# Patent

## Title
Hydroxamic acid derivatives and the method for preparing thereof

## Abstract

The present invention provides hydroxamic acid derivatives which have anti-aging efficacy and a method for preparation thereof. It is further provided skin-care external compositions for preventing skin aging, containing the hydroxamic acid derivatives represented by the formula (I) as an active ingredient.

## Background
FIELD OF THE INVENTION
The present invention relates to hydroxamic acid derivatives represented by the following formula (I), having anti-aging efficacy and to a method for the preparation thereof:




wherein,

    R1 is






herein, R5 and R6 each independently represents a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms or a cyclic alkyl group having from 3 to 6 carbon atoms;

    R2 is CONH, NHCO, CONR7 or NR7CO, herein, R7 represents an alkyl group having from 1 to 10 carbon atoms;
    R3 is —(CH)n—, herein, n=0 or 1; and
    R4 is a hydrogen atom or an alkyl group having from 1 to 10 carbon atoms.


BACKGROUND OF THE INVENTION
The skin of all living things grows aged as it grows older. In order to delay this skin aging, many efforts have been made extensively. As a result, the questions on the essence and cause of the aging have always been raised. Skin aging is classified into two kinds depending on its cause. The first is intrinsic aging that the structure of and the physiological function of the skin decline successively as aging goes on. And, the second is extrinsic aging that is caused by accumulated stress such as UV radiation. Particularly, UV radiation is well-known cause of aging. In case of the skin exposed to UV radiation for a long time, stratum corneum of the skin becomes thicker and collagen and elastin, which are main components of the skin, get denatured so that skin loses its elasticity. Thus, skin aging is accompanied by several functional and structural changes.
As structural changes caused by skin aging, epidermis, dermis and hypoderm of the skin become thinner. And, dermal ECM (extracelluar matrix), which is in charge of skin elasticity and elongation, is experienced with its component's change. ECM is composed of two components, i.e. elastic fiber which amounts to 2 ̃4% of total ECM and collagen which amounts to 70 ̃80%. As skin aging goes on, the skin loses elasticity due to the reduction of collagen and elastin. These reductions are caused by several factors in biosynthesis. For example, matrix metallo proteases, such as collagenase and elastase, are expressed to decompose collagen and elastin, and the collagen content within the skin is reduced. The reduction of collagen and elastin within the dermis leads the epidermis to be rough and to lose elasticity. That is, the skin becomes aged.
In order to suppress the reductions of collagen and elastin, which are a cause of the skin elasticity reduction, some materials have been developed and used. Specially, retinoid such as retinol and retinoic acid has been known to be very effective in lessening skin wrinkles and improving skin elasticity (Dermatology therapy, 1998, 16, 357 ̃364). In spite of its anti-wrinkle efficacy and elasticity-improving efficacy, retinoid has some drawbacks that only a small quantity of application causes irritation to the skin and is easily oxidized in an air due to its instability, thus there are lots of limitation in using it. In order to stabilize retinoid, many studies have been conducted. However, the irritation of retinoid onto the skin, that is troubles in safety onto the skin, remains unsolved.
Retinoid includes retinol, retinoic acid or its derivatives. It exhibits various biological activities. With regard to the skin, the efficacy on abnormal keratinization or on pimple was reported. And, with regard to the skin wrinkles, it has been known that it can promote collagen biosynthesis and inhibit the activity of collagenase, i.e. an enzyme for decomposing collagen (The Journal of Investigative Dermatology, 1991, 96, 975 ̃978). In addition, retinoid can inhibit the expression of elastase, with regard to the elasticity-reduction.
Up to now, retinoid has been developed as follows:
In the first stage, simple derivatives of retinol or retinoic acid were developed. As a derivative, retinyl palmitate may be exemplified. In the next, retinoid derivative including benzoic acid was developed. This derivative is named as arotinoid (J. Med. Chem, 1988, 31, 2182 ̃2192). Recently, compounds including heteroatom introduced into the benzene ring of arotinoid, called as heteroarotinoid, have been developed (J. Med. Chem., 1999, 42, 4434 ̃4445).
Retinoid was reported to exhibit biological efficacy on the skin by interacting with the intercellullar receptor called as retinoic acid receptor (British Journal of dermatology, 1999, 140, 12 ̃17). The structural feature of retinoid is based on tetramethyl cyclohexane, unsaturated carbon bond and carboxylic acid. Specially, carboxylic acid moiety is essential in the action of retionids and can be easily converted into an anion when interacting with the receptor (Chem. Pharm. Bull, 2001, 49, 501 ̃503).
Arotinoid includes benzoic acid substituted for carboxylic acid moiety of retinoic acid. Benzoic acid moiety can be easily ionized to act as an anion. Recent studies have synthesized derivatives including various substituents for carboxylic acid moiety. These substituent-conversions are in order to maintain original efficacy of retinoid and to lessen toxicity or irritation and instability thereof. For the purpose, many studies have been conducted.
SUMMARY OF THE INVENTION
Under these circumstances, the present inventors have conducted many studies in order to lessen skin irritation of retinoid and to provide a solution for instability in external formulations for skin care. As a result, we synthesized a novel type of retinoid, i.e. hydroxamic acid derivatives. Furthermore, we found that these hydroxamic acid derivatives had good safety to the skin and improved stability in the formulations, without skin irritation and discoloration and odorizing, caused by the conventional retinal or retinoic acid. Based on these findings, the present invention has been completed.
Therefore, an object of the invention is to provide novel hydroxamic acid derivatives, which function as a retinoid to promote collagen biosynthesis and to inhibit the expression of collagenase, i.e. an enzyme for decomposing collagen and the expression of elastase, i.e. an enzyme for decomposing elastin, and to provide a method for preparing the same.
Hydroxamic acid has been widely known as a metal chelator. Judging from the structural feature of hydroxamic acid, hydroxy group of hydroxylamine adjacent to carbonyl group forms chelation with metal cation.
In additional feature, hydroxy group of hydroxylamine can be easily converted into an anion, to be used in similar to carboxylic acid. The present inventors utilized these structural features of hydroxamic acid to synthesize a novel retinoid and found that it functioned as an agonist to retinoic acid receptor. Such a compound having the stucture of hydroxamic acid and functioning as a retinoid has not been reported yet.




wherein,

    R1 is






herein, R5 and R6 each independently represents a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms or a cyclic alkyl group having from 3 to 6 carbon atoms;

    R2 is CONH, NHCO, CONR7 or NR7CO, herein, R7 represents a C1-C10 alkyl group;
    R3 is —(CH2)n—, herein, n=0 or 1; and
    R4 is a hydrogen atom or an alkyl group having from 1 to 10 carbon atoms.


The novel type of retinoid in the present invention, hydroxamic acid derivatives may be prepared by either of two methods exemplified below.
In detail, the method for preparing said hydroxamic acid derivatives represented by said formula (I) may comprise the steps of:

    (1) Reacting benzoic acid or adamantanecarboxylic acid with methyl 4-aminobenzoate or 4-aminophenylacetic acid methylester, to form an amide bond; or reacting aniline or adamantamine wih monomethylterephthalate, to form an amide bond;
    (2) Substituting an alkyl group for amide bond of benzamide formed in said step;
    (3) Hydrolyzing the ester bond of benzamide or alkyl-substituted benzamide formed in said steps; and
    (4) Converting the acid formed by said hydrolysis to a hydroxamic acid.


Specially, in the last step of producing a hydroxamic acid derivative, one-step processing without protective/deprotective reactions is used to increase efficiency.


DETAILED DESCRIPTION OF THE INVENTION
The following is a detailed description of the present invention.
The present hydroxamic acid derivative, as a novel retinoid, may be prepared by either of two methods exemplified below.
The first method 1 may comprise the steps of:

    (a) Reacting benzoic acid or adamantanecarboxylic acid with methyl 4-aminobenzoate or 4-aminophenylacetic acid methylester, to produce a benzamide compound;
    (b) Substituting an alkyl group for amide bond of benzamide formed in said step;
    (c) Hydrolyzing methylester of benzamide or alkyl-substituted benzamide compounds formed in said steps, to produce an acid; and
    (d) Reacting said acid with hydroxylamine hydrochloride or N-methyl hydroxylamine hydrochloride, to produce a hydroxamic acid derivative.


Said method of the present invention will be described in more detail by the following reaction scheme. Firstly, said method 1 may be exemplified by the following reaction scheme 1:




wherein, R5 and R6 each independently represents a hydrogen atom, a C1-C10 alkyl group or C3-C6 cyclic alkyl group; R2 is CONH, NHCO, CONR7 or NR7CO, herein, R7 represents a C1-C10 alkyl group; R3 is —(CH2)n—, herein, n=0 or 1; and R4 is a hydrogen atom or a C1-C10 alkyl group.

In the first place, benzoic acid or adamantanecarboxylic acid may be converted to an anhydride by employing ethyl chloroformate in an equivalent ratio of 1.2. A solvent employed herein may be pyridine, N-methylmorpholine and the like. Then, the anhydride may be reacted with methyl 4-aminobenzoate or 4-aminophenylacetic acid methylester, to produce a benzamide compound. A solvent employed in this reaction may be pyridine, N-methylmorpholine and the like. Additionally, in a solvent such as N,N-dimethylformamide, methylene chloride, chloroform and the like, the reaction may be performed by further employing trimethylamine, in an equivalent ratio of 1.2 to methyl 4-aminobenzoate or 4-aminophenylacetic acid methylester. Most preferably, it may be pyridine. Further, the reaction may be preferably performed at a temperature of 10 ̃20° C. At a lower temperature than this, methyl 4-aminobenzoate or 4-aminophenylacetic acid methylester may remain unreacted and it is difficult to withdraw it from the product. While, at a higher temperature than 20° C., the anhydride may be hydrolyzed, resulting in the decrease of the yield of the product.
Benzamide compound formed herein may be reacted with an alkyl halide in a solvent of N,N-dimethylformamide, to produce a benzamide compound with an alkyl group substituted for amide bond thereof. Herein, as a base, sodium hydride may be employed in an equivalent ratio of 1.2 to benzamide. Also, alkyl halide may be employed in an equivalent ratio of 1.2 to benzamide. As an alkyl halide, it may include bromomethane, bromoethane, bromopropane, bromo-isopropane, bromobutane, bromo-tert-butane and the like.
Subsequently, methylester of benzamide with or without alkyl group substituted to amide bond may be hydrolyzed to an acid. Then, the acid formed may be converted to an anhydride by employing ethyl chloroformate. Herein, ethyl chloroformate may be employed in an equivalent ratio of 1.2 to the acid. A solvent employed herein may be pyridine, N-methylmorpholine and the like.
Then, the anhydride formed in said step may be reacted with hydroxylamine hydrochloride or N-methyl hydroxylamine hydrochloride, to produce a hydroxamic acid compound. A solvent employed in this reaction may be pyridine, N-methylmorpholine and the like. Additionally, in a solvent such as N,N-dimethylformamide, methylene chloride, chloroform and the like, the reaction may be performed by further employing triethylamine, in an equivalent ratio of 1.2 to hydroxylamine hydrochloride. Most preferably, it may be pyridine. Further, the reaction may be preferably performed at a temperature of 0 ̃10° C. At a lower temperature than this, hydroxylamine hydrochloride or N-methyl hydroxylamine hydrochloride may remain unreacted, resulting in the decrease of the yield of the product. While, at a higher temperature than this, by-products reacting with hydroxyl group of hydroxylamine or N-methyl hydroxylamine may be produced and it is difficult to withdraw it from the product.
The other method 2 for preparing the present hydroxamic acid derivative may comprise the steps of:

    (a) Reacting aniline or adamantamine with monomethylterephthalate, to produce a benzamide compound;
    (b) Substituting an alkyl group for amide bond of benzamide formed in said step;
    (c) Hydrolyzing methylester of benzamide or alkyl-substituted benzamide compounds formed in said steps, to produce an acid; and
    (d) Reacting said acid with hydroxylamine hydrochloride or N-methyl hydroxylamine hydrochloride, to produce a hydroxamic acid derivative and may be exemplified by the following reaction scheme 2:






wherein, R5 and R6 each independently represents a hydrogen atom, a C1-C10 alkyl group or C3-C6 cyclic alkyl group; R2 is CONH, NHCO, CONR7 or NR7CO, herein, R7 represents a C1-C10 alkyl group; R3 is —(CH2)n—, herein, n=0 or 1; and R4 is a hydrogen atom or a C1-C10 alkyl group.

As shown in the reaction scheme 2, firstly, monomethylterephthalate may be converted to an anhydride by employing ethyl chloroformate. Then, the anhydride may be reacted with aniline or adamantamine, to produce a benzamide compound. The next reactions may be performed by the same procedure described in the reaction scheme 1.
Hydroxamic acid derivatives of the formula (I) obtained in said methods may include, but not limited hereto,

    1. N-[4-(N-hydroxycarbamoyl)phenyl]benzamide,
    2. N-[4-(N-hydroxycarbamoyl)phenyl][4-methylphenyl]carboxyamide,
    3. N-[4-(N-hydroxycarbamoyl)phenyl][3-methylphenyl]carboxyamide,
    4. N-[4-(N-hydroxycarbamoyl)phenyl][4-ethylphenyl]carboxyamide,
    5. N-[4-(N-hydroxycarbamoyl)phenyl][4-propylphenyl]carboxyamide,
    6. N-[4-(N-hydroxycarbamoyl)phenyl][4-isopropylphenyl]carboxyamide,
    7. N-[4-(N-hydroxycarbamoyl)phenyl][4-butylphenyl]carboxyamide,
    8. N-[4-(N-hydroxycarbamoyl)phenyl][4-tert-butylphenyl]carboxyamide,
    9. N-[4-(N-hydroxycarbamoyl)phenyl][3,4-dimethylphenyl]carboxyamide,
    10. N-[4-(N-hydroxycarbamoyl)phenyl]adamantyl carboxyamide,
    11. adamantyl-N-[4-(N-hydroxy-N-methylcarbamoyl)phenyl]carboxyamide,
    12. N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-benzamide,
    13. N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-methylphenyl]carboxyamide,
    14. N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[3-methylphenyl]carboxyamide,
    15. N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-ethylphenyl]carboxyamide,
    16. N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-propylphenyl]carboxyamide,
    17. N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-isopropylphenyl]carboxyamide,
    18. N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-butylphenyl]carboxyamide,
    19. N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-tert-butylphenyl]carboxyamide,
    20. N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[3,4-dimethylphenyl]carboxyamide,
    21. N-[4-(N-hydroxycarbamoyl)phenyl]adamantyl-N-methylcarboxyamide,
    22. adamantyl-N-[4-(N-hydroxy-N-methylcarbamoyl)phenyl]-N-methylcarboxyamide,
    23. N-[4-(N-hydroxycarbamoylmethyl)phenyl]benzamide,
    24. N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-methylphenyl]carboxyamide,
    25. N-[4-(N-hydroxycarbamoylmethyl)phenyl][3-methylphenyl]carboxyamide,
    26. N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-ethylphenyl]carboxyamide,
    27. N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-propylphenyl]carboxyamide,
    28. N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-isopropylphenyl]carboxyamide,
    29. N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-butylphenyl]carboxyamide,
    30. N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-tert-butylphenyl]carboxyamide,
    31. N-[4-(N-hydroxycarbamoylmethyl)phenyl][3,4-dimethylphenyl]carboxyamide,
    32. N-[4-(N-hydroxycarbamoylmethyl)phenyl]adamantyl carboxyamide,
    33. 2-[4-(adamantylcarbonylamino)phenyl]-N-hydroxy-N-methylacetamide,
    34. [4-(N-hydroxycarbamoyl)phenyl]-N-benzamide,
    35. [4-(N-hydroxycarbamoyl)phenyl]-N-[4-methylphenyl]carboxyamide,
    36. [4-(N-hydroxycarbamoyl)phenyl]-N-[3-methylphenyl]carboxyamide,
    37. [4-(N-hydroxycarbamoyl)phenyl]-N-[4-ethylphenyl]carboxyamide,
    38. [4-(N-hydroxycarbamoyl)phenyl]-N-[4-propylphenyl]carboxyamide,
    39. [4-(N-hydroxycarbamoyl)phenyl]-N-[4-isopropylphenyl]carboxyamide,
    40. [4-(N-hydroxycarbamoyl)phenyl]-N-[4-butylphenyl]carboxyamide,
    41. [4-(N-hydroxycarbamoyl)phenyl]-N-[4-tert-butylphenyl]carboxyamide,
    42. [4-(N-hydroxycarbamoyl)phenyl]-N-[3,4-dimethylphenyl]carboxyamide,
    43. [4-(N-hydroxycarbamoyl)phenyl]-N-adamantyl carboxyamide,
    44. N-adamantyl[4-(N-hydroxy-N-methylcarbamoyl)phenyl]carboxyamide,
    45. [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-benzamide,
    46. [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-methylphenyl]carboxyamide,
    47. [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[3-methylphenyl]carboxyamide,
    48. [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-ethylphenyl]carboxyamide,
    49. [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-propylphenyl]carboxyamide,
    50. [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-isopropylphenyl]carboxyamide,
    51. [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-butylphenyl]carboxyamide,
    52. [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-tert-butylphenyl]carboxyamide,
    53. [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[3,4-dimethylphenyl]carboxyamide,
    54. [4-(N-hydroxycarbamoyl)phenyl]-N-adamantyl-N-methylcarboxyamide, and
    55. N-adamantyl [4-(N-hydroxy-N-methylcarbamoyl)phenyl]-N-methylcarboxyamide.


Hydroxamic acid derivatives of the formula (I) obtained in said methods is a retinoid and function as an agonist to retinoic acid receptor and, based on retinoid's efficacy, can promote collagen biosynthesis and inhibit the expressions of collagenase, i.e. an enzyme for decomposing collagen and of elastase, i.e. an enzyme for decomposing elastin. Therefore, hydroxamic acid derivatives of the formula (I) provided by the present invention may be incorporated into medicines or external applications for improving skin elasticity.
PREFERRED EMBODIMENT OF THE INVENTION
The methods for preparing hydroxamic acid derivatives according to the present invention will be described in more detail by way of the following examples. However, these examples are provided for the purpose of illustration only and should not be construed as limiting the scope of the invention, which will be apparent to one skilled in the art.
EXAMPLE 1
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl]benzamide
20.0 g (0.16 mol) of benzoic acid was dissolved in 250 ml of pyridine and then was cooled in a ice bath of 10° C. Thereto, 23.1 g (0.21 mol) of ethyl chloroformate was added dropwise for 30 minutes. The mixture was stirred at room temperature for 2 hours and then filtered to remove salts, to give an anhydride (30.2 g, 0.15 mol). 24.1 G (0.16 mol) of metyl aminobenzoate was dissolved in 250 ml of pyridine and then was cooled in a ice bath of 10° C. Thereto, the anhydride formed in the previous step was added dropwise for 30 minutes. The mixture was stirred for another 2 hours. After distillation of the solvent, the residue was dissolved in 300 ml of ethyl acetate. The ethyl acetate solution was washed with 5% hydrochloric acid and with distilled water, dried over magnesium sulfate, decolorized with active charcoal, and then filtered. The filtrate was dried under reduced pressure, to give methyl 4-(phenylcarbonylamino) benzoate (34.7 g, 85% yield) as a pale yellow solid.
Subsequently, 34.7 g of methyl 4-(phenylcarbonylamino)benzoate was dissolved in 500 mg of methanol and thereto 50 mg of 10% KOH was added. After stirring for 3 hours, the mixture was neutralized with hydrochloric acid and then filtered, to give an acid compound, 4-(phenylcarbonylamino) benzoic acid (26.2 g, 80% yield).
4-(phenylcarbonylamino) benzoic acid formed (24.1 g, 0.10 mol) was dissolved in 200 ml of pyridine and then was cooled in a ice bath of 10° C. Thereto, 22.9 g (0.13 mol) of ethyl chloroformate was added dropwise for 30 minutes. The mixture was stirred at room temperature for 2 hours and then filtered to remove salts, to give an anhydride (38.7 g, 0.12 mol).
6.9 g (0.10 mol) of hydroxylamine hydrochloride was dissolved in 100 ml of pyridine and then was cooled in a ice bath of 10° C. Thereto, the anhydride formed in the previous step was added dropwise for 30 minutes. The mixture was stirred for another 2 hours. After distillation of the solvent, the residue was dissolved in 300 ml of ethyl acetate. The ethyl acetate solution was washed with 5% hydrochloric acid and with distilled water, dried over magnesium sulfate, decolorized with active charcoal, and then filtered. The filtrate was dried under reduced pressure, to give a final product, N-[4-(N-hydroxycarbamoyl)phenyl]benzamide (16.6 g, 65% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.53
1H-NMR(DMSO-d6): δ11.23(s, 1H), 10.39(s, 1H), 9.04(s, 1H), 8.01(m, 5H), 7.64(m, 4H).
EXAMPLE 2
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl][4-methylphenyl]carboxyamide
Except that 4-methylbenzoic acid was used instead of benzoic acid, the same procedure described in Example 1 was performed to give the title compound (11.9 g, 44% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.41(s, 1H), 9.07(s, 1H), 7.94(m, 4H), 7.80(d, 2H, J=7.8Hz), 7.49(d, 2H, J=7.8 Hz), 2.33(s, 3H).
EXAMPLE 3
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl][3-methylphenyl]carboxyamide
Except that 3-methylbenzoic acid was used instead of benzoic acid, the same procedure described in Example 1 was performed to give the title compound (11.2 g, 43% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.50
1H-NMR(DMSO-d6): δ11.21(s, 1H), 10.39(s, 1H), 9.05(s, 1H), 7.90(m, 6H), 7.23(m, 2H), 2.40(s, 3H).
EXAMPLE 4
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl][4-ethylphenyl]carboxyamide
Except that 4-ethylbenzoic acid was used instead of benzoic acid, the same procedure described in Example 1 was performed to give the title compound (11.4 g, 39% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:4); Rf=0.54
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.43(s, 1H), 9.05(s, 1H), 7.91(m, 4H), 7.81(d, 2H, J=7.8 Hz), 7.50(d, 2H, J=7.8 Hz), 2.51(m, 2H), 1.19(m, 3H).
EXAMPLE 5
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl][4-propylphenyl]carboxyamide
Except that 4-propylbenzoic acid was used instead of benzoic acid, the same procedure described in Example 1 was performed to give the title compound (12.5 g, 42% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.55
1H-NMR(DMSO-d6): δ11.23(s, 1H), 10.40(s, 1H), 9.03(s, 1H), 7.92(m, 4H), 7.83(d, 1H, J=7.8 Hz), 7.48(d, 1H, J=7.8 Hz), 2.60(m, 2H), 1.51(m, 2H), 0.95(m, 3H).
EXAMPLE 6
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl][4-isopropylphenyl]carboxyamide
Except that 4-isopropylbenzoic acid was used instead of benzoic acid, the same procedure described in Example 1 was performed to give the title compound (14.3 g, 48% yield) as a pale yellow solid.
TLC(in ethyl acetate:hexane=1:1); Rf=0.50
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.41(s, 1H), 9.07(s, 1H), 7.94(m, 4H), 7.80(d, 2H, J=7.8 Hz), 7.49(d, 2H, J=7.8 Hz), 2.80(m, 1H), 1.30(d, 6H, J=6.9 Hz).
EXAMPLE 7
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl][4-butylphenyl]carboxyamide
Except that 4-butylbenzoic acid was used instead of benzoic acid, the same procedure described in Example 1 was performed to give the title compound (12.8 g, 41% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.53
1H-NMR(DMSO-d6): 11.20(s, 1H), 10.42(s, 1H), 9.06(s, 1H), 7.94(m, 4H), 7.80(d, 2H, J=7.8 Hz), 7.49(d, 2H, J=7.8 Hz), 2.60(m, 2H), 1.60(m, 2H), 1.41(m, 2H), 0.95(m, 3H).
EXAMPLE 8
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl][4-tert-butylphenyl]carboxyamide
Except that 4-tert-butylbenzoic acid was used instead of benzoic acid, the same procedure described in Example 1 was performed to give the title compound (11.8 g, 46% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): 11.20(s, 1H), 10.41(s, 1H), 9.07(s, 1H), 7.92(m, 4H), 7.81(d, 2H, J=7.8 Hz), 7.51(d, 2H, J=7.8 Hz), 1.25(s, 9H).
EXAMPLE 9
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl][3,4-dimethylphenyl]carboxyamide
Except that 3,4-dimethylbenzoic acid was used instead of benzoic acid, the same procedure described in Example 1 was performed to give the title compound (11.9 g, 44% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.53
1H-NMR(DMSO-d6): δ11.23(s, 1H), 10.40(s, 1H), 9.05(s, 1H), 7.93(m, 3H), 7.80(d, 2H, J=7.8 Hz), 7.50(d, 2H, J=7.8 Hz), 2.47(s, 3H), 2.45(s, 3H).
EXAMPLE 10
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl]adamantyl carboxyamide
Except that adamatanecarboxylic acid was used instead of benzoic acid, the same procedure described in Example 1 was performed to give the title compound (16.6 g, 65% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.53
1H-NMR(DMSO-d6): δ11.22(s, 1H), 9.24(s, 1H), 8.87(s, 1H), 7.76(m, 4H), 1.96(m, 3H), 1.85(m, 6H), 1.64(m, 6H).
EXAMPLE 11
Preparation of adamantyl-N-[4-(N-hydroxy-N-methylcarbamoyl)phenyl]carboxyamide
Except that N-methyl hydroxylamine hydrochloride was used instead of hydroxylamine hydrochloride, the same procedure described in Example 10 was performed to give the title compound (11.2 g, 43% yield) as apale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.50
1H-NMR(DMSO-d6): δ9.98(s, 1H), 9.12(s, 1H), 7.55(m, 4H), 3.09(s, 3H), 1.94(m, 3H), 1.87(m, 6H), 1.62(m, 6H).
EXAMPLE 12
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-benzamide
Methyl 4-(phenylcarbonylamino)benzoate (34.7 g, 0.16 mol) obtained in the intermediate step of Example 1 was dissolved in 250 ml of N,N-dimethylformamide and then was cooled in a ice bath of 10° C. Thereto sodium hydride (20.7 g, 0.16 mol) in 50 ml of N,N-dimethylformamide was added dropwise. Subsequently, bromomethane (32 g, 0.16 mol) was added dropwise to this mixture and further stirred for 1 hour. After stirring for another 2 hours, the mixture was distilled to remove the solvent and then the residue was dissolved in 300 ml of ethyl acetate. The ethyl acetate solution was washed with 5% hydrochloric acid and with distilled water, dried over magnesium sulfate, decolorized with active charcoal, and then filtered. The filtrate was dried under reduced pressure, to give methyl 4-(phenylcarbonylamino)-N-methyl-benzoate (33.5 g, 85% yield) as a pale yellow solid.
The subsequent procedures were the same as described in Example 1, to give the title compound (12.8 g, 38% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.52
1H-NMR(DMSO-d6): δ11.23(s, 1H), 10.39(s, 1H), 9.04(s, 1H), 8.01(m, 5H), 7.64(m, 4H), 3.32(s, 3H).
EXAMPLE 13
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-methylphenyl]carboxyamide
Except that methyl 4-[(4-methylphenyl)carbonylamino]benzoate obtained in the intermediate step of Example 2 was used, the procedure described in Example 12 was performed to give the title compound (12.2 g, 44% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.53
1H-NMR(DMSO-d6): δ11.21(s, 1H), 10.41(s, 1H), 9.08(s, 1H), 7.94(m, 4H), 7.83(d, 2H, J=7.8 Hz), 7.52(d, 2H, J=7.8 Hz), 3.30(s, 3H), 2.45(s, 3H).
EXAMPLE 14
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[3-methylphenyl]carboxyamide
Except that methyl 4-[(3-methylphenyl)carbonylamino]benzoate obtained in the intermediate step of Example 3 was used, the procedure described in Example 12 was performed to give the title compound (12.2 g, 44% yield) as a pale yellow solid.
TLC(in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.43(s, 1H), 9.07(s, 1H), 7.93(m, 6H), 7.20(m,2H), 3.32(s, 3H), 2.44(s, 3H).
EXAMPLE 15
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-ethylphenyl]carboxyamide
Except that methyl 4-[(4-ethylphenyl)carbonylamino]benzoate obtained in the intermediate step of Example 4 was used, the procedure described in Example 12 was performed to give the title compound (10.4 g, 42% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:4); Rf=0.50
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.43(s, 1H), 9.05(s, 1H), 7.91(m, 4H), 7.81(d, 2H, J=7.8 Hz), 7.50(d, 2H, J=7.8 Hz), 3.31(s, 3H), 2.51(m, 2H), 1.40(m, 3H).
EXAMPLE 16
Preparation of N-[4-N-hydroxycarbamoyl)phenyl]-N-methyl-[4-propylphenyl]carboxyamide
Except that methyl 4-[(4-propylphenyl)carbonylamino]benzoate obtained in the intermediate step of Example 5 was used, the procedure described in Example 12 was performed to give the title compound (11.4 g, 43% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.55
1H-NMR(DMSO-d6): δ11.23(s, 1H), 10.40(s, 1H), 9.03(s, 1H), 7.92(m, 4H), 7.83(d, 1H, J=7.8 Hz), 7.48(d, 1H, J=7.8 Hz), 3.34(s, 3H), 2.50(m, 2H), 1.51(m, 2H), 0.95(m, 3H).
EXAMPLE 17
Preparation of N-[4-N-hydroxycarbamoyl)phenyl]-N-methyl-[4-isopropylphenyl]carboxyamide
Except that methyl 4-[(4-isopropylphenyl)carbonylamino]benzoate obtained in the intermediate step of Example 6 was used, the procedure described in Example 12 was performed to give the title compound (10.1 g, 40% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.50
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.41(s, 1H), 9.07(s, 1H), 7.94(m, 4H), 7.80(d, 2H, J=7.8 Hz), 7.49(d, 2H, J=7.8 Hz), 3.35(s, 3H), 3.0(m, 1H), 1.30(d, 6H, J=6.9 Hz).
EXAMPLE 18
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-butylphenyl]carboxyamide
Except that methyl 4-[(4-butylphenyl)carbonylamino]benzoate obtained in the intermediate step of Example 7 was used, the procedure described in Example 12 was performed to give the title compound (12.1 g, 47% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.53
1H-NMR(DMSO-d6): 11.23(s, 1H), 10.41(s, 1H), 9.03(s, 1H), 7.92(m, 4H), 7.83(d, 2H, J=7.8 Hz), 7.53(d, 2H, J=7.8 Hz), 3.30(m, 3H), 2.49(m, 2H), 1.60(m, 2H), 1.41(m, 2H), 0.95(m, 3H).
EXAMPLE 19
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-tert-butylphenyl]carboxyamide
Except that methyl 4-[(4-tert-butylphenyl)carbonylamino]benzoate obtained in the intermediate step of Example 8 was used, the procedure described in Example 12 was performed to give the title compound (11.1 g, 43% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): 11.21(s, 1H), 10.41(s, 1H), 9.05(s, 1H), 7.90(m, 4H), 7.79(d, 2H, J=7.8 Hz), 7.43(d, 2H, J=7.8 Hz), 3.32(s, 3H), 1.25(s, 9H).
EXAMPLE 20
Preparation of N-[4-(N-hydroxcarbamoly)phenyl]-N-methyl-[3,4-dimethylphenyl]carboxyamide
Except that methyl 4-[(3,4-dimethylphenyl)carbonylamino]benzoate obtained in the intermediate step of Example 9 was used, the procedure described in Example 12 was performed to give the title compound (12.2 g, 44% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.52
1H-NMR(DMSO-d6): δ11.25(s, 1H), 10.43(s, 1H), 9.07(s, 1H), 7.94(m, 3H), 7.82(d, 2H, J=7.8 Hz), 7.49(d, 2H, J=7.8 Hz), 3.30(s, 3H), 2.48(s, 3H), 2.45(s, 3H).
EXAMPLE 21
Preparation of N-[4-(N-hydroxycarbamoyl)phenyl]adamantyl-N-methylcarboxyamide
Except that methyl 4-(adamantylcarbonylamino) benzoate obtained in the intermediate step of Example 10 was used, the procedure described in Example 12 was performed to give the title compound (12.8 g, 38% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.53
1H-NMR(DMSO-d6): δ11.20(s, 1H), 9.23(s, 1H), 7.76(m, 4H), 3.74 (s, 3H), 1.96(m, 3H), 1.85(m, 6H), 1.64(m, 6H).
EXAMPLE 22
Preparation of adamantyl-N-[4-(N-hydroxy-N-methylcarbamoyl)phenyl]-N-methylcarboxyamide
Except that N-methyl hydroxylamine hydrochloride was used instead of hydroxylamine hydrochloride, the procedure described in Example 21 was performed to give the title compound (11.4 g, 39% yield) as apale yellow solid.
TLC(in ethyl acetate:hexane=1:4); Rf=0.54
1H-NMR(DMSO-d6): δ9.95(s, 1H), 7.57(m, 4H), 3.72(s, 3H), 3.07(s, 3H), 1.94(m, 3H), 1.87(m, 6H), 1.62(m, 6H).
EXAMPLE 23
Preparation of N-[4-(N-hydroxycarbamoylmethyl)phenyl]benzamide
Except that 4-aminophenylacetic acid methylester was used instead of methyl 4-aminobenzoate, the procedure described in Example 1 was performed to give the title compound (10.0 g, 39% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.53
1H-NMR(DMSO-d6): δ11.23(s, 1H), 10.39(s, 1H), 9.04(s, 1H), 8.01(m, 5H), 7.64(m, 4H), 3.20(s, 2H).
EXAMPLE 24
Preparation of N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-methylphenyl]carboxyamide
Except that 4-aminophenylacetic acid methylester was used instead of methyl 4-aminobenzoate, the procedure described in Example 2 was performed to give the title compound (11.9 g, 44% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.52
1H-NMR(DMSO-d6): 11.22(s, 1H), 10.41(s, 1H), 9.07(s, 1H), 7.94(m, 4H), 7.80(d, 2H, J=7.8 Hz), 7.49(d, 2H, J=7.8 Hz), 3.21(s, 2H), 2.45(s, 3H).
EXAMPLE 25
Preparation of N-[4-(N-hydroxycarbamoylmethyl)phenyl][3-methylphenyl]carboxyamide
Except that 4-aminophenylacetic acid methylester was used instead of methyl 4-aminobenzoate, the same procedure described in Example 3 was performed to give the title compound (11.9 g, 44% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.54
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.40(s, 1H), 9.04(s, 1H), 7.91(m, 6H), 7.22(m, 2H), 3.21(s, 2H), 2.44(s, 3H).
EXAMPLE 26
Preparation of N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-ethylphenyl]carboxyamide
Except that 4-aminophenylacetic acid methylester was used instead of methyl 4-aminobenzoate, the procedure described in Example 4 was performed to give the title compound (12.9 g, 45% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:4); Rf=0.50
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.43(s, 1H), 9.05(s, 1H), 7.91(m, 4H), 7.81(d, 2H, J=7.8 Hz), 7.50(d, 2H, J=7.8 Hz), 3.21(s, 2H), 2.51(m, 2H), 1.40(m, 3H).
EXAMPLE 27
Preparation of N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-propylphenyl]carboxyamide
Except that 4-aminophenylacetic acid methylester was used instead of methyl 4-aminobenzoate, the procedure described in Example 5 was performed to give the title compound (13.1 g, 46% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.55
1H-NMR(DMSO-d6): δ11.23(s, 1H), 10.40(s, 1H), 9.03(s, 1H), 7.92(m, 4H), 7.83(d, 1H, J=7.8 Hz), 7.48(d, 1H, J=7.8 Hz), 3.20(s, 2H), 2.50(m, 2H), 1.51(m, 2H), 0.95(m, 3H).
EXAMPLE 28
Preparation of N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-isopropylphenyl]carboxyamide
Except that 4-aminophenylacetic acid methylester was used instead of methyl 4-aminobenzoate, the procedure described in Example 6 was performed to give the title compound (11.1 g, 43% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.50
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.41(s, 1H), 9.05(s, 1H), 7.93(m, 4H), 7.81(d, 2H, J=7.8 Hz), 7.48(d, 2H, J=7.8 Hz), 3.23(s, 2H), 3.01(m, 1H), 1.30(d, 6H, J=6.9 Hz).
EXAMPLE 29
Preparation of N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-butylphenyl]carboxyamide
Except that 4-aminophenylacetic acid methylester was used instead of methyl 4-aminobenzoate, the procedure described in Example 7 was performed to give the title compound (11.9 g, 44% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.53
1H-NMR(DMSO-d6): 11.22(s, 1H), 10.40(s, 1H), 9.07(s, 1H), 7.91(m, 4H), 7.83(d, 2H, J=7.8 Hz), 7.52(d, 2H, J=7.8 Hz), 3.19(s, 2H), 2.49(m, 2H), 1.60(m, 2H), 1.41(m, 2H), 0.95(m, 3H).
EXAMPLE 30
Preparation of N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-tert-butylphenyl]carboxyamide
Except that 4-aminophenylacetic acid methylester was used instead of methyl 4-aminobenzoate, the procedure described in Example 8 was performed to give the title compound (12.0 g, 42% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): 11.22(s, 1H), 10.41(s, 1H), 9.06(s, 1H), 7.91(m, 4H), 7.83(d, 2H, J=7.8 Hz), 7.52(d, 2H, J=7.8 Hz), 3.20(s, 2H), 1.25(s, 9H).
EXAMPLE 31
Preparation of N-[4-(N-hydroxycarbamoylmethyl)phenyl][3,4-dimethylphenyl]carboxyamide
Except that 4-aminophenylacetic acid methylester was used instead of methyl 4-aminobenzoate, the procedure described in Example 9 was performed to give the title compound (11.9 g, 44% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.52
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.41(s, 1H), 9.05(s, 1H), 7.92(m, 3H), 7.80(d, 2H, J=7.8 Hz), 7.47(d, 2H, J=7.8 Hz), 3.21(s, 2H), 2.48(s, 3H), 2.44(s, 3H).
EXAMPLE 32
Preparation of N-[4-(N-hydroxycarbamoylmethyl)phenyl]adamantyl carboxyamide
Except that 4-aminophenylacetic acid methylester was used instead of methyl 4-aminobenzoate, the procedure described in Example 10 was performed to give the title compound (11.9 g, 44% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.52
1H-NMR(DMSO-d6): δ11.22(s, 1H), 9.25(s, 1H), 8.87(s, 1H), 7.76(m, 4H), 3.27(s, 2H), 1.96(m, 3H), 1.87(m, 6H), 1.63(m, 6H).
EXAMPLE 33
Preparation of 2-[4-(adamantlycarbonylamino)phenyl]-N-hydroxy-N-methylacetamide
Except that N-methyl hydroxylamine hydrochloride was used instead of hydroxylamine hydrochloride, the procedure described in Example 32 was performed to give the title compound (12.8 g, 41% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.53
1H-NMR(DMSO-d6): δ9.95(s, 1H), 9.12(s, 1H), 7.55(m, 4H), 3.27(s, 2H), 3.09(s, 3H), 1.94(m, 3H), 1.84(m, 6H), 1.60(m, 6H).
EXAMPLE 34
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-benzamide
Except that monomethylterephthalate and aniline were used instead of benzoic acid and methyl 4-aminobenzoate, the procedure described in Example 1 was performed to give the title compound (11.8 g, 46% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6):δ11.21(s, 1H), 10.29(s, 1H), 9.10(s, 1H), 8.01(m, 4H), 7.60(m, 5H).
EXAMPLE 35
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-[4-methylphenyl]carboxyamide
Except that monomethylterephthalate and 4-methylaniline were used instead of benzoic acid and methyl 4-aminobenzoate, the procedure described in Example 1 was performed to give the title compound (11.6 g, 43% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.49
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.32(s, 1H), 9.11(s, 1H), 8.10(d, 2H, J=7.8 Hz), 7.98(d, 2H, J=7.8 Hz), 7.80(m, 4H), 2.44(s, 3H).
EXAMPLE 36
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-[3-methylphenyl]carboxyamide
Except that monomethylterephthalate and 3-methylaniline were used instead of benzoic acid and methyl 4-aminobenzoate, the procedure described in Example 1 was performed to give the title compound (11.6 g, 43% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.49
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.32(s, 1H), 9.10(s, 1H), 8.10(m, 6H), 7.90(m, 2H), 2.42(s, 3H).
EXAMPLE 37
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-[4-ethylphenyl]carboxyamide
Except that monomethylterephthalate and 4-ethylaniline were used instead of benzoic acid and methyl 4-aminobenzoate, the procedure described in Example 1 was performed to give the title compound (12.8 g, 45% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.33(s, 1H), 9.09(s, 1H), 8.12(d, 2H, J=7.8 Hz), 7.97(d, 2H, J=7.8 Hz), 7.81(m, 4H), 2.53(m, 2H), 1.42(m, 3H).
EXAMPLE 38
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-[4-propylphenyl]carboxyamide
Except that monomethylterephthalate and 4-propylaniline were used instead of benzoic acid and methyl 4-aminobenzoate, the procedure described in Example 1 was performed to give the title compound (11.6 g, 39% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.53
1H-NMR(DMSO-d6): δ11.22(s, 1H), 10.33(s, 1H), 9.10(s, 1H), 8.13(d, 2H, J=7.8 Hz), 7.96(d, 2H, J=7.8 Hz), 7.88(m, 4H), 2.46(m, 2H), 1.50(m, 2H), 0.98(m, 3H).
EXAMPLE 39
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-[4-isopropylphenyl]carboxyamide
Except that monomethylterephthalate and 4-isopropylaniline were used instead of benzoic acid and methyl 4-aminobenzoate, the procedure described in Example 1 was performed to give the title compound (12.2 g, 41% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR (DMSO-d6): 11.20(s, 1H), 10.31(s, 1H), 9.11(s, 1H), 8.11(d, 2H, J=7.8 Hz), 7.99(d, 2H, J=7.8 Hz), 7.81(m, 4H), 2.99(m, 1H), 1.30(d, 6H, J=6.9 Hz).
EXAMPLE 40
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-[4-butylphenyl]carboxyamide
Except that monomethylterephthalate and 4-butylaniline were used instead of benzoic acid and methyl 4-aminobenzoate, the procedure described in Example 1 was performed to give the title compound (12.8 g, 41% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H NMR (DMSO-d6): δ11.21(s, 1H), 10.33(s, 1H), 9.13(s, 1H), 8.13(d, 2H, J=7.8 Hz), 7.95(d, 2H, J=7.8 Hz), 7.88(m, 4H), 2.50(m, 2H), 2.00(m, 2H), 1.48(m, 2H), 0.95(m, 3H).
EXAMPLE 41
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-[4-tert-butylphenyl]carboxyamide
Except that monomethylterephthalate and 4-tert-butylaniline were used instead of benzoic acid and methyl 4-aminobenzoate, the procedure described in Example 1 was performed to give the title compound (12.8 g, 41% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): δ11.21(s, 1H), 10.31(s, 1H), 9.10(s, 1H), 8.15(d, 2H, J=7.8 Hz), 7.94(d, 2H, J=7.8 Hz), 7.85(m, 4H), 1.40(s, 9H).
EXAMPLE 42
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-[3,4-dimethylphenyl]carboxyamide
Except that monomethylterephthalate and 3,4-dimethylaniline were used instead of benzoic acid and methyl 4-aminobenzoate, the procedure described in Example 1 was performed to give the title compound (11.6 g, 43% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.49
1H-NMR (DMSO-d6): δ11.20(s, 1H), 10.30(s, 1H), 9.11(s, 1H), 8.10(d, 2H, J=7.8 Hz), 7.98(d, 2H, J=7.8 Hz), 7.84(m, 3H), 2.46(s, 3H), 2.42(s, 3H).
EXAMPLE 43
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-adamantyl carboxyamide
Except that monomethylterephthalate and adamantamine were used instead of adamantanecarboxylic acid and methyl 4-aminobenzoate, the procedure described in Example 10 was performed to give the title compound (11.8 g, 46% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR (DMSO-d6): δ11.20(s, 1H), 9.21(s, 1H), 8.87(s, 1H), 7.73(m, 4H), 1.94(m, 3H), 1.84(m, 6H), 1.62(m, 6H).
EXAMPLE 44
Preparation of N-adamantyl [4-(N-hydroxy-N-methylcarbamoyl)phenyl]carboxyamide
Except that N-methyl hydroxylamine hydrochloride was used instead of hydroxylamine hydrochloride, the procedure described in Example 43 was performed to give the title compound (11.8 g, 46% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): δ9.99(s, 1H), 9.10(s, 1H), 7.53(m, 4H), 3.10(s, 3H), 1.91(m, 3H), 1.83(m, 6H), 1.60(m, 6H).
EXAMPLE 45
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-benzamide
Except that methyl 4-(phenylcarbamoyl) benzoate obtained in the intermediate step of Example 34 was used, the procedure described in Example 12 was performed to give the title compound (12.0 g, 40% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): δ11.21(s, 1H), 10.29(s, 1H), 9.10(s, 1H), 8.01(m, 4H), 7.60(m, 5H), 3.20(s, 3H).
EXAMPLE 46
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-methylphenyl]carboxyamide
Except that methyl 4-[(4-methylphenyl)carbamoyl]benzoate obtained in the intermediate step of Example 35 was used, the procedure described in Example 12 was performed to give the title compound (11.0 g, 39% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.39(s, 1H), 9.11(s, 1H), 8.11(d, 2H, J=7.8 Hz), 7.98(d, 2H, J=7.8 Hz), 7.91(m, 4H), 3.20(s, 3H), 2.50(s, 3H).
EXAMPLE 47
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[3-methylphenyl]carboxyamide
Except that methyl 4-[(3-methylphenyl)carbamoyl]benzoate obtained in the intermediate step of Example 36 was used, the procedure described in Example 12 was performed to give the title compound (11.0 g, 39% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): δ11.21(s, 1H), 10.30(s, 1H), 9.13(s, 1H), 8.10(m, 6H), 7.88(m, 2H), 2.50(s, 3H).
EXAMPLE 48
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-ethylphenyl]carboxyamide
Except that methyl 4-[(4-ethylphenyl)carbamoyl]benzoate obtained in the intermediate step of Example 37 was used, the procedure described in Example 12 was performed to give the title compound (12.0 g, 40% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.55
1H-NMR(DMSO-d6): δ11.22(s, 1H), 10.33(s, 1H), 9.10(s, 1H), 8.13(d, 2H, J=7.8 Hz), 7.97(d, 2H, J=7.8 Hz), 7.89(m, 4H), 3.20(s, 3H), 2.46(m, 2H), 0.98(m, 3H).
EXAMPLE 49
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-propylphenyl]carboxyamide
Except that methyl 4-[(4-propylphenyl)carbamoyl]benzoate obtained in the intermediate step of Example 38 was used, the procedure described in Example 12 was performed to give the title compound (12.8 g, 41% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.55
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.31(s, 1H), 9.13(s, 1H), 8.12(d, 2H, J=7.8 Hz), 7.96(d, 2H, J=7.8 Hz), 7.89(m, 4H), 3.20(s, 3H), 2.46(m, 2H), 1.50(m, 2H), 0.98(m, 3H).
EXAMPLE 50
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-isopropylphenyl]carboxyamide
Except that methyl 4-[(4-isopropylphenyl)carbamoyl]benzoate obtained in the intermediate step of Example 39 was used, the procedure described in Example 12 was performed to give the title compound (13.2 g, 44% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): δ11.21(s, 1H), 10.32(s, 1H), 9.15(s, 1H), 8.10(d, 2H, J=7.8 Hz), 7.94(d, 2H, J=7.8 Hz), 7.83(m, 4H), 3.21(s, 3H), 2.50(m, 1H), 1.32(d, 6H, J=6.9 Hz).
EXAMPLE 51
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-butylphenyl]carboxyamide
Except that methyl 4-[(4-butylphenyl)carbamoyl]benzoate obtained in the intermediate step of Example 40 was used, the procedure described in Example 12 was performed to give the title compound (12.0 g, 40% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): δ11.20(s, 1H), 10.33(s, 1H), 9.14(s, 1H), 8.12(d, 2H, J=7.8 Hz), 7.95(d, 2H, J=7.8 Hz), 7.84(m, 4H), 3.22(s, 3H), 2.50(m, 2H), 2.00(m, 2H), 1.48(m, 2H), 0.95(m, 3H).
EXAMPLE 52
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-tert-butylphenyl]carboxamide
Except that methyl 4-[(4-tert-butylphenyl)carbamoyl]benzoate obtained in the intermediate step of Example 41 was used, the procedure described in Example 12 was performed to give the title compound (12.5 g, 41% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): δ11.22(s, 1H), 10.33(s, 1H), 9.12(s, 1H), 8.11(d, 2H, J=7.8 Hz), 7.96(d, 2H, J=7.8 Hz), 7.84(m, 4H), 3.20(s, 3H), 1.24(s, 9H).
EXAMPLE 53
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[3,4-dimethylphenyl]carboxyamide
Except that methyl 4-[(3,4-dimethylphenyl)carbamoyl]benzoate obtained in the intermediate step of Example 42 was used, the procedure described in Example 12 was performed to give the title compound (11.0 g, 39% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-4): δ11.20(s, 1H), 10.30(s, 1H), 9.11(s, 1H), 8.11(d, 2H, J=7.8 Hz), 7.95(d, 2H, J=7.8 Hz), 7.94(m, 3H), 3.20(s, 3H), 2.53(s, 3H), 2.50(s, 3H).
EXAMPLE 54
Preparation of [4-(N-hydroxycarbamoyl)phenyl]-N-adamantyl-N-methylcarboxyamide
Except that methyl 4-(N-adamantyl-N-methylcarbamoyl)benzoate obtained in the intermediate step of Example 43 was used, the procedure described in Example 12 was performed to give the title compound (11.8 g, 46% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): δ11.22(s, 1H), 9.22(s, 1H), 7.74(m, 4H), 3.71 (s, 3H), 1.93(m, 3H), 1.83(m, 6H), 1.63(m, 6H).
EXAMPLE 55
Preparation of N-adamantyl [4-(N-hydroxy-N-methylcarbamoyl)phenyl]-N-methyl carboxyamide
Except that N-methyl hydroxylamine hydrochloride was used instead of hydroxylamine hydrochloride, the procedure described in Example 54 was performed to give the title compound (11.8 g, 46% yield) as a pale yellow solid.
TLC (in ethyl acetate:hexane=1:1); Rf=0.51
1H-NMR(DMSO-d6): δ9.93(s, 1H), 7.59(m, 4H), 3.70(s, 3H), 3.05(s, 3H), 1.92(m, 3H), 1.86(m, 6H), 1.60(m, 6H).
EXPERIMENTAL EXAMPLE 1
Affinity to Retinoic Acid Receptor
This example illustrates affinities of hydroxamic acid derivatives obtained in Examples 1 to 55 to retinoic acid receptor, in comparison with retinol and retinoic acid.
Receptor-expression plasmid, pECE-RARα and pECE-RARγ were engineered by the prior method (Mol. Cell. Biol. 1996, 16, 1138-1149). RARE-tk-Luc, i.e. RARE reporter was obtained by inserting RARE fragment from b-RARE-tk-CAT into pGL3 luciferase basic vector. CV-1 cells were obtained from ATCC (American Type Culture Collection).
CV-1 cells were seeded into 96-well microtiter plate at 5,000 cells per well and cultured in DMEM (Dulbecco's Modified Eagle's Media) supplemented with 2.5% fetal bovine serum. 24 Hours later, the cells were transfected with 10 ng of pECE-RARα, long of pECE-RARγ, 100 ng of reporter plasmid and 100 ng of β-galactosidase-expression vector, using LipofectaminPlus (GIBCO BRL, grand island, N.Y.). 24 Hours post-transfection, the cells were treated for 24 hours with hydroxamic acid derivatives of Examples 1 ̃55 or retinol at a final concentration of 10−4M or with retinoic acid at a final concentration of 10−5M, which is 10 times lower concentration than those of the former.











TABLE 1








Luciferase
Luciferase




activity
activity



Materials
RARα
RARγ




















Control group
1000
5000



(without



Retinol
2500
6000



Retinoic acid
25000
10000



Example 1
10000
12000



Example 2
12000
11200



Example 3
11600
10000



Example 4
12000
12300



Example 5
18000
11000



Example 6
14500
12300



Example 7
12000
11700



Example 8
10002
12000



Example 9
12000
12000



Example 10
11000
12000



Example 11
11600
10000



Example 12
14500
11300



Example 13
12000
11200



Example 14
18000
10300



Example 15
14500
10400



Example 16
12300
11200



Example 17
12400
11700



Example 18
12900
11400



Example 19
10020
11200



Example 20
12200
12300



Example 21
12500
11200



Example 22
12100
12400



Example 23
13000
13200



Example 24
12100
11210



Example 25
13200
12100



Example 26
17500
11200



Example 27
13920
11300



Example 28
12900
10700



Example 29
18900
10600



Example 30
23500
12000



Example 31
23100
10700



Example 32
18000
10000



Example 33
13400
11000



Example 34
13900
11000



Example 35
14500
11300



Example 36
16700
11200



Example 37
19000
10300



Example 38
17500
10400



Example 39
18700
10100



Example 40
14300
11200



Example 41
14300
11211



Example 42
14500
11200



Example 43
18900
10600



Example 44
23100
10700



Example 45
12300
11212



Example 46
13200
11123



Example 47
12200
11700



Example 48
15500
11200



Example 49
14500
12100



Example 50
12300
11212



Example 51
13400
12210



Example 52
12400
12130



Example 53
14500
12300



Example 54
22500
11000



Example 55
13400
11000










The above results for affinity to retinoic acid receptor indicate that hydroxamic acid derivatives obtained in Examples 1 to 55 can be regarded as retinoid compounds.
EXPERIMENTAL EXAMPLE 2
Effect on Collagen Biosynthesis
This example illustrates effects of hydroxamic acid derivatives obtained in Examples 1 to 55 on collagen biosynthesis, in comparison with retinol and retinoic acid.
Human fibroblasts were seeded into 24-well plate at 1×105 cells per well and then cultured to 90% of growth. Then, the fibroblastes were cultured in serum-free DMEM for 24 hours and treated with 10−4M of hydroxamic acid derivatives of Examples 1 ̃55, retinol or retinoic acid in serum-free medium, and then incubated in CO2 incubator for 24 hours.
For each supernatant, procollagen production was measured with procollagen type I ELISA kit. The results are shown in Table 2 and collagen biosynthesis was evaluated as a relative value, in consideration that the value of control group with no material treated is 100.










TABLE 2








Collagen biosynthesis



Materials
(%)









Control group
100



Retinol
120



Retinoic acid
125



Example 1
105



Example 2
118



Example 3
120



Example 4
119



Example 5
125



Example 6
124



Example 7
109



Example 8
112



Example 9
120



Example 10
106



Example 11
110



Example 12
122



Example 13
117



Example 14
115



Example 15
112



Example 16
120



Example 17
111



Example 18
130



Example 19
120



Example 20
122



Example 21
118



Example 22
120



Example 23
131



Example 24
121



Example 25
120



Example 26
123



Example 27
112



Example 28
121



Example 29
132



Example 30
121



Example 31
109



Example 32
125



Example 33
112



Example 34
108



Example 35
111



Example 36
121



Example 37
121



Example 38
109



Example 39
105



Example 40
108



Example 41
115



Example 42
116



Example 43
130



Example 44
107



Example 45
108



Example 46
121



Example 47
112



Example 48
107



Example 49
109



Example 50
110



Example 51
121



Example 52
127



Example 53
122



Example 54
121



Example 55
108










EXPERIMENTAL EXAMPLE 3
Inhibition of Collagenase Expression
This example illustrates inhibition by hydroxamic acid derivatives obtained in Examples 1 to 55 of collagenase expression, in comparison with retinol and retinoic acid.
Human fibroblasts were seeded into 96-well microtiter plate at 5,000 cells per well and then cultured to 90% of growth in DMEM (Dulbecco's Modified Eagle's Media) supplemented with 2.5% fetal bovine serum. Then, the fibroblastes were cultured in serum-free DMEM for 24 hours and treated for 24 hours with 10−4M of hydroxamic acid derivatives of Examples 1 ̃55, retinol or retinoic acid in serum-free medium, and then the culture fluid was collected.
For each culture fluid, collagenase production was measured with collagenase kit (commercialized by AmershamPharmacia Biotech). Firstly, the culture fluid was added to 96-well plate spread with primary collagenase antibody and then antigen-antibody reaction was performed in an incubator for 3 hours. Later, chromophore-conjugated secondary antibody was added to the 96-well plate and then reacted for 15 minutes. Then, color former was added thereto, to induce development at room temperature for 15 minutes. 1M of sulfuric acid was added to stop the reaction. The reaction solution got yellow. The color density depends on the progress of the reaction. The absorbance of the yellow 96-well plate was measured at 405 nm using absorptiometer. Collagenase expression was calculated by the following equation 1. Herein, the absorbance of the culture fluid collected from the medium with no material treated was used as a control.

Collagenase expression (%)=(Absorbance of test group with said material treated/Absorbance of control group with no material treated)×100   [Equation 1]

The results for inhibition of collagenase expression in the cells are shown in Table 3 and confirmed that hydroxamic acid derivatives of the present invention could inhibit collagenase expression in vitro. Collagenase expression was evaluated as a relative value, in consideration that the value of control group with no material treated is 100.










TABLE 3








Collagenase expression



Materials
(%)



















Control group
100



Retinol
85



Retinoic acid
60



Example 1
78



Example 2
68



Example 3
80



Example 4
78



Example 5
79



Example 6
85



Example 7
84



Example 8
90



Example 9
65



Example 10
75



Example 11
81



Example 12
64



Example 13
70



Example 14
72



Example 15
79



Example 16
80



Example 17
81



Example 18
78



Example 19
70



Example 20
68



Example 21
69



Example 22
77



Example 23
77



Example 24
76



Example 25
70



Example 26
78



Example 27
87



Example 28
67



Example 29
77



Example 30
83



Example 31
81



Example 32
79



Example 33
70



Example 34
85



Example 35
90



Example 36
68



Example 37
70



Example 38
87



Example 39
78



Example 40
77



Example 41
88



Example 42
78



Example 43
77



Example 44
83



Example 45
81



Example 46
83



Example 47
79



Example 48
87



Example 49
81



Example 50
80



Example 51
76



Example 52
77



Example 53
75



Example 54
83



Example 55
85










EXPERIMENTAL EXAMPLE 4
Inhibition of Elastase Expression
This example illustrates inhibition by hydroxamic acid derivatives obtained in Examples 1 to 55 of elastase expression, in comparison with retinol and retinoic acid.
Human fibroblasts were seeded into 96-well microtiter plate at 5,000 cells per well and then cultured to 90% of growth in DMEM (Dulbecco's Modified Eagle's Media) supplemented with 2.5% fetal bovine serum. Then, the fibroblastes were cultured in serum-free DMEM for 24 hours and treated for 24 hours with 10−4M of hydroxamic acid derivatives of Examples 1 ̃55, retinol or retinoic acid in serum-free medium, and then the culture fluid was collected.
For each culture fluid, elastase production was measured with elastase kit (commercialized by AmershamPharmacia Biotech). Firstly, the culture fluid was added to 96-well plate spread with primary elastase antibody and then antigen-antibody reaction was performed in an incubator for 3 hours. Later, chromophore-conjugated secondary antibody was added to the 96-well plate and then reacted for 15 minutes. Then, color former was added thereto, to induce development at room temperature for 15 minutes. 1M of sulfuric acid was added to stop the reaction. The reaction solution got yellow. The color density depends on the progress of the reaction. The absorbance of the yellow 96-well plate was measured at 405 nm using absorptiometer. Elastase expression was calculated by the following equation 2. Herein, the absorbance of the culture fluid collected from the medium with no material treated was used as a control.

Elastase expression (%)=(Absorbance of test group with said material treated/Absorbance of control group with no material treated)×100   [Equation 2]

The results for inhibition of elastase expression in the cells are shown in Table 4 and confirmed that hydroxamic acid derivatives of the present invention could inhibit elastase expression in vitro. Elastase expression was evaluated as a relative value, in consideration that the value of control group with no material treated is 100.










TABLE 4







Materials
Elastase expression (%)



















Control group
100



Retinol
88



Retinoic acid
68



Example 1
79



Example 2
78



Example 3
69



Example 4
70



Example 5
78



Example 6
79



Example 7
77



Example 8
69



Example 9
67



Example 10
77



Example 11
65



Example 12
80



Example 13
84



Example 14
75



Example 15
76



Example 16
77



Example 17
82



Example 18
79



Example 19
80



Example 20
78



Example 21
78



Example 22
70



Example 23
79



Example 24
82



Example 25
80



Example 26
86



Example 27
87



Example 28
79



Example 29
70



Example 30
69



Example 31
63



Example 32
74



Example 33
82



Example 34
70



Example 35
71



Example 36
79



Example 37
80



Example 38
69



Example 39
87



Example 40
90



Example 41
78



Example 42
76



Example 43
70



Example 44
63



Example 45
81



Example 46
80



Example 47
83



Example 48
87



Example 49
87



Example 50
78



Example 51
77



Example 52
87



Example 53
80



Example 54
67



Example 55
70










EXPERIMENTAL EXAMPLE 5
Primary Skin Irritation Test on Animals
1) Method
Test was performed using fifty-six (56) of healthy male rabbits whose backs were depilated. The compounds of Examples 1 ̃55 were dissolved in solvent (1,3-butylene glycol: ethanol 7:3) to give 1% solution of test samples. 0.5ml of the test sample solution was applied to the right site of 2.5 cm×2.5 cm region on each of the depilated back. Left site with no sample treated was compared as a control. 24 hours or 72 hours later, skin abnormality such as erythema, crust and edema was observed. Skin response was scored according to “standard guide for toxicity test of foods and drugs”, as shown in Table 5.
Based on the score of skin response, skin irritation was evaluated according to Draize's P.I.I.(Primary Irritation Index) and compared with retinoic acid. The results are shown in Table 6.








TABLE 5





Skin responses
Score

















1) Erythema
No erythema
0


and crust
A slight erythema (scarcely visible)
1



Significant erythema
2



Severe erythema
3



Crimson extremely-severe erythema and crust
4


2) Edema
No edema
0



A slight edema (scarcely visible)
1



Significant edema (distinct from periphery)
2



Severe edema (swelled up about 1 mm)
3



Extremely-severe edema (swelled up 1 mm or more
4



and expanded out of the exposed site)




















TABLE 6







Materials
P.I.I.
Evaluation









Retinoic acid
1.830
Light irritation



Example 1
0.375
No irritation



Example 2
0.345
No irritation



Example 3
0.375
No irritation



Example 4
0.350
No irritation



Example 5
0.375
No irritation



Example 6
0.315
No irritation



Example 7
0.312
No irritation



Example 8
0.330
No irritation



Example 9
0.470
No irritation



Example 10
0.375
No irritation



Example 11
0.375
No irritation



Example 12
0.410
No irritation



Example 13
0.500
No irritation



Example 14
0.231
No irritation



Example 15
0.789
No irritation



Example 16
0.567
No irritation



Example 17
0.123
No irritation



Example 18
0.321
No irritation



Example 19
0.223
No irritation



Example 20
0.421
No irritation



Example 21
0.345
No irritation



Example 22
0.350
No irritation



Example 23
0.321
No irritation



Example 24
0.321
No irritation



Example 25
0.423
No irritation



Example 26
0.321
No irritation



Example 27
0.568
No irritation



Example 28
0.765
No irritation



Example 29
0.234
No irritation



Example 30
0.456
No irritation



Example 31
0.567
No irritation



Example 32
0.375
No irritation



Example 33
0.765
No irritation



Example 34
0.678
No irritation



Example 35
0.245
No irritation



Example 36
0.456
No irritation



Example 37
0.456
No irritation



Example 38
0.567
No irritation



Example 39
0.145
No irritation



Example 40
0.546
No irritation



Example 41
0.367
No irritation



Example 42
0.987
No irritation



Example 43
0.456
No irritation



Example 44
0.678
No irritation



Example 45
0.900
No irritation



Example 46
0.345
No irritation



Example 47
0.367
No irritation



Example 48
0.468
No irritation



Example 49
0.342
No irritation



Example 50
0.234
No irritation



Example 51
0.331
No irritation



Example 52
0.412
No irritation



Example 53
0.321
No irritation



Example 54
0.567
No irritation



Example 55
0.245
No irritation










As shown in Table 6, hydroxamic acid derivatives obtained in Examples 1 to 55 were confirmed to be non-irritative to the skin.
These results illustrate that hydroxamic acid derivatives of the present invention have the same efficacy in improving skin elasticity as that of retinol or retinoic acid, and additionally good safety and less skin irritation, to be incorporated into skin-care external compositions for improving skin elasticity.
EXPERIMENTAL EXAMPLE 6
Phototoxicity Test
Test was performed for twenty-five (25) of white guinea pigs whose backs were depilated and fixed. On both sides of the back, six(6) sites of 2 cm×2 cm, three(3) per side were sectioned. Right sites were compared as controls with no irradiation (UV non-irradiation sites) and left sites were irradiated (UV irradiation sites). As a negative control, vehicle of 1,3-butylene glycol:ethanol=7:3 and as a positive control, 0.1% 8-MOP(methoxypsoralene) were prepared, and then hydroxamic acid derivatives of Examples 1 ̃55 were dissolved in 1,3-butylene glycol:ethanol=7:3, to give 1%(w/v) of solutions, of which each 50 μl was applied.
30 Minutes later, right sites were shielded with aluminum foil and UVA(320 ̃380 nm) was irradiated at a distance of about 10 cm therefrom using Waldmann to the final energy of 15 J/cm2. After 24, 48 and 72 hours elapsed, skin response of guinea pig was observed. Erythema and edema were scored from 0 to 4, as shown in said Table 5 and skin response was evaluated by the sum of scores. Evaluation was estimated for each elapsed time, i.e. 24, 48 and 72 hours and maximum scores were selected, to calculate irritation index by the following equation 3. Then, phototoxic index was calculated by the following equation 4. The results are shown in Table 7.

Irritation index=(ΣMaximum of erythema+ΣMaximum of edema)/Number of animals   [Equation 3]

Phototoxic index=(Irritation index of UV irradiation site)−(Irritation index of UV non-irradiation site)   Equation 4]












TABLE 7








Phototoxic




Materials
index
Evaluation









Example 1
0
No phototoxicity



Example 2
0
No phototoxicity



Example 3
0
No phototoxicity



Example 4
0
No phototoxicity



Example 5
0
No phototoxicity



Example 6
0
No phototoxicity



Example 7
0
No phototoxicity



Example 8
0
No phototoxicity



Example 9
0
No phototoxicity



Example 10
0
No phototoxicity



Example 11
0
No phototoxicity



Example 12
0
No phototoxicity



Example 13
0
No phototoxicity



Example 14
0
No phototoxicity



Example 15
0
No phototoxicity



Example 16
0
No phototoxicity



Example 17
0
No phototoxicity



Example 18
0
No phototoxicity



Example 19
0
No phototoxicity



Example 20
0
No phototoxicity



Example 21
0
No phototoxicity



Example 22
0
No phototoxicity



Example 23
0
No phototoxicity



Example 24
0
No phototoxicity



Example 25
0
No phototoxicity



Example 26
0
No phototoxicity



Example 27
0
No phototoxicity



Example 28
0
No phototoxicity



Example 29
0
No phototoxicity



Example 30
0
No phototoxicity



Example 31
0
No phototoxicity



Example 32
0
No phototoxicity



Example 33
0
No phototoxicity



Example 34
0
No phototoxicity



Example 35
0
No phototoxicity



Example 36
0
No phototoxicity



Example 37
0
No phototoxicity



Example 38
0
No phototoxicity



Example 39
0
No phototoxicity



Example 40
0
No phototoxicity



Example 41
0
No phototoxicity



Example 42
0
No phototoxicity



Example 43
0
No phototoxicity



Example 44
0
No phototoxicity



Example 45
0
No phototoxicity



Example 46
0
No phototoxicity



Example 47
0
No phototoxicity



Example 48
0
No phototoxicity



Example 49
0
No phototoxicity



Example 50
0
No phototoxicity



Example 51
0
No phototoxicity



Example 52
0
No phototoxicity



Example 53
0
No phototoxicity



Example 54
0
No phototoxicity



Example 55
0
No phototoxicity










As shown in Table 7, hydroxamic acid derivatives obtained in Examples 1 to 55 were confirmed to have 0 of phototoxic index, which was lower value than 0.5, criterion value to be estimated as no phototoxicity.
Hydroxamic acid derivatives according to the present invention may be incorporated into skin-care external compositions. The present composition may be formulated into, but not limited to, cosmetic compositions such as skin softners, astringents, nutrient toilet water, nutrient creams, massage creams, essences, eye creams, eye essences, cleansing creams, cleansing foams, cleansing water, packs, powders, body lotions, body creams, body oils, body essences, make-up bases, foundations, hairdyes, shampoos, hair-conditioners and body cleansers; and pharmaceutical compositions such as ointment, gels, creams, patches, and sprays. And, each formulation may further contain bases and additives suitable for the preparation thereof, if necessary, whose kind and amount can be easily selected in this art.
<Formulation 1> Nutrient Toilet Water (Milk Lotion)
Nutrient toilet water containing said hydroxamic acid derivatives obtained in Examples 1 to 55 was prepared.














Ingredients
Amount (wt %)









 1. Distilled water
To 100



 2. Glycerin
8.0



 3. Butylene glycol
4.0



 4. Extracts with hyaluronic acid
5.0



 5. β-glucan
7.0



 6. Carbomer
0.1



 7. Hydroxamic acid derivative
q.s.



 8. Caprylic/Capric triglyeride
8.0



 9. Squalane
5.0



10. Cetearyl glucoside
1.5



11. Sorbitan stearate
0.4



12. Cetearyl alcohol
1.0



13. Preservative
q.s.



14. Perfume
q.s.



15. Pigments
q.s.



16. Triethanolamine
0.1










<Formulation 2> Nutrient Cream

Nutrient cream containing said hydroxamic acid derivatives obtained in Examples 1 to 55 was prepared.














Ingredients
Amount (wt %)









 1. Distilled water
To 100



 2. Glycerin
3.0



 3. Butylene glycol
3.0



 4. Liquid paraffin
7.0



 5. β-glucan
7.0



 6. Carbomer
0.1



 7. Hydroxamic acid derivative
q.s.



 8. Caprylic/Capric triglyeride
3.0



 9. Squalane
5.0



10. Cetearyl glucoside
1.5



11. Sorbitan stearate
0.4



12. Polysorbate 60
1.2



13. Preservative
q.s.



14. Perfume
q.s.



15. Pigments
q.s.



16. Triethanolamine
0.1










<Formulation 3> Massage Cream

Massage cream containing said hydroxamic acid derivatives obtained in Examples 1 to 55 was prepared.














Ingredients
Amount (wt %)









 1. Distilled water
To 100



 2. Glycerin
8.0



 3. Butylene glycol
4.0



 4. Liquid paraffin
45.0 



 5. β-glucan
7.0



 6. Carbomer
0.1



 7. Hydroxamic acid derivative
q.s.



 8. Caprylic/Capric triglyeride
3.0



 9. Beeswax
4.0



10. Cetearyl glucoside
1.5



11. Sorbitan sesquioleate
0.9



12. Vaseline
3.0



13. Preservative
q.s.



14. Perfume
q.s.



15. Pigments
q.s.



16. Paraffin
1.5










<Formulation 4> Ointment

Ointment containing said hydroxamic acid derivatives obtained in Examples 1 to 55 was prepared.














Ingredients
Amount (wt %)









 1. Distilled water
To 100



 2. Glycerin
8.0



 3. Butylene glycol
4.0



 4. Liquid paraffin
15.0 



 5. β-glucan
7.0



 6. Carbomer
0.1



 7. Hydroxamic acid derivative
q.s.



 8. Caprylic/Capric triglyeride
3.0



 9. Squalane
1.0



10. Cetearyl glucoside
1.5



11. Sorbitan stearate
0.4



12. Cetearyl alcohol
1.0



13. Preservative
q.s.



14. Perfume
q.s.



15. Pigments
q.s.



16. Beeswax
4.0










INDUSTRIAL APPLICATION OF THE INVENTION
As described in the above, hydroxamic acid derivatives according to the present invention can promote collagen biosynthesis and inhibit the expressions of collagenase and elastase by interacting to retinoic acid receptor. Furthermore, they do not cause skin irritation and skin toxicity, which have been drawbacks of retinoid compounds to be solved. Therefore, they can be incorporated into medicines or skin-care external compositions for improving skin elasticity and preventing skin aging.

## Claims

1. A hydroxamic acid derivative represented by the following formula(I):



wherein,
R1is





wherein, R5 and R6 each independently represents a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms or a cyclic alkyl group having from 3 to 6 carbon atoms;
R2 is CONH, NHCO, CONR7 or NR7CO, herein, R7 represents an alkyl group having from 1 to 10 carbon atoms;
R3 is —(CH2)n—, herein, n=0 or 1; and
R4 is a hydrogen atom or an alkyl group having from 1 to 10 carbon atoms;
on the proviso that compounds in which R1 is





wherein R5 and R6 each are H,
R2 is CONH, and n=0, and compounds in which R1 is




wherein R5 is H and R6 is CH3, R2 is CONH and n=0 or 1 are excluded.

2. The hydroxamic acid derivative according to claim 1, which is selected from the group consisting of
N-[4-(N-hydroxycarbamoyl)phenyl]benzamide,
N-[4-(N-hydroxycarbamoyl)phenyl][3 -methyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl][4-ethyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl][4-propyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl][4-isopropylphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl][4-butyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl][4-tert-butyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl][3,4-dimethylphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl]adamantyl carboxyamide, adamantyl-
N-[4-(N-hydroxy-N-methylcarbamoyl)phenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-benzamide,
N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-methyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[3 -methyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-ethyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-propyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-isopropylphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-butylphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[4-tert-butylphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-[3,4-dimethylphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoyl)phenyl]adamantyl-N-methylcarboxyamide, adamantyl-N-[4-(N-hydroxy-N-methylcarbamoyl)phenyl]-N-methylcarboxyamide,
N-[4-(N-hydroxycarbamoylmethyl)phenyl]beuzamide,
N-[4-(N-hydroxycarbamoylmethyl)phenyl][3 -methyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-ethyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-propyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-isopropyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-butyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoylmethyl)phenyl][4-tert-butyiphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoylmethyl)phenyl][3,4-dimethylphenyl]carboxyamide,
N-[4-(N-hydroxycarbamoylmethyl)phenyl]adamantyl carboxyamide,
2-[4-(adamantylcarbonylamino)phenyl]-N-hydroxy-N-methylacetamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-[4-methyiphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-[3-methyiphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-[4-ethyiphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-[4-propylphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-[4-isopropylphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-[4-butyiphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-[4-tert-butyiphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-[3,4-dimethylphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-adamantyl carboxyamide,
N-adamantyl [4-(N-hydroxy-N-methylcarbamoyl)phenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-benzamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-methyiphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[3-methyiphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-ethyiphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-propyiphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-isopropyiphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-butylphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[4-tert-butylphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-methyl-N-[3,4-dimethylphenyl]carboxyamide,
[4-(N-hydroxycarbamoyl)phenyl]-N-adamantyl-N-methylcarboxyamide, and
N-adamantyl [4-(N-hydroxy-N-methylcarbamoyl)phenyl]-N-methylcarboxyamide.

3. A method for preparing a hydroxamic acid represented by the following formula (I):



wherein
R1 is





wherein, R5 and R6 each independently represents a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms or a cyclic alkyl group having from 3 to 6 carbon atoms:
R2 is CONH, NHCO. CONR7 or NR7CO, herein, R7 represents an alkyl group having from 1 to 10 carbon atoms:
R3is —(CH2)n—, herein, n=0 or1: and
R4 is a hydrogen atom or an alkyl group having from 1 to 10 carbon atoms:
on the proviso that compounds in which R1 is





wherein R5 and R6 each are H,
R2 is CONH, and n=0, and compounds in which R1 is




wherein R5 is H and R6 is CH3, R2 is CONH and n=0 or 1 are excluded, which comprises the steps of:
(a) reacting benzoic acid or adamantanecarboxylic acid with methyl 4-aminobenzoate or 4-aminophenylacetic acid methylester, to produce a benzamide compound;
(b) optionally, substituting an amide bond of the benzamide formed in step (a) with an alkyl group, to produce an akyl-substituted benzamide compound;
(c) hydrolyzing a methylester of the benzamide formed in step (a) or the alkyl-substituted benzamide compounds formed in step (b), to produce an acid; and
(d) reacting said acid with hydroxylamine hydrochloride or N-methyl hydroxylamine hydrochloride, to produce a hydroxamic acid derivative.

4. A method for preparing a hydroxamic acid derivative represented by the following formula (I):



wherein,
R1 is





wherein, R5 and R6 each independently represents a hydrogen atom, an alkyl group having from 1 to 10 carbon atoms or a cyclic alkyl group having from 3 to 6 carbon atoms;
R2 is CONH, NHCO, CONR7 or NR7CO, herein, R7 represents an alkyl group having from 1 to 10 carbon atoms;
R3 is —(CH2)n—, herein, n=0 or 1: and
R4 is a hydrogen atom or an alkyl group having from 1 to 10 carbon atoms:
on the proviso that compounds in which R1 is





wherein R5 and R6 each are H,
R2 is CONH, and n=0, and compounds in which R1 is




wherein R5 is H and R6 is CH3,
R2 is CONH and n=0 or 1 are excluded which comprises the steps of:
(a) reacting aniline or adamantamine with monomethylterephthalate, to produce a benzamide compound;
(b) optionally, substituting an amide bond of the benzamide formed in step (a) with an alkyl group, to produce an akyl-substituted benzamide compound
(c) hydrolyzing a methylester of the benzamide formed in step (a) or the alkyl-substituted benzamide compounds formed in step (b), to produce an acid; and
(d) reacting said acid with hydroxylamine hydrochloride or N-methyl hydroxylamine hydrochloride, to produce a hydroxamic acid derivative.

5. A skin-care external composition for preventing skin aging, containing the hydroxamic acid derivative according to claim 1 as an active ingredient.

6. A collagenase expression-inhibiting agent containing the hydroxamic acid derivative according to claim 1 as an active ingredient.

7. An elastase expression-inhibiting agent containing the hydroxamic acid derivative according to claim 1 as an active ingredient.