbon atom. Protecting groups
of the sp' aliphatic
trigonal carbon type that are suitable for the present invention include (a)
aliphatic trigonal
carbon atoms double bonded to O, S, N, or C,
M'
R S ~ ~ X'
which includes derivatives of the, following acids: thiocarboxylic (R-S-
C(O)CHz-A~),
carbonodithioic (R-S-C(O)S-A', R-S-C(S)O-A'), carbonothioic (R-S-C(O)O-A'),
carbamothioic
(R-S-C(O)N-A'A2), dithiocarboxylic (R-S-C(S)CH2-A'), carbonotrithioic (R-S-
C(S)S-A'),
carbamodithioic (R-S-C(S)N-A'Ai), carboximidothioic (R-S-C(NA')CH2-A'),
carbonimidodithioic (R-S-C(NA')S-A'), and carbonimidothioic (R-S-C(NA')O-__A~)
acids.
Suitable sp'' aliphatic trigonal carbon type protecting groups for use in the
topical compositions of
the present invention do not include carbamimidothioic acids.
The invention also includes (b) related spz carbon derivatives that are
capable of releasing a
cosmetic thiol via an intramolecular nucleophilic attack and release
mechanism,
CA 02519205 2000-O1-07
I8
Mt
M
11 E,
If
R S C E~-Q'-Nu --~- R S- +
Nu-Q
(c) sp' carbon derivatives that are capable of rearranging to produce a
cosmetic containing thiol
via an intramolecular nucleophilic attack and rearrangement mechanism,
Mt M'
R E'-C S-Qt-Nu R E~-G-Nu-Q~-S
as well as (d) trigonal carbon electrophiles of the anhydride, thioanhydride,
and
secondary/tertiary amide type,
M' MZ
R S II EWCI
and related aliphatic trigonal carbon variations. The cationic protecting
groups will also
incorporate a Cf, Br',1~ or other suitable negatively charged counterion.
M', Mz are O, S, NA', NOA', NA'AZ+, CA'=CAzY', SA+, OA'.
E' is O, S, NA', CA'A~.
Nu is NHA'A~+, NA'A~, OHA'+, OA'.
X' represents an electron withdrawing or electron donating group with a
Hammett sigma
para value between -1.0 and +1.5 which can be non-ionic, zwitterionic,
cationic or anionic
comprising for example C-linked groups of the classes defined below as A', AZ,
A3; S-linked
groups including SA', SCN, SO2A1, S03A', SSA', SOA', SONA'A'', SOzNA'A'',
SNA'A2,
S(NA')A~, S(O)(NA')A~, SA'(NAZ); O-linked groups including OA', OOA', OCN,
ONA'AZ; N-
linked groups including NA'A2, NA'AZA'+, NC, NA'OA~, NA'SAZ, NCO, NCS, NOz,
N=NA',
N=NOA', NA'CN, N=C=NA', NA'NAzA', NA'NAzNA'A', NA'N=NAz; other misceiianeous
groups including COI~aI, CONS, CONA',, CONA'COAz, C(=NA')NA'A~, CHO, CHS, CN,
NC,
Hal, and derived groups that connect one or more of X', X2, X3, X4, XS ~7a a
ring system;
A', Az represent, independently from one another, a monovalent group which can
be the
cosmetic active group, R, or H or any of the following: a straight, branched
or mono- or poly-
cyclic aliphatic, mono or polyunsaturated alkyl, aryl, heteroalkyl,
heteroaliphatic or
heteroolefinic system including 1 to 30 carbon atoms together with 0-1S
heteroatoms, especially
O, N, S, P, Si, and can incorporate one or more substituents including, but
not limited to, poly or
per fluoro substitution.
CA 02519205 2000-O1-07
19
Q is a divalent group comparable to A' but with the open valencies separated
by 2 to 7
atoms.
Hal is F, Cl, Br, or I.
Y' represents electron an withdrawing substituent with a Hammett sigma para
value more
positive than 0.10. Such electron withdrawing substituents which can be
nonionic, zwitterionic,
cationic or anionic include the following non-limiting examples: N02, CN,
COOA', CONA'A',
C(O)A', SO~A', SO~OA', NO, COHaI, CONS, CONA'A', CONA'COAZ, C(=NA')NA''A',
C(S)A', NC, SCN, SO~A', S03A', SOA', SO,NA'A'', SNA'Az, S(NA')Az, S(O)(NA')A',
NA'A'A3T, SA'A''+.
H is hydrogen, O is oxygen, N is nitrogen, C is carbon, S is sulfur, Cl is
chlorine, Br is
bromine, I is iodine, F is fluorine, R is any cosmetically active functional
group or benefit agent
as described herein below.
Non-limiting examples of suitable X' groups are as follows:
N(CH2)2
-N+~ ~ N(CH3)2
N+-CH3
N~2
OZN
CA 02519205 2000-O1-07
0
-NON
~ N+, CH3
- N
~J
or related derivatives.
Preferred protected thiol compounds of the sp' carbon thiol protective type
include the
following non-limiting examples:
N(CHg)2+ BI
R S C OCH2CH3
S
R S C OCH2CH3
N(CH3~+ Br
R S C CH3
NH2 Br
~N
R S C N
CA 02519205 2000-O1-07
21
NH2 Br
N(CH3)2
R S C
N+~
R S C N Br
I
NHz Br
R S
O
I l 2a Br
R S C B Na\ ~ N(CH3)z
NH2 Br
R S C
NN+n~:
OCH3
R S C
H3C0
CA 02519205 2000-O1-07
22
0
I!
R S C CHZ-CHI-CHZ-CH2-NH3+ CI'
O
R S C CH2-CH2-CH2-NH3+ Cf
O
R C S CH2-CH2-CH2-CH2-NH3+Ci-
O
R C S CH2-CHz-CH2-NH3~ Cf
sp' Carbon Protecting GrouQs The protecting groups of the present invention
may comprise an
sp' carbon moiety wherein the divalent sulfur atom is bonded on one side to
the cosmetic active
and on the other side to a spa carbon atom. Protecting groups of the sp'
carbon type that are
suitable for the present invention include those of the thioether type,
X1
R-S-C-X2
13
X (I)
including the monothioacetal (II. X' = H), monothioketal (II. X', XZ = H),
monothioortho ester
()?I) and monothioorthocarbonate (N) type,
x' oA' oA'
R-S-C=X2 R-S-C-X' R-S-C-OA2
OA' (~ OAZ (~ OA3 (N)
the dithioacetal(V. X' = H), dithioketal (V. X', XZ = H), dithioorthoester
(V)) and
dithioorthocarbonate (VD) type,
X~ OA' OA'
R- S- C- XZ R- S-C- X' R-S-C-OAS
SA' (V)' SA2 (Vn SA3 (VV)
CA 02519205 2000-O1-07
23
the trithioorthoester type (VIII),
SA1
R-S-C-OA''
SA3 (VIII)
the thiohemiaminal {IX), monothioorthoamide (X) and dithioorthoamide (XI)
type,
X' OA3 SA3
R-S-C-X2 R-S-C-X2 R-S-C-X'
I 1 2 ~ 1 2 ~ t 2
NA A (~) NA A (X) NA A (XI)
and related classes wherein X', Xz, X3 represent, independently from one
another, electron
withdrawing, electron neutral, or electron donating groups with Hammett sigma
para values
between -1.0 and t1.5 which can be non-ionic, zwitterionic, cationic or
anionic comprising for
example C-linked groups of the classes defined below as A', A'', Aj; S-linked
groups including
SA', SCN, SOZA', S03A', SSA', SOA', SONA'AZ, SO~NA'A'', SNA'A2, S(NA')A2,
S(O)(NA')A2, SA'(NAZ); O-linked groups including OA', OOA', OCN, ONA'A'; N-
linked
groups including NA'Az, NA'A''A3', NC, NA'OA2, NA'SA~, NCO, NCS, NO~, N=NA',
N=NOA', NA'CN, N=C=NA', NA'NA~A', NA'NAZNA3A", NA'N=NA2; other miscellaneous
groups including COHaI, CON,, CONA'2, CONA'COAZ, C(=NA')NA'A2, CHO, CHS, CN,
NC,
Hal, and derived groups that cormect one or more of X', Xz, X3, X", XS via a
ring system. Hal is
F, CI, Br, or I.
For the thioether class, as defined above, at least one of X', X', or X3
groups is electron
donating such that the sum of the Hammett sigma para values for X', XZ, X' is
negative for this
class.
A', AZ, A3, A4 represent, independently from one another, a monovalent group
which can
be the cosmetic active group, R, or H or any of the following: a straight,
branched or mono- or
poly- cyclic aliphatic, mono or polyunsaturated alkyl, aryl, heteroalkyl,
heteroaliphatic or
heteroolefinic system including 1 to 30 carbon atoms together with 0-15
heteroatoms, especially
O, N, S, P, Si, and can incorporate one or more substituents including, but
not limited to, poly or
per fluoro substitution.
H is hydrogen, O is oxygen, N is nitrogen, C is carbon, S is sulfur, Cl is
chlorine, Br is
bromine, I is iodine, F is fluorine, R is any cosmetic active, functional
group or benefit agent as
described herein below.
Preferred electron donating substituents for X', X~, X3 are aromatic or
heteroaromatic
derivatives which include the following non-limiting examples:
CA 02519205 2000-O1-07
24
OCH3
OH
l\
s
/\
0
N
I
CH3
plus other related derivatives.
Preferred protected thiol compounds chosen from classes I through XI above
include the
following non-limiting examples:
CA 02519205 2000-O1-07
25
OCH3
C ~ ~ OCH3
OCH3
OH
R S C ~ ~ OH
H
H
R S C ~ ~ N(CH3jl
H ,
CA 02519205 2000-O1-07
26
,_5 1N\
O
R S C
O
H
S
R S C
S
S
T'he present invention also includes organosulfur molecular "hooks" wherein
the potential
cosmetic thiol is bonded directly to an spa carbon atom that is part of a
group capable of
undergoing heterolytic ~-elimination, the reversal of Michael Addition
reactions, to liberate a
thiol. Suitable sp' carbon groups capable of undergoing heterolytic p-
elimination are represented
in the compounds,
H ,
Y
R S CH - ~ Y ~ ~ R S' + H2C
2 Yz
I' (V)
CA 02519205 2000-O1-07
27
H i
Y
R S CH - ~ -Y ~ ---~ R S~ + H2C C/
At
A~ (VI)
wherein Y' and Y'' represent, independently from one another, electron
withdrawing substituents
with a combined Hammett sigma para value more positive than 0.10. Such
electron withdrawing
substituents include the following non-limiting examples: NO~, CN, COOA',
CONA'A',
C(O)A', SO~A', SOZOA', NO, COHal, CONS, CONA'Az, CONA'COA'', C(=NA')NA'A',
C(S)A', NC, SCN, SOZA', SO,A', SOA', SONA'Az, S02NA'A', SNA'AZ, S{NA')A',
z
S(O)(NA')A2, NA'A A3+, SA'A'- and aromatic and heteroaromatic derivatives.
Some non-limiting examples of aromatic and heteroaromatic electron withdrawing
groups
for Y' and Y' include the following:
~\
~N
N
\ /N
N--~
Q+
,
CH3
plus other related derivatives.
CA 02519205 2000-O1-07
Z$
Preferred hook compounds that are capable of undergoing heterolytic ~i-
elimination, the
reversal of Michael Addition reactions. to liberate a thiol include the
following non-limiting
examples:
O
II
R S CH2-CH2-II CH3
O
O
H II
R S CH2--C II
O
O
H II
R S CH2-C C OCH3
C O
OCH3
O
H II
R S CH2-C C NH2
C O
NH2
The present invention also includes cases wherein the cosmetic thiol is
protected by being
bonded directly to an spa carbon atom that is incorporated within a ring
structure. Suitable spa
carbon ring systems are represented by the following,
CA 02519205 2000-O1-07
29
L' Z L1
L' ~~ L'
S
R (vll)
wherein Z is O, NAk; S, (CHz)o_z or
L' L~
L' is A' or pan of a S to 7 membered fused ring system. The above ring
systems) can carry any
substituents. Specific examples of sp' carbon ring compounds covered by the
present invention
include the following non-limiting examples:
/ O \
i I
S
R
CH3
/ N \
S
R
I
S
I
R
CA 02519205 2000-O1-07
S
I
R
S \
S
I
R
and other related derivatives.
A', A2, A', represent, independently from one another, a monovalent group
which can be
the cosmetic active group, R, or H or any of the following: a straight,
branched or mono- or poly-
cyclic aliphatic, mono or polyunsaturated alkyl, aryl, heteroalkyl,
heteroaliphatic or
heteroolefinic system including 1 to 30 carbon atoms together with 0-15
heteroatoms, especially
O, N, S, P, Si, and can incorporate one or more substituents including; but
not limited to, poly or
per fluoro substitution.
H is hydrogen, O is oxygen, N is nitrogen, C is carbon, S is sulfur, Cl is
chlorine, Br is
bromine, I is iodine, F is fluorine, R is any cosmetically active functional
group or benefit agent
as described herein below,
Metal Based Protectin~~ Groups - The molecular "hooks" of the present
invention comprise a
divalent sulfur atom that is bonded on one side to the cosmetic active and on
the other side to an
alkaline earth metal, transition metal or a representative metal in groups
IIA, IIIA, NA, VA,
VIA, VIIA, V1II, IB, IIB, IIIB, 1VB, VB, VIB, and V>TB of the periodic table
of the elements
including Mg, Ca, Sr, Ha, La, Ti, Zr, V, Cr, Mo, W, Mn, Fe, Co, Rh, Ni, Pd,
Pt, Cu, Ag, Au, 2n,
In, Sn, and Bi. Protected ihiol compounds comprising such heavy metal
mercaptides are
represented by the following: ,
R S Met Xr,
or
CA 02519205 2000-O1-07
31
Ilm
R S Met-X"
wherein Met is an alkaline earth metal, transition metal or a representative
metal in groups IIA,
IIlA, IVA, VA, VIA, VI1A, VIII. IB, IIB, IIIB, IVB, VB, VIB, and VIIB of the
periodic table of
the elements including Mg, Ca, Sr, Ba, La, Ti, Zr, V, Cr, Mo, W, Mn, Fe, Co,
Rh, Ni, Pd, Pt, Cu,
Ag, Au, Zn, In, Sn, and Bi. Also, wherein n and rn are zero or integers such
that 1 + 2m + n
equals the valency of Met.
X represents independent electron withdrawing, electron neutral or electron
donating
groups with Hammett sigma para values between -1.0 and +1.5 which can be non-
ionic,
zwitterionic, cationic or anionic comprising for example C-linked groups of
the classes defined
below as A', A'', A3; S-linked groups including SA', SCN, SO~A', S03A', SSA',
SOA',
SONA'A', SO,NA'A'', SNA'A'', S(NA')AZ, S(O)(NA')Az, SA'(NA''); O-linked groups
including
OA', OOA', OCN, ONA'AZ; N-linked groups including NA'A~, NA'A2A'+, NC, NA'OA',
NA'SA2, NCO, NCS, NO~, N=NA', N=NOA', NA'CN, N=C=NA', NA'NA2A',
NA'NA'NA3A°,
NA'N=NA'; other miscellaneous groups including COHaI, CON,, CONA'~, CONA'COA',
C(=NA')NA'A'', CHO, CHS, CN, NC, Hal, and derived groups that connect one or
more of X',
X~, X', X', X' via a ring system. Hal is F, Gl, Br, or I.
A', A', A3, A° represent, independently from one another, a monovalent
group which can
'~e the cosmetic active group, R, or H or any of the following: a straight,
branched or mono- or
poly- cyclic aliphatic, mono or polyunsaturated alkyl, aryl, heteroalkyl,
heteroaliphatic or
heteroolefnic system including 1 to 30 carbon atoms together with 0-15
heteroatoms, especially
O, N, S, P, Si, and can incorporate one or more substituents including, but
not limited to, poly or
per fluoro substitution.
M is a divalent group such as O, S, NA' or CA'A2.
H is hydrogen, O is oxygen, N is nitrogen, C is carbon, S is sulfur, CI is
chlorine, Br is
bromine, I is iodine, F is fluorine, B is boron, A1 is aluminum, Si is
silicon, N is nitrogen, Mg is
magnesium, Ca is calcium, Sr is strontium, Ba is barium, La is lanthanum, Ti
is titanium, Zr is
zirconium, V is vanadium, Cr is chromium, Mo is molybdenum, W is tungsten, Mn
is manganese,
Fe is iron. Co is cobalt, Rh is rhodium, Ni is nickel. Pd is palladium, Pt is
platinum, Cu is copper,
Ag is silver, Au is gold, Zn is zinc, In is indium, Sn is tin, Bi is bismuth,
and R is any cosmetic
active, functional group or benefit agent as described herein below.
CA 02519205 2000-O1-07
32
Also wherein at least one substituent, X, or the cosmetic active, R, contains
salt forming or
water solubilizing groups including, but not limited to, COO', S03', NH~a, OH,
COOA~,
(CH~CH,O)~A', CONA'A'', OS03', OP03H', NA~A''A3', and the like.
Preferred metal based protecting groups of the present invention include, but
are not
limited to, the following examples,
N(CH3)2
R- S- Ti-N(CH3)2
I
N(CH3)2
O
il
R-S- V-S-R
I
S-R
I H2CH3
R-S-Sn-CHZCH3
CH2CH3
OCH2CH2CHZCH3
I
R-S-Ti-OCH2CH2CH2CH3
OCH2CHZCH2CH3
R-S- Ni-S- R
S-R
I
R- S- Mo-S- R
I
S-R , and
OCH2CH2CHZCH3
I
R-S-~-OCHZCHZCH2CH3
OCH2CH2CH2CH3
CA 02519205 2000-O1-07
33
Non-metal and metalloid based Protecting Grou,~s - The molecular "hooks" of
the present
invention comprise a divalent sulfur atom that is bonded on one side to the
cosmetic active and
on the other side to a representative non-metal or metalloid atom including
boron, aluminum,
silicon, germanium, nitrogen, phosphorus, sulfur, selenium, antimony, and
tellurium. Molecular
"hooks" whereby a divalent sulfur atom of a potential cosmetic thiol is bonded
directly to these
representative non-metals and metalloids are represented by the following:
R S E X~
or
Mm
R S E X~
wherein E is a representative non-metal or metalloid element including B, Al,
Si, Ge, N, P, S, Se;
Sb, and Te. Also, wherein n and m are zero or integers such that 1 + Zm + n
equals the valency
of E.
X represents independent electron withdrawing, electron neutral or electron
donating
groups with Hammett sigma para values between -1.0 and +1.5 which can be non-
ionic,
zwitterionic, cationic or anionic comprising for example C-linked groups of
the classes defined
below as A', A~, A3; S-linked groups including SA', SCN, SOzA', S03A', SSA'',
SOA',
SONA'AZ, SO,NA'A2, SNA'A2, S(NA')AZ, S(O)(NA')Az, SA'(NA2); O-linked groups
including
OA', OOA', OCN, ONA'Az; N-linked groups including NA'A2, NA'A'A'+, NC, NA'OAZ,
NA'SA2, NCO, NCS, NOZ, N=NA', N=NOA', NA'CN, N=C=NA', NA'NA~A',
NA'NA~NA'A°,
NA'N=NA'; other miscellaneous groups including COHaI, CONS, CONA'~,
CONA'COA'',
C(=NA')NA'A2, CHO, CHS, CN, NC, Hal, and derived groups that connect one or
more of X',
X~, X', X°, XS via a ring system. Hal is F, Cl, Br, or I.
M is a divalent group such as O, S, NA' or CA'A2.
A', AZ, A3, A° represent, independently from one another, a monovalent
group which can
be the cosmetic active group, R, or H or any of the following: a straight,
branched or mono- or
poly- cyclic aliphatic, mono or polyunsaturated alkyl, aryl, heteroalkyl,
heteroaliphatic or
heteroolefinic system including 1 to 30 carbon atoms together with 0-I S
heteroatoms, especially
O, N, S, P, Si, and can incorporate one or more substituents including, but
not limited to, poly or
per fiuoro substitution.
H is hydrogen, O is oxygen, N is nitrogen, C is carbon, S is sulfur, Cl is
chlorine, Br is
bromine, 1 is iodine, F is fluorine, B is boron, A1 is aluminum, Si is
silicon, Ge is germanium, N
CA 02519205 2000-O1-07
34
is nitrogen, P is phosphorus, Te is tellurium, and R is any cosmetic active,
functional group or
benefit agent as described herein below.
Preferred thiol protective systems utilizing non-metals and metalloids of the
present
invention include, but are not limited to, the following examples,
OCH~CH3
I
R-S-Si-OCH~CH3
OCH2CH3
CH3
R-S-Si-CH3
CH3
O
I I
R-S-S-CH3
O
R-S-B-S-R
I
S- R
O O
11 II
R-S-Ge-O-Ge-S-R~ ~d
S-R
I
R-S-Sb-S-R
I
S-R
Energy-sensitive Protecting Groups - The topical compositions of the present
invention may also
comprise a protected thiol compound wherein the protecting group is energy-
sensitive. Protected
thiol compounds comprising energy-sensitive protecting groups are chemically
stable in solution.
Such potential thiols are protected until a suitable source of energy is
applied to the composition.
Upon application of a 'suitable energy source, the energy-sensitive protecting
groups become
CA 02519205 2000-O1-07
labile, thereby releasing the reactive thiol. Typically, the energy source
will be light. Once the
thiols are released, they are capable of reacting with amino acid residues
present in keratinaceous
substrates to enable durable cosmetic benefits.
As mentioned above, the protected thiols are activated by applying a suitable
energy source
to the composition, i.e., irradiation, which converts the photoactivatable
protected thiol
compounds to fully reactive thiol compounds. The byproducts of the energy
activation of the
protecting group will usually be removed from the substrate by washing.
Many different energy-sensitive groups can be employed for protecting thiols
used in the
topical compositions of the present invention. Typically, the thiol groups are
protected with a
photoactivatable protecting group that is capable of liberating or releasing
the reactive thiol by
irradiation. The properties and uses of photoreactive compounds have been
reviewed. See
McCray et al, 1989, Ann. Rev. Biophys. Chem. 18:239-270, which is incorporated
herein by
reference. The photosensitive groups will preferably be activatable by low
energy ultraviolet or
visible light. Many, although not all, of the energy-sensitive protecting
groups are aromatic
compounds. Suitable photoremovable protecting groups are also described in;
for example,
Patchornik, 1970, J. Am. Chem. Soc. 92:6333, and Amit et al, 1974, J. Org.
Chem. 39:192, which
are incorporated herein by reference. More preferably, the energy-sensitive
protecting group will
be a nitrobenzylic compound, such as o-nitrobenzyl or benzytsulfonyl groups.
Suitable examples
include 6-nitroveratryloxycarbonyl (NVOC); 6-nitropiperonyloxycarbonyl (NPOC);
alpha,
alpha-dimethyldimethoxybenryloxycarbonyl (DDZ), methyl 6-
nitroveratryloxycarbonyl
(MenVOC), methyl-6-nitropiperonyloxycarbonyl (MeNPOC), or I-pyrenylmethyl. The
energy-
sensitive protecting group may also be of the silyl type as described in
Pirrung and Lee, I 993, J.
Org. Chem. 5$:6961-6963 and Pirrung and U.S. Patent Number 5,4$6,633, issued
to Lee, both
incorporated by reference herein. Suitable examples include
(hydroxystyryl)dimethylsilyl
(HSDMS) and (hydroxystyryl)diisopropylsilyl (HSDIS).
Clearly, many energy-sensitive protecting groups are suitable for use in the
present method.
Some examples of acceptable energy-sensitive protecting groups are presented
in Table I, below,
together with their corresponding wavelengths for deprotection.
TABLE 1
Energy-sensitive ProtectingLGroups
Deprotection
Group Wavelength
6-nitroveratryloxycarbonyl (NVOC) LJV (300-350 nm)
CA 02519205 2000-O1-07
36
dimethyldimethoxybenzyloxycarbonyl (DDZ) W (280-300 nm)
nitrobenzyloxycarbonyl (NBOC) IJV (300-350 nm)
5-bromo-7-nitroindolinyl (BNI) UV (420 nm)
O-hydroxy-alpha-methyl-cinnamoyl (HMC) LIV (300-350 nm)
2-oxymethylene anthraquinone (OMA) UV (350 nm)
The composition containing the cosmetic active protected with the energy-
sensitive group
may be activated with energy both prior or during usage. For instance, the
energy source may be
applied to the composition for a sufficient time period to activate the energy
sensitive protecting
group either before, during or after the composition is applied to the
substrate. The energy source
may include various types of electromagnetic radiation including ultraviolet,
visible, near
infrared, infrared, far infrared or microwave. In a preferred embodiment, the
radiation is W,
near IR or visible light.
Examples of suitable protecting groups that are capable of undergoing
photochemical or
thermal thiol deprotection include, but are not limited to, the following:
I. 2-Nitrobenzyl derivatives
o , o,N x'
R-5' X2 h~ R-SH + A''-C ~ ~ X~
X° X3
Examples:
02N
H
R-S-C
I
H and
02N
H
I
R-S-C ~ ~ OCH3
H
OCH3
II. 2-Nitrobenzyloxycarbo~l Derivatives
CA 02519205 2000-O1-07
37
o x' o,N x'
R--S-C-~O_-~ ~ / X~ -- R--SH + p _ ' ,qt-C ~ x2
A'
x, xa X' \x'
Examples:
O~N
O H
R-S-C-O-C
I
H
02N
O H
R-S-C-O-C
OZN
O H
R-S-C-O-C ~ ~ OCH3
I
H
OCH3 , and '
OZN
O H
R-S-C-O-C
02N \ .
III. Benzvloxycarbon~l Derivatives
CA 02519205 2000-O1-07
38
x5 x'
O H
by
2
R-S-C-O-C X R-SH + Side products
A
X° X'
Examples:
O H
II I
R-S-C-O-C
H and
OCH3
O H
II I
R-S-C-O-C
H
OCH3
IV. a a-Dimethvlbenzyloxycarbonyt Derivatives
XS X1 XS XI
O CH3 CHZ
R-S-C-O-C ~ ~ Xz ~ R-SH + COZ + CH3-C ~ ~ Xz
I
CH3
?C4 X3 X° X3
Ex ample:
OCH3
O CH3
R-'S-C-O-C
CH3
OCH3
V, 3-Nitrophcnyloxycarbonyl Derivatives
X' N02
O
R-S-C-O ~ ~ X2 ~ R-SH
X4 X3
Example:
CA 02519205 2000-O1-07
39
NO~
O
R-S-C-O
VI. Phenacyl Derivatives
X~ Xz X~ Xz
A' O A' O
R-S-C-C ~ ~ X3 ~ R-SH + H-C-C ~ ~ X3
I I
H H
X5 X4 XS X~
Examples:
H O
R-S-C-C ~ ~ OCH3
I
H and
H O
R-S-C-C
I
CH3
V.II. tent-Butvloxvcarbonyl Derivatives
CH3 O
I II heat + CO + CH3-C=CH
CH3-C-O-C-S-R --; R-SH z I z
CH3 CH3
X', X2, X3, X4, and XS can be selected from electron withdrawing, electron
neutral, or
electron donating groups with Hammett sigma para values between -1.0 and +I.5
which can be
non-ionic, z;witterionic, cationic or anionic comprising for example C-linked
groups of the classes
defined below as A', A~, A3; S-linked groups including SA', SCN, S02A', S03A',
SSA', SOA',
SONA'AZ, SOZNA'A2, SNA'Az, S(NA')A~, S(O)(NA')Az, SA'(NA~); O-linked groups
including
OA', OOA', OCN, ONA'A2; N-linked groups including NA'AZ, NA'AZA3+, NC, NA'OA',
NA'SA~, NCO, NCS, NOz, N=NA', N=NOA', NA'CN, N=C=NA', NA'NAzA',
NA'NA'NA;A°,
NA'N=NA2; other miscellaneous groups including COHaI, CONS, CONA'~, CONA'COAz,
C(=NA')NA'A2, CHO, CHS, CN, NC, Hal, and derived groups that connect one or
more of X',
X'', X3, X°, XS via a ring system;
A', A'' represent, independently from one another, a monovalent group which
can be the
cosmetic active group, it, or H or any of the following. a straight, branched
or mono- or poly-
CA 02519205 2000-O1-07
cyclic aliphatic, mono or polyunsaturated alkyl, aryl, heteroaikyl,
heteroaliphatic or
heteroolefinic system including 1 to 30 carbon atoms together with 0-15
heteroatoms, especially
O, N, S, P, Si, and can incorporate one or more substituents including, but
not limited to, poly or
per fluoro substitution.
Mono or Mukivalent Cosmetically Active Functional Group
The mono or multivalent cosmetically active functional, R, suitable for
inclusion in the
present invention may be any compound that imparts one or more visual, tactile
or other cosmetic
beneficial effects on proteinaceous materials such as keratin, i.e., hair,
animal fur or wool. Any
cosmetic compound may be included as a functional group in the compositions of
the present
invention as Long as the compound can be modified to contain at least one
divalent sulfur atom
linked to a suitable protecting group as described herein.
Suitable functional groups that can be protected as thiol derivatives include
but are not
limited to antimicrobial compounds, UV-absorbing compounds, skin conditioning
agents, hair
conditioning agents, hair repair agents, hair styling agents, hair dyes, scalp
treatment agents, anti-
inflammatory compounds, antioxidants, dyes and coloring agents, perfumes, oral
care actives,
skin moisturizers, pharmaceutical agents, antidandruff agents, insect
repellents, moisturizers,
humectants, pearlescent and/or opacifying materials, fabric care actives, pet
grooming actives,
fabric anti-wrinkling agents, shrink-resistant actives, laundry care actives,
hard surfaces actives,
textile actives, textile dyes, water-proofing agents, cationic polymers,
cationic surface modifiers,
hydrophobic swface modifiers, anionic surface modifiers, absorbents,
antifungal agents,
insecticidal agents, textile color guards, nail actives such as enamel and
polish, eyelash actives
and mascara, antiperspirant and deodorant actives, anti-acne actives, odor
control actives,
fluorescent actives, bleaching agents, enzymes, antibodies, dispersing aids,
emollients,
stabilizers, anti-static agents, anti-seborrhea agents, optical brighteners,
fluorescent dyes,
softeners, cross-linking agents, photobleaches, bactericides, and mixtures
thereof.
Examples of suitable antinvcrobials which can be protected as thiol
derivatives include but
are not limited to derivatives of phenol, cresol, hydroxybenzoates,
Triclosan~, Tricarban~,
chlorhexidine, metal salts (e.g. zinc citrate, sodium zinc citrate, zinc
pyridinethione, and stannous
pyrophosphate) sanguinarine extract, metronidazole, quaternary ammonium
compounds
(chlorhexidine digluconate, hexetidione, octenidine, alexidine), halogenated
bisphenolic
compounds such as 2,2'-methylenebis-(4-chloro-6-bromophenol), and
salicylanilide.
Examples of suitable UV-absbrbing materials which can be protected as thiol
derivatives
include but are not limited to derivatives of benzoates, oxybenzones, cinnamic
acid, PARSOL
MC?~ esters, benzotriazoles, and benzophenones.
CA 02519205 2000-O1-07
41
Examples of suitable skin conditioners or moisturizers which can be protected
as thiol
derivatives, include but are not limited to derivatives of alpha-hydroxy
acids, polyols, hyaluronic
acid, petrolatum, vegetable oils, esters of fatty acids, and mineral oil. Such
skin conditioners or
moisturizers are bound to the velus hairs present on the skin, and not the
skin directly, to achieve
the long lasting skin benefits.
Examples of suitable anti-inflammatory agents which can be protected as thioi
derivatives
include but are not limited to corticosteroids or salicylates.
Examples of suitable antioxidants which can be protected as thiol derivatives
include but
are not limited to ascorbates and gallates.
Examples of suitable hair conditioners which can be protected as thiol
derivatives include
but are not limited to intact or modified proteins, such as hydrolyzed
keratin, collagen, elastin,
hemoglobin, silk, rice, soy, wheat protein, corn, fibronectin, reticulum,
serum protein, wheat
gluten, peptides and peptide derivatives; amino acids; hydroxylated fats;
glycinates; silicone
polymers, such as siloxane gums and resins, volatile or non-volatile silicone
oils, amino- (or
other) functional silicones, and other silicone-containing polymers;
hydrocarbon based
conditioners including Ce-C3o alkyl, aIkenyl, modified alkyl or modified
alkenyl, branched alkyl
and branched alkenyl groups as well as long chain alkyl groups that are
ethoxylated or substituted
with various non-ionic, cationic or anionic functional groups including quats,
amines, amides,
esters, hydroxyls, carboxylates, and the like; polysaccharides or
monosaccharides, and alkyl
cationic conditioning polymers such as cationic derivatives of guar gum and
cellulose ether
derivatives; poly(ethyleneoxides) and alkyl capped poly{ethyleneoxides) of
molecular weights
ranging from 100 to 10,000,000; and herb or other plant extracts, essential
oils etc.
Examples of suitable hair styling agents which can be protected as thiol
derivatives include
but are not limited to film-forming polymers such as
polyvinylpyrrolidone/vinyl acetate
copolymer; styling copolymers comprising silicone macromonomers, U.S. Patent
Nos. 5,618,524
and 5,658,557, cationic polymers, such as those disclosed in GB-A-2161172
(Beecham); GB-A-
2122214 (Unilever) and GB-A-2050166 (L'Oreal); and hydrocarbon polymers, such
as
polyisobutylene; perfluoro-aliphatic and perfluoro-aromatic compounds.
Examples of suitable dyes and coloring agents which can be protected as thiol
derivatives
include but are not limited to phenol, naphthols, acid dyes, azo derivatives;
vegetable dyes,
metallized dyes, nitrobenzene dyes, quinone-imine dyes, basic dyes, quaternary
dyes, and
oxidation dyes.
Examples of suitable fragrances that can be protected as thioI derivatives
include but are
not limited to phenols such as menthyl salicylate, thymol, and vanillin.
CA 02519205 2000-O1-07
42
Examples of suitable cationic polymers that can be protected as thiol
derivatives include
but are not limited to derivatives of quaternary ammonium salts of
hydroxyethylcellulose,
cationic copolymers of acrylic acid and acrylamide, cationic guar polymers,
copolymers of
vinylimidazolium methochloride and vinylpyrrolidone, polyethylenimines, and
other cationic
polymers and resins known to those skilled in the an.
Examples of suitable oral care active agents that can be protected as thiol
derivatives
include but are not limited to anti-caries agents such as amine fluorides,
monosodium
fluorophosphate, casein; plaque buffers such as urea, calcium lactate, calcium
glycerophosphate;
anti-plaque agents; agents for alleviating sensitive teeth, e.g. potassium and
strontium salts,
particularly those of carboxylic acids; materials that form films and block
pores; oral
pharmaceutical actives, (e.g. ibuprofen, flurbipiofen, aspirin and
indomethacin); biomolecules
such as peptides, antibodies and enzymes; anti-tartar agents; agents for
treating bad breath such
as zinc salts; and anti-calculus agents (e.g. alkali metal pyrophosphates,
hypophosphite-
containing polymers, organic phosphonates, and phosphocitrates).
Examples of suitable pharmaceutical agents that can be protected as thiol
derivatives
include but are not limited to medicinal agents, metabolic agents and other
therapeutic agents of
benefit in treating the human body.
Examples of antidandruff agents that can be protected as thiol derivatives
include but are
not limited to zinc pyridinethione, Octopirox~, climbazole and itroconazole.
An example of odor control actives that can be protected as thiol derivatives
include the
class of cyclodextrins. In addition to trapping odors on the substrate, the
cyclodextrins can
plausibly be utilized to deliver cosmetic actives molecules to the substrate
such as perfumes that
can be liberated slowly.
Other non-limiting classes of benefcial cosmetic actives include sealants,
binders, resins,
adhesives, waxes, drying oils, varnishes, and latex finishes which comprise
urethanes,
polysulfides, acrylics, butyl polymers, maleated oils, cellulosics, starches
etc.
The mono or multivalent cosmetically active functional preferably used in the
present
compositions is dependent on the product form desired. Hair care compositions
preferably use
hair conditioners, hair styling agents, dyes and coloring agents, sunscreens,
fragrances,
antidandruff agents, or mixtures thereof as the functional group. Preferable
functional groups in
textile care compositions include dyes and coloring agents, odor control
actives, sealants,
fragrances, and mixtwes thereof. Cosmetic compositions preferably comprise
dyes and coloring
agents, sealants, resins, varnishes, latex finishes, and mixtures thereof.
Oral care compositions
preferably comprise anti-caries agents, plaque buffers, anti-plaque agents,
agents for alleviating
CA 02519205 2000-O1-07
43
sensitive teeth, materials that form films and block pores, oral
pharmaceutical actives,
biomolecules, anti-tartar agents, agents for treating bad breath, anti-
calculus agents, and mixtures
thereof as functional groups. Pharmaceutical composition preferably select
mono or multivalent
cosmetically active functional groups from the group consisting of medicinal
agents, metabolic
agents, therapeutic agents, anti-inflammatory compounds, and mixtures thereof.
Animal care
composition preferably comprise antimicrobial agents, insect repellents,
grooming actives, and
mixtures thereof as functional groups.
OPTIONAL ACTIVATING MECHANISMS
As explained above, the molecular 'hooks' of the present invention may be
activated via a
number of mechanisms either before, during or after the application of the
topical compositions
containing the protected thiol to the substrate. Various embodiments of the
present invention are
systems which comprise both the topical composition herein with an activating
mechanism.
Such activation could be achieved via hydrolysis by the use of a mechanism to
manipulate
the pH of the environment surrounding the compound. Such pH adjusting
mechanisms may
include acidic or alkaline solutions. Whether acidic or alkaline mechanisms
are required is
dependent on the protecting group used. Hydrolysis may also be achieved via
simply mixing the
compound, delivered in its purified form or from a non-aqueous solution, with
water.
Furthermorc, the molecular 'hook' could be activated by coming in contact with
a suitable
nucleophile. Such nucleophiles include, but are not limited to, nitrogen-
containing functional
groups, for example amines, oxygen-containing functional groups, for example
hydroxyl groups,
phosphorus-containing functional groups, for example phosphines, and sulfur-
containing
functional groups, for example thiol groups and sulfites. For instance, the
solution containing the
'hook' compound could be inter-mixed with a separate solution containing a
nucleophile
including reducing agents such as ammonium thioglycolate or sodium bisulfate,
either before,
during or after application of the compound to the substrate.
Conversely, the 'hook' compound could be activated by nucleophilic groups
present in the
substrate itself as in the case of hair that has been reduced or cold waved,
i.e. hair that has been
treated with a reducing agent either prior to or simultaneous to the
application of the 'hook'
compound. The resulting activated thiol 'hook' could then react directly as a
nucleophile with
keratinaceous disulfides or oxidatively with the nucleophilic groups present
in the substrate, e.g.
with free thiol groups that were formed during cold waving or reduction. Of
course, the latter
process could be accelerated or enhanced via the addition of oxidation
reagents, i.e, peroxide as
in the neutralization step of cold waving of hair.
CA 02519205 2000-O1-07
44
The activation could also be accented via heat or a suitable energy source.
For instance,
the energy source could be applied to the composition for a sufficient time
period to activate the
protecting group either before, during or after the composition is applied to
the substrate. The
energy source may include various types of electromagnetic radiation including
ultraviolet,
visible, near infrared, infrared, far infrared or microwave radiation.
Other various adjuncts that could possibly influence the activation and/or the
performance
of the "hook" compounds of the present invention include, but are not limited
to, (i) Lewis acids
such as zinc acetate, tin chloride, zinc chloride, zinc stearate, titanium
ethoxide, and aluminum
tosylate, metal salts such as zinc sulfate, and magnesium sulfate, (ii)
chelators such as
tetrasodium EDTA, disodium EDTA, (iii) ionic species capable of ion-pairing
including anions,
cations, quats, amphoterics zwitterions etc, (iv) dispersing aids such as
anionic surfactants, non-
ionic surfactants, anionic surfactants, amphoteric surfactants, and
zwitterionic surfactants, (v)
keratin swelling aids such as ammonia, amines, urea, phosphoric acid, acetic
acid and other
swelling aids known to those skilled in the art, and (vi) solvent systems
wherein the individual
solvent molecules are nucleophiles themselves as defined above.
Another embodiment of the present invention comprises a kit comprising the
system
comprising the topical compositions of the present invention and either a pH
manipulating
mechanism or a nucleophile mechanism, and a package comprising a first and
second chamber;
wherein the topical composition is packaged in and delivered out of one
chamber and the
activation mechanism is packaged in and delivered out of the second chamber.
OTHER OPTIONAL INGREDIENTS
The topical composition according to the invention can also typically include
an acceptable
vehicle to act as a dilutant, dispersant, or carrier for the protected thiol
compounds in the
composition, so as to facilitate the distribution of the protected thiol
compounds when the
composition is applied to the keratinaceous substrate, i.e., hair, nails,
wool, skin etc.
Vehicles other than water can include liquid or solid emollients, solvents,
humectants,
thickeners and powders. Examples of each of these types of vehicle, which can
be used singly or
as a mixture of one or more vehicles, are as follows:
Emollients, such as stearyl alcohol, glyceryl monoricinoleate, glyceryl
monostearate, mink
oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate,
isocetyl stearate, oleyl
alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol,
isododecane, isocetyl
alcohol, eicosanyl alcohol, behenyl alcohol, cetyl palmitate, silicone oils
such as
polydimethylsiloxane, cyclomethicone, di-n-butyl sebacate, isopropyl
myristate, isopropyl
palmitate, isopropyl stearate, butyl stearate, dimethyl malonate, polyethylene
glycol, triethylene
CA 02519205 2000-O1-07
glycol, lanolin, cocoa butter, corn oil, cotton seed oil, tallow lard, olive
oil, palm kernel oil.
rapeseed oil, safflower seed oil, evening primrose oil, soybean oil, sunflower
seed oil, avocado
oil, olive oil, sesame seed oil, coconut oil, arachis oil, castor oil,
acetylated lanolin alcohols,
petroleum jelly, mineral oil, butyl myristate, isostearic acid, palmitic acid,
isopropyl Iinoleate,
lauryl lactate, rnyristyl lactate, decyl oleate, myristyl myristate;
Propellants, such as trichlorofluoromethane; dichlorodifluoromethane,
dichlorotetrafluoroethane, monochlorodifluoromethane,
trichlorotrifluoroethane, propane, butane,
isobutane, dimethyl ether, carbon dioxide, nitrous oxide;
Solvents include, but are not limited to, ethyl alcohol, n-propanol, n-
butanol, tent-butanol,
ethylene glycol dimethyl ether, hexane, tetramethylwea, sulfolane, low
molecular weight
polyethylene oxide), glycerol, propylene glycol, 2-butoxyethanol, amyl
alcohol, n-octanoI, n-
decanol, acetone, acetic acid, butyl acetate, methylene chloride, isopropanol,
acetone, ethylene
glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol
monoethyl ether,
dimethyl sulphoxide, dirnethylformamide, tetrahydrofuran;
Powders, such as chalk, talc, fullezs earth, kaolin, starch, gums, colloidal
silica, sodium
polyacrylate, tetraalkyl- and/or trialkyl-arylammonium smectites, chemically
modified
magnesium aluminum silicate, organically modified montmorillonite clay,
aluminum silicate,
fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene
glycol
monostearate.
The cosmetically acceptable vehicle will usually form from 10 to 99.9%,
preferably from
to 99% by weight of the composition and can, in the absence of other cosmetic
adjuncts, form
the balance of the composition.
The topical compositions according to the invention may be provided in any
suitable
physical form, for example as low to moderate viscosity liquids, lotions,
milks, mousses,
dispersions, sprays, gels, foams, aerosols, and creams. These compositions may
be produced by
procedures well known to the skilled artisan. The cosmetic compositions can be
used in various
manners as other known compositions in the art including but not limited to
various rinse-off and
leave-on applications such as hair shampoos, skin cleansers, skin lotions,
hair conditioners,
styling sprays, hair mousses, two-in-one shampoos, fabric softeners, lotions,
nail polishes, hair
serums, hair dyes, hair waving, etc. The contact time between the cosmetic
composition of the
present invention and the substrate varies between 10 seconds and about 1
hour, preferably
between 20 seconds and 30 minutes; more preferably between 30 seconds and 15
minutes.
The cosmetic composition of the present invention can be formulated as a
fluid, lotion,
fluid cream or cream having a viscosity from 500 to 100,000 mPas or above. The
composition
CA 02519205 2000-O1-07
46
can be packaged in a suitable container to suit its viscosity and intended use
by the consumer.
For example, a lotion or fluid cream can be packaged in a bottle or a roll-
ball applicator or a
propellant-driven aerosol device or a container fitted with a pump suitable
for hand or finger
operation. When the composition is a cream, it can simply be stored in a non-
deformable bottle
or squeeze container, such as a tube or a lidded jar.
The topical product or composition of the present invention may include an
activator as
described above. In such a case, the inventive composition must be designed to
prevent pre-
mature activation of the protected thiol compound prior to use. For instance,
the protected thiol
compound and the activator may be placed in separate chambers in a dual
chamber package, or
either of the 'hook' compound or the activator can be placed within shear
sensitive (or other
induced release) capsules which rupture prior or during use. Alternatively,
the protected thiol
compound and the activator can be placed in separate packages to enable pre-
mixing or
sequential application by the consumer. For examples of typical dual chamber
packages see PCT
Application WO 96/02230, by Unilever PLC, published February i, 1996. (Herein
incorporated
by reference.)
Conversely, the cosmetic active of the present invention can be supplied in
the purified
form, i.e., as a powder, crystal, wax, gum or liquid. The purified cosmetic
active could be
intermixed with any of the above suitable carriers either prior to or
simultaneous to the usage by
the consumer. For instance, the purified cosmetic active, could be placed
within a compartment
that is separated from the carrier by a barrier wall. Upon usage, the barrier
wall could be broken,
disrupted or even removed to enable the purified cosmetic active to come in
contact with and
inter-mix with the carrier.
The topical composition of the present invention comprises at least one of the
above
described protected thiol compounds, together with any additional ingredients
which are
normally to be found in cosmetic treatment compositions for use on hair, skin,
or other substrates
such as other fibers, textiles, fabrics, or the like. One or more of the
protected thiol compounds
may be used, the use of two or more being beneficial for example where a
combination of
cosmetic benefits is wanted, each derivable from a different cosmetic agent
species.
While aqueous or aqueous/alcoholic solution based compositions, or possibly
organic-
based compositions, in which one or more protected thiol compounds are
dissolved by solution
are preferred, the compositions if desired or appropriate may comprise stable
emulsions or
dispersions of the one or more functionalized cosmetic agents which are
designed to be water
insoluble. In both of these cases, conventional means for achieving successful
deposition and
activation of the actives) may be required. for instance, an emulsion or a
dispersion could be
CA 02519205 2000-O1-07
47
intermixed with a separate solvent solution via a dual phase package to enable
solubilization and
subsequent activation during usage.
The topical composition according to the invention may include optional
benefit materials
and cosmetic adjuncts, as long as the benefit materials or the adjuncts do not
eliminate or
substantially reduce the performance of the organosulfur functionalized
cosmetic agent. The
additional ingredients may include, for example dyes and coloring agents,
fragrances-, anionic,
cationic, non-ionic, amphoteric or zwitterionic surfactants; buffers, masking
fragrances,
dispersing agents, stabilizers, cationic polymers, perfumes, non-ionic
polymers, anionic
polymers, complex coacervates, complex coacervate capsules, metal salts, Lewis
acids, buffering
agents, particulate thickeners, polymeric thickeners, wax, thickeners, oils,
emollients, .humectants,
moisturizers, dyes, dyes and coloring agents, enzymes, antibodies,
preservatives, viscosity
enhancers, gelling agents, chelators, silicones or other emulsifying agents,
and other common
adjuvants well known to those skilled in the art.
Nonlirniting examples of anionic~lathering surfactants useful in the
compositions of the
present invention are disclosed in McCutcheon's, Detergents and Emulsifiers,
North American
edition ( 1990), published by The Manufacturing Confectioner Publishing Co.;
McCutcheon's,
Functional Materials, North American Edition (1992); and U.S. Patent No.
3,929,678, to
Laughlin et aL, issued December 30, 1975, all of which are incorporated by
refercnce.
A wide variety of anionic surfactants are potentially useful herein.
Nonlimiting examples
of anionic lathering surfactants include those selected from the group
consisting of alkyl and
alkyl ether sulfates, sulfated monoglycerides, suIfonated olefins, alkylaryl
sulfonates, primary or
secondary alkanesulfonates, alkyl sulfosuccinates, acyltaurates,
acylisethionates, alkyl glyceryl
ether sulfonates, sulfonated methyl esters, sulfonated fatty acids, alkyl
phosphates,
acylglutamates, acylsarcosinates, alkyl sulfoacetates, acylated peptides,
alkyl ether carboxylates,
acyllactylates, anionic fluorosurfactants, and mixtures thereof. Mixtures of
anionic surfactants
can be used effectively in the present invention.
Suitable nonionic surfactants include polyoxyalkylene alcohol surfactants,
especially allryl
polyethyleneglycol ethers, alkyl polypropyleneglycol ethers, alkyl
poIyethyleneglycol esters, and
alkyl polypropyleneglycol esters and mixtures thereof.
Suitable amphoteric surfactant components for use in the shampoo composition
herein
include those which are known for use in shampoo compositions or other
personal care cleansing
composition, and which contain a group that is anionic at the pH of the
shampoo composition.
Concentration of such surfactant components in the shampoo composition
preferably ranges from
about 0.5 % to about ZO%, preferably from about 1 % to about 10%, more
preferably from about
CA 02519205 2000-O1-07
48
2% to about 5% by weight of the composition. Examples of amphoteric
surfactants suitable for
use in the shampoo composition herein are described in U.S. Patents 5,104,646
(Bolich Jr. et al.),
U.S. Patent 5,106,609 (Bolich Jr. et al.), which descriptions are incorporated
herein by reference.
Examples of amphoteric detersive surfactants which can be used in the
compositions of the
present invention are those which are broadly described as derivatives of
aliphatic secondary and
tertiary amines in which the aliphatic radical can be straight or branched
chain and wherein one
of the aliphatic substituents contains from about 8 to about 18 carbon atoms
and one contains an
anionic water solubilizing group, e.g., carboxy, sulfonate, sulfate,
phosphate, or phosphonate.
Examples of compounds falling within this definition are sodium 3-
dodecylaminopropionate,
sodium 3-dodecylaminopropanesulfonate, sodium laurylsarcosinate, N-
aIkyltaurines such as the
one prepared by reacting dodecylamine with sodium isethionate according to the
teaching of U.S.
Patent 2,658,072, N-higher alkyl aspartic acids such as those produced
according to the teaching
of U.S. Patent 2,438,091, and the products sold under the trade name
"MIRANOL"~ and
described in U.S. Patent 2,528,378.
Other amphoteric surfactants, sometimes classified as zwitterionic
surfactants, such as
betaines can also be useful in the present invention. Such zwitterionics are
considered as
amphoterics in the present invention where the zwitterionic has an attached
group that is anionic
at the pH of the composition. Examples of betaines useful herein include the
high alkylbetaincs,
such as cocodimethylcarboxymethylbetaine, cocoamidopropylbetaine, cocobetaine,
laurylamidopropylbetaine, oleylbetaine, lauryldimethylcarboxymethylbetaine,
lauryldimethyl-
alpha-carboxyethylbetaine, cetyldimethylcarboxymethylbetaine, lauryl-bis-(2-
hydroxyethyl)carboxymethylbetaine, stearyI-bis-(2-hydroxypropyl)carboxymethyl
betaine,
oleyldimethyl-gamma-carboxypropylbetaine, and lauryl-bis-(2-hydroxypropyl)-
alpha-
carboxyethylbetaine. The sulfobetaines may be represented by cocodimethyl
sulfopropylbetaine,
stearyldimethylsulfopropylbetaine, lauryldimethylsulfoethylbetaine, lauryl-bis-
(2-
hydroxyethyl)sulfopropylbetaine and the like; amidobetaines and
amidosulfobetaines, wherein
the RCON(CH2)3 radical is attached to the nitrogen atom of the betaine are
also useful in this
invention. Most preferred for use herein is cocoamidopropytbetaine.
If desired or as necessary, one or more additional benefit agents may also be
included in
the compositions of the invention, for example to modify the overall cosmetic
benefit or
combination of benefits imparted to the substrate treated with the
composition. Suitable
additional cosmetic benefit agents include the following:
(i) conditioning agents, i.e., materials which impart one or more visual or
tactile benef is such as
softness, smoothness, shine, non-flyaway, anti-static, ease of dry and/or wet
combing, e.g.,
CA 02519205 2000-O1-07
49
cationic surfactants, cationic polymers, volatile and/or non-volatile
silicones or derivatives
thereof, quaternary ammonium salts having at least one long chain alkyl or
alkenyl group, protein
hydrolysates, quaternized protein hydrolysates, perfluoropolyether materials,
fatty alcohols,. and
mixtures thereof;
(ii) sryling/setting/bodying agents, i.e., materials which give enhanced body
and fell to the hair or
other fibers or enable them to hold a given shape or style, e.g., various
polymers, gums and
resins, for example adhesive andlor resinous hydrocarbon materials such as per-
alk(en)ylhydrocarbon materials, silicone/siloxane gums or resins, waxes,
chitosan and
derivatives, salts and complexes thereof, and mixtures thereof;
(iii) fiber straightening agents;
(iv) colourants and dyeing agents;
(v) antidandruff agents, e.g., zinc pyridinethione, Octopirox~, climbazole;
(vi) sun-protective materials, e.g. sunscreens, especially UV absorbers;
(vii) hair growth promoters or regulators, e.g. diacylglycerols,
glucarolactams, glucarolactones,
Minoxidol~;
(viii) moisturizers, e.g. 2-hydroxyalkanoic acids, acid soap and complexes
thereof, and other
emollients, occlusives, humectants;
(ix) pearlescent and/or opacifying materials;
(x) oils, e.g. silicone oils, oleic acid, hydrocarbons, isopropyl myristate,
oleyl alcohol, oleates,
squalene, sunflower seed oil, rapeseed oil, other plant derived oils, mineral
oil;
(xi) proteins, vitamins, nutrients, stimulants, antiradicals, astringents;
(xii) herb or other plant extracts, essential oils etc.
(xiii) antimicrobial agents, e.g. antibacterial or anti-infestive agents;
(xiv) other adjunct materials commonly used in cosmetic compositions, e.g.,
buffeting and/or pH
adjusting agents, perfumes, colorings, preservatives, proteins etc.
(xv) anti-malodor agents as those disclosed to treat post-perm odors in US
5,554,364 and EP
0610892. -
(xvi) highly substantive polymers and other moieties including
polyethylenimines (PEI's) such as
those included within the Polymin~ series supplied by BASF.
(xvii) metal salts comprising alkaline earth metals such as magnesium and
calcium, transition metals
such as zinc, manganese and copper, and the group B1A metals such as Al. The
use of these
metal salts for hair treatment is disclosed in W09609030 and W09703640 where
they are
claimed to form metal-sulfur bonds with the hair for use in hair styling and
resryling. Such metal
salts could conceivably be employed to complex and interact with the cosmetic
active of the
CA 02519205 2000-O1-07
present invention. Such interactions should not interfere too greatly with the
performance of the
cosmetic actives and could potentially positively influence the performance,
i.e., metals could
complex with the sulfur atom within cosmetic active and facilitate or induct
activation in the
form of thiol release.
(xviii) chelating agents including disodium EDTA and tetrasodium EDTA.
Chelators could enhance
the diffusion and adsorption by binding to and removing metals present in hard
water such as
calcium and magnesium. Such hard water ions could conceivably complex with
certain ionized
"hooks" of the present invention electrostaticatly and inhibit their
solubility.
(xix) hydrotropes such as ammonium xylene sulfate. For instance, if the
"hooks" of the present
invention are incorporated within a surfactant matrix, hydrotropes could
improve performance by
freeing up the "hook" compounds during dilution to facilitate improved binding
to the substrate.
(xx) dispersing aids which may encompass, but are not limited to, non-ionic
surfactants, amphoteric
surfactants, and ionic surfactants. If the "hooks" of the present invention
are incorporated within
a non-aqueous matrix of as an insoluble dispersion, dispersing aids could be
utilized to enhance
solubilization and subsequent activation.
(xxi) Ion-pair ingredients. Far certain ionic "hooks" of the present
invention, compounds could be
employed that ion-pair with the "hooks" including, but not linvted to cations,
anions, quaternized
ammonium compounds, arnphotcric compounds, and metals. Such charged species
could be
utilized to manipulate the diffusion, adsorption and the binding of the "hook"
compounds of the
present invention.
(xxii) Drying agents designed to minimize residual levels of water in non-
aqueous solvent, including,
but not limited to molecular sieves.
The pH of the compositions of the present invention is frequently important in
achieving
optimized chen>isotption of the protected thiol compound. The most suitable pH
for a given
composition may depend principally on the type and structure of the protecting
group as it
pertains to activation. For instance, many of the protecting group can be
activated for improved
performance via pH catalyzed hydrolysis. In these cases, the pH of the
composition would need
to be such that the molecular 'hook' is not activated prior to usage. As
descn'bed above, during
usage the pH of the composition containing the molecular 'hook' can be
manipulated, i.e., via
inter-mixing with separate pH activating composition, such that the molecular
'hook' is activated
during or immediately prior to usage.
The protecting groups of the present invention are to be used within a pH
range from about
1 to about 12, preferably from about 3 to about 11, more preferably from about
4 to about I0. In
the cases wherein the protecting group are activated at any of the above pH's,
the composition
CA 02519205 2000-O1-07
51
would need to be non-aqueous and essentially free of water or moisture to such
a degree that
prohibits significant hydrolysis induced activation prior to usage. As such,
the water imparted to
the composition during usage from the shower, bath or from the wetted
substrate could provide
the activation required to optimize the resulting chemisorption.
As mentioned above, it has surprisingly been found that certain protecting
groups are not
activated hydrolytically at pH's within the above ascribed relevant range
while still providing
durable benefits on hair. For these compounds, the pH of the composition is
irrelevant in as
much as the composition pH suits the cosmetically active group, R.
Many of the embodiments of the present invention comprise a silicone
composition
which includes at least one polysiloxane or silicone resin, at least one
linker, and at least one
molecular hook. For example, said silicone composition typically imparts
improved hair care
benefits when added to hair care compositions.
The at least one linker is bound to both a molecular hook and to an atom of a
polysiloxane or silicone resin. Preferably the at least one linker is bound to
a polysiloxane or
silicone resin through a silicon, carbon, oxygen, nitrogen, or sulfur atom,
and most preferably to a
silicon atom. When more than one linker is present, it is also contemplated
that linkers may be
bound to a polysiloxane or silicone resin through more than one type of atom,
for example
through both silicon and carbon atoms.
Therefore, in one embodiment the present invention comprises at least one
polysiloxane
or silicone resin having the formula:
MaM.bDcD,dTeT.fQg
where the subscripts a, c, d, e, f and g are zero or a positive integer,
subject to the
limitation that the sum of the subscripts b, d and f is one or greater; where
M has the formula:
R13Si0~/2,
M ~ has the formula:
(Z-x)R22Si01/2~
D has the formula:
CA 02519205 2000-O1-07
52
R32Si02/~,
D ~ has the formula:
(Z-X)R4Si02/2
T has the formula:
RSSi03/2~
T' has the formula:
(Z-X)Si03/2,
and Q has the formula Si04/2, where each R1, R2, R3, R4, RS is independently
at each occurrence a hydrogen atom, C,_~~ alkyl, C,_Z~ alkoxy, CZ_a, alkenyl,
C~,4 aryl, and C6.,~
alkyl-substituted aryl, and C~2~ aralkyl which groups may be halogenated, for
example,
flourinated to contain fluorocarbons such as C,.r_ fluoroalkyl; Z,
independently at each
occurrence, represents the molecular hook; and X, independently at each
occurrence, represents
the linker. The term "alkyl" as used in various embodiments of the present
invention is intended
to designate both normal alkyl, branched alkyl, aralkyl, and cycloalkyl
radicals. Normal and
branched alkyl radicals are preferably those containing from 1 to about 12
carbon atoms, and
include as illustrative non-limiting examples methyl, ethyl, propyl,
isopropyl, butyl, tertiary-
butyl, pentyl, neopentyl, and hexyl. Cycloalkyl radicals represented are
preferably those
containing from 4 to about 12 ring carbon atoms. Some illustrative non-
limiting examples of
these cycloalkyl radicals include cyclobutyl, cyclopentyl, cyclohexyl,
methylcyclohexyl, and
cycloheptyl. Preferred aralkyl radicals are those containing from 7 to about
14 carbon atoms;
these include, but are not limited to, benzyl, phenylbutyl, phenylpropyl, and
phenylethyl. Aryl
radicals used in the various embodiments of the present invention are
preferably those containing
from 6 to 14 ring carbon atoms. Some illustrative non-limiting examples of
these aryl radicals
include phenyl, biphenyl, and naphthyl. An illustrative non-limiting example
of a halogenated
moiety suitable for R1-5 groups is trifiuoropropyl.
The polysiloxanes or silicone resins of the present invention are typically
prepared by the
CA 02519205 2000-O1-07
53
hydrosilyiation of an organohydrogen silicone having the formula:
MaMHbDcDHdTeTHfQg
where the subscripts a, c, d, e, f and g are zero or a positive integer,
subject to the
limitation that the sum of the subscripts b, d and f is one or greater; where
M has the formula:
R13Si01/Z~
~1~1H has the formula:
R23_hHhSi01/2~
D has the formula:
R32Si02/2~
DH has the formula:
H2_iR4iSi02/2
T has the formula:
RSSi03/2~
TH has the formula:
HSi03/2;
and Q has the formula Si04/2, where each Rl, R2, R3, R4, RS is independently
as defined
above.
1-lydrosilylation is typically accomplished in the presence of a suitable
hydrosilylation
catalyst. The catalyst preferred for use with these compositions are described
in U.S. Pat. Nos.
3,715,334; 3,775,452; and 3,814,730 to Karstedt. Additional background
concerning the art may
CA 02519205 2000-O1-07
54
be found at J. L. Spier, "Homogeneous Catalysis of Hydrosilation by Transition
Metals, in
.4duances in Organomerallic Ghemisrry, volume 17, pages 407 through 447, F. G.
A. Stone and
R. West editors, published by the Academic Press (New York, 1979). Persons
skilled in the art
can easily determine an effective amount of platinum catalyst. Generally, an
effective amount
ranges from about 0.1 to 50 parts per million of the total organopolysiloxane
composition.
The organohydrogen silicone compounds that are the precursors to the compounds
of the
present invention may be prepared by the process disclosed in LJ.S. Pat. No.
5,698,654 herewith
specifically incorporated by reference. The '654 patent discloses a sequential
catalysis of the ring
opening polymerization of cyclic organosiloxanes using a base catalyst that
can be neutralized by
a subsequent redistribution and condensation catalyst such as a Lewis acid
catalyst, preferably a
phosphonitriiic compound, that permits the rapid synthesis of functionalized
and poly-
functionalized silicone copolymers.
It is to be noted that as pure compounds the subscripts describing the
organohydrogen
siloxane precursor and the hydrosilylation adduct of the present invention are
integers as required
by the various nales of chemical stoichiometry. As mixtures of compounds that
are described by
these formulas the subscripts will assume non-integral values, for the
mixtures. The restrictions
on the subscripts heretofore described for the stoichiometric subscripts of
these compounds are
for the pure compounds, not the mixtures.
In specific embodiments of the present invention, the silicone composition
typically
comprises at least one compound of the following formulas, (17, (In, (III,
(X), (Xn, and
Ri R3 Rs
Zt-Xt- O Si- O Si -O Si-XZ- Z2
R2 R4 R6
m n
CA 02519205 2000-O1-07
55
s to x3_Z3 Rt3
j I ~ I
R7- Si- O Si- O Si-O Si R1s
I ~z Rta
R R R
m n
RI6 xs-ZS Rt9
I I
z4-x~ o si- o si -o si-x6- z6
i I I
Rt7 Rts R2o
n
Rz t R23 R2s
I
Z7-x~ ~ si- ~ Si - ~ S1- R26
R22 R24 R27
m n
R28 x9-Z9 R3 t
Zs-Xg O Si- O Si-O Si-R32
R3o R33
R29
m n
CA 02519205 2000-O1-07
56
(xrl)
p \ / 9
where each Rl, R2, R3, R4, R5, R6, R~, R8, R9, RIO, R11~ R12~ R13~ R14~ R15,
R16, R17~ R18
R19, R20, R21, R22, R23, R24, R25. R26, R2~, R28, R29, R30, R31, R32, R33.
R34, R35, and
R36 is independently at each occurrence a hydrogen atom, C,.~z alkyl, C,_»
alkoxy, C~_Z~ alkenyl,
C6.,,, aryl, and C6z, alkyl-substituted aryl, and C~.=, aralkyl which groups
may be halogenated, for
example, flourinated to contain fluorocarbons; 2, independently at each
occurrence, represents a
molecular hook; and X, independently at each occurrence, represents a linker;
wherein "m" in
each formula has a value in a range between about 0 and about 13,000,
preferably about 0 and
about 1000, more preferably between about I and about 250, still more
preferably between about
S and about 1 S0, even more preferably between about 10 and about 100, and
most preferably
between about 20 and about 50; "n" in each formula has a value in a range
between about 0 and
about 13,000, more preferably between about 0 and about 50, more preferably
between about 1
and about 20, still more preferably between about 2 and about 10, and most
preferably between
about 2 and about 5; "m+n" in each formula has a value in a range between
about 1 and about
13,000, preferably between about 3 and about 70, more preferably between about
5 to about 50,
and most preferably between about 15 and about 50; "q" has a value of at least
one and "p+q" has
a value of at least 3, preferably in the range of 3-20, more preferably in the
range of 3-10, and
most preferably in the range of 3-6. The polysiloxane or silicone resin
typically has a molecular
weight ranging from about 100 to about 1.000,000, preferably from about 250 to
about 50,000,
more preferably from about 500 to about 25,000, and most preferably from about
500 to about
7,000. The at least one polysiloxane or silicone resin typically has a
viscosity in a range between
about 20 centipoise and about 2,500,000 centipoise (about 0.02 to about 2500
Pas).
CA 02519205 2000-O1-07
The number of X-Z moieties on a polysiloxane or silicone resin in the
composition is at
least one. In preferred embodiments the average number of X-Z moieties on a
polysiloxane or
silicone resin is between about 1 and about 100, more preferably between about
1 and about ?0,
still more preferably between about 1 and about 6, and most preferably between
about 3 and
about 6.
In one embodiment of the present invention a poiysiloxane- or silicone resin-
containing
composition comprises a preponderance of a specific linear, branched, cross-
linked, or cyclic
polysiloxane or silicone resin. In other embodiments a polysiloxane- or
silicone resin-containing
composition comprises a mixture of polysiloxanes and/or silicone resins which
may include
linear, branched, cross-linked, and cyclic species. Also; suitable
compositions may comprise one
or more polysiloxanes and/or silicone resins which may contain adventitious
amounts of other
species, for example arising during the synthesis .process for said
polysiloxanes and/or silicone
resins, for example at a level of about 0.0001 wt.% to about 5 wt.% based on
total silicon-
containing species. In illustrative examples suitable compositions may contain
adventitious
amounts of D4, or species containing Si-H, Si-OH, and/or Si-O-alkyl bonds.
(~ Y ~ ~ s x
1~
A
The molecular hook may be a heterocyclic pyridinium compound (IV), a
heterocyclic
triazinium (V), or a heterocyclic pyrimidinium compound (Vn
wherein Y represents optional substituents on the heterocyclic ring or ring
system, X represents
the linker, Q-represents a counterion, and A is defined below.
N
~~ N
(V) I ~ S X
+J
N Q_
A
CA 02519205 2000-O1-07
5$
,Y
N
S X
+~
N Q-
A
Optional substituents, Y, which can be present on the heterocyclic ring or
ring system can
be selected from hydrogen or electron withdrawing, electron neutral, or
electron donating groups
with Hammett sigma para values between -1.0 and +1.5 comprising carbon-linked
groups of the
classes defined as A', AZ, A3, and A~'; S-linked groups including SA', SCN,
SO,A', S03A',
SSA', SOA', SOzNA'A~, SNA'A2, S(NA')A', SA'(NA'), SONA'A2; O-linked groups
including
OA', OCN, ONA'A'; N-linked groups including NA'A~, NA'A''A'+, NA'OA', NA'SA~,
NCO,
NCS, NO2, N=NA', N=NOA', NA'CN, N=C=NA', NA'NA''A', NA'NA~NA'A', NA'N=NAB;
other miscellaneous groups including CONA'2, CONA'COA'', C(=NA')NA'A2, CHO,
CHS, CN,
NC, Hal, and derived groups that connect one or more of the optional
substituents via a ring
system; Hal is fluorine, chlorine, bromine, or iodine.
A, A', A2, A', and A4 each represent, independently from one another, a
monovalent
group which can be the cosmetic active group, R, or H or any of the following:
a straight,
branched or mono- or polycyclic aliphatic, mono- or polyunsaturated alkyl,
aryl, heteroalkyl,
heteroaliphatic or heteroolefinic system including 1 to 30 carbon atoms
together with 0 to 15
heteroatoms, especially oxygen (O), nitrogen (I~, sulfur (S), phosphorus (P),
silicon (Si) and can
incorporate one or more substituents including, but not limited to, poly or
perfluoro substitution.
The counterion, Q-, can include halides, borates, phosphates, tosylates,
mesylates, triflates,
and other counterions known to those skilled in the art.
The linker comprises a C~-Cso alkyl, aryl, or alkylaryl group, or C,-Csa
heteroaryl group
containing one or more heteroatoms, and is optionally functionalized. Optional
functionalization
on the linker includes ketones, alkoxys, esters, amides, trifluoromethyl,
halogens, nitrites and
other polar functional groups known to those skilled in the art. The linker is
typically derived
from a linker precursor which comprises a linker bound to a Leaving group (L).
Illustrative
leaving groups include halides such as chloride, bromide and iodide; tosylate,
mesylate,
phosphate; cyclic leaving groups (that is, those in which the Leaving group
remains bound in the
linker) such as epoxy or other cyclic leaving group containing at least one
heteroatom; and other
CA 02519205 2000-O1-07
59
leaving groups known to those skilled in the art. Preferred leaving groups are
bromide and
iodide, with iodide being particularly preferred.
In synthesis, the leaving group is replaced by a molecular hook, so that the
linker becomes
bound to a molecular hook. In one embodiment the at least one linker precursor
may be combined
with the at least molecular hook before combining with a polysiloxane or
silicone resin. In a
particularly preferred embodiment the at least one linker precursor may be
combined with a
polysiloxane or silicone resin before combining with the at least molecular
hook.
Typically, the linker precursor has the formula (VII)
(VII) -D-Ar(Y)" - CHZ-L
Wherein D comprises a group bound to a polysiloxane or a silicone resin; "Ar"
is an aromatic or
heteroaromatic goup, optionally substituted with one or more substituents; "Y"
is a substituent;
"L" is as defined above; and "n" has a value between zero and the number of
free valence sites on
the aromatic or heteroaromatic ring. Non-limiting examples of suitable
aromatic and
heteroaromatic groups in linkers include phenyl, biphenyl, toluyl, naphthyl,
pyridyl, quinolyl,
triazinyl, pyrimidyl, pyridazinyl, furyl, furoyl, and thienyl. Illustrative
examples of substituents
(Y) which may be bound to~ said aromatic or heteroaromatic group include C,_~z
straight chain,
branched. cycloaliphatic, or aralkyl; C~.,4 aryl; fluoro, chloro, bromo, iodo,
vitro, nitroso, nitrile,
trifluoromethyl, trifluoropropyl, alkyloxycarbonyl, alkylcarbonyl, alkylamido,
alkyl ether, aryl
ether, and similar electron-withdrawing, electron-donating, and electron-
neutral groups. The "D"
group may comprise a straight chain, branched, cycloaliphatic, or aralkyl
group which optionally
may contain a functional group, said functional group being bound to D in a
pendent position or
separating D from the aromatic or heteroaromatic group, or separating D from a
polysiloxane or a
silicone resin, or in more than one of these positions. Illustrative examples
of D groups include
C,_~2 alkyl and preferably Cz_3 alkyl. Dlustrative examples of functional
groups which may be
present with D include carbonyl, alkylcarbonyl, oxycarbonyl, alkyloxycarbonyl,
nitrile, amido,
alkylamido, trifluoromethyl, and halogen, such as chloro, bromo, andlor
fluoro. Preferred
examples of linkers are shown in formulas (VIII) and (IX)
CA 02519205 2000-O1-07
CHI Z
(~)
) CHZ Z
Silicone-containing compositions comprising at least one polysiloxane or
silicone resin, at
least one linker, and at least one molecular hook typically impart cosmetic
and other benefits in
applications such as hair care (for example durable hair care benefit),
textile care, cosmetics, oral
care, and animal care.
In order that those skilled in the art will be better able to practice the
invention, the
following examples are given by way of illustration and not by way of
limitation.
CHARACTERISTICS
T'he protected thiol compounds of the present invention, when applied to a
amino acid
based substrate, have improved uptake levels and reduced levels of fade or
removal. That is the
thiol functional groups demonstrate improved attachment of the functional
group, R, to the amino
acid based substrate and longer lasting attachment than alternative reactive
technologies. These
benefits are demonstrated without requiring addition steps of reducing or
oxidizing the substrate
which typically are required in the art to achieve dwable cosmetic benefits.
Reduction as defined herein comprises chemical compositions and treatments
that induce
the nucleophilic cleavage of disulfide bonds in keratin substrates resulting
in the formation of
free thiol groups in the form of cysteinyl amino acid residues. Reduction is
employed in several
commercial products and processes including the permanent-waving of human
hair, human hair
straightening, human hair depilation, and in the dyeing of wool with fiber
reactive dyes. Several
compounds and processes known io induce keratin reduction include (i) low
molecular weight
thiols such as thioglycolic acid, thiolactic acid, cysteine, thioglycerol,
thioglycolic hydra2ide,
thioglycolamide, and glycerol monothioglycolate, (ii) sulfides such as salts
of hydrogen sulf de,
CA 02519205 2000-O1-07
61
(iii) high temperature and alkali wherein the keratin is heated to around
100°C or above by a
heating source or steam and wherein the keratin can be contacted with an
alkaline solution, (iv)
cyanide such as the salts of hydrogen cyanide, (v) phosphines such as
trihydroxymethyl
phosphine or its precursor, tetrahydroxymethyl phosphonium chloride, (vi)
other miscellaneous
reducing agents such as borohydride, dithionite, hydrosulfite, and sulfoxylate
and (vii)
combinations thereof. Reduction as defined herein generally refers to the
above processes and
compositions which reduce greater than 10% of the disulfide bonds in the
keratinaceous
substrate. The relative quantities of reduced versus unreduced keratin fiber
depend on the type of
reducing agent, its concentration (or degree of application.in the case of
heat), the solution-to-hair
ratio, pH of the reaction medium, time of reaction, fiber diameter, and the
condition of the hair.
A more detailed discussion on disulfide reduction can be found in the article
by Gershon et al.
(Gershon, S. D.; Goldberg, M. A.; Rieger, M. In Cosmetics Science and
Technology, Sagarin. E.
eds., pp. 583-627. Interscience, New York (1963)).
Oxidation as defined herein comprises chemical compositions and treatments
that induce
the oxidative cleavage of disulfide bonds in keratin substrates resulting in
the formation of
sulfonic acid groups in the form of cysteic acid amino acid residues.
Oxidation is employed in
several commercial products and processes including the bleaching of human
hair, permanent
dyeing of human hair with oxidation dyes, and in the dyeing of wool with fiber
reactive dyes.
Hydrogen peroxide is the principle oxidizing agent used in most oxidizing
compositions and is
delivered liberally to the substrate as a 3 to 12% solution which may be
alkaline. Persulfates, in
the form of their sodium potassium and ammonium salts, may also be used to be
mixed with the
hydrogen peroxide just before use. Other ingredients that may be additionally
included in the
composition include sodium percarbonate, sodium perborate, magnesium
perborate, magnesium
dioxide and barium binoxide. Oxidation as defined herein generally refers to
the above processes
and compositions which degrade greater than 10% of the disulfide bonds in the
keratinaceous
substrate. A more detailed discussion on disulfide oxidation can be found in
the articles by Zahn
and Bobbins (Z.ahn, H. J. Soc. Cosmet. Chem. 17:687 ( 1966); Bobbins, C.;
Kelly, C. J. Soc.
Cosmet. Chem. 20:555 (1969)).
Both reduction and oxidation of anuno acid based substrates lead to
irreparable damage
to the substrate by virtue of their destructive chemical reactions. For
instance, both reduction and
oxidation result in disulfide bond cleavage which has been shown to
significantly reduce the wet
tensile properties of human hair through 30% extension (Clarence Bobbins book:
Chemical and
Physical Behaviour of Human Hair). Also, reduced hair has been shown to be
less rigid in the
wet state than unreduced hair (Bogaty, H. J. Soc. Cosmet. Chem. 18:575 (1967))
and the wet
CA 02519205 2000-O1-07
62
bending stiffness and wet stretching stiffness were demonstrated to decrease
on oxidized hair
(Robbins Book). Furthermore, reduced hair has been shown to exhibit increased
frictional
resistance (Schwartz, A.; Knowles, D. J. Soc. Cosmet. Chem. 14:455 (1963))
which is evidence
of imparted damage to the hair. These demonstrated destructive chemical
interactions with
keratin have been shown to translate into keratin that is drier, more brittle
to the touch, more
porous, weaker and which tangles more easily (The Science of Hair Care, by
Charles Zviak).
PROCESSES FOR PREPARING THE PROTECTED THIOL COMPOUNDS
The compounds of the invention can be prepared by any of ~a number of
procedures known
to those skilled in the art. Several nonlimiting examples are described herein
below.
HETEROCYCLIC PROTECTING GROUPS
Alkylthio substituted pyridines can be prepared by reaction of halopyridines
with a variety
of thiols in the foam of metal salts [Takahashi, Saikachi, Akai, J. Pharm.
Soc. Japan, 1943, 63,
153; Adams, Ferreti, J. Am. Chem. Soc., 1959, 81, 4927]. Another method of
preparation
involves alkylation of pyridinethiols [Marckwald, Klemm, Trabert, Ber., I900,
H33, 1156;
Forrest, Walker, J. Chem. Soc., 1948, 1939].
Alkylthio substituted pyrinlidines can be prepared by alkylation of
mercaptopyrimidines
[Southon, Pfeiderer, Chem. Ber., 1978, 111, 982; A. G. Geigy, Chem. Abstr.,
1969, 70, 68418] or
directly from halogenopyrimidines [Semga, Ichiba, Kanazawa, Nishigaki, J.
Xeterocyclic. Chem.,
1982, 30, 610].
Alkylthio substituted pyrazines can be prepared from halogenopyrazines and
appropriate
sodium (or potassium) alkyl thiolate at elevated temperatures [Konakahara, Y.
Takagi, Bull.
Chem. Soc. Japan, 1960, 80, 349]. The alternative method is alkylation of
mercaptopyrazines [A.
Albert, G.B. Barlin, J. Chem. Soc., 1962, 3129].
Alkylthio substituted pyridazines can be prepared by treatment of
halopyridazines with a
thiol in the form bf its alkali salt or with a thiol in the presence of base
[Druey, K. Meier, K.
Eichenberger, Helv. Chim. Acta, 1954, 37, 121; M. Fujisaka, Y. Neno, H.
Shinobara, E. Imoto,
Bull. Chem. Soc. Japan, 1964, 37, 1107; T. Horie, K. Kinjo, T. Ueda, Chem.
Pharm. Bull., 1962,
10, 580]. Alkylation of pyridazinethiones and pyridazinethiols as well as some
other
methodologies are also published. [M. Tisler and B. Stanovnik "Pvridazines and
their Benzo
Derivatives", in "Comprehensive Heterocyclic Chemistry", 1984, Pergamon Press,
Ltd.; M.
Tisler and B. Stanovnik "Su~r Compounds of Pyridazines", in "The Chemistry of
Heterocyclic
Compounds", 1973, John Wiley&Sons, Inc.]
CA 02519205 2000-O1-07
63.
For the alkylthiol substituted triazines and tetrazines, a comprehensive
review on the
synthesis of these compounds is found in the literature. [M. Tisler and B.
Stanovnik, J.Het.
Chem., 1971, 785: Reissert and Grube, Chem. Ber., 42, 1909, 3720; Gompper and
Schoenafinger,
Chem. Ber., 112. 1979, 1529; Amdt, Eistert, Chem. Ber., 60, 2602, 1927;
Grundmann et al, J.
Org. Chem., 23, 1958, 1522; Cristescu, Panaitescu, Pharmazie, 17, 1962, 209;
H. Neunhoeffer,
H. Hammann, Ter. Lett., 24, 1983, 1767; J. L. Johnson, B. Whimey, L.M. Leslie,
J .Het. Chern.,
I7, 1980, 501; S. C. Fields, M. H. Parker, W. R. Erickson, J. Org. Chern.,
1994, 8284.]
The six membered O, N, and/or S containing heterocyclics with C=O, C=S or C=C
exocyclic groups can be prepared from halogen derivatives of corresponding
heterocycles and
thiols. [Tominaga, A. Ushirogochi, Y. Matsuda, J. Het.. Chem., 24, 1987, 1557;
Y. Tominaga, et
al, Chem Pharm, Bull., 32, 3384, 1981; L. Adelfang, J. Org. Chem., 31, 2389,
1966; L. W. Singh,
H. Junjappa, Synthesis, 5, 531, 1985; W. D. Rudorf, R. Schawrz, Tet. Lett., 28
4267, 1987; B.
Deb, H. Ila, et al, Synthesis, 10, 893, 1987.)
Alkylthio substituted pyridinium derivatives can be prepared by quatemization
of the
corresponding pyridine alkyl thioethers and other methods. [Yamada, et al, J.
Org. Chem., 42,
2180, 1977; M. Yamada, et aI, J. Chem. Soc., Chem. Comm., 179, 1979; T.
Sakakibara, Y.
Watabe, M. Yamada, R. Sudoh, Bull. Chem. Soc. Jpn, 61, 247, 1988.]
Alkylthio substituted xanthenes can be prepared from thiols and xanthene with
a suitable
leaving group [K. J. Divakar, C.B. Reese, et. al., J. Chem. Soc., Perkin
Trans. l, 1990 (6), 1753]
Alkylthio substituted pyrimidinium derivatives can be prepared by
quaternization of the
corresponding pyrimidine alkylthioethers and other methods. [Deichmeister,
Platoshkiin, Khim.
Geterosicl. Soedin., 1, 1961, 333; Hrown, England, J. Chem. Soc. C, 1971,
2507; Ueda, Ohtsuka,
Chem. Pharm. Bull., 21, 1973, 1451.)
Alkylthio substituted pyrazinium derivatives can be prepared by quaternization
of the
corresponding pyrimidine alkyl thioethers and other methods. [Harlin, Benbow,
J. Chem. Soc.,
Perkin Trans. l, 1975, 1385; Honz, et al, Tetrahedron, 26, 1970, 2305; B.
Geutsen et al,
Tetrahedron, 1989, 6519; S. Batori, A. Messmer, J. Het. Chem., 1990, 1673.)
Alkylthio substituted fwans can be prepared from the corresponding furan
thiols and alkyl
halides. [Gorzynski, D. Rewicki, Liebigs Ann. Chem., 1986, 625; P.G. McDougal,
Y-I Oh, Tet.
Lett., 27, 139, 1986; R. Tanikaga, et al, J. Chem. Soc., Chem. Com., 1106,
1981; H. Gotthatdt,
C.M. Weisshuhn, K. Dorhofer, Chem. Ber., 111, 3336, 1978; R. Adams, A.
Ferretti, J. Am. Chem.
Soc., 81, 4927, 1959; A. Ferretti, G. Tesi, Chem Ind., p. 1987, 1964; L. M.
Yagupolskii, N.V.
Kondratenko, V.P. Sambur, Synthesis, 721, 1975; B.L. Feringa, et al,
Synthesis, 316, 1988; S.P.
Tanis, D.H. Head, Tet. Lett., 25, 4451, 1984.]
CA 02519205 2000-O1-07
G4
Alkylthio substituted pyrroles can be prepared by S-alkylation of 2- and 3-
pyn:oIethiols
under standard base-catalyzed conditions. [K. Olsen, H.R. Snyder, ,I. Org.
Chem., 30, 184, I965;
S. Apparao; H. Ila, H. Junjappa, Synthesis, 65, 1981; M. Cardellini et al,
Synthesis, 1980, 886; A.
K. Gupta, H. Ila, et al, Synthesis, 141, 1989; S. Gronowitz, R. Kada, J. Het.
Chem.; 1041, 1984;
M. Colonna, M. Polni, Gazz. Chim. Ital., 116, 449, 1986; H. Kojima, H. moue,
eL al, Chem. Lett.,
1499, 1989; Y. Tonninaga, et al, J. Het. Chem., 26, 477, 1989.]
Alkylthio substituted thiophenes can be prepared by reacting the alkali salts
of thiophene
thiols with aliphatic halogen compounds. [Thomas, G. Singly H. Ila, H.
Junjappa, Tet. Lett., 30,
3093, 1989; W.-D. Rudorf, A. Schierhom, M. Augustin, J. Prakt. Chem., 321,
1021, 1979; J.
Cymerman-Craig, J. W. Loder, Org. Synth. 667, 1963; J. Cymetman-Craig, J. W.
Loder, J. Chem.
Soc., 237, 1954; E.J. Smutny, J. Am. Chem. Soc., 91, 208, 1969.]
Alkylthio substituted pyrazoles, the 3- and 5- derivatives, can be prepared by
the alkylation
of the corresponding pyrazolethiones (Michaelis, Lachwitz, Chem. Ber., 1910,
43, 2106;
Michaelis, Ann., 1908, 283].
Alkylthio substituted isoxazoles can be prepared by alkylating the thio group
at the 3
position of isoxazoles [A.Thuiller and J.ViaIle, Bull.Soc. Chim. Fr., 1959,
1398; W. D.
Rudrorf and M. Augustin, J. Prakt. Chem., 1978, 320, 585; : K. Tomita, S.
Sugai and
M.Saito, Chem. Pharm. Bull., 1979, 27, 2415; S. Sugai and K. Tomita, Chem.
Pharm.
Bull., 1980, 28, 552J.
Alkylthio substituted isothiazoles can be prepared by alkylating both 3- and S-
mercaptoisothiazoles (K. R. H. Wooldridge, Adv. Heterocycl. Chem., 1972, 14,
1; B.
Torretta, G. Ronsisvalle, E. Bousquet, F. Guerrera and M. A. Siracusa, Gazz.
Chim. Ital.,
1980, 133; : K. Gewald, W. Radke and U. Hain, J. Prakt. Chem., 1980, 322, 1021
].
Alkylthio substituted triazoles can be prepared from the corresponding
thiotriazoles by S-
alkylation with various alkyl bromides [M.A. Weaver, R.R. Giles, Ger. Pat.,
1970, 1,919,045; J.
Heindl, E. Schroeder, H.W. Kelm, Eur. J. Med Chem. - Chim. Ther., 1975, 10,
121.].
Alkylthio substituted 1,2,4-oxadiazoles can be prepared from the corresponding
halogen
oxadiazoles and thiols. (M. Paton, D.G. Hamilton, Tet. Lett., 24, 5141, 1983;
D.J. Greig, et al, J.
Chem. Soc., Perkin Trans., 607, 1987; Sumitorno Chem Ind KK, Japan Patent,
1005072 (J6-
1005072), 86-05143, 1986.)
Alkylthio substituted 1,2,4-thiadiazoles can be prepared via dipotassium
cyanodithioiminocabonate followed by alkylation (W. A. Thaler and J. R.
McDivitt, J. Org.
CA 02519205 2000-O1-07
Chem., 1971, 36, 10; : Badische Anilin and Soda-Fabrik A.-G., Br. Pat. 1
116198 (1968),
CChem. Abstr., 1968, 69, 86995)].
Alkyithio substituted pyrazolium derivatives can be prepared by reaction of
the
corresponding alkylthiopyrazoles with alkyl halides. [Michaelis, Justus Lieb.
Ann. Chem., 331,
1904, 230; v. Auwers, Bergmann, Justus Lieb. Ann. Chem., 472, 1929, 310;
Michaelis, Justus
Lieb. Ann. Chem., 361, 1908, 270; K. Hartke, X.-P. Popp, Arch. Fharm, 1994,
385.]
AIkylthio substituted triazolium derivatives can be prepared from halogen
derivatives of
the corresponding triazoles and lithium thiolates [M. Begmup, Bull. Soc. Chim.
Belg., 1988, 573].
Alkylthio substituted azepines can be obtained from the corresponding halogen
derivatives
[W. Steglich, H. Hauek, B.M. Grosse, R. Leschke, T. Josten, J. Klein, J.
Heterocycl. Chem.,
1990, 107].
Alkylthio substituted thiepinium derivatives can be prepared from the
corresponding
thiepins and an aikylation agent [H. Hofmann, A. Molnar, Tetrahedron Lett.,
1977, 1985; H.
Hofmann, A. Molnar, C. Gottfent, Liebigs Ann. Chem., 1983, 425; H. Hofmann, H.
Fisher, M.
De Vries, Z. Naturforsch, Teil B, 1990, 1573].
Synthesis routes for heterocyclic protected thiol compounds are exemplified by
the
following non-limiting examples:
EXAMPLE 1
Pvrimidinium, 2-113-1i[L4~f2-hvdroxv=1-naphthalenyl)-
azolnhenyllsulfonvllaminol
propvl)thiol-1-methyl-, bromide
OH
_ H
W N ~ ~ S/N
o \\ ~I
Bf
3~4-Acetamidophenylsulfonamido)pr~yl bromide
To a stirred solution of N-acetylsulfanilyl chloride (S?.15 g, 0.244 mol) in
acetone (S00
mL) and H20 (187.5 mL) at 0°C was added 3-bromopropylamine hydrobromide
(25.0 g, 0.114
mol). When a clear solution was obtained, a solution of sodium
hydrogencarbonate (44.15 g,
0.526 mol) in H20 (550 mL) was added dropwise, maintaining the internal
temperature at 0-5°C.
When the addition was completed, the reaction mixture was heated at
50°C for 5 h, then cooled to
room temperature and poured into ice Hi0 with stirring. After stirring at
5°C for 4 h, the
CA 02519205 2000-O1-07
66
suspension was filtered and the filter cake was washed with HBO and dried in
vacuo to give 34.6
g (90%). An additional reaction was performed to give an additional 63.7 g of
similar material.
3-(4-Aminophenylsulfonamid~propyl bromide
A mixture of 3-(4-acetamidophenylsulfonamido)propyl bromide (34.5 g, 0.103
mol),
conc. HCl (43 mL) and EtOH (86 mL) was heated at reflex for O.S h, and the
suspension was
poured into a solution of Ha0 (200 mL) and EtOH (I50 mL). The suspension was
neutralized
with 30% NaHC03 (aq) to pH 7-8, then filtered. The filter cake was washed with
H=O and dried
in vacuo to give 27.2 g (90%). An additional reaction was performed to give an
additional 48.8 g
of similar material.
2-I-Iydroxynaphthalene, 1-[4-[[([3-(bromopropyl)]aminol-sulfonyllphen~rl]az~,~-
A solution of 3-(4-aminophenylsulfonamido)propyl bromide (25.0 g, 0:085 mol)
in H,O
(300 mL) and conc. HCl (35.5 mL, 0.426 mol) was cooled to 5-10°C then a
solution of sodium
nitrite (6.70 g, 0.094 rnol) in H20 (54 mL) was added portionwise, maintaining
the internal
temperature below 10°C. When the addition was completed, the solution
was stirred for 5 min at
5-10°C, and then the solution was added in three portions (maintaining
the internal temperature
below 10°C) to a solution of 2-naphthol (12.3 g, 0.085 mol) and sodium
hydroxide (22.2 g, 0.554
mol) in HBO (150 mL). Additional sodium hydroxide was added during the
addition of the
diazonium salt to maintain the pH above pH 7. When the addition was completed,
the red-orange
suspension was stirred at 5-10°C for 10 min then allowed to stand at
room temperature for 20 h.
The suspension was acidified with conc. HCl (45 mL) (pH <S), stirred for 2 h
and filtered. The
filter cake was triturated with HBO (4 x 500 mL), then filtered and dried in
vacuo at 60°C to give
37.1 g (97%).
I H)-Pvrimidinethione. 1-metl~l-.
To a stirred mixture of 1-methyl-2-thiourea (76.6 g, 0.85 mol) and
malonaldehyde
bis(dimethyl acetal) (126.8 g, 0.77 mol) in EtOH (1.5 L) was added lOM HCl
(76.6 mL, 0.77
moI) in one portion. The resulting mixture was stirred at 25°C for 18
h, then spin-evaporated in
vacuo. The residue was dissolved in HBO (1.25 L). The solution was made
alkaline by the
portionwise addition of KZCO3 and extracted with CH~Cl2 (4 x 500 mL). The
combined extracts
were dried over MgS04 and spin-evaporated in vacuo to a solid. The crude
product was
recrystallized from EtOH (600 rnL) then dried to constant weight in vacuo at
room temperature to
give 22.9 g (23%) of product; mp 186-I88°C (uncorrected). An additional
reaction was
performed to give a total of 40.7 g.
Py_rimidinium, 2-(f3-([L-j(2-hydroxy-1-naphthaleny~azoj-
phenyl)sulfonY]amino~probytl
thiol-1-methyl-, bromide
CA 02519205 2000-O1-07
67
A solution of 2-hydroxynaphthalene, 1-[4-[[[[3-(bromo-
propyl)]amino]sutfonyl)phenyl]azo]- y(22.4 g, 0.05 mol) and 2(1H)-
pyrimidinethione, 1-methyl-
(6.30 g, 0.0~ mol) in N.N-dimethylformamide (100 mL) was heated at 80°C
for 4 h. The reaction
mixture was cooled to room temperature and diluted with Et~O (400 mL) to give
a gummy red
suspension. The solvent was decanted, and the residue was dissolved in
MeOH:acetone (I:1, 300
mL). The solution was concentrated to dryness to a foam. The foam was
triturated with acetone
(2.5 L) for 5 h at room temperature. The resulting suspension was filtered and
the filter cake was
washed with acetone and dried in vacuo at 45°C to constant weight to
give I6.1 g (56%) of solid;
mp (uncorrected) 169-172°C. The proton NMR spectrum was consistent with
the proposed
structure.
Elemental analysis: C H N S Br
Calc. 50.44 4.21 12.19 11.16 13.91
Obs. 50.27 4.47 12.02 11.13 13.97
EXAMPLE 2
Pyrimidinium, 1-methyl-2-[2-[[[[5-(dimethvlamino)-1-
naphthalenyllsulfonyllaminol
ethv)lthiol-, bromide
S N
HN
O S O ~,N ~/
Bi
Pyrimidine. 1,2-dihydro-1-meth 1-Y 2-thio-
To a stirred mixture of I-methyl-2-thiourea (76.6 g, 0.850 mol) and
malonaldehyde
bis(dimethyl acetal) (126.8 g, 0.7722 mol) in EtOH (1.5 L) was added lOM HCl
(76.6 mL, 0.766
mol) in one portion. The resulting mixture was stirred at 25°C for 18
h, then spin-evaporated in
vacuo. The residue was dissolved in Hz0 (1.5 L). The solution was made
alkaline by the
portionwise addition of K~C03 (60 g), then extracted with CHzCh (3 x 1.0 L).
The combined
extracts were dried over MgS04 (20 g) and spin-evaporated in vacuo to give
100.6 g (103.3%) of
crude product as a solid. This was combined with 24.5 g of previously obtained
material and
N(CH3)2
CA 02519205 2000-O1-07
68
dissolved in refluxing EtOH (900 mL). The solution was stored at 3°C
for 18 h, The resulting
precipitate was collected by filtration and dried to constant weight in vacuo
to give 30.0 g (24.0%
recovery) of purified product.
Pyrimidinium, 1-methyl-2-[2-[[![[-~-(dimethvlaminol-1-
nanhthalenyllsulfonyllamino],ethyll thio]-.
bromide
A stirred mixture of the preceding intermediate (10.0 g, 79.3 mmol) and
naphthalenesulfonamide, 5-(dirnethylamino)-N-(2-bromoethyl)- (28.3 g, 79.3
mmol) in 1-
propanol (150 rnL,) was heated at reflex for 2 h. The mixture was spin-
evaporated in vacuo to a
solid residue. The residue was triturated with acetone (200 mL), then
collected by filtration and
dried to constant weight in vacuo at 25°C to give 32.0 g (83.6%) of the
target compound, mp 196-
198°C (d) (uncorrected). Proton NMR and 1R spectra were consistent with
the proposed structure.
Elemental analysis: C H N S Br
Calc. 47.20 4.79 11.59 13.27 16.53
0bs. 47.25 4.73 11.60 13.19 i 6.68
EXAMPLE 3
Pvridinium, 1-methyl-5-(trifluoromethyl]i-2-12-(I[(5-(dimethvlamino)-1-
naphthalenyll
sulfonvl amin~ethyll-thiol-; bromide
S
I
O=S O / N
+ CF3
BT
N(CH3)z
N-Methyl-5-tri fluoromethYlpyridone
A stirred mixture of 5-(trifluoromethyl)-2-pyridinol (34.8 g, 0.213 nunol),
potassium
carbonate (IOI g, 0.730 mol) and iodomethane (48.7 mL, 0.783 mol) in dry
acetone (750 mL) in a
sealed bottle was heated at 59°C for 7 h then cooled to ambient
temperature. The reaction
mixture was filtered and concentrated to dryness to give a yellow solid. The
crude product was
purified by column chromatography (1 kg silica gel) eluted with hexanes:EtOAc
(1:1) to give a
CA 02519205 2000-O1-07
69
white solid. The solid was dried in vacuo at room temperature for 2 h to give
34.3 g (90% yield).
Additional reactions were performed fo give a total of 86.9 g of similar
product.
2~ 1 H)-Pyridinethione, 1-methyl-5-(trifluoromethyl)-
A stirred mixture of the preceding intermediate (34.3 g, 0.194 mol) and
Lawesson's
Reagent (39.2 g, 0.097 mol) in dry toluene (195 mL) was heated at reflux for
10 min, then the
toluene was removed by evaporation. The residue was distilled in vacuo
(Kugelrohr apparatus)
at 120-140°C/3 mrn Hg to give pure product as a yellow solid (36.2 g,
96%). Additional reactions
were performed to give a total of 89.9 g of similar material.
Pvridinium, 1-methyl-5-(trifluoromethvl)-2 j2-1~[5-(dimethylamino)-1-
naphthalenvll
sulfony>aminojethyl)-thio]-, bromide.
A stirred mixture of the preceding intermediate (46.7 g, 0.242 mol) and
naphthalenylsulfonamide, 5-(dimethylamino)-N-(2-bromoethyl)- (86.3 g, 0.242
mol) in dry 1-
propanol (270 mL) was refluxed for 4.5 h. The reaction mixture was
concentrated to give the
crude product as a yellow foam. This foam was dissolved in acetone (450 mL)
and slowly added
to a stirring solution of hexanes:isopropyl ether (2:1, 12 L) to give a yellow
precipitate. The
precipitate was collected by filtration, washed with hexanes (500 mL) and
dried in vacuo at 40°C.
This solid was reprecipitated twice more in a similar fashion to give 92.4 g
(69%) of pure target.
An additional reaction was performed to give a total of 119.9 g of the target
compound; m.p. 125-
129 degrees C (uncorrected). Proton NMR and 1R spectra were consistent with
the proposed
structure.
Elemental analysis: C H N S Br
Calc. 45.82 4.21 7.63 11.65 14.52
Calc.* 45.87 4.61 7.23 11.03 13.75
Obs. 45.91 4.62 7.01 10.78 14.15
*Calc. for CZ,H23BrF3N302Sz ~0.1 i-PrZO ~0.2 acetone ~0.5 Hz0
EXAMPLE 4
Pvrimidinium, 2-((3,3,4,4,5,5,6,6,7,7,8,8L9 9,10,10,10-
heptadecafluorodecyl)thiol-1-methyl-,
iodide
CA 02519205 2000-O1-07
N
CF3(CFz)7CH2CHZ N
I-
2~lITl-Pyrimidinethione, 1-methyl
To a stirred mixture of I-methyl-2-thiourea (76.6 g, 0.85 mol) and
malonaldehyde
bis(dimethyl acetal) (126.8 g, 0.77 mol) in EtOH (1.5 L) was added lOM HCI
(76.6 mL, 0.77
rnol) in one portion. The resulting mixture was stirred at 25°C for 18
h, then spin-evaporated in
vacuo. The residue was dissolved in H2-O (1.25 L). The solution was made
alkaline by the
portionwise addition of KZC03 and extracted with CHZCIz (4 x 500 mL). The
combined extracts
were dried over MgS04 and spin-evaporated in vacuo to a solid. The crude
product was
recrystallized from EtOH (600 mL) then dried to constant weight in vacuo at
room temperature to
give 22.9 g (23%) of product; mp 186-188°C (uncorrected). An additional
reaction was
performed to give a total of 40.7 g.
Pyrimidinium, 253,3,4.4.5.5,6,6,7,7,8,8,9.9,10,10.10-
heptadecafluorodecyl)thio]-1-methyl-,
iodide
A solution of the preceding intermediate (22.9 g, 0.181 mol) and 1-iodo-
1H,IH,2H,2H-
perfiuorodecane (100.5 g, 0.175 mol) in acetone (1.2 L) was heated at reflux
for 20 h, cooled to
15°C and filtered. The filter cake was washed with hexanes (500 mL) and
dried in vacuo at room
temperature to give 48.6 g (40% yield); mp 196-196.5°C (uncorrected). A
second reaction was
performed to give 11.1 g(38°./° yield); mp 206-206.5°C
(uncorrected). The proton NMR spectrum
was consistent with the proposed structure.
Elemental analysis: C H N S
Calc. 25.73 1.44 4.00 4.58
Obs. 25.68 1.47 4.05 4.56
EXAMPLE 5
Benzothiaaolium. Z-((2-1((5-(dimethvlamino)-1-naphthalenvll-sulfonvllaminol
ethvllthiol-3-
methvl-, bromide
CA 02519205 2000-O1-07
71
N(CH3)2
+ Bi
N
S
HN
S ,.
O S O
Naphthalenesulfonamide, 5-(dimethviamino~N-i;,2-bromo-ethvl)-
A suspension of 5-dimethylaminonaphthalene-I-sulfonyl chloride (52.5 g, 0.194
mol) and
2-bromoethylamine hydro-bromide (42.3 g, 0.206 rrol) in THF (550 mL) was
cooled to 2°C. A
solution of triethylamine (40.3 g, 0.398 mol) in THF (230 mL) was added
dropwise over a 2 h
period while maintaining the internal temperature below 6°C. After
complete addition the .
mixture was stirred at ambient temperature for 72 h. Tire mixture was
clarified then concentrated
to an orange oil which was chromatographed over silica (2.2 kg) packed and
eluted with hexanes-
EtOAc (3:1 ). Fractions (500 mL) containing the purified product were
combined, clarified then
concentrated to a damp solid. This material was triturated in hexanes (250
mL), collected on a
filter, washed with hexanes (50 mL) then dried to constant weight in vacuo at
room temperature
to give 61.7 g (89% yield) of product as off white crystalline solid.
Benzothiazolium. 2-j[2-[f f 5-(dimethylamino)-1-
naphthalenyl]sulfonyl~amino]gthyl]thio]-3-
meth~-, bromide
A solution of naphthalenylsulfonamide, 5-(dirnethyl-amino)-N-(2-bromoeihyl)-
(15.0 g,
42.0 mmol) and 3-methyl-benzothiazole-2-thione (1I.0 g, 60.7 mrnol) in acetone
(25 mL) was
heated at reflux for 4 days (Note I). After cooling to 5°C, the mixture
was diluted with Et20 (150
mL) and suction filtered. The filter cake was washed with Et20 (200 mL) and
sucked dry to give
the crude product. The crude product was dissolved in a mixture of CH2Ch (140
mL) and
MeOH (30 mL) then diluted with EtOAc:hexanes (1:2, 750 mL). The suspension was
suction
filtered and the filter cake was washed with Et20 (200 mL), then dried in
vacuo at room
temperature for 4 h to give the target compound (9.0 g, 40%) as a yellow
solid: An additional
CA 02519205 2000-O1-07
72
N(CH3)2
reaction was performed to give a total of 22.9 g of target compound,
mp(uncorrected) 156-159°C.
Proton NwIR and IR spectra were consistent with the proposed structure.
Elemental analysis: C H N S Br
Calc. 49.06 4.49 7.80 17.86 14.84
Obs. 49.01 4.33 7.69 17.68 t 5.02
EXAMPLE 6
1H Imidazolium. 1,3-dimethyl-2-12-1f f(5-(dimethvlaminoLnaehthalenvllsulfonvll
aminolethvllthiol-. iodide
+ Br
N
S
HN I
N
O S O
i
Naphthalenesulfonamide, 5-(dimethylamino~-N~2-bromo-ethvl)-
A suspension of 5-dimethylaminonaphthalene-I-sulfonyl chloride (50.0 g, 0.185
mol) and
2-bromoethylamine hydro-bromide (40.4 g, 0.197 mol) in THF (500 mL.) was
cooled to 2°C. A
solution of triethylamine (38.5 g, 0.380 mol) in THF (250 mL) was added
dropwise over a 2 h
period while maintaining the internal temperature below 6°C. After
complete addition the
mixture was stirred at ambient temperature for 17 h. The mixture was
clarified, and the filter
cake rinsed with THF to remove all of the product. The combined filtrates were
concentrated to
an orange oil which was chromatographed over silica (2.2 kg) packed and eluted
with hexanes-
EtOAc (3:1 ). Fractions (500 mL) containing the purified product were
combined, clarif ed, then
concentrated to a damp solid. This material was triturated in hexanes (250
mL), collected on a
filter, washed with hexanes (50 mL) then dried to constant weight in vacuo at
40°C to give 56.9 g
(86.1% yield) of product as an off white crystalline solid.
CA 02519205 2000-O1-07
73
1H Imidazole, 1-methyl-2-j2-[[[[5-(dimethvlaminol-1-
naphthalenvllsulfonyl]aminolethyll thiol-
A suspension of sodium hydride (2.1 g of 60%, 52 mmol) in DMF (25 tnL) was
cooled to
10°C. A solution of 2-mercapto-1-methylimidazole (6.0 g, 52 mmol) in
DMF (50 mL) was added
dropwise over a 30 min period while maintaining the internal temperature below
15°C. After
complete addition, the reaction mixture was stirred at ambient temperature for
I.S h. A solution
of the preceding intermediate (I8.7 g, 52.3 mmol) in DMF (75 mL) was added in
one portion and
the resulting solution was stirred at 50°C for 1.5 h then cooled to
ambient temperature. The
reaction solution was poured over cold H20 (3 L) then extracted with CHiCI= (1
x 1 L and 1 x
S00 mL). The combined extracts were washed with HBO (750 mL) and saturated
brine (750
mL), dried over Na=SO4, clarified, then concentrated in vacuo to a green oil.
This material was
combined with similar material from a smaller reaction and passed through a
pad of silica (750 g)
packed with EtOAc-hexanes (1:1) then eluted with I:1, 6 L; 2:1, 3 L; 3:1, 4 L
and finally EtOAc,
3 L. Fractions containing the purified product were combined, clarified then
concentrated to a
green glass which was triturated in THF (50 mL). The resulting solid was dried
to constant
weight in vacuo to give 23.6 g (93% yield) of material as a light green solid.
1H Imidazolium. 1,3-dimethvl-2 j2-j[[j5-(dimethylarninol-1
naphthalenyljsulfonyl)amino~
eth 1 thiol-, iodide
A solution of the preceding intermediate (23.6 g, 60.4 mmol), DMF (51 mL) and
iodomethane (3.76 mL, 60.4 mmol) was stirred in a flask sealed with a rubber
septum for 18 h at
ambient temperature. The reaction solution was diluted with EtZO {1.5 L) and
vigorously stirred
for 30 min. The resulting solid was collected on a filter, washed with Et20 (2
x 50 mL) then
dried in situ. This material was dissolved in CHzCIZ (300 mL) and MeOH (15
mL), clarified,
diluted with EtOAc (300 mL), theft concentrated to a thick slunry. The
resulting solid was
collected on a filter, washed with EtOAc (2 x 75 mL), then dried to constant
weight in vacuo to
give 27.0 g (7I % yield) of product, mp(uncorrected) 184-186 degrees C. Proton
NMR and 1R
spectra were consistent with the proposed structure.
Elemental analysis: C H N S
Calc. 42.86 4.73 10.52 12.04
Obs. 42.89 4.73 10.54 12.20
EXAMPLE 7
Pvrimidinium,_1-methyl-2-f j8-[(3;4,5-trihydroxvbenzovl~oxyloctvllthiol-,
bromide
CA 02519205 2000-O1-07
74
N
O
HO C (CH2)8-S N ;. Br
8-Bromooctyl Qallate
A suspension of gallic acid (23.5 g, 0.138 mol), 8-bromo-1-octanol (90.0 g,
0.430 moI), and
conc. sulfuric acid (3.0 mL) was stirred and heated at 120-130°C for
0.5 h, then cooled to 100°C
and stirred at 100°C for 1 h. Cooled to room temperature, diluted with
EtOAc (300 mL), and
washed with H20 (2 x 200 mL) and brine (200 mL). The organic layer was 'dried
(MgSO,),
filtered, and concentrated to give the crude product (111 g). The crude
material was purified by
column chromatography (2.2 kg silica gel eluted with EtOAc:hexanes (2:3)) to
give 33.3 g (67%)
as a white pasty solid.
2( 1 H)-Pyrimidinethione. l -methyl-
To a stirred mixture of 1-methyl-2-thiourea (76.6 g, 0.85 mol) and
malonaldehyde
bis(dimethyl acetal) (126.8 g, 0.77 mol) in EtOH (1.5 L) was added lOM HCl
(76.6 mL, 0.77
mol) in one portion. The resulting mixture was stirred at 25°C for 18
h, then spin-evaporated in
vacuo. The residue was dissolved in H20 (1.25 L). The solution was made
alkaline by the
portionwise addition of KZC03 and extracted with CHZC12 (4 x 500 rftL). The
combined extracts
were dried over MgSOq and spin-evaporated in vacuo to a solid. The crude
product was
recrystallized from EtOH (600 mL) then dried to constant weight in vacuo at
room temperature to
give 22.9 g (23%) of product; mp 186-188°C (uncorrected). An additional
reaction was
performed to give a total of 40.7 g.
Pyrimidinium. 1-methyl-2-f[8 I(3,4,5-trihydrox by enzoyl -oxyloct3rl]this-.
bromide
To a solution of 8-brornooctyl gallate (33.3 g, 0.092 mol) in I-propanol (1?0
mL) was
added the above intermediate (11.7 g, 0.093 mol), and the resulting suspension
was heated at
reflux (97°C) for 1.5 h (a solution was obtained at 90°C). The
hot solution was cooled to 20°C to
give a suspension. The suspensian was diluted with EtOAc (1.0 L) and suction
filtered. The filter
cake was washed with EtOAc (400 mL) and air dried. The crude product (42.4 g
of yellow solid)
was triturated in acetone (3.0 L) at room temperature for 20 h. The suspension
was suction
filtered; the filter cake was washed with acetone (50 mL) and dried to
constant weight in vacuo at
CA 02519205 2000-O1-07
35°C to give 25.4 g (57%) as a light yellow solid; mp 141-143°C
(dec) (uncorrected). The proton
NMR spectrum was consistent with the proposed structure.
Elemental analysis: C H N S Br
Calc. 49.28 5.58 5.75 6.58 16.39
Obs. 49.21 5.53 5.79 6.50 16.32
EXAhIPLE 8
Pvrimidinium, 1-methv!-2-113-1(3.4,5-trihvdroxvbenzovll-oxyluropvllthiol-,
bromide
N
0
HO C (CH2~-S N + Br
HO
3-Bromoprogy~al late
A suspension of gallic acid (40.0 g, 0.235 mol), 3-bromo-1-propanol (100 g,
0.719 mo1),
and conc. sulfuric acid (3.0 mL) was stirred and heated at 115-120°C
until a solution was
obtained (10-20 min), then cooled to 100°C and ,stirred at 100°C
for .3 h. Cooled to room
temperature, diluted with EtOAc {500 mL), and washed with H20 (250 mL), 20%
NaHC03 (2 x
250 mL), and brine (250 mL). The organic layer was dried (MgS04), filtered,
and concentrated
to give the crude product (137 g). The crude material was purified by column
chromatography
(2.2 kg silica gel eluted with EtOAc:hexanes (1:1)) to give 65.1 g (95%)as a
cream-colored pasty
solid.
2( l I~-Pyrimidinethione. 1-methvl-
To a stirred mixture of 1-methyl-2-thiourea (573.8 g, 6.365 mol) and
malonaldehyde
bis(dimethylacetal) (949.6 g, 5.783 mol) in EtOH (11.3 L) was added IOM HCl
(575 mL, 5.75
mol) in one portion. The resulting mixture was stirred at 25°C for 18 h
then concentrated in
vacuo. The residue was dissolved in HzO (11.1 L) and the solution was made
alkaline by
portionwise addition of KzC03 (448 g). The alkaline solution was extracted
with CH~CIz (3 x
7.2 L) and the combined extracts were dried (MgS04), filtered, and
concentrated to give the
crude product. The crude product was dissolved in refluxing EtOH (4.0 L) and
stored at 3°C for
18 h. The resulting precipitate was collected by suction filtration and dried
to constant weight in
vacuo at 40°C to give 94.1 g (12.9%) as a yellow solid.
CA 02519205 2000-O1-07
Pvrimidinium 1-methyl-2-[[3-[(3,4.5-trihydroxybenzovl)-oxv]propvl]thio~-,
bromide
To a solution of 3-bromopropyl gallate (54.9 g, 0.19 mol) in 1-propanol (350
mL) was
added the preceding intermediate (23.8 g, 0.19 mol), and the resulting
suspension was heated at
reflux (97°C) for 0.5 h (a solution was obtained at 90°C, then
after a few minutes at reflux a
precipitate began to fall out of solution). The hot suspension was suction
filtered, and the filter
cake was washed with 1-propanol (4 x 75 mL) and dried to constant weight in
vacuo at 35°C to
give 33.5 g (42%) as a light yellow solid; mp 223-225°C (dec)
(uncorrected). The proton NMR
spectrum was consistent with the proposed structure.
Elemental analysis: C H N S Br
Galc. 43.18 4.11 6.71 7.68 19.15
Obs. 42.91 4.14 6.68 7.63 19.15
EXAMPLE 9
Pvridinium,~l-methyl-2-[(hexadecvl)thiol-, bromide
S S W
a. ~ ~ ;- CH3p \ / p~ ~p ~ ~ OCH3 --s
O ~S~S N S
GH3 CH3
1
b. ~ + Br(CHZ)ISCI-I3 --
N+ S-(CH2)tsCH3
Br CH3
MethvI-2-thio~vridone (I)
A stirred mixtwe of 1-methyl-2-pyridone (20.0 g, 183 mmol) and Lawesson's
Reagent
(37.0 g, 91.5 mmol) in dry toluene (100 mL) was heated at reflux for 15 min.
then the toluene
was removed by evaporation in vacuo at 60°C. The residue was distilled
in vacuo to give crude
product; bp, 175-177°C (13 torr). This yellow liquid was dissolved in
MeOH (15 mL), and the
solution was cooled to 0°C with stirring. The precipitated solid was
collected by filtration, rinsed
with hexanes (2 x 40 mL) and dried to constant weight in vacuo to give 14.0 g
(61%) of material
suitable for further transformation. One additional reaction was performed to
furnish another
27.7 g lot of similarly pure intermediate.
Pyridinium 1-methyl-2-((hexadecyhlthio~-. bromide (2)
A stirred mixture of the preceding intermediate (11.1 g, 88.7 mmol) and 1-
bromohexadecane (27.1 g, 88.8 numol) in 1-PrOH (I00 mL) was heated at reflux
for 3.5 h then
CA 02519205 2000-O1-07
77
clarified by filtration and stored at 3°C for 18 h. The resulting
crystalline precipitate was
collected by filtration, rinsed with EtOH (3 x 15 mL.) followed by Bt~O (2 x
~0 mL), then dried to
constant weight in vacuo at 60°C to give 31.I g (81%) of purified
product. One additional
reaction was performed to give another 66.7 g lot of purified material. The
two lots were
thoroughly blended to give a total of 97.8 g of product as a white solid;
mp(uncorrected) I I 1-I 14
degrees C. Proton NMR and IR spectra were consistent with the proposed
structure.
Elemental analysis: C H N S Br
Calc. 61.37 9.37 3.25 7.45 18.56
Obs. 61.46 9.32 3.23 7.40 18.65
EXAMPLE 10
1N Imidazolium. 1:3-dimethvl-Z-(hexadecvlthiol-. iodide
Reaction sequence:
CH3
CH3(CH2)tsBr N CH3I N+ I _
~~-S(CHZ)~sCH3 -~ C ~~'-S(CHZ)lsCH3
CH3 CH3 CH3
To a stirred solution of 2-mercapto-1-methylimidazole (36.3 g, 318 mmol) in
dry DMF
(250 ml ) was added NaH (I2.7 g, 60% in mineral oil, 318 mmol) in portions
over 0.5 h. The
resulting solution was stirred for an additional 1 h, then hexadecyl bromide
(IOOg, 97%, 3I8
mmol) was added in one portion. The reaction mixture was heated for 1 h with
stirring at 50°C,
then cooled and added to stirred ice-H~0 (I.S L). The resulting biphasic
mixture was extracted
with hexanes (2 x 500 mL). The combined hexane extracts were dried over Na~S04
(25 g), then
clarified and treated, in one portion, with Md (IOOg, 705 mmol). The stirred
mixture was heated
at reflex for 1.0 h then cooled to room temperature. The precipitated solid
was collected by
filtration and dissolved in CHCl3 (1.0 L). The resulting solution was
clarified, diluted with
hexanes ( 1.0 L) then concentrated in vacuo at 40°C to a volume of
approximately 1.0 L. The
resulting precipitate was collected by filtration and dried to constant weight
in vacuo at 40°C to
give 80.9 g (53%) of purified product; mp, 124-126°C (corrected).
Elemental analysis: C H N S I
Calc. 52.49 8.60 5.83 6.67 26.41
Obs. ~ 52.63 8.60 5.75 6.59 26.28
CA 02519205 2000-O1-07
7g
Spy CARBON PROTECTING GROUPS
The sp'' protected thiol compounds of the present invention can be prepared by
any of a
number of procedures known to those skilled in the art.
For example, the thiocarboxylic acid derivatives can be prepared by reacting
acyl chlorides
with HAS or alkylthiols. The carbamothioic acid derivatives can be prepared
via hydrolysis of
thiocyanates. The dithiocarboxylic acid derivatives can be prepared by
treating carboxylic acids
with P4S~o and a primary alcohol. The carbonodithioic acid derivatives can be
prepared by the
addition of alcohols to carbon disulfide in the presence of base to form a
salt of the acid and by
imparting an alkyl halide to the reaction mixture to form the ester. The
carbatnodithioic acid
derivatives can be prepared by the addition of primary or secondary amines to
carbon disulfide.
The following non-limiting examples illustrate exemplary methods of preparing
a few
compounds of the invention.
EXAMPLE 11
1-Naphthalenesulfonamide, 5-(dimethvlamino)-N-12-11(2-
(ethoxv)thioxomethvllthioi ethvll-
S S
HN
O
Naphthalenesulfonamide, S-(dimethylamino)-N-(2-bromoethyl)
A suspension of 5-dimethylaminonaphthalene-1-sulfonyl chloride (50:0 g, 0.185
mol) and
2-bromoethylamine hydro-bronvde (40.4 g, 0.197 moI) in THF (500 mL) was cooled
to 2°C. A
solution of triethylamine (38.5 g, 0.380 mol) in THF (250 mL) was added
dropwise over a 2 h
period while maintaining the internal temperature below a6°C. After
complete addition the
mixture was stirred at ambient temperature for I7 h. The mixture was clarified
then concentrated
to an orange oil which was chromatographed over silica (2.2 kg) packed and
eluted with hexanes-
EtOAc (3:1). Fractions (500 mL) containing the purified product were combined,
clarifed, then
concentrated to a damp solid. This material was triturated in hexanes (250
mL), collected on a
CA 02519205 2000-O1-07
79
filter, washed with hexanes (50 mL) then dried to constant weight in vacuo at
40°C to give 56.9 g
(86. I % yield) of product as a off white crystalline solid.
I -Naphthalenesulfonamide. 5-(dimethylamino~ N-j2-jj(ethoxy)-
thioxomethyllthiolethyll-
A mixture of the preceding intermediate (43.3 g, 12 i mmol) and O-ethylxanthic
acid,
potassium salt (19.7 g, 123 mmol) in anhydrous acetone (430 mL) was heated at
reflux for 18 h.
The mixture was cooled to ambient temperature, clarified, and the filtrate was
concentrated in
vacuo to an oil. This material was chromatographed over silica gel (1 kg)
packed and eluted with
hexanes-EtOAc (3:1 ). Fractions containing the purified product were combined,
clarified, then
concentrated to a thick slurry which was diluted with hexanes (200 mL). The
resulting solid was
collected on a filter, rinsed with hexanes (2 x 75 mL), then dried to constant
weight in vacuo to
give 19.1 g of product. The mixed fractions from this column were combined,
concentrated, then
rechromatographed over silica gel (2.0 kg) packed and eluted with hexanes-
EtOAc (3:1).
Fractions containing the purified product were combined, clarified, then
concentrated in vacuo to
a thick oil. This was dissolved in CH2Clz (50 mL), diluted with hexanes (200
mL), then cold
evaporated to a thick slurry. The resulting solid was collected on a filter,
washed with hexanes
( l 00 mL), then dried to constant weight in vacuo to give 18.9 g of product.
A second crop of
material was obtained by cold evaporating the two combined filtrates to give
0.5 g of product
(total yield 38.5 g, 82%), mp(uncorrected) 85-86 degrees C. Proton NMR and IR
spectra were
consistent with the proposed structure.
Elemental analysis: C H N S
Calc. 51.23 5.5C 7.03 24.13
Obs. 51.19 5.56 6.99 24.14
E?LAMPLE 12
S-hexadecyl ethanethioate
Reaction sequence:
O O
li II
CH3CCl + HS(CH2)tsCH3 --~--~ CH~CS(CHZ)tsCH3
A mixture of acetyl chloride (1.0 L, l.l. kg, 14 mol) and 1-hexadecanethiol
(95%, 168 g,
0.62 mol) was stirred at reflex for 3 h, then volatile components were removed
by evaporation in
vacuo (60°C, S ton). The residue was recrystallized from warm
(35°C) hexanes (500 mL) by
cooling at 4°C for 18 h., The weight in vacuo to give 174.5 g (94%) of
purified product; mp, 29-
31 °C (corrected).
CA 02519205 2000-O1-07
Elemental analysis: C H S
Calc. 71.93 12.07 10.67;
Found 72.17 12.12 10.$4.
The NMR (500 MHz) and IR agreed with the proposed structure.
EXAMPLE 13
S (4-Aminobutvi) hexadecanethioate hydrochloride
Reaction sequence:
O O
S
a. / ~ N(CH2)4Br CH3CHZOCS2- K+ ----s / I N(CH~qSCOCH2CH3
\ \
1 O
b, 1 HZNNHZ * H2O ~ HCl * H2N(CHz)4SH
2
O O
II I!
c. 2_ + CH3(CH2)~4CCI ~-~~ CH3(CH2)14CS(CH2)aNH2 * HCl
3
a. (4-Phthalimidobuyl)xanthic acid. O-ethyl ester (1)
A mixture of N-(4-bromobutyl)phthalimide (138 g, 489 mmol) and O-ethylxanthic
acid,
potassium salt (97.7 g, 609 mmol) in DMF (400 mL) was stirred for 1 h then
blended into stirred
ice-Hz0 (2 kg). The precipitated solid was collected by filtration, air-dried
and doubly
recrystallized from boiling EtOH (2 x 700 mL). The recovered solid was dried
to constant weight
in vacuo at 50°C to give 114.8 g (73%) of material suitable for further
transformation.
b. 4-Amino-1-butanethiol hydrochloride (2)
To a solution of (~ (105.8 g, 327.4 mmol) in CH3CN (400 mL.) was added HzNNHi
* HBO
(47.6 mL, 49.2 g, 980 mmol). The mixture was stirred for 0.5 h at 60°C
then evaporated in vacuo
at 40°C to a solid residue. This material was dissolved in Hz0 (450 mL)
and the pH of the
solution was adjusted to 2-3 with concentrated HCI. The resulting suspension
was stored for 1.0
h at 0°C, then the precipitate was removed by filtration. Additional
concentrated HCl (200 mL)
was added to the filtrate and the yellow solution was heated at reflux for 6.0
h, during which time
the evolution of COS gradually slowed to a stop. The resulting solution was
evaporated in vacuo
CA 02519205 2000-O1-07
$1
at 60°C to a semi-solid residue. This residue was dried by azeotropic
distillation with toluene (3
x 100 mL) and then extracted into CH~CIa (900 mL). Evaporation of the
clarified CHzC1= extract
yielded 31.4 g (68%) of the hydrochloride salt as a very pale yellow semi-
solid suitable for
further transformation.
c. S (4-Aminob~l) hexadecanethioate hydrochloride (3)
A solution of (Ii) (31.4 g, 222 mmol) and palmitoyl chloride (60.9 g, 222
mmol) in dry
CH3CN (400 mL) was stirred at 70°C for 2.0 h and then at 10°C
for 1.0 h. The precipitated solid
was collected by filtration and air-dried. This material was recrystallized
from boiling EtOH
(400 mL,) to give a white crystalline solid which was collected by filtration,
washed with Et~O (3
x 100 mL) and dried to constant weight in vacuo at 60°C to give 52.0 g
(62%) of purified
product; mp, 138-141°C (corrected).
Elemental analysis: C H CI N S
Calc. 63.20 II.14, 9.33 3.69 8.44;
Found 63.32 11.16 9.22 3.71 8.37.
The NMR (500 MHz) and lR agreed with the proposed structure.
EyCAMPLE 14
:VlethanaminiumsN-methyl-N-(1-(hexadecvlthio)ethvlidenei-, bromide
S N(CH3)2+ Bi
II il
CH3CN(CH3)Z + CH3(CH2)iSBr ----~ CH3(CH2)tsS-C-CH3
1
To a stirring solution of N,N-dimethylthioacetamide (33.8 g, 0.33 mol) in
acetonitrile (300
mL) was added 97% 1-bromohexadecane ( 103.1 g, 0.33 mol) and tetrahydrofuran
(200 mL), to
give a complete solution . The mixture was heated at reflux for 72 h. After
cooling to 10°C, the
suspension was suction filtered, and the filter cake was washed with Et20 (500
mL). The white
solid was dried in vacuo at room temperature for 6 h to give 68.2 g (51%) of
target compound as
a white solid; mp 80-92°C (uncorrected). Proton NMR and IR spectra were
consistent with the
proposed structure.
Elemental analysis: C H N S Br
Calc. 58.80 10.36 3.43 7.85 19.56
Obs. 58.56 10.43 3.41 7.76 19.60
spa Carbon Protecting Groups
CA 02519205 2000-O1-07
g2
The compounds of the invention can be prepared by any of a number of
procedures known
to those skilled in the art.
For example, the thioether compounds can be prepared by the treatment of a
suitable alkyl
halide with a thiol. The thioacetal and dithioacetal compounds can be prepared
by 'the treatment
of suitable aldehydes and ketones with a thiol. The compounds capable of
undergoing heterolytic
(3-elimination can be prepared via nucleophiIic addition of a thiol onto a
suitable activated olefin
in a Michael-type addition reaction.
The following non-limiting examples illustrate exemplary methods of preparing
a few
compounds of the invention.
E!CAMPLE 15
1-Nanhthalenesulfonamide, 5-(dimethvlamino)-N-[2-[[2-(methyl-sulfonvllethvll
thiolethvll-
S O
HN . S
O S O
To a stirred suspension of 2-(methylsulfonyl)ethanethiol (17.5 g, 0.12 mol)
and 5-
(dimethylamino)-N-(2-bromoethyl)-1-naphthalenesulfonamide (43.8 g, 0.12 moI)
in acetone (1.8
L) was added anhydrous potassium carbonate (19.6 g, 0.142 mol) at room
temperature under
argon. The reaction nuxture was refluxed for 1 h, then additional potassium
carbonate (58.5 g,
0.42 mol) and acetone (50 mL) were added followed by continued reflux for 1.5
h. The reaction
mixture was cooled to room temperature, then poured into stirred water (8 L)
and extracted with
EtOAc (2 x 4 L). The combined EtOAc extracts were washed with water (I x 4 L)
then washed
with brine ( 1 x 4 L) and dried over magnesium sulfate. The clear EtOAc
extract was
concentrated to give crude product. The crude product was chromatographed on
silica gel (2.2
kg) with EtOAc:hexanes 1:1 (12 L) and 4:1 (8L,). Appropriate fractions were
combined, filtered
and concentrated to give 47.6 g (93.7 % yield) of product as a viscous oil.
Proton NMR and IR
spectra were consistent with the proposed structure.
N(CHg)2
CA 02519205 2000-O1-07
83
Elemental analysis:C H N S
Calc. 49.015.816.72 23.09
Calc.* 49.346.Oi6.32 21.71
Obs. 49,525.986,41 21.96
*Calc. for C"Hz4N~04S,
. 0.3 EtOAc
EXAMPLE 16
Methvl 3-(Hexadecvlthiolpropanoate
Reaction Sequence:
O O
I I 11
CH3(CHz),SSH + CH2=CHCOCH3 -T CH3(CH2)tSSCHzCHZCOCH3
Hexadecyl mercaptan (95%, 180 g, 661 mmol) was added, dropwise over 0.5 h, to
a stirred
mixture of methyl acrylate (60.0 g, 697 mmol) and benzyltrimethylammonium
hydroxide (40
wt.% in methanol, 400 mg, 1.0 mmol). The resulting warm (~60°C)
solution was stirred for one
additional hour then volatiles were removed in vacuo at 90°C. The
resulting oil was
recrystallized from warm (-~40°C) hexanes (500 ml), cooled to -
30°C, collected by filtration and
dried to constant weight in vacuo at room temperature to give 222.3 g (98%) of
purified product;
mp, 38-39°C (corrected).
Elemental analysis: C H S
Calc. 69.71 11.70 9.30;
Found 69.78 11.54 9.26.
The'H NMR and 1R agree with the proposed structure.
EXAMPLE 1?
4-1(IEIexadecvlthiolmethyll-NON-dimethylbenzenamine
Reaction Sequence:
CA 02519205 2000-O1-07
84
NaOEt
a. OzN ~ ~ CH?Br -t- HS(CHZ)~;CH3 ----> OzN ~ / CHzS(CHz),;CH3
EtOH
1
MeOH
b. 1 + Fe/NH4C1 ----~ HZN ~ ~ CHaS(CHz)isCH3
2~
NaHC03
c. 2 + (CH30)zSOz --~ (CH3)zN ~ J CHaS(CHz)1;CH3
Tf~/HzO
3
a. 4-f(Hexadecylthio)methyl)-1-nitrobenzene (1):
A solution of 4-niirobenzyl bromide in ethanol (I50.0 g, 0.694 mol in 1.5 L)
was brought to
reflux. Separately, a solution of 1-hexadecanethiol in ethanol (231 mL, 0.691
mol in 1.5 L) was
treated with sodium ethoxide in ethanol (258 mL, 0.691 mol of a 21 % solution)
over ten minutes,
stirred at room temperature for 15 minutes, then warmed to dissolve the
precipitate. This was
then added to the benzyl bromide solution over twenty minutes, stirred at room
tempcraturc for
two hours, then allowed to sit undisturbed overnight. The crystallized
thioether was collected
and combined with the product from a 230 mmol run. This light yellow solid was
dissolved in
CH~CIZ (3 L), washed with water ( 1 L}, then dried (Na,S04), filtered, and
spin-evaporated to give
324.5 g of ! (89.5% yield). The material was a single spot by TLC (I9:1
hexaneslEtOAc), and
was suitable for further transformation.
b. 4-[(Hexadecvlthiolmethyllbenzeneamine (2):
Ammonium chloride (152.9 g, 2.858 mol), 1 (225.0 g, 0.572 mot), water (2.8 L),
methanol
(3.8 L) were combined and mechanically stirred at 50°C, then powdered
iron (95.9 g, 1.715 mot)
was 'added portionwise over ten minutes. The suspension was vigorously stirred
at reflux for 2.5
hours, then hot filtered through a celite pad. The pad was rinsed with water
(3 x 700 mL) and
CHZCI2 (5 x 700 mL}. The aqueous layer was extracted with CH~Cl2 (3 x 1 L},
then concentrated
to remove methanol and again extracted with CHzCh (3 x 500 ntl). The combined
organics were
washed with water (2 x 3L), dried (Na2S04), filtered, and spin-evaporated to
give 198.1 g (95.3%
yield) of _2 as a pale yellow solid. TLC (7:1 hexaneslEtOAc) indicated a
single spot. This lot
was combined with that of a 100 mmol run to give a total of 231 g of 2 (94.3%
yield) which was
suitable for further transformation.
c. 4-((Hexadecylthio)methyll-N,N-dimethylbenzeneamine (3):
CA 02519205 2000-O1-07
A solution of sodium bicarbonate in water (168 g, 2.0 mol in 1.3 L) was added
to a
vigorously stirred solution of 2 in THF ( 181 g, 0.5 mot in 1.5 L), under
argon, at OoC. Dimethyl
sulfate (165 mL, 1.75 mol) was added dropwise over 30 minutes, and stirring
was continued for a
total of 20 h. The ice bath was removed after the first hour. The reaction was
followcd by TLC
(9:1 hexanes/EtOAc), and initially showed mono-methylated material at Rf =
0.56. After 20 h,
concentrated NHaOH (300 mL) was added and stirred for 15 minutes, then EtOAc
and brine (1 L
each) were added and the layers were separated. The aqueous portion was
saturated with solid
NaCl, extracted with EtOAc (5 x 500 mL), and discarded. The combined organics
were washed
with brine (500 mL), dried (Na2S04), and spin-evaporated to a yellow oil. A
similar rcaction was
done previously on 137.7 mmol of 2. The combined lots were dissolved in
CH,C12, then eluted
from a silica gel pad with CHZCh. The eluent was spin-evaporated to give 160.1
g of 3_ as an oil,
which was purified by chromatography (1.8 kg Si0= eluted with 39:1
hexaneslEtOAc) to give
91.1 g of 3. This material was recrystallized from ethanol containing 1%
water, then dried in
vacuo at room temperature to give 57.9 g (23.3% yield) of pure 3_; m.p. 41-
43°C.
Elemental analysis: C H N S
Calc. 76.66 11.58 3.57, 8.19;
Found 76.37 11.63 3.61 8.43.
The 'H NMR, '3C NMR, and IR agree with the proposed structure.
EXAMPLE 18
1.3,5-Cvcloheptatriene, 7-fhexadecvlthio~-
Tropylium tetrafluoroborate (10.0 g, 0.056 mol) was ground and placed in a
reaction flask
with MeOH (100.0 mL). This suspension was stirred under argon for 10 min at
room
temperature, and then n-hexadecanethiol, (90%) ( 15.0 g, 0.052 mot) was added
over 5 min. The
reaction mixture (suspension) was stirred for 2 h. At this point, TLC showed
Only a small
amount of unreacted thiol. To the reaction mixture was added NaHC03 (8 g,
0.095 mol)
followed by stirring for 15 min. and filtration through a small pad of silica
gel (--20 g) with
elution by hexanes (200 mL). The solution was evaporated (bath temp
~30°C) to give an oil
which was purified by column chromatography with silica gel ( 100 g) eluting
with hexanes to
give 17.2 g (95%) as a colorless oil. Additional reactions were performed to
give a total of 58.1
g of target compound. Proton NMR and IR spectra were consistent with the
proposed structure.
Elemental analysis: C H S
Calc. 79.24 11.56 9.20
CA 02519205 2000-O1-07
86
Obs. 78.63 11.85 9.43
Metal Based Protecting Groups
The metal mercaptides of the present invention can be prepared by a number of
methods
known to those who are skilled in the art.
R-S-Met-Xn can be made by reactions of the type:
Met(OA~)"+1 + gS ----> RSMet(OAl)n + OA~
e.g., for Ti and Zr.
R-S-Met(M)";X~ can be made by reactions of the type:
Met(M)mXn+1 + RS --~ RSMet(M)n,X" + X"-
e.g., for V and Bi.
Furthermore, metal mercaptides of the present invention can be made via the
addition of
the cosmetic thiol to a solution of salts of heavy metals. This can be
accomplished by adding the
thiol to an aqueous, hydroalcoholic or alcoholic solution of a salt of the
metal. The formed
mercaptides of the heavy metals may then precipitate. The precipitated
mercaptide can then be
filtered and washed with an aqueous, hydro-alcoholic or alcoholic solution
containing some of
the thiol to prevent hydrolysis {E. Reid, Organic Chemistry of Bivalent
Sulfur, Volume L 1958].
Nonmetal and me alloic[yasedProtecting Groups
Thiol derivatives of non-metals and metalloids can be prepared from their
halides in the
presence of a hydrogen halide acceptor hydrogen halide acceptor or by using a
metal thiolate,
such as lead, where Et represents an ethyl group, Pb is lead, and the other
symbols are as defined
above [M. E. Peach, "Thiols as Nucleophiles", in The ChemistrX,of the Thiol
Group, 1974, John
Wiley and Sons, pp. 747.]:
E- Hal + RSH + Et3N -----~ E-S- R + Et3NH+ HaT
E- Hal + Pb(SR)2 ---s E-S- R + PbHalz
Energy Sensitive Protective Gronps
I. 2-Nitrobenz~ derivatives
The 2-nitrobenzyl derivatives can be prepared by reaction of the corresponding
2-
nitrobenzyl halide with a thiol in the presence of a base:
CA 02519205 2000-O1-07
87
O~N O~N
R-SH + BrCH2 ~ / --~- R-S-CH2
II. 2-Nitrobenzyloxycarbonyl Derivatives
The 2-nitrobenzyloxycarbonyi derivatives can be prepared by the reaction of
phosgene with the corresponding alcohol, i.e., 2-nitrobenzyl alcohol, b-
nitroveratryl
alcohol, 2-nitrobenzhydrol, and 2,2'-dinitrodiphenylmethanol. The resulting
aryl chloride
can then be reacted with a thiol to yield the corresponding 2-
nitrobenzyloxycarbonyl
derivative:
NOZ NOZ NOZ
i j; COCH ~ H 10( .RSH i - N O
z ~ ~ c-oH ----~ z ~ ~ ~-o-c-ci -~~ z ~ ~ c-o-c-s-R
z' z3
z1 z= zZ
where Z' and ZZ are H, or OCH3 and Z3 is H, C~IS or o-02N-C6H,.
III. Benz~loxycarbonyl Derivatives
The 3,5-dimethoxybenzyloxycarbonyl group can be introduced by reacting 3,5-
dimethoxybenzyI p-nitrophenyl carbonate with a thiol:
CH30 CH30
O ~ ~ RSH O
CHz-O-C-O~N02 ----~ \~/ CHZ-O-C-S-R
CH30 CH30
IV. a.a-Dimethylbenzyloxycarbonyl Derivatives
The a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl compounds can be prepared by
the reaction of a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl azide with a
thiol:
CH30 CH30
- CH3 O ~H CH3 O
~ -O-C-N3 > ~ ~ C-O-C-S-R
CH3 CH3
CH30 CH30
CA 02519205 2000-O1-07
88
V. 3-Nitrophenyloxycarbonvl Derivatives
The 3-nitrophenyloxycarbonyl compound can be prepared by reaction of 3-
nitrophenol with phosgene to yield 3-nitrophenyloxycarbonyl chloride. The
latter can then
be reacted with a thiol:
02N O~N O~N
_ O RSH O
off c-°~ ~~~ o-c-cl ----. ~ ~ o-c-s-R
VI. Phenacyl_Derivatives
The 4-methoxyphenacyl compound can be prepared by reaction of phenacyl bromide
with a
thiol:
O O
If RSH ' 11
CH30 ~ ~ C-CH2-Br -~ CH30 ~ ~ C-CH2-S-R
The a-methylphenacyl compound can be prepared by reaction of alpha-
methylphenacyl
bromide with a thiol:
O CH3 ~H O CH3
C-CH-Br -----~ ~ ~ C-CH-S-R
VII. tert-Butyloxycarbonyl Derivatives
The tent-butyloxycarbonyl compound can be prepared by reaction of tent-
butyloxycarbonyl
chloride with a thiol:
CH3 O CH3 O
CH3-C-O-C-Cl ---~ CH3-C-D-C-S-R
CH3 CH3
EXAMPLES OF PREFERRED MODIFIED COSMETICALLY ACTIVE AGENTS
The following are non-limiting examples of preferred cosmetically active
functional group,
R. and "hook" combinations for use in topical formulas:
EXAMPLE I9
CA 02519205 2000-O1-07
89
N
~N N =N \
N
a S \\
Modified Dispers
Black No. 9 ~ + Br'
EXAMPLE 2~
O
O-
NH
S
Modified D&C
N Red No. 31
N~
\ ~ + Br-
EXAMPLE ZIZI
OH
0
o~~~
l \ /
NH
S
Modified F
N Yellow t~
N~ OH
+ Br'
EXA- MPLE 2Z
CA 02519205 2000-O1-07
90
N
H
N' ~
~S N + Br'
Moditred D&C
Violet No. 2
EXAI~tPLE 23
Modified Silicone
+ Bi
N
S-Linker-Si p-Si p-Si-Linker S
N + Bi N
x
x = Z to s00
E?G1MPLE 24
Modified Silicone
+ Br
N
Linker N
! l I
Si p Si p Si p Si
i 1 l
y =1.to 100
x = 2 to soo
CA 02519205 2000-O1-07
91
EXAMPLE 25
Modified Anti-oxidant
HO N ,/
O
O ~ ~ C (CHZ)s-S N + Br
HO
EXAMPLE 26
Modified Perfluoro Conditioner
N
CF3(CF2)~CH2CH2 N +
I.
EXAMPLE 27
Modified ITV Absorber
~N~
N
'N/ \ + Bt
N
O/ S 1 S
N
H N
CA 02519205 2000-O1-07
92
E:~CAMPLE 28
Modified Anti-oxidant
H
N
O
+ Br
~~ \ N
HN
S \
N
E!C.4MPLE 29
Modified Conditioner
N
CH3(CH~)~5(OCH2CH2)6
Br
wherein Linker represents any straight, branched or mono- or polycyclic
aliphatic, mono or
polyunsaturated alkyl, aryl, heteroalkyl, heteroaliphatic or heteroolefinic
system including 1 to 30
carbon atoms together with 0-IS heteroatoms, especially O, N, S, P, Si, and
can incorporate one
or more substituents including, bui not limited to, poly or perfIuoro
substitution.
These compounds are made by synthesis methods known in the art, including but
not
limited to those described above and those described in Sokolowska-Gaida, J.
and Freeman, H.,
Dyes and Pigments (1990) Vol. 14, pp. 35-48, European Patent Application EP
0437099 A1
Published by Dow Coming Cotp. (Inventors: Halloran, D. J., et al.) and the
preparation section
herein.
E?~AMPLE 30
"Terminal" benrylchloride-substituted silicone polymer.
The hydride terminated silicone polymer HMe;Si-(OSiMe;),-OSiMe:H (35 g, 53.56
mmol,
Gelest) was weighed into a 250 mL round bottom flask containing a stir bar.
2,6-di-ten-butylphenol (26 mg, 489 ppm by weight) was added followed by Sl ppm
platinum in
CA 02519205 2000-O1-07
93
the form of Karstedt's catalyst (GE Silicones Product, 10.2% platinum by
weight). The pale
yellow solution was placed in a 50°C oil bath. Vinylbenzylchloride
(16.8 mL, 119.2 mmol,
Aldrich) was added slowly dropwise by syringe with stirring. The solution
quickly became
cloudy yellow and remained that way until about one minute at3er the addition
was complete. At
this time the reaction mixture turned dark brown. The mixture was stirred at
52°C for 1.5 hours'
after the addition was complete. The brown mixture was then washed with
methanol (1/3 by
volume) two times to remove excess vinylbenzylchloride. The product, a cloudy
brown oil, was
isolated after drying under vacuum in 83.5 °ro yield (42.89 g, 44.74
mmol). ~H NMR (acetone-
d,,): 7.33 (pseudo t, J = 8.0 Hz, aryl), 7.23 (pseudo d, J = 8.0 Hz, aryl),
7.13 (pseudo d, J = 8.2
Hz, aryl). 4.66 (s, 4H, CH~CI), 2.70 (m, 2.4H, SiCH=CH~Ar), 2.27 (q, J = 7.6
Hz, 0.8H,
SiCH(Me)Ar), 1.38 (d. J = 7.6 Hz, 2.4H, SiCH(Me)Ar), 0.94 (m, 2.4H,
SiGH~CH=Ar), 0.12 (s,
54H, SiMe). The aryl resonances integrate to be 8H total. This product is
cloudy brown due to
the presence of colloidal platinum. Alternatively, we have found that a very
pale yellow product,
identical by 'H NMR spectroscopy, can be isolated when the material (mixture
of hydrosilation
isomers) is prepared using the heterogeneous catalyst PdAhO; (5% Pt). Also
noteworthy is the
fact that with higher molecular weight silicones, it is possible and
recommended to use larger
amounts of methanol in the washing step. See Scheme 1.
Pyridinium-substituted silicone polymer.
Inside a helium filled dry box, 42.89 g (44.74 mmoI) of the "terniinal"
benzylchloride-
substituted silicone polymer was added to a 250 mL round bottom flask
containing a stir bar. To
this was added 10 mL acetone (dried over drierite) and 35 mL anhydrous
acetonitrile. Sodium
iodide (13.45 g, 89.73 mmol, dried under vacuum at 1 i0°C) was added
slowly as a solid to the
amber solution while sodium chloride quickly precipitated. The NaI addition
was followed by 1-
methyl-5-(trifluoromethyl)-2(IH)-pyridinethione (17.30 g, 89.55 mmol, prepared
by Starks
Associates, Buffalo, NIA, added piecewise as a solid. The orange mixture was
allowed to stir at
room temperatwe for 3 days. Outside the drybox, the mixture was filtered, and
the volatile
materials were then removed from the solution under vacuum. The crude product
was dissolved
in a minimum amount of acetone (about 75 mL) forming a dark orange solution.
Pentane (250
mL) was added to precipitate the product which was filtered on a frit and
washed with pentane (5
x 50 mL). The product was isolated in 88% yield (59 g) as a yellow powder. 'H
NMR (acetone-
d~,): 9.73 (s, 2H, pyH), 8.73 (m, 4H, pyH), 7.56 (pseudo t, J = 8 Hz, phenyl),
7.29 (pseudo d, J =
8Hz, phenyl), 7.20 (pseudo d, J = BHz, phenyl), (the three phenyl resonances
inte~-ate to 8H
total), 5.03 (s, 4H, CH2S), 4.49 (s, 6H, NMe),.2.71 (m, 2.4H, SiCH2CH2Ar),
2.29 (q, J = 7.4 Hz,
CA 02519205 2000-O1-07
94
O.SH, SiCH(Me)Ar), 1.39 (d, J = 7.4 Hz, 2.4H, SiCH(Me)Ar), 0.94 (m, 2.~1H;
SiCH?CH2Ar),
0.12 (s, 54H, SiMe). See Scheme 1.
Scheme 9 CI
2
I I Pt2(M"'M"')3 ~ I
H- i ' O- i i Q- ~ i-H 50 ppm Pt -Si O- i ' O- i i-
7 1.5h, 55C 7
500 ppm 2,6-di-t-butylphenol + product of a-
hydrosilation
I
83.5°~ yield
CI
Nal
acetone
acetonitrile, 25C
,, CF3
S
I \+I-
F3 ~w ~ S ~ / Si O-Si O-Si / ~ S / ~ CF3
i I 7 I V
88.3% yield + product of a-
yellow powder hydrosilation
EXAMPLE 31
"On-chain" benzylcbloride-substituted silicone polymer.
The "on-chain" hydride silicone polymer Me;Si-(OSiMe~)~,-(OSiHMe),-OSiMe: (200
g,
102.0 mmol, GE Silicones Product) was weighed into a 250 mL round bottom flask
containing a
stir bar. To this was first added 2,6-di-tert-butylphenol (128 mg, 504 ppm by
weight) and then
150 ppm platinum in the form of the heterogeneous catalyst PdAhOs (5% Pt by
weight). The
pale yellow solution was placed in a 50°C oil bath and
vinylben2ylchloride (50.1 mL, 355.3
mmol, Aldrich) was added by syringe with stirring. The mixture was stirred at
60°C for 4 days.
The dark yellow-green reaction mixture was then washed with methanol (1/2 by
volume) three
times to remove excess vinylbenzylchloride. The product, a clear yellow oil,
was isolated in 79.0
% yield after drying under vacuum (I94.99 g, 80.64 mmol). 'J-1 NMR (acetone-
d~): ?.33 (pseudo
CA 02519205 2000-O1-07
t, J = 7.8 Hz, 6 H, aryl), 7.21 (m, 6 H, aryl), 4.65 (s, 6:0 H, CH:CI), 2.73
(m, 4H, SiCH=C.'H~Ar),
2.23 (m, 1H, SiCH(Me)Ar), 1.40 (m, 3H, SiCH(Me)Ar), 0.93 (m, 4H, SiCH,CH;Ar),
0.12 (s,
1 ~4H, SiMe). The aryl resonances integrate to be 12H total. The final product
showed Borne
solubility in methanol so smaller amounts may be recommended in the washing
step.
Significantly lower reaction times (ca. 1-2 hours) are needed when the
heterogeneous catalyst is
replaced with Karstedt's catalyst, particularly for on-chain substituted
hydrides, or when the
described reaction is heated to a higher temperature. See Scheme 2.
Pyrimidinium-substituted silicone polymer.
This "on-chain" benzylchloride-substituted silicone polymer (31.32 g, 12.95
mmol) was
added to a 250 mL round bottom flask containing a stir bar inside a helium-
filled dry box. To
this was added 20 mL acetone (dried over drierite) and sodium iodide (5.46 g,
36.39 mmol, dried
under vacuum at 110°C) as a solid. The solution became cloudy and
quickly precipitated sodium
chloride. Another 10 mL of acetone was added followed by 4.49 g (35.58 mmol)
of the 2(1H)-
pyrimidinethione (prepared by Starks Associates, Buffalo, NY), added piecewise
as a solid. The
orange mixture was allowed to stir overnight (approximately 16 hrs.) at room
temperature.
Outside the dry box, the precipitate was removed and the volatile materials
evaporated under
vacuum. The product was isolated in 97.3% yield (35.43 g) as a waxy, dark
orange solid: ~H
NMR (acetone-d~): 9.72 (s, 3 H, pyH), 9.39 (m, 3 H, pyH), 8.02 (pseudo t, J =
4.8 Hz, 3 H, pyH),
7.48 (pseudo d, J = 6.7 Hz, 6H, phenyl), 7.22 (m, 6H, phenyl), 4.82 (s, 6.3 H,
CH=S), 4.34 (s, 9.0
H, NMe), 2.72 (m, 4H, SiCH~CH~Ar), 2.20 (q, J = 7.4 Hz, 1H, SiCH(Me)Ar), 1.39
(m, 3H,
SiCH(Me)Ar), 0.92 (m, 4H, SiCH,GH~Ar), 0.12 (s, 154 H, SiMe). Further studies
revealed that
the reaction with the pyrimidine thione can be performed under air with
solvent used as received
with the same results. See Scheme 2. The distribution of the on-chain
substitution is random, not
blocked as depicted schematically. However, the invention is not limited to
randomly distributed
polymer.
CA 02519205 2000-O1-07
Scheme 2
96
~CI
21
i
) ) 59~o Pt/alumina
-Si O-Si O-Si O-Si-
150 ppm Pt
3 2~ 500 ppm 2,G-d~t butylphenol + product of a-
hydrosilation
_ N'~ Nat, -NaCt
+ t S ~ ~ acetone
\ S N 25C
) ) + roduct of a-
dark orange waxy solid -Si p-Si O-Si O--Si- p
) ~ I ~ hydrosilation
E,~~AMPLES 32-38
Other pyrimidinium-substituted silicone polymers.
A number of other hook-functionalized silicone polymers were prepared. Vinyl
benzylchloride hydrosilation reactions were performed as described in both
Examples 1 and 2
while the method used to prepare the pvrimidinium-substituted materials was as
described in the
second part of Example Z. The new materials synthesized are shown as follows:
CA 02519205 2000-O1-07
97
+t~S
.'''~ I v
r
I I t
(a1 ) --si o--si o-si o--si-
I
43
~+ I
(,"'~ I v
~N
t i
(a2) -si o--si o-s~ o-si--
i l I I
21 184
+I-S
.''' ~( I v
r
(a3) -Si O-Si O-Si O-Si-
I I I I
3 45
+I-
,''' ,( I v
~N r
i I
(a4) -si o-si o-si o-si-
5 19
CA 02519205 2000-O1-07
98
N ~r \
(a5) / \ S ~ / Si O-Si O-Si
/ \ +N-
N+ 193 \~ ,-1
I_ \
N ~ ~ r
(a6) / ~ S~~Si O-Si O-Si
/ ~ +N
N + 19 \~.~ ~ ~ I
I-\
N
(a7) / v S ~ / Si O-Si O-Si r
~ ~ ~ /
N + ~ \-=J / n
I- \
g +I l-
All hydrosilation reactions
led also to the isomer resulting ~ NJ
from a-addition across the / '~
double bond. Thus products
contain isomers of the type: ~, -SI O-Si O-Si t3-Si-
3 21
EXAMPLE 39
Benzvichloride-substituted silicone resin.
The hydride substituted silicone resin lvlH=Q ( 101.058, 0.932 mol Si-H) was
weighed info a 500 mL round-bottom flask containing a stir bar. 2,6-di-tert-
butylphenol (61.0
mg, 529 ppm by weight) was added followed by 37.6 ppm of platinum in the form
of Karstedt's
catalyst (GE Silicones Product 89023, 10.0% platinum by weight). The mixture
was placed in a
55°C oil bath and vinylbenzylchloride (14.34 g, 93.7 mmol, Aldrich) was
added dropwise over a
period of one hour. At the end of the addition, the solution went from clear
yellow to cloudy
yellow. The mixture was stirred at 55°C for 17 hours and then at
95°C for four hours to
complete the reaction as determined by '1-1 NMR spectroscopy. The mixture was
transferred to a
500-mL three-necked round-bottom flask which was placed in a hot' oil bath.
The internal
temperature was raised to I20°C and 1-hexene ( 150 mL) was added
dropwise over the course of
about three hours. The mixture was stirred for an additional 16 hours,
however, the temperature
dropped due to excess 1-hexene and this hindered the reaction. The excess 1-
hexene was
removed under vacuum. The reaction was set up again, this time with a slower
addition of 1-
hexene at 120°C. After a total of 3 days of reaction time, which
includes the previous removal
step, the final product, 'a cloudy dark brown liquid, was isolated in 94.8%
yield (176.18 g). 'H
CA 02519205 2000-O1-07
99
NMR (acetone-iii): 7.32 (m, phenyl), 7.2.~ (pseudo d, J = 5.5 Hz, phenyl),
7.1G (m, phenyl), 4.G5
(s, rlrCl-l~Cl), 2.73 (m, SiCH(Me)Ar), 2.03 (s, SiCH(Me)Ar), 1.31 (br m,
SiCH~CH_Ar and
hexyl). 0.88 (br m, hexyl), 0.65 (br m, hexyl), 0.18 (br m, SiC:Ii,CI-1=Ar and
hexyl), -0.24 (br s,
SiMe). Shorter reaction times are required if the temperature of the reaction
with I-hexene is
maintained at 120°C.
Pvrimidinium-substituted silicone resin.
The benzylchloride-functionaiized resin was converted to the pyrimidinium
substituted
material as described in Example 3I. The product was isolated in 87.8% yield
(25.9 g) as a
viscous dark orange liquid.
Hair care benefits.
In order to measure hair care benefits imparted by the new silicone materials,
treated hair
switches (4 grams) were contacted with formulations containing the
pyrimidinium-substituted
silicone polymer described in Example 3I which is referred to as the "3Hook
Polymer".
Following treatment and simulated consumer use, combing forces were measured
using a Reed
Combing Machine.
The study of combining forces showed that hair switches treated with the hook-
substituted
silicone polymer consistently exhibited lower combing forces than the
controls. The sample
which did contain the hook silicone polymer demonstrated combining benefits
over the sample
which did not contain the hook silicone polymer. Combing benefits are also
evident in the
samples containing the 3Hook Polymer compared with the analogous samples which
contained
PDMS (polydimethylsiloxane, 5 centistokes, 5% by weight) as a control.
3Hook Polymer:
~+ I-S
( v
_N
-Si O-Si O-Si O--S
3 21
Overall, use of the 3Hook Polymer in the hair treatment formulation clearly
led to wet
combing benefits whether or not conditioner was used. Wet combing benefits
were found when
the hair was treated once and them subjected to four simulated weeks of
shampooing. The
combing benefit imparted to hair treated only once was just as profound as
that found for hair
that was treated weekly with the hook silicone polymer. In addition, the
benefit imparted to the
hair by the 3I~ook polymer was durable, lasting through at least 16 shampoos.
CA 02519205 2000-O1-07
10U
While typical embodiments have been set forth for the purpose of illustration,
the foregoing
descriptions should not be deemed to be a limitation on the scope of the
invention: Accordingly,
carious modifications, adaptations, and alternatives may occur to one skilled
in the art without
departing from the spirit and scope of the present invention
METHODS OF USING THE PROTECTED THIOL COMPOUNDS OF THE PRESENT
INVENTION
The method of use of the various protected thiol compounds is dependent on the
product
form utilized. The use would be as typically used for the product chosen.
The protected thiol compound of the present invention can be used in a variety
of ways in
hair care compositions. For example, in the most basic sense the cosmetic
actives of the present
invention can be applied directly to the hair in a alcohol/solventJwater
solution comprising:
Protected thiol cosmetic active of Examples 1-20, 30, 31, 39 0.5 to 10%
Hydroalcoholic solvent 0 to 95.00%
pH modifier, i.e., NaOH or citric acid pH 3 to 10"'
Water Q-S
* Note, the pH will vary based on the particular "hook" compound of use and
can be adjusted
either just prior to treatment with hair or simultaneously with the treatment
of hair.
After application, the hair is washed or rinsed to remove excess solvent. The
resulting protected
thiol cosmetic active will be delivered and bound to the hair permanently,
e.g, benefit will last
beyond 40 to 80 or more shampoos.
A simple non-limiting dye composition using the protected thiol compounds of
the present
invention comprises the following composition ranges (depending on what colour
is desired):
Modified D&C Violet No. 2 of Example 21 0.00% to 3.00%
Modified D&C Red No. 3 I of Example 19 0.00% to 3.00%
Modified D&C Yellow No. 6 of Example 20 0.00% to 3.00%
Modified D&C Black No. 9 of Example I 8 0.00% to 3.00%
2-propanol 50.00%
Sodium Hydroxide to pH 9-10
Water Q-S-
wherein the total dye concentration is between I% and 5%. The preparation of
this composition
and treatment with hair for proof of performance is described as follows: The
dyes are added to
the water and 2-propanol solution in a jar and stirred until thoroughly
dissolved at room
CA 02519205 2000-O1-07
101
temperature. The hair to be treated is submerged into the solution such that
the hair weight
comprises 10 to 40 wt% of the composition. The sodium hydroxide is then added,
a cap is placed
on the jar and the jar containing the solution plus hair is shaken for five
minutes. The hair is then
removed from the jar and rinsed thoroughly.
A simple non-limiting conditioning composition using a protected thiol
compound of the
present invention comprises:
The Modified Silicone of Example 23 5.00%
Methanol 90.00%
NaOH . to pH 8-10
Water Q.S.
The preparation of this composition and treatment with hair for proof of
performance is described
as follows: The modified silicone is added to the methanol in a jar and
stirred until thoroughly
dissolved at 100°F. The water and NaOH is then added with stirring
until the solution is
thoroughly mixed. With a syringe, one gram of the resulting solution is
applied per gram of the
hair to be treated. The applied solution is then worked through the hair while
wearing rubber
gloves. The hair is then covered with plastic wrap and let sit for up to two
hours. The hair is
then rinsed thoroughly.
The protected thiol compounds can be achieved with any of the protected hooks
described
herein. Of course, the protected thiol compounds of the present inventions caa
be applied in
differing matrices and formulas as described previously herein.
The protected thiol compounds may also be added to technologies currently well
known in
the art to treat substrates such as hair, teeth, finger nails, textiles, and
animal fur. Nonlimiting
examples of such compositions are described in the references below, each of
which is
incorporated herein by reference in its entirety:
Shampoos - U.S. Patent No. RE 34,584 (Grote et al.) issued April 12, 1994;
U.S. Patent No.
4,345,080 (BoIich) issued August 17, 1982; U.S. Patent No. 4,379,753 (Bolich)
issued April 12,
1983; and U.S. Patent No. 4,705,681 (Maes et al.) issued November 10, 1987.
Hair conditioners - U.S. Patent No. 4,387,090 (Bolich) issued June 7, 1983;
U.S. Patent No.
5,674,478 (Dodd et a1.) issued October 7, 1997; and U.S. Patent No. 5,750,122
(Evans et al.)
issued May 12, 1998.
Hair stylin composirions - U.S. Patent No. 5,166,276 (Hayama et al.) issued
November 24,
1992; U.S_ Patent No. 5,565,193 (Midha et al.) October I5, 1996; and U.S.
Patent No. 5,658,557
(Bolich et al.) issued August 19, 1997.
CA 02519205 2000-O1-07
102
Hair colorin compositions - U.S. Patent No. 4,197,865 (Jacquet et al.) issued
April 15, 1980,
U.S. Patent No. 4,125,367 (Bugaut et al.) issued November 14, 1978, U.S.
Patent No. 5,114,429
(Junino et al.) issued May 19,1992, and U.S. Patent No. 5.279,620 {Junino et
al.) issued January
18, 1994. .
Mascara compositions - Commonly assigned U.S. Patent Application Serial Nos.
08/951,285
(Alwatarri et al.), filed October 16, 1997, (Attorney's Docket 6345C);
081757,538 (Hartholomey
et al.), filed November 27, 1996 (Attorney's Docket 6397); and 09/121,138
(Alwatarri et al.),
filed July 23, 1998 {Attorney's Docket 5654C2); and in PCT Application Nos.
US96104154,
published October 3I, 1996; US97/19786, published May 7, 1998; and US97/21890,
published
June 4, 1998.
Nail polish and nail polish subcoat compositions - U.S. Patent 4,179,304
(Rossomando) issued
December 18, 1979, U.S. Patent 5,538,717 (LaPoterie) issued July 23, 1996, and
U.S. Fatent
5,639,447 (Patel) issued June I7, 1997, U.S. Patent 5,567,428 (Hughes) issued
October 22, 1996.
Toothpaste compositions - U.S. Patent 4,254,101(Denny) issued March 3, 1981;
and U.S. Pateni
4,314,990 (Denny et al.) issued February 9, 1982, and PCT Application No. WO
96/I5767
(Unilever PLC) published May 30, 1996.
Textile dye and treatment compositions -
Other typical compositions are found in Cosmetic and Toiletry Forrnuiations.
2nd Ed,
Flick, E. W., Noyes Publications (N.J.), Harrv's CosmeticoloRy, 7'~ Ed.;
Harry, R.G., Willcinson,
J.B., and Moore R.J., Chenucal Pub. Co. (NY) ( 1982); and Cosmetics. Science
and Technology,
2°d Ed., Balsam, M.S. and Sagarin, E.S., Wiley-Interscience (IVY)
(I972) (3 volumes).
Other embodiments of the present invention comprise a system comprising a
topical
composition containing the protected thiol compound and an activating
mechanism. For example
the conditioner composition:
EXAMPLE 40
Pyridinium, 1-methyl-2-[(hexadecyl)thio]-, bromide 3.00%
Urea 10.00%
Cocoamidopropyi Betaine 0.80% .
isopropanol 50.00%
Water Q.S.
can be applied simultaneously with a 5% solution of thioglycolic acid. A
preferred embodiment
is a kit wherein the dye solution and the thioglyc.olic acid are packaged in
separate chambers of a
dual chamber package and delivered simultaneously from the package.
