WO1996017589A1

WO1996017589A1 - Method of smoothing or removing wrinkles and method of stimulating collagen synthesis

Info

Publication number: WO1996017589A1
Application number: PCT/JP1995/002498
Authority: WO
Inventors: Tsutomu Fujimura; Ayumi Ogawa; Hiroyuki Ohsu; Yoshinori Takema; Kimihiko Hori; Shinya Amano; Taketoshi Fujimori; Yukihiro Ohashi; Yasuto Suzuki
Original assignee: Kao Corporation
Priority date: 1994-12-08
Filing date: 1995-12-06
Publication date: 1996-06-13

Abstract

The present invention relates to methods of stimulating collagen synthesis and of smoothing or removing wrinkles, which comprise administering an effective amount of a benzoic acid derivative of formula (1) or a salt thereof, wherein X is -O- or -N(R4)- (R4 is H or the like), R1 is a C¿4-25?-alkyl or C4-25-alkenyl group, R?2¿ is H, OH, or a C¿1-6?-alkoxyl or C1-6-alkanoyloxy group, and R?3 is -OR5¿ or -N(R?6)R7 (R5? is H, or a C1-25-alkyl or C1-25-alkenyl group), and R?6 and R7¿ are individually H, or a C¿1-3?-alkyl or C1-3-alkenyl group, and use of this compound for agents for stimulating synthesis of collagen, and smoothing or removing wrinkles. This compound (1) stimulates collagen synthesis in human dermal fibroblasts and consequently smooths or removes wrinkles caused by aging and/or photoaging.

Description

DESCRIPTION

TITLE OF THE INVENTION

METHOD OF SMOOTHING OR REMOVING WRINKLES AND

METHOD OF STIMULATING COLLAGEN SYNTHESIS

BACKGROUND OF THE INVENTION Field of the Invention:

The present invention relates to methods of smoothing or removing wrinkles and of stimulating collagen synthesis using benzoic acid derivatives, and use of the benzoic acid derivatives for an agent for smoothing or removing wrinkles (hereinafter referred to as "wrinkle-smoothing agent") and an agent for stimulating collagen synthesis.

Discussion of the Background:

The skin consists of epidermis, dermis and subcutaneous tissue. Of these, the dermis plays an important role as a connective tissue in support of the skin, maintenance of homeostasis and the like. In the dermis, fibroblasts produce fibrous proteins such as collagen, elastin and fibronectin and glycosa inoglycans such as hyaluronic acid. These compounds form a three-dimensional structure which maintains the elasticity^"of the connective tissue.

The skin undergoes aging and photoaging in response to chronic ultraviolet irradiation. First, the dermal thickness decreases and atrophies. Second, skin elasticity is decreased, which finally leads to formation of wrinkles and saggings, which are the most characteristic changes found on aged skin (Marks R. , Biochemistry and Physiology of the Skin, Oxford Univ. Press, 1983).

When these phenomena are biochemically observed, the aging of the dermis is biochemically linked to the amount of collagen in the skin. Collagen is a major component of connective tissue. The amount of collagen in the skin decreases by 35% from 20 years to 80 years of age, resulting in an overall decrease of dermal thickness (Shuster S., British Journal of Dermatology, 9__ , 639 (1975)). This decrease is a result of (1) declining collagen metabolism with age and (2) increasing amounts of disordered intermolecular crosslinking (A.M. Kligman, "Aging and Skin", p. 221 (1986)), glycosylation and the like in collagen fibers. Not only do these changes lead to an overall decrease in the amount of collagen, but they also lead to an increase in the amount of insoluble collagen (Legraed Y., Pathological Biology, 3/7_. 991 (1969)). These cumulative changes result in connective tissue hardening and loss of flexibility and expansibility, eventually leading to the formation of wrinkles and the like in the skin.

To combat the loss of collagen, cosmetic compositions containing collagen have been marketed with a view to supplying the skin with collagen. However, collagen applied to the skin does not sufficiently penetrate into the dermis. Therefore, such cosmetic compositions fail to smooth or remove wrinkles. If collagen synthesis in dermal fibroblasts can be stimulated, it is expected that the skin would be supplemented with newly synthesized collagen. Moreover, it is expected that the metabolic turnover of collagen would also be activated, thereby increasing the amount of newly synthesized soluble collagen. As a result, the flexibility and expansibility of the connective tissue would be improved, and so the morphological changes of the cutaneous aging typified by wrinkles would be halted, if not improved.

Retinoic acid has attracted attention as a wrinkle- smoothing agent. Application of retinoic acid to the skin correlates with an increase in skin smoothness or removal of wrinkles and stimulation of collagen synthesis in the dermis (E. Schwartz et al, J. Invest. Dermatol., ___, 975 (1991); F. Bryce et al, Photoder atol. , 190. 352 (1990); and R. Marks et al, Br. J. Dermatol., 122, 91 (1990)). However, retinoic acid application can lead to such side effects as irritation, erythema, pachymenia and teratogenesis. Therefore, it cannot be added into general drugs, guasi-drugs, cosmetic compositions and the like.

Vitamin C and derivatives thereof, lc_,25-dihydroxyvitamin D₃, extract of ginseng, milk sera of mammals have all been used as agents for stimulating collagen synthesis (J. Dobak et al, J. Dermatol. Sci., 8_, 18 (1984); and Japanese Patent Application Laid-Open Nos. 29080/1990 and 20206/1991) , and the like. However, these agents are not yet fully satisfactory in points of percutaneous absorption, stability, effects and the like.

SUMMARY OF THE PRESENT INVENTION It is, therefore, an object of the present invention to provide an agent for stimulating collagen synthesis and a wrinkle-smoothing agent, which are good in percutaneous absorption, chemical stability and the like.

In view of the foregoing circumstances, the present inventors have conducted screening of various compounds as to effects of stimulating collagen synthesis and of smoothing or removing wrinkles. As a result, they found that a benzoic acid derivative of the formula (1) , which will be described subsequently, has excellent effects of stimulating collagen synthesis and of smoothing or removing wrinkles.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides a method of smoothing or removing wrinkles, which comprises administering an effective amount of a benzoic acid derivative of the formula (l) or a salt thereof:

wherein

X is -O- or -N(R⁴)-; in which R⁴ is a hydrogen atom, C₁._l - alkyl, C₂. _:-alkenyl, C^.-alkanoyl or C-^.-alkoxycarbonyl group;

R^: is a C₄.,_E-alkyl or a C₄._2£-alkenyl group, which can be substituted with a hydroxyl group and which can contain a heteroatom in a carbon chain or which can be substituted with a heteroatom;

R² is a hydrogen atom, a hydroxyl group, a C.._e-alkoxyl group or a C.^-alkanoyloxy group; and

R³ represents -OR⁵ or -N(R⁶)R⁷, in which R⁵ is a hydrogen atom or C._₂₅-alkyl or C₂.₂₅-alkenyl group, which can contain a heteroatom in the carbon chain or which can be substituted with a heteroatom, and R⁶ and R⁷ are, independently, a hydrogen atom or a C..₃-alkyl or C₂_ -alkenyl group, which can be substituted by a hydroxyl group.

The present invention also provides a method of stimulating collagen synthesis in the skin, which comprises administering an effective amount of the benzoic acid derivative of the formula (1) or the salt thereof.

The present invention further provides a use of the benzoic acid derivative of the formula (1) or the salt thereof as a wrinkle-smoothing agent.

The present invention still further provides a use of the benzoic acid derivative of the formula (1) or the salt thereof as an agent for stimulating collagen synthesis in the skin.

The present invention provides novel benzoic acid amide derivatives of the formula (lα) or a salt thereof:

wherein

R^lα is a C₈_₂₄-hydroxyalkyl group or a 3,7,11-trimethyl- 2, 6,10-dodecatrienyl group; and

R^6Q and R⁷⁰ are, independently, a hydrogen atom or a C._.3- alkyl group, which can be substituted by a hydroxyl group.

The present invention also provides a use of the benzoic acid amide derivative of the formula (lα) or a salt thereof in an external skin care preparation. The present invention further provides an external skin care composition comprising the benzoic acid amide derivative represented of the formula (lα) or the salt thereof.

Benzoic acid derivatives (1) useful in the practice of the present invention have heretofore been known, for example, as insecticides and synthetic intermediates thereof (USP 3,718,618, USP 4,051,319, DE 2144936, DE 2021227, etc.), depressants of sebum secretion (Japanese Patent Application Laid-Open Nos. 153616/1989 and 153617/1989), seborrhea- inhibiting cosmetics (Japanese Patent Application Laid-Open Nos. 165313/1986 and 165352/1986 and DE 4033562) , insect juvenile hormones (Fiziol. Art. Veshchestva, l , 27 (1977) and USP 3,847,907), and the like. However, their effects on collagen synthesis and smoothing or removing wrinkles have not been known at all.

Suitable heteroato s which can be in a carbon chain include -0-, -S-, -S(O)-, -S(0)₂-, -NH- and the like. Suitable heteroatoms which can be substituents include =0, -OH, =S, -SH, -S0₂ ^~, -S0₃, -NH₂, and the like.

Suitable halogen atoms include fluorine, chlorine, bromine and iodine.

R¹ is a C₄._2E-alkyl or a C₄__2E-alkenyl group, which can be substituted by a hydroxyl group, and which can be linear, branched or cyclic.

Preferred unsubstituted, linear C₄.₂₅-alkyl groups include n-butyl, n-pentyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, n-tetradecyl and n-hexadecyl groups. Preferred unsubstituted, branched C₄.₂₅-alkyl groups include isobutyl, sec-butyl, t- butyl, 4-methylpentyl, 5-methylhexyl, 2,4-dimethylpentyl, 3,5- dimethylhexyl, 6-methylheptyl, 4,6-dimethylheptyl, 2,4,6- trimethylheptyl, 2-ethylhexyl, 7-methyloctyl, 11- ethyldodecyl, 3,7-dimethyloctyl, 3,5,5-trimethylhexyl and 3,7,li-trimethyldodecyl groups. Preferred unsubstituted, cyclic C₄.₂₅-alkyl groups include cyclopentyl, cyclohexyl, cyclohexylmethyl and cyclohexylethyl groups.

Preferred unsubstituted, linear C₄_₂₅-alkenyl groups include 4-pentenyl, 5-hexenyl, 7-octenyl, 9-decenyl and 11- dodecenyl groups. Preferred unsubstituted, branched C ._2S- alkenyl groups include 4-methyl-2-pentenyl, 5-methyl-2- hexenyl, 6-methyl-2-heptenyl, 3,7-dimethyl-2-octenyl, 3,7,11- tri ethy1-2-dodecenyl, 3,7-dimethyl-2,6-octadienyl and 3,7,11- trimethyl-2,6,10-dodecatrienyl groups. Preferred unsubstituted, cyclic C_<.₂₅-alkenyl groups include l- cyclopentenyl and 1-cyclohexenyl groups and groups derived from vitamins, such as a retinyl group.

Preferred linear, branched or cyclic

or C₄.₂₅- alkenyl groups substituted by a hydroxyl group include 8- hydroxyoctyl, 10-hydroxydecyl, 11-hydroxyundecyl, 12- hydroxydodecyl and 12-hydroxyoctadecyl groups. Preferred C₄.₂₅- alkyl or C₄.₂₅-alkenyl group which contain a heteroatom in a carbon chain or which are substituted with a heteroatom include groups derived from vitamins such as vitamin E and vitamin C, such as tocopheryl and ascorbyl groups.

R² is a

group or C..₆-alkanoyloxy group, which can be linear or branched. Preferred C^-alkoxyl groups include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and n-pentyloxy groups. Preferred C-^-alkanoyloxy groups include formyloxy, acetyloxy, propanoyloxy, butanoyloxy and hexanoyloxy groups.

R⁴ is a C_j.^-alkyl, C₂._n-alkenyl, C.^.-alkanoyl or C₁.₁₁- alkoxycarbonyl group, which can be linear or branched. Preferred C-.^-alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-octyl and 3,7-dimethyloctyl groups. Preferred C₂._n-alkenyl groups include allyl, butenyl and 3,7-dimethyl-2,6-octadienyl groups. Preferred C.._1:ι- alkanoyl groups include acetyl, propanoyl and octanoyl groups. Preferred

groups include methoxycarbonyl, ethoxycarbonyl and octyloxycarbonyl groups.

R⁵ is a C_j.^-alkyl or C₂_₂--alkenyl group, preferably a C_:_ _1£-alkyl or C.,₁₅-alkenyl group, which can contain a heteroatom in a carbon chain or which can be substituted with a heteroatom and which can be linear, branched or cyclic. Preferred linear C.._2E-alkyl group include methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-octyl, n-decyl, n- dodecyl, n-tetradecyl and n-hexadecyl groups. Preferred branched C-._2E-alkyl groups include isopropyl, isobutyl, sec- butyl, t-butyl, 4-methylpentyl, 5-methylhexyl, 2,4- di ethylpentyl, 3,5-dimethyl hexyl, 6-methylheptyl, 4,6- dimethylheptyl, 2,4,6-trimethylheptyl, 2-ethylhexyl, 7- methyloctyl, 11-methyldodecyl, 3,7-dimethyloctyl and 3,7,11- tri ethyldodecyl groups. Preferred cyclic C.._2E-alkyl groups include cyclopentyl and cyclohexyl groups.

Preferred linear C₂,₂₅-alkenyl groups include vinyl, allyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 7-octenyl, 9-decenyl and 11- dodecenyl groups. Preferred branched C₂.₂₅-alkenyl groups include 4-methyl-2-pentenyl, 5-methyl-2-hexenyl, 6-methyl-2- heptenyl, 3,7-dimethyl-2-octenyl, 3,7,ii-trimethyl-2- dodecenyl, 3,7-dimethyl-2,6-octadienyl and 3,7,11-trimethyl- 2,6,10-dodecatrienyl groups. Preferred cyclic C₂.₂₅-alkenyl groups include 1-cyclopentenyl and 1-cyclohexenyl groups, and groups derived from vitamins, such as a retinyl group.

Preferred C^-_s-alkyl or C₂.₂₅-alkenyl group which contain a heteroatom in a carbon chain or which are substituted with a heteroatom groups derived from vitamins such as vitamin E and vitamin C, such as tocopheryl and ascorbyl groups.

R⁶ and R⁷ are, independently C..₃-alkyl or C₂.₃-alkenyl groups, which can be substituted by a hydroxyl group. Preferably R^£ and R⁷ are, independently, methyl, ethyl, n- propyl, isopropyl, 2-hydroxyethyl, 3-hydroxypropyl, vinyl and allyl groups. Most preferably, R^€ is a hydrogen atom and R⁷ is a hydrogen atom or a C-^-alkyl or C₂.₃-alkenyl group, which can be substituted by a hydroxyl group.

In the general formula (1) , particular preference is given to the case where: X is -0- or -NH-;

R¹ is the C_<._2E-alkyl or C₄._2E-alkenyl group, which can be substituted by a hydroxyl group;

R² is a hydrogen atom, a hydroxyl group, a C-^-alkoxyl or C^-alkanoyloxy group;

R⁵ is a hydrogen atom or a C^.-alkyl or C₂.₂₅-alkenyl group; R⁶ is a hydrogen atom; and is a hydrogen atom or a

oITr- rC '₂2_-3₃-alkenyl group, which can be substituted by a hydroxyl group.

In the general formula (1) , -X-R¹ and -R² can be substituted at any positions on the benzene ring. However, it is particularly preferred that they be substituted at positions indicated in the following formula (A) , (B) or (C) .

wherein R^:, R², R³ and X have the same meaning as defined above. No particular limitation is imposed on the salts of the benzoic acid derivatives (1) so far as they are pharmaceutically permissible salts. Examples thereof include salts of alkali metals such as sodium and potassium, salts of alkaline earth metals such as calcium and magnesium, ammonium salts, salts of mono-, di- or trialkanolamines, and salts of basic a ino acids such as lysine and arginine. In the benzoic acid derivatives (1) , stereoisomerism can be present in some cases. In the present invention, however, all stereoiso ers and mixtures thereof can be used.

Specific preferable examples of the benzoic acid derivatives represented by the general formula (1) include: methyl 4-(2-ethylhexyloxy)-2-hydroxybenzoate, methyl 2-hydroxy-4-(3,5,5-trimethylhexyloxy)benzoate, methyl 4-cyclohexylmethoxy-2-hydroxybenzoate, methyl 4-(2-eyelohexylethoxy)-2-hydroxybenzoate, methyl 4-(3,7-dimethyl-6-octenyloxy)-2-hydroxybenzoate, ethyl 3-(2-ethylhexyloxy)-5-hydroxybenzoate, methyl 5-(2-ethylhexyloxy)-2-hydroxybenzoate, methyl 2-hydroxy-5-(3,5,5-trimethylhexyloxy) enzoate, methyl 5-(2-cyclohexylethoxy)-2-hydroxybenzoate, methyl 4-n-hexyloxy-2-hydroxybenzoate, methyl 2-hydroxy-4-n-octyloxybenzoate, methyl 4-n-decyloxy-2-hydroxybenzoate, methyl 5-n-hexyloxy-2-hydroxybenzoate, 4-(2-ethylhexyloxy)-2-hydroxybenzoic acid, 2-hydroxy-4-(3,5,5-trimethylhexyloxy)benzoic acid, 4-cyclohexylmethoxy-2-hydroxybenzoic acid, 4- (2-cyclohexylethoxy)-2-hydroxybenzoic acid, 4-(3,7-dimethyl-6-octenyloxy)-2-hydroxybenzoic acid, 3-(2-ethylhexyloxy)-5-hydroxybenzoic acid, 5-(2-ethylhexyloxy)2-hydroxybenzoic acid, 2-hydroxy-5-(3,5,5-trimethylhexyloxy)benzoic acid, 5-(2-cyclohexyl-ethoxy)2-hydroxybenzoic acid, 4-n-hexyloxy-2-hydroxybenzoic acid, 5-n-hexyloxy-2-hydroxybenzoic aci , 2-hydroxy-4-n-octyloxybenzoic acid, 4-n-decyloxy-2-hydroxybenzoic acid,

N- (2-hydroxyethyl)-4-(2-ethylhexyloxy)-2-hydroxybenzamide,

N-ethyl-4-(2-ethylhexyloxy)-2-hydroxybenzamide,

2-acetoxy-4-cyclohexylmethoxybenzoic acid, sodium 4-(2-ethylhexyloxy)-2-hydroxybenzoate, methyl 4- ( (2E)-3,7-dimethyl-2,6-octadienyl-oxy)-2- hydroxybenzoate, ethyl 4-( (2E)-3,7-dimethy1-2,6-octadienyloxy)-2- hydroxybenzoate, ethyl 5-( (2E)-3,7-dimethyl-2,6-octadienyloxy)-

2-hydroxybenzoate, ethyl 3-( (2E)-3,7-dimethyl-2,6-octadienyloxy)-2- hydroxybenzoate, ethyl 3- ( (2E)-3,7-dimethyl-2, 6-octadienyloxy)-5-hydroxy- benzoate, ethyl 4-( (2E)-3,7-dimethyl-2,6-octadienyloxy)-3- methoxybenzoate,

(2E)-3,7-dimethyl-2,6-octadienyl 4-( (2E)3,7-dimethyl-2,6- octadienyloxy)-2-hydroxybenzoate,

4-( (2E) 3,7-dimethyl-2,6-octadienyloxy)-2-hydroxybenzoic acid,

5-( (2E)-3,7-dimethyl-2,6-octadienyloxy)-2-hydroxybenzoic acid,

3-( (2E)-3,7-dimethyl-2,6-octadienyloxy)-2-hydroxybenzoic acid,

3-( (2E) -3,7-dimethyl-2,6-octadienyloxy)-5-hydroxybenzoic acid,

2-hydroxy-4-( (2E,6E)-3,7,ll-trimethyl-2,6,10- dodecatrienyloxy)benzoic acid,

4-( (2E)-3,7-dimethyl-2,6-octadienyloxy)-3-methoxybenzoic acid,

2-acetoxy-4-( (2E)-3,7-dimethyl-2,6-octadienyloxy)benzoic acid,

N-(2-hydroxyethyl)4-( (2E)-3,7-dimethyl-2 ,6-octadienyloxy)-2- hydroxybenza ide,

4-( (2E)-3,7-dimethyl-2,6-octadienyl)amino-2-hydroxybenzoic acid,

4-( ( (2E)-3,7-dimethyl-2,6-octadienyl)a inobenzoic acid,

3-( ( (2E)-3,7-dimethyl-2,6-octadienyl)aminobenzoic acid,

4- ( ( (2E,6E)-3,7,11-trimethyl-

2,6,10-dodecatrienyl)amino)benzoic acid,

4-( ( (2E,6E)-3,7,ll-trimethyl-2,6,10-octatrienyl)amino)benzoic acid, 3-( ( (2E,6E)-3,7,ll-trimethyl-2, 6,10-octatrienyl)amino)benzoic acid,

4-(2-ethylhexylamino)benzoic acid,

3-(2-ethylhexylamino)benzoic acid,

4-(3,5,5-trimethylhexyl amino)benzoic acid,

3- (3,5,5-trimethylhexylamino)benzoic acid,

4-N,N-bis( (2E)-3,7-dimethyl-2,6-octadienyl amino)benzoic acid,

4-(N-methoxycarbonyl-N-( (2E)-3,7-dimethyl-2,6- octadienyl)amino)benzoic acid,

4-(N-acetyl-N-( (2E)-3,7-dimethyl-2,6-octadienyl)amino)benzoic acid,

4-(3,7-dimethyl-9-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2,4,6,8- nonatetraenyl)amino)benzoic acid,

3-(2-ethylhexyloxy)benzoic acid,

4- (2-ethylhexyloxy)benzoic acid,

3-(3,5,5-trimethylhexyloxy)benzoic acid,

4-(3,5,5-trimethylhexyloxy)benzoic acid,

3-dodecyloxybenzoic acid,

3-(12-hydroxydodecyloxy)benzoic acid,

4-dodecyloxybenzoic acid,

4-(12-hydroxydodecyloxy) enzoic acid,

3-(12-hydroxyoctadecyloxy)benzoic acid,

4-(12-hydroxyoctadecyloxy)benzoic acid,

3-(ll-hydroxyundecyloxy) enzoic acid,

4-(ll-hydroxyundecyloxy)benzoic acid,

3-( (2E)-3,7-dimethyl-2,6-octadienyloxy)benzoic acid,

3-( (2E,6E)-3,7,ll-trimethyl-2,6,10-dodecatrienyloxy)benzoic acid,

4- ( (2E,6E)-3,7,ll-trimethyl-2,6,10-dodecatrienyloxy)benzoic acid,

4- ( 3 , 7-dimethyl-9- (2 , 6 , 6-trimethyl-l-cyclohexen-l-yl ) -2 , 4 , 6 , 8- nonatetraenyloxy) benzoic acid ,

4- ( 3 , 4-dihydro-2 , 5 , 7 , 8-tetramethyl-2- (4 , 8 , 12-trimethyl- tridecyl ) -2H-l-benzopyran-6-oxy ) benzoic acid ,

4- ( (2E, 6E) 3 , 7 , ll-trimethyl-2 , 6 , 10-dodecatrienyloxy) benzamide ,

4- ( (2E) 3 , 7-dimethyl-2 , 6-octadienyloxy) benzamide ,

4- ( 2-methyl-2-butenyloxy) benzamide , 4-(2-ethylhexyloxy)benzamide,

4-dodecyloxybenzamide,

4-(12-hydroxydodecyloxy)benzamide, -(12-hydroxyoctadecyloxy)benzamide,

4- (ll-hydroxyundecyloxy)benzamide,

4-(10-hydroxydecyloxy)benzamide,

4-isostearyloxybenzamide,

N-(2-hydroxyethyl)-4-( (2E,6E)-3 , 1,ll-trimethyl-2, 6,10- dodecatrienyloxy)benzamide,

N,N-dimethyl-4-( (2E,6E)3,7,ll-trimethyl-2,6,10- dodecatrienyloxy)benzamide,

4-(N,N-bis-( (2E)-3,7-dimethyl-2,6-octadienyl)amino)benzamide,

4-(N-methoxycarbonyl-N-( (2E)-3,7-dimethyl-2,6-octadienyl) amino)benzamide,

4-( N-acetyl-N-( (2E)-3,7-dimethyl-2,6-octadienyl)amino)- benzamide,

N-(2-hydroxyethyl)-4-( (2E,6E)-3,7,ll-trimethyl-2,6,10- dodecatrienyloxy)-2-hydroxybenzamide, and

N,N-diethyl-4-( (2E,6E)-3,7,ll-trimethyl-2,6,10-dodecatrienyl- oxy)-2-hydroxybenzamide.

In the general formula (lα) , examples of the C₈._2<- hydroxyalkyl group represented by R¹" includes linear, branched and cyclic hydroxyalkyl groups. Specific examples of the C_e_₂₄- hydroxyalkyl group include 8-hydroxyoctyl, lO-hydroxydecyl, ll-hydroxyundecyl, 12-hydroxydodecyl and 12-hydroxyoctadecyl groups.

Examples of the C-^-alkyl groups, which can be substituted by a hydroxyl group, represented by R^6Q and R⁷° include methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl and 3-hydroxypropyl groups.

In the general formula (lα) , the group represented by -0-R^lQ can be substituted at any position of 2-, 3- and 4- positions on the benzene ring. However, it is preferably substituted at a 2- or 4-position, with the 4-position being particularly preferred.

Specific preferable examples of the benzoic acid amide derivatives represented by the general formula (lα) include 4-( (2E,6E)-3,7,ll-trimethyl-2, 6,10-dodecatrienyloxy)benzamide,

4-(12-hydroxydodecyloxy)benzamide,

4-(12-hydroxyoctadecyloxy)benzamide,

4-(ll-hydroxyundecyloxy)benzamide,

4-(10-hydroxydecyloxy)benzamide,

N-(2-hydroxyethyl)-4-( (2E,6E)-3,7,11-trimethyl-

2,6,10-dodecatrienyloxy) enzamide, and

N,N-dimethyl-4-( (2E,6E)-3,7,ll-trimethyl-2,6,10-dodecatrienyl- oxy)benzamide.

The benzoic acid derivatives (1) or the salts thereof are prepared, for example, in accordance with the following reaction schemes 1 to 4.

Reaction Scheme 1: (a case where R³ in the formula (1) is the group other than a hydroxyl group)

(2) (3) (la)

wherein, R^3a is a group other than a hydroxyl group represented by R³,

Y¹ is a leaving group such as a halogen atom, or a p- toluenesulfonyloxy or methanesulfonyloxy group, and

R , R² and X have the same meaning as defined above.

A compound (3) is reacted with a compound (2) , thereby preparing a benzoic acid derivative (la) . This reaction is preferably carried out by using 0.5-3.0 moles of the compound (3) per mole of the compound (2) and stirring the resultant mixture at a temperature of generally 1 to 150°C, preferably 20 to 100°C for several hours. This reaction is preferably performed in the presence of a base. Any base can be used as the base so far as it adversely affects the reaction. Preferred bases include sodium hydride, potassium carbonate, sodium hydroxide, potassium hydroxide and sodium carbonate. Any solvent can be used as a solvent used in the above reaction so far as it is inert to the reaction. Preferred solvents include N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethanol, ethanol and acetone. After completion of the reaction, the solvent is distilled off, and the residue is purified by any suitable means such as chromatography or recrystallization, whereby the benzoic acid derivative (la) can be isolated.

Reaction Scheme 2:

( lb) ( 1C)

wherein R¹, R², R⁵ and X have the same meaning as defined above.

Namely, a compound (lb) is hydrolyzed, thereby preparing a compound (lc) . This reaction is preferably carried out by using 1.03.0 moles of a base such as sodium hydroxide or potassium hydroxide per mole of the compound (lb) and stirring the resultant mixture at 20 to 100°C for several hours.

Any solvent can be used as a solvent used in the above reaction so far as it is inert to the reaction. Preferred solvents include N,N-dimethylformamide, dimethyl sulfoxide, ethanol, methanol, water, or mixtures thereof. After completion of the reaction, purification is conducted by any suitable means such as recrystallization or chromatography, whereby the compound (lc) is isolated. Reaction Scheme 3

(ld) (le)

wherein R⁹ means an C-.₆-alkanoyl group,

Y² is a halogen atom, and

R^:, R³ and X have the same meaning as defined above.

Namely, an acid anhydride or acid halide is reacted with a compound (Id) in the presence of a base, whereby a benzoic acid derivative (le) , which is an O-acylated product, can be prepared. In this reaction, any base can be used as the base so far as it adversely affects the reaction. Pyridine or triethylamine is preferred.

This reaction is preferably carried out by using 1.0- 3.0 moles of the acid anhydride or acid halide per mole of the compound (id) and stirring the resultant mixture at a temperature of generally 0 to 150°C, preferably 20 to 100°C for several hours. Any solvent can be used as a solvent used in this reaction so far as it is inert to the reaction. Preferred solvents include N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethanol, methanol and acetone. After completion of the reaction, the solvent is distilled off, and the residue is purified by a means such as chromatography or recrystallization, whereby the compound (_le) can be isolated. Reaction Scheme 4

(1C) (if)

wherein R¹, R², R⁶, R^" and X have the same meaning as defined above.

Namely, a compound (lc) is treated with an acid halide- for ing agent such as thionyl chloride, and the resultant acid halide is then reacted with an amine in the presence of a base, whereby a compound (If) can be prepared. The reaction of the compound (lc) with the acid halide-for ing agent is carried out, for example, by adding the acid halide-forming agent to the compound (lc) in a solvent such as tetrahydrofuran, diethyl ether, methylene chloride, N,N- dimethylformamide or dimethyl sulfoxide and stirring the resultant mixture at a temperature of 0 to 100°C. The reaction of the thus-obtained acid halide with the amine is carried out, for example, by stirring the reactants in the presence of a base such as sodium hydroxide, potassium hydroxide or sodium carbonate at a temperature of -20 to 100°C. The resultant benzoic acid derivatives (1) can be converted into salts in accordance with a method known per se in the art.

Since the thus-obtained benzoic acid derivatives (1) or the salts thereof have an effect of markedly stimulating collagen synthesis in human skin fibroblasts, and moreover possess an effect of smoothing or removing wrinkles, they can be used as agents for stimulating collagen synthesis and wrinkle-smoothing agents. The agents for stimulating collagen synthesis according to the present invention can be administered in either way of external application and internal use. External application is preferred. The wrinkle-smoothing agents are preferably administered in a manner of external application. In the agents for stimulating collagen synthesis and the wrinkle- smoothing agents according to the present invention, external skin care compositions as one of their manner of use can contain a base for external application and other medicinally- effective agents, which are routinely used, in addition to the benzoic acid derivative or the salt thereof.

As the base for external application used herein, any of an oily base, an oil/water or water/oil emulsion-type base and water can be used. No particular limitation is imposed on the oily bases. For example, plant oils, animal oils, synthetic oils, fatty acids, natural and synthetic glycerides, etc. can be mentioned. No specific limitation is imposed on the medicinally-effective agents. It is also possible to contain moisturizers, ultraviolet adsorbents, alcohols, chelating agents, pH adjustors, antiseptics, thickeners, coloring matters, perfume bases, plants extracts and the like in combination as needed.

No particular limitation is imposed on the medicinally- effective ingredients. For example, one or more of analgesic and antiphlogistic agents, disinfectants, astringents, emollients, hormones, vitamins and the like can be used suitably as needed.

Examples of the preparation form of these external skin care compositions include ointments, creams, milk lotions, liquid lotions, packs and foundations.

No particular limitation is imposed on the proportion of the benzoic acid derivative (1) or the salt thereof in the external skin care composition. In the case of the emulsion- type external skin care composition, however, its proportion can preferably be 0.001-10 wt.% (hereinafter indicated.merely by "%"), particularly 0.001-5% of the total weight of the composition. In the case of the oil-based external skin care composition containing a liquid hydrocarbon such as squalane as a base ingredient, its proportion can preferably be 0.001- 20%, particularly 0.01-10% of the total weight of the composition.

Having generally described this invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified.

EXAMPLES Synthesis Example 1;

A 100-ml flask equipped with a dropping funnel was charged with 2.00 g (14.6 mmol) of 4-hydroxy-benzamide, 2.42 g (17.5 mmol) of potassium carbonate and 15 ml of N,N- dimethylformamide. While stirring the contents at room temperature, 7.03 g (29.2 mmol) of farnesyl chloride were added dropwise over 10 minutes. After the addition, the resultant mixture was heated to 80°C and stirred for 3 hours. The mixture was poured into 300 ml of diluted hydrochloric acid, followed by extraction with ethyl acetate. The extract was washed with 100 ml of water and 200 ml of saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resultant crude product was purified by chromatography on silica gel, thereby obtaining 3.09 g (yield: 62%) of 4- ( (2E, 6E) -3 , 7, ll-trimethyl-2, 6, 10- dodecatrienyl)benzamide. The results of its analysis are described below. Form: Colorless solid. Melting point: 76.5-77.7°C. "H-NMR (CDC1_3/ ppm) :

1.60-1.75(m,12H) ,

2.00-2.16(m,8H) ,

4.59 (d,2H,J=6.5Hz) ,

4.98-5.22 (m,2H) ,

5.48 (t,lH,J=6.3Hz) , 5.79(brs,2H) , 6.94 (d,2H,J=8.8Hz) , 7.77(d,2H,J=8.8Hz) . IR (KBr, cm^"1) :

3404, 3176, 2924, 1648, 1620, 1426, 1398, 1254.

Synthesis Example 2:

1-Bromododecane, 12-bromododecanol and l-bromo-2- ethylhexane, were separately used in place of farnesyl chloride in Synthesis Example 1, thereby synthesizing 4-dodecyloxybenzamide, 4- (12-hydroxydodecyloxy) benzamide and 4- (2-ethylhexyloxy)benzamide, respectively. 4-Dodecyloxybenzamide: Form: Colorless solid. Melting point: 142.5-143.3°C. ^AH-NMR (CDC1₃, ppm) :

0.88(t,3H,J=6.4Hz) ,

1.18-1.94 (m,20H) ,

4.00(t,2H,J=6.5Hz) ,

5.83 (brs,2H) ,

6.92(d,2H,J=8.8Hz) ,

7.76(d,2H,J=8.8Hz) . IR (KBr, cm^"1):

3420, 3192, 2928, 2856, 1648, 1616, 1424, 1396, 1256. 4- (12-Hydroxydodecyloxy)benzamide: Form: Colorless solid. Melting point: 141.4-142.1°C. "H-NMR (CD_jOD, ppm) :

1.66-1.90(m,20H) ,

3.52 (t,2H,J=6.5HZ) ,

4.02 (t,2H,J=6.4Hz) ,

6.81(d,2H,J=8.9Hz) ,

7.82 (d,2H,J=8.9Hz) . IR (KBr, cm^"1) :

3436, 3316, 3204, 2924, 2856, 1648, 1620, 1424, 1400, 1256. ₄-(2-Ethylhexyloxy)benzamide: Form: Colorless solid. Melting point: 98.3-99.4°C. -NMR (CDC1₃, ppm):

0.80-1.05(m,6H) ,

1.18-1.90(m,7H) ,

3.89(d,2H,J=5.70Hz) ,

5.81(brs,2H) ,

6.94 (d,2H,J=8.7HZ) ,

7.77 (d,2H,J=8.7Hz) .

Test Example 1:

Effect of benzoic derivatives (1) on collagen synthesis in human dermal fibroblasts (Dulbecco's modified essential medium (hereinafter abbreviated as "DMEM")).

Fibroblasts were cultured to confluency in DMEM containing 5% FCS (fetal calf serum) . The medium was replaced with DMEM containing 0.5% FCS, to which each test compound was added to give a concentration of 1 μM to 10 μM, thereby incubating the culture at 37°C for 24 hours. Thereafter, tritium labeled proline (³H-proline) was added (5 μCi/ml of the medium) to further continue the incubation at 37°C, thereby incorporating 3H-proline into collagenous protein. After 24 hours, the medium was recovered to determine the amount of ³H-labeled collagen after purification (D. F. Webster and W. Harvey, Analytical Bioche . , 96., 220 (1979)). The results are shown in Table 1. As a result, it was revealed that the benzoic acid derivatives (1) markedly stimulate collagen synthesis in human dermal fibroblasts. Table 1

Test compound Concentration (μM) Rate of Synthesis of collagen (%)

Control 100

Compound 1 10 145

Compound 2 10 128

Compound 3 1 138

Compound 4 10 175

Compound 5 10 158

Compound 6 10 172

Compound 7 10 186

Compound 8 10 129

Compound 9 10 185

Compound 10 10 138

Compound 11 10 141

Compound 12 10 163

Compound 13 10 160

Compound 14 10 123

Compound 15 10 142

Compound 16 10 158

Compound 17 10 112

Compound 18 10 144

Compound 19 10 148

Compound 20 10 129

Compound 21 10 180 Compound 1 4-(3,7-dimethyl-6-octenyloxy)-2-hydroxy-benzoic acid

Compound 2: 4-{ (2E)-3,7-dimethyl-2,6-octadienyloxy}-

2-hydroxybenzoic acid

Compound 3: 2-hydroxy-4-{ (2E,6E)-3,7,ll-trimethyl-

2,6,10-dodecatrienyloxy}benzoic acid

Compound : 4-{ (2E,6E)-3,7, ll-trimethyl-2,6, 10-dodeca- trienyloxy)benzamide

Compound 5 4-dodecyloxybenzamide Compound 6 4-(12-hydroxydodecyloxy)benzamide Compound 7 4-{ (2E)-3,7-dimethyl-2,6-octadienyloxy)benzoic acid

Compound 8: 4-{ (2E)-3,7-dimethyl-2,6-octadienylamino}benzoic acid

Compound 9: 4-{ (2E,6E)-3,7,ll-trimethyl-2, 6,10-dodeca- trienylamino}-2-hydroxybenzoic acid

Compound 10: methyl 4-( (2E,6E)-3,7,ll-trimethyl-

2,6,10-dodecatrienylamino)-2-hydroxybenzoate

Compound 11: 4-( (2E)-3,7-dimethyl-2,6-octadienyloxy)-2- methoxybenzoic acid

Compound 12: N-(2-hydroxyethyl)-4-( (2E,6E)-3,7,11-trimethyl-

2,6,10-dodecatrienyloxy)-2-hydroxy enzamide

Compound 13: N,N-diethyl-4-( (2E,6E)-3,7,ll-trimethyl-2,6, 10- dodecatrienyloxy)-2-hydroxybenzamide

Compound 14: N,N-diethyl-4-( (2E,6E)-3,7,ll-trimethyl-2,6,10- dodecatrienyloxy)benzamide

Compound 15: N-(2-hydroxyethyl)-4-( (2E,6E)-3,7,11-trimethyl-

2,6,10-dodecatrienyloxy)benzamide

Compound 16: 4-( (9Z)-9-octadecenyloxy)benzamide Compound 17: 4-( ethylheptadecyloxy)benzamide Compound 18: 4-(methylheptadecyloxy)benzoic acid Compound 19: 2-hydroxy-4-(methylheptadecyloxy)benzoic acid Compound 20: 2-hydroxy-5-(methylheptadecyloxy)benzoic acid Compound 21: 4-(methylheptadecyla ino)benzoic acid. Test Example 2:

Effect of the benzoic acid derivatives (1) on wrinkles formed on hairless mice by UVB irradiation.

(a) Hairless mice (HR/ICR, 9 week age at the beginning of the experiment) were irradiated by UVB 3 times a week by using 6 Toshiba health light lamps, 20SE. The amount of energy was measured by means of a UV-Radio eter UVR-305/365D manufactured by TOKYO OPTICAL Co. The dose upon one irradiation was determined to be 1 MED or less, i.e., 65 mJ in an amount of energy of 0.28 mW/cm². The irradiation was continued for 20 weeks. After confirming the fact that the mice had got wrinkles at their backs, they were divided into groups each consisting of 8 mice. Ethanol solutions separately containing the benzoic acid derivatives (1) in a concentration of 0.005% were applied 5 times a week to their corresponding groups of mice for 6 weeks in a dose of 80 μl. As a control, ethanol alone was applied in a dose of 80 μl like the samples. After completion of the application, the degree of wrinkles was visually observed to rank the samples in accordance with the following standard (wrinkle index) (Table 2) .

Wrinkle index

1: Wrinkles were completely removed;

2: Wrinkles were scarcely observed;

3: Wrinkles were somewhat observed;

4: Wrinkles were observed to a great extent.

(b) In order to further analyze the particulars of wrinkles, upon elapsed time of 0 week (at the time each test compound was applied) and 6 weeks after the test compound was applied, skin replicas of the size of 1 cm² in diameter were gathered from 3 portions of the back in each of the mice using a Hydrophilic Exaflex hydrophilic vinylsilicone impression material. Each of these replicas was held horizontally and illuminated at an angle of 30 degrees from the horizontal direction, thereby finding the proportion of shadows of the wrinkles as an area percent (%) by means of an image analyzer. A rate of smoothing of wrinkles upon the elapsed time of 6 weeks after the application to that upon 0 week was then determined in accordance with the following equation.

Smoothing rate = f/

The results are shown in Table 2. As a result, it was found that the wrinkles formed on the backs of the hairless mice can be removed by applying the benzoic acid derivatives (1) thereto.

Table 2

Test compound Wrinkle index Smoothing rate (%)

Control 3.75 0

Compound 1 3.25 27.5

Compound 2 3.1 14.2

Compound 3 3 18.9

Compound 4 2.375 63.4

Compound 5 2.875 38.8

Compound 6 2.5 56.8

Compound 7 3.25 12.3

Compound 8 2.5 52.5

Compound 9 3.1 16.0

Compound 10 2.875 42.1

Compound 11 2.875 61.2

Compound 12 3.25 21.7

Compound 13 2.375 67.3

Compound 14 2.75 44.1

Compound 15 2.75 51.3

Compound 16 2.50 50.7

Compound 17 3.125 30.3

Compound 18 3.0 31.2

Compound 19 2.875 39.6

Compound 20 2.875 35.2

Compound 21 2.75 43.8 Preparation Example 1:

(wt.%)

(1) Compound 1 0.01

(2) Cholesterol 0.5

(3) Cholesteryl isostearate 1.0

(4) Polyether-modified silicone 1.5

(5) Cyclic silicone 20.0

(6) Methylphenylpolysiloxane 2.0

(7) Methylpolysiloxane 2.0

(8) Magnesium sulfate 0.5

(9) 55% Ethanol 5.0

(10) Carboxymethylchithin (Chithin Liquid 0.5 HV, product of Ichimaru Pharcos Co., Ltd.)

(11) Purified water Balance

Components (l)-(7) were heated to 80°C to melt them, and the components (8) -(11) were added to the melt. The resultant mixture was intimately mixed to prepare a W/0 type cream.

Preparation Example 2 :

(wt.%)

(1) Polyoxyethylene (10) hardened castor oil l.o

(2) Sorbitan monostearate 0.5

(3) Sodium stearoylmethyltaurine 0.5

(4) Cetostearyl alcohol 2.0

(5) Stearic acid 1.8

(6) Compound 2 0. l

(7) Cholesterol 1.5

(8) Cholesteryl isostearate 1.₀

(9) Neopentyl glycol dicaprate 8.0

(10) Methylpolysiloxane 5.0

(11) Glycerol 5.0

( 12 ) Purif ied water Balance Components (1)-(10) were heated to 80°C to melt them, and the components (11) -(12) were added to the melt. The resultant mixture was intimately mixed to prepare an O/W type cream.

Preparation Example 3:

(wt.%)

(1) Compound 3 0.2

(2) Silicon-coated zinc oxide 7.0

(3) 2-Ethylhexyl p-methoxycinnamate 3.0

(4) Cholesteryl isostearate 1.0

(5) Polyether-modified silicone 2.0

(6) Methylpolysiloxane 5.0

(7) Cyclic silicone 15.0

(8) Magnesium sulfate 1.0

(9) Glycerol 5.0

(10) Purified water Balance

Components (l)-(7) were heated to 80°C to melt them, and the components (8) -(10) were added to the melt. The resultant mixture was intimately mixed to prepare a cream.

Preparation Example 4 :

(wt.%)

(1) Compound 4 0.05

(2) White petrolatum Balance

(3) Cholesteryl isostearate 3.0

(4) Liquid paraffin 10. o

(5) Glyceryl ether 1.0

(6) Glycerol 10.0 Components (l)-(6) were heated to 80°C to melt them, and then cooled, thereby preparing an ointment.

Preparation Example 5:

(wt.%)

(1) Compound 5 1.0

(2) Polyvinyl alcohol 15.0

(3) Sodium carboxymethylcellulose 5.0

(4) Propylene glycol 3.0

(5) Ethanol 8.0

(6) Purified water 67.5

(7) Perfume base 0.5

(8) Antiseptic, oxidizing agent q.s.

Components (l)-(8) were heated to 70°C to melt them, and then cooled, thereby preparing a wrinkle-smoothing agent of the pack type.

Preparation Example 6

(wt.%)

(1) 1,3-Butylene glycol 8.0

(2) Glycerol 4.0

(3) Sodium hyaluronate 1.0

(4) Ethanol 3.0

(5) Polyoxyethylene polyoxypropylene 0.3 decyl tetradecyl ether

(6) Compound 6 0.05

(7) Purified water Balance

(8) Antiseptic q.s.

(7) Perfume base q.s.

Components (l)-(8) were stirred into a dispersion, and 60% of purified water was then added to the dispersion, thereby providing a mixture A. On the other hand, components (4) , (5) , (6), (8) and (9) were stirred into a solution, and the remaining purified water was then added to the solution, thereby providing a mixture B. The mixture B was added to the mixture A while stirring the mixture A, and the resultant mixture was stirred to prepare a wrinkle-smoothing agent of the lotion type.

Preparation Example 7:

(wt.%)

( 1 ) 1,3-Butylene glycol 8.0

( 2 ) Glycerol 4.0

( 3 ) Xanthan gum 0.3

( 4 ) Sodium chondroitin sulfate 0.1

( 5 ) Sodium hyaluronate 0.05

( 6 ) Ethanol 3.0

( 7 ) Polyoxyethylene polyoxypropylene 0.3 decyl tetradecyl ether

( 8 ) Compound 7 0.2

( 9 ) Purified water Balance

( 10 ) Antiseptic q.s.

( 11 ) Perfume base q.s.

Components (l)-(5) were stirred into a dispersion, and 65% of purified water was then added to the dispersion, thereby providing a mixture A. On the other hand, components (6) , (7) , (8) , (10) and (11) were stirred into a solution, and the remaining purified water was then added to the solution, thereby providing a mixture B. The mixture B was added to the mixture A while stirring the mixture A, and the resultant mixture was stirred to prepare a wrinkle-smoothing agent of the liquid lotion (beauty wash) type.

INDUSTRIAL APPLICABILITY

The benzoic acid derivatives (1) or the salts thereof stimulate collagen synthesis in human dermal fibroblasts and consequently smooth or remove wrinkles caused by aging and/or photoaging. Having now fully described the invention, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the invention as set forth herein.

Claims

CAL I MS

1. A method of smoothing or removing wrinkles, which comprises administering an effective amount of a benzoic acid derivative of the formula (1) or a salt thereof:

wherein X is -O- or -N(R⁴)-, in which R⁴ is a hydrogen atom or a C-_^-.-alkyl, C₂__n-alkenyl, C-^.-alkanoyl or C_:._:1-alkoxycarbonyl group,

R¹ is an C₄.₂₅-alkyl or C₄._2E-alkenyl group, which can be substituted by a hydroxyl group, which can contain a heteroatom in a carbon chain or which can be substituted with a heteroatom,

R² is a hydrogen atom, a hydroxyl group, an C-^-alkoxyl group or an

group, and

R³ is -OR⁵ or -N(R⁶)R⁷, in which R⁵ is a hydrogen atom or an C.._2E-alkyl or C₂_₂₅-alkenyl group, which can contain a heteroatom in a carbon chain or which can be substituted with a heteroatom, and

R^£ and R⁷ are, independently, a hydrogen atom or C^-alkyl or C₂.₃-alkenyl group, which can be substituted by a hydroxyl group.

2. The method according to Claim l, wherein

X is -0- or -NH-,

R^: is the C₄._2E-alkyl or C₄.₂₅-alkenyl group, which can be substituted by a hydroxyl group,

R² is a hydrogen atom, a hydroxyl group, a C.._£-alkoxyl group or a C.._e-alkanoyloxy group, R^£ is a hydrogen atom or a C_:._2E-alkyl or C-_₂₅-alkenyl group,

R⁶ is a hydrogen atom, and

R⁷ is a hydrogen atom or a C₂.₃-alkyl or C₂_₃-alkenyl group, which can be substituted by a hydroxyl group.

3. A method of stimulating collagen synthesis in the skin, which comprises administering an effective amount of the benzoic acid derivative or salt thereof according to Claim 1.

4. The method of stimulating collagen synthesis according to Claim 3, wherein

X is -0- or -NH-,

R¹ is the C_<__2E-alkyl or C₄.₂₅-alkenyl group, which can be substituted by a hydroxyl group,

R² is a hydrogen atom, a hydroxyl group, a C-^-alkoxyl group or a C-^-alkanoyloxy group,

R⁵ is a hydrogen atom or a C₁.₂₅-alkyl or C₂_₂₅-alkenyl group,

R⁶ is a hydrogen atom, and

R⁷ is a hydrogen atom or a C-^-alkyl or C₂.₃-alkenyl group, which can be substituted by a hydroxyl group.

5. Use of the benzoic acid derivative or the salt thereof according to Claim 1 for an agent for smoothing or removing wrinkles.

6. The use according to Claim 5, wherein X is -0- or -NH-,

R¹ is the C._₂_-alkyl or C_<._2E-alkenyl group, which can be substituted by a hydroxyl group,

R² is a hydrogen atom, a hydroxyl group, a C_:._£-alkoxyl group or a C..₆-alkanoyloxy group,

R⁵ is a hydrogen atom or a C..₂c-alkyl or C₂.₂₅-alkenyl group,

R^€ is a hydrogen atom, and R⁷ is a hydrogen atom or a C-^-alkyl or C₂_₃-alkenyl group, which can be substituted by a hydroxyl group.

7. Use of the benzoic acid derivative or salt thereof according to Claim 1 for an agent for stimulating collagen synthesis in the skin.

8. The use according to Claim 7, wherein X is -0- or -NH-,

R- is the C_<__2E-alkyl or C_«._2E-alkenyl group, which can be substituted by a hydroxyl group,

R² is a hydrogen atom, a hydroxyl group, a C.._£-alkoxyl group or a C.._e-alkanoyloxy group,

R⁵ is a hydrogen atom or a C.._2Ξ-alkyl or C₂_₂₅-alkenyl group,

R⁶ is a hydrogen atom, and

9. A benzoic acid amide derivative of the formula (lα) or a salt thereof:

wherein ^~R^la is a C₈.₂₄-hydroxyalkyl group or a 3,7, ll-trimethyl- 2,6, 10-dodecatrienyl group, and

R^6D and R^7Q are, independently, a hydrogen atom or a C._₃- alkyl group, which can be substituted by a hydroxyl group.

10. Use of the benzoic acid amide derivative or salt thereof according to Claim 9 for an external skin care preparation.

11. An external skin care composition comprising the benzoic acid amide derivative or salt thereof according to Claim 9.