U.S. patent application number 11/792745 was filed with the patent office on 2008-12-11 for anti-radical agents.
Invention is credited to Werner Baschong, Sebastien Mongiat, Oliver Reich.
Application Number | 20080305055 11/792745 |
Document ID | / |
Family ID | 40096074 |
Filed Date | 2008-12-11 |
United States Patent
Application |
20080305055 |
Kind Code |
A1 |
Baschong; Werner ; et
al. |
December 11, 2008 |
Anti-Radical Agents
Abstract
Compounds of the formulae (1), (2) and selected hindered
nitroxyl, hydroxylamine and hydroxylamine salt compounds such as
the compound of formula (3), wherein Gi is hydrogen;
C.sub.1-C.sub.22alkyl; C.sub.1-C.sub.22alkylthio;
C.sub.2-C.sub.22alkylthioalkyl; C.sub.5-C.sub.7cycloalkyl; phenyl;
C.sub.7-C.sub.9phenylalkyl; or SO.sub.3M; G.sub.2 is
C.sub.1-C.sub.22alkyl; C.sub.5-C.sub.7cycloalkyl; phenyl; or
C.sub.7-C.sub.9phenylalkyl; E is oxyl or hydroxyl; V is --O--; or
--NH--; a is 0 or 1 or 2; b, c and d and g are each independently
of one another 0 or 1; e is an integer from 1 to 4; f, m, n and p
are each independently of one another an integer from 1 to 3; q is
0 or an integer from 1 to 3; Q, T and G.sub.3 are as defined in
claim 1; G.sub.4 and G.sub.5 are each independently of the other
hydrogen; or C.sub.1-C.sub.22alkyl; exhibit marked antiinflammatory
action. ##STR00001##
Inventors: |
Baschong; Werner; (Basel,
CH) ; Reich; Oliver; (Grenzach-Wyhlen, DE) ;
Mongiat; Sebastien; (Sierentz, FR) |
Correspondence
Address: |
JoAnn Villamizar;Ciba Corporation/Patent Department
540 White Plains Road, P.O. Box 2005
Tarrytown
NY
10591
US
|
Family ID: |
40096074 |
Appl. No.: |
11/792745 |
Filed: |
October 24, 2005 |
PCT Filed: |
October 24, 2005 |
PCT NO: |
PCT/EP05/55475 |
371 Date: |
March 18, 2008 |
Current U.S.
Class: |
424/59 ; 514/241;
514/245; 514/327; 514/470; 514/532; 514/622; 514/729 |
Current CPC
Class: |
A61K 31/165 20130101;
A61K 31/222 20130101; A61Q 19/00 20130101; A61K 8/37 20130101; A61K
31/445 20130101; A61Q 5/02 20130101; A61K 8/676 20130101; A61P
17/00 20180101; A61K 8/4926 20130101; A61K 8/4966 20130101; A61K
8/42 20130101; A61K 8/375 20130101; A61K 31/34 20130101; A61Q 17/04
20130101; A61K 8/4973 20130101; A61P 29/00 20180101; A61K 8/14
20130101; A61K 8/11 20130101; A61K 8/347 20130101; A61K 8/671
20130101; A61K 8/498 20130101; A61K 8/553 20130101; A61P 17/16
20180101; A61K 2800/412 20130101; A61P 43/00 20180101; A61P 17/18
20180101; A61Q 1/02 20130101; A61Q 19/10 20130101; A61K 31/255
20130101; A61K 2800/522 20130101; A61K 31/05 20130101; A61K
2800/413 20130101; A61P 27/14 20180101; A61P 37/08 20180101; A61K
8/46 20130101; A61K 8/466 20130101; A61Q 11/00 20130101 |
Class at
Publication: |
424/59 ; 514/729;
514/532; 514/470; 514/622; 514/245; 514/241; 514/327 |
International
Class: |
A61K 8/49 20060101
A61K008/49; A61K 31/05 20060101 A61K031/05; A61K 31/216 20060101
A61K031/216; A61K 31/365 20060101 A61K031/365; A61Q 17/00 20060101
A61Q017/00; A61P 17/00 20060101 A61P017/00; A61K 31/165 20060101
A61K031/165; A61K 31/53 20060101 A61K031/53; A61K 31/445 20060101
A61K031/445 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 22, 2004 |
EP |
04106821.4 |
Claims
1. A pharmaceutical composition comprising at least one of the
following compounds ##STR00083## (3) hindered nitroxyl compounds,
hindered hydroxylamine compounds, hindered hydroxylamine salt
compounds of the formulae ##STR00084## where in the above formulae
G.sub.1 is hydrogen; C.sub.1-C.sub.22alkyl;
C.sub.1-C.sub.22alkylthio; C.sub.2-C.sub.22alkylthioalkyl;
C.sub.5-C.sub.7cycloalkyl; phenyl; C.sub.7-C.sub.9phenylalkyl; or
SO.sub.3M; G.sub.2 is C.sub.1-C.sub.22alkyl;
C.sub.5-C.sub.7cycloalkyl; phenyl; or C.sub.7-C.sub.9phenylalkyl; Q
is --C.sub.mH.sub.2m--, ##STR00085## --C.sub.mH.sub.2m--NH; a
radical of formula ##STR00086## T is --C.sub.nH.sub.2n--;
--(CH.sub.2).sub.n--O--CH.sub.2--; phenylene; ##STR00087## or a
radical of formula ##STR00088## V is --O--; or --NH--; a is 0; 1;
or 2; d and g are each independently of one another 0; or 1; e is
an integer from 1 to 4; f is an integer from 1 to 3; and m, n and p
are each independently of one another an integer from 1 to 3; q is
0 or an integer from 1 to 3; if e=1, each of b and c is 1; G.sub.3
is hydrogen; C.sub.1-C.sub.22alkyl; C.sub.5-C.sub.7cycloalkyl;
C.sub.1-C.sub.22alkylthio; C.sub.2-C.sub.22alkylthioalkyl;
C.sub.2-C.sub.18alkenyl; C.sub.1-C.sub.18phenylalkyl; M; SO.sub.3M;
a radical of formula ##STR00089## or G.sub.3 is propyl substituted
by OH and/or by C.sub.2-C.sub.22alkanoyloxy; M is alkali; ammonium;
H; if e=2, then each of b and c independently is selected from 0
and 1; G.sub.3 is a direct bond; --CH.sub.2--; ##STR00090## or
--S--; or G.sub.3 is propyl substituted by OH or
C.sub.2-C.sub.22alkanoyloxy; if e=3, then each of b and c
independently is selected from 0 and 1; G.sub.3 is the radical of
formula ##STR00091## if e=4, then each of b and c independently is
selected from 0 and 1; G.sub.3 is ##STR00092## G.sub.4 and G.sub.5
are each independently of the other hydrogen; or
C.sub.1-C.sub.22alkyl; A.sub.1 and A.sub.2 are independently alkyl
of 1 to 4 carbon atoms or are together pentamethylene, Z.sub.1 and
Z.sub.2 are each methyl, or Z.sub.1 and Z.sub.2 together form a
linking moiety which may additionally be substituted by an ester,
ether, hydroxy, oxo, cyanohydrin, amide, amino, carboxy or urethane
group, h is the number of positive charges and j is the number of
negative charges, X is an inorganic or organic anion, and where the
total charge of cations h is equal to the total charge of anions j,
or a compound of the formulae (16), (18), (20), (21), (22), (23)
##STR00093## together with a pharmaceutically acceptable carrier or
adjuvant.
2. Pharmaceutical composition of claim 1 comprising at least one
compound of formulae (1), (2) and/or (3) ##STR00094## or an acid
addition salt thereof, wherein in formulae (1), (2) and (3) G.sub.1
is hydrogen; C.sub.1-C.sub.22alkyl; C.sub.1-C.sub.22alkylthio;
C.sub.2-C.sub.22alkylthioalkyl; C.sub.5-C.sub.7cycloalkyl; phenyl;
C.sub.7-C.sub.9phenylalkyl; or SO.sub.3M; G.sub.2 is
C.sub.1-C.sub.22alkyl; C.sub.5-C.sub.7cycloalkyl; phenyl; or
C.sub.7-C.sub.9phenylalkyl; E is oxyl or hydroxyl; Q is
--C.sub.mH.sub.2m--; ##STR00095## --C.sub.mH.sub.2m--NH; a radical
of formula ##STR00096## T is --C.sub.nH.sub.2n--;
--(CH.sub.2).sub.n--O--CH.sub.2--; phenylene; ##STR00097## or a
radical of formula ##STR00098## V is --O--; or --NH--; ; a is 0; 1;
or 2; b, c and d and g are as defined in claim 1; e is an integer
from 1 to 4; f is an integer from 1 to 3; and m, n and p are each
independently of one another an integer from 1 to 3; q is 0 or an
integer from 1 to 3; if e=1, or in formula (3), then G.sub.3 is
hydrogen; C.sub.1-C.sub.22alkyl; C.sub.5-C.sub.7cycloalkyl;
C.sub.1-C.sub.22alkylthio; C.sub.2-C.sub.22alkylthioalkyl;
C.sub.2-C.sub.18alkenyl; C.sub.1-C.sub.18phenylalkyl; M; SO.sub.3M;
a radical of formula (1d) ##STR00099## or G.sub.3 is propyl
substituted by OH and/or by C.sub.2-C.sub.22alkanoyloxy; M is
alkali; ammonium; H; if e=2, then G.sub.3 is a direct bond;
--CH.sub.2--; ##STR00100## or --S--; or G.sub.3 is propyl
substituted by OH or C.sub.2-C.sub.22alkanoyloxy; if e=3, then
G.sub.3 is the radical of formula (1g) ##STR00101## if e=4, then
G.sub.3 is ##STR00102## G.sub.4 and G.sub.5 are each independently
of the other hydrogen; or C.sub.1-C.sub.22alkyl; together with a
pharmaceutically acceptable carrier or adjuvant.
3. A pharmaceutical composition according to claim 2, where in the
compounds a is 1; Q, where present, is --C.sub.mH.sub.2m-- and,
preferably, a methylene or ethylene radical, T, where present, is
--C.sub.nH.sub.2m-- or phenylene; G.sub.3 is hydrogen;
C.sub.1-C.sub.22alkyl; SO.sub.3M; propyl substituted by OH and/or
by C.sub.2-C.sub.22alkanoyloxy; or G.sub.3 is a direct bond;
--CH.sub.2--; ##STR00103## or propylene substituted by OH or
C.sub.2-C.sub.22alkanoyloxy; or G.sub.3 is ##STR00104##
4. A pharmaceutical composition according to claim 2, where in the
compound of the formula (1) or (2) G.sub.1 and G.sub.2 are,
independently of each other, C.sub.1-C.sub.5alkyl, especially
tert.-butyl, and G.sub.1 is located in meta-position relative to
G.sub.2; and G.sub.4 and G.sub.5 independently are H or
C.sub.1-C.sub.4alkyl, especially methyl.
5. A pharmaceutical composition according to claim 2, where in the
compound of the formula (1), e is 1 or 2 or 4 and G.sub.3 is
SO.sub.3M or propyl substituted by OH and/or by
C.sub.12-C.sub.22alkanoyloxy; or G.sub.3 is a direct bond;
--CH.sub.2--; ##STR00105## or propylene substituted by OH or
C.sub.12-C.sub.22alkanoyloxy; or G is ##STR00106## where M is
alkali and q is 0 or 1; Q, where present, is ethylene, T, where
present, is p-phenylene; and where the compound of the formula (3)
conforms to the formula ##STR00107## where E is oxyl or hydroxyl;
or a pharmaceutically acceptable acid addition salt thereof.
6. A pharmaceutical composition according to claim 1, wherein the
compound (1), (2), (3) is selected from the group consisting of
compounds of formulae (7) to (35) ##STR00108## ##STR00109##
##STR00110## ##STR00111## ##STR00112## ##STR00113## the reaction
product of glycerine, coconut oil and a compound of the formula
##STR00114## citrate.
7. A pharmaceutical composition according to claim 1, wherein the
compounds (1), (2) and/or (3) are present in a total amount of
0.001 to 10% by weight of the total composition.
8. A pharmaceutical composition according to claim 1 for the
treatment of radical-induced skin damage or inflammatory or
allergic conditions.
9. (canceled)
10. A medicament or formulation for the treatment or prevention of
radical-induced skin damage or inflammatory or allergic conditions
comprising an effective amount of compound (1), (2) and/or (3) as
defined in claim 1.
11. A pharmaceutical composition according to claim 1, which
additionally comprises at least one substance selected from the
group consisting of antiphlogistic agents, antiinflammatory agents,
vitamins, antipsoriatic agents, further skin actives, cell
proliferation regulators, antiallergic, UV protecting,
moisturizing, antiageing agents, and DNA-protectants.
12. A pharmaceutical composition according to claim 1, which
contains the compounds (1), (2) and/or (3), and optionally a
further active ingredient, in nanodispersed or encapsulated
form.
13. A process for the preparation of a pharmaceutical composition,
which process comprises addition of an effective amount of the
pharmaceutically active compound (1), (2) and/or (3) as defined in
claim 1 to a pharmaceutically acceptable carrier.
14. A method for the local treatment or prevention of radical
induced body impairments comprising administering to a patient in
need of such treatment an effective amount of the pharmaceutical
composition according to claim 1.
15. A method according to claim 14 for the local treatment or
prevention of inflammatory conditions comprising administering to a
patient in need of such treatment an effective amount of said
pharmaceutical composition.
16. A method according to claim 14 for the local treatment or
prevention of allergic conditions comprising administering to a
patient in need of such treatment an effective amount of said
pharmaceutical composition.
17. A method according to claim 14 for the local treatment or
prevention of skin impairments comprising administering to a
patient in need of such treatment an effective amount of said
pharmaceutical composition.
Description
[0001] The present invention relates to the use especially of
carbon or ester/amide bridged phenols or lactones thereof, or some
sterically hindered amines, as pharmaceutically active agents and
to pharmaceutical, especially dermatological, compositions
containing them. The invention further relates to the use of these
compounds for the preparation of medicaments or formulations for
the treatment of radical induced impairments such as inflammatory
or allergic conditions, collagen damages, DNA-damage, or
reperfusion-damage (use as anti aging).
[0002] It is standard practice to use glucocorticoids for the
topical treatment of inflammatory and allergic conditions. It is
common knowledge that these compounds can have unwanted
side-effects.
[0003] Owing to their insufficient ability to penetrate the skin,
nonsteroidal antiinflammatory medicaments containing therapeutic
agents such as ketoprofen, BW755c, piroxicam, diclofenac or
indomethazin cannot effectively be applied topically, but only
systemically. Also some phenol ethers have been proposed having
antioxidant, anti-inflammatory and antiallergic properties (see
EP-A-1366763 and literature cited therein).
[0004] It is the object of this invention to provide pharmaceutical
compositions having surprisingly good pharmacologically properties,
in particular antioxidant, anti-inflammatory and antiallergic
properties, especially when administered locally.
[0005] It has been found that compounds of the formulae
##STR00002## [0006] (3) hindered nitroxyl compounds, hindered
hydroxylamine compounds, hindered hydroxylamine salt compounds of
the formulae
##STR00003##
[0006] where in the above formulae [0007] G.sub.1 is hydrogen;
C.sub.1-C.sub.22alkyl; C.sub.1-C.sub.22alkylthio;
C.sub.2-C.sub.22alkylthioalkyl; C.sub.5-C.sub.7cycloalkyl; phenyl;
C.sub.7-C.sub.9-phenylalkyl; or SO.sub.3M; [0008] G.sub.2 is
C.sub.1-C.sub.22alkyl; C.sub.5-C.sub.7cycloalkyl; phenyl; or
C.sub.7-C.sub.9-phenylalkyl; [0009] Q is --C.sub.mH.sub.2m--;
##STR00004##
[0009] --C.sub.mH.sub.2m--NH; a radical of formula
##STR00005## [0010] T is --C.sub.nH.sub.2n--;
--(CH.sub.2).sub.n--O--CH.sub.2--; phenylene;
##STR00006##
[0010] or a radical of formula
##STR00007## [0011] V is --O--; or --NH--; [0012] a is 0; 1; or 2;
[0013] b, c and d and g are each independently of one another 0; or
1; [0014] e is an integer from 1 to 4; [0015] f is an integer from
1 to 3; and [0016] m, n and p are each independently of one another
an integer from 1 to 3; [0017] q is 0 or an integer from 1 to 3; if
e=1, or in formula (3), then [0018] G.sub.3 is hydrogen;
C.sub.1-C.sub.22alkyl; C.sub.5-C.sub.7cycloalkyl;
C.sub.1-C.sub.22alkylthio; C.sub.2-C.sub.22alkylthioalkyl;
C.sub.2-C.sub.18alkenyl; C.sub.1-C.sub.18phenylalkyl; M; SO.sub.3M;
a radical of formula
[0018] ##STR00008## [0019] or G.sub.3 is propyl substituted by OH
and/or by C.sub.2-C.sub.22alkanoyloxy; [0020] M is alkali;
ammonium; H; if e=2, then [0021] G.sub.3 is a direct bond;
--CH.sub.2--;
##STR00009##
[0021] or --S--; or G.sub.3 is propyl substituted by OH or
C.sub.2-C.sub.22alkanoyloxy; if [0022] e=3, then [0023] G.sub.3 is
the radical of formula
##STR00010##
[0023] if [0024] e=4, then [0025] G.sub.3 is
[0025] ##STR00011## [0026] G.sub.4 and G.sub.5 are each
independently of the other hydrogen; or C.sub.1-C.sub.22alkyl;
[0027] A.sub.1 and A.sub.2 are independently alkyl of 1 to 4 carbon
atoms or are together pentamethylene, [0028] Z.sub.1 and Z.sub.2
are each methyl, or Z.sub.1 and Z.sub.2 together form a linking
moiety which may additionally be substituted by an ester, ether,
hydroxy, oxo, cyanohydrin, amide, amino, carboxy or urethane group,
[0029] h is the number of positive charges and j is the number of
negative charges, [0030] X is an inorganic or organic anion, and
where the total charge of cations h is equal to the total charge of
anions j, exhibit marked radical scavenging and antiinflammatory
action in cellular and enzymatic in vitro assays and in in vivo
assays on human volunteers, while showing good skin and cell
compatibility. Present compounds can be used alone or as mixtures
with each other and/or further components, e.g. those described
further below. Present invention therefore pertains to a
pharmaceutical composition comprising at least one compound of
formulae (1), (2) and/or (3), together with a pharmaceutically
acceptable carrier or adjuvant, as well as to the use of a compound
of formulae (1), (2) and/or (3) for the preparation of a medicament
or a formulation, such as a cosmetic or pharmaceutic formulation,
for the treatment or prevention of radical-induced skin damage and
inflammatory and allergic conditions.
[0031] Compounds of the formula 1, where e is 1, usually contain
the spacer groups Q and (CO)--V, which corresponds to the condition
b=c=1. Also useful are the compounds of formulae
##STR00012##
[0032] Radical Oxygen Species (ROS) are known to oxidize lipids,
break down enzymes and matrix proteins, affect the DNA or the RNA
and are leading to the premature ageing of the skin with drying
effect, loss of elasticity, strong irritation and promoting the
destruction of constituents inside skin. Inflammation and ROS
generation activate the matrix metalloproteinases (MMP) but also
cause oxidative damage to cellular proteins, lipids and
carbohydrates.
[0033] MMPs are a group of Zinc-dependent endopeptidases capable of
degrading Extra Cellular Matrix (ECM) components such as collagen,
elastin, fibronectin, gelatine, laminin, leading to photo-aged skin
with wrinkle lines and dispigmentation reactions. The present
compounds are able to enhance the endogeneous antioxidant defense
system which includes enzymatic components such as Glutathione
peroxidase, Catalase, Superoxide dismutase, Methallothionein; or
non enzymatic components such as Glutathione, vitamin E, Vitamin C,
Ubiquinol, .beta.-carotene.
[0034] After the application to the skin, the compounds can protect
intercellular and intracellular lipids, lipoproteins, cell
membranes, low molecular compounds, such as lipids, sugars, labile
amino acids (e.g. with thiol group), glutathione, and further
macromolecules such as proteins, proteoglycanes and
glycosaminoglycanes against direct oxidation.
[0035] An additional effect from those substances is their
protective effect upon the components of the preparation in
question that are sensitive to oxidation by air oxygen, which
offers the benefit of higher stability of the product and its
longer shelf life. A part of pharmaceutical or cosmetic carrier
emulsions are lipids and also emulsifiers containing lipid
segments, which makes them easily prone to chemical conversions
induced by reaction with oxygen.
[0036] According to the chemical structure and solubility in
various phases of typical pharmaceutical or cosmetic carriers, the
compounds may be hydrophilic or lipophilic. The choice of an
optimum antioxidant does not depend just on the solubility in a
certain carrier system, but it is also affected by undesirable
interactions with a carrier, skin penetration ability after a
topical application of the preparation, possibly the production of
cytotoxic or immunosuppressive products of a reaction with free
radicals, with or without combined action of UV light.
[0037] Damage of radicals in the organism of animals and humans,
which may be prevented by the present compounds, has been described
in further detail in U.S. Pat. No. 4,698,360.
[0038] The present compounds, e.g. those of formulae (1), (2)
and/or (3), are useful for the treatment of inflammatory and
allergic conditions (e.g. as described by Skaper et al., Free
Radical Biology and Medicine 22, 669-78 (1997)), as well as for the
treatment of conditions involving disturbances of cell
proliferation. They are preferably used for the local treatment of
radical-induced adverse reactions such as inflammatory and allergic
conditions collagen damage, reperfusion damage, DNA-damage;
especially for the skin treatment.
[0039] In vitro assays show that the present compounds inhibit the
formation of different mediators that are an important factor in
inflammation.
[0040] The present compounds take effect as radical inhibitor. They
represent lipoxygenase/-cyclooxigenase inhibitors, i.e. they can
intervene in the inflammatory cascade. It can be shown that they
take effect as anti-inflammatory agent for the UV induced erythema.
They show anti-inflammatory and antioxidant effect, which in
certain applications is comparable to the one of vitamin E.
[0041] The hindered nitroxyl, hydroxylamine and hydroxylamine salt
compounds (3) are for example of formulae A to EE and A* to EE*
##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017##
##STR00018## ##STR00019## ##STR00020##
wherein [0042] E is oxyl or hydroxyl, [0043] R is hydrogen or
methyl, in formula A and A*, [0044] n is 1 or 2, when n is 1,
[0045] R.sub.1 is hydrogen, alkyl of 1 to 18 carbon atoms, alkenyl
of 2-18 carbon atoms, propargyl, glycidyl, alkyl of 2 to 50 carbon
atoms interrupted by one to twenty oxygen atoms, said alkyl
substituted by one to ten hydroxyl groups or both interrupted by
said oxygen atoms and substituted by said hydroxyl groups, or
[0046] R.sub.1 is alkyl of 1 to 4 carbon atoms substituted by a
carboxy group or by --COOZ where Z is hydrogen, alkyl of 1 to 4
carbon atoms or phenyl, or where Z is said alkyl substituted by
--(COO.sup.-).sub.n M.sup.n+ where n is 1-3 and M is a metal ion
from the 1st, 2nd or 3rd group of the periodic table or is Zn, Cu.
Ni or Co, or M is a group N.sup.n+ (R.sub.2).sub.4 where R.sub.2 is
alkyl of 1 to 8 carbon atoms or benzyl, when n is 2, [0047] R.sub.1
is alkylene of 1 to 12 carbon atoms, alkenylene of 4 to 12 carbon
atoms, xylylene or alkylene of 1 to 50 carbon atoms interrupted by
one to twenty oxygen atoms, substituted by one to ten hydroxyl
groups or both interrupted by said oxygen atoms and substituted by
said hydroxyl groups, in formula B and B*, [0048] m is 1 to 4, when
m is 1, [0049] R.sub.2 is alkyl of 1 to 18 carbon atoms, alkyl of 3
to 18 carbon atoms interrupted by --COO--, or [0050] R.sub.2 is
--CH.sub.2(OCH.sub.2CH.sub.2).sub.nOCH.sub.3 where n is 1 to 12, or
[0051] R.sub.2 is cycloalkyl of 5 to 12 carbon atoms, aryl of 6 to
12 carbon atoms, or said aryl substituted by one to four alkyl
groups of 1 to 4 carbon atoms, or [0052] R.sub.2 is --NHR.sub.3
where R.sub.3 is alkyl of 1 to 18 carbon atoms, cycloalkyl of 5 to
12 carbon atoms, aryl of 6 to 12 carbon atoms, or said aryl
substituted by one to four alkyl of 1 to 4 carbon atoms, or [0053]
R.sub.2 is --N(R.sub.3).sub.2 where R.sub.3 is as defined above,
when m is 2, [0054] R.sub.2 is alkylene of 1 to 12 carbon atoms,
alkenylene of 4 to 12 carbon atoms, xylylene, alkylene of 2 to 12
carbon atoms interrupted by --COO--, or R.sub.2 is
--CH.sub.2(OCH.sub.2CH.sub.2).sub.nOCH.sub.2--where n is 1 to 12,
or [0055] R.sub.2 is cycloalkylene of 5 to 12 carbon atoms,
aralkylene of 7 to 15 carbon atoms or arylene of 6 to 12 carbon
atoms, or [0056] R.sub.2 is --NHR.sub.4NH-- where R.sub.4 is
alkylene of 2 to 18 carbon atoms, cycloalkylene of 5 to 12 carbon
atoms, aralkylene of 8 to 15 carbon atoms or arylene of 6 to 12
carbon atoms, or [0057] R.sub.2 is --N(R.sub.3)R.sub.4N(R.sub.3)--
where R.sub.3 and R.sub.4 are as defined above, or [0058] R.sub.2
is --CO-- or --NH--CO--NH--, when m is 3, [0059] R.sub.2 is
alkanetriyl of 3 to 8 carbon atoms or benzenetriyl, or when m is 4,
[0060] R.sub.2 is alkanetetrayl of 5 to 8 carbon atoms or
benzenetetrayl, in formula C and C*, [0061] R.sub.10 is hydrogen,
alkyl of 1 to 18 carbon atoms, cycloalkyl of 5 to 12 carbon atoms,
aralkyl of 7 to 15 carbon atoms, alkanoyl of 2 to 18 carbon atoms,
alkenoyl of 3 to 5 carbon atoms or benzoyl, [0062] x is 1 or 2,
when x is 1, [0063] R.sub.11 is hydrogen, alkyl of 1 to 18 carbon
atoms, alkenyl of 2 to 18 carbon atoms, propargyl, glycidyl, alkyl
of 2 to 50 carbon atoms interrupted by one to twenty oxygen atoms,
said alkyl substituted by one to ten hydroxyl groups or both
interrupted by said oxygen atoms and substituted by said hydroxyl
groups, or [0064] R.sub.11 is alkyl of 1 to 4 carbon atoms
substituted by a carboxy group or by --COOZ where Z is hydrogen,
alkyl of 1 to 4 carbon atoms or phenyl, or where Z is said alkyl
substituted by --(COO.sup.-).sub.n M.sup.n+ where n is 1-3 and M is
a metal ion from the 1st, 2nd or 3rd group of the periodic table or
is Zn, Cu, Ni or Co, or M is a group N.sup.n+ (R.sub.2).sub.4 where
R.sub.2 is hydrogen, alkyl of 1 to 8 carbon atoms or benzyl, or
when x is 2, [0065] R.sub.11 is alkylene of 1 to 12 carbon atoms,
alkenylene of 4 to 12 carbon atoms, xylylene or alkylene of 1 to 50
carbon atoms interrupted by one to twenty oxygen atoms, substituted
by one to ten hydroxyl groups or both interrupted by said oxygen
atoms and substituted by said hydroxyl groups, in formula D and D*,
[0066] R.sub.10 is as defined above, [0067] y is 1 to 4, and [0068]
R.sub.12 is defined as R.sub.2 above in formula E and E*, [0069] k
is 1 or 2, when k is 1, [0070] R.sub.20 and R.sub.21 are
independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12
carbon atoms or aralkyl of 7 to 15 carbon atoms, or R.sub.20 is
also hydrogen, or [0071] R.sub.20 and R.sub.21 together are
alkylene of 2 to 8 carbon atoms or said alkylene substituted by
hydroxyl, or are acyloxy-alkylene of 4 to 22 carbon atoms, or when
k is 2, [0072] R.sub.20 and R.sub.21 are together
(--CH.sub.2).sub.2C(CH.sub.2--).sub.2, in formula F and F*, [0073]
R.sub.30 is hydrogen, alkyl of 1 to 18 carbon atoms, benzyl,
glycidyl, or alkoxyalkyl of 2 to 6 carbon atoms, [0074] g is 1 or
2, when g is 1, R.sub.31 is defined as R.sub.1 above when n is 1,
when g is 2, R.sub.31 is defined as R.sub.1 above when n is 2, in
formula G and G*, [0075] Q.sub.1 is --NR.sub.41-- or --O--, [0076]
E.sub.1 is alkylene of 1 to 3 carbon atoms, or E.sub.1 is
--CH.sub.2--CH(R.sub.42)--O-- where R.sub.42 is hydrogen, methyl or
phenyl, or E.sub.1 is --(CH.sub.2).sub.3--NH-- or E.sub.1 is a
direct bond, [0077] R.sub.40 is hydrogen or alkyl of 1 to 18 carbon
atoms, [0078] R.sub.41 is hydrogen, alkyl of 1 to 18 carbon atoms,
cycloalkyl of 5 to 12 carbon atoms, aralkyl of 7 to 15 carbon
atoms, aryl of 6 to 10 carbon atoms, or R.sub.41 is
--CH.sub.2--CH(R.sub.42)--OH where R.sub.42 is as defined above, in
formula H and H*, [0079] p is 1 or 2, [0080] T.sub.4 is as defined
for R.sub.11 when x is 1 or 2, [0081] M and Y are independently
methylene or carbonyl, for instance M is methylene and Y is
carbonyl, in formula I and I*, [0082] this formula denotes a
recurring structural unit of a polymer where T.sub.1 is ethylene or
1,2-propylene or is the repeating structural unit derived from an
alpha-olefin copolymer with an alkyl acrylate or methacrylate, and
where [0083] q is 2 to 100, [0084] Q.sub.1 is --N(R.sub.41)-- or
--O-- where R.sub.41 is as defined above, in formula J and J*,
[0085] r is 1 or 2, [0086] T.sub.7 is as defined for R.sub.1 when n
is 1 or 2 in formula A, for example T.sub.7 is octamethylene when r
is 2, in formula L and L*, [0087] u is 1 or 2, [0088] T.sub.13 is
as defined for R when n is 1 or 2 in formula A, with the proviso
that T.sub.13 is not hydrogen when u is 1, in formula M and M*,
[0089] E.sub.1 and E.sub.2, being different, each are --CO-- or
--N(E.sub.5)- where E.sub.5 is hydrogen, alkyl of 1 to 12 carbon
atoms or alkoxycarbonylalkyl of 4 to 22 carbon atoms, for instance
E.sub.1 is --CO-- and E.sub.2 is --N(E.sub.5)-, [0090] E.sub.3 is
hydrogen, alkyl of 1 to 30 carbon atoms, phenyl, naphthyl, said
phenyl or said naphthyl substituted by chlorine or by alkyl of 1 to
4 carbon atoms, or phenylalkyl of 7 to 12 carbon atoms, or said
phenylalkyl substituted by alkyl of 1 to 4 carbon atoms, [0091]
E.sub.4 is hydrogen, alkyl of 1 to 30 carbon atoms, phenyl,
naphthyl or phenylalkyl of 7 to 12 carbon atoms, or [0092] E.sub.3
and E.sub.4 together are polymethylene of 4 to 17 carbon atoms, or
said polymethylene substituted by one to four alkyl of 1 to 4
carbon atoms, for example methyl, in formula N, [0093] R.sub.1 is
as defined for R.sub.1 in formula A when n is 1, [0094] G.sub.3 is
a direct bond, alkylene of 1 to 12 carbon atoms, phenylene or
--NH-G.sub.1-NH-- where G.sub.1 is alkylene of 1 to 12 carbon
atoms, in formula O and O*, [0095] R.sub.10 is as defined for
R.sub.10 in formula C, in formula P and P*, [0096] E.sub.6 is an
aliphtic or aromatic tetravalent radical, for example
neopentanetetrayl or benzenetetrayl, in formula T and T*, [0097]
R.sub.51 is hydrogen, alkyl of 1 to 18 carbon atoms, cycloalkyl of
5 to 12 carbon atoms, or aryl of 6 to 10 carbon atoms, [0098]
R.sub.52 is hydrogen or alkyl of 1 to 18 carbon atoms, or [0099]
R.sub.51 and R.sub.52 together of alkylene of 4 to 8 carbon atoms,
[0100] f is 1 or 2, when f is 1, [0101] R.sub.50 is as defined for
R.sub.11 in formula C when x is 1, or R.sub.50 is
--(CH.sub.2).sub.zCOOR.sub.54 where z is 1 to 4 and R.sub.54 is
hydrogen or alkyl of 1 to 18 carbon atoms, or R.sub.54 is a metal
ion from the 1st, 2nd or 3rd group of the periodic table or a group
--N(R.sub.55).sub.4 where R.sub.55 is hydrogen, alkyl of 1 to 12
carbon atoms or benzyl, when f is 2, R.sub.50 is as defined for
R.sub.11 in formula C when x is 2, in formula U and U*, [0102]
R.sub.53, R.sub.54, R.sub.55 and R.sub.56 are independently alkyl
of 1 to 4 carbon atoms or are together pentamethylene. in formula V
and V*, [0103] R.sub.57, R.sub.58, R.sub.59 and R.sub.60 are
independently alkyl of 1 to 4 carbon atoms or are together
pentamethylene. in formula W and W*, [0104] R.sub.61, R.sub.62,
R.sub.63 and R.sub.64 are independently alkyl of 1 to 4 carbon
atoms or are together pentamethylene, [0105] R.sub.65 is alkyl of 1
to 5 carbon atoms, [0106] M is hydrogen or oxygen, wherein in
formulas X to CC and X* to CC* [0107] n is 2 to 3, [0108] G.sub.1
is hydrogen, methyl, ethyl, butyl or benzyl, [0109] m is 1 to 4,
[0110] x is 1 to 4, when x is 1, [0111] R.sub.1 and R.sub.2 are
independently alkyl of 1 to 18 carbon atoms, said alkyl interrupted
by one to five oxygen atoms, said alkyl substituted by 1 to 5
hydroxyl groups or said alkyl both interrupted by said oxygen atoms
and substituted by said hydroxyl groups; cycloalkyl of 5 to 12
carbon atoms, aralkyl of 7 to 15 carbon atoms, aryl of 6 to 10
carbon atoms or said aryl substituted by one to three alkyl of 1 to
8 carbon atoms, or R.sub.1 is also hydrogen, or R.sub.1 and R.sub.2
are together tetramethylene, pentamethylene, hexamethylene or
3-oxapentamethylene, when x is 2, [0112] R.sub.1 is hydrogen, alkyl
of 1 to 8 carbon atoms, said alkyl interrupted by one or two oxygen
atoms, said alkyl substituted by a hydroxyl group, or said alkyl
both interrupted by one or two oxygen atoms and substituted by a
hydroxyl group, [0113] R.sub.2 is alkylene of 2 to 18 carbon atoms,
said alkylene interrupted by one to five oxygen atoms, said
alkylene substituted by 1 to 5 hydroxyl groups or said alkylene
both interrupted by said oxygen atoms and substituted by said
hydroxyl groups; o-, m- or p-phenylene or said phenylene
substituted by one or two alkyl of 1 to 4 carbon atoms, or [0114]
R.sub.2 is
--(CH.sub.2).sub.kO[(CH.sub.2).sub.kO]h(CH.sub.2).sub.k-- where k
is 2 to 4 and h is 1 to 40, or [0115] R.sub.1 and R.sub.2 together
with the two N atoms to which they are attached are
piperazin-1,4-diyl, when x is 3, [0116] R.sub.1 is hydrogen [0117]
R.sub.2 is alkylene of 4 to 8 carbon atoms interrupted by one
nitrogen atom, when x is 4, [0118] R.sub.1 is hydrogen, [0119]
R.sub.2 is alkylene of 6 to 12 carbon atoms interrupted by two
nitrogen atoms, [0120] R.sub.3 is hydrogen, alkyl of 1 to 8 carbon
atoms, said alkyl interrupted by one or two oxygen atoms, said
alkyl substituted by a hydroxyl group, or both interrupted by one
or two oxygen atoms and substituted by a hydroxyl group, [0121] P
is 2 or 3, and [0122] Q is an alkali metal salt, ammonium or
N.sup.+(G.sub.1).sub.4, in formula DD and DD* [0123] m is 2 or 3,
when m is 2, [0124] G is --(CH.sub.2CHR--O).sub.rCH.sub.2CHR--,
where r is 0 to 3, and R is hydrogen or methyl, and when m is 3,
[0125] G is glyceryl, in formula EE and EE* [0126] G.sub.2 is --CN,
--CONH.sub.2 or --COOG.sub.3 where G.sub.3 is hydrogen, alkyl of 1
to 18 carbon atoms or phenyl, [0127] X is an inorganic or organic
anion, such as phosphate, phosphonate, carbonate, bicarbonate,
nitrate, chloride, bromide, bisulfite, sulfite, bisulfate, sulfate,
borate, formate, acetate, benzoate, citrate, oxalate, tartrate,
acrylate, polyacrylate, fumarate, maleate, itaconate, glycolate,
gluconate, malate, mandelate, tiglate, ascorbate, polymethacrylate,
a carboxylate of nitrilotriacetic acid,
hydroxyethylethylenediaminetriacetic acid,
ethylene-diaminetetraacetic acid or of
diethylenetriaminepentaacetic acid, a
diethylenetriamine-pentamethylenephosphonate, an alkylsulfonate or
an arylsulfonate, and where the total charge of cations h is equal
to the total charge of anions j.
[0128] For example, the compounds (3) are those of formulas A, A*,
B, B*, C, C*, D, D*, Q, Q*, R, R*, S, S*, X, X*, Y, Y*, Z and Z*,
[0129] R is hydrogen, in formula A and A* [0130] n is 1 or 2, when
n is 1, [0131] R.sub.1 is hydrogen, alkyl of 1 to 6 carbon atoms,
alkenyl of 2-6 carbon atoms, propargyl, glycidyl, alkyl of 2 to 20
carbon atoms interrupted by one to ten oxygen atoms, said alkyl
substituted by one to five hydroxyl groups or both interrupted by
said oxygen atoms and substituted by said hydroxyl groups, or
[0132] R.sub.1 is alkyl of 1 to 4 carbon atoms substituted by a
carboxy group or by --COOZ where Z is hydrogen or alkyl of 1 to 4
carbon atoms, when n is 2, [0133] R.sub.1 is alkylene of 1 to 8
carbon atoms, alkenylene of 4 to 8 carbon atoms, alkylene of 1 to
20 carbon atoms interrupted by one to ten oxygen atoms, substituted
by one to five hydroxyl groups or both interrupted by said oxygen
atoms and substituted by said hydroxyl groups, in formula B and B*
[0134] m is 1 or 2 when m is 1, [0135] R.sub.2 is alkyl of 1 to 4
carbon atoms or R.sub.2 is
CH.sub.2(OCH.sub.2CH.sub.2).sub.nOCH.sub.3 where n is 1 to 12, or
[0136] R.sub.2 is phenyl, or said phenyl substituted by one to
three methyl groups, [0137] R.sub.2 is --NHR.sub.3 where R.sub.3 is
alkyl of 1 to 4 carbon atoms or phenyl, or said phenyl substituted
by one or two methyl groups, when m is 2, [0138] R.sub.2 is
alkylene of 1 to 8 carbon atoms, alkenylene of 4 to 8 carbon atoms,
or R.sub.2 is --CH.sub.2(OCH.sub.2CH.sub.2).sub.nOCH.sub.2-- where
n is 1 to 12, [0139] R.sub.2 is NHR.sub.4NH where R.sub.4 is of 2
to 6 carbon atoms, aralkylene of 8 to 15 carbon atoms or arylene of
6 to 12 carbon atoms, [0140] R.sub.2 is --CO-- or --NHCONH, in
formula C and C*, [0141] R.sub.10 is hydrogen or, alkanoyl of 1 to
3 carbon atoms, [0142] x is 1 or 2, when x is 1, [0143] R.sub.11 is
hydrogen, alkyl of 1 to 6 carbon atoms or glycidyl, [0144] R.sub.11
is alkyl of 1 to 4 carbon atoms substituted by a carboxy group or
by COOZ where Z is hydrogen or alkyl of 1 to 4 carbon atoms, when x
is 2, [0145] R.sub.11 is alkylene of 1 to 6 carbon atoms, in
formula D and D*, [0146] R.sub.10 is hydrogen, [0147] y is 1 or 2,
[0148] R.sub.12 is defined as R.sub.2 above, in formula Y. Y*, Z
and Z*, [0149] x is 1 or 2, when x is 1, [0150] R.sub.1 and R.sub.2
are independently alkyl of 1 to 4 carbon atoms, or R.sub.1 and
R.sub.2 are together tetramethylene, or pentamethylene, [0151]
R.sub.2 is hydrogen or alkyl of 1 to 4 carbon atoms, said alkyl
group substituted by a hydroxyl group, when x is 2, [0152] R.sub.1
is hydrogen, alkyl of 1 to 4 carbon atoms, said alkyl substituted
by a hydroxyl group, [0153] R.sub.2 is alkylene of 2 to 6 carbon
atoms, [0154] R.sub.3 is as defined above.
[0155] For instance, the compounds (3) are those of formulas A, A*,
B, B*, C, C*, D, D*, Q, Q*, R and R*, [0156] R is hydrogen, in
formula A and A*, [0157] h is 1, [0158] R.sub.1 is hydrogen, alkyl
of 1 to 4 carbon atoms, glycidyl, alkyl of 2 to 4 carbon atoms
interrupted by one or two oxygen atoms, said alkyl substituted by
one or two hydroxyl groups or both interrupted by said oxygen atoms
and substituted by said hydroxyl groups, or [0159] R.sub.1 is alkyl
of 1 to 4 carbon atoms substituted by --COOZ where Z is hydrogen or
alkyl of 1 to 4 carbon atoms, in formula B and B*, [0160] m is 1 or
2, [0161] R.sub.2 is alkyl of 1 to 4 carbon atoms or R.sub.2 is
CH.sub.2(OCH.sub.2CH.sub.2).sub.nOCH.sub.3 where n is 1 to 4, when
m is 2, [0162] R.sub.2 is alkylene of 1 to 8 carbon atoms, in
formula C and C*, [0163] R.sub.10 is hydrogen or alkanoyl of 1 or 2
carbon atoms, [0164] x is 1 or 2, when x is 1, [0165] R.sub.11 is
hydrogen, alkyl of 1 to 4 carbon atoms or glycidyl, [0166] R.sub.11
is alkyl of 1 to 4 carbon atoms substituted by COOZ where Z is
hydrogen or alkyl of 1 to 4 carbon atoms, when x is 2, [0167]
R.sub.11 is alkylene of 1 to 6 carbon atoms, in formula D and D*,
[0168] R.sub.10 is hydrogen, [0169] y is 1 or 2, [0170] R.sub.12 is
defined as R.sub.2 above.
[0171] The selected hindered nitroxyl, hydroxylamine and
hydroxylamine salt compound (3) preferably conforms to the
formula
##STR00021##
where E is oxyl or hydroxyl and G.sub.3, V, c are as defined for
formula (1), or a salt thereof.
[0172] Compounds (3), such as those of formulae A to EE, especially
those of the above formula (3), may be used as such or in form of
suitable acid addition salts, as indicated, for example, in the
above formulae A* to EE*. These are, for example, salts of
pharmaceutically acceptable inorganic or organic acids. Useful acid
addition salts include those with inorganic acids, such as
chlorides or sulfates, or with organic acids, e.g. sulfonic or
carbonic acids, e.g. as hydrogen (or, where appropriate,
dihydrogen) phosphate, phosphonate, carbonate, bicarbonate,
nitrate, chloride, bromide, bisulfite, sulfite, bisulfate, sulfate,
borate, formate, acetate, benzoate, citrate, oxalate, tartrate,
acrylate, polyacrylate, fumarate, maleate, itaconate, glycolate,
gluconate, pyruvate, malate, mandelate, tiglate, ascorbate,
polymethacrylate, a carboxylate of nitrilotriacetic acid,
hydroxyethylethylenediaminetriacetic acid,
ethylenediaminetetraacetic acid or of diethylenetriaminepentaacetic
acid, a diethylenetriaminepentamethylenephosphonate, an
alkylsulfonate or an arylsulfonate, such as methane sulfonates,
benzoates, oxalates or acetates, where appropriate and expedient;
these ions also correspond to preferred meanings of X. The salts
are preferably pharmaceutically acceptable salts. Pharmaceutically
acceptable salts are salts of acids mostly known in the art, e.g.
of acids like alkanecarboxylic acids (especially of
C.sub.1-C.sub.4acids); di- or polycarboxylic and/or
hydroxycarboxylic acids such as oxalic, malonic, succinic, fumaric,
citric, maleic, tartaric, lactic acid, glucuronic acid and other
acids derived from sugars, each of these acids in both enantiomeric
forms where optically active; phosphoric, sulfuric, methylsulfonic,
toluenesulfonic, benzoic acid; some preferred salts include
hydrochlorides, hydrobromides, hydroiodides, benzoates, phosphates,
hydrogenphosphates, sulfates, hydrogensulfates and especially
citrates. Preferred are, for example, citrates, hydrochlorides,
oxalates.
[0173] C.sub.1-C.sub.22Alkyl is straight-chain or branched alkyl
radicals, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
sec-butyl, tert-butyl, amyl, isoamyl or tert-amyl, heptyl, octyl,
isooctyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, pentadecyl,
hexadecyl, heptadecyl, octadecyl or eicosyl.
[0174] C.sub.1-C.sub.22Alkylthio is straight-chain or branched
alkylthio radicals, such as methylthio, ethylthio, n-propylthio,
isopropylthio, n-butylthio, sec-butylthio, tert-butylthio,
amylthio, heptylthio, octylthio, isooctylthio, nonylthio,
decylthio, undecylthio, dodecylthio, tetradecylthio,
pentadecylthio, hexadecylthio, heptadecylthio, octadecylthio or
eicosylthio.
[0175] C.sub.2-C.sub.22Alkylthioalkyl is alkylthio as described
above attached by its sulfur atom to alkyl, where the total residue
contains 2-22 carbon atoms.
[0176] C.sub.2-C.sub.18Alkenyl is, for example, allyl, methallyl,
isopropenyl, 2-butenyl, 3-butenyl, isobutenyl, n-penta-2,4-dienyl,
3-methyl-but-2-enyl, n-oct-2-enyl, n-dodec-2-enyl, isododecenyl,
n-dodec-2-enyl or n-octadec-4-enyl.
[0177] C.sub.5-C.sub.7Cycloalkyl is cyclopentyl, cycloheptyl or,
preferably, cyclohexyl.
[0178] C.sub.7-C.sub.9-Phenylalkyl includes phenylpropyl (such as
cumyl), phenylethyl and, preferably, benzyl.
[0179] M as alkali often is Li, Na, K, Cs.
[0180] Useful compounds of present formulae (1) and (2) include
those listed in Table 1:
TABLE-US-00001 TABLE 1 compound of formula (7) ##STR00022## (8)
##STR00023## (9) ##STR00024## (10) ##STR00025## (11) ##STR00026##
(12) ##STR00027## (13) ##STR00028## (14) ##STR00029## (15)
##STR00030## (16) ##STR00031## (17) ##STR00032## (18) ##STR00033##
(19) ##STR00034## (20) ##STR00035## (21) ##STR00036## (22)
##STR00037## (23) ##STR00038## (24) ##STR00039## (25) ##STR00040##
(26) ##STR00041## (27) ##STR00042## (28) ##STR00043## (29)
##STR00044## (30) ##STR00045## (31) ##STR00046## (32) ##STR00047##
(33) ##STR00048##
[0181] Useful hindered amine compounds (3) include the following
ones: hindered nitroxyl, hydroxylamine and hydroxylamine salt
compounds selected from
bis(1-oxy-2,2-6-6-tetramethylpiperidin-4-yl) sebacate;
bis(1-hydroxy-2,2-6-6-tetramethyl piperidin-4-yl) sebacate;
1-hydroxy-2,2-6-6-tetramethyl-4-acetoxypiperidinium citrate;
1-oxyl-2,2,6,6-tetramethyl-4-acetamidopiperidine;
1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidine;
1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium bisulfate;
1-oxyl-2,2,6,6-tetramethyl-4-oxo-piperidine;
1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidine;
1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium acetate;
1-oxyl-2,2,6,6-tetramethyl-4-methoxy-piperidine;
1-hydroxy-2,2,6,6-tetramethyl-4-methoxy-piperidine;
1-hydroxyl-2,2,6,6-tetramethyl-4-methoxy-piperidinium acetate;
1-oxyl-2,2,6,6-tetramethyl-4-acetoxypiperidine;
1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidine;
1-oxyl-2,2,6,6-tetramethyl-4-propoxy-piperidine;
1-hydroxy-2,2,6,6-tetramethyl-4-propoxy-piperidinium acetate;
1-hydroxy-2,2,6,6-tetramethyl-4-propoxy-piperidine;
1-oxyl-2,2,6,6-tetramethyl-4-(2-hydroxy-4-oxapentoxy)piperidine;
1-hydroxy-2,2,6,6-tetramethyl-4-(2-hydroxy-4-oxapentoxy)piperidinium
acetate; 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine;
1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidine;
1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium chloride;
1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium acetate;
1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium bisulfate;
1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium citrate;
bis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) citrate;
tris(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) citrate;
tetra(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium)
ethylenediaminetetraacetate;
tetra(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium)
ethylenediaminetetraacetate;
tetra(1-hydroxy-2,2,6,6-tetramethyl-4-oxopiperidinium)
ethylenediaminetetraacetate;
penta(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium)
diethylenetriaminepentaacetate;
penta(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium)
diethylenetriaminepentaacetate;
penta(1-hydroxy-2,2,6,6-tetramethyl-4-oxopiperidinium)
diethylenetriaminepentaacetate;
tri(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium)
nitrilotriacetate;
tri(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium)
nitrilotriacetate;
tri(1-hydroxy-2,2,6,6-tetramethyl-4-oxopiperidinium)nitrilotriacetate;
penta(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium)
diethylenetriamine-pentamethylenephosphonate;
penta(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium)
diethylenetriaminepentamethylenephosphonate; and
penta(1-hydroxy-2,2,6,6-tetramethyl-4-oxopiperidinium)
diethylenetriaminepentamethylenephosphonate.
[0182] Preferred hindered nitroxyl, hydroxylamine and hydroxylamine
salt compounds of formula (3) are selected from
1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine;
1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidine;
1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium chloride;
1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium acetate;
1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium bisulfate;
1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperi-dinium citrate;
bis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) citrate;
tris(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) citrate;
tetra(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium)
ethylenediaminetetraacetate;
tetra(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium)
ethylenediaminetetraacetate;
tetra(1-hydroxy-2,2,6,6-tetramethyl-4-oxopiperidinium)
ethylenediaminetetraacetate;
penta(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium)
diethylenetriaminepentaacetate;
penta(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium)
diethylenetriaminepentaacetate; and
penta(1-hydroxy-2,2,6,6-tetramethyl-4-oxopiperidinium)
diethylenetriaminepentaacetate.
[0183] For example, the compounds of formula (3) are hydroxylamine
salts selected from
1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium citrate;
bis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) citrate;
tris(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) citrate;
1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium DTPA;
bis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) DTPA;
tris(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) DTPA;
tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) DTPA;
pentakis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) DTPA;
1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium EDTA;
bis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) EDTA;
tris(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) EDTA;
tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) EDTA;
1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium citrate;
bis(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) citrate;
tris(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) citrate;
1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium DTPA;
bis(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) DTPA;
tris(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) DTPA;
tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) DTPA;
pentakis(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) DTPA;
1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium EDTA;
bis(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) EDTA;
tris(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) EDTA;
tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-oxo-piperidinium) EDTA;
1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium citrate;
bis(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium) citrate;
tris(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium)
citrate; 1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium
DTPA; bis(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium)
DTPA; tris(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium)
DTPA; tetrakis(1-hydroxy-2,2,6,6-tetra
methyl-4-acetamidopiperidinium) DTPA;
pentakis(1-hydroxy-2,2,6,6-tetramethyl-4-acetamido-piperidinium)
DTPA; 1'-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium EDTA;
bis(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium) EDTA;
tris(1-hydroxy-2,2,6,6-tetramethyl-4-acetamidopiperidinium) EDTA;
tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) EDTA;
1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium citrate;
bis(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) citrate;
tris(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) citrate;
1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium DTPA;
bis(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) DTPA;
tris(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) DTPA;
tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) DTPA;
pentakis(1-hydroxy-2,2,6,6-tetramethyl-4- acetoxypiperidinium)
DTPA; 1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium EDTA;
bis(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium) EDTA;
tris(1-hydroxy-2,2,6,6-tetra methyl-4-acetoxypiperid in ium) EDTA
and tetrakis(1-hydroxy-2,2,6,6-tetramethyl-4-acetoxypiperidinium)
EDTA.
[0184] The above named counter-ions are ethylenediaminetetraacetic
acid (EDTA), diethylene-triaminepentaacetic acid (DTPA),
hydroxyethylethylenediaminetriacetic acid (HEDTA), nitrilotriacetic
acid (NTA) or diethylenetriaminepentamethylenephosphonic acid
(DTPMPA).
[0185] G.sub.1 and G.sub.2 preferably are, independently of each
other, C.sub.1-C.sub.18alkyl and, in particular,
C.sub.1-C.sub.5alkyl, especially tert.-butyl. In preferred
compounds of the formula (1) or (2), G.sub.1 is located in
meta-position relative to G.sub.2.
[0186] G.sub.3 is most preferred as hydrogen;
C.sub.1-C.sub.22alkyl; SO.sub.3M; propyl substituted by OH and/or
by C.sub.2-C.sub.22alkanoyloxy; a direct bond; --CH.sub.2--;
##STR00049##
propyl substituted by OH or C.sub.2-C.sub.22alkanoyloxy;
##STR00050##
[0187] Preferred G.sub.4 and G.sub.5 independently are H or
C.sub.1-C.sub.4alkyl, especially methyl.
[0188] Of specific technical interest are those compounds of the
formula (1) containing a thio group, i.e. those wherein G.sub.1
and/or G.sub.3 are selected from alkylthio, alkylthioalkyl,
--S--.
[0189] It is preferred to use compounds of formula (1) and/or (2),
especially wherein [0190] a is 1; each of b, c, d, e, n, M, q, V is
as defined above; [0191] Q, where present, is --C.sub.mH.sub.2m--
and, preferably, a methylene or ethylene radical, [0192] T, where
present, is --C.sub.nH.sub.2n-- or phenylene; [0193] G.sub.3 is
hydrogen; C.sub.1-C.sub.22alkyl; SO.sub.3M; propyl substituted by
OH and/or by C.sub.2-C.sub.22alkanoyloxy; or G.sub.3 is a direct
bond; --CH.sub.2--;
##STR00051##
[0193] or propyl substituted by OH or
C.sub.2-C.sub.22alkanoyloxy;
or G.sub.3 is
[0194] ##STR00052## [0195] G.sub.4 and G.sub.5 independently are H
or C.sub.1-C.sub.4alkyl, especially methyl; most preferred among
them are those compounds of the formula (1), wherein [0196] e is 1
or 2 and G.sub.3 is SO.sub.3M; propyl substituted by OH and/or by
C.sub.2-C.sub.22alkanoyloxy; or G.sub.3 is a direct bond;
--CH.sub.2--;
##STR00053##
[0196] or propyl substituted by OH or C.sub.2-C.sub.22alkanoyloxy;
where M is alkali and q is 0 or 1; or of the formula (2).
[0197] Most preferred compound of the formula (3) is of the
formula
##STR00054##
or is an acid addition salt thereof, especially as defined
above.
[0198] Particularly interesting compounds (1) include those of
formula
##STR00055##
wherein [0199] G.sub.1 and G.sub.2 are each independently of the
other C.sub.1-C.sub.5alkyl, or G.sub.1 and G.sub.2 especially are
2,6-di-tert. butyl; [0200] a is 1 or 2, especially 1; and [0201]
G.sub.3, Q, V, T, b, c, d and e have the meanings cited for formula
(1), or especially [0202] b is 1 and Q is ethylene; [0203] c is 1
and V is O or NH; [0204] d is 1 and T is CH.sub.2 or phenylene; and
[0205] e is 1 and G.sub.3 is H, C.sub.1-C.sub.18alkyl such as
methyl or C.sub.17alkyl, or is SO.sub.3Na; or [0206] e is 4 and
G.sub.3 is a carbon atom; or each of b, c and d is 0, e is 2 and
G.sub.3 is methylene or ethylidene.
[0207] Most preferred compounds are those of formula (1),
especially wherein G.sub.1 and G.sub.2 are the tert-butyl radical;
and a is 1.
[0208] It is also preferred to use compounds of formula
##STR00056##
wherein [0209] G.sub.1 and G.sub.2 are each independently of the
other C.sub.1-C.sub.5alkyl; [0210] Q is --C.sub.mH.sub.2m--; or
--C.sub.mH.sub.2m--NH--; [0211] G.sub.3 is a direct bond; --O--;
--S--; --CH.sub.2--; or
[0211] ##STR00057## [0212] a is 1 or 2; [0213] m is 1 to 5; and
[0214] T has the meaning cited in formula (1).
[0215] Interesting compounds of formula (1) are those, wherein
[0216] Q is ethylene; or
[0216] ##STR00058## [0217] G.sub.3 is a direct bond; and [0218]
G.sub.1, G.sub.2, T and a have the meanings given in formula
(3).
[0219] Likewise preferred are compounds of formula
##STR00059##
(6) wherein [0220] Q is --C.sub.mH.sub.2m--; [0221] T is
--C.sub.nH.sub.2n--; [0222] G.sub.1 and G.sub.2 are each
independently of the other C.sub.1-C.sub.5alkyl; [0223] G.sub.3 is
the radical of formula (1g); (1h); (1i); or (1k); [0224] m and n
are each independently of the other 1 to 3; [0225] a is 1 or 2; and
[0226] b and d are each independently of the other 0 or 1.
[0227] Other antioxidants which are preferably used conform to
formula
##STR00060##
wherein [0228] A is a radical of formula
[0228] ##STR00061## [0229] G.sub.1, G.sub.2 and G.sub.3 are each
independently of one another C.sub.1-C.sub.5alkyl; and [0230] m is
1 to 3.
[0231] Other preferred antioxidants are those of formula
##STR00062##
wherein [0232] B is a radical of formula
[0232] ##STR00063## [0233] G.sub.1 and G.sub.2 are each
independently of the other C.sub.1-C.sub.5alkyl; [0234] V is --O--;
or --NH--; [0235] a is 1; or 2; [0236] m is 1 to 3; and [0237] n is
0 to 3.
[0238] Present compounds, e.g. those of formulae (1), (2) and (3),
previously have been known as antioxidants for plastics and certain
other organic materials.
[0239] Within the present invention, they can be used as individual
compounds or as mixtures of several individual compounds. Owing to
their good solubility, they can be easily incorporated into the
respective formulations.
[0240] Present compounds, e.g. those of formulae (1), (2), (3), can
also be used together with tocopherol and/or tocopherol acetate,
ascorbic acid and/or derivatives or esters thereof, retinal,
retinal, retinoic acid and/or derivatives thereof.
[0241] Such further hydrophilic or lipophilic components are
usually contained within the concentration range from 0.001% to 10%
of the total weight of the preparation. Those additional components
are preferably selected from the group consisting of [0242]
tocopherol (.alpha., .beta., .gamma., .delta. isomers) and its
esters of acids with general formulas
[0242] H(CH2)n(CHR)COOH (1)
CH3(CH2)mCH.dbd.CH(CH2)nCOOH (2)
where R is hydrogen atom or OH group, m, n are integral numbers
from 0 to 22 where m+n sum is maximally 22; [0243] tocotrienol
(.alpha., .beta., .gamma., .delta. isomers), containing one
unsaturated fatty chain, and its esters of acids; [0244] ascorbic
acid and its esters of acids such as phosphoric acid and also
sodium, potassium, lithium and magnesium salts, Ascorbyl
Tetraisopalmitate, further ester with pyrrolidoncarboxylic acid and
esters of acids with general formulas
[0244] H(CH2)n(CHR)COOH (3)
CH3(CH2)mCH.dbd.CH(CH2)nCOOH (4)
where R is hydrogen atom or OH group, m, n are integral numbers
from 0 to 20 where m+n sum is maximally 21; [0245] retinoids
including all natural and/or synthetic analogs of vitamin A or
retinal-like compounds which possess the biological activity of
vitamin A in the skin as well as the geometric isomers and
stereoisomers of these compounds. Preferred compounds are retinal,
retinol esters (e.g., C2-C22 alkyl esters (saturated or unsaturated
alkyl chains) of retinal, including retinyl palmitate, retinyl
acetate, retinyl propionate), retinal, and/or retinoic acid
(including all trans retinoic acid and/or 13-cis-retinoic acid) or
derivatives. Other retinoids which are useful herein are described
in U.S. Pat. N.sup.o 4,677,120, issued Jun. 30, 1987 to Parish et
al; 4,885,311, issued Dec. 5, 1989 to Parish et al; 5,049,584,
issued Sep. 17, 1991 to Purcell et al., 5,124,356, issued Jun. 23,
1992 to Purcell et al. Other suitable retinoids are
tocopheryl-retinoate [tocopherol ester of retinoic acid (trans or
cis)], adapalene [6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphtoic
acid] and tazarotene (ethyl
6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl]nicotinate); [0246]
carotenoids such as .alpha.-, .beta.-, .gamma.-, and
.delta.-carotene, lutein, xanthophylls, zeaxanthine, violaxanthine,
cryptoxanthine, fukoxanthine, antheraxanthine, lycopene,
didehydrolycopene and tetradehydrolycopene carotenoids [0247]
enzymatic antioxidants such as Glutathione peroxidase, Catalase,
Superoxide dismutase; [0248] Ubiquinone and Idebenone(hydroxydecyl
Ubiquinone), Ubiquinol and its derivatives; [0249] lipoic acid and
its derivatives such as alpha-lipoic acid; [0250] rutinic acid and
its derivatives such as .alpha.-glucosylrutin, a water soluble
flavonoid, rutin hydrate (vitamin P); [0251] plant extracts such as
white and green tea extracts, chicory leaf extract (Cichorium
intubybus), Passionflower extract (Passiflora incarnata),
Aspalathus linearis extract, rosmary extract, red leaf extract of
Aceraceae Maple tree or of Rosaceae Cherry tree, Curcuma longa L
(curcuminoids active ingredients), Leontopodium alpinum extract,
Emblica officinalis (phyllanthus emblica) tree extract; [0252]
phenolic acids such as caffeic acid, 3,4-dihydroxyphenyl acetic
acid, 3,4-dihydroxybenzoic acid; [0253] flavonoids and polyphenols
such as flavanones selected from the group consisting of
unsubstituted flavanones, mono-substituted flavanones, and mixtures
thereof; chalcones selected from the group consisting of
unsubstituted Chalcones, mon-substituted chalcones, di-substituted
chalcones, tri-substituted chalcones, and miture thereof; flavones
selected from the group consisting of unsubstituted flavones,
mono-substituted flavones, di-substituted flavones, and mixtures
thereof; one or more isoflavones; coumarins selected from the group
consisting of unsubstituted coumarins, mono-substituted coumarins,
di-substituted coumarins, and mixtures thereof; flavonols,
anthocyanins, catechins, proanthocyanidins (Grape seed extract).
Flavonoids which are broadly disclosed in U.S. Pat. Nos. 5,686,082
and 5,686,367 can also be used; [0254] chlorogenic acid and ferulic
acid.
[0255] It is also possible to use a further kind of antioxidant
that interrupts the photochemical reaction chain triggered when UV
radiation penetrates the skin or hair. Typical examples of such
antioxidants are amino acids (e.g. glycine, histidine, tyrosine,
tryptophan) and derivatives thereof, imidazoles (e.g. urocanic
acid) and derivatives thereof, peptides, such as D,L-carnosine,
D-carnosine, L-carnosine and derivatives thereof (e.g. anserine),
carotinoids, carotenes, lycopene and derivatives thereof,
chlorogenic acid and derivatives thereof, lipoic acid and
derivatives thereof (e.g. dihydrolipoic acid), aurothioglycose,
propylthiouracil and other thiols (e.g. thioredoxin, glutathione,
cysteine, cystine, cystamine and the glycosyl, N-acetyl, methyl,
ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl, linoleyl,
cholesteryl and glyceryl esters thereof) and also salts thereof,
dilauryl thiodipropionate, distearyl thiodipropionate,
thiodipropionic acid and derivatives thereof (esters, ethers,
peptides, lipids, nucleotides, nucleosides and salts) and also
sulfoximine compounds (e.g. buthionine sulfoximines, homocysteine
sulfoximine, buthionine sulfones, penta-, hexa-, hepta-thionine
sulfoximine), also (metal) chelating agents (e.g. hydroxy fatty
acids, palmitic acid phytic acid, lactoferrin, chitosan and
derivatives such as phosphonomethylated chitosan) and preferably
those disclosed in U.S. Pat. N.sup.0 5,487,884; WO91/16035;
WO91/16034; hydroxy acids (e.g. citric acid, lactic acid, malic
acid), humic acid, bile acid, bile extracts, bilirubin, biliverdin,
EDTA, EDDS, EGTA and derivatives thereof, unsaturated fatty acids
and derivatives thereof (e.g. linolenic acid, linoleic acid, oleic
acid), folic acid and derivatives thereof, ubiquinone and ubiquinol
and derivatives thereof, vitamin C and derivatives (e.g. ascorbyl
palmitate, magnesium ascorbyl phosphate, ascorbyl acetate),
tocopherols and derivatives (e.g. vitamin E acetate), vitamin A and
derivatives (e.g. vitamin A palmitate) and also coniferyl benzoate
of benzoin resin, rutinic acid and derivatives thereof,
glycosylrutin, ferulic acid, furfurylidene glucitol, carnosine,
butyl hydroxytoluene, butyl hydroxyanisole, nordihydroguaiaretic
acid, trihydroxybutyrophenone, uric acid and derivatives thereof,
mannose and derivatives thereof, superoxide dismutase,
N-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyl]sulfanilic acid
(and salts thereof, for example the disodium salts), zinc and
derivatives thereof (e.g. ZnO, ZnSO.sub.4), selenium and
derivatives thereof (e.g. selenium methionine), stilbene and
derivatives thereof (e.g. stilbene oxide, trans-stilbene oxide) and
the derivatives suitable according to the invention (salts, esters,
ethers, sugars, nucleotides, nucleosides, peptides and lipids) of
those mentioned active ingredients. Further HALS ("Hindered Amine
Light Stabilizers") compounds may also be mentioned.
[0256] Further synthetic and natural antioxidants are listed e.g.
in WO 00/25731 (see e.g. structures 1-3 (page 2), structure 4 (page
6), structures 5-6 (page 7) and compounds 7-33 (page 8-14)).
[0257] The topical application may additionally contain at least
one further component with anti-inflammatory effect, preferably
from 0.01% to 10% more preferably about 0.5% to about 5%, of the
composition, such as: [0258] steroidal anti-inflammatory agents,
including but not limited to, corticosteroids such as
hydrocortisone and their derivatives; [0259] non-steroidal
anti-inflammatory agents, including but not limited to, oxicams,
salycilates, acetic acid derivatives, fenamates, propionic acid
derivatives, pyrazoles; [0260] natural anti-inflammatory agents
including, but not limited to, .alpha.-bisabolol, allantoin,
lyophilized extract of aloe vera, panthenol, betulin, compounds of
the Licorice (Glycyrrhiza glabra) including glycyrrhetic acid,
glycyrrhizic acid, and derivatives thereof (salts and esters) such
as sodium glycyrrhizinate, potassium glycyrrhizinate, ammonium
glycyrrhizinate; botulinic acid, alkaline salts thereof and salts
of alkaline-earth metals, boswellic acid, alkaline salts thereof
and salts of alkaline-earth metals, rosemaric acid, alkaline salts
thereof and salts of alkaline-earth metals; polynonsatured fatty
acids, as linoleic (18:2n6), .alpha.-linolenic (18:3n3),
.gamma.-linolenic (18:3n6), octadekanetetraenic (18:4n3),
dihomo-.gamma.-linolenic (20:3n6), eikosantetraenic (20:4n3),
arachidonic (20:4n6), eikosanpentaenic (20:5n3) acids and esters
thereof with alcohols of the general formula
[0260] R1(CH2)m-(CHOH)--(CH2)nR2 (5)
where R1 and R2 are hydrogen atoms or OH group, m, n are integral
numbers from 0 to 17 where m+n sum is maximally 21; phytosterols
and their polyethoxylate derivatives of the general formulas (6)
and(7) below, where R is isoalkyl or isoalkenyl group with 8-10
carbon atoms, where n is integral number from 0 to 50, especially
campesterol, .beta.-sitosterol, stigmasterol, cholesterol,
.DELTA.-5-avenasterol, .DELTA.-7-avenasterol, brassicasterol,
spinasterol and fukosterol
##STR00064##
[0261] The pharmaceutical compositions include liquid, semisolid or
solid preparations.
[0262] Examples of liquid pharmaceutical compositions are
injectable solutions, infusion solutions, drops, sprays, aerosols,
emulsions, lotions, suspensions, drinking solutions, gargles and
inhalants.
[0263] Examples of semisolid pharmaceutical compositions are
ointments, creams (O/W emulsions), rich creams (W/O emulsions),
gels, lotions, foams, pastes, suspensions, ovula, plasters,
including applications for transdermal systems such as masks,
compresses, pads.
[0264] Examples of solid pharmaceutical compositions are tablets,
coated tablets, capsules, granules, effervescent granules,
effervescent tablets, lozenges, sucking and chewing tablets,
suppositories, implants, lyophilisates, adsorbates or powders.
[0265] Preferred are liquid or semisolid preparations.
[0266] Galenic pharmaceutical compositions comprising the present
compounds will be understood as meaning in particular emulsions,
ointments, gels, sprays and powders; for example creams, gels,
lotions, alcoholic and aqueous/alcoholic solutions, emulsions,
wax/fat compositions, stick preparations such as lip sticks or
deodorants, powders or ointments.
[0267] The final formulations listed may exist in a wide variety of
presentation forms, for example: [0268] in the form of liquid
preparations as a W/O, O/W, O/W/O, W/O/W or PIT emulsion and all
kinds of microemulsions, [0269] in the form of a gel, [0270] in the
form of an oil, a cream, milk or lotion, [0271] in the form of a
powder, a lacquer, a tablet or make-up, [0272] in the form of a
stick, [0273] in the form of a spray (spray with propellent gas or
pump-action spray) or an aerosol, [0274] in the form of a foam, or
[0275] in the form of a paste.
[0276] Several particulate skin care delivery systems are
proposed:
[0277] A] Nanoemulsions and nanoparticles are mainly based on
lecithin or fractionated phospholipids, especially [0278]
nanoemulsions with particle size range of 20 nm-50 nm represented
by a single layer membrane, including Nanotopes (lipid core
surrounded by a membrane composed of phospholipids and
co-surfactants; stable and small size particle (smaller than
liposomes) due to the intecalation of co-surfactant between the
extending lecithin molecules) and Nanosomes; [0279] nanoparticles
with particle size range of 100 nm-300 nm represented by a bi-layer
membrane; Liposomes, i.e. spherical vesicles comprising amphiphilic
lipids (predominantly phospholipids) enclosing an aqueous core and
forming one or several concentric bi-layers; small unilamellar
vesicles (SUV), large unilamellar vesicles (LUV), large
multilamellar vesicles (MLV) or multivesicullar vesicles
(MVV)).
[0280] The compounds of the invention may, for example, be
incorporated into the bi-layers, into the aqueous core or
distributed in both.
[0281] B] Microcapsules with particle size >1 .mu.m based on
matrix or encapsulation layer (spherical system based on a core
material containing the active; the core is, then, surrounded by
one or several coating layers or shells).
[0282] Polymers used to form those microcapsules include natural
gums, cellulosic ingredients, polysaccharides, synthetic
polyacrylates or polyacrylamides, polyvinyl alcohol (PVA), lipids,
inorganics (silicates/clays), high molecular weight proteins such
as gelatin, albumin etc.; examples include Nylon micro-porous
spheres (Orgasol range from Elf Atochem), Mineral fillers such as
sericite surface-treated by bifunctional coating (reaction between
reactive fatty acid derivatives and the aqueous solution of
sericite); Glycospheres (core based on modified starch and outer
lipid membrane based on fatty acids and polar lipids); carbon
nanotubes; Silica shells, made of silicates, for non aqueous and
solid end-products such as sticks, dry powders etc.
[0283] C] Matrix particulate systems which entrap the active
ingredient within the uniform core matrix; examples: [0284] Solid
Lipid Nanoparticle (SLN) technology based only on solid lipids;
[0285] Nanostructured Lipid Carriers (NLC) made of blend of solid
lipid and liquid lipid (typical particle size diameter within the
range 80 nm-1 .mu.m); [0286] Nanospheres (e.g. U.S. Pat. No.
6,491,902) represented by solid hydrophobic and highly cationic
nanospheres (typical particle size range 10 nm to 1 .mu.m) and
based on solid hydrophobic matrix coated with highly cationic or
bioadhesive layer.
[0287] D] Multi-walled delivery systems, e.g. systems similar to
liposome structures but made only of non-phospholipidic
"membrane-mimetic" amphiphiles such as oleic acid, saturated or
unsaturated fatty acids, long-chain soaps combined with non ionic
surfactants, derivatives of polyglycerol, di-ammonium amphiphiles,
cationic surfactants, cationic amphiphiles involving aminoacid
residues, sucrose fatty acid esters, aqueous mixture of anionic and
cationic surfactants.
[0288] E] Microsponge technology such as a system based on
microscopic polymer-based sphere that consist of interconnecting
voids within a non collapsible structure (non continuous shell);
examples include a copolymer of styrene and divinylbenzene, or
vinyl derivatives, water-swellable particles made of lactose,
cellulose and cellulose derivatives such as Unispheres from
Induchem etc.
[0289] F] Silicone-based vesicles such as multi-layers vesicles
similar to liposome structures, where layers are made of
polyether-modified dimethicone (dimethicone copolyol), silicone
elastomers, blends of dimethicone crosspolymer,
dimethicone/vinyidimethicone crosspolymer or PEG-modified
dimethicone crosspolymer etc.
[0290] G] Cyclodextrins, usually oligomeric and cyclic carbohydrate
compounds containing 6 to 8 glucose units such as .alpha.-, .beta.-
and .gamma.-cyclodextrin.
[0291] According to a preferred method, the present compounds are
applied in nanodispersed or encapsulated form such as described in
US-2005-0191330 (see especially sections [0007-0079], [0120-0133]
and examples) and US-2003-0190347 (see especially sections
[0005-0087] and examples).
[0292] A further aspect of technical importance within the present
invention is the finding that the present compounds are able to
protect other active ingredients, especially oxidizable natural
substances or active ingredients such as vitamins, plant extracts,
fragrances etc., most effectively from premature degradation when
encapsulated together with the ingredient. The present compounds in
such cases thus are also useful in purely cosmetic formulations,
where none of their pharmacological advantages are required, but
the protection of another active, e.g. a vitamin such as vitamin A,
E or C is sought.
[0293] Examples for end formulations containing the composition of
the invention also include [0294] skin-care preparations, e.g.
skin-washing and cleansing preparations in the form of tablet-form
or liquid soaps, soapless detergents or washing pastes, [0295] bath
preparations, e.g. liquid (foam baths, milks, shower preparations)
or solid bath preparations, e.g. bath cubes and bath salts; [0296]
skin-care preparations, e.g. skin emulsions, multi-emulsions or
skin oils; [0297] personal care preparations, e.g. facial make-up
in the form of day creams or powder creams, face powder (loose or
pressed), rouge or cream make-up, eye-care preparations, e.g.
eyeshadow preparations, mascara, eyeliner, eye creams or eye-fix
creams; lip-care preparations, e.g. lipsticks, lip gloss, lip
contour pencils, nail-care preparations, such as nail varnish, nail
varnish removers, nail hardeners or cuticle removers; [0298]
foot-care preparations, e.g. foot baths, foot powders, foot creams
or foot balsams, special deodorants and antiperspirants or
callus-removing preparations; [0299] light-protective preparations,
such as sun milks, lotions, creams or oils, sunblocks or tropicals,
pre-tanning preparations or after-sun preparations; [0300]
skin-tanning preparations, e.g. self-tanning creams; [0301]
depigmenting preparations, e.g. preparations for bleaching the skin
or skin-lightening preparations including rinse off preparations
such as soaps and leave on preparations such as creams etc.;
medicated bar soaps and liquid containing antifungals, anti
bacterials etc.; [0302] insect-repellents, e.g. insect-repellent
oils, lotions, sprays or sticks; [0303] deodorants, such as
deodorant sprays, pump-action sprays, deodorant gels, sticks or
roll-ons; [0304] antiperspirants, e.g. antiperspirant sticks,
creams or roll-ons; [0305] preparations for cleansing and caring
for blemished skin, e.g. synthetic detergents (solid or liquid),
peeling or scrub preparations or peeling masks; [0306] hair-removal
preparations in chemical form (depilation), e.g. hair-removing
powders, liquid hair-removing preparations, cream- or paste-form
hair-removing preparations, hair-removing preparations in gel form
or aerosol foams; [0307] shaving preparations, e.g. shaving soap,
foaming shaving creams, non-foaming shaving creams, foams and gels,
preshave preparations for dry shaving, aftershaves or aftershave
lotions; [0308] fragrance preparations, e.g. fragrances (eau de
Cologne, eau de toilette, eau de parfum, parfum de toilette,
perfume), perfume oils or perfume creams; [0309] hair-treatment
preparations, e.g. hair-washing preparations in the form of
shampoos and conditioners, hair-care preparations, e.g.
pretreatment preparations, hair tonics, styling creams, styling
gels, pomades, hair rinses, treatment packs, intensive hair
treatments, hair-structuring preparations, e.g. hair-waving
preparations for permanent waves (hot wave, mild wave, cold wave),
hair-straightening preparations, liquid hair-setting preparations,
hair foams, hairsprays, bleaching preparations, e.g. hydrogen
peroxide solutions, lightening shampoos, bleaching creams,
bleaching powders, bleaching pastes or oils, temporary,
semi-permanent or permanent hair colourants, preparations
containing self-oxidising dyes, or natural hair colourants, such as
henna or camomile.
[0310] Of special importance as preparations for the skin are daily
care and/or anti-aging preparations, including light-protective
preparations, such as sun milks, lotions, creams, oils, sunblocks
or topicals, pretanning preparations or after-sun preparations,
also skin-tanning preparations, for example self-tanning creams,
skin whitener preparations, skin lightener preparations or
combinations of such systems. Of particular interest are anti-aging
preparations in combination with UV-protecting systems such as
dayly care creams, dayly care lotions, dayly care milk and dayly
care preparations in the form of a spray.
[0311] The compositions/preparations according to the invention
may, where appropriate, also contain one or one more additional
compounds as described below, especially in preparations for skin
treatment:
Fatty Alcohols
[0312] Guerbet alcohols based on fatty alcohols having from 6 to
18, preferably from 8 to 10 carbon atoms including cetyl alcohol,
stearyl alcohol, cetearyl alcohol, oleyl alcohol, octyidodecanol,
benzoate of C.sub.12-C.sub.15 alcohols, acetylated lanolin alcohol,
etc.
Esters of Fatty Acids
[0313] Esters of linear C.sub.6-C.sub.24 fatty acids with linear
C.sub.3-C.sub.24 alcohols, esters of branched
C.sub.6-C.sub.13carboxylic acids with linear C.sub.6-C.sub.24 fatty
alcohols, esters of linear C.sub.6-C.sub.24 fatty acids with
branched alcohols, especially 2-ethylhexanol, esters of
hydroxycarboxylic acids with linear or branched C.sub.6-C.sub.22
fatty alcohols, especially dioctyl malates, esters of linear and/or
branched fatty acids with polyhydric alcohols (for example
propylene glycol, dimer diol or trimer triol) and/or Guerbet
alcohols, for example caproic acid, caprylic acid, 2-ethylhexanoic
acid, capric acid, lauric acid, isotridecanoic acid, myristic acid,
palmitic acid, palmitoleic acid, stearic acid, isostearic acid,
oleic acid, elaidic acid, petroselinic acid, linoleic acid,
linolenic acid, elaeostearic acid, arachidic acid, gadoleic acid,
behenic acid and erucic acid and technical-grade mixtures thereof
(obtained, for example, in the pressure removal of natural fats and
oils, in the reduction of aldehydes from Roelen's oxosynthesis or
in the dimerisation of unsaturated fatty acids) with alcohols, for
example, isopropyl alcohol, caproic alcohol, capryl alcohol,
2-ethylhexyl alcohol, capric alcohol, lauryl alcohol, isotridecyl
alcohol, myristyl alcohol, cetyl alcohol, palmoleyl alcohol,
stearyl alcohol, isostearyl alcohol, oleyl alcohol, elaidyl
alcohol, petroselinyl alcohol, linoyl alcohol, linolenyl alcohol,
elaeostearyl alcohol, arachidyl alcohol, gadoleyl alcohol, behenyl
alcohol, erucyl alcohol and brassidyl alcohol and technical-grade
mixtures thereof (obtained, for example, in the high-pressure
hydrogenation of technical-grade methyl esters based on fats and
oils or aldehydes from Roelen's oxosynthesis and as monomer
fractions in the dimerisation of unsaturated fatty alcohols).
[0314] Examples of such ester oils are isopropylmyristate,
isopropylpalmitate, isopropylstearate, isopropyl isostearate,
isopropyloleate, n-butylstearate, n-hexyllaurate, n-decyloleate,
isooctyl-stearate, iso-nonylstearate, isononyl isononanoate,
2-ethylhexylpalmitate, 2-hexyllaurate, 2-hexyldecylstearate,
2-octyldodecylpalmitate, oleyloleate, oleylerucate, erucyloleate,
erucylerucate, cetearyl octanoate, cetyl palmitate, cetyl stearate,
cetyl oleate, cetyl behenate, cetyl acetate, myristyl myristate,
myristyl behenate, myristyl oleate, myristyl stearate, myristyl
palmitate, myristyl lactate, propylene glycol dicaprylate/caprate,
stearyl heptanoate, diisostearyl malate, octyl hydroxystearate,
etc.
Other Adjuvants
[0315] alpha glucosylrutin (CAS No. 130603-71-3), 2-butyloctyl
o-hydroxybenzoate (CAS No. 190085-41-7), vitamin E (CAS No.
1406-18-4), vitamin E acetate(CAS No. 58-95-7), diethylhexyl
2,6-naphthalate, di-n-butyl adipate, di(2-ethylhexyl)-adipate,
di(2-ethylhexyl)-succinate and diisotridecyl acelaat, and also diol
esters, such as ethylene glycol dioleate, ethylene glycol
diisotridecanoate, propylene glycol di(2-ethylhexanoate), propylene
glycol diisostearate, propylene glycol dipelargonate, butanediol
diisostearate and neopentyl glycol dicaprylate. Esters of
C.sub.6-C.sub.24 fatty alcohols and/or Guerbet alcohols with
aromatic carboxylic acids, saturated and/or unsaturated, especially
benzoic acid, esters of C.sub.2-C.sub.12dicarboxylic acids with
linear or branched alcohols having from 1 to 22 carbon atoms or
polyols having from 2 to 10 carbon atoms and from 2 to 6 hydroxy
groups, or iminodisuccinic acid and iminodisuccinic acid salts [CAS
7408-20-0] or latex particles, aloe vera, chamomile, ginko biloba,
ginseng, coenzyme Q10, laminaria ochroleuca extract, magnolia
oborata extract, melalenca alternifolia leaf oil, rubus idaeus seed
oil, vaccinium macrocarpon seed oil, pumpkin seed extract, pumpkin
seed oil, grape seed extract, carnosine, alpha-arbutin,
madecassoside, termino-laside, tetrahydrocurcuminoids (THC),
mycosporines, mycosporine like amino acids from the red alga
porphyra umbilicalis, mycosporine-like amino acids (as described in
WO2002039974), cis-9-octadecenedioic acid, lipoic acid, laurimino
dipropiomic acid tocopheryl phosphates (LDTP), microcrystalline
cellulose (MCC), polycarbonates as described in WO 0341676, sterols
(cholesterol, lanosterol, phytosterols), as described in WO0341675
and linear poly-alpha-glucans as described in U.S. Pat. No.
6,616,935
Natural or Synthetic Triglycerides Including Glyceryl Esters and
Derivatives
[0316] Di- or tri-glycerides, based on C.sub.6-C.sub.18 fatty
acids, modified by reaction with other alcohols (caprylic/capric
triglyceride, wheat germ glycerides, etc.). Fatty acid esters of
polyglycerin (polyglyceryl-n such as polyglyceryl-4 caprate,
polyglyceryl-2 isostearate, etc. or castor oil, hydrogenated
vegetable oil, sweet almond oil, wheat germ oil, sesame oil,
hydrogenated cottonseed oil, coconut oil, avocado oil, corn oil,
hydrogenated castor oil, shea butter, cocoa butter, soybean oil,
mink oil, sunflower oil, safflower oil, macadamia nut oil, olive
oil, hydrogenated tallow, apricot kernel oil, hazelnut oil, borago
oil, etc.
[0317] Waxes including esters of long-chain acids and alcohols as
well as compounds having wax-like properties, e.g., carnauba wax,
beeswax (white or yellow), lanolin wax, candellila wax, ozokerite,
japan wax, paraffin wax, microcrystalline wax, ceresin, cetearyl
esters wax, synthetic beeswax, etc. Also, hydrophilic waxes as
Cetearyl Alcohol or partial glycerides.
Pearlescent Waxes:
[0318] Ikylene glycol esters, especially ethylene glycol
distearate; fatty acid alkanolamides, especially coco fatty acid
diethanolamide; partial glycerides, especially stearic acid
monoglyceride; esters of polyvalent, unsubstituted or
hydroxy-substituted carboxylic acids with fatty alcohols having
from 6 to 22 carbon atoms, especially long-chained esters of
tartaric acid; fatty substances, for example fatty alcohols, fatty
ketones, fatty aldehydes, fatty ethers and fatty carbonates, which
in total have at least 24 carbon atoms, especially laurone and
distearyl ether; fatty acids, such as stearic acid, hydroxystearic
acid or behenic acid, ring-opening products of olefin epoxides
having from 12 to 22 carbon atoms with fatty alcohols having from
12 to 22 carbon atoms and/or polyols having from 2 to 15 carbon
atoms and from 2 to 10 hydroxy groups, and mixtures thereof.
Hydrocarbon Oils:
[0319] Mineral oil (light or heavy), petrolatum (yellow or white),
microcrystalline wax, paraffinic and isoparaffinic compounds,
hydrogenated isoparaffinic molecules as polydecenes and polybutene,
hydrogenated polyisobutene, squalane, isohexadecane, isododecane
and others from plant and animal kingdom.
Silicones or Siloxanes (Organosubstituted Polysiloxanes)
[0320] Dimethylpolysiloxanes, methylphenylpolysiloxanes, cyclic
silicones, and also amino-, fatty acid-, alcohol-, polyether-,
epoxy-, fluorine-, glycoside- and/or alkyl-modified silicone
compounds, which at room temperature may be in either liquid or
resinous form. Linear polysiloxanes, dimethicone (Dow Corning 200
fluid, Rhodia Mirasil DM), dimethiconol, cyclic silicone fluids,
cyclopentasiloxanes volatiles (Dow Corning 345 fluid),
phenyltrimethicone (Dow Corning 556 fluid). Also suitable are
simethicones, which are mixtures of dimethicones having an average
chain length of from 200 to 300 dimethylsiloxane units with
hydrogenated silicates. A detailed survey by Todd et al. of
suitable volatile silicones may in addition be found in Cosm. Toil.
91, 27 (1976).
[0321] The term "silicones" stands for any organosilicon polymer or
oligomer having a linear or cyclic, branched or crosslinked
structure, of variable molecular weight, and essentially is based
on recurring structural units in which the silicone atoms are
linked to each other by oxygen atoms (siloxane bond SiOSi),
optionally substituted hydrocarbon radicals being directly linked
via a carbon atom to the silicone atoms.
Examples Include:
[0322] Cyclic siloxane polymers; Cyclomethicones of the general
formula
##STR00065##
such as cyclopentasiloxane, cyclohexasiloxane (low viscous,
volatile fluid; the INCI names for labeling specific cyclic
dimethyl polysiloxane compounds are: Cyclotrisiloxane (q.v.) when n
is equal to 3, Cyclotetrasiloxane (q.v.) when n is equal to 4,
Cyclopentasiloxane (q.v.) when n is equal to 5, Cyclohexasiloxane
(q.v.) when n is equal to 6, and Cycloheptasiloxane when n is equal
to 7 (q.v.));
[0323] Linear siloxane polymer end-blocked with Trimethylsiloxy
units (M unit) Dimethicones; non polar liquid with broad range of
viscosity of the general formula
##STR00066##
[0324] Silanol compounds or dimethiconols, such as Dimethyl
siloxane terminated with hydroxyl groups (--OH) of the general
formula
##STR00067##
[0325] Silicone elastomers and resins obtained by crosslinking of
siloxane structures such as Dimethicones (elastomer: medium
crosslinking with a density that allows elongation/distortion of
the molecule, usually excluding PEG-modified Dimethicone
Crosspolymers; resin: high crosslinking with a density that
provides some rigidity to the molecule).
[0326] Silicone elastomers useful as co-emulsifier systems include
Dimethicone Crosspolymer in Cyclopentasiloxane (e.g. DC 9045
silicone elastomer blend by Dow Corning); Dimethicone Crosspolymer
in Dimethicone (e.g. DC 9041 silicone elastomer blend by Dow
Corning); polymer of Dimethicone (q.v.) crosslinked with a C.sub.3
to C.sub.20 alkyl group; Dimethicone/Vinyidimethicone Crosspolymer
(DC 9506 powder, Dow Corning); Dimethicone/Vinyidimethicone
Crosspolymer in Cyclopentasiloxane (e.g. SFE 839 (GE silicones) or
KSG 15 (Shin-Etsu));
copolymer of dimethylpolysiloxane crosslinked with vinyl
dimethylpolysiloxane.
[0327] Resin silicones include dispersing agents such as KP-545
(Shin-Etsu);
Acrylates/Dimethicone copolymer in Cyclopentasiloxane; copolymer of
dimethicone and one or more monomers of acrylic acid, methacrylic
acid or one of their simple esters; Siloxysilicates such as
Trimethylsiloxysilicates; T-resins; branched polymer of T-Units;
Q-resins; branched polymer of Q-Units:
##STR00068##
film-forming and water-resistant agents such as
Trimethylsiloxysilicate (e.g. SR 399 (GE Silicones) or
Wacker-Belsil TMS803 (Wacker Chemie), mixtures from Dow Corning
such as DC 749 cosmetic fluid (Trimethylsiloxysilicate in
Cyclopentasiloxane) or DC 593 fluid (Trimethylsiloxysilicate in
Dimethicone)); alkyl-modified siloxanes (AMS), which improve
spreadability and wash-off resistance or, e.g. for inorganic
sunscreens, improve particle dispersion, reduce re-agglomeration,
improve long-lasting effect on skin. Examples:
Alkyl Dimethicone of the General Formula
##STR00069##
[0328] wherein R is --(CH2)n-CH3 such as bis-phenylpropyl
Dimethicone (SF 1555 fluid; GE Silicone);
Alkyl Methicone of the General Formula
##STR00070##
[0329] wherein R is --(CH2)n-CH3 i.e. silicone waxes such as DC
2503 cosmetic wax (Dow Corning); Stearyl Dimethicone DC 2502 fluid
(Dow Corning); Cetyl Dimethicone; DC AMS-C30 wax (Dow Corning);
30-C45 Alkyl Methicone; DC 580 wax (Dow Corning);
Stearoxytrimethylsilane and Stearyl Alcohol.
Fluorinated or Perfluorinated Oils
[0330] Perfluorhexane, dimethylcyclohexane, ethylcyclopentane,
polyperfluoromethylisopropyl ether.
Emulsifiers
[0331] Any conventionally usable emulsifier can be used for the
compositions. Emulsifier systems may comprise for example:
carboxylic acids and their salts: alkaline soap of sodium,
potassium and ammonium, metallic soap of calcium or magnesium,
organic basis soap such as Lauric, palmitic, stearic and oleic acid
etc. . . . Alkyl phosphates or phosphoric acid esters, acid
phosphate, diethanolamine phosphate, potassium cetyl phosphate.
Ethoxylated carboxylic acids or polyethyleneglycol esters, PEG-n
acylates. Linear fatty alcohols having from 8 to 22 carbon atoms,
branched from 2 to 30 mol of ethylene oxide and/or from 0 to 5 mol
propylene oxide with fatty acids having from 12 to 22 carbon atoms
and with alkylphenols having from 8 to 15 carbon atoms in the alkyl
group. Fatty alcohol polyglycolether such as laureth-n,
ceteareth-n, steareth-n, oleth-n. Fatty acid polyglycolether such
as PEG-n stearate, PEG-n oleate, PEG-n cocoate. Monoglycerides and
polyol esters. C12-C22 fatty acid mono- and di-esters of addition
products of from 1 to 30 mol of ethylene oxide with polyols. Fatty
acid and polyglycerol ester such as monostearate glycerol,
diisostearoyl polyglyceryl-3-diisostearates,
polyglyceryl-3-diisostearates, triglyceryl diisostearates,
polyglyceryl-2-sesquiisostearates or polyglyceryl dimerates.
Mixtures of compounds from a plurality of those substance classes
are also suitable. Fatty acid polyglycolesters such as monostearate
diethylene glycol, fatty acid and polyethylene glycol esters, fatty
acid and saccharose esters such as sucro esters, glycerol and
saccharose esters such as sucro glycerides. Sorbitol and sorbitan,
sorbitan mono- and di-esters of saturated and unsaturated fatty
acids having from 6 to 22 carbon atoms and ethylene oxide addition
products.
[0332] Polysorbate-n series, sorbitan esters such as
sesquiisostearate, sorbitan, PEG-(6)-isostearate sorbitan,
PEG-(10)-sorbitan laurate, PEG-17-dioleate sorbitan. Glucose
derivatives, C.sub.8-C.sub.22 alkyl-mono and oligo-glycosides and
ethoxylated analogues with glucose being preferred as the sugar
component. O/W emulsifiers such as methyl gluceth-20
sesquistearate, sorbitan stearate/sucrose cocoate, methyl glucose
sesquistearate, cetearyl alcohol/cetearyl glucoside. W/O
emulsifiers such as methyl glucose dioleate/methyl glucose
isostearate. Sulfates and sulfonated derivatives,
dialkylsulfosuccinates, dioctyl succinate, alkyl lauryl sulfonate,
linear sulfonated parafins, sulfonated tetraproplyne sulfonate,
sodium lauryl sulfates, ammonium and ethanolamine lauryl sulfates,
lauyl ether sulfates, sodium laureth sulfates, sulfosuccinates,
aceyl isothionates, alkanolamide sulfates, taurines, methyl
taurines, imidazole sulfates. Amine derivatives, amine salts,
ethoxylated amines, oxide amine with chains containing an
heterocycle such as alkyl imidazolines, pyridine derivatives,
isoquinoteines, cetyl pyridinium chlorure, cetyl pyridinium
bromide, quaternary ammonium such as cetyltrimethylbroide amonium
broide (CTBA), stearylalkonium. Amide derivatives, alkanolamides
such as acylamide DEA, ethoxylated amides such as PEG-n acylamide,
oxy-deamide. Polysiloxane/polyalkyl/polyether copolymers and
derivatives, dimethicone, copolyols, silicone polyethylene oxide
copolymer, silicone glycol copolymer. Propoxylated or POE-n ethers
(Meroxapols), Polaxamers or
poly(oxyethylene)m-block-poly(oxypropylene)n-block(oxyethylene).
Zwitterionic surfactants that carry at least one quaternary
ammonium group and at least one carboxylate and/or sulfonate group
in the molecule. Zwitterionic surfactants that are especially
suitable are betaines, such as N-alkyl-N,N-dimethylammonium
glycinates, cocoalkyldimethylammonium glycinate,
N-acylaminopropyl-N,N-dimethylammonium glycinates,
cocoacylaminopropyldimethylammonium glycinate and
2-alkyl-3-carboxymethyl-3-hydroxyethylimidazolines each having from
8 to 18 carbon atoms in the alkyl or acyl group and also
cocoacylaminoethylhydroxyethylcarboxymethylglycinate,
N-alkylbetaine, N-alkylaminobetaines. Alkylimidazolines,
alkylopeptides, lipoaminoacides, self emulsifying bases and the
compounds as described in K. F. DePolo, A short textbook of
cosmetology, Chapter 8, Table 8-7, p250-251.
[0333] Non ionic emulsifiers such as PEG-6 beeswax (and) PEG-6
stearate (and) polyglyceryl-2-isostearate [Apifac], glyceryl
stearate (and) PEG-100 stearate. [Arlacel 165], PEG-5 glyceryl
stearate [arlatone 983 S], sorbitan oleate (and) polyglyceryl-3
ricinoleate.[Arlacel 1689], sorbitan stearate and sucrose cocoate
[arlatone 2121], glyceryl stearate and laureth-23 [Cerasynth 945],
cetearyl alcohol and ceteth-20 [Cetomacrogol Wax], cetearyl alcohol
and colysorbate 60 and PEG-150 and stearate-20[Polawax GP 200,
Polawax NF], cetearyl alcohol and cetearyl polyglucoside [Emulgade
PL 1618], cetearyl alcohol and ceteareth-20 [Emulgade 1000NI,
Cosmowax], cetearyl alcohol and PEG-40 castor oil [Emulgade F
Special], cetearyl alcohol and PEG-40 castor oil and sodium
cetearyl sulfate [Emulgade F], stearyl alcohol and steareth-7 and
steareth-10 [Emulgator E 2155], cetearyl alcohol and szeareth-7 and
steareth-10 [Emulsifying wax U.S.N.F], glyceryl stearate and PEG-75
stearate [Gelot 64], propylene glycol ceteth-3 acetate.[Hetester
PCS], propylene glycol isoceth-3 acetate [Hetester PHA], cetearyl
alcohol and ceteth-12 and oleth-12 [Lanbritol Wax N 21], PEG-6
stearate and PEG-32 stearate [Tefose 1500], PEG-6 stearate and
ceteth-20 and steareth-20 [Tefose 2000], PEG-6 stearate and
ceteth-20 and glyceryl stearate and steareth-20 [Tefose 2561],
glyceryl stearate and ceteareth-20 [Teginacid H, C, X].
[0334] Anionic emulsifiers such as PEG-2 stearate SE, glyceryl
stearate SE [Monelgine, Cutina KD], propylene glycol stearate
[Tegin P], cetearyl Alcohol and Sodium cetearyl sulfate [Lanette N.
Cutina LE, Crodacol GP], cetearyl alcohol and sodium lauryl sulfate
[Lanette W], trilaneth-4 phopshate and glycol stearate and PEG-2
stearate [Sedefos 75], glyceryl stearate and sodium lauryl Sulfate
[Teginacid Special]. Cationic acid bases such as cetearyl alcohol
and cetrimonium bromide.
[0335] Silicone emulsifiers particularly suitable for W/Si
emulsions are those corresponding to the following formula:
##STR00071##
wherein [0336] m is a number from 1 to 20 [0337] n is a number from
0 to 500 [0338] p is a number from 0 to 50 [0339] R1 is linear or
branched C1-C30 Alkyl radical or phenyl radical [0340] R2 is
--C.sub.cH2.sub.c(--O--C2H4).sub.a--(--O--C3H6).sub.b--(--O--C4H8).sub.d--
-R3 [0341] R3 is --H, --OH; linear or branched alkyl C1-C12; linear
or branched alkoxy C1-C6; linear or branched acyloxy C2-C12;
--NHCH2CH2COOM; aminoalkyl radical optionally substituted on the
amine function; --NHCO(CH2).sub.d-- COOM, C1-C30 carboxyacyl
radical; where M is H, Na, K, Li, NH4 or organic amine; optionally
substituted phosphono group; --NHCO(CH2).sub.d OH; --NH3Y where Y
is a monovalent organic or inorganic anion such as Cl, Br, Sulfate,
Carboxylate (Acetate, Lactate, Citrate). [0342] a is a number from
0 to 100 [0343] b is a number from 0 to 50; and [0344] c is a
number from 0 to 5 [0345] d is a number from 0 to 10.
[0346] These compounds represent the oxyalkylenated organo-modified
silicones. Other denominations used are PEG/PPG Dimethicones
(Dimethicone copolyols) or Silicone polyethers that clearly show
surface active properties necessary to emulsify.
[0347] Preferred silicone emulsifiers which are particularly
recommended correspond to formula
##STR00072##
wherein [0348] n is a number from 1 to 500 [0349] R is linear or
branched C1-C30 Alkyl radical or phenyl radical [0350] R2 is
--C.sub.cH2.sub.c(--O--C2H4).sub.a--(--O--C3H6).sub.b--O(--C4H8).sub.d--R-
3 [0351] R3, a, b, c & d have the same meaning as previously
described
[0352] A non exhaustive list of W/Si emulsifers is given in the
following table:
TABLE-US-00002 INCI denomination Oxyalkylenated organo-modified
slicones: PEG/PPG Dimethicones & Silicone polyethers
Bis-PEG/PPG-14/14 Dimethicone Bis-PEG/PPG-20/20 Dimethicone
Bis-PEG/PPG-16/16 PEG/PPG-16/16Dimethicone Bis_PEG-15 Methyl Ether
Dimethicone Bis(PPG-7 Undeceneth-21) Dimethicone Cetyl
PEG/PPG-15/15 Butyl Ether Dimethicone Cetyl PEG/PPG-7/3 Dimethicone
Cetyl PEG/PPG-10/1 Dimethicone Dimethicone Copolyol Dimethicone
PEG-8 Adipate Dimethicone PEG-7 Avocadoate Dimethicone PEG-8
Avocadoate Dimethicone PEG-8 Beeswax Dimethicone PEG-n esters . . .
Dimethicone/PEG-10 Crosspolymer Dimethicone/PEG-15 Crosspolymer
Dimethicone/PEG-7 Phosphate Dimethicone/PEG-n Phosphates . . .
Dimethicone PEG/PPG-7/4 Phosphate Dimethicone PEG/PPG-12/4
Phosphate Dimethicone PEG-7 Undecylenate Laurylmethicone copolyol
PEG-10 Dimethicone crosspolymer PEG-12 Dimethicone crosspolymer
PEG-10 Lauryl Dimethicone Crosspolymer PEG-15 Lauryl Dimethicone
Crosspolymer PEG-6 Methyl ether Dimethicone PEG-n Methyl ether
Dimethicones . . . PEG-32 Methyl ether Dimethicone PEG/PPG-20/22
Butyl Ether Dimethicone PEG/PPG-22/22 Butyl Ether Dimethicone
PEG/PPG-23/23 Butyl Ether Dimethicone PEG/PPG-24/18 Butyl Ether
Dimethicone PEG/PPG-27/9 Butyl Ether Dimethicone PEG/PPG-3/10
Dimethicone PEG/PPG-5/3 Trisiloxane PEG/PPG-n/m Dimethicones . . .
PEG/PPG-30/10 Dimethicone Potassium Dimethicone PEG-7 Phosphate
PPG-12 Butyl Ether Dimethicone PPG-12 Dimethicone PPG-27
Dimethicone TEA-Dimethicone PEG-7 Phosphate Caprylyl Dimethicone
Ethoxy Glucoside Dimethicone Ethoxy Glucoside
Dimethicone/Polyglycerin-3 Crosspolymer PEG-9
Polydimethylsiloxyethyl Dimethicone Polydimethylsiloxy
PEG/PPG-24/19 Butyl Ether Silsesquioxane Polydimethylsiloxy PPG-13
Butyl Ether Silsesquioxane Polyglyceryl-3 Disiloxane Dimethicone
Polyglyceryl-3 Polydimethylsiloxyethyl Dimethicone Sodium
Carboxydecyl PEG-8 Dimethicone Non-oxyalkylenated organo-modified
silicones: C6-8 Alkyl C3-6 Alkyl Glucoside Dimethicone
[0353] The emulsifiers may be used in an amount of, for example,
from 1 to 30% by weight, especially from 4 to 20% by weight and
preferably from 5 to 10% by weight, based on the total weight of
the composition.
[0354] When formulated in O/W emulsions, the preferably amount of
such emulsifier system could represent 5% to 20% of the oil
phase.
Adjuvants and Additives
[0355] Cosmetic/pharmaceutical preparations, for example creams,
gels, lotions, alcoholic and aqueous/alcoholic solutions,
emulsions, wax/fat compositions, stick preparations, powders or
ointments, may in addition contain, as further adjuvants and
additives, mild surfactants, super-fatting agents, consistency
regulators, thickeners, polymers, stabilisers, biogenic active
ingredients, deodorising active ingredients, anti-dandruff agents,
film formers, swelling agents, further UV light-protective factors,
antioxidants, hydrotropic agents, preservatives, insect repellents,
self-tanning agents, solubilisers, perfume oils, colourants,
bacteria-inhibiting agents and the like.
Super-Fatting Agents
[0356] Substances suitable for use as super-fatting agents are, for
example, lanolin and lecithin and also polyethoxylated or acrylated
lanolin and lecithin derivatives, polyol fatty acid esters,
monoglycerides and fatty acid alkanolamides, the latter
simultaneously acting as foam stabilisers.
Anti-Wrinkle Actives
[0357] The composition of the present preparation may further
comprise suitable anti-wrinkle agents including sulfur-containing D
and L amino acids and their derivatives and salts, particularly the
N-acetyl derivatives, a preferred example of which is
N-acetyl-L-cyteine; thiols; hydroxy acids (salicylic acid, glycolic
acid), keto acids (pyruvic acid), phytic acid, lipoic acid;
lysophophatidic acid, skin peel agents, flavonoids, stilbenes,
cinnamates, resveratrol, kijnetin, zeatin, dimethylaminoethanol,
peptides from natural and synthetic sources, salts of sugar acids
(Mn gluconate), terpene alcohols, vitamin B compounds such as
vitamin B3, vitamin B1 (Thiamine), vitamin B2 (riboflavin), vitamin
B5 (Pantothenic acid), vitamin Bt (carnitine), Vitamin B12
(cobalamine), vitamin B15 (pangamic acid or diisopropylamine
dichloroacetate) and their derivatives salts.
metalloproteinase-inhibitors, trace-elements and
trace-element-complexes such as Cu. Zn, Mn Co, Mg, or Se containing
peptides,
Skin Lightening Agents
[0358] The composition of the present preparation may further
comprise suitable skin lightening ingredients including kojic acid,
arbutin, tranexamic acid, ascorbic acid and derivatives thereof,
e.g., magnesium ascorbyl phosphate or sodium ascorbyl phosphateor
other salts of ascorbyl phosphate. Also those ingredient displayed
in the PCT application N.sup.o US 95/07432, filed on Feb. 24, 1995
and PCT application N.sup.o US 95/02809, filed on Jan. 3, 1995.
Surfactants
[0359] Examples of suitable mild surfactants, that is to say
surfactants especially well tolerated by the skin, include fatty
alcohol polyglycol ether sulfates, monoglyceride sulfates, mono-
and/or di-alkyl sulfosuccinates, fatty acid isethionates, fatty
acid sarcosinates, fatty acid taurides, fatty acid glutamates,
.alpha.-olefin sulfonates, ethercarboxylic acids, alkyl
oligoglucosides, fatty acid glucamides, alkylamidobetaines and/or
protein fatty acid condensation products, the latter preferably
being based on wheat proteins.
Consistency Regulators/Thickeners and Rheology Modifiers
[0360] Silicium dioxide, magnesium silicates, aluminium silicates,
polysaccharides or derivatives thereof for example hyaluronic acid,
xanthan gum, guar-guar, agar-agar, alginates, carraghenan, gellan,
pectines, or modified cellulose such as hydroxycellulose,
hydroxypropyl-methylcellulose. In addition polyacrylates or
homopolymer of reticulated acrylic acids and polyacrylamides,
carbomer (carbopol types 980, 981, 1382, ETD 2001, ETD2020, Ultrez
10) or Salcare range such as Salcare SC80(steareth-10 alkyl
ether/acrylates copolymer), Salcare SC81 (acrylates copolymer),
Salcare SC91 and Salcare AST(sodium acrylates copolymer/PPG-1
trideceth-6), sepigel 305(polyacrylamide/laureth-7), Simulgel NS
and Simulgel EG (hydroxyethyl acrylate/sodium acryloyidimethyl
taurate copolymer), Stabilen 30 (acrylates/vinyl isodecanoate
crosspolymer), Pemulen TR-1 (acrylates/C10-30 alkyl acrylate
crosspolymer), Luvigel EM (sodium acrylates copolymer), Aculyn 28
(acrylates/beheneth-25 methacrylate copolymer), etc.
[0361] Viscosity additives set up network structures throughout the
base fluid, and exhibit the "yield value". Clay and polymer
additives possess high yield values, and are therefore used to
positively support suspension problems. Regarding particle
suspension, the addition of such viscosity building agents will
help to decrease the density difference between the particle and
the fluid media surrounding, and therefore will lead to better
resistance to the settling down of the particles.
[0362] Thickeners can be divided into at least 2 general
categories: those that show the best performance in water, and
those that show the best performance in oils.
[0363] In addition, it is also possible to differentiate them
according to their nature, for example synthetic polymers, natural
polymers and their derivatives, mineral polymers etc., but also
according to their ionic character such as anionic, cationic,
nonionic or amphoteric.
TABLE-US-00003 TABLE 4a Natural thickeners Most of them are derived
from the Polysaccharides category RM 1 Cellulose gum such as
cross-linked or not Sodium Carboxymethylcellulose . . . or even
Cocodimonium Hydroxypropyloxyethyl Cellulose RM 2 Microcrystalline
cellulose and Carboxymethyl Cellulose Sodium RM 3 Guar gum and
derivatives (except hydroxypropyl-modified), -Biosacccharide gum-1
(Fucogel 1000 from Solabia), -Sclerotium Gum (Amigel from Alban
Muller) or Scleroglucan (Tinocare GL from Ciba SC) RM 4
Galactoarabinan from Larch extract (Laracare A200) RM 5
Acaccia/Arabic Gum RM 6 Konjac mannan; linear chains of glucose and
mannose units linked in (.beta.-1,4) RM 7 Pectin polysaccharides;
backbone of galacturonic acid and rhamnose with side chains as
Rhamnogalacturonan I or Rhamnogalacturonan II RM 8 Xanthan Gum;
(.beta.-1,4) linked Glucose residues or Dehydroxanthan Gum (Amaze
XT from National Starch) RM 9 Starch and derivatives: Potato starch
modified (Structure Solanace from National Starch); Hydroxypropyl
Starch Phosphate (Structure XL or ZEA from National Starch);
Amylose and Amylopectin polymeric forms; Maltodextrins RM 10
Carrageenan from red algae as Sulfated linear polysaccharides RM 11
Alginic acid and alginates from brown algae; polymers of mannuronic
acid and Guluronic acid
TABLE-US-00004 TABLE 4b Mineral thickeners Most of them are derived
from smectite clays and silica derivatives RM 12 Aluminum Silicates
or Bentonites or Montmorillonites such as Magnesium Aluminum
Silicates (Veegum range from R. T. Vanderbilt) and Quaternized
compounds such as Stearalkonium Bentonite RM 13 Magnesium Silicates
or Hectorites such as Bentone Series (from Elementis Specialties)
and Quaternized compounds such as Disteardimonium Hectorite (to
disperse in lipophilic media) RM 14 Magnesium sodium Fluorosilicate
or modified Mica RM 15 Synthetic layered Silicates; similar
structure to Hectorites; Sodium Magnesium Silicates (Laponite range
from Solvay) RM 16 Fumed Silicas such as Aerosil range from
Degussa
TABLE-US-00005 TABLE 4c Synthetic Rheology modifiers Poly(acrylic
acid) PAA and its copolymers; within such structure, it can be
incorporated ester groups, with hydrophilic character such as
2-Hydroxyethyl Methacrylate etc. RM 17 Carbomer or crosslinked
polyacrylic acid polymer such as Carbopol Ultrez 10, Carbopol
ETD2001, Carbopol ETD2050 from Noveon Inc RM 18 Sodium polyacrylate
(Cosmedia SP from Cognis), Acrylates copolymer (Carbopol Aqua SF-1
from Noveon Inc.), Acrylates/acrylamides Coplymer (Noveon EC-1 from
Noveon Inc.) RM 19 Hydroxyethyl/Acrylate/Sodium Acryloyldimethyl
Taurate copolymer (Simulgel NS or EG from Seppic); combination with
Tinosorb M claimed in PCA N.sup.o161 November 2001 RM 20 Ammonium
Polyacrylates (Simulgel A from Seppic) i.e. "Hydro Swelling
Droplets" concept RM 21 - Glyceryl Polyacrylates (e.g., Hispagel
100) or Polymethacrylates (e.g., Lubrajel range from ISP Corp.) RM
22 Poly(Acrylamide) PAAm and its copolymers; copolymers of ammonium
acrylate and acrylamide; copolymers of AAam with long hydrophobic
chain and acrylates RM 23 Poly(Ethylene oxide) PEO and Poly
(Propylene oxide) PPO and their copolymers; these are block
terpolymers of EO and PO with the structure ABA or BAB; A: PEO with
good water solubility B: PPO with limited water solubility RM 24
Poly(VinylPyrrolidone)PVP homopoplymers or
Poly(VinylPyrrolidone)/Vinyl Acetate coplymers RM 25 Poly
(vinylalcohol) PVA RM 26 VA/Crotonates copolymer
Poly(vinylacetate)/Crotonic acid or VA/Crotonates/Vinyl
Neodecanoate copolymer RM 27 Ethylene/VinylAcetate copolymer such
as A.C.coplymer400 (Allied-Signal) RM 28 PVM/MA copolymers and
their esterified derivatives such Ethyl, Isopropyl or Butyl esters
RM 29 PVM/MA Decadiene Crosspolymer; copolymer of methyl vinyl
ether/Maleic Anhydric (PVM/MA) crosslinked with 1,9-decadiene RM 30
Polyethylene resins such as PEG-2M to PEG-9M (RITA Corp.) RM 31
polysiloxanes and copolymers; copolymers of polysiloxanes and other
blocks such as PEO blocks RM 32 PEG-modified materials, the most
commonly used class of non ionic thickeners with the following
basic structure: R(OCH.sub.2CH.sub.2).sub.n OH, werein R is the
fatty moiety, like fatty alcohol, glyceryl ester, propylene glycol
ester or carboxylic acid; for example; PEG-150 Distearate; these
thickeners are not susceptible to hydrolysis and offer better
viscosity stability under a broad range of pH and temperature
profiles RM 33 Trihydroxystearin or Glycol Tri-(12-Hydroxystearate)
RM 34 Glyceryl Tribehenate such as Syncrowax HRS-C from Croda
TABLE-US-00006 TABLE 4d Phospholipid derivatives RM 35 Alkylated
Phosphatidyl Choline forming fluid lamellar assembly as the
stableliquid crystalline phase of general formula: ##STR00073##
wherein R is C.sub.2-C.sub.4alkyl RM 36 Phosphobetaines (amphoteric
ingredients); alkylamido Phosphobetaine ofgerneral formula
##STR00074## wherein R is C.sub.2-C.sub.14alkyl RM 37 Alkyl
Phosphate Quaternary compounds of general formula ##STR00075##
wherein R is C.sub.2-C.sub.14alkyl
Polymers
[0364] Suitable cationic polymers are, for example, cationic
cellulose derivatives, for example a quaternised hydroxymethyl
cellulose obtainable under the name Polymer JR 400 from Amerchol,
cationic starches, copolymers of diallylammonium salts and
acrylamides, quarternised vinyl-pyrrolidone/vinyl imidazole
polymers, for example Luviquat.RTM. (BASF), condensation products
of polyglycols and amines, quaternised collagen polypeptides, for
example lauryidimonium hydroxypropyl hydrolyzed collagen
(Lamequat.RTM.L/Grunau), quaternised wheat polypeptides,
polyethyleneimine, cationic silicone polymers, for example
amidomethicones, copolymers of adipic acid and
dimethylaminohydroxypropyldiethylenetriamine(Cartaretin/Sandoz),
copolymers of acrylic acid with dimethyldiallylammonium chloride
(Merquat 550/Chemviron), polyaminopolyamides, as described, for
example, in FR-A-2 252 840, and the crosslinked water-soluble
polymers thereof, cationic chitin derivatives, for example of
quaternised chitosan, optionally distributed as microcrystals;
condensation products of dihaloalkyls, for example dibromobutane,
with bisdialkylamines, for example bisdimethylamino-1,3-propane,
cationic guar gum, for example Jaguar C-17, Jaguar C-16 from
Celanese, quaternised ammonium salt polymers, for example Mirapol
A-15, Mirapol AD-1, Mirapol AZ-1 from Miranol. As anionic,
zwitterionic, amphoteric and non-ionic polymers there come into
consideration, for example, vinyl acetate/crotonic acid copolymers,
vinylpyrrolidone/vinyl acrylate copolymers, vinyl acetate/butyl
maleate/isobornyl acrylate copolymers, methyl vinyl ether/maleic
anhydride copolymers and esters thereof, uncrosslinked polyacrylic
acids and polyacrylic acids crosslinked with polyols,
acrylamidopropyl-trimethylammonium chloride/acrylate copolymers,
octyl acrylamide/methyl methacrylatetert-butylaminoethyl
methacrylate/2-hydroxypropyl methacrylate copolymers,
polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetate copolymers,
vinylpyrrolidone/dimethylaminoethyl methacrylate/vinyl caprolactam
terpolymers and also optionally derivatised cellulose ethers and
silicones. Furthermore the polymers as described in EP 1093796
(pages 3-8, paragraphs 17-68) may be used.
Biogenic Active Ingredients
[0365] Biogenic active ingredients are to be understood as meaning,
for example, tocopherol, tocopherol acetate, tocopherol palmitate,
ascorbic acid, deoxyribonucleic acid, retinol, bisabolol,
allantoin, phytantriol, panthenol, AHA acids, amino acids,
ceramides, pseudoceramides, essential oils, plant extracts and
vitamin complexes.
Deodorising Active Ingredients
[0366] As deodorising active ingredients there come into
consideration, for example, antiperspirants, for example aluminium
chlorohydrates (see J. Soc. Cosm. Chem. 24, 281 (1973)). Under the
trade mark Locron.RTM. of Hoechst AG, Frankfurt (FRG), there is
available commercially, for example, an aluminium chlorohydrate
corresponding to formula Al.sub.2(OH).sub.5Cl.times.2.5H.sub.2O,
the use of which is especially preferred (see J. Pharm. Pharmacol.
26, 531 (1975)). Besides the chlorohydrates, it is also possible to
use aluminium hydroxyacetates and acidic aluminium/zirconium salts.
Esterase inhibitors may be added as further deodorising active
ingredients. Such inhibitors are preferably trialkyl citrates, such
as trimethyl citrate, tripropyl citrate, triisopropyl citrate,
tributyl citrate and especially triethyl citrate (Hydagen CAT,
Henkel), which inhibit enzyme activity and hence reduce odour
formation. Further substances that come into consideration as
esterase inhibitors are sterol sulfates or phosphates, for example
lanosterol, cholesterol, campesterol, stigmasterol and sitosterol
sulfate or phosphate, dicarboxylic acids and esters thereof, for
example glutaric acid, glutaric acid monoethyl ester, glutaric acid
diethyl ester, adipic acid, adipic acid monoethyl ester, adipic
acid diethyl ester, malonic acid and malonic acid diethyl ester and
hydroxycarboxylic acids and esters thereof, for example citric
acid, malic acid, tartaric acid or tartaric acid diethyl ester.
Antibacterial active ingredients that influence the germ flora and
kill or inhibit the growth of sweat-decomposing bacteria can
likewise be present in the preparations (especially in stick
preparations). Examples include chitosan, phenoxyethanol and
chlorhexidine gluconate. 5-chloro-2-(2,4-dichlorophenoxy)-phenol
(Triclosan, Irgasan, Ciba Specialty Chemicals Inc.) has also proved
especially effective.
Anti-Dandruff Agents
[0367] As anti-dandruff agents there may be used, for example,
climbazole, octopirox and zinc pyrithione. Customary film formers
include, for example, chitosan, microcrystalline chitosan, qua
ternised chitosan, polyvinylpyrrolidone, vinylpyrrolidone/vinyl
acetate copolymers, polymers of quaternary cellulose derivatives
containing a high proportion of acrylic acid, collagen, hyaluronic
acid and salts thereof and similar compounds.
Hydrotropic Agents
[0368] To improve the flow behaviour it is also possible to employ
hydrotropic agents, for example ethoxylated or non ethoxylated
mono-alcohols, diols or polyols with a low number of carbon atoms
or their ethers (e.g. ethanol, isopropanol, 1,2-dipropanediol,
propyleneglycol, glyerin, ethylene glycol, ethylene glycol
monoethylether, ethylene glycol monobutylether, propylene glycol
monomethylether, propylene glycol monoethylether, propylene glycol
monobutylether, diethylene glycol monomethylether; diethylene
glycol monoethylether, diethylene glycol monobutylether and similar
products). The polyols that come into consideration for that
purpose have preferably from 2 to 15 carbon atoms and at least two
hydroxy groups. The polyols may also contain further functional
groups, especially amino groups, and/or may be modified with
nitrogen. Typical examples are as follows: glycerol, alkylene
glycols, for example ethylene glycol, diethylene glycol, propylene
glycol, butylene glycol, hexylene glycol and also polyethylene
glycols having an average molecular weight of from 100 to 1000
Dalton; technical oligoglycerol mixtures having an intrinsic degree
of condensation of from 1.5 to 10, for example technical diglycerol
mixtures having a diglycerol content of from 40 to 50% by weight;
methylol compounds, such as, especially, trimethylolethane,
trimethylol-propane, trimethylolbutane, pentaerythritol and
dipentaerythritol; lower alkyl-glucosides, especially those having
from 1 to 8 carbon atoms in the alkyl radical, for example methyl
and butyl glucoside; sugar alcohols having from 5 to 12 carbon
atoms, for example sorbitol or mannitol; sugars having from 5 to 12
carbon atoms, for example glucose or saccharose; amino sugars, for
example glucamine; dialcohol amines, such as diethanolamine or
2-amino-1,3-propanediol.
Preservatives and Bacteria-Inhibiting Agents
[0369] Suitable preservatives include, for example, Methyl-,
Ethyl-, Propyl-, Butyl-parabens, Benzal-konium chloride,
2-Bromo-2-nitro-propane-1,3-diol, Dehydroacetic acid, Diazolidinyl
Urea, 2-Dichloro-benzyl alcohol, DMDM hydantoin, Formaldehyde
solution, Methyldibromoglutanitrile, Phenoxyethanol, Sodium
Hydroxymethylglycinate, Imidazolidinyl Urea, Triclosan and further
substance classes listed in the following reference: K. F.
DePolo--A short textbook of cosmetology, Chapter 7, Table 7-2, 7-3,
7-4 and 7-5, p210-219.
[0370] Typical examples of bacteria-inhibiting agents are
preservatives that have a specific action against gram-positive
bacteria, such as 2,4,4'-trichloro-2'-hydroxydiphenyl ether,
chlorhexidine (1,6-di(4-chlorophenyl-biguanido)hexane) or TCC
(3,4,4'-trichlorocarbanilide). A large number of aromatic
substances and ethereal oils also have antimicrobial properties.
Typical examples are the active ingredients eugenol, menthol and
thymol in clove oil, mint oil and thyme oil. A natural deodorising
agent of interest is the terpene alcohol farnesol
(3,7,11-tri-methyl-2,6,10-dodecatrien-1-ol), which is present in
lime blossom oil. Glycerol monolaurate has also proved to be a
bacteriostatic agent. The amount of the additional
bacteria-inhibiting agents present is usually from 0.1 to 2% by
weight, based on the solids content of the preparations.
Perfume Oils
[0371] mixtures of natural and/or synthetic aromatic substances,
for example, extracts from blossom (lilies, lavender, roses,
jasmine, neroli, ylang-ylang), from stems and leaves (geranium,
patchouli, petitgrain), from fruit (aniseed, coriander, carraway,
juniper), from fruit peel (bergamot, lemons, oranges), from roots
(mace, angelica, celery, cardamom, costus, iris, calmus), from wood
(pinewood, sandalwood, guaiacum wood, cedarwood, rosewood), from
herbs and grasses (tarragon, lemon grass, sage, thyme), from
needles and twigs (spruce, pine, Scots pine, mountain pine), from
resins and balsams (galbanum, elemi, benzoin, myrrh, olibanum,
opoponax). Animal raw materials also come into consideration, for
example civet and castoreum. Typical synthetic aromatic substances
are, for example, products of the ester, ether, aldehyde, ketone,
alcohol or hydrocarbon type. Aromatic substance compounds of the
ester type are, for example, benzyl acetate, phenoxyethyl
isobutyrate, p-tert-butylcyclohexyl acetate, linalyl acetate,
dimethylbenzylcarbinyl acetate, phenylethyl acetate, linalyl
benzoate, benzyl formate, ethylmethylphenyl glycinate,
allylcyclohexyl propionate, styrallyl propionate and benzyl
salicylate. The ethers include, for example, benzyl ethyl ether;
the aldehydes include, for example, the linear alkanals having from
8 to 18 hydrocarbon atoms, citral, citronellal, citronellyl
oxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, lilial and
bourgeonal; the ketones include, for example, the ionones,
isomethylionone and methyl cedryl ketone; the alcohols include, for
example, anethol, citronellol, eugenol, isoeugenol, geraniol,
linalool, phenyl ethyl alcohol and terpinol; and the hydrocarbons
include mainly the terpenes and balsams. It is preferable, however,
to use mixtures of various aromatic substances that together
produce an attractive scent. Ethereal oils of relatively low
volatility, which are chiefly used as aroma components, are also
suitable as perfume oils, e.g. sage oil, camomile oil, clove oil,
melissa oil, oil of cinnamon leaves, lime blossom oil, juniper
berry oil, vetiver oil, olibanum oil, galbanum oil, labolanum oil
and lavandin oil. Preference is given to the use of bergamot oil,
dihydromyrcenol, lilial, lyral, citronellol, phenyl ethyl alcohol,
hexyl cinnamaldehyde, geraniol, benzyl acetone, cyclamen aldehyde,
linalool, boisambrene forte, ambroxan, indole, hedione, sandelice,
lemon oil, tangerine oil, orange oil, allyl amyl glycolate,
cyclovertal, lavandin oil, muscatel sage oil, damascone, bourbon
geranium oil, cyclohexyl salicylate, vertofix coeur, iso-E-Super,
Fixolide NP, evernyl, iraldein gamma, phenylacetic acid, geranyl
acetate, benzyl acetate, rose oxide, romillat, irotyl and floramat
alone or in admixture with one another.
Colourants
[0372] There may be used as colourants the substances that are
suitable and permitted for cosmetic purposes, as compiled, for
example, in the publication "Kosmetische Farbemittel" of the
Farbstoffkommission der Deutschen Forschungsgemeinschaft, Verlag
Chemie, Wein-heim, 1984, pages 81 to 106. The colourants are
usually used in concentrations of from 0.001 to 0.1% by weight,
based on the total mixture.
Other Adjuvants
[0373] Anti-foams, such as silicones, structurants, such as maleic
acid, solubilisers, such as ethylene glycol, propylene glycol,
glycerol or diethylene glycol, opacifiers, such as latex,
styrene/PVP or styrene/acrylamide copolymers, complexing agents,
such as EDTA, NTA, alaninediacetic acid or phosphonic acids,
propellants, such as propane/butane mixtures, N.sub.2O, dimethyl
ether, CO.sub.2, N.sub.2 or air, so-called coupler and developer
components as oxidation dye precursors, reducing agents, such as
thioglycolic acid and derivatives thereof, thiolactic acid,
cysteamine, thiomalic acid or mercaptoethanesulfonic acid, or
oxidising agents, such as hydrogen peroxide, potassium bromate or
sodium bromate.
[0374] Suitable insect repellents are, for example,
N,N-diethyl-m-toluamide, 1,2-pentanediol or insect repellent 3535;
suitable self-tanning agents are, for example, dihydroxyacetone
and/or erythrulose or dihydroxy acetone and/or dihydroxy acetone
precursors as described in WO 01/85124 and/or erythrulose.
[0375] Polymeric beads or hollow spheres may be used as SPF
enhancers.
[0376] Present compounds, e.g. those of formulae (1), (2) and/or
(3), may also be contained in liposomes or used in pharmacological
compositions with conventional carriers and penetration enhancers,
for example urea, dextrane, propylene glycol, oleic acid and the
like.
[0377] The pharmaceutical composition will usually contain the
present compounds in amounts of 0.001 to 10% by weight, preferably
of 0.01 to 5%, especially 0.01 to 2% by weight, of the total
mixture. For the treatment of the conditions listed hereinabove,
the pharmaceutical composition of this invention may contain, in
addition to the present compounds, further pharmaceutical or
cosmetic agents, e.g. having antiphlogistic activity, typically
including antiinflammatory agents, vitamins, and/or, where
appropriate, antipsoriatic agents, further skin actives, cell
proliferation regulators, antiallergic, UV protecting,
moisturizing, antiageing, gastroprotective, antiasthmatic agents,
DNA-protectants.
[0378] The pharmaceutical composition of this invention may contain
antioxidants and/or light stabilisers apart from present formulae
(1)-(3), especially UV absorbers. Suitable components of these
classes include those described in EP-A-955355, WO00/25730,
WO00/25731, WO03/103622, EP-A-1366763.
[0379] Examples are components listed below:
TABLE-US-00007 Suitable UV filter substances which can be
additionally used with the present compounds p-aminobenzoic acid
derivatives, for example 4-dimethylaminobenzoic acid 2-ethylhexyl
ester; salicylic acid derivatives, for example salicylic acid
2-ethylhexyl ester; benzophenone derivatives, for example
2-hydroxy-4-methoxybenzophenone and its 5-sulfonic acid derivative;
dibenzoylmethane derivatives, for example
1-(4-tert-butylphenyl)-3-(4-methoxyphenyl)- propane-1,3-dione;
diphenylacrylates, for example 2-ethylhexyl
2-cyano-3,3-diphenylacrylate, and 3-(benzo- furanyl)
2-cyanoacrylate; 3-imidazol-4-ylacrylic acid and esters; benzofuran
derivatives, especially 2-(p-aminophenyl)benzofuran derivatives,
described in EP-A-582 189, US-A-5 338 539, US-A-5 518 713 and
EP-A-613 893; polymeric UV absorbers, for example the benzylidene
malonate derivatives described in EP-A-709 080; cinnamic acid
derivatives, for example the 4-methoxycinnamic acid 2-ethylhexyl
ester and isoamyl ester or cinnamic acid derivatives described in
US-A-5 601 811 and WO 97/00851; camphor derivatives, for example
3-(4'-methyl)benzylidene-bornan-2-one, 3-benzylidene- bornan-2-one,
N-[2(and 4)-2-oxyborn-3-ylidene-methyl)-benzyl]acrylamide polymer,
3-(4'- trimethylammonium)-benzylidene-bornan-2-one methyl sulfate,
3,3'-(1,4-phenylenedimethine)-
bis(7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptane-1-methanesulfonic
acid) and salts, 3-(4'-sulfo)benzylidene-bornan-2-one and salts;
camphorbenzalkonium methosulfate; hydroxyphenyltriazine compounds,
for example 2-(4'-methoxyphenyl)-4,6-bis(2'-hydroxy-4'-
n-octyloxyphenyl)-1,3,5-triazine;
2,4-bis{[4-(3-(2-propyloxy)-2-hydroxy-propyloxy)-2-hydroxy]-
phenyl}-6-(4-methoxyphenyl)-1,3,5-triazine;
2,4-bis{[4-(2-ethyl-hexyloxy)-2-hydroxy]-
phenyl}-6-[4-(2-methoxyethyl-carboxyl)-phenylamino]-1,3,5-triazine;
2,4-bis{[4-(tris-
(trimethylsilyloxy-silylpropyloxy)-2-hydroxy]-phenyl}-6-(4-methoxyphenyl)--
1,3,5-triazine;
2,4-bis{[4-(2''-methylpropenyloxy)-2-hydroxy]-phenyl}-6-(4-methoxyphenyl)--
1,3,5-triazine;
2,4-bis{[4-(1',1',1',3',5',5',5'-heptamethyltrisilyl-2''-methyl-propyloxy)-
-2-hydroxy]-phenyl}-6- (4-methoxyphenyl)-1,3,5-triazine;
2,4-bis{[4-(3-(2-propyloxy)-2-hydroxy-propyloxy)-2-
hydroxy]-phenyl}-6-[4-ethylcarboxy)-phenylamino]-1,3,5-triazine;
benzotriazole compounds, for example
2,2'-methylene-bis(6-(2H-benzotriazol-2-yl)-4-
(1,1,3,3-tetramethylbutyl)-phenol; trianilino-5-triazine
derivatives, for example
2,4,6-trianiline-(p-carbo-2'-ethyl-1'-oxy)-1,3,5- triazine and the
UV absorbers disclosed in US-A-5 332 568, EP-A-517 104, EP-A-507
691, WO 93/17002 and EP-A-570 838; 2-phenylbenzimidazole-5-sulfonic
acid and salts thereof; menthyl o-aminobenzoates; physical
sunscreens coated or not as titanium dioxide, zinc oxide, iron
oxides, mica, MnO, Fe.sub.2O.sub.3, Ce.sub.2O.sub.3,
Al.sub.2O.sub.3, ZrO.sub.2. (surface coatings:
polymethylmethacrylate, methicone (methylhydrogenpolysiloxane as
described in CAS 9004-73-3), dimethicone, isopropyl titanium
triisostearate (as described in CAS 61417-49-0), metal soaps as
magnesium stearate (as described in CAS 4086-70-8),
perfluoroalcohol phosphate as C9-15 fluoroalcohol phosphate (as
described in CAS 74499-44-8; JP 5-86984, JP 4-330007)). The primary
particle size is an average of 15 nm-35 nm and the particle size in
dispersion is in the range of 100 nm-300 nm.
aminohydroxy-benzophenone derivatives disclosed in DE 10011317, EP
1133980 and EP 1046391 phenyl-benzimidazole derivatives as
disclosed in EP 1167358 the UV absorbers described in "Sunscreens",
Eds. N. J. Lowe, N. A. Shaath, Marcel Dekker, Inc., New York and
Basle or in Cosmetics & Toiletries (107), 50ff (1992) also can
be used as additional UV protective substances.
TABLE-US-00008 No. Chemical Name CAS No. 1
(+/-)-1,7,7-trimethyl-3-[(4-methylphenyl)methylene]bicyclo[2.2.1]-
36861-47-9 heptan-2-one; p-methyl benzylidene camphor 2
1,7,7-trimethyl-3-(phenylmethylene)bicyclo[2.2.1]heptan-2-one;
15087-24-8 benzylidene camphor 3
(2-Hydroxy-4-methoxyphenyl)(4-methylphenyl)methanone 1641-17-4 4
2,4-dihydroxybenzophenone 131-56-6 5
2,2',4,4'-tetrahydroxybenzophenone 131-55-5 6 2-Hydroxy-4-methoxy
benzophenone 131-57-7 7 2-Hydroxy-4-methoxy benzophenone-5-sulfonic
acid 4065-45-6 8 2,2'-dihydroxy-4,4'-dimethoxybenzophenone 131-54-4
9 2,2'-Dihydroxy-4-methoxybenzophenone 131-53-3 10
Alpha-(2-oxoborn-3-ylidene)toluene-4-sulphonic acid and its salts;
56039-58-8 Mexoryl SL 11
1-[4-(1,1-dimethylethyl)phenyl]-3-(4-methoxyphenyl)propane-1,3-
70356-09-1 dione; avobenzone 12 Methyl
N,N,N-trimethyl-4-[(4,7,7-trimethyl-3-oxobicyclo[2,2,1]hept-2-
52793-97-2 ylidene)methyl]anilinium sulphate; Mexoryl SO 22
3,3,5-Trimethyl cyclohexyl-2-hydroxy benzoate; homosalate 118-56-9
23 Isopentyl p-methoxycinnamate; isoamyl methoxy cinnamate
71617-10-2 27 Menthyl-o-aminobenzoate 134-09-8 28 Menthyl
salicylate 89-46-3 29 2-Ethylhexyl 2-cyano,3,3-diphenylacrylate;
Octocrylene 6197-30-4 30 2-ethylhexyl 4-(dimethylamino)benzoate
21245-02-3 31 2-ethylhexyl 4-methoxycinnamate; octyl methoxy
cinnamate 5466-77-3 32 2-ethylhexyl salicylate 118-60-5 33 Benzoic
acid, 4,4',4''-(1,3,5-triazine-2,4,6-triyltriimino)tris-,
88122-99-0 tris(2-ethylhexyl)ester;
2,4,6-Trianilino-(p-carbo-2'-ethylhexyl-1'-oxi)- 1,3,5-triazine;
octyl triazone 34 4-aminobenzoic acid 150-13-0 35 Benzoic acid,
4-amino-, ethyl ester, polymer with oxirane 113010-52-9 38
2-phenyl-1H-benzimidazole-5-sulphonic acid; 27503-81-7
phenylbenzimidazolsulfonic acid 39 2-Propenamide,
N-[[4-[(4,7,7-trimethyl-3-oxobicyclo[2.2.1]hept-2- 147897-12-9
ylidene)methyl]phenyl]methyl]-, homopolymer 40 Triethanolamine
salicylate 2174-16-5 41
3,3'-(1,4-phenylenedimethylene)bis[7,7-dimethyl-2-oxo- 90457-82-2
bicyclo[2.2.1]heptane-1 methanesulfonic acid]; Cibafast H 42
Titanium dioxide 13463-67-7 44 Zinc oxide 1314-13-2 45
2,2'-Methylene-bis-[6-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethyl-
103597-45-1 butyl)-phenol]; Tinosorb M 46
2,4-bis{[4-(2-ethylhexyloxy)-2-hydroxy]-phenyl}-6-(4- 187393-00-6
methoxyphenyl)-(1,3,5)-triazine; Tinosorb S 47
1H-Benzimidazole-4,6-disulfonic acid,2,2'-(1,4-phenylene)bis-,
180898-37-7 disodium salt 48 Benzoic acid,
4,4'-[[6-[[4-[[(1,1-dimethylethyl)amino]carbonyl]phenyl]-
154702-15-5 amino]1,3,5-triazine-2,4-diyl]diimino]bis-,
bis(2-ethylhexyl)ester; di- ethylhexyl butamido triazone; Uvasorb
HEB 49 Phenol,
2-(2H-benzotriazol-2-yl)-4-methyl-6-[2-methyl-3-[1,3,3,3-
155633-54-8
tetramethyl-1-[(trimethylsilyl)oxy]disiloxanyl]propyl]-;
drometrizole trisiloxane; Mexoryl XL 50
Dimethicodiethylbenzalmalonate; Polysilicone 15; Parsol SLX
207574-74-1 51 Benzenesulfonic acid,
3-(2H-benzotriazol-2-yl)-4-hydroxy-5-(1- 92484-48-5 methylpropyl)-,
monosodium salt; Tinogard HS 52 Benzoic acid,
2-[4-(diethylamino)-2-hydroxybenzoyl]-, hexyl ester; 302776-68-7
Uvinul a plus 53 1-Dodecanaminium,
N-[3-[[4-(dimethylamino)benzoyl]amino]propyl]- 156679-41-3
N,N-dimethyl-, salt with 4-methylbenzenesulfonic acid (1:1);
Escalol HP610 54 1-Propanaminium,
N,N,N-trimethyl-3-[(1-oxo-3-phenyl-2-propenyl)- 177190-98-6
amino]-, chloride 55 1H-Benzimidazole-4,6-disulfonic acid,
2,2'-(1,4-phenylene)bis- 170864-82-1 56 1,3,5-Triazine,
2,4,6-tris(4-methoxyphenyl)- 7753-12-0 57 1,3,5-Triazine,
2,4,6-tris[4-[(2-ethylhexyl)oxy]phenyl]- 208114-14-1 58
1-Propanaminium, 3-[[3-[3-(2H-benzotriazol-2-yl)-5-(1,1-
340964-15-0
dimethylethyl)-4-hydroxyphenyl]-1-oxopropyl]amino]-N,N-diethyl-N-
methyl-, methyl sulfate (salt) 59 2-Propenoic acid,
3-(1H-imidazol-4-yl)- 104-98-3 60 Benzoic acid, 2-hydroxy-,
[4-(1-methylethyl)phenyl]methyl ester 94134-93-7 61
1,2,3-Propanetriol, 1-(4-aminobenzoate); glyceryl PABA 136-44-7 62
Benzeneacetic acid, 3,4-dimethoxy-a-oxo- 4732-70-1 63 2-Propenoic
acid, 2-cyano-3,3-diphenyl-, ethyl ester 5232-99-5 64 Anthralinic
acid, p-menth-3-yl ester 134-09-8 65
2,2'-bis(1,4-phenylene)-1H-benzimidazole-4,6-disulphonic acid mo-
349580-12-7, no sodium salt or Disodium phenyl dibenzimidazole
tetrasulfonate or Neoheliopan AP 66 1,3,5-Triazine-2,4,6-triamine,
N,N'-bis[4-[5-(1,1-dimethylpropyl)-2- 288254-16-0
benzoxazolyl]phenyl]-N''-(2-ethylhexyl)- or Uvasorb K2A 67
Merocyanine derivatives as described in WO 2004006878 and in
IPCOM000022279D 68 ##STR00076## 68 sterols (cholesterol,
lanosterol, phytosterols), as described in WO0341675 69
mycosporines and/or mycosporine-like amino acids as described in
WO2002039974, e.g. Helioguard 365 from Milbelle AG, isolated
mycosporine like amino acids from the red alga porphyra umbilicalis
(INCI: Porphyra Umbilicalis) that are encapsulated into liposomes,)
70 alpha-lipoic-acid as described in DE 10229995 71 synthetic
organic polymers as described in EP 1371358, [0033]- [0041] 72
phyllosilicates as described in EP 1371357 [0034]-[0037] 73 silica
compounds as described in EP1371356, [0033]-[0041] 74 inorganic
particles as described in DE10138496 [0043]-[0055] 75 latex
particles as described in DE10138496 [0027]-[0040] 76
1H-Benzimidazole-4,6-disulfonic acid, 2,2'-(1,4-phenylene)bis-,
180898-37-7 disodium salt; Bisimidazylate; Neo Heliopan APC
TABLE-US-00009 Suitable UV filter substances which can be
additionally used (Abbreviations T: table, R: row, Comp: compound,
Ex: compound(s) of patent example, p: page); the generic scope of
the UV absorbers is described in the left-hand column; specific
compounds are indicated in the right-hand column DE 100331804 Tab 1
p 4, tab 2 + 3 p 5 EP 613893 Ex 1-5 + 15, T 1, pp 6-8 EP 1000950
Comp. in table 1, pp 18-21 EP 1005855 T 3, p 13 EP 1008586 Ex 1-3,
pp 13-15 EP 1008593 Ex 1-8, pp 4-5 EP 1027883 Compound VII, p 3 EP
1027883 Comp I-VI, p 3 EP 1028120 Ex 1-5, pp 5-13 EP 1059082 Ex 1;
T 1, pp 9-11 EP 1060734 T 1-3, pp 11-14 EP 1064922 Compounds 1-34,
pp 6-14 EP 1081140 Ex 1-9, pp 11-16 EP 1103549 Compounds 1-76, pp
39-51 EP 1108712 4,5-Dimorpholino-3-hydroxypyridazine EP 1123934 T
3, p 10 EP 1129695 Ex 1-7, pp 13-14 EP 1167359 Ex 1 p11 and ex 2 p
12 EP 1258481 Ex 1, pp 7,8 EP 420707 B1 Ex 3, p 13 (CAS Regno
80142-49-0) EP 503338 T 1, pp 9-10 EP 517103 Ex 3, 4, 9, 10 pp 6-7
EP 517104 Ex 1, T 1, pp 4-5; Ex 8, T 2, pp 6-8 EP 626950 all
compounds EP 669323 Ex 1-3, p 5 EP 780382 Ex 1-11, pp 5-7 EP 823418
Ex 1-4, pp 7-8 EP 826361 T 1, pp 5-6 EP 832641 Ex 5 + 6 p 7; t 2, p
8 EP 832642 Ex 22, T 3 pp, 10-15; T 4, p 16 EP 852137 T 2, pp 41-46
EP 858318 T 1, p 6 EP 863145 Ex 1-11, pp 12-18 EP 895776 Comp. in
rows 48-58, p 3; R 25 + 33, p 5 EP 911020 T 2, p 11-12 EP 916335 T
2-4, pp 19-41 EP 924246 T 2, p 9 EP 933376 Ex 1-15, pp 10-21 EP
944624 Ex 1 + 2, pp13-15 EP 945125 T 3 a + b, pp 14-15 EP 967200 Ex
2; T 3-5, pp 17-20 EP 969004 Ex 5, T 1, pp 6-8 JP 2000319629 CAS
Regno. 80142-49-0, 137215-83-9, 307947-82-6 US 5635343 all
compounds on pp 5-10 US 5338539 Ex 1-9, pp 3 + 4 US 5346691 Ex 40,
p 7; T 5, p 8 US 5801244 Ex 1-5, pp 6-7 WO 0149686 Ex 1-5, pp 16-21
WO 0168047 Tables on pp 85-96 WO 0181297 Ex 1-3 pp 9-11 WO 0238537
All componds p 3, compounds on rows 1-10 p 4 WO 9217461 Ex 1-22, pp
10-20 WO 9220690 Polymeric comp in examples 3-6 WO 9301164 T 1 + 2,
pp 13-22 WO 9714680 Ex 1-3, p 10
[0380] As water- and oil-containing emulsions (e.g. W/O, O/W, O/W/O
and W/O/W emulsions or microemulsions) the preparations contain,
for example, from 0.1 to 30% by weight, preferably from 0.1 to 15%
by weight and especially from 0.5 to 10% by weight, based on the
total weight of the composition, of one or more UV absorbers, from
1 to 60% by weight, especially from 5 to 50% by weight and
preferably from 10 to 35% by weight, based on the total weight of
the composition, of at least one oil component, from 0 to 30% by
weight, especially from 1 to 30% by weight and preferably from 4 to
20% by weight, based on the total weight of the composition, of at
least one emulsifier, from 10 to 90% by weight, especially from 30
to 90% by weight, based on the total weight of the composition, of
water, and from 0 to 88.9% by weight, especially from 1 to 50% by
weight, of further cosmetically acceptable adjuvants.
[0381] Cosmetic or pharmaceutical preparations in general can be
prepared by physically mixing the active component(s) with the
adjuvant using customary methods, for example by simply stirring
together the individual components.
[0382] Examples for compounds especially useful in the present
invention include those listed below: [0383] A03: Reaction product
of glycerine, coconut oil and a compound of the formula
[0383] ##STR00077## [0384] (mixture of mono-, di- and triglycerides
of .beta.-(3,5-di-tert.butyl-4-hydroxyphenyl) propanoic acid and
fatty acids, CAS Reg.-No. 179986-09-5) [0385] A04:
[0385] ##STR00078## [0386] A05 is a mixture of the compounds of the
formulae:
[0386] ##STR00079## [0387] A06: [0388] A07:
pentaerythritol-tetrakis(3-[3',5'-di-tert.
butyl-4'-hydroxyphenyl]-propionate)
##STR00080##
[0388] (CAS Reg.-No. 006683-19-8)
[0389] A08:
##STR00081##
[0389] citrate.
[0390] The following Examples will serve to illustrate the
invention without implying any restriction to what is described
therein. Unless otherwise indicated, percentages are by weight.
ABBREVIATIONS
[0391] DMSO dimethylsulfoxide EDTA ethylene-diamine tetraacetic
acid ELISA enzyme linked immunosorbent assay FCS fetal calf
serum
EXAMPLE 1
Cell Toxicity
[0392] Cell cultures: Primary human dermal fibroblasts (HDF-N2) are
maintained in Dulbecco's culture media (DMEM; 1 g/l glucose),
supplemented with 10% of fetal calf serum (FCS), 100 .mu.g/ml of
streptomycin sulphate, 100 U/ml of penicillin and 2 mM of
L-glutamine, all of them from Biowhitaker, USA. Confluent cells are
detached by incubation for 3 minutes in 0.055 trypsin/0.53 mM EDTA
at 37.degree. C. and plated at the established cell density
(normally, 15.times.10.sup.4 cells/cm.sup.2).
[0393] Testing: Stock solutions of each test compound (active) in
DMSO or in ethanol (5%) are diluted into the cell culture medium
containing 10% FCS (see above) as indicated in table 1. Culture
media of negative controls are containing 10 mMol NaCl or 0.05%
DMSO or 0.05% ethanol, respectively. Positive control is a culture
medium containing 0.02% of Sodium Lauryl Sulfate (SDS).
[0394] For comparative purposes, a further culture medium is used
containing the compound of the formula
##STR00082##
(comparison) in the same dilution.
[0395] The test media thus obtained are added for 24 h to
48h-cultures of Human Dermal Fibroblast (HDF) described above, and
the rate of survival is measured via a specific color marker
penetrating only into live-cells (The more absorption at
OD.sub.450, the more viable cells: Living dermal fibroblast possess
an esterase that liberates a color, which absorbs at 450 nm. Dead
cells do not. Measuring in cell cultures in presence of test
substances the OD450 and comparing it to non-treated controls
yields thus a measure for cell toxicity).
[0396] Results are compiled in the following table.
TABLE-US-00010 TAB. 1 Absorbance (OD.sub.450) after 24 h treatment
active OD.sub.450 none (NaCl) 2.2 none (DMSO) 2.1 control (SDS)
0.25 AO3 1:500 1.55 AO4 1:500 1.0 AO5 1:500 1.45 AO6 1:500 1.9 AO7
1:500 2.0 AO8 1:500 1.65 comparison 1:500 0.25
[0397] Cytotoxicity of the present test compounds is in an
acceptable range.
EXAMPLE 2
Anti-Inflammatory Activity (in vitro)
[0398] Compounds are tested for anti-inflammatory activities via
their capability of modifying the basal PGE.sub.2 release in HDF-N2
cultivated as described in example 1.
[0399] For this purpose, cells are cultured in 24 well culture
plates for 3 days. Before treatment confluent cells are arrested
for 24 h with culture media containing 1% FCS and then treated for
18-24 h with selected concentrations of the test compounds. Each of
the test compounds AO3, AO5, AO6 and AO7, respectively, is applied
in dilutions 1:500, 1:1000 and 1:1500, each prepared by adding
appropriate amounts of the stock solution described in example 1 to
the culture medium.
[0400] After treatment, cells supernatants are removed and aliquots
stored at -20.degree. C. until analysis of PGE.sub.2 using an ELISA
kit from Amersham Biosciences. The PGE.sub.2 values (pg/well) are
individually corrected for the total protein, measured by the BCA
Method (Pierce) and expressed as PGE.sub.2 (pg/mg protein or ng/mg
protein).
[0401] Morphological control of culture at 24 h of product
application is performed by phase contrast microscopy.
[0402] Results: The test compounds show good PGE.sub.2 inhibition
activity.
EXAMPLE 3
Evaluation of the Efficacy of Present Compounds Against
Photooxidative Stress in the Skin Induced by UVA Irradiation
[0403] Anti-oxidant activity in vivo is measured via the capacity
of a test compound to reduce radical induced
lipid-peroxidation.
TABLE-US-00011 Persons tested: 10 individuals (4 female, 6 male);
age range: 18 to 32 years Body region tested: inner forearm
Application phase: once a day Test period 7 days Evaluation method:
Determination of squalene Determination of squalenehydroperoxide
Time of Evaluation: after UVA radiation Evaluation: Descriptive
statistics: average, median, minimum, maximum, variance, standard
error, standard deviation; Multiple range test.
Test Method
[0404] Each test compound (active) is applied as a 1% b.w. solution
in ethanol, except for A07 where a 0.1% b.w. solution in ethanol is
applied; in the following, these test solutions are also recalled
as formulation. On the inner forearm of each subject symmetrically
opposed areas are defined. The different formulations are applied
once a day at a dose of about 2 mg of test solution/cm.sup.2 for
one week (application with a syringe for fine dosage:
Omnifix.RTM.-F 1 ml; manufacturer: Braun Melsungen AG,
Germany).
[0405] Two areas remain untreated.
[0406] The unique application of a solution of tocopherol in
ethanol (0,2%) before irradiation serves as control.
[0407] Use of other cosmetic products is restricted on the test
areas throughout the whole study. The areas (exception: one of the
two untreated areas was not irradiated and can be attributed to
environmental UVA radiation during the test) of the subject's back
were then irradiated with UVA light (10 joule/cm.sup.2). The lipids
present on the test areas are harvested via a solvent extraction (4
ml ethanol for 2 minutes). The samples are first filtered through
hydrophobic polypropylene filters to decant squames and other
insoluble material, then dried under nitrogen at room temperature
and taken up in 1 ml ethanol. Squalene (SQ) and
squalenehydroperoxide (SQOOH) are then analysed by High Performance
Liquid Chromatography (HPLC).
[0408] The results are expressed as the rate of inhibition relative
to the untreated area:
%
inhibition=100.times.[SQOOH(untreated)-SQOOH(active)]/SQOOH(untreated)
(SQOOH in pmoles Hydrogen Peroxide Per Pg Squalene)
HPLC Analysis for SQ
[0409] column: LiChrospher.RTM. 100 RP-18 (5 .mu.m, 125.times.4 mm)
Merck-Germany mobile phase: [0410] acetonitrile/isopropanol (1/1;
V/V) [0411] detection: UV 210 nm [0412] flow rate: 1 ml/min [0413]
injection volume: 20 .mu.l [0414] equipment: Beckman System Gold
(USA) with Programmable Solvent Module 126 and Programmable
Detector Module 166
HPLC Analysis for SQOOH
TABLE-US-00012 [0415] column: LiChrospher .RTM. 100 RP-Select B (5
.mu.m, 125 .times. 4 mm) Merck-Germany mobile phase: methanol
detection: Chemiluminescence (post column detection) flow rate: 1
ml/min injection volume: 20 .mu.l reaction solution: Luminol (1
.mu.g/ml) and Cytochrom C (10 .mu.g/ml solved in 50 mM
Borate-buffer, pH 10) equipment: Beckman System Gold (USA) with
Programmable Solvent Module 126 and fluorometer RF-551 (Shimadzu,
Japan)
[0416] The fluorometer is used as a photon detector with the
excitation source turned off.
[0417] This assay measures the hydroperoxy groups themselves and
not indirect indices of lipid peroxidation such as conjugated
dienes or breakdown products of lipid hydroperoxides.
Chemiluminescence also detects ubiquinols. To confirm that any
chemiluminescence observed in this assay was due to a
hydroperoxide, not a hydroquinone, some samples were reduced with
triphenyl phosphine and rerun. Since the chemiluminescence response
of hydroperoxides, but not of hydroquinones, is eliminated by
triphenyl phosphine, the disappearance of chemiluminescence peaks
in the treated samples indicated that chemiluminescence observed in
this assay was due to hydroperoxides and not hydroquinones.
Biometry
[0418] Measuring data are centrally computerised after validity
check and quality assurance. Evaluation is done using the software
Statgraphics for Windows, Version 5.0--Manugistics, USA. Data are
analysed by multiple range test (LSD: Least Significant
Differences). The 0.05 level is selected as the point of minimal
acceptance statistical significance.
Results
[0419] The present skincare formulations significantly (p<0.05)
reduce squalene peroxidation, compared to UV radiated non-treated
control.
[0420] In the untreated, non-irradiated area the formation of
ethanol extractable squalenehydro-peroxide is not detected.
[0421] The average inhibition in % of peroxidation is:
TABLE-US-00013 Formulation Inhibition AO4 28% AO5 26.5% AO6 28% AO7
21.5% AO8 21% Control 22.5%
Conclusion:
[0422] Pretreatment of the epidermal surface before exposure to UVA
irradiation with the formulations according to the present
invention significantly reduces UV-induced sebum peroxidation.
These studies provide compelling evidence for the free radical
hypothesis of UVA light induced cutaneous pathology: Lipid
peroxidation increased on irradiation, and the topical application
with an antioxidant system protected from this damage.
EXAMPLE 3
Dermatological Formulations
General Preparation:
[0423] A clear homogenous prephase is obtained by mixing
(a) 5 to 20% by weight of a phospholipid (e.g. lecithin), (b) 15 to
40% by weight of a coemulsifier (e.g. a polyethoxylated sorbitan
fatty acid ester, polyethoxylated fatty alcohol, polyethoxylated
fatty acid, polyethoxylated vitamin E derivative, polyethoxylated
lanoline or lanoline derivative, polyethoxylated fatty acid
glyceride or partial glyceride, polyethoxylated alkylphenol,
sulfuric acid semiester of a polyethoxylated fatty alcohol or salt
thereof, polyethoxylated fatty amine or amide, polyethoxylated
carbon hydrate), (c) 30 to 70% by weight of a lipophilic component
consisting of a triglyceride, a compound of the invention such as
AO3-AO8, and optionally a further active agent, where the weight
ratio of active agent(s): triglyceride usually ranges from 1:5 to
5:1, and (d) 3 to 30% by weight of an alcohol such as ethanol, with
the sum of percentages of the components (a), (b), (c) and (d)
adding to 100%, and adding the liquid obtained to a water phase.
The water phase (e.g. 90 kg) is placed, with stirring (e.g.
magnetic agitator), at 50.degree. C. in a vessel. The liquid
prephase (e.g. 10 kg) is added to the water phase with stirring
(e.g. with a magnetic agitator). The formulation thus obtained may
be further diluted or admixed.
Vitamin A Palmitate Cream
TABLE-US-00014 [0424] A dispersion is obtained by mixing a clear
prephase containing: vitamin A palmitate (1.7 .times. 10.sup.6
IU/g) 0.45% compound AO7 0.45% soybean lecithin 1.73% miglyol 812
3.00% polysorbate 80 3.40% ethanol 1.42% to a water phase: 10 mm
phosphate buffer, pH 6 ad 100.00% Final preparation contains: cetyl
alcohol 10.00% hydrogenated groundnut oil 20.00% polysorbate 60
5.00% propylene glycol 20.00% phenoxyethanol 0.50% dispersion shown
above 23.00% aqua purificata ad 100.00%
[0425] Good results are also achieved when compound A07 is replaced
by AO3, A04 or A05.
Solcoseryl 0.5% Hydroqel
TABLE-US-00015 [0426] A dispersion is obtained by mixing a clear
prephase containing: solcoseryl 1.00% compound AO7 1.00% soybean
lecithin 1.73% polysorbate 80 3.40% miglyol 812 3.45% ethanol 1.42%
to a water phase: 10 mm phosphate buffer, pH 6 ad 100.00% Final
preparation contains: sodium carboxymethylcellulose 450 cP 3.50%
dispersion shown above 50.00% aqua purificata ad 100.00%
[0427] The preparation is pleasantly cooling and has good
antiphlogistic action.
Skin Protecting W/O Lotion
TABLE-US-00016 [0428] A dispersion is obtained by mixing a clear
prephase containing: vitamin E acetate 2.00% compound AO3 1.00%
soybean lecithin 0.49% polysorbate 80 1.86% miglyol 812 0.71%
ethanol 0.63% to a water phase: aqua purificata ad 100.00% Final
preparation contains: glycerol sorbitan fatty acid ester 2.0%
polyethoxy fatty acid ester 2.0% isopropylisostearate 5.0% mineral
oil 7.0% isopropylpalmitate 4.0% wheat germ oil 3.0% propylene
glycol 3.8% dispersion shown above 5.0% MgSO.sub.4 .times. 7H2O
0.7% perfume 0.5% perservative, water
[0429] Good results are also achieved when compound A03 is replaced
by A07, A06 or A08.
Day Cream with UV Protection (O/W)
TABLE-US-00017 A dispersion is obtained by mixing a clear prephase
containing: parsol MCX 2.59% (octyl methoxycinnamate) Parsol 5000
1.11% (4-methylbenzylidene camphor) compound AO7 1.00% miglyol 812
1.30% soybean lecithin 0.50% polysorbate 80 3.40% ethanol 1.10% to
a water phase: aqua purificata ad 100.00% Final preparation
contains: PEG-5 glycerol stearate 5.0% steareth-21 2.0% mineral oil
30.0% cetyl alcohol 2.0% microcrystalline wax 1.0% propylene glycol
6.0% dispersion shown above 10.0% phenoxyethanol + methyl-, ethyl-,
propyl-, butylparabene 0.3% water ad 100.0%
* * * * *