KR101312422B1 - Anti-radical agents - Google Patents

Abstract

(1)

(1)의 화합물;

Compound of (1);

Formula (2)

(2)의 화합물; 및

The compound of (2); And

(3)의 화합물과 같은 선택된 입체장애 니트록시, 히드록실아민 및 히드록실아민 염 화합물은 현저한 항염증 작용을 타나낸다: Formula (3)

Selected hindered nitroxy, hydroxylamine and hydroxylamine salt compounds, such as the compound of (3), exhibit marked anti-inflammatory action:

In the above formulas (1), (2) and (3),

G ₁ is hydrogen; C ₁ -C ₂₂ alkyl; C ₁ -C ₂₂ alkylthio; C ₂ -C ₂₂ alkylthioalkyl; C ₅ -C ₇ cycloalkyl; Phenyl; C ₇ -C ₉ phenylalkyl; Or SO ₃ M; G ₂ is C ₁ -C ₂₂ alkyl; C ₅ -C ₇ cycloalkyl; Phenyl; Or C ₇ -C ₉ phenylalkyl; 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 0 or 1; e is an integer from 1 to 4; f, m, n and p are each independently an integer from 1 to 3; q is 0 or an integer from 1 to 3; Q, T and G ₃ are as defined in claim 1; G ₄ and G ₅ are independently of each other hydrogen; Or C ₁ -C ₂₂ alkyl.

Anti-inflammatory action, steric hindrance nitroxyl, hydroxylamine, hydroxylamine, pharmaceutical composition, allergy, skin damage

Description

Anti-radical agents

The present invention relates to the use as a pharmaceutical active agent of carbon or ester / amide bridged phenols or lactones, or some hindered amines, and to pharmaceutical compositions, especially dermatological compositions containing them. The invention also relates to the use of such compounds (anti-aging applications) for the manufacture of a medicament or agent for treating radical-induced damage such as inflammatory or allergic conditions, collagen damage, DNA damage, or reperfusion-damage. .

It is standard practice to use glucocorticoids for topical treatment of inflammatory and allergic conditions. It is generally known that these compounds may have undesirable side effects.

Due to insufficient ability to penetrate the skin, nonsteroidal anti-inflammatory drugs containing therapeutic agents such as ketoprofen, BW755c, pyroxicam, diclofenac or indomethazine cannot be applied topically effectively and are applied systemically only. Some phenol ethers are also known to have antioxidant, anti-inflammatory and anti-allergic properties (EP-A-1366763 and references cited therein).

It is an object of the present invention to provide pharmaceutical compositions having surprisingly good pharmacological properties, in particular antioxidant properties, anti-inflammatory properties and antiallergic properties, when administered topically.

(1) The compound of formula (1)

및/또는

And / or

(2) a compound of formula (2)

및/또는

And / or

(3) hindered nitoxyl compounds, hindered hydroxylamine compounds, hindered hydroxylamine salt compounds of the general formula

This good skin and cell affinity has been shown to show cellular and enzymatically significant radical disruption and anti-inflammatory activity in in vitro and in vivo assays of human volunteers:

Where

G ₁ is hydrogen; C ₁ -C ₂₂ alkyl; C ₁ -C ₂₂ alkylthio; C ₂ -C ₂₂ alkylthioalkyl; C ₅ -C ₇ cycloalkyl; Phenyl; C ₇ -C ₉ phenylalkyl; Or SO ₃ M;

G ₂ is C ₁ -C ₂₂ alkyl; C ₅ -C ₇ cycloalkyl; Phenyl; Or C ₇ -C ₉ phenylalkyl;

또는 하기 화학식(1a) 또는 (1b)Q is

Or the following formula (1a) or (1b)

(1a)

(1a)

(1b)

(1b)

 Lt; / RTI >

; 또는 화학식(1c)T is -C _n H _2n- ; -(CH ₂ ) _n -O-CH _2- ; Phenylene;

; Or formula (1c)

Is a radical of;

V is -O-; Or -NH-; _;

a is 0; One; Or 2;

b, c and d and g are each independently 0; Or 1;

e is an integer from 1 to 4;

f is an integer from 1 to 3; In addition

m, n and p are each independently an integer from 1 to 3;

q is 0 or an integer from 1 to 3;

If e = 1, in formula (3),

G ₃ is hydrogen; C ₁ -C ₂₂ alkyl; C ₅ -C ₇ cycloalkyl; C ₁ -C ₂₂ alkylthio; C ₂ -C ₂₂ alkylthioalkyl; C ₂ -C ₁₈ alkenyl; C ₁ -C _{18 -} phenylalkyl; M; SO ₃ M; A radical of formula (1d), (1e) or (1f)

Or G ₃ is propyl substituted by OH and / or C ₂ -C ₂₂ alkanoyloxy;

M is an alkali; ammonium; H;

If e = 2,

; 또는 -S-이거나; 또는 G₃은 OH 또는 C₂-C₂₂알카노일옥시에 의해 치환된 프로필이고;G ₃ is a direct bond; -CH ₂ -;

; Or -S-; Or G ₃ is propyl substituted with OH or C ₂ -C ₂₂ alkanoyloxy;

if e = 3,

G ₃ is

의 라디칼이고;

Is a radical of;

if e = 4,

이며; G ₃ is

;

G ₄ and G ₅ are independently of each other hydrogen; Or C ₁ -C ₂₂ alkyl;

A ₁ and A ₂ are independently alkyl of 1 to 4 carbon atoms or combined pentamethylene;

Z ₁ and Z ₂ are each methyl or Z ₁ And Z ₂ combine to form a linkage moiety that may be further substituted by ester, ether, hydroxy, oxo, cyanohydrin, amide, amino, carboxy or urethane groups;

h is the number of positive charges; J is the number of negative charges;

X is an inorganic or organic anion; In addition

The total charge of the cation h is equal to the total charge of the anion j. The compounds of the present invention can be used alone or in mixtures with one another and / or with other components as described in detail below. Accordingly, the present invention is directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier or adjuvant with one or more of the compounds of formulas (1), (2) and / or (3), as well as radical induced skin damage and inflammatory diseases and allergies. It relates to the use of a compound of formula (1), (2) and / or (3) for the manufacture of a medicament or preparation, such as a cosmetic or pharmaceutical preparation for treating or preventing a condition.

Compounds of formula (1) wherein e is 1 usually contain spacer groups Q and (CO) -V and correspond to the condition b = c = 1. Also useful are compounds of the formula:

Radical Oxygen Species (ROS) oxidize lipids, destroy enzymes and matrix proteins, affect DNA or RNA, and lead to premature aging of the skin with drying effects, elasticity, and strong irritation It is known to promote the destruction of. Inflammation and ROS production activate matrix metalloproteinases (MMPs) but cause oxidative damage to cellular proteins, lipids and carbohydrates. MMP is a group of zinc-dependent endopeptidase capable of breaking down extracellular matrix (ECM) components such as collagen, elastin, fibronectin, gelatin, laminin, resulting in photoaging skin and pigmentation reactions with wrinkles. Compounds of the invention include enzyme components such as glutathione peroxidase, catalase, superox side dismutase, metallothionein; Or an endogenous antioxidant defense system comprising non-enzymatic components such as glutathione, vitamin E, vitamin C, ubiquinol, β-carotene.

After application to the skin, the compounds of the present invention are derived from direct oxidation of intracellular and intercellular lipids, lipoproteins, cell membranes; Low molecular weight compounds such as lipids, sugars, weak amino acids (eg amino acids with thiol groups), glutathione; And polymers such as proteins, proteoglycans and glycosaminoglycans.

The additional effect obtained from these materials is their protective effect on the components of the formulation which are sensitive to oxidation by air oxygen, providing higher stability and longer shelf life of the product. Some of the pharmaceutical or cosmetic carrier emulsions are emulsifiers containing lipids and also lipid fragments and facilitate the chemical transformation induced by reaction with oxygen.

Depending on the chemical structure of the typical pharmaceutical or cosmetic carrier and the solubility in the various phases, the compound may be hydrophilic or lipophilic. The choice of the optimal antioxidant may not only depend on the solubility in a particular carrier system, but also the undesirable interaction with the carrier with or without the combination of UV light, skin penetration after topical administration of the agent, reaction with free radicals. It is also affected by the production of cytotoxic or immunosuppressive products.

Damage to radicals in organs of animals and humans, which can be prevented by the compounds of the present invention, is described in US Pat. No. 4698360.

Compounds of the invention, i.e. compounds of formulas (1), (2) and / or (3), are useful for treating inflammatory and allergic diseases (e.g., Skaper et al., Free Radical Biology and Medicine 22, 669-78 (1997) As well as useful for treating diseases including disruption of cell proliferation. They are preferably for topical treatment of radical induced bad reactions such as inflammatory and allergic diseases, collagen damage, reperfusion damage, DNA-damage; It is especially used for skin treatment.

In vitro analysis shows that the compounds of the present invention inhibit the formation of different mediators, which are important factors in inflammation.

The compounds of the present invention are effective as radical inhibitors. These are lipoxygenase / cyclooxygenase inhibitors, ie they can interfere with inflammatory step reactions. The compounds of the present invention have been shown to be effective as anti-inflammatory agents for UV induced erythema. They also exhibit anti-inflammatory and antioxidant effects and are comparable to one of vitamin E in certain applications.

The hindered nitoxyl, hydroxylamine and hydroxylamine salt compounds (3) are compounds of the formulas (A) to (EE) and (A ^* ) to (EE ^* ):

In the formula,

E is oxyl or hydroxyl,

R is hydrogen or methyl,

In formulas (A) and (A ^* ),

n is 1 or 2,

If n = 1,

R 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 segmented by 1 to 20 oxygen atoms, 1 to 10 carbon atoms The alkyl substituted by a hydroxyl group or segmented by the oxygen atom and substituted by the hydroxyl group, or

R ₁ is alkyl of 1 to 4 carbon atoms substituted by a carboxy group or by —COOZ, wherein Z is hydrogen, alkyl or phenyl of 1 to 4 carbon atoms, or Z is (COO ⁻ ) _n M ^{n +} Substituted alkyl, wherein n is 1 to 3 and M is a group 1, 2 or 3 metal ion of the periodic table or Zn, Cu, Ni or Co, or M is N ^{n +} (R ₂ ) ₄ groups, wherein R ₂ is alkyl or benzyl of 1 to 8 carbon atoms,

If n = 2,

R ₁ is branched by alkylene of 1 to 12 carbon atoms, alkenylene, xylene or 1 to 20 oxygen atoms of 4 to 12 carbon atoms, substituted by 1 to 10 hydroxyl groups, or by said oxygen atoms Alkylene of 1 to 50 carbon atoms which is segmented and substituted by said hydroxyl group,

In the formulas (B) and (B ^* ),

m is 1 to 4,

If m = 1

R ₂ is alkyl of 1 to 18 carbon atoms, alkyl of 3 to 18 carbon atoms segmented by -COO-, or R ₂ is -CH ₂ (OCH ₂ CH ₂ ) _n OCH ₃ , where n is 1 to 12, or

R ₂ is said aryl substituted by cycloalkyl of 5 to 12 carbon atoms, aryl of 6 to 12 carbon atoms, or 1 to 4 alkyl groups of 1 to 4 carbon atoms, or

R ₂ is —NHR _3, wherein R ₃ is alkyl of 1 to 18 carbon atoms, cycloalkyl of 5 to 12 carbon atoms, aryl of 6 to 12 carbon atoms, or 1 to 4 alkyl of 1 to 4 carbon atoms Said aryl substituted by, or

R ₂ is —N (R ₃ ) ₂ , wherein R ₃ is as defined above,

if m = 2,

R ₂ is alkylene of 1 to 12 carbon atoms, alkenylene of 4 to 12 carbon atoms, xylylene, alkylene of 2 to 12 carbon atoms segmented by -COO-, or R ₂ is -CH ₂ ( OCH ₂ CH ₂ ) _n OCH _2- , wherein n is 1 to 12, or

R 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

R ₂ is —NHR ₄ NH—, wherein R ₄ is alkylene of 2 to 18 carbon atoms, cycloalkylene of 5 to 12 carbon atoms, aralkylene of 8 to 15 carbon atoms or aryl of 6 to 12 carbon atoms Ren, or

R ₂ is -N (R ₃ ) R ₄ N (R ₃ )-, wherein R ₃ and R ₄ are as defined above, or

R ₂ is -CO- or -NH-CO-NH-,

if m = 3,

R ₂ is alkantriyl or benzenetriyl of 3 to 8 carbon atoms, or

if m = 4,

R ₂ is alkane tetrayl or benzene tetrayl of 5 to 8 carbon atoms,

In the formulas (C) and (C ^* ),

R 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 or benzoyl of 3 to 5 carbon atoms ego,

x is 1 or 2,

if x = 1,

R 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 segmented by 1 to 20 oxygen atoms, 1 Or is alkyl substituted with 10 hydroxyl groups or segmented with oxygen atoms and substituted with hydroxyl groups, or

R ₁₁ is 1 to 4 carbon atoms or alkyl substituted by carboxy by a -COOZ, wherein Z is hydrogen, alkyl of 1 to 4 carbon atoms or phenyl, or Z is ^{_{- (COO -) n M n}} + Wherein said alkyl substituted by n wherein n is from 1 to 3 and M is a Group 1, 2 or 3 metal ion of the periodic table or Zn, Cu, Ni or Co, or M is N ^{n +} (R ₂ ) ₄ groups, where R ₂ is hydrogen, alkyl or benzyl of 1 to 8 carbon atoms, or

if x = 2,

R ₁₁ is branched by alkylene of 1 to 12 carbon atoms, alkenylene, xylylene or 1 to 20 oxygen atoms of 4 to 12 carbon atoms, substituted by 1 to 10 hydroxyl groups, or substituted by the oxygen atoms Alkylene of 1 to 50 carbon atoms, segmented by and substituted by said hydroxyl groups,

In the formulas (D) and (D ^* ),

R ₁₀ is as defined above,

y is 1 to 4, and

R ₁₂ is as defined above in R ₂ ,

In the formulas (E) and (E ^* ),

k is 1 or 2,

if k = 1

R ₂₀ and R 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 ₂₀ is also hydrogen, or

R ₂₀ and R ₂₁ combined are said alkylene substituted by alkylene or hydroxyl of 2 to 8 carbon atoms, or acyloxy-alkylene of 4 to 22 carbon atoms, or

if k = 2,

R ₂₀ And R ₂₁ combined are (—CH ₂ ) ₂ C (CH ₂ —) ₂ ,

In the formulas (F) and (F ^* ),

R ₃₀ is hydrogen, alkyl of 1 to 18 carbon atoms, benzyl, glycidyl, or alkoxyalkyl of 2 to 6 carbon atoms,

g is 1 or 2,

if g = 1, then R ₃₁ is as defined for R ₁ above when n = 1;

when g = 2, then R ₃₁ is as defined for R ₁ when n = 2,

In the formulas (G) and (G ^* ),

Q ₁ is -NR ₄₁ -or -O-,

E ₁ is alkylene of 1 to 3 carbon atoms, or E ₁ is -CH ₂ -CH (R ₄₂ ) -O-, wherein R ₄₂ is hydrogen, methyl or phenyl, or E ₁ is-(CH ₂ ) ₃ -NH- or E ₁ is a direct bond,

R ₄₀ is hydrogen or alkyl of 1 to 18 carbon atoms,

R 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 ₄₁ is -CH ₂ -CH ( R ₄₂ ) -OH, wherein R ₄₂ is as defined above,

In the formulas (H) and (H ^* ),

p is 1 or 2,

T ₄ is as defined for R ₁₁ when x is 1 or 2,

M and Y are independently methylene or carbonyl, for example M is methylene and Y is carbonyl,

In the formulas (I) and (I ^* ),

The formula is a repeating structural unit of the polymer where T ₁ is ethylene or 1,2-propylene or a repeating structural unit derived from an alpha-olefin copolymer having an alkyl acrylate or methacrylate, where q is 2 And 100, Q ₁ is -N (R ₄₁ )-or -O-, wherein R ₄₁ is as defined above,

In the formulas (J) and (J ^* ),

r is 1 or 2,

T ₇ is the same as defined in R ₁ when n in the formula (A) is 1 or 2,

For example when r is 2, T ₇ is octamethylene,

In formulas (L) and (L ^* ),

u is 1 or 2,

T ₁₃ is as defined for R ₁ when n in Formula (A) is 1 or 2, provided that T ₁₃ is not hydrogen when u is 1,

In the formulas (M) and (M ^* ),

E ₁ and E ₂ are different from each other and are -CO- or -N (E ₅ )-, wherein E ₅ is hydrogen, alkyl of 1 to 12 carbon atoms or alkoxycarbonylalkyl of 4 to 22 carbon atoms, for example E ₁ is -CO- and E ₂ is -N (E ₅ )-,

E ₃ is hydrogen, alkyl of 1-30 carbon atoms, phenyl, naphthyl, phenyl substituted by alkyl of 1-4 carbon atoms, or phenylalkyl of 7-12 carbon atoms, or Or phenylalkyl substituted by alkyl of 1 to 4 carbon atoms,

E ₄ is hydrogen, alkyl of 1 to 30 carbon atoms, phenyl, naphthyl or phenylalkyl of 7 to 12 carbon atoms, or said phenylalkyl substituted by alkyl of 1 to 4 carbon atoms, or

E ₃ and E ₄ combined are polymethylene of 4 to 17 carbon atoms, or the polymethylene substituted by 1 to 4 alkyl of 1 to 4 carbon atoms such as methyl,

In formula (N),

R ₁ is as defined in R ₁ in Formula (A) when n is 1,

G ₃ is a direct bond, alkylene of 1 to 12 carbon atoms, phenylene or -NH-G ₁ -NH-, wherein G ₁ is alkylene of 1 to 12 carbon atoms,

In the formulas (O) and (O ^* ),

R ₁₀ is as defined for R ₁₀ in formula (C),

In the formulas (P) and (P ^* ),

E ₆ is an aliphatic or aromatic tetravalent radical, such as neopentanetetrayl or bengentatel,

In the formulas (T) and (T ^* ),

R 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,

R ₅₂ is hydrogen or alkyl of 1 to 18 carbon atoms, or

R ₅₁ and R ₅₂ together are alkylene of 4 to 8 carbon atoms,

f is 1 or 2,

if f = 1

R ₅₀ is as defined for R ₁₁ in formula (C) when x is 1, or R ₅₀ is — (CH ₂ ) _z COOR ₅₄ , wherein z is 1 to 4 and R ₅₄ is hydrogen or 1 to Alkyl of 18 carbon atoms, or R ₅₄ is a metal ion of Group 1, 2 or 3 of the periodic table or a -N (R ₅₅ ) ₄ group wherein R ₅₅ is hydrogen, alkyl of 1 to 12 carbon atoms or Benzyl,

if f = 2,

R ₅₀ is as defined for R ₁₁ in formula (C) when x is 2,

In the formulas (U) and (U ^* ),

R ₅₃ , R ₅₄ , R ₅₅ and R ₅₆ are independently alkyl of 1 to 4 carbon atoms or combined pentamethylene,

In the formulas (V) and (V ^* ),

R ₅₇ , R ₅₈ , R ₅₉ and R ₆₀ are independently alkyl of 1 to 4 carbon atoms or combined pentamethylene,

In the formulas (W) and (W ^* ),

R ₆₁ , R ₆₂ , R ₆₃ and R ₆₄ are independently alkyl of 1 to 4 carbon atoms or combined pentamethylene,

R ₆₅ is alkyl of 1 to 5 carbon atoms,

M is hydrogen or oxygen,

In the formulas (X) to (CC) and (X ^* ) to (CC ^* ),

n is 2 to 3,

G ₁ is hydrogen, methyl, ethyl, butyl or benzyl,

m is 1 to 4,

x is 1 to 4,

If x = 1,

R ₁ and R ₂ are independently alkyl having 1 to 18 carbon atoms substituted by alkyl, 1 to 5 hydroxyl groups which are segmented by 1 to 5 oxygen atoms or segmented by said oxygen atoms and Said alkyl substituted by a hydroxyl group; 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 1 to 3 alkyl of 1 to 8 carbon atoms, or R ₁ is hydrogen Or R ₁ and R _{2 taken} together are tetramethylene, pentamethylene, hexamethylene or 3-oxapentamethylene,

if x = 2,

R ₁ is hydrogen, alkyl of 1 to 8 carbon atoms, said alkyl segmented by 1 or 2 oxygen atoms, said alkyl substituted by hydroxyl groups, or 1 or 2 oxygen atoms and is further bound to hydroxyl groups Is alkyl substituted by

R ₂ is alkylene of 2 to 18 carbon atoms, the alkylene segmented by 1 to 5 oxygen atoms, the alkylene substituted by 1 to 5 hydroxyl groups or the oxygen atom and is separated Said alkylene substituted by a hydroxyl group; Or said phenylene substituted by o-, m- or p-phenylene or 1 or 2 alkyl of 1 to 4 carbon atoms, or

R ₂ is — (CH ₂ ) _k O [(CH ₂ ) _k O] _h (CH ₂ ) _k −, where k is 2 to 4 and h is 1 to 40, or

R ₁ and R _{2 taken} together with the two N atoms to which they are attached are piperazine-1,4-diyl,

if x = 3,

R < ₁ > is hydrogen,

R ₂ is alkylene of 4 to 8 carbon atoms segmented by 1 nitrogen atom,

if x = 4,

R < ₁ > is hydrogen,

R ₂ is alkylene of 6 to 12 carbon atoms divided by 2 nitrogen atoms,

R ₃ is hydrogen, alkyl of 1 to 8 carbon atoms, said alkyl segmented by 1 or 2 oxygen atoms, said alkyl substituted by hydroxyl groups, or is branched and hydroxylated by 1 or 2 oxygen atoms Said alkyl substituted by a group,

P is 2 or 3, and

Q is an alkali metal salt, ammonium or N ⁺ (G ₁ ) ₄ ,

In the formulas (DD) and (DD ^* ),

m is 2 or 3,

if m = 2,

G is-(CH ₂ CHR-O) _r CH ₂ CHR-, where r is 0 to 3 and R is hydrogen or methyl, and

if m = 3,

G is glyceryl,

In the formulas (EE) and (EE ^* ),

G ₂ is —CN, —CONH ₂ or —COOG ₃ , wherein G ₃ is hydrogen, alkyl of 1 to 18 carbon atoms or phenyl,

X is phosphate, phosphonate, carbonate, bicarbonate, nitrate, chloride, bromide, bisulfite, sulfite, bisulfate, sulfate, borate, formate, acetate, benzoate, citrate, oxalate, tartrate Acrylates, polyacrylates, fumarates, maleates, itaconates, glycolates, gluconates, maleates, mandelate, tiglate, ascorbates, polymethacrylates; Carboxylates of nitrilotriacetic acid, hydroxyethylethylenediaminetriacetic acid, ethylene-diaminetetraacetic acid or diethylenetriaminepentaacetic acid; Inorganic or organic anions such as diethylenetriamine-pentamethylphosphonate, alkylsulfonate or arylsulfonate, and

The total charge of the cation h is equal to the total charge of the anion j.

For example, Formula (3) is represented by Formulas A, A ^* , B, B ^* , C, C ^* , D, D ^* , Q, Q ^* , R, R ^* , S, S ^* , X, X ^* , Y, Y ^* , Z and Z ^* is a compound, R is hydrogen,

In formulas (A) and (A ^* ),

n is 1 or 2,

If n = 1,

R ₁ is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, propargyl, glycidyl, alkyl of 2 to 20 carbon atoms segmented by 1 to 10 oxygen atoms, 1 to The alkyl substituted by 5 hydroxyl groups or segmented by the oxygen atom and substituted by the hydroxyl group, or

R ₁ is alkyl of 1 to 4 carbon atoms substituted by carboxy group or to —COOZ, wherein Z is hydrogen or alkyl of 1 to 4 carbon atoms,

If n = 2,

R ₁ is branched by alkylene of 1 to 8 carbon atoms, alkenylene of 4 to 8 carbon atoms, 1 to 10 oxygen atoms, substituted by 1 to 5 hydroxyl groups, or branched by said oxygen atoms And alkylene of 1 to 20 carbon atoms substituted by the hydroxyl group,

In the formulas (B) and (B ^* ),

m is 1 or 2,

if m = 1

R ₂ is alkyl of 1 to 4 carbon atoms or R ₂ is CH ₂ (OCH ₂ CH ₂ ) _n OCH ₃ , where n is 1 to 12, or

R ₂ is phenyl or the phenyl substituted by 1 to 3 methyl groups,

R ₂ is -NHR _3, wherein R ₃ is alkyl or phenyl of 1 to 4 carbon atoms, or said phenyl substituted by 1 to 3 methyl groups,

if m = 2,

R ₂ is alkylene of 1 to 8 carbon atoms, alkenylene of 4 to 8 carbon atoms, or R ₂ is —CH ₂ (OCH ₂ CH ₂ ) _n OCH ₂ —, where n is 1 to 12,

R ₂ is —NHR ₄ NH, wherein R ₄ is alkylene of 2 to 6 carbon atoms, aralkylene of 8 to 15 carbon atoms or arylene of 6 to 12 carbon atoms,

R ₂ is -CO- or -NHCONH,

In the formulas (C) and (C ^* ),

R ₁₀ is hydrogen or alkanoyl of 1 to 3 carbon atoms,

x is 1 or 2,

If x = 1,

R ₁₁ is hydrogen, alkyl of 1 to 6 carbon atoms or glycidyl,

R ₁₁ is alkyl of 1 to 4 carbon atoms substituted by carboxy group or by COOZ, wherein Z is hydrogen or alkyl of 1 to 4 carbon atoms,

if x = 2,

R ₁₁ is alkylene of 1 to 6 carbon atoms,

In the formulas (D) and (D ^* ),

R < ₁₀ > is hydrogen,

y is 1 or 2,

R ₁₂ is as defined above in R ₂ ,

In the formulas (Y), (Y ^* ), (Z) and (Z ^* ),

x is 1 or 2,

if x = 1,

R ₁ and R ₂ are independently alkyl of 1 to 4 carbon atoms, or

R ₁ and R _{2 taken} together are tetramethylene or pentamethylene,

R ₂ is hydrogen or the alkyl group substituted by an alkyl, hydroxyl group of 1 to 4 carbon atoms,

if x = 2,

R ₁ is hydrogen, alkyl of 1 to 4 carbon atoms, said alkyl substituted by a hydroxyl group,

R ₂ is alkylene of 2 to 6 carbon atoms,

R ₃ is as defined above.

For example, compound (3) may be represented by the formula (A), (A ^* ), (B), (B ^* ), (C), (C ^* ), (D), (D ^* ), (Q), (Q ^* ), (R) and (R ^* ) compounds,

R is hydrogen,

In formulas (A) and (A ^* ),

h is 1,

R ₁ is substituted by or substituted with hydrogen, alkyl of 1 to 4 carbon atoms, glycidyl, alkyl of 1 to 2 carbon atoms, or 1 to 2 hydroxyl groups, which is segmented by 1 or 2 oxygen atoms The alkyl segmented by and substituted by the hydroxyl group, or

R ₁ is alkyl of 1 to 4 carbon atoms substituted by —COOZ, wherein Z is hydrogen or alkyl of 1 to 4 carbon atoms,

In the formulas (B) and (B ^* ),

m is 1 or 2,

R ₂ is alkyl of 1 to 4 carbon atoms or R ₂ is CH ₂ (OCH ₂ CH ₂ ) _n OCH ₃ , where n is 1 to 4,

if m = 2,

R ₂ is alkylene of 1 to 8 carbon atoms,

In the formulas (C) and (C ^* ),

R ₁₀ is hydrogen or alkanoyl of 1 or 2 carbon atoms,

x is 1 or 2,

if x = 1,

R ₁₁ is hydrogen, alkyl or glycidyl of 1 to 4 carbon atoms,

R ₁₁ is alkyl of 1 to 4 carbon atoms substituted by COOZ, wherein Z is hydrogen or alkyl of 1 to 4 carbon atoms,

if x = 2,

R ₁₁ is alkylene of 1 to 6 carbon atoms,

In the formulas (D) and (D ^* ),

R < ₁₀ > is hydrogen,

y is 1 or 2,

R ₁₂ is as defined as R ₂ above.

The hindered nitroxyl, hydroxylamine and hydroxylamine salt compounds (3) selected preferably correspond to the formula (3) or salts thereof:

In the formula,

E is oxyl or hydroxyl and G ₃ , V and c are as defined in formula (1) above.

Compounds (3), in particular compounds of formula (3), such as those of formulas (A) to (EE), can be used as such or in the form of suitable acid addition salts, as shown in formulas (A ^* ) to (EE ^* ). These are for example salts of pharmaceutically acceptable inorganic or organic acids. Useful acid addition salts are advantageously salts with inorganic acids, such as chlorides or sulfates, or salts with sulfonic or carbonic acid, such as hydrogen (or optionally dihydrogen) phosphates, phosphonates, carbonates, bicarbonates. , Nitrate, chloride, bromide, bisulfite, sulfite, bisulfate, sulfate, borate, formate, acetate, benzoate, citrate, oxalate, tartrate, acrylate, polyacrylate, fumarate, male Ate, itaconate, glycolate, gluconate, pyruvate, malate, mandelate, tiglate, ascorbate, polymethacrylate, nitriloacetic acid, hydroxyethylethylenediaminetriacetic acid, ethylenediaminetetraacetic acid or Carboxylate, diethylenetri of diethyl triamine pentaacetic acid Includes a Min pentamethylene phosphonate, alkyl sulfonate or aryl sulfonate, such as methane sulfonates, benzoates, oxalates or acetates, these ions corresponds to the preferred meanings of X. The salt is preferably a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include salts of acids most known to those skilled in the art, such as alkancarboxylic acids (particularly C ₁ -C ₄ acids); Di- or polycarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, citric acid, maleic acid, tartaric acid, lactic acid, glucuronic acid and / or hydroxycarboxylic acids and other acids derived from sugars, each of which is enantio Present in mermer form and optically active; Phosphoric acid, sulfuric acid, methylsulfonic acid, toluenesulfonic acid, benzoic acid; Some preferred salts are hydrochloride, hydrobromide, hydroiodide, benzoate, phosphate, hydrogen phosphate, sulphate, hydrogen sulphate and especially citrate. Preferred for example are citrate, hydrochloride, oxalate.

C ₁ -C ₂₂ alkyl is a straight or branched chain alkyl radical such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, amyl, isoamyl or t-amyl, heptyl, Octyl, isooctyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl or icosyl.

C ₁ -C ₂₂ alkylthio is a straight or branched chain alkylthio radical such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, t-butylthio, amylthio, Heptylthio, octyl-thio, isooctylthio, nonylthio, decylthio, undecylthio, dodecylthio, tetradecylthio, pentadecyl-thio, hexadecylthio, heptadecylthio, octadecylthio or icosylthio .

C ₂ -C ₂₂ alkylthioalkyl is alkylthio as described above attached to alkyl by a sulfur atom, and the total residue contains 2 to 22 carbon atoms.

C ₂ -C ₁₈ alkenyl is for example allyl, metallyl, 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.

C ₅ -C ₇ cycloalkyl is cyclopentyl, cycloheptyl or preferably cyclohexyl.

C ₇ -C ₉ phenylalkyl includes phenylpropyl (such as cumyl), phenylethyl, preferably benzyl.

As alkali, M is Li, Na, K, Cs.

Useful compounds of formulas (1) and (2) of the present invention include the compounds listed in Table 1 below:

Useful hindered amine compounds (3) include the following compounds: bis (1-oxyl-2,2-6-6-tetramethylpiperidin-4-yl) sebacate; Bis (1-hydroxy-2,2-6-6-tetramethylpiperidin-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-acetamido-piperidinium bisulfate; 1-oxyl-2,2,6,6-tetramethyl-4-oxo-piperidine; 1-hydroxy-2,2,6,6-tetra-methyl-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-hydroxy-2,2,6,6-tetramethyl-4-methoxy-piperidinium acetate; 1-oxyl-2,2,6,6-tetra-methyl-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-tetra-methyl-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-acetamido-piperidinium) nitrilotriacetate; Tri (1-hydroxy-2,2,6,6-tetramethyl-4-oxopiperidinium) nitrilo-triacetate; Penta (1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium) diethylenetriamine-pentamethylenephosphonate; Penta (1-hydroxy-2,2,6,6-tetramethyl-4-acetamido-piperidinium) diethylenetriaminepentamethylene-phosphonate; And penta (1-hydroxy-2,2,6,6-tetramethyl-4-oxopiperidinium) diethylene-triaminepentamethylenephosphonate sterically hindered nitroxyl, hydroxylamine and hydroxyl Amine salt compounds.

Preferred hindered nitoxyl, hydroxylamine and hydroxylamine salt compounds of formula (3) include 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-hydroxy-piperidinium 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-hydroxy-piperidinium 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.

For example, the compound of formula (3) may be selected from the group consisting of 1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidinium citrate; Bis (1-hydroxy-2,2,6,6-tetramethyl-4-hydroxy-piperidinium) 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-hydroxy-piperidinium) 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-tetra-methyl-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-tetra-methyl-4-acetamidopiperidinium citrate; Bis (1-hydroxy-2,2,6,6-tetramethyl-4-acetamido-piperidinium) 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-tetra-methyl-4-acetamidopiperidinium) DTPA; Tris (1-hydroxy-2,2,6,6-tetramethyl-4-acetamido-piperidinium) DTPA; Tetrakis (1-hydroxy-2,2,6,6-tetramethyl-4-acetamido-piperidinium) 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-acetamido-piperidinium) 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-tetra-methyl-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-tetramethyl-4-acetoxypiperidinium) EDTA and tetrakis (1-hydroxy-2,2,6,6-tetramethyl-4-acet Oxypiperidinium) is a hydroxylamine salt selected from EDTA.

The above-mentioned counterions are ethylenediaminetetraacetic acid (EDTA), diethylene-triaminepentaacetic acid (DTPA), hydroxyethylethylenediaminetriacetic acid (HEDTA), nitrile acetic acid (NTA) or diethylenetriaminepentamethylene phosphonic acid (DTPMPA).

G ₁ and G ₂ are preferably independently of each other C ₁ -C ₁₈ alkyl and in particular C ₁ -C ₅ alkyl, in particular t-butyl. In a preferred compound of formula (1) or (2), G ₁ is at the meta-position relative to G ₂ .

; OH 또는 C₂-C₂₂알카노일옥시에 의해 치환된 프로필;

이다. G ₃ is most preferably hydrogen; C ₁ -C ₂₂ alkyl; SO ₃ M; Propyl substituted by OH and / or C ₂ -C ₂₂ alkanoyloxy; Direct bond; -CH ₂ -;

; Propyl substituted by OH or C ₂ -C ₂₂ alkanoyloxy;

to be.

Preferably, G ₄ and G ₅ are independently H or C ₁ -C ₄ alkyl, in particular methyl.

Compounds of formula (1) containing thio groups, ie compounds of formula (1) wherein G ₁ and / or G ₃ are selected from alkylthio, alkylthioalkyl, -S-, are of industrial importance.

Preference is given to using compounds of the formulas (1) and / or (2) having the following definitions:

a is 1;

b, c, d, e, n, M, q, V are each as defined above;

Q, when present, is —C _m H _2m —, preferably a methylene or ethylene radical;

T, if present, is —C _n H _2n — or phenylene;

; 또는 OH 또는 C₂-C₂₂알카노일옥시에 의해 치환된 프로필이거나; 또는 G₃은

이고; G ₃ is hydrogen; C ₁ -C ₂₂ alkyl; SO ₃ M; Propyl substituted by OH and / or C ₂ -C ₂₂ alkanoyloxy; Or G ₃ is a direct bond; -CH ₂ -;

; Or propyl substituted by OH or C ₂ -C ₂₂ alkanoyloxy; Or G ₃ is

ego;

G ₄ and G ₅ are independently H or C ₁ -C ₄ alkyl, especially methyl;

The most preferable of these,

; 또는 OH 또는 C₂-C₂₂알카노일옥시에 의해 치환된 프로필이고; M은 알칼리이며 또 q는 0 또는 1인 화학식(1)의 화합물; 또는 화학식(2)의 화합물이다. e is 1 or 2 and G ₃ is SO ₃ M; Propyl substituted by OH and / or C ₂ -C ₂₂ alkanoyloxy; Or G ₃ is a direct bond; -CH ₂ -;

; Or propyl substituted by OH or C ₂ -C ₂₂ alkanoyloxy; A compound of formula (1) wherein M is an alkali and q is 0 or 1; Or a compound of formula (2).

Most preferred compounds of formula (3) are the compounds of the following formula or acid addition salts thereof as defined above:

Particularly important compound (1) has the formula

(4)

(4)

In the formula,

G ₁ and G ₂ are independently of each other C ₁ -C ₅ alkyl, or G ₁ and G ₂ are especially 2,6-di-t-butyl;

a is 1 or 2, in particular 1; In addition

G ₃ , Q, V, T, b, c, d and e have the meanings mentioned in formula (1), or in particular

b is 1 and Q is ethylene;

c is 1 and V is O or NH;

d is 1 and T is CH ₂ or phenylene; In addition

e is 1 and G ₃ is H, C ₁ -C ₁₈ alkyl, such as methyl or C ₁₇ alkyl, or SO ₃ Na; or

e is 4 and G ₃ is a carbon atom;

Or b, c and d are each 0, e is 2 and G ₃ is methylene or ethylidene.

Most preferred are compounds of formula (I) wherein G ₁ and G ₂ are t-butyl radicals and a is 1.

Preference is also given to using compounds of the formula (5):

(5)

(5)

In the formula,

G ₁ and G ₂ are independently of each other C ₁ -C ₅ alkyl;

이며; Q is -C _m H _2m- ; or

;

이고; G ₃ is a direct bond; -O-; -S-; -CH ₂ -; or

ego;

a is 1 or 2;

m is 1 to 5; In addition

T has the meaning as defined in formula (1).

Important compounds of formula (1) have the following definitions:

이고; Q is ethylene or

ego;

G ₃ is a direct bond; In addition

G ₁ , G ₂ , T and a have the same meanings as in formula (3).

Likewise preferred are compounds of formula (6):

(6)

(6)

In the formula,

Q is -C _m H _2m- ;

T is -C _n H _2n- ;

G ₁ and G ₂ are independently of each other C ₁ -C ₅ alkyl;

G ₃ is represented by the formula (1 g); (1h); (1i); Or a radical of (1k);

m and n are each independently 1 to 3;

a is 1 or 2; In addition

b and d are each independently 0 or 1.

Other antioxidants preferably used correspond to formula (5):

(5)

(5)

In the formula,

A is formula (5a)

(5a)의 라디칼이고,

Is a radical of (5a),

G _{1 ,} G ₂ and G ₃ Are independently of each other C ₁ -C ₅ alkyl; In addition

m is 1 to 3.

Another preferred antioxidant is a compound of formula (6)

(6)

(6)

In the formula,

B is the following formula (6a)

(6a)의 라디칼이고;

Is a radical of (6a);

G ₁ and G ₂ are independently of each other C ₁ -C ₅ alkyl;

V is -O-; Or -NH-;

a is 1; Or 2;

m is 1 to 3; In addition

n is 0 to 3;

Compounds of the invention, such as the compounds of formulas (1), (2) and (3), are known as antioxidants for plastics and certain other organic materials.

In the present invention, they can be used as individual compounds or as mixtures of several compounds. Because of their good solubility, they can be easily incorporated into each formulation.

Compounds of the present invention, such as those of Formulas (1), (2) and (3), may be used in combination with tocopherols and / or tocopherol acetates, ascorbic acids and / or derivatives or esters, retinal, retinal, retinoic acid and / or its Can be used with derivatives.

Such additional hydrophilic or lipophilic components are often contained in a concentration range of 0.001 to 10% by weight of the total weight of the formulation. These additional ingredients are preferably selected from the group comprising:

Tocopherols (α, β, γ, δ isomers) and esters of these with acids having the general formula:

H (CH2) n (CHR) COOH (1)

CH3 (CH2) mCH = CH (CH2) nCOOH (2)

Where

R is a hydrogen atom or an OH group, m, n is an integer from 0 to 22 and the sum of m + n is up to 22;

Tocotrienols (α, β, γ, δ isomers) containing one unsaturated fatty acid, and esters with acids thereof;

Esters of ascorbic acid and acids such as phosphoric acid and other esters with sodium, potassium, lithium and magnesium salts, ascorbyl tetraisopalmitate, pyrrolidonecarboxylic acid and esters with the formula:

H (CH2) n (CHR) COOH (3)

CH3 (CH2) mCH = CH (CH2) nCOOH (4)

Where

R is a hydrogen atom or an OH group, m, n is an integer from 0 to 20 and the sum of m + n is up to 21;

-Geometric isomers and stereoisomers of these compounds as well as retinoids including all natural and / or synthetic analogues of vitamin A or retinal-like compounds which retain the biological activity of vitamin A in the skin. Preferred compounds are retinal, retinol esters of retinal (such as C2-C22 alkyl esters (saturated or unsaturated alkyl chains) such as retinyl palmitate, retinyl acetate, retinyl propionate), retinal, and / or retinal Non-acid (all trans retinoic acid and / or 13-cis-retinoic acid) or derivatives. Other retinoids useful herein include US Pat. No. 4,677,120, issued to Parish et al. On June 30, 1987; U.S. Patent 4,885,311 to Parish et al. On December 5, 1989; US Patent No. 5,049,584 to Purcell et al. On September 17, 1991; US Patent No. 5,124,356 to Purcell et al., June 23, 1992. Other suitable retinoids are tocopheryl-retinoate [tocopherol ester of retinoic acid (trans or cis)], adapalene [6- (3- (1-adamantyl) -4-methoxyphenyl) -2-naphthoic Acid] and tazarotene (ethyl 6- [2- (4,4-dimethylthiochroman-6-yl) -ethynyl] nicotinate);

Carotenoids such as α-, β-, γ- and δ-carotene, lutein, xanthophylls, zeaxanthin, violaxanthin, cryptoxanthin, fucoxanthin, anteraxanthin, lycopene, didehydrolycopene and Tetradehydrolycopene carotenoids;

Enzymatic antioxidants such as glutathione peroxidase, catalase, superoxide dismutase;

Ubiquinones and idebenones (hydroxydecyl ubiquinones), ubiquinol and derivatives thereof;

Lipoic acid and its derivatives such as alpha-lipoic acid;

Rutinic acid and derivatives thereof such as α-glucolutin, water soluble flavonoids, rutin hydrate (vitamin P);

Plant extracts such as white tea and green tea extracts, chicory leaf extracts ( Cichorium intubybus), Passion extract (Pacific Le Flora Ica appear (Passiflora incarnata ), rooibos ( Aspalathus) linearis ) extract, rosemary extract, maple ( Aceraceae Red Leaf Extract of Maple or Rosaceae Cherry Red Leaf Extract, Curcuma longa L ) ( curcuminoid active ingredient), Austrian edelweiss ( Leontopodium alpinum extract, Emblica offincinalis ) (Yukan: phyllanthus emblica) tree extract;

Phenolic acids such as caffeic acid, 3,4-dihydroxyphenyl acetic acid, 3,4-dihydroxybenzoic acid;

Flavonoids and polyphenols such as flavanones selected from the group consisting of unsubstituted flavanones, monosubstituted flavanones, and mixtures thereof; Chalcones selected from the group consisting of unsubstituted chalcones, monosubstituted chalcones, disubstituted chalcones, trisubstituted chalcones and mixtures thereof; Flavones selected from the group consisting of unsubstituted flavones, monosubstituted flavones, disubstituted flavones and mixtures thereof; At least one isoflavone; Coumarins selected from the group consisting of unsubstituted coumarins, monosubstituted coumarins, disubstituted coumarins and mixtures thereof; Flavonols, anthocyanins, catechins, proanthocyanidins (grape seed extract). Flavonoids described broadly in US Pat. Nos. 5,686,082 and 5,686,367 may also be used;

Chlorogenic acid and ferulic acid.

Other types of antioxidants can be used that interfere with the photochemical reactions that occur when UV radiation penetrates the skin or hair. Typical examples of such antioxidants are amino acids (such as glycine, histidine, tyrosine, tryptophan) and derivatives thereof, imidazoles (such as urokanoic acid) and derivatives thereof, peptides such as D, L-carnosine, D-carnosine, L Carnosine and its derivatives (such as anserine), carotenoids, carotene, lycopene and its derivatives, chlorogenic acid and its derivatives, lipoic acid and its derivatives (e.g. dihydrolipoic acid), aurothioglycose, propylthiouracil and Other thiols (such as thioredoxin, glutathione, cysteine, cystine, cystamine and glycosyl, its N-acetyl, methyl, ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl, linoleyl, cholesteryl And glyceryl esters) and salts thereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof (esters, Teres, peptides, lipids, nucleotides, nucleosides and salts) and also sulfoximine compounds (such as butionine sulfoximine, homocysteine sulfoximine, butionine sulfone, penta-, hexa-, hepta-thionine sulfoximine), (Metal) chelating agents (such as hydroxy fatty acids, palmitic phytic acid), lactoferrins, chitosans and derivatives such as phosphonomethylated chitosans and preferably US Pat. No. 5,487,884; WO 91/16035; Those described in WO91 / 16034; Hydroxy acids (such as citric acid, lactic acid, malic acid), humic acids, bile acids, bile extracts, bilirubin, biliverdine, EDTA, EDDS, EGTA and derivatives thereof, unsaturated fatty acids and derivatives thereof (such as linolenic acid, linoleic acid, Oleic acid), folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof, vitamin C and derivatives (such as ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), tocopherols and derivatives (such as vitamin E acetate) , Vitamin A and derivatives (such as vitamin A palmitate) and coniferyl benzoate, benzoic acid and derivatives thereof of benzoin resins, glycosiltin, ferulic acid, furfurylidene glutitol, carnosine, butyl hydroxytoluene , Butyl hydroxyanisole, nordihydroguaiaretinic acid, trihydroxybutyrophenone, uric acid and derivatives thereof, mannose and its derivatives , Superoxide dismutase, N- [3- (3,5-di-t-butyl-4-hydroxyphenyl) propionyl] sulfanylic acid (and salts thereof, such as disodium salts), zinc and derivatives thereof ( Such as ZnO, ZnSO ₄ ), selenium and its derivatives (such as selenium methionine), stilbenes and their derivatives (such as stilbene oxide, trans-stilbene oxide) and suitable derivatives according to the invention (salts, esters) of the aforementioned active ingredients , Ethers, sugars, nucleotides, nucleosides, peptides and lipids). HALS ("steric amine light stabilizers") compounds may also be mentioned. Other synthetic and natural antioxidants are disclosed, for example, in WO 00/25731 (such as structure 1-3 (page 2), structure 4 (page 6), structure 5-6 (page 7) and compounds 7-33 (page 8-14) (See reference).

Topical administration may further contain from 0.01% to 10% by weight, more preferably from about 0.5% to about 5% by weight of the composition with one or more additional ingredients having an anti-inflammatory effect:

Steroidal anti-inflammatory agents, including but not limited to corticosteroids such as hydrocortisone and derivatives thereof;

Non-steroidal anti-inflammatory agents including but not limited to oxycams, salicylates, acetic acid derivatives, phenamate, propionic acid derivatives, pyrazoles;

- Apollos α- are not limited to bis-ol, allantoin, aloe (Aloe vera ) lyophilized extracts, panthenol, betulin such as glycyrrhizate, potassium glycyrginate, glycyrrhetic acid such as ammonium glycyrginate, glycyrginic acid and derivatives thereof (salts and esters) Licorice ( Glysirhiza glabra ) ( Glycyrrhiza ) glabra ); Botulinic acid, its alkali salts and salts of alkaline earth metals, boswellic acid, its alkaline salts and alkaline earth metal salts, rosemary acid, its alkaline salts and alkaline earth metal salts; Polyunsaturated fatty acids such as linoleic acid (18: 2n6), α-linolenic acid (18: 3n3), γ-linolenic acid (18: 3n6), octadecantetraenine (18: 4n3), dihomo-γ-linolenic acid (20: 3n6), icosanetetraenine (20: 4n3), arachidonic acid (20: 4n6), icosane pentanic acid (20: 5n3) and esters thereof with alcohols having the formula:

R1 (CH2) m- (CHOH)-(CH2) nR2 (5)

In the formula,

R 1 and R 2 are hydrogen atoms or OH groups, m, n are integers from 0 to 17 and the sum of m + n is up to 21;

Phytosterols of formulas (6) and (7) and their polyethoxylated derivatives, in particular camphorsterol, β-sitosterol, stigmasterol, cholesterol, Δ-5-avenasterol, Δ-7-avenasterol, bra Cicasterol, Spinasterol and Fucosterol:

(6)

(6)

(7)

(7)

Wherein R is an isoalkyl or isoalkenyl group having 8 to 10 carbon atoms and n is an integer from 0 to 50.

Pharmaceutical compositions include liquid, semisolid or solid preparations.

Examples of liquid pharmaceutical compositions are injections, infusion solutions, drops, sprays, aerosols, emulsions, lotions, suspensions, drinking solutions, gargles and inhalants.

Examples of semisolid pharmaceutical compositions are ointments, creams (O / W emulsions), rich creams (W / O emulsions), gels, lotions, foams, pastes, suspensions, eggs, plasters, transdermal systems such as masks, poultices, pads Includes application.

Examples of solid pharmaceutical compositions are tablets, dragees, capsules, granules, foamy granules, foamable tablets, lozenges, sucking or chewing tablets, suppositories, implants, lyophilisates, adsorbents or powders.

Liquid or semisolid formulations are preferred.

Galenic pharmaceutical compositions comprising a compound of the invention mean emulsions, ointments, gels, sprays and powders; Such as creams, gels, lotions, alcohols and aqueous / alcoholic solutions, emulsions, wax / fat compositions, stick preparations such as lip sticks or deodorants, powders or ointments.

The final formulations listed may exist in a variety of forms, including:

Liquid formulations such as W / O, O / W, O / W / O, W / O / W or PIT emulsions and all kinds of microemulsion forms,

- gel form,

- in the form of oils, creams, milks or lotions,

In powder, lacquer, tablet or make-up form,

- Stick form,

In the form of a spray (spray or pump action spray with a propellant gas) or aerosol,

Bubble form, or

- Paste form.

Several particulate skin care delivery systems have been proposed:

A] Nanoemulsions and nanoparticles are based primarily on lecithin or fractionated phospholipids, in particular

Nanoemulsions, such as nanotops (the lipid core is surrounded by a membrane consisting of phospholipids and cosurfactants; intercalation of cosurfactants between elongated lecithin molecules) ranging from 20 nm to 50 nm particle size and represented by a monolayer membrane Stable and small sized particles (smaller than liposomes) and nanosomes due to intercalation;

Nanoparticles in the range of 100 nm to 300 nm particle size represented by a bilayer membrane;

Liposomes, ie spherical endoplasmic reticulum comprising an amphoteric lipid (mainly phospholipid) comprising an aqueous core and forming one or several concentric bilayers; Small single lamella vesicles (SUV), large single lamella vesicles (LUV), large multiple lamella vesicles (MLV) or multivesicular vesicles (MVV).

The compounds of the present invention may be incorporated into, for example, bilayers, aqueous cores, or distributed in both.

B] Particle size> 1 μm based on matrix or encapsulated layer (spherical system based on core material containing active material; core is surrounded by one or more coating layers or shells) Microcapsules.

Polymers used to form these microcapsules include natural gums, cellulose components, polysaccharides, synthetic polyacrylates or polyacrylamides, polyvinyl alcohol (PVA), lipids, inorganics (silicates / clays), high molecular weight proteins such as Gelatin, albumin and the like; Examples include mineral fillers such as serimcite surface treated with nylon micro-porous spheres (Orgasol, Elf Atochem) such as dual functional coatings (reactions between reactive fatty acid derivatives and aqueous solutions of mica); Glycospheres (core based on denatured starch and outer lipid membranes based on fatty acids and polar lipids); Carbon nanotubes; For non-aqueous solid final products such as silica shells and sticks made of silicates, dry powders and the like.

C] a matrix particulate system comprising the active ingredient in a uniform core matrix; for example:

Solid lipid nanoparticulates (SLN) technology based solely on solid lipids;

Nanostructured lipid carriers (NLC) made from a combination of solid lipids and liquid lipids (typical particle size particle diameters range from 80 nm-1 μm);

Nanospheres based on a solid hydrophobic matrix, represented by solid hydrophobic and high cationic nanospheres (typical particle size range 10 nm to 1 μm) and coated with a high cationic or biocompatible layer (eg US-6491902).

D] Cationic amphiphiles similar to liposome structures but including oleic acid, saturated or unsaturated fatty acids, long chain soap soaps in combination with nonionic surfactants, derivatives of polyglycerols, diammonium amphiphiles, cationic surfactants, amino acid residues Multi-walled delivery systems, such as systems formed solely of non-phospholipid "membrane-mimetic" amphiphilic materials such as materials, sucrose fatty acid esters, aqueous mixtures of anionic and cationic surfactants.

E] Microsponge techniques such as those based on microscopic polymeric spheres consisting of interconnecting voids in non-destructive structures (discontinuous shells); Examples include copolymers of styrene and divinylbenzene, or vinyl derivatives, water-swellable particles made from lactose, cellulose and cellulose derivatives such as Unispheredhk from Induchem.

F] Silicone-based vesicles, such as multi-layer vesicles similar to liposome structures, wherein the layers are polyether-modified dimethicones (dimethicone copolyols), silicone elastomers, blends of dimethicone crosspolymers, dimethicone / vinyldimethicone cross polymers, or PEG-modified dimethicone crosspolymers and the like.

G] Oligomeric and cyclic carbohydrate compounds containing usually 6 to 8 glucose units such as cyclodextrins, α-, β- and γ-cyclodextrins.

According to a preferred method, the compounds of the present invention are described in US-2005-0191330 (see in particular [0007-0079], [0120-0133] and Examples) and US-2003-0190347 (in particular [0005-0087] and in practice). In nanodispersed or encapsulated form.

An industrially important point in the present invention is the discovery that the compounds of the present invention are most effectively protected from premature degradation if they are encapsulated in other active ingredients, in particular oxidizable natural substances or active ingredients such as vitamins, plant extracts, flavors and the like. Thus in this case the compounds of the present invention are also useful in pure cosmetic preparations which do not require pharmacological benefit but which require the protection of other active ingredients such as vitamins such as vitamins A, E or C.

Examples of final formulations containing a composition of the present invention include:

Skin-care preparations, such as skin-washing and cleaning preparations in the form of tablets or liquid soaps, cinenu detergents or cleaning pastes;

Bath preparations such as liquids (foam baths, milks, shower preparations) or solid bath preparations such as bath cubes and bath salts;

Skin-care preparations such as skin emulsions, multi-emulsions or skin oils;

Such as eye creams, eye creams, mascara, eyeliners, eye creams or eye-fix creams such as face creams, face creams, face creams, face creams, face creams (loose or compressed) Care formulations; Lip-care preparations such as lipsticks, lip glosses, lip contour pencils; Nail-care preparations such as nail polish, nail polish remover, nail hardener or exfoliant.

Foot-care preparations such as foot baths, foot powders, foot creams or foot balms, special deodorants and restraints or nail-stripping preparations;

Photoprotective preparations such as sun milks, lotions, creams or oils, sunblocks or tropicals, pre-tanning preparations or after-sun creams;

Skin tanning preparations such as self tanning creams;

Anti-pigmentation preparations such as skin bleaching or skin whitening preparations;

Medicated solid soaps and liquids containing antifungal agents, antibacterial agents and the like, including rinsing preparations such as soaps and leave-on preparations such as creams;

Insect repellent agents such as oil, lotion, spray or stick;

Deodorants such as deodorant sprays, pump-action sprays, deodorant gels, sticks or roll-ons;

Antiperspirants such as antiperspirant sticks, creams or roll-ons;

Preparations for protecting and cleaning blemished skin such as synthetic detergents (solid or liquid), dermabrasion or scrub preparations or dermabrasion masks;

Hair removal preparations in chemical form (epilation), such as hair removal powders, liquid hair removal preparations, cream- or paste-form hair removal preparations, hair removal preparations in the form of gels or aerosol foams;

Shaving preparations, such as shaving soaps, foam shaving creams, non-inspecting shaving creams, foams and gels, preshaving preparations for dry shaving, aftershave or aftershave lotions;

Fragrance preparations, such as fragrance and deodorant-containing preparations (fragrances, eau de cologne, eau de toilette, eau de parfum, parfum de toilette, parfum), perfume oils or perfume creams;

Cosmetic hair treatment preparations, such as shampoos and conditioner hair-washing preparations, pretreatment preparations, hair tonics, styling creams, styling gels, pomades, hair rinses, treatment packs, hair-care preparations such as intensive hair treatments, perms Hair structured preparations, such as hair wave preparations for waves (hot wave, mild wave, cold wave), hair straightening preparations, liquid hair-setting preparations, hair foams, hair sprays, hydrogen peroxide solutions, bleaching shampoos, bleaching creams, bleaching powders , Bleaching preparations such as bleaching pastes or oils, temporary, semi-permanent or permanent hair colorants, preparations containing self-oxidizing dyes or natural hair colorants such as henna or camomile.

Of particular importance as skin preparations are for example photoprotective preparations, such as sunmilk, lotions, creams, oils, sunblocks or topical administrations, pretanning preparations or aftersun preparations, skin tanning preparations such as self-tanning creams, skin whitening Daily care and / or anti-aging agents, including formulations, skin lightening agents or combinations of these systems. Of particular importance are anti-aging agents in combination with UV protection systems such as daily care creams, daily care lotions, daily care milks and daily care preparations in the form of sprays.

The compositions / formulations according to the invention may optionally contain one or more additional compounds as described below, in particular as preparations for skin treatment.

Fatty alcohol

Guerbet alcohols based on fatty alcohols having from 6 to 18, preferably from 8 to 10 carbon atoms, such as cetyl alcohol, cetearyl alcohol, oleyl alcohol, octyldodecanol, C ₁₂ -C ₁₅ benzoate of alcohol, acetylated lanolin alcohol and so on.

Esters of fatty acids

Esters of straight C ₆ -C ₂₄ fatty acids with straight C ₃ -C ₂₄ alcohols, with branched C ₆ -C ₁₃ carboxylic acids Straight-chain C ₆ -C ₂₄ fatty alcohol esters of, straight-chain C ₆ -C ₂₄ fatty acids with branched alcohols, especially 2-ethylhexanol esters of, hydroxy carboxylic acids and linear or branched C ₆ -C ₂₂ fatty alcohols, in particular Esters of dioctyl malate, straight and / or branched chain fatty acids and polyhydric alcohols (such as propylene glycol, dimer diols or trimer triols) and / or gerbe alcohols such as capronic acid, caprylic acid, 2-ethylhexanoic acid , Capric acid, lauric acid, isotridecanoic acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, eladinic acid, petroleic acid, linoleic acid, linolenic acid, elaeostearic acid Esters of acids, arachidic acid, gadolenic acid, behenic acid and erucic acid and alcohols with these, such as isopropyl alcohol, capro alcohol, capryl alcohol, 2-ethylhexyl alcohol, capric alcohol, lauryl alcohol, isotridecyl Alcohol, Myristyl Alcohol, Cetyl Alcohol, Palmoreyl Alcohol, Stearyl Alcohol, Isostearyl Alcohol, Oleyl Alcohol, Ellidyl Alcohol, Petroselinyl Alcohol, Renoyl Alcohol Allols, ninolenyl alcohols, elaeostearyl alcohols, arachidyl alcohols, gadoleyl alcohols, behenyl alcohols, erucyl alcohols and brassidyl alcohols and their industrial mixtures (such as industrial methyl esters or roel based on fats and oils) Reduction of aldehydes from the oxosynthesis of loelen, for industrial mixtures with high pressure hydrogenation of aldehydes obtained from ethylene oxosynthesis and as monomeric fractions in dimerization of unsaturated fatty alcohols, for example in the pressure relief of natural fats and oils Or obtained from dimerization of unsaturated fatty acids).

Examples of such ester oils are isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl isostearate, isopropyl oleate, n-butyl stearate, n-hexyl stearate, n- 2-ethylhexyl palmitate, 2-hexyl laurate, 2-hexyldecyl stearate, 2-octyldodecyl palmitate, 2-ethylhexyl palmitate, , Oleyl oleate, oleyl erucate, erucyl oleate, erucyl erucate, cetearyl octanoate, cetyl palmitate, cetyl stearate, cetyl oleate, cetyl behenate, cetyl acetate, State, myristyl behenate, myristyl oleate, myristyl stearate, myristyl palmitate, myristyl lactate Sites, propylene glycol dicarboxylic frill rate / caprate, stearyl heptanoate, stearyl diisopropyl maleate, octyl hydroxy stearate.

Other supplements

Alpha glucolutin (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 acetate, and diol esters, such as ethylene glycol dioleate, ethylene glycol diisotridecanoate, propylene glycol di (2-ethylhexanoate), propylene glycol diisostearate, propylene glycol dipellago , Butanediol diisostearate and neopentyl glycol dicaprylate. C ₆ -C ₂₄ fatty alcohols and / or germ alcohols with aromatic carboxylic acids, saturated and / or unsaturated, in particular esters of benzoic acid, C ₂ -C ₁₂ dicarboxylic acids with 1 to ₆ carbon atoms, Straight or branched chain alcohols having 22 carbon atoms or esters with polyols having 2 to 10 carbon atoms and 2 to 6 hydroxy groups, or iminodisuccinic and iminodisuccinic acid salts [CAS 7408-20-0] or latex Particles, Aloe Vera, Chamomile, Ginkgo, Ginseng, Coenzyme Q10, Laminaria ocinoleuca Extract, Magnolia oborata Extract, Melaleca 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 Mycoporin-like amino acids obtained from tetrahydrocurcuminoids (THC), mycosporin, red alga porphyra umbilicalis Sporin, Mycosporin-Like Amino Acids (as described in WO2002039974), Cis-9-octadecenedionate, Lipoic Acid, Laurimino Dipropioate Tocopheryl Phosphate (LDTP), Microcrystalline Cellulose (MCC) such as Polycarbonates as described in WO 0341676, sterols (cholesterol, lanosterol, phytosterol) as described in WO 0341675 and straight chain poly-alpha-glycans as described in US6616935.

Glyceryl  Natural or synthetic, including esters and derivatives Triglyceride

Di- or tri-glycerides based on C ₆ -C ₁₈ fatty acids and modified by reaction with other alcohols (caprylic / capric triglycerides, wheat germicides, etc.). Fatty acid esters or castor oils of polyglycerols (polyglyceryl-n such as polyglyceryl-4 caprate, polyglyceryl-2 isostearate, etc.), hydrogenated vegetable oils, 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 grain oil, hazelnut oil, laver oil etc.

(White or yellow), lanolin wax, candelilla wax, ozokerite, japanese wax, paraffin wax, microcrystalline wax, and the like, as well as waxes including esters of long chain acids and alcohols as well as compounds having wax properties such as carnauba wax, Wax, ceresin, cetearyl ester wax, synthetic beeswax, and the like. Also hydrophobic waxes such as cetearyl alcohol or partial glycerides.

Pearl Light Wax :

Alkylene glycol esters, in particular ethylene glycol distearate; Fatty acid alkanolamides, especially coco fatty acid diethanolamides; Partial glycerides, in particular stearic acid monoglycerides; Esters of unsubstituted or unsubstituted or hydroxy-substituted carboxylic acids with fatty alcohols having from 6 to 22 carbon atoms, in particular long-chain esters with tartaric acid; Fatty substances such as fatty alcohols having a total of at least 24 carbon atoms, fatty ketones, fatty aldehydes, fatty ethers and fatty carbonates, especially lauro- and distearyl ethers; Fatty acids such as stearic acid, hydroxystearic acid or benzenic acid, ring-opening products of olefin epoxides having 12 to 22 carbon atoms and fatty alcohols having 12 to 22 carbon atoms and / or ring opening products of 2 to 15 carbon atoms and 2 to 10 Polyols having a hydroxy group and mixtures thereof.

Hydrocarbon oil :

Inorganic oils (light or heavy oil), mineral oils (yellow or white), microcrystalline waxes, paraffins and isoparaffinic compounds, hydrogenated isoparaffinic molecules, hydrogenated isoparaffinic molecules such as polydecenes and polybutenes, hydrogenated polyiso moieties Ten, squalene, isohexadecane, isododecane and other oils of plant or animal origin.

Silicon or siloxane (organic-substituted Polysiloxane )

Dimethylpolysiloxane, cyclic silicone, and amino-, fatty acid-, alcohol-, polyether-, epoxy-, fluorine-, glycoside- and / or alkyl- modified silicone compounds . Linear poly-siloxanes, dimethicone (Dow Corning 200 fluid, Rhodia Mirasil DM), dimethiconol, cyclic silicone fluid, cyclopentasiloxane volatiles (Dow Corning 345 fluid), phenyltrimethicone (Dow Corning 556 fluid). Simethicone, which is a mixture of dimethicones having hydrogenated silicates and having an average chain length of 200-300 dimethylsiloxane units, is also suitable. A detailed study by Todd et al. On suitable volatile silicon can be found in the literature (Cosm. Toil. 91, 27 (1976)).

The term "silicone" is based on repeating structural units (siloxane bound SiOSi), which have a linear or cyclic, branched or crosslinked structure, vary in molecular weight and in which silicon atoms are bonded to each other by oxygen atoms, in which case Accordingly refers to an organosilicon polymer or oligomer in which a hydrocarbon radical substituted is bonded directly to a silicon atom via a carbon atom.

Examples include:

Cyclic siloxane polymers; Cyclomethicones of the following formulas such as cyclopentasiloxane, cyclohexaxyl acid:

(Low viscosity, volatile liquid; INCI name for labeling certain cyclic dimethyl polysiloxane compounds is cyclotrisiloxane (qv) with n = 3, cyclotetrasiloxane with n = 4, cyclopentasil with n = 5 Oxane (qv), cyclohexaxyloxane (qv) with n = 6 and cycloheptasiloxane (qv) with n = 7);

Linear siloxane polymers terminal blocked with trimethylsiloxy units (M units) dimethicone; Nonpolar liquids with a wide range of viscosity of the formula:

Silanol compounds or dimethiconols, such as dimethyl siloxane, terminally terminated with a hydroxyl group (-OH) of the formula:

Silicone elastomers and resins obtained by crosslinking of siloxane structures, such as dimethicone (elastomers: moderate crosslinking with a density that allows stretching / distortion of molecules, typically excluding PEG-modified dimethicone crosspolymers; resins : High crosslinking with density giving some stiffness to the molecule).

Useful silicone elastomers as covalent agent systems include dimethicone crosspolymers in cyclopentasiloxane, such as DC 9045 silicone elastomer blends manufactured by Dow Corning; Dimethicone crosspolymer in dimethicone (DC 9041 silicone elastomer blend manufactured by Dow Corning); Polymers of dimethicone (q.v) crosslinked by C3 to C20 alkyl groups; Dimethicone / vinyldimethicone crosspolymer (DC 9506 powder, Dow Corning); Dimethicone / vinyldimethicone crosspolymers in cyclopentasiloxane, such as SFE 839 (GE silicone) or KSG 15 (from Shin-Etsu));

Copolymers of dimethylpolysiloxanes crosslinked with vinyl dimethylpolysiloxanes.

Resin silicones include dispersants such as KP-545 (manufactured by Shin-Etsu);

Acrylate / dimethicone copolymers in cyclopentasiloxane; Copolymers of dimethicone with at least one monomer of acrylic acid, methacrylic acid or one of these simple esters;

Siloxysilicates such as trimethylsiloxysilicate; T-resin; Branched polymers of T-units; Q-resin; Branched polymers of Q-units:

;

;

Trimethylsiloxysilicate (such as SR 399 (manufactured by GE Silicone) or Wacker-Belsil TMS 803 (manufactured by Wacker Chemie), a mixture prepared by Dow Corning, such as DC 749 cosmetic liquid (trimethylsiloxysilicate in cyclopentasiloxane) or DC Film forming agents and water resistant agents such as 593 liquid (trimethylsiloxysilicate in dimethicone);

Alkyl-modified siloxanes (AMS), for example, to improve spreadability and wash resistance to inorganic sunscreens, to improve particle dispersion, to reduce reagglomeration and to enhance long-lasting effects on the skin. An example is this:

Alkyl dimethicones of the following formula such as bis-phenylpropyl dimethicone (SF 1555 liquid; manufactured by GE Silicone):

Wherein R is-(CH2) n-CH3;

Alkyl methicones of the formula: DC 2503 cosmetic wax (manufactured by Dow Corning); Stearyl dimethicone DC 2502 (manufactured by Dow Corning); Cetyl dimethicone; DC AMS-C30 wax (manufactured by Dow Corning); 30-C45 alkyl methicone; DC 580 wax (Dow Corning); Silicone waxes such as stearoxytrimethylsilane and stearyl alcohol:

Wherein R is-(CH2) n-CH3.

Fluorine addition ( fluorinated ) Or fluorine Superaddition ( 퍼fluorinated ) oil

Perfluorohexane, dimethylcyclohexane, ethylcyclopentane, polyperfluoromethylisopropyl ether.

Emulsifier

Any of the conventionally available emulsifiers may be used in the present compositions. Emulsifier systems include, for example: carboxylic acids and their salts: alkaline soaps of sodium, potassium and ammonium, metallic soaps of calcium or magnesium, lauric acid, palmitic acid, stearic acid and oleic acid, and the like. It may include. Alkyl phosphates or phosphate esters, acid phosphates, diethanolamine phosphates, potassium cetyl phosphate. Ethoxylated carboxylic acid or polyethylene glycol ester, PEG-n acylate. A fatty acid having 8 to 22 carbon atoms, branched, 2 to 30 moles of ethylene oxide, 0 to 5 moles of propylene oxide and 12 to 22 carbon atoms, and an alkyl group having 8 to 15 carbon atoms in the alkyl group Linear fatty alcohol. Fatty alcohol polyglycol ethers such as laureth-n, cetearates-n, steareth-n, oleth-n. Fatty acid polyglycol ethers such as PEG-n-stearate, PEG-n-oleate, PEG-n-cocoate. Monoglycerides and polyol esters. 1 of additional products of ethylene oxide with a polyol to 30 mol of C ₁₂ -C ₂₂ fatty acid mono-, di-esters. Monostearate glycerol, diisostearoyl polyglyceryl-3-diisostearate, polyglyceryl-3-diisostearate, triglyceryl diisostearate, polyglyceryl-2-sesquiisostea Fatty acids and polyglycerol esters such as late or polyglyceryl dimerate. A compound in which a plurality of these component systems are mixed is also suitable. Fatty acid polyglycol esters such as monostearate diethylene glycol, fatty acid and polyethylene glycol esters, saccharose esters such as fatty acids and sucrose esters, saccharose esters such as glycerol and sucrose 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 adducts. Polysorbate-n series, sorbitan esters such as sesquiisostearate, sorbitan, PEG- (6) -isostearate sorbitan, PEG- (10) -sorbitan laurate, PEG-17-diol Leight sorbitan. Glucose derivatives, C ₈ -C ₂₂ alkyl-mono and oligo-glycosides and ethoxylated analogs, with glucose being preferred as a sugar component. O / W emulsifiers such as methylglucose-20 sesquistearate, sorbitan stearate / sucrose cocoate, methylglucos sesquistearate, cetearyl alcohol / cetearyl glucoside. O / W emulsifiers such as methyl glucose diolate / methyl glucose isostearate. Sulfate and sulfonated derivatives, dialkylsulfosuccinates, dioctyl succinates, alkyl lauryl sulfonates, linear sulfonated paraffins, sulfonated tetrapropylene sulfonates, sodium lauryl sulfate, ammonium and ethanolamine lauryl sulfide Pate, lauryl ether sulfate, sodium laureth sulfate, sulfosuccinate, acetyl isothionate, alkanolamide sulfate, taurine, methyl taurine, imidazole sulfate. Cetylpyridinium bromide, cetyltrimethylammonium bromide (CTBA), pyridine derivatives, isoquinoline, cetylpyridinium bromide, cetyltrimethylammonium bromide (CTBA) having a chain containing a heterocycle such as amine derivatives, amine salts, ethoxylated amines, Such as tetravalent ammonium, stearylalkonium. Amide derivatives, alkanolamides such as acylamide DEA, ethoxylated amides such as PEG-n acylamide, oxydiamides. Polysiloxane / polyalkyl / polyether copolymers and derivatives, dimethicone, copolyols, silicone polyethylene oxide copolymers, silicone glycol copolymers. Propoxylated or POE-n ether (Meroxapols), poloxamer or poly (oxyethylene) m-block-poly (oxypropylene) n-block (oxyethylene). Zwitterionic surfactants capable of transporting at least one tetravalent ammonium group and at least one carboxylate and / or sulfonate group in the molecule. Particularly suitable as zwitterionic surfactants are N-alkyl-N, N-dimethylammonium glycinate, cocoalkyldimethylammonium glycinate, N-, each having 8 to 18 carbon atoms in the alkyl or acyl group Betaine and cocoacylaminoethyl, such as acylaminopropyl-N, N-dimethylammonium glycinate, cocoacylaminopropyldimethylammonium glycinate and 2-alkyl-3-carboxymethyl-3-hydroxyethylimidazoline Hydroxyethylcarboxymethylglycinate, N-alkylbetaine, N-alkylaminobetaine. Alkylimidazolines, alkyl peptides, lipoamino acids, self-emulsifying bases, and compounds described in KFDePolo (a short textbook in aesthetics, Chapter 8, Tables 8-7, p250-251).

Nonionic emulsifiers such as PEG-6 beeswax (and) PEG-6 stearate (and) polyglyceryl 2-isostearate [Apifac], glyceryl stearate and 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 polysorbate 60 and PEG-150 and stearate-20 [polar Wax 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], cetearyl alcohol and steareth-7 and steareth-10 [Emulgator E 2155], cetearyl Alcohols and steareth-7 and steareth-10 [emulsifier wax USNF], glyceryl Stearate and PEG-75 Stearate [Gelot 64], Propylene Glycol Ceteth-3 Acetate [Hetester PCS], Propylene Glycol Isoseth-3 Acetate [Hetester PHA], Cetearyl Alcohol and Ceteth-12 and Oleth- 12 [Lanbritol Wax N21], 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].

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 phosphate and glycol stearate and PEG-2 stearate [Sedefos 75], glyceryl stearate and sodium lauryl sulfate [Teginacid Special] Nonionic emulsifiers, such as. Cationic acid bases such as cetearyl alcohol and the set remium bromide.

Particularly suitable silicone emulsifiers for W / Si emulsions correspond to the formula:

Where

m is a number from 1 to 20,

n is a number from 0 to 500,

p is a number from 0 to 50,

R 1 is a straight or branched C 1 -C 30 alkyl radical or a phenyl radical,

이고,R2 is

ego,

카르복시아실 라디칼이고;R3 is-H, -OH; Straight or branched chain alkyl C1-C12; Straight or branched chain alkoxy C1-C6; Straight or branched acyloxy C2-C12;

Is a carboxyacyl radical;

M is H, Na, Li, NH 4 or an organic amine; Optionally substituted phosphono groups; -NHCO (CH2) dOH; -NH3Y, wherein Y is a monovalent organic or inorganic anion such as Cl, Br, sulfate, carboxylate (acetate, lactate, citrate);

a is a number from 0 to 100;

b is a number from 0 to 50; In addition

c is a number from 0 to 5,

d is a number from 0 to 10.

These compounds represent oxyalkylenated organic modified silicones. Another indication used is PEG / PPG dimethicone (dimethicone copolyol) or silicone polyether which clearly shows the surface activity properties required for emulsification.

Particularly recommended preferred silicone emulsifiers correspond to the formula:

Where

n is a number from 1 to 500,

R is a straight or branched C1-C30 alkyl radical or phenyl radical,

이고, R2 is

ego,

R3, a, b, c and d have the same meaning as defined above.

A non-limiting list of W / Si emulsifiers is shown in the following table:

Emulsifiers can be used, for example in amounts of 1 to 30% by weight, in particular 4 to 20% by weight, preferably 5 to 10% by weight, based on the total weight of the composition.

When formulated into O / W emulsions, the preferred amount of such emulsifier systems can represent 5% to 20% in oil phase.

Supplements and Additives

In the case of cosmetic / pharmaceutical preparations such as creams, gels, lotions, alcoholic and aqueous / alcoholic solutions, emulsions, waxes / fat compositions, tacky preparations, powders or ointments, etc., as additional auxiliaries and additives, mild surfactants, Superfatting agents, consistency regulators, thickeners, polymers, stabilizers, biogenic active ingredients, deodorising active ingredients, anti-dandruff agents dandruff agents, film formers, swelling agents, UV light-protective factors, antioxidants, hydrotropic agents, preservatives, insect repellents ), Self-tanning agents, solubilizers, perfume oils, colorants, antibacterial agents and the like.

Super patting agent

Suitable superfitting agents are, for example, lanolin and lecithin and polyethoxylated or acrylated lanolin and lecithin derivatives, polyol fatty acid esters, monoglycerides and fatty acid alkanolamides, which, in the latter case, function simultaneously as a foam stabilizer.

Anti Wrinkle Active Material

The composition of the present invention may further comprise a suitable anti-wrinkle agent, examples of which are sulfur-containing D and L amino acids and their derivatives and salts, in particular N-acetyl derivatives, preferred examples being N-acetyl-L-cysteine Is; Thiol; Hydroxy acids (salicylic acid, glycolic acid), keto acids (pyruvic acid), phytic acid, lipoic acid; Lysophosphatic acid, skin peeler, flavonoids, stilbenes, cinnamates, resveratrol, kinetin, zeatine, 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 (panmic acid or diisopropylamine dichloroacetate) And derivative salts thereof, metalloproteinase-inhibitors, trace elements and trace element complexes such as Cu, Zn, Mn, Co, Mg, or Se containing peptides.

skin Lightening agent

The compositions of the present invention may also further comprise suitable skin lightening ingredients, examples of which are kojic acid, arbutin, transexamic acid, ascorbic acid and derivatives thereof such as magnesium ascorbyl phosphate or sodium ascorbyl Phosphate, other salts of ascorbyl phosphate. Also included are PCT Application No. US95 / 07432, filed February 24, 1995 and PCT Application No. US95 / 02809, filed January 3, 1995.

Surfactants

Examples of suitable surfactants that are gentle as skin-friendly surfactants include fatty alcohol polyglycol ether sulfates, monoglyceride sulfates, mono- and / or di-alkyl sulfosuccinates, fatty acid isothionates, Fatty acid sarcosinates, fatty acid taurides, fatty acid glutamate, α-olefin sulfonates, ethercarboxylic acids, alkyl oligoglucosides, fatty acid glucoamides, alkylamidobetaines and / or protein fatty acid concentrate products, the last one being Is preferably wheat protein based.

Viscosity ( consistency ) Regulators / Thickener  And flow improvers ( rheology modifers )

Silicon dioxide, magnesium silicate, aluminum silicate, polysaccharides or derivatives thereof such as hyaluronic acid, xanthan gum, guar-gua, agar-agar, alginate, carrageenan, gellan, pectin or hydroxycellulose, hydroxypropyl methylcellulose Such as modified cellulose. In addition to homopolymers or polyacrylates of reticulated acrylic acid and polyacrylamides, Carbopol types 980, 981, 1382, ETD 2001, ETD2020, Ultrez10 or Scalcares such as Salcare SC80 (Steare) Ts-10 allyl ether / acrylate copolymer), Salcare SC81 (acrylate copolymer), Salcare SC91 and Salcare AST (sodium acrylate copolymer / PPG-1 Trideceth-6), Sepigel 305 (polyacrylamide / Laureth-7), Simulgel NS and Simulgel EG (hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer) Stabilen 30 (acrylate / vinyl isodicanoate crosspolymer), Pemulen TR-1 (acrylate / C ₁₀ -C ₃₀ alkyl acrylate crosspolymer), Luvigel EM (sodium acrylate copolymer), Aculyn 28 (acrylate / beheneth-25 methacrylate copolymer) and the like.

Viscosity additives form a network structure through the base liquid and exhibit a "Yield value." Clay and polymer additives have high yield values and are therefore used to support suspension problems. In the case of particle suspensions, the addition of such viscosity formers will help to reduce the difference in density between the particles and the fluid medium surrounding them, resulting in better resistance to the setting down of the particles.

Thickeners can be roughly divided into at least two general classes: thickeners which perform best in water and thickeners which perform best in oil. It is also possible to distinguish, for example, synthetic polymers, natural polymers and their derivatives, mineral polymers according to their properties as well as their ionic characteristics such as anionic, cationic, nonionic or amphoteric.

Table 4a: Natural Thickeners
Most of them are derived from the polysaccharide category
RM 1 Cellulose gums such as crosslinked or uncrosslinked sodium carboxymethylcellulose ... or cocodimonium hydroxypropyloxyethyl cellulose
RM 2 Microcrystalline Cellulose and Carboxymethyl Cellulose Sodium
RM 3 Guar gum and derivatives (except for hydroxypropyl-modified), -biosaccharide gum-1 (Fucogel 1000, manufactured by Solavia),-sclerotium gum (Amigel, Alban Muller) or scleroglucan ( Tinocare GL, manufactured by Ciba SC)
RM 4 Galacto Arabian (Laracare A200) from Larch Extracts
RM 5
Acacia / Arabian Sword RM 6 Konjak Met; straight chain of glucose and mannose linked by (β-1,4)
RM 7 Pectin polysaccharides; Main chain of galacturonic acid and rhamnose having a branched chain such as rhamnogalacturonan I or rhamnogalacturonan II
RM 8 Xanthan gum; (β-1,4) linked glucose residues or dehydroxanthan gum (Amaze XT, manufactured by National Starch)
RM 9 Starches and derivatives: potato starch denaturation (Structure Solanace, manufactured by National Starch); Hydroxypropyl starch phosphate (Structure XL or ZEA, manufactured by National Starch); Amylose and amylopectin polymer forms; Maltodextrin
RM 10 Carrageenan, sulfated linear polysaccharides from red algae
RM 11 Alginic acid and alginate obtained from brown algae; Polymers of Manuronic Acid and Glucuronic Acid

Table 4b: Mineral Thickeners
Most of these are derived from smectite clays and silica derivatives
RM 12 Aluminum silicate or bentonite or montmorillonite such as magnesium aluminum silicate (Qeegum, manufactured by RT Vanderbilt) and quaternized compounds such as stearalkonium bentonite
RM 13 Magnesium silicate or fectolite, such as benton siris (manufactured by Elementis Specialities) and quaternized compounds such as disteadimonium hectorite (to disperse in lipophilic media)
RM 14 Magnesium Sodium Fluorosylate or Modified Mica
RM 15 Synthetic layered silicates; Hectorite-like structures; Sodium Magnesium Silicate (Laponite, Solvay)
RM 16 Fumed silica, such as aerosil, manufactured by Degussa

Table 4c: Synthetic Flow Enhancers
Poly (acrylic acid) PAA and copolymers thereof; Ester groups having hydrophilic characteristics such as 2-hydroxyethyl methacrylate and the like can be incorporated into the structure.
RM 17 Carbomer or crosslinked polyacrylic acid polymers such as Carbopol Ultrez 10, Carbopol ETD2001, Carbopol ETD2050 manufactured by Noveon Inc.
RM 18 Sodium polyacrylate (Cosmedia SP manufactured by Cognis), acrylate copolymer (Carbopol Aqua SF-1 manufactured by Noveon Inc), acrylate / acrylamide copolymer (Noveon EC-1 manufactured by Noveon Inc)
RM 19 Hydroxyethyl / acrylate; Sodium acryloyldimethyl taurate copolymer (Simpicel NS or EG manufactured by Seppic); In combination with Tinosorb M claimed in PCA No. 161 (Nov. 2001)
RM 20 Ammonium Polyacrylate (Simpic, manufactured by Seppic)
In other words, "hydro swelling drops" concept
RM 21 Glyceryl polyacrylate (such as Hispagel 100) or polymethacrylate (such as Lubrajel manufactured by ISP Corp.)
RM 22 Poly (acrylamide) PAAm and copolymers thereof; Copolymers of ammonium acrylate and acrylamide; Copolymer of AAam and Long Chain Hydrophobic Acrylate
RM 23 Poly (ethylene oxide) PEO and poly (propylene oxide) PPO and copolymers thereof; These are block terpolymers of EO and PO and the structure ABA or BAB; PEO has good water solubility for B; PPO has limited water solubility
RM 24 Poly (vinylpyrrolidone) PVP homopolymer or poly (vinylpyrrolidone) / vinyl acetate copolymer
RM 25 Poly (vinyl alcohol) PVA
RM 26 VA / crotonate copolymer poly (vinylacetate) / crotonic acid or VA / crotonate / vinyl neodecanoate copolymer

Table 4c: Synthetic Flow Enhancers
Poly (acrylic acid) PAA and copolymers thereof; In this structure, ester groups having hydrophilic characteristics such as 2-hydroxyethyl methacrylate and the like can be incorporated. VA / crotonate / vinyl neodecanoate copolymer
RM 27 Ethylene / vinylacetate copolymers, such as AC copolymer 400, manufactured by Allied-Signal
RM 28 PVM / MA copolymers and their esterified derivatives such as ethyl, isopropyl or butyl esters
RM 29 PVM / MA Decadiene Crosspolymer; Copolymer of 1,9-decadiene with methyl vinyl ether / maleic anhydride (PVM / MA)
RM 30 Polyethylene resins such as PEG-2M to PEG-9M (manufactured by RITA Corp.)
RM 31 Polysiloxanes and copolymers; Copolymers of other blocks, such as polysiloxanes and PEO blocks
RM 32 PEG-modified materials, the most commonly used nonionic thickeners having the following basic structure R (OCH ₂ CH ₂ ) _n OH, wherein R is a fatty residue such as fatty alcohol, glyceryl ester, propylene glycol ester or carboxylic acid; Such as PEG-150 distearate; These thickeners do not hydrolyze and provide better stability over a wide range of pH and temperature characteristics
RM 33 Trihydroxystearin or glycol Tri- (12-hydroxystearate)
RM 34 Glyceryl tribehenate such as Syncrowax HRS-C from Croda

Table 4d: Phospholipid Derivatives
RM 35

식중, R은 C₂-C₄ 알킬임
Alkylated phosphatidyl choline to form a fluid lamellae assembly, such as a stable liquid crystal phase of the formula:

Wherein R is C ₂ -C ₄ alkyl
RM 36 Phosphobetaine (amphoteric component); Alkylamido Phosphobetaines of Formula

RM 37 Alkyl phosphate quaternary compounds of the formula:

Polymer

Suitable cationic polymers are, for example, cationic cellulose derivatives, such as quaternary hydroxymethyl cellulose, cationic starch, diallyl ammonium salts and acrylamide, available under the trade name Polymer JR400 manufactured by Amerchol. Copolymers, quaternary vinylpyrrolidone / vinyl imidazole polymers such as the trade name Luviquat (BASF) (concentrated products of polyglycols and amines), condensation products of polyglycols and amines, quaternary collagen polypeptides, eg Lauryldimonium hydroxypropyl hydrolyzed collagen (Lamequat ^® L / Grunau), quaternary wheat polypeptide, polyethyleneimine, cationic silicone polymers such as aminomethicones, adips Copolymers of acid and dimethylaminohydroxypropyl diethylenetriamine (Cartaretin / Sandoz), copolymers of acrylic acid and dimethyldiallylammonium chloride (Merquat 550 / Chemviron), polya Minopolyamides, which are as disclosed in FR-A-2 252 840, and their crosslinked water soluble polymers, cationic chitin derivatives, for example quaternary chitosans circulated as optionally microcrystals; Concentrated products of dihaloalkyl, for example dibromobutane with bisdialkylamine, for example bisdimethylamino-1,3-propane, cationic guar gum, for example Jaguar C-17 from Celanese, Jaguar C-16, quaternary ammonium salt polymer, for example Mirapol AD-1, Mirapol A-15 from Miranol. Examples of anionic, zwitterionic, positive and nonionic polymers that may be considered include vinyl acetate / crotonic acid copolymers, vinylpyrrolidone / vinyl acrylate copolymers, vinyl acetate / butyl maleate / iso Boryl acrylate copolymers, methyl vinyl ether / maleic anhydride copolymers and their esters, polyacrylic acids crosslinked with uncrosslinked polyacrylic acids and polyols, acrylamidopropyl trimethylammonium chloride / acrylate copolymers, octyl acryl Amide / methyl methacrylate t-butylaminoethyl methacrylate / 2-hydroxypropyl methacrylate copolymer, polyvinyl pyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, vinylpyrrolidone / dimethylaminoethyl Methacrylate / vinyl caprolactam terpolymer and optionally derived cellulose ether And silicone. Also, the polymers described in EP 1 093 796 (pp. 3-8, lines 17-68) can be used.

The bioactive component

Bioactive components should be understood to include the following, for example, tocopherol, tocopherol acetate, tocopherol palmitate, ascorbic acid, deoxyribonucleic acid, retinol, bisabool, allantoin, phytantriol, panthenol, AHA Acids, amino acids, ceramides, pseudoceramides, essential oils, plant extracts and vitamin complexes.

Deodorizing active ingredient

Examples of deodorizing active ingredients that may be considered are, for example, antiperspirants, aluminum chlorohydrate (J. Soc. Cosm. Chem. 24, 281 (1973)). Examples of those commercially available under the trade name Locron ^® (Hoechst AG, Frankfurt (FRG)) are aluminum chlorohydrates corresponding to the formula of Al ₂ (OH) ₅ Clx2.5H ₂ O, the use of which is particularly preferred ( J. Pharm. Pharmacol. 26, 531 (1975). In addition to chlorohydrate, the use of hydroxyacetates and acydic aluminum / zirconium salts is also possible. An esterase inhibitor may be added as an additional deodorizing active ingredient. Preferred as such inhibitors are trialkyl citrate, such as trimethyl citrate, tripropyl citrate, triisopropyl citrate, tributyl citrate and especially triethyl citrate (Hydagen CAT, Henkel), which are responsible for enzymatic activity. Suppresses and reduces the formation of odors. Further components contemplated as esterase inhibitors are sterol sulfates or phosphates such as lanosterol, cholesterol, campestrol, stigmasterol and cytosterol sulfates or phosphates, dicarboxylic acids and their esters such as 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 acid and its Esters such as citric acid, malic acid, tartaric acid or tartaric acid diethyl ester. Antimicrobial active ingredients that affect the germ flora and inhibit or kill the growth of sweat-degrading bacteria may be present in the formulation (especially in stick formulations). Examples include chitosan phenoxyethanol and chlorhexidine gluconate. 5-Chloro-2- (2,4-dichlorophenoxy) -phenol (Triclosan, Irgasan, Ciba Specialty Chemicals Inc.) has been found to be particularly useful.

Dandruff remover

Dandruff removers such as climbazole, octopirox and zinc pyrithione may be used. Typical film formers include, for example, chitosan, microcrystalline chitosan, quaternized chitosan, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymers, quaternized cellulose derivatives containing a high proportion of acrylic acid, collagen, Hyaluronic acid and its salts and similar compounds.

Oyster Hydrotropic agents )

Oysters may be employed to improve flow behavior, for example, ethoxylated or non-ethoxylated mono-alcohols, diols or polyols having a high number of carbon atoms, or ethers thereof (e.g., ethanol, Ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, Glycol monomethyl ether, diethylene glycol ether, diethylene glycol monobutyl ether, and the like). For this purpose it is preferred that the polyols contemplated have from 2 to 15 carbon atoms and at least two hydroxy groups. The polyol may further contain functional groups, especially amino groups, and may be modified with nitrogen. Typical examples include: glycerol, alkylene glycols such as ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, hexylene glycol and polyethylene glycols having an average molecular weight of 100 to 1000 Daltons; An industrial oligoglycerol mixture having an inherent degree of concentration of from 1.5 to 10, for example an industrial diglycerol mixture having a diglycerol content of from 40 to 50% by weight; Methylol compounds such as trimethylolethane, trimethylolpropane, trimethylolbutane, pentaerythritol and dipentaerythritol; Lower alkyl-glucosides, especially those having 1 to 8 carbon atoms in the alkyl radical, such as methyl and butyl glucoside; Sugar alcohols having from 5 to 12 carbon atoms, such as sorbitol or mannitol; Sugars having from 5 to 12 carbon atoms, such as glucose or saccharose; Amino sugars such as glucamine; Dialcohol amines, such as diethanolamine or 2-amino-1,3-propanediol.

Preservative and bactericide inhibitor

Examples of suitable preservatives are methyl-, ethyl-, propyl- and butyl-parabens, benzalkonium chloride, 2-bromo-2-nitro-propane-2-nitro-propane-1,3-diol, dihydro Acetic acid, diazolidinyl urea, 2-dichloro-benzyl alcohol, DMDM hydantoin, formaldehyde solution, methyldibromo glutannitrile, phenoxyethanol, sodium hydroxymethylglycinate, imidazolidinyl urea, triclosan and Additional ingredients of the kind listed in the following literature: KFDePolo-Cosmetology related textbooks, Chapter 7, Tables 7-2, 7-3, 7-4 and 7-5, p210-219).

Typical examples of bactericidal agents are preservatives having specific activity against Gram-positive bacteria, for example 2,4,4'-trichloro-2'-hydroxydiphenyl ether, chlor-hexidine (1,6- Di (chlorophenyl-biguanido) hexane) or TCC (3,4,4'-trichlorocarbanilide). A large number of aromatic materials and etheric oils also have antimicrobial properties. Typical examples are clove oil, mint oil and eugenols in time oil, menthol and thymol. Interesting as a natural deodorizer is terpene alcohol parnesol (3,7,11-trimethyl-2,6,10-dodecatrien-1-ol), which is present in lime flower oil. Glycerol monolaurate was found to be a bacterial growth inhibitor. The amount of the additional germicidally inhibiting agent is usually 0.1 to 2% by weight based on the solids content of the preparation.

enjoyment

(Geraniums, lavender, rose, jasmine, neroli, ylang-ylang), extracts from the stems and leaves (geraniums, papyrus, petit grains), mixtures of natural and / or synthetic aromatics, Extracts from fruits (Anise, coriander, caraway, juniper), extracts from berries (bergamot, lemon, oranges), extracts from roots (mace, angelica, celery, cardamom, caster, iris, Extracts from wood (pine, sandalwood, cedarwood, rosewood), extracts from herbs and grass (tarragon, lemon grass, sage, thyme), extracts from needles and branches (fir, pine, scotland) Pine, mountain pine), extracts from rosin and balsam (galbanum, elemi, benzoin, myrrh, olivanum, opopanax). Examples of animal raw materials that can be considered include musk and beaver flavors. Typical synthetic aromatics are, for example, products in the form of esters, ethers, aldehydes, ketones, alcohols or hydrocarbons. Examples of the aromatic compound in the form of an ester include benzyl acetate, phenoxyethyl isobutyrate, pt-butyl cyclohexyl acetate, linalyl acetate, dimethylbenzylcarbinyl acetate, phenyl ethyl acetate, linalyl benzoate, benzyl formate, Ethyl methylphenyl glycinate, allyl cyclohexyl propionate, stearyl propionate and benzyl salicylate. Examples of ethers include benzyl ethyl ether; Examples of aldehydes include linear alkanols, citral, citronellal, citronellyoxyacetaldehyde, cyclamenaldehyde, hydroxycitronelal, lilial and attractant materials having 8 to 18 hydrocarbon atoms; Ketones such as ionone, isomethylionone and methyl sebacate ketone; Examples of alcohols include anethole, citronellol, eugenol, isougenol, geraniol, linalool, phenylethyl alcohol and terpinol; And hydrocarbons such as terpenes and balsam. However, it is preferred to use a mixture of various aromatic materials which emit attractive fragrances. Low volatile, etheric oils, which are primarily used as aromatic components, are also suitable as fragrances, such as sage oil, chamomile oil, clove oil, melissa oil, cinnamon oil, lime flower oil, juniper berry oil, vetiver oil, olivanum oil, galbanum oil, lavolanum oil and laventine oil. Preferably Bergamo Oil, Dihydromycenol, Lilial, Lyral, Citronellol, Phenyl Ethyl Alcohol, Hexyl Cinnamicaldehyde, Geraniol, Benzyl Acetone, Cyclamenaldehyde, Linalool, Bosambrene Forte (boisambrene) forte), ambroxane, indole, hedion, sandelis, lemon oil, tangerine oil, orange oil, allyl amyl glycolate, cyclovertal, ravandine oil, muscatel sage oil, damascone, borbon gelatin Oils, cyclohexyl salicylates, vertofix coeur, iso-E-Super, Fixolide NP, everyl, iraldine gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, lomilat, iro Irotyl and flora flavors alone or a mixture of each other.

coloring agent

Suitable and acceptable materials as colorants for cosmetic purposes are listed, for example, in the "Kosmetische Farbemittel" described in the Farb-stoffkommission der Deutschen Forschungsgemeinschaft, Verlag Chemie, Wein-heim, 1984, pages 81 to l106. Colorants are commonly used in concentrations of 0.001 to 0.1% by weight, based on the total mixture.

Other supplements

Examples of auxiliaries additionally used in cosmetic preparations include antifoams such as silicones, structurants such as maleic acid, solubilizers such as ethylene glycol, propylene glycol, glycerol or diethylene glycol, latex, styrene / PVP or styrene / Opacifiers such as acrylamide copolymers, complexing agents such as EDTA, NTA, alanine diacetic acid or phosphonic acid, propane / butane mixtures, N ₂ O, dimethylether, CO ₂ , N ₂ or air Propellants such as, so-called couplers and developer components as oxidizing pigment precursors, reducing agents, for example triglycolic acid and derivatives thereof, thiolactic acid, cysteamine, thiomalic acid or mercaptoethanesulfonic acid Or oxidizing agents such as hydrogen peroxide, potassium bromate or sodium bromate.

Examples of suitable insect repellents include N, N-diethyl-m-toluamide, 1,2-pentanediol or insect repellent 3535; Examples of suitable self-tanning agents are dihydroxyacetone and / or erythrulose, or dihydroxyacetone and / or dihydroxyacetone precursors and / or erythrulose, as disclosed in WO 01/85124.

Polymer beads or hollow spheres can be used as SPF enhancers.

Compounds of the invention, such as those of formulas (1), (2) and / or (3), are contained in liposomes or used in pharmaceutical compositions with conventional carriers and penetration enhancers such as dextran, propylene glycol, oleic acid, and the like. do.

Pharmaceutical compositions usually contain a composition of the invention in an amount of 0.001 to 10% by weight, preferably 0.01 to 5% by weight, in particular 0.01 to 2% by weight of the total mixture. In order to treat the above-mentioned conditions, the pharmaceutical compositions of the present invention may further contain, in addition to the compounds of the present invention, additional pharmaceutical or cosmetic agents such as anti-inflammatory agents, typically anti-inflammatory agents, vitamins and / or psoriasis treatments, skin active agents, cell active agents, cell proliferation agents, It may further contain an antiallergic agent, a UV protector, a humectant, an anti-aging agent, a gastric protector, an anti-asthmatic agent, a DNA protectant.

The pharmaceutical compositions of the present invention may contain antioxidants and / or light stabilizers, in particular UV absorbers, in addition to the compounds of the formulas (1) to (3) of the invention. Suitable components of these types include those described in EP-A-955355, WO00 / 25730, WO00 / 25731, WO03 / 103622, EP-A-1366763.

Examples are components listed below:

Suitable for use additionally with the compounds of the invention UV  Filter material
p-aminobenzoic acid derivatives such as 4-dimethylaminobenzoic acid 2-ethylhexyl ester;
Salicylic acid derivatives such as salicylic acid 2-ethylhexyl ester;
Benzophenone derivatives such as 2-hydroxy-4-methoxybenzophenone and 5-sulfonic acid derivatives thereof;
Dibenzoylmethane derivatives such as 1- (4-t-butylphenyl) -3- (4-methoxyphenyl) -propane-1,3-dione;
Diphenylacrylates such as 2-ethylhexyl 2-cyano-3,3-diphenylacrylate, and 3- (benzofuranyl) 2-cyanoacrylate;
3-imidazol-4-ylacrylic acid and esters;
Benzofuran derivatives, in particular 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 such as the benzylidene malonate derivatives described in EP-A-709 080
Cinnamic acid derivatives such as 4-methoxycinnamic acid 2-ethylhexyl ester and isoamyl ester or cinnamic acid derivatives as described in US-A-5 601 811 and WO 97/00851;
Camphor derivatives such as 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-phenylene-di Methine) -bis (7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptan-1-methanesulfonic acid) and salts, 3- (4'-sulfo) benzylidene-bornan-2-one and salt; Camphor benzalkonium methosulfate;
Hydroxyphenyltriazine compounds such as 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'-heptanemethyltrisilyl-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 such as 2,2'-methylene-bis (6- (2H-benzotriazol-2-yl) -4- (1,1,3,3-tetramethylbutyl) -phenol;
Trianilino-s-triazine derivatives such as 2,4,6-trianiline- (p-carbo-2'-ethyl-1'-oxy) -1,3,5-triazine and US-A- UV absorbers as described in 5 332 568, EP-A-517 104, EP-A-507 691, WO93 / 17002 and EP-A-570 838;
2-phenylbenzimidazole-5-sulfonic acid and salts thereof;
Menthyl o-aminobenzoate;
Coated or uncoated physical sunscreens such as titanium dioxide, zinc oxide, iron oxide, mica, MnO, Fe ₂ O ₃ , Ce ₂ O ₃ , Al ₂ O ₃ , ZrO ₂ (surface coatings: polymethylmethacrylate, meth Ticon (methylhydrogenpolysiloxane) (as described in CAS 9004-73-3), dimethicone, isopropyl titanium triisostearate (as described in CAS 61417-49-O), magnesium stearate (CAS Metal soap, such as as described in 4086-70-8, perfluoro such as C ₉ -C ₁₅ fluoroalcohol phosphate (as described in CAS 74499-44-8; JP 5-86984; JP 4-330007) Low alcohol phosphate, primary particle size averages 15 nm-35 nm and particle size distribution ranges from 100 nm-300 nm.
Aminohydroxy-benzophenone derivatives as described in DE 100 11 317, EP 1 133 980 and EP 1 046 391
Phenyl-benzimidazole derivatives as described in EP 1 167 358
"Sunscreens", Eds. NJ Lowe, NAShaath, Marcel Dekker, Inc. UV absorbers described in New York and Basle or Cosmetics & Toiletries (107), 50ff (1992) can also be used as additional UV protective materials.

As aqueous- and oil-containing emulsions (such as W / O, O / W, O / W, O / W / O and W / O / W emulsions or microemulsions), the formulations are for example based on the total weight of the composition 0.1 to 30% by weight, preferably 0.1 to 15% by weight, in particular 0.5 to 10% by weight of at least one UV absorber, 1 to 60% by weight, in particular 5 to 50% by weight, preferably based on the total weight of the composition 10 to 35% by weight of at least one oil component, 0 to 30% by weight, in particular 1 to 30% by weight, preferably 4 to 20% by weight, based on the total weight of the composition 10 to 90% by weight, in particular 30 to 90% by weight of water, and 0 to 88.9% by weight, in particular 1 to 50% by weight, based on the total weight of the composition.

In general, cosmetic or pharmaceutical preparations may be prepared by physically mixing the active ingredient (s) with the adjuvant in a conventional manner, such as by simply stirring the individual ingredients together.

Examples of compounds useful in the present invention are the compounds listed below:

AO3: Glycerin, Coconut Oil and Chemical Formula

의 화합물의 반응 생성물

Reaction product of a compound of

(A mixture of mono-, di- and triglycerides of β- (3,5-di-t-butyl-4-hydroxyphenyl, propanoic acid and fatty acids, CAS Reg.-No. 179986-09-5)

AO4:

AO5 is a mixture of compounds of the formula:

AO6:

AO7: pentaerythritol-tetrakis (3- [3 ', 5'-di-t-butyl-4'-hydroxyphenyl] -propionate)

(CAS Reg.-No. 006683-19-8)

(CAS Reg.-No. 006683-19-8)

AO8:

The following examples are intended to illustrate the invention and are not meant to be limited to those described herein. Unless indicated otherwise,% are by weight.

Abbreviation:

DMSO: dimethylsulfoxide

EDTA: ethylene-diamine tetraacetic acid

ELISA: enzyme-linked immunosorbent assay

FCS: Fetal Bovine Serum

Example  1: cytotoxicity

Cell cultures: Human primary skin fibroblasts (HDF-N2), 10% fetal bovine serum (FCS), 100 μg / ml streptomycin sulfate, 100 U / ml penicillin and 2 mM L-glutamine (all of them) Was maintained in Dulbecco's culture medium (DMEM; 1 g / l glucose) supplemented with US BioWitecker. Confluent cells were isolated by incubating in 0.055 trypsin / 0.53 mM EDTA at 37 ° C. for 3 minutes and plated at established cell density (usually 15 × 10 ⁴ cells / cm ² ).

Test: Stock solutions of each test compound (active) in DMSO or ethanol (5%) were diluted with cell culture medium containing 10% FCS (see above) as shown in Table 1. The culture medium of the negative control contains 10 mMol NaCl or 0.05% DMSO or 0.05% ethanol, respectively. Positive control is a culture medium containing 0.02% sodium lauryl sulfate (SDS).

For control purposes, culture media containing compounds of the formula: are used at the same dilution:

(대조군)

(Control group)

The test medium thus obtained was added to 24h to 48h-culture of human skin fibroblasts (HDF) as described above, and viability was measured through specific color markers penetrating only live cells (the greater the absorption at OD ₄₀ ) More viable cells: viable skin fibroblasts have esterases that release color absorbing at 450 nm Dead cells do not, OD450 measurement in cell culture in the presence of test substance and in contrast to untreated control To obtain a degree of cytotoxicity).

The results are shown in the table below.

The cytotoxicity of the test compounds of the invention is in the acceptable range.

Example  2: anti-inflammatory activity ( In vitro )

Compounds were tested for anti-inflammatory activity via modifying baseline PGE ₂ release in HDF-N2 cultured as described in Example 1. For this purpose, cells were incubated for 3 days in 24-well culture plates. Prior to treatment, confluent cells were obtained for 24 hours using a culture medium containing 1% FCS and then treated for 18 to 24 hours with the selected concentration of test compound. Each test compound AO3, AO5, AO6 and AO7 was used at 1: 500, 1: 1000 and 1: 1500 dilution ratios, respectively, which were prepared by adding the appropriate amount of the stock solution described in Example 1 to the culture medium, respectively. .

After treatment, the cell supernatant was removed and the aliquots were stored at −20 ° C. until analysis of PGE ₂ using an ELISA kit purchased from Amersham Biosciences. PGE ₂ values (pg / well) are individually corrected for total protein measured by BCA method (Pierce) and are expressed as PGE ₂ (pg / mg protein or ng / mg protein).

Morphological control of the cultures to which the product was applied for 24 hours was performed by phase contrast microscope.

Results: The test compound showed good PGE ₂ inhibitory activity.

Example 3 Evaluation of the Efficacy of Compounds of the Invention on Photooxidative Stress in Skin Induced by UVA Irradiation

In vivo antioxidant activity was determined through the ability of the test compound to reduce radical induced lipid peroxidation.

Testers: 10 (4 females, 6 males); Age range: 18 to 32 years old

Body parts tested: inner forearm

Trial period: 7 days

Evaluation method:-measurement of squalene

 -Measurement of squalene hydroperoxide

Evaluation time: after UVA irradiation

Assessment: Descriptive statistics: mean, median, minimum, maximum, variance, standard error, standard deviation; Multiple range test.

Test Methods

Each test compound (active) was applied as a 1 wt% solution in ethanol except for AO7 where a 0.1 wt% solution in ethanol was applied; In the following, these test solutions are also referred to as formulations. A symmetrically opposed area is defined for the inner forearm of each specimen. Different formulations were applied at a dose of about 2 mg of test solution / cm ² per day for 1 week (administration with syringe for fine administration: Omnifix ^® -F1 ml; manufacturer: Braun Melsungen AG (Germany).

Two areas were left untreated.

Application of tocopherol solution (0.2%) in ethanol prior to irradiation was used as a control.

The use of other cosmetic products was confined to the testing area throughout the study. Areas such as specimens (exception: one of the two untreated areas may not be exposed and may be exposed to environmental UVA irradiation during the test) were irradiated with UVA light (10 Joules / cm ² ). Lipids present on the test zone were collected via solvent extraction (2 minutes using 4 ml ethanol). Samples were first filtered through a hydrophobic polypropylene filter to drain squames and other insoluble material, then dried under nitrogen at room temperature and dissolved in 1 ml ethanol. Squalene (SQ) and squalene hydroperoxide (SQOOH) were analyzed by high pressure liquid chromatography (HPLC).

The results are expressed as inhibition rates for the untreated area:

% Suppression = 100 x [SQOOH (untreated) -SQOOH (active)] / SQOOH (untreated)

(SQOOH is picomolar hydrogen peroxide / pg squalene)

SQ For HPLC  analysis

Column: LiChrospher ^® 100 RP-18 (5 μm, 125 x 4 mm) Merck-Germany

Mobile phase: acetonitrile / isopropanol (1/1; V / V)

Detection: UV 210 nm

Flow rate: 1 ml / min

Injection volume: 20 μl

Device: Beckman System Gold (USA) with programmable solvent module 126 and programmable detector module 166

SQOOH For HPLC  analysis

Column: LiChrospher ^? 100 RP-18 (5 μm, 125 x 4 mm) Merck-Germany

Mobile phase: methanol

Detection: chemiluminescence (post column detection)

Flow rate: 1 ml / min

Injection volume: 20 μl

Reaction solution: luminol (1 μg / ml) and cytochrome C (10 μg / ml dissolved in 50 mM borate-buffer, pH 10)

Device: Beckman System Gold (USA) using programmable solvent module 126 and fluorometer RF-551 (Shimazu, Japan)

The fluorometer is used as the photon detector when the excitation source is turned off.

The assay measures the hydroperoxy group itself and does not detect indicators of lipid peroxidation, such as degradation products of conjugated dienes or lipid hydroperoxides. Chemiluminescence detects ubiquinol. To confirm that the chemiluminescence found in this analysis is due to hydroperoxide and not due to hydroquinone, some samples are reduced to triphenyl phosphine and again subjected to chromatography. The chemiluminescence reaction of hydroperoxides, not the chemiluminescence of hydroquinones, is eliminated by triphenyl phosphine, and the disappearance of these chemiluminescent peaks in the treated samples indicates that the chemiluminescence found in this assay is not hydroquinone but hydroquinone. It is due to.

Biometry ( Biometry )

Measurement data were centralized after validation and quality assurance. The evaluation was performed using the software Statgraphics for Windows, Version 5.0-Manugistics (United States). Data were analyzed by a multiple range test (LSD: Least Significant Difference). The 0.05 level was chosen as the minimum acceptable statistical significance score.

result

The skin care formulations of the present invention significantly reduced squalene peroxidation (P <0.05) compared to untreated UV controls.

In the untreated, unirradiated area, no preparation of ethanol extractable squalenehydroperoxide was detected.

Average inhibition rates in% peroxide are as follows:

Formulation control AO4 28% AO5 26.5% AO6 28% AO7 21.5% AO8 21% Control group 22.5%

Conclusion :

Pretreatment of the epidermal surface with the formulations according to the invention prior to UVA irradiation significantly reduced UV induced sebum peroxidation. These studies provide conclusive evidence of the free radical hypothesis of UVA light-induced subcutaneous pathology that lipid peroxidation is increased upon irradiation and topical administration with an antioxidant system protects against such damage.

Example  3: Dermatological  Formulation

General Formulations:

(a) 5 to 20 weight percent of phospholipids (such as lecithin),

(b) coemulsifiers (such as polyethoxylated sorbitan fatty acid esters, polyethoxylated fatty alcohols, polyethoxylated fatty acids, polyethoxylated vitamin E derivatives, polyethoxylated lanolin or lanolin derivatives, polyethoxylated) Fatty acid glycerides or partial glycerides, polyethoxylated alkylphenols, sulfuric acid semiesters or salts thereof of polyethoxylated fatty alcohols, polyethoxylated fatty amines or amides, polyethoxylated carbohydrates) 15 to 40% by weight,

(c) 30 to 70% by weight of a lipophilic component consisting of triglycerides, compounds of the invention such as AO3-AO8 and optionally additional active agents, wherein the weight ratio of active agent to triglycerides is usually in the range from 1: 5 to 5: 1, and

(d) mixing 3 to 30% by weight of an alcohol such as ethanol such that the total of% of components (a), (b), (c) and (d) is 100% and adding the obtained liquid to the aqueous phase. To obtain a transparent homogeneous prephase. The water phase (eg 90 kg) was stirred (eg using a magnetic stirrer) at 50 ° C. in the vessel. This liquid phase (eg 10 Kg) was added to the water phase with stirring (eg using a magnetic stirrer). The formulations obtained can be further diluted or mixed.

Vitamin A Palmitate  cream

The dispersion was mixed with 10 mm phosphate buffer (pH 6), an aqueous phase, containing 100.00% of the clear phase containing:

Vitamin A Palmitate (1.7 x 10 ⁶ IU / g) 0.45%

Compound AO7 0.45%

Soy Lecithin 1.73%

Migliool 812 3.00%

Polysorbate 80 3.40%

Ethanol 1.42%

The final formulation contains:

Cetyl Alcohol 10.00%

Hydrogenated Peanut 20.00%

Polysorbate 60 5.00%

Propylene Glycol 20.00%

Phenoxyethanol 0.50%

23.00% of the dispersion shown above

Addition of 100.00% of purified water (aqua purificata)

Good results were also obtained when compound AO7 was replaced with AO3, AO4 or AO5.

Solcoseryl  0.5% Hydrogel

The dispersion was mixed with 10 mm phosphate buffer (pH 6), an aqueous phase, containing 100.00% of the clear phase containing:

Solcoseryl 1.00%

Compound AO7 1.00%

Soy Lecithin 1.73%

Polysorbate 80 3.40%

Migliool 812 3.45%

Ethanol 1.42%

The final formulation contains:

Sodium Carboxymethylcellulose 450 cP 3.50%

50.00% of the dispersion shown above

Addition of 100.00% of purified water (aqua purificata)

The formulation is pleasantly cooled and has good anti-inflammatory action.

skin  Protective W / O Lotion

The dispersion was mixed with 10 mm phosphate buffer (pH 6), an aqueous phase, containing 100.00% of the clear phase containing:

Vitamin E Acetate 2.00%

Compound AO3 1.00%

Soy Lecithin 0.49%

Polysorbate 80 1.86%

Migliool 812 0.71%

Ethanol 0.63%

The final formulation contains:

Glycerol Sorbitan Fatty Acid Ester 2.0%

Polyethoxy fatty acid ester 2.0%

Isopropylisostearate 5.0%

Mineral oil 7.0%

Isopropyl palmitate 4.0%

Malt 3.0%

Propylene glycol 3.8%

5.0% of the dispersion shown above

MgSO ₄ x 7H ₂ O 0.7%

Perfume 0.5%

Preservative, water

Good results were also obtained when compound AO3 was replaced with AO7, AO6 or AO8.

UV  Protective day  Cream (O / W)

A dispersion was obtained by mixing transparent aqueous phase containing 100.00% of aqueous phase with the following content:

Parsol MCX 2.59%

(Octyl methoxycinnamate)

Parsol 5000 1.11%

(4-Methylbenzylidene camphor)

Compound AO7 1.00%

Migliool 812 1.30%

Soy Lecithin 0.50%

Polysorbate 80 3.40%

Ethanol 1.10%

The final formulation 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%

10.0% of the dispersion shown above

Phenoxyethanol + methyl-, ethyl-, propyl-, butylparaben 0.3%

Addition to make up 100.0% of water.

Claims (14)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier or adjuvant with at least one of the following compounds: (9)

(29)

(30)

(31)

(34)

delete delete delete delete delete The pharmaceutical composition according to claim 1, wherein the compound of formula (9), (29), (30), (31) or (34) is present in a total amount of 0.001 to 10% by weight of the total composition. The pharmaceutical composition of claim 1 for treating radical induced skin damage or inflammatory or allergic conditions. delete delete The method of claim 1, further comprising at least one substance selected from anti-inflammatory agents, anti-inflammatory agents, vitamins, psoriasis agents, other skin active agents, cell proliferation regulators, anti-allergic agents, UV protective agents, wetting agents, anti-aging agents and DNA-protecting agents. Pharmaceutical compositions comprising. A pharmaceutical composition according to claim 1 which contains compounds (9), (29), (30), (31) and (34), and optionally other active ingredients in nanodispersed or encapsulated form. Composition. A method for preparing a pharmaceutical composition comprising adding an effective amount of the pharmaceutically active compounds (9), (29), (30), (31) and (34) as defined in claim 1 to a pharmaceutically acceptable carrier. delete