JP4939941B2 - Hydroxamic acid derivative and method for producing the same - Google Patents

Description

ここで、Ｒ₅及びＲ₆は、水素、Ｃ_1-10のアルキルまたはＣ_3-6の環状アルキルであり；
Ｒ₂は、ＣＯＮＨ、ＮＨＣＯ、ＣＯＮＲ₇またはＮＲ₇ＣＯであり、この時、Ｒ₇は、Ｃ_1-10のアルキルであり；
Ｒ₃は、−（ＣＨ ₂ ）_n−であり、ｎ＝０、１であり；
Ｒ₄は、水素またはＣ_1-10のアルキルである（但し、Ｎ−［４−（Ｎ−ヒドロキシカルバモイル）フェニル］［４−メチルフェニル］カルボキシアミド、Ｎ−［４−（Ｎ−ヒドロキシカルバモイルメチル）フェニル］［４−メチルフェニル］カルボキシアミド、及び［４−（Ｎ−ヒドロキシカルバモイル）フェニル］−Ｎ−ベンズアミドの場合を除く）。 The present invention relates to a hydroxamic acid derivative having an anti-aging effect represented by the following chemical formula 1 and a method for producing the same:

Wherein R ₅ and R ₆ are hydrogen, C _1-10 alkyl or C _3-6 cyclic alkyl ;
R ₂ is CONH, NHCO, CONR ₇ or NR ₇ CO, wherein R ₇ is C _1-10 alkyl;
R ₃ is — (CH ₂ ) _n —, n = 0, 1;
R ₄ is hydrogen or C _1-10 alkyl (provided that N- [4- (N-hydroxycarbamoyl) phenyl] [4-methylphenyl] carboxamide, N- [4- (N-hydroxycarbamoylmethyl) ) Phenyl] [4-methylphenyl] carboxamide and [4- (N-hydroxycarbamoyl) phenyl] -N-benzamide) .

  All living organisms age with age, and so does the skin. This endeavor to delay aging continues continually, which continually raises questions about what aging is and why aging occurs. Skin aging is roughly divided into two types depending on the factor. First, natural aging results in a continuous decline as the skin structure and physiological function age. Secondly, extrinsic aging is caused by accumulated external stress such as sunlight. In particular, sunlight is one of the well-known causes of aging. Skin exposed to ultraviolet rays for a long time has a thickened stratum corneum, and collagen and elastin, which are the main components of the skin, have changed, and the elasticity of the skin Loses sex. Thus, skin aging is accompanied by various functional and structural changes.

  First, looking at the structural changes in the skin due to aging, the thickness of the epidermis, dermis and subcutaneous tissue, which are constituents of the skin, is reduced. In addition, the extracellular matrix (ECM) component of the dermis tissue responsible for skin elasticity and tension changes. The ECM is mainly composed of two components. One is elastic fiber that accounts for about 2-4% of the total ECM, and the other is collagen that accounts for about 70-80% of the total ECM. As aging progresses, the elasticity of the skin is greatly reduced due to a decrease in collagen and elastin. Collagen and elastin are regulated by various factors, but collagen and elastin produced by the expression of matrix metalloproteases such as collagenase and elastase are degraded, As a result, a phenomenon occurs in which the collagen content in the skin decreases. If collagen and elastin decrease in the dermis, the epidermis of the skin becomes rough and a decrease in elasticity, an aging phenomenon, appears.

  Various substances have been developed and used in order to suppress the decrease in collagen and elastin, which cause such a decrease in elasticity, but retinoids such as retinol and retinoic acid are particularly known to improve wrinkles or improve elasticity. (Dermatology therapy, 1998, 16, 357-364). However, these retinoids have the positive effect of improving wrinkles or elasticity, as well as the disadvantage that irritation appears when only a small amount is applied to the skin, and if exposed to the air due to instability, There are many restrictions on its use because it is easily oxidized and altered. As a result, research for stabilizing retinoids has been ongoing, but the present situation is that the problem of irritation to the skin, that is, safety, has not yet been solved.

  The retinoid refers to retinol, retinoic acid or a derivative thereof. Retinoids have a variety of biological effects, but they have been reported to have effects on hyperkeratinization and acne in relation to the skin. In relation to skin wrinkles, collagen production is promoted and collagenase, a collagenolytic enzyme. Inhibitory ability is generally accepted (The Journal of Investigative Dermatology, 1991, 96, 975-978). In addition, there is an effect of suppressing the expression of elastase in association with the decrease in elasticity.

  Looking at the development background of retinoids to date, it was initially developed as a derivatization by a simple modification of retinol and retinoic acid, and an example of such a modification is retinyl palmitate. Next, a derivative using benzoic acid, such a compound is called an arotinoid (J. Med. Chem, 1988, 31, 2182-2192). Recently, a compound in which a hetero atom is introduced into the benzene ring of an allotenoid compound has been developed, and this is called a heteroarotinoid (J. Med. Chem, 1999, 42, 4434-4445).

  The biological effects of retinoids appearing on the skin appear when the retinoids act on inter cellullar receptors called retinoic acid receptors (British Journal of dermatology, 1999, 140, 12-17). The structural features of retinoids are manifested by being composed of tetramethylcyclohexane, an unsaturated carbon bond and a carboxylic acid. In particular, the carboxylic acid moiety is an essential part for the effect of retinoids, and when acting on a receptor, it easily transforms into an anion (Chem. Pharm. Bull, 2001, 49 , 501-503).

Alloinoids have a structure in which benzoic acid is substituted for carboxylic acid of retinoic acid. Benzoic acid is easily transformed into an anion and acts as an anion. Recent research trends have synthesized derivatives that substitute for carboxylic acids using a variety of substituents. Research is progressing toward reducing the toxicity, unsafety and instability, which are the disadvantages of retinoids, while maintaining the efficacy of existing retinoids, while trying to obtain such substitutional modifications. It has been.
Dermatology therapy, 1998, 16, 357-364 The Journal of Investigative Dermatology, 1991, 96, 975-978 J. Med. Chem, 1988, 31, 2182-2192 J. Med. Chem, 1999, 42, 4434-4445 British Journal of dermatology, 1999, 140, 12-17 Chem. Pharm. Bull, 2001, 49, 501-503

  Under such circumstances, the present inventors studied a method that can solve the problem of skin irritation, which is a problem of retinoids, and at the same time, can solve the instability of the dosage form as a topical skin preparation. As a result, the hydroxamic acid derivatives have safety and stability without the skin irritation, discoloration, odor change, etc. exhibited by the conventional retinol and retinoic acid. It was discovered that it was a compound, and the present invention was completed.

  Accordingly, an object of the present invention is to provide a novel hydroxamic acid derivative that exhibits an effect of producing collagen by acting as a retinoid, suppresses expression of collagenase that is an enzyme that degrades collagen, and suppresses expression of elastase that is an enzyme that degrades elastin and its production It is to provide a method.

Hydroxamic acid is a substance widely known as a metal ion chelator. Looking at the structural characteristics of hydroxamic acid, the hydroxyl group of hydroxylamine adjacent to the carbonyl group forms a chelation with a metal ion.
Another feature is that the hydroxyl group of hydroxylamine easily forms an anion and can be used in a form similar to carboxylic acid. Using the structural properties of hydroxamic acid, a new retinoid was synthesized and confirmed to act as an agonist at the retinoic acid receptor. Thus, the example which acted as a retinoid while having the structure of hydroxamic acid has not been reported yet.

ここで、Ｒ₅及びＲ₆は、水素、Ｃ_1-10のアルキルまたはＣ_3-6の環状アルキルであり；
Ｒ₂は、ＣＯＮＨ、ＮＨＣＯ、ＣＯＮＲ₇またはＮＲ₇ＣＯであり、この時、Ｒ₇は、Ｃ_1-10のアルキルであり；
Ｒ₃は、−（ＣＨ ₂ ）_n−であり、ｎ＝０または１であり；
Ｒ₄は、水素またはＣ_1-10のアルキルである（但し、Ｎ−［４−（Ｎ−ヒドロキシカルバモイル）フェニル］［４−メチルフェニル］カルボキシアミド、Ｎ−［４−（Ｎ−ヒドロキシカルバモイルメチル）フェニル］［４−メチルフェニル］カルボキシアミド、及び［４−（Ｎ−ヒドロキシカルバモイル）フェニル］−Ｎ−ベンズアミドの場合を除く）。 The present invention relates to a hydroxamic acid derivative represented by the following chemical formula 1, which is a kind of retinoid:

Wherein R ₅ and R ₆ are hydrogen, C _1-10 alkyl or C _3-6 cyclic alkyl ;
R ₂ is CONH, NHCO, CONR ₇ or NR ₇ CO, wherein R ₇ is C _1-10 alkyl;
R ₃ is — (CH ₂ ) _n —, n = 0 or 1;
R ₄ is hydrogen or C _1-10 alkyl (provided that N- [4- (N-hydroxycarbamoyl) phenyl] [4-methylphenyl] carboxamide, N- [4- (N-hydroxycarbamoylmethyl) ) Phenyl] [4-methylphenyl] carboxamide and [4- (N-hydroxycarbamoyl) phenyl] -N-benzamide) .

The hydroxamic acid derivative, which is a new concept retinoid produced in the present invention, can be obtained by the following two production methods specifically exemplified below.
Looking at the process of preparing the hydroxamic acid derivative of Formula 1,
1) reacting benzoic acid or adamantanecarboxylic acid with methyl 4-aminobenzoate or 4-aminophenylacetic acid methyl ester to form an amide bond; or reacting monomethyl terephthalate with aniline or adamantamine; Forming an amide bond;
2) replacing the amide bond of the benzamide produced in the previous step with alkyl;
3) hydrolyzing the benzamide produced in the above step or an ester of benzamide substituted with an alkyl group; and 4) transforming the acid produced by the hydrolysis into hydroxamic acid;
Is provided.
In particular, in the last step, the efficiency was increased by reacting in one step without undergoing the protection / deprotection reaction in the process of producing the hydroxamic acid derivative.

Hereinafter, the present invention will be described more specifically.
The hydroxamic acid derivative, which is a new concept retinoid produced in the present invention, can be obtained by the following two production methods specifically exemplified below.
First, the manufacturing process 1 which is a manufacturing method of the hydroxamic acid derivative based on this invention,
a) reacting benzoic acid or adamantanecarboxylic acid with methyl 4-aminobenzoate or 4-aminophenylacetic acid methyl ester to produce a benzamide compound;
b) replacing the amide bond of the resulting benzamide with alkyl;
c) hydrolyzing the methyl ester of the resulting benzamide or alkyl group-substituted benzamide compound to produce an acid; and d) said acid and hydroxylamine hydrochloride or N-methylhydroxylamine hydrochloride; Reacting to produce a hydroxamic acid derivative;
Is provided.

上記式中、Ｒ₅及びＲ₆は、水素、Ｃ_1-10のアルキルまたはＣ_3-6の環状アルキルであり；
Ｒ₂は、ＣＯＮＨ、ＮＨＣＯ、ＣＯＮＲ₇またはＮＲ₇ＣＯであり、この時、Ｒ₇は、Ｃ_1-10のアルキルであり；
Ｒ₃は、−（ＣＨ ₂ ）_n−であり、ｎ＝０、１であり；
Ｒ₄は、水素またはＣ_1-10のアルキルである。 The production method according to the present invention will be specifically described with reference to the following reaction formula. First, the production process 1 can be represented by the following reaction formula 1.

Wherein R ₅ and R ₆ are hydrogen, C _1-10 alkyl or C _3-6 cyclic alkyl ;
R ₂ is CONH, NHCO, CONR ₇ or NR ₇ CO, wherein R ₇ is C _1-10 alkyl;
R ₃ is — (CH ₂ ) _n —, n = 0, 1;
R ₄ is hydrogen or C _1-10 alkyl.

  First, ethyl chloroformate is converted to an anhydrous compound using 1.2 equivalents of benzoic acid or adamantanecarboxylic acid. In this case, examples of the solvent that can be used include pyridine and N-methylmorpholine. The anhydrous compound synthesized at this stage is reacted with methyl 4-aminobenzoate or 4-aminophenylacetic acid methyl ester to produce a benzamide compound. Solvents that can be used for this reaction include pyridine, N-methylmorpholine, and the like. Also, in a solvent such as N, N-dimethylformamide, methylene chloride, chloroform, etc., the reaction can be allowed to proceed by using triethylamine together with 1.2 equivalent ratio of methyl 4-aminobenzoate or 4-aminophenylacetic acid methyl ester. it can. Most preferably pyridine is used. The reaction temperature is most preferably 10 to 20 ° C. At lower temperatures, the reaction product methyl 4-aminobenzoate or 4-aminophenylacetic acid methyl ester may remain and be removed from the reaction product. Not easy. Further, at a temperature of 20 ° C. or higher, the anhydrous compound is hydrolyzed and the yield of the reaction product is reduced.

  The synthesized benzamide compound is reacted with an alkyl halide in an N, N-dimethylformamide solvent to synthesize a benzamide compound in which an alkyl group is substituted on the amide bond. At this time, sodium hydride is used as a base in a 1.2 equivalent ratio of benzamide, and an alkyl halide is also used in a 1.2 equivalent ratio of benzamide. As the alkyl halide, bromomethane, bromoethane, bromopropane, bromoisopropane, bromobutane, bromotert-butane, or the like can be used.

  Next, a benzamide in which the alkyl group is not substituted on the amide bond and a methyl ester which is contained in the benzamide compound in which the alkyl group is substituted on the amide bond are hydrolyzed and converted to an acid. The acid produced is converted to the anhydrous compound using ethyl chloroformate, wherein the amount of ethyl chloroformate is used at 1.2 equivalents relative to the acid. Also at this time, pyridine, N-methylmorpholine, or the like can be used as the solvent.

  The anhydrous compound synthesized in the above step is reacted with hydroxylamine hydrochloride or N-methylhydroxylamine hydrochloride to produce a hydroxamic acid compound. Also in this reaction, pyridine, N-methylmorpholine, or the like can be used as a solvent, or in a solvent such as N, N-dimethylformamide, methylene chloride, chloroform or the like, triethylamine is converted to hydroxylamine hydrochloride 1. The reaction can be allowed to proceed using both at a 2 equivalent ratio. Most preferably, pyridine is used as the solvent. The ideal reaction temperature is 0 to 10 ° C, and at lower temperatures, the reaction product hydroxylamine hydrochloride or N-methylhydroxylamine hydrochloride remains, and the yield of the reaction product decreases. At higher temperatures, a by-product is obtained that reacts with hydroxylamine or the hydroxy group of N-methylhydroxylamine and is not easily removed from the reaction product.

上記式中、Ｒ₅及びＲ₆は、水素、Ｃ_1-10のアルキルまたはＣ_3-6の環状アルキルであり；
Ｒ₂は、ＣＯＮＨ、ＮＨＣＯ、ＣＯＮＲ₇またはＮＲ₇ＣＯであり、この時、Ｒ₇は、Ｃ_1-10のアルキルであり；
Ｒ₃は、−（ＣＨ ₂ ）_n−であり、ｎ＝０、１であり；
Ｒ₄は、水素またはＣ_1-10のアルキルである。 Production process 2 which is another method for producing the hydroxamic acid derivative according to the present invention comprises:
a) reacting aniline or adamantamine with monomethyl terephthalate to produce a benzamide compound;
b) replacing the amide bond of the resulting benzamide with alkyl;
c) hydrolyzing the methyl ester of the produced benzamide or alkyl group-substituted benzamide compound to produce an acid; and d) the produced acid and hydroxylamine hydrochloride or N-methylhydroxylamine hydrochloride. Reacting with a salt to produce a hydroxamic acid derivative;
This is represented by the following reaction formula 2.

Wherein R ₅ and R ₆ are hydrogen, C _1-10 alkyl or C _3-6 cyclic alkyl ;
R ₂ is CONH, NHCO, CONR ₇ or NR ₇ CO, wherein R ₇ is C _1-10 alkyl;
R ₃ is — (CH ₂ ) _n —, n = 0, 1;
R ₄ is hydrogen or C _1-10 alkyl.

  First, as can be seen from Reaction Scheme 2, monoterephthalate is converted to an anhydrous compound using ethyl chloroformate. The anhydrous compound thus synthesized is reacted with aniline or adamantamine to produce a benzamide compound. Subsequent reactions are carried out in the same manner as in Reaction Scheme 1.

As a specific example of the hydroxamic acid derivative of Chemical Formula 1 obtained by the above production method,
1. N- [4- (N-hydroxycarbamoyl) phenyl] benzamide,
2. N- [4- (N-hydroxycarbamoyl) phenyl] [4-methylphenyl] carboxamide,
3. N- [4- (N-hydroxycarbamoyl) phenyl] [3-methylphenyl] carboxamide;
4). N- [4- (N-hydroxycarbamoyl) phenyl] [4-ethylphenyl] carboxamide;
5. N- [4- (N-hydroxycarbamoyl) phenyl] [4-propylphenyl] carboxamide;
6). N- [4- (N-hydroxycarbamoyl) phenyl] [4-isopropylphenyl] carboxamide,
7). N- [4- (N-hydroxycarbamoyl) phenyl] [4-butylphenyl] carboxamide;
8). N- [4- (N-hydroxycarbamoyl) phenyl] [4-tert-butylphenyl] carboxamide,
9. N- [4- (N-hydroxycarbamoyl) phenyl] [3,4-dimethylphenyl] carboxamide,
10. N- [4- (N-hydroxycarbamoyl) phenyl] adamantylcarboxamide,
11. Adamantyl-N- [4- (N-hydroxy-N-methylcarbamoyl) phenyl] carboxamide;
12 N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-benzamide,
13. N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl- [4-methylphenyl] carboxamide;
14 N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl- [3-methylphenyl] carboxamide;
15. N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl- [4-ethylphenyl] carboxamide;
16. N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl- [4-propylphenyl] carboxamide;
17. N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl- [4-isopropylphenyl] carboxamide;
18. N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl- [4-butylphenyl] carboxamide;
19. N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl- [4-tert-butylphenyl] carboxamide;
20. N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl- [3,4-dimethylphenyl] carboxamide;
21. N- [4- (N-hydroxycarbamoyl) phenyl] adamantyl-N-methylcarboxamide;
22. Adamantyl-N- [4- (N-hydroxy-N-methylcarbamoyl) phenyl] -N-methylcarboxamide;
23. N- [4- (N-hydroxycarbamoylmethyl) phenyl] benzamide,
24. N- [4- (N-hydroxycarbamoylmethyl) phenyl] [4-methylphenyl] carboxamide,
25. N- [4- (N-hydroxycarbamoylmethyl) phenyl] [3-methylphenyl] carboxamide,
26. N- [4- (N-hydroxycarbamoylmethyl) phenyl] [4-ethylphenyl] carboxamide,
27. N- [4- (N-hydroxycarbamoylmethyl) phenyl] [4-propylphenyl] carboxamide,
28. N- [4- (N-hydroxycarbamoylmethyl) phenyl] [4-isopropylphenyl] carboxamide,
29. N- [4- (N-hydroxycarbamoylmethyl) phenyl] [4-butylphenyl] carboxamide,
30. N- [4- (N-hydroxycarbamoylmethyl) phenyl] [4-tert-butylphenyl] carboxamide,
31. N- [4- (N-hydroxycarbamoylmethyl) phenyl] [3,4-dimethylphenyl] carboxamide,
32. N- [4- (N-hydroxycarbamoylmethyl) phenyl] adamantylcarboxamide,
33.2- [4- (adamantylcarbonyl) phenyl] -N- hydroxy -N- methylacetamide,
34. [4- (N-hydroxycarbamoyl) phenyl] -N-benzamide,
35. [4- (N-hydroxycarbamoyl) phenyl] -N- [4-methylphenyl] carboxamide,
36. [4- (N-hydroxycarbamoyl) phenyl] -N- [3-methylphenyl] carboxamide,
37. [4- (N-hydroxycarbamoyl) phenyl] -N- [4-ethylphenyl] carboxamide,
38. [4- (N-hydroxycarbamoyl) phenyl] -N- [4-propylphenyl] carboxamide,
39. [4- (N-hydroxycarbamoyl) phenyl] -N- [4-isopropylphenyl] carboxamide,
40. [4- (N-hydroxycarbamoyl) phenyl] -N- [4-butylphenyl] carboxamide,
41. [4- (N-hydroxycarbamoyl) phenyl] -N- [4-tert-butylphenyl] carboxamide,
42. [4- (N-hydroxycarbamoyl) phenyl] -N- [3,4-dimethylphenyl] carboxamide,
43. [4- (N-hydroxycarbamoyl) phenyl] -N-adamantylcarboxamide,
44. N-adamantyl [4- (N-hydroxy-N-methylcarbamoyl) phenyl] carboxamide;
45. [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N-benzamide,
46. [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N- [4-methylphenyl] carboxamide,
47. [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N- [3-methylphenyl] carboxamide,
48. [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N- [4-ethylphenyl] carboxamide,
49. [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N- [4-propylphenyl] carboxamide,
50. [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N- [4-isopropylphenyl] carboxamide,
51. [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N- [4-butylphenyl] carboxamide,
52. [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N- [4-tert-butylphenyl] carboxamide,
53. [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N- [3,4-dimethylphenyl] carboxamide,
54. [4- (N-hydroxycarbamoyl) phenyl] -N-adamantyl-N-methylcarboxamide,
55. N-adamantyl [4- (N-hydroxy-N-methylcarbamoyl) phenyl] -N-methylcarboxamide is mentioned.

  The hydroxamic acid derivative of Formula 1 prepared by the above-described process is a retinoid, acts as an agonist at the retinoic acid receptor, and increases collagen production due to the retinoid effect and collagen. It has the effect of suppressing the expression of collagenase, an enzyme that degrades, and elastase, an enzyme that degrades elastin. Therefore, the hydroxamic acid derivative of Chemical Formula 1 produced in the present invention can be used as an active ingredient of pharmaceuticals and skin external preparations that exhibit an effect of improving skin elasticity.

[Mode for carrying out the present invention]
Hereinafter, the manufacturing method of the hydroxamic acid compound according to the present invention will be specifically described by way of examples. However, these examples are for explaining the present invention, and it is obvious to those skilled in the art that the scope of the present invention is not limited to these examples.

[Example 1] Preparation of N- [4- (N-hydroxycarbamoyl) phenyl] benzamide 20.0 g of benzoic acid (0.16 mol) was dissolved in 250 mL of pyridine, cooled in an ice water bath at 10 ° C, and ethyl chloroformic acid. 23.1 g (0.21 mol) of salt was added dropwise for 30 minutes. After stirring at room temperature for 2 hours, the reaction solution was filtered to remove salts, and then an anhydrous compound (30.2 g, 0.15 mol) was obtained. 24.1 g (0.16 mol) of methylaminobenzoate was dissolved in 250 mL of pyridine, cooled in an ice water bath at 10 ° C., and the anhydrous compound obtained in the previous step was added dropwise for 30 minutes. After further stirring for 2 hours, the solvent was distilled off and the residue was dissolved in 300 mL of ethyl acetate. The ethyl acetate solution was washed with 5% hydrochloric acid and distilled water, dried over magnesium sulfate and activated carbon, and decolorized. Insolubles were filtered, and the filtrate was evaporated under reduced pressure to give the reaction product methyl 4- (phenylcarbonylamino) benzoate (34.7 g, 85% yield) as a rice solid.

  Next, methyl 4- (phenylcarbonylamino) benzoate (34.7 g) was dissolved in 500 mL of methanol, and then 50 mL of a 10% KOH solution was added and stirred for 3 hours. After stirring, the solution was neutralized with a hydrochloric acid solution, and the resulting solid was filtered to obtain 4- (phenylcarbonylamino) benzoic acid (26.2 g, 80% yield) as an acid compound.

  The produced 4- (phenylcarbonylamino) benzoic acid (24.1 g, 0.10 mol) was dissolved in 200 mL of pyridine, cooled in an ice water bath at 10 ° C., and 22.9 g (0.13 mol) of ethyl chloroformate was added to 30 mL. Added dropwise for minutes. After stirring at room temperature for 2 hours, the reaction solution was filtered to remove the salt to obtain an anhydrous compound (38.7 g, 0.12 mol).

6.9 g of hydroxylamine hydrochloride (0.10 mol) was dissolved in 100 mL of pyridine, cooled in an ice water bath at 10 ° C., and the anhydrous compound obtained in the previous step was added dropwise for 30 minutes. After further stirring for 2 hours, the solvent was distilled off and the residue was dissolved in 300 mL of ethyl acetate. The ethyl acetate solution was washed with 5% hydrochloric acid and distilled water, dried over magnesium sulfate and activated carbon, and decolorized. Insolubles were filtered and the filtrate was evaporated under reduced pressure to give the final product N- [4- (N-hydroxycarbamoyl) phenyl] benzamide (16.6 g, 65% yield) as a rice solid. .
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.53
¹ H NMR (DMSO-d ₆ ): δ 11.23 (s, 1H), 10.39 (s, 1H), 9.04 (s, 1H), 8.01 (m, 5H), 7.64 ( m, 4H)

Reference Example 1 Preparation of N- [4- (N-hydroxycarbamoyl) phenyl] [4-methylphenyl] carboxamide Example 1 was used except that 4-methylbenzoic acid was used instead of benzoic acid. A similar method was used to obtain the target product (11.9 g, 44%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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), 2.33 (s, 3H)

Example 3 Preparation of N- [4- (N-hydroxycarbamoyl) phenyl] [3-methylphenyl] carboxamide Example 1 was used except that 3-methylbenzoic acid was used instead of benzoic acid. A similar method was used to obtain the desired product (11.2 g, 43%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.50
¹ H NMR (DMSO-d ₆ ): δ 11.21 (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] carboxamide Example 1 was used except that 4-ethylbenzoic acid was used instead of benzoic acid. A similar method was used to obtain the desired product (11.4 g, 39%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 4); R _f = 0.54
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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] carboxamide Example 1 was used except that 4-propylbenzoic acid was used instead of benzoic acid. A similar method was used to obtain the desired product (12.5 g, 42%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.55
¹ H NMR (DMSO-d ₆ ): δ 11.23 (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] carboxamide Example 1 was used except that 4-isopropylbenzoic acid was used instead of benzoic acid. A similar method was used to obtain the desired product (14.3 g, 48%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.50
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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] carboxamide Example 1 was used except that 4-butylbenzoic acid was used instead of benzoic acid. A similar method was used to obtain the target product (12.8 g, 41%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.53
¹ H NMR (DMSO-d ₆ ): 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] carboxamide Except for using 4-tert-butylbenzoic acid instead of benzoic acid, The target product (11.8 g, 46%) was obtained as a rice-colored solid using the same method as in Example 1.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): 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] carboxamide Except for using 3,4-dimethylbenzoic acid instead of benzoic acid, The target product (11.9 g, 44%) was obtained as a rice-colored solid using the same method as in Example 1.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.53
¹ H NMR (DMSO-d ₆ ): δ 11.23 (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] adamantylcarboxamide Using a method similar to Example 1 except that adamantanecarboxylic acid is used instead of benzoic acid. The desired product (16.6 g, 65%) was obtained as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.53
¹ H NMR (DMSO-d ₆ ): δ 11.22 (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) phenylcarboxamide Performed except that N-methylhydroxylamine hydrochloride was used instead of hydroxylamine hydrochloride. The same method as in Example 10 was used to obtain the desired product (11.2 g, 43%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.50
¹ H NMR (DMSO-d ₆ ): δ 9.98 (s, 1H), 91.2 (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) obtained in the intermediate stage of Example 1 .16 mol) was dissolved in 250 mL of N, N-dimethylformamide, cooled in an ice water bath at 10 ° C., and sodium hydride (20.7 g, 0.16 mol) was dissolved in 50 mL of N, N-dimethylformamide and slowly added dropwise. . Bromomethane (32 g, 0.16 mol) was added dropwise to the reaction solution, and the reaction solution was further stirred for 1 hour. After further stirring for 2 hours, the solvent was distilled off and the residue was dissolved in 300 mL of ethyl acetate. The ethyl acetate solution was washed with 5% hydrochloric acid and distilled water, dried over magnesium sulfate and activated carbon, and decolorized. Insolubles were filtered and the filtrate was evaporated under reduced pressure to give the reaction product methyl 4- (phenylcarbonylamino) -N-methyl-benzoate (33.5 g, 85% yield) as a rice solid. . Subsequent methods used the same method as Example 1, and obtained the target object (12.8g, 38%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.52
¹ H NMR (DMSO-d ₆ ): δ 11.23 (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] carboxamide Methyl 4-[(4-methyl) obtained in the intermediate stage of Example 2 The target product (12.2 g, 44%) was obtained as a rice-colored solid using the same method as in Example 12 except that phenyl) carbonylamino] benzoate was used.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.53
¹ H NMR (DMSO-d ₆ ): δ 11.21 (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] carboxamide Methyl 4-[(3-methyl) obtained in the intermediate stage of Example 3 The target product (12.2 g, 44%) was obtained as a rice-colored solid using the same method as in Example 12 except that phenyl) carbonylamino] benzoate was used.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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] carboxamide Methyl 4-[(4-ethyl) obtained in the intermediate stage of Example 4 The target product (10.4 g, 42%) was obtained as a rice-colored solid using the same method as in Example 12 except that phenyl) carbonylamino] benzoate was used.
TLC (ethyl acetate: hexane = 1: 4) R _f = 0.50
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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] carboxamide Methyl 4-[(4-propyl) obtained in an intermediate stage of Example 5 The target product (11.4 g, 43%) was obtained as a rice-colored solid using the same method as in Example 12, except that phenyl) carbonylamino] benzoate was used.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.55
¹ H NMR (DMSO-d ₆ ): δ 11.23 (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] carboxamide Methyl 4-[(4-isopropyl) obtained in an intermediate stage of Example 6 The target product (10.1 g, 40%) was obtained as a rice-colored solid using the same method as in Example 12 except that phenyl) carbonylamino] benzoate was used.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.50
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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 = 6.9Hz)

Example 18 Preparation of N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl- [4-butylphenyl] carboxamide Methyl 4-[(4-butyl) obtained in an intermediate stage of Example 7 The target product (12.1 g, 47%) was obtained as a rice-colored solid using the same method as in Example 12, except that phenyl) carbonylamino] benzoate was used.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.53
¹ H NMR (DMSO-d ₆ ): 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] carboxamide Methyl 4-[(tert The target product (11.1 g, 43%) was obtained as a rice-colored solid using the same method as in Example 12, except that -butylphenyl) carbonylamino] benzoate was used.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): 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-hydroxycarbamoyl) phenyl] -N-methyl- [3,4-dimethylphenyl] carboxamide Methyl 4-[(3 , 4-Dimethylphenyl) carbonylamino] benzoate was used in the same manner as in Example 12 to obtain the desired product (12.2 g, 44%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.52
¹ H NMR (DMSO-d ₆ ): δ 11.25 (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-methylcarboxamide The use of methyl 4- (adamantylcarbonylamino) benzoate obtained in the intermediate stage of Example 10 Except for the above, the target product (12.8 g, 38%) was obtained as a rice-colored solid using the same method as in Example 12.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.53
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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-methylcarboxamide Substituting N-methylhydroxylamine hydrochloride for hydroxylamine hydrochloride The target product (11.4 g, 39%) was obtained as a rice-colored solid using the same method as in Example 21, except for.
TLC (ethyl acetate: hexane = 1: 4) R _f = 0.54
¹ H NMR (DMSO-d ₆ ): δ 9.95 (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 Similar to Example 1 except that 4-aminophenylacetic acid methyl ester was used instead of methyl 4-aminobenzoate. The target product (10.0 g, 39%) was obtained as a rice-colored solid using the above method.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.53
¹ H NMR (DMSO-d ₆ ): δ 11.23 (s, 1H), 10.39 (s, 1H), 9.04 (s, 1H), 8.01 (m, 5H), 7.64 ( m, 4H), 3.20 (s, 2H)

Reference Example 2 Preparation of N- [4- (N-hydroxycarbamoylmethyl) phenyl] [4-methylphenyl] carboxamide Except for the use of methyl 4-aminophenylacetate instead of methyl 4-aminobenzoate In the same manner as in Example 2, the target product (11.9 g, 44%) was obtained as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.52
¹ H NMR (DMSO-d ₆ ): δ 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] carboxamide Except using 4-aminophenylacetic acid methyl ester instead of methyl 4-aminobenzoate In the same manner as in Example 3, the target product (11.9 g, 44%) was obtained as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.54
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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] carboxamide Except for the use of 4-aminophenylacetic acid methyl ester instead of methyl 4-aminobenzoate In the same manner as in Example 4, the target product (12.9 g, 45%) was obtained as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 4) R _f = 0.50
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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] carboxamide Except for the use of methyl 4-aminophenylacetic acid instead of methyl 4-aminobenzoate In the same manner as in Example 5, the target product (13.1 g, 46%) was obtained as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.55
¹ H NMR (DMSO-d ₆ ): δ 11.23 (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] carboxamide Except for the use of 4-aminophenylacetic acid methyl ester instead of methyl 4-aminobenzoate In the same manner as in Example 6, the target product (11.1 g, 43%) was obtained as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.50
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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 = 6.9Hz)

Example 29 Preparation of N- [4- (N-hydroxycarbamoylmethyl) phenyl] [4-butylphenyl] carboxamide Except for the use of methyl 4-aminophenylacetic acid instead of methyl 4-aminobenzoate In the same manner as in Example 7, the target product (11.9 g, 44%) was obtained as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.53
¹ H NMR (DMSO-d ₆ ): 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] carboxamide Using 4-aminophenylacetic acid methyl ester instead of methyl 4-aminobenzoate The target product (12.0 g, 42%) was obtained as a rice-colored solid using the same method as in Example 8, except for.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): 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] carboxamide Using 4-aminophenylacetic acid methyl ester instead of methyl 4-aminobenzoate The target product (11.9 g, 44%) was obtained as a rice-colored solid using the same method as in Example 9, except for.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.52
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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] adamantylcarboxamide Example 10 except that 4-aminophenylacetic acid methyl ester was used instead of methyl 4-aminobenzoate Was used to obtain the desired product (11.9 g, 44%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.52
¹ H NMR (DMSO-d ₆ ): δ 11.22 (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] 2- except using [4- (adamantylcarbonyl) phenyl] -N- hydroxy-N-N-methylhydroxylamine hydrochloride instead of manufacturing hydroxylamine hydrochloride methylacetamide The target product (12.8 g, 41%) was obtained as a rice-colored solid using the same method as in Example 32.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.53
¹ H NMR (DMSO-d ₆ ): δ 9.95 (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)

Reference Example 3 Preparation of [4- (N-hydroxycarbamoyl) phenyl] -N-benzamide Example 1 except that monoterephthalate is used in place of benzoic acid and aniline is used in place of methyl 4-aminobenzoate Was used to obtain the desired product (11.8 g, 46%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.21 (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] carboxamide Monoterephthalate instead of benzoic acid, 4-methylaniline instead of methyl 4-aminobenzoate A target product (11.6 g, 43%) was obtained as a rice-colored solid using the same method as in Example 1 except that it was used.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.49
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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] carboxamide Monoterephthalate instead of benzoic acid, 3-methylaniline instead of methyl 4-aminobenzoate A target product (11.6 g, 43%) was obtained as a rice-colored solid using the same method as in Example 1 except that it was used.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.49
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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] carboxamide Monoterephthalate was used instead of benzoic acid and 4-methylbenzoate was used instead of methyl 4-aminobenzoate. The target product (12.8 g, 45%) was obtained as a rice-colored solid using the same method as in Example 1 except that ethylaniline was used.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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] carboxamide Monoterephthalate was used instead of benzoic acid and 4-methylbenzoate was used instead of methyl 4-aminobenzoate. The target product (11.6 g, 39%) was obtained as a rice-colored solid using the same method as in Example 1 except that propylaniline was used.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.53
¹ H NMR (DMSO-d ₆ ): δ 11.22 (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] carboxamide Monoterephthalate was used instead of benzoic acid and 4-methylbenzoate was used instead of methyl 4-aminobenzoate. The target product (12.2 g, 41%) was obtained as a rice-colored solid using the same method as in Example 1 except that isopropylaniline was used.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.20 (s, 1H), 10.31 (s, 1H), 9.11 (s, 1H), 8.11 (d, 2H, J = 7.8 Hz ), 7.9 (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] carboxamide Monoterephthalate was used instead of benzoic acid and 4-methylbenzoate was used instead of methyl 4-aminobenzoate. The target product (12.8 g, 41%) was obtained as a rice-colored solid using the same method as in Example 1 except that butylaniline was used.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.21 (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] carboxamide Substituting monoterephthalate for benzoic acid and replacing methyl 4-aminobenzoate The target product (12.8 g, 41%) was obtained as a rice-colored solid using the same method as in Example 1 except that 4-tert-butylaniline was used.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.21 (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] carboxamide Substituting monoterephthalate for benzoic acid and replacing methyl 4-aminobenzoate The target product (11.6 g, 43%) was obtained as a rice-colored solid using the same method as in Example 1, except that 3,4-dimethylaniline was used.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.49
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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-adamantylcarboxamide Except for the use of monoterephthalate instead of adamantanecarboxylic acid and adamantamine instead of methyl 4-aminobenzoate In the same manner as in Example 10, the target product (11.8 g, 46%) was obtained as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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] carboxamide Performed except that N-methylhydroxylamine hydrochloride was used instead of hydroxylamine hydrochloride. The same method as in Example 43 was used to obtain the target product (11.8 g, 46%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 9.99 (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 Example 12 using methyl 4- (phenylcarbamoyl) benzoate obtained in an intermediate stage of Example 34 Was used to obtain the desired product (12.0 g, 40%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.21 (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] carboxamide Methyl 4-[(4-methyl) obtained in an intermediate stage of Example 35 The target product (11.0 g, 39%) was obtained as a rice-colored solid using the same method as Example 12 using [phenyl] carbamoyl] benzoate.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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] carboxamide Methyl 4-[(3-methyl) obtained in an intermediate stage of Example 36 The target product (11.0 g, 39%) was obtained as a rice-colored solid using the same method as Example 12 using [phenyl] carbamoyl] benzoate.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.21 (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] carboxamide Methyl 4-[(4-ethyl) obtained in an intermediate stage of Example 37 The target product (12.0 g, 40%) was obtained as a rice-colored solid using the same method as in Example 12 using [phenyl] carbamoyl] benzoate.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.55
¹ H NMR (DMSO-d ₆ ): δ 11.22 (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] carboxamide Methyl 4-[(4-propyl) obtained in an intermediate stage of Example 38 The target product (12.8 g, 41%) was obtained as a rice-colored solid using the same method as Example 12 using [phenyl] carbamoyl] benzoate.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.55
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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] carboxamide Methyl 4-[(4-isopropyl) obtained in an intermediate stage of Example 39 The target product (13.2 g, 44%) was obtained as a rice-colored solid using the same method as Example 12 using [phenyl] carbamoyl] benzoate.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.21 (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 = 6.9Hz)

Example 51 Preparation of [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N- [4-butylphenyl] carboxamide Methyl 4-[(4-butyl) obtained in an intermediate stage of Example 40 The target product (12.0 g, 40%) was obtained as a rice-colored solid using the same method as in Example 12 using [phenyl] carbamoyl] benzoate.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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 Methyl 4-[(tert -Butylphenyl) carbamoyl] benzoate was used in the same manner as in Example 12 to obtain the desired product (12.5 g, 41%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.22 (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] carboxamide Methyl 4-[(3 , 4-Dimethylphenyl) carbamoyl] benzoate was used in the same manner as in Example 12 to obtain the desired product (11.0 g, 39%) as a rice-colored solid.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.20 (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-methylcarboxamide Methyl 4- (N-adamantyl-N-methylcarbamoyl) obtained in the intermediate stage of Example 43 The target product (11.8 g, 46%) was obtained as a rice-colored solid using the same method as in Example 12 using benzoate.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 11.22 (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-methylcarboxamide Substituting N-methylhydroxylamine hydrochloride for hydroxylamine hydrochloride. Except for the above, the target product (11.8 g, 46%) was obtained as a rice-colored solid using the same method as in Example 54.
TLC (ethyl acetate: hexane = 1: 1); R _f = 0.51
¹ H NMR (DMSO-d ₆ ): δ 9.93 (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)

[Test Example 1] Affinity measurement of retinoic acid receptor The retinoic acid receptor affinity of the hydroxamic acid derivatives obtained in Examples 1 to 55 and Reference Examples 1 to 3 was measured in comparison with retinol and retinoic acid.
Receptor expression plasmids (plasmid), pECE-RAR alpha and pECE-RAR gamma were prepared by the previous method (Mol. Cell. Biol. 1996, 16, 1138-1149). The RARE reporter RARE-tk-Luc was obtained by inserting the RARE fragment obtained from b-RARE-tk-CAT into the pGL3 luciferase basic vector. CV-1 cells were obtained from ATCC (American Type culture collection). In the test, 5,000 cells of CV-1 cells were placed in a 96-well microtiter plate containing DMEM (Dulbecco's Modified Eagle's Media) medium containing 2.5% fetal bovine serum. / The cells were separated and cultured to form wells. After 24 hours, pECE-RAR alpha (10 ng), pECE-RAR gamma (10 ng) were converted to reporter plasmid (100 ng), beta-galactosidase (Lipofectamine Plus (GIBCO BRL, grandisland, NY)). ) The expression vector (100 ng) was transfected. After 24 hours, the hydroxamic acid derivatives of Examples 1 to 55 and Reference Examples 1 to 3 , retinol were treated at 10 ⁻⁴ molar concentration, and retinoic acid was 10 ⁻⁵ molar concentration, which is 10 times lower than this. For 24 hours.

From the results of such retinoic acid receptor affinity, it can be seen that the hydroxamic acid derivatives obtained from Examples 1 to 55 and Reference Examples 1 to 3 are regarded as retinoid compounds.

[Test Example 2] Collagen Biosynthesis Promotion The collagen biosynthesis promotion effect of the hydroxamic acid derivatives obtained in Examples 1 to 55 and Reference Examples 1 to 3 was measured in comparison with retinol and retinoic acid.
Fibroblasts were seeded at 10 ⁵ per well in 24 wells and cultured until they grew to about 90%. After culturing this in a serum-free DMEM medium for 24 hours, the hydroxamic acid derivatives, retinol and retinoic acid of Examples 1 to 55 and Reference Examples 1 to 3 dissolved in the serum-free medium were treated at a concentration of 10 ⁻⁴ . The cells were cultured for 24 hours in a CO ₂ incubator. These supernatants were scooped and the increase or decrease of procollagen was examined using a procollagen type (I) ELISA kit. The results are shown in Table 2, and the synthetic ability is compared with the untreated group as 100.

[Test Example 3] Measurement of Collagenase Expression Inhibitory Efficacy The hydroxamic acid derivatives obtained from Examples 1 to 55 and Reference Examples 1 to 3 were measured for their ability to inhibit collagenase production in comparison with retinol and retinoic acid.
The test was performed by placing 5,000 human fibroblasts in a 96-well microtiter plate containing DMEM (Dulbecco's Modified Eagle's Media) medium containing 2.5% fetal bovine serum. The cells were added so as to become cells / well and cultured until they were grown to about 90%. Then, after culturing in a serum-free DMEM medium for 24 hours, the hydroxamic acid derivatives, retinol and retinoic acid of Examples 1 to 55 and Reference Examples 1 to 3 dissolved in the serum-free DMEM medium for 24 hours at a concentration of 10 ^−4. After the treatment, the cell culture medium was collected.

  The degree of collagenase production was measured for the collected cell culture solution using a commercially available collagenase measuring instrument (Amersham Pamasha, USA). First, the collected cell culture solution was added to a 96-well plate uniformly coated with the primary collagenase antibody, and the antigen-antibody reaction was carried out in a thermostatic bath for 3 hours.

  After 3 hours, a secondary collagen antibody to which a chromophore was bound was added to the 96-well plate and allowed to react for another 15 minutes. After 15 minutes, a color-inducing substance is added, color development is induced at room temperature for 15 minutes, and further, 1M sulfuric acid is added to stop the reaction (color development). The degree of yellow appeared differently depending on the degree.

The absorbance of the 96-well flat plate exhibiting yellow was measured at 405 nm using an absorptiometer, and the degree of collagenase synthesis was calculated according to the following mathematical formula 1. At this time, the reaction absorbance of the cell culture solution collected from the group not treated with the composition was used as a control group.
[Mathematical Formula 1]
Collagenase expression level (%) = (absorbance of the above-mentioned substance-treated cell group / absorbance of the control group) × 100

  The results of measuring inhibition of collagenase expression in cells are shown in Table 3 below, and it was confirmed that the hydroxamic acid derivative according to the present invention inhibits collagenase expression in vitro. The expression inhibition ability is a comparison with the synthesis ability of the untreated group as 100.

[Test Example 4] Measurement of Elastase Expression Inhibitory Efficacy The hydroxamic acid derivatives obtained from Examples 1 to 55 and Reference Examples 1 to 3 were measured for the elastase production inhibitory ability in comparison with retinol and retinoic acid.
In the test, 5,000 human fibroblasts were placed in a 96-well microtiter plate containing DMEM (Dulbecco's Modified Eagle's Media) medium containing 2.5% fetal bovine serum. / It added so that it might become a well (well), and it culture | cultivated until it grew about 90%. Then, after culturing in a serum-free DMEM medium for 24 hours, the hydroxamic acid derivatives, retinol and retinoic acid of Examples 1 to 55 and Reference Examples 1 to 3 dissolved in the serum-free DMEM medium for 24 hours at a concentration of 10 ^−4. After the treatment, the cell culture medium was collected.

  The degree of elastase production was measured using the commercially available elastase measuring instrument (Amersham Pamasha, USA). First, the collected cell culture solution was added to a 96-well plate uniformly coated with the primary elastase antibody, and the antigen-antibody reaction was carried out in a thermostatic bath for 3 hours.

  After 3 hours, a secondary elastin antibody to which a chromophore was bound was added to the 96-well plate and allowed to react for an additional 15 minutes. After 15 minutes, a color-inducing substance is added, color development is induced at room temperature for 15 minutes, and further, 1M sulfuric acid is added to stop the reaction (color development). The degree of yellow appeared different depending on the degree.

The absorbance of the 96-hole flat plate exhibiting yellow was measured at 405 nm using an absorptiometer, and the degree of synthesis of elastase was calculated by the following mathematical formula 2. At this time, the reaction absorbance of the cell culture solution collected from the group not treated with the composition was used as a control group.
[Mathematical formula 2]
Elastase expression level (%) = (absorbance of the above-mentioned substance-treated cell group / absorbance of the control group) × 100

  The results of measuring the inhibition of elastase expression in cells are shown in Table 4 below, and it was confirmed that the hydroxamic acid derivative according to the present invention inhibits elastase expression in vitro. The expression inhibition ability is a comparison with the synthesis ability of the untreated group as 100.

[Test Example 5] Primary skin irritation test for animals 1) Test method Using 56 healthy male rabbits, after removing the hair on each back part, the size of about 2.5 cm x 2.5 cm, left side The compartment is a control compartment, nothing is applied, and the right compartment is a 1% solution of the compound of Examples 1 to 55 and Reference Examples 1 to 3 (1,3-butylene glycol: ethanol = 7 as solvent): 3 use) was applied 0.5 mL each. Examine the presence of irritation such as erythema, scab formation and edema formation occurring 24 hours and 72 hours after application. Evaluation of skin reaction is based on the following table using the “toxicity test criteria for pharmaceuticals”. Scored as 5.
In addition, determination of the degree of irritation with respect to the evaluation result is based on Draize's P.A. I. I. (Primary Irritation Index) was calculated and the results are shown in Table 6 below in comparison with retinoic acid.

As can be seen from Table 6, the hydroxamic acid derivatives prepared in Examples 1 to 55 and Reference Examples 1 to 3 did not cause skin irritation. Accordingly, since the hydroxamic acid derivative according to the present invention maintains the same level of elasticity improvement effect as that of conventional retinol or retinoic acid, it has excellent stability and less skin irritation. It turned out that it can be used conveniently for a composition.

[Test Example 6] Phototoxicity test After removing the hair parts of the 25 white guinea pigs, the fixing device was fixed, and 3 parts were determined on each side of the back by 2 cm x 2 cm sections. The right compartment was the light blocking control site and the left compartment was the light irradiated site. As a negative control group, an excipient (vehicle; 1,3-butylene glycol: ethanol = 7: 3 used) was used, and 0.1% 8-MOP (methoxypsoralene) was used as a positive control group. 55 and 1% (w / v) solution of hydroxamic acid derivatives of Reference Examples 1 to 3 dissolved in a solvent mixed with 1,3-butylene glycol: ethanol = 7: 3 was applied in an amount of 50 μL.

After 30 minutes, the left part of the animal was shielded with aluminum foil, and irradiated with UVA (320-380 nm) from a distance of about 10 cm using a UV device (Waldmann) so that the final energy was 15 J / cm ² . . Thereafter, after 24, 48, and 72 hours, the skin reaction of Guinea pigs was observed, and the skin reaction was evaluated by scoring erythema and edema on the basis of 0 to 4 respectively, and calculating the total. .

Evaluation is made after 24, 48, and 72 hours, respectively, and the value when the highest value is shown is selected, and the animal skin irritation index is obtained by the following mathematical formula 3, and then the following mathematical formula 4 The phototoxicity index was calculated by The results are shown in Table 7 below.
[Formula 3]
Animal skin irritation index
= (Maximum value of Σ erythema index + maximum value of Σ edema index) / number of animals [Mathematical formula 4]
Phototoxic index
= (Irritation index of UV non-irradiation site)-(Irritation index of UV non-irradiation site)

As can be seen from Table 7, the phototoxicity index of the hydroxamic acid derivatives prepared in Examples 1 to 55 and Reference Examples 1 to 3 is 0, which is generally a criterion for determining that there is no phototoxicity. It was confirmed that the value was much lower than 0.5.

  Although the hydroxamic acid derivative based on this invention can be used for a skin external preparation composition, it is not specifically limited in the dosage form. For example, soft lotion, astringent lotion, nutrition lotion, nutrition cream, massage cream, essence, eye cream, eye essence, cleansing cream, cleansing foam, cleansing water, pack, powder, body lotion, body cream, body oil, Cosmetic compositions such as body essences, make-up bases, foundations, hair dyes, shampoos, rinses or body cleansers; or formulated with pharmaceutical compositions such as ointments, gels, creams, patches or sprays be able to. Each of these dosage forms can contain various bases and additives that are necessary and appropriate for the formulation of the dosage form, and the types and amounts of these components can be easily selected by the inventors. .

[Formulation Example 1] Nutrition lotion (milky lotion) production Nutrition lotions containing the hydroxamic acid derivatives produced in Examples 1 to 55 and Reference Examples 1 to 3 were produced.

[Formulation Example 2] Production of Nutrition Cream Nutrition creams containing the hydroxamic acid derivatives produced in Examples 1 to 55 and Reference Examples 1 to 3 were produced.

[Formulation Example 3] Production of Massage Cream Massage creams containing the hydroxamic acid derivatives produced in Examples 1 to 55 and Reference Examples 1 to 3 were produced.

[Formulation Example 4] Production of Ointment Ointments containing the hydroxamic acid derivatives produced in Examples 1 to 55 and Reference Examples 1 to 3 were produced.

  As described above, the hydroxamic acid derivative according to the present invention exerts the effect of suppressing collagen collagen and elastase expression by acting on the retinoic acid receptor, and is the biggest problem of retinoid compounds. Since it does not show skin irritation and skin toxicity, it can be usefully used as a pharmaceutical and an external preparation for skin for the purpose of improving elasticity reduction, which is an aging phenomenon.

Claims (7)

Hydroxamic acid derivative represented by the following chemical formula 1:

Wherein R ₅ and R ₆ are hydrogen, C _1-10 alkyl or C _3-6 cyclic alkyl ;
R ₂ is CONH, NHCO, CONR ₇ or NR ₇ CO, wherein R ₇ is C _1-10 alkyl;
R ₃ is — (CH ₂ ) _n —, n = 0 or 1;
R ₄ is hydrogen or C _1-10 alkyl (provided that N- [4- (N-hydroxycarbamoyl) phenyl] [4-methylphenyl] carboxamide, N- [4- (N-hydroxycarbamoylmethyl) ) Phenyl] [4-methylphenyl] carboxamide and [4- (N-hydroxycarbamoyl) phenyl] -N-benzamide) . The hydroxam compound of Formula 1 includes N- [4- (N-hydroxycarbamoyl) phenyl] benzamide , N- [4- (N-hydroxycarbamoyl) phenyl] [3-methylphenyl] carboxamide, N- [4- (N-hydroxycarbamoyl) phenyl] [4-ethylphenyl] carboxamide, N- [4- (N-hydroxycarbamoyl) phenyl] [4-propylphenyl] carboxamide, N- [4- (N-hydroxycarbamoyl) Phenyl] [4-isopropylphenyl] carboxamide, N- [4- (N-hydroxycarbamoyl) phenyl] [4-butylphenyl] carboxamide, N- [4- (N-hydroxycarbamoyl) phenyl] [4-tert -Butylphenyl] carboxamide, N- [4 -(N-hydroxycarbamoyl) phenyl] [3,4-dimethylphenyl] carboxamide, N- [4- (N-hydroxycarbamoyl) phenyl] adamantylcarboxamide, adamantyl-N- [4- (N-hydroxy-N -Methylcarbamoyl) phenyl] carboxamide, N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-benzamide, N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl- [4- Methylphenyl] carboxamide, N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl- [3-methylphenyl] carboxamide, N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl -[4-Ethylphenyl] carboxamide, N- [4- (N Hydroxycarbamoyl) phenyl] -N-methyl- [4-propylphenyl] carboxamide, N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl- [4-isopropylphenyl] carboxamide, N- [4 -(N-hydroxycarbamoyl) phenyl] -N-methyl- [4-butylphenyl] carboxamide, N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl- [4-tert-butylphenyl] carboxy Amido, N- [4- (N-hydroxycarbamoyl) phenyl] -N-methyl- [3,4-dimethylphenyl] carboxamide, N- [4- (N-hydroxycarbamoyl) phenyl] adamantyl-N-methylcarboxy Amido, adamantyl-N- [4- (N-hydroxy-N Methylcarbamoyl) phenyl] -N- methyl-carboxamide, N- [4- (N- hydroxycarbamoyl) phenyl] benzamide, N- [4- (N- hydroxycarbamoyl) phenyl] [3-methylphenyl] carboxamide N- [4- (N-hydroxycarbamoylmethyl) phenyl] [4-ethylphenyl] carboxamide, N- [4- (N-hydroxycarbamoylmethyl) phenyl] [4-propylphenyl] carboxamide, N- [ 4- (N-hydroxycarbamoylmethyl) phenyl] [4-isopropylphenyl] carboxamide, N- [4- (N-hydroxycarbamoylmethyl) phenyl] [4-butylphenyl] carboxamide, N- [4- (N -Hydroxycarbamoylmethyl) Enyl] [4-tert-butylphenyl] carboxamide, N- [4- (N-hydroxycarbamoylmethyl) phenyl] [3,4-dimethylphenyl] carboxamide, N- [4- (N-hydroxycarbamoylmethyl) phenyl] adamantyl carboxamide, 2- [4- (adamantylcarbonyl) phenyl] -N- hydroxy -N- methylacetamide, [4- (N-hydroxycarbamoyl) phenyl] -N- [4-methyl-phenyl] carboxy Amido, [4- (N-hydroxycarbamoyl) phenyl] -N- [3-methylphenyl] carboxamide, [4- (N-hydroxycarbamoyl) phenyl] -N- [4-ethylphenyl] carboxamide, [4 -(N-hydroxycarbamoyl) phenyl]- -[4-propylphenyl] carboxamide, [4- (N-hydroxycarbamoyl) phenyl] -N- [4-isopropylphenyl] carboxamide, [4- (N-hydroxycarbamoyl) phenyl] -N- [4- Butylphenyl] carboxamide, [4- (N-hydroxycarbamoyl) phenyl] -N- [4-tert-butylphenyl] carboxamide, [4- (N-hydroxycarbamoyl) phenyl] -N- [3,4- Dimethylphenyl] carboxamide, [4- (N-hydroxycarbamoyl) phenyl] -N-adamantylcarboxyamide, N-adamantyl [4- (N-hydroxy-N-methylcarbamoyl) phenyl] carboxamide, [4- (N -Hydroxycarbamoyl) phenyl] -N-methyl -N-benzamide, [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N- [4-methylphenyl] carboxamide, [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N- [3-Methylphenyl] carboxamide, [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N- [4-ethylphenyl] carboxamide, [4- (N-hydroxycarbamoyl) phenyl] -N— Methyl-N- [4-propylphenyl] carboxamide, [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N- [4-isopropylphenyl] carboxamide, [4- (N-hydroxycarbamoyl) phenyl ] -N-methyl-N- [4-butylphenyl] carboxamide, [4- (N- Roxycarbamoyl) phenyl] -N-methyl-N- [4-tert-butylphenyl] carboxamide, [4- (N-hydroxycarbamoyl) phenyl] -N-methyl-N- [3,4-dimethylphenyl] carboxy From amides, [4- (N-hydroxycarbamoyl) phenyl] -N-adamantyl-N-methylcarboxamide, and N-adamantyl [4- (N-hydroxy-N-methylcarbamoyl) phenyl] -N-methylcarboxamide The hydroxamic acid derivative according to claim 1, wherein the hydroxamic acid derivative is selected from the group consisting of: A method for producing the hydroxamic acid derivative according to claim 1, comprising:
a) reacting benzoic acid or adamantanecarboxylic acid with methyl 4-aminobenzoate or 4-aminophenylacetic acid methyl ester to produce a benzamide compound;
b) replacing the amide bond of the resulting benzamide with alkyl;
c) hydrolyzing the methyl ester of the resulting benzamide or alkyl group-substituted benzamide compound to produce an acid; and d) said acid and hydroxylamine hydrochloride or N-methylhydroxylamine hydrochloride; Reacting to produce a hydroxamic acid derivative;
A method comprising the steps of: A method for producing the hydroxamic acid derivative according to claim 1, comprising:
a) reacting aniline or adamantamine with monomethyl terephthalate to produce a benzamide compound;
b) replacing the amide bond of the resulting benzamide with alkyl;
c) hydrolyzing the methyl ester of the produced benzamide or alkyl group-substituted benzamide compound to produce an acid; and d) the produced acid and hydroxylamine hydrochloride or N-methylhydroxylamine hydrochloride. Reacting with a salt to produce a hydroxamic acid derivative;
A method comprising the steps of:   A skin external preparation for preventing skin aging comprising the hydroxamic acid derivative according to claim 1 as an active ingredient.   A collagenase expression inhibitor comprising the hydroxamic acid derivative according to claim 1 as an active ingredient.   An elastase expression inhibitor comprising the hydroxamic acid derivative according to claim 1 as an active ingredient.