JP2014141487A - Benzotriazole compound, and cosmetic ultraviolet absorber and skin external preparation using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel compound exhibiting, despite having a low melting point, compatibility with various cosmetic bases, absorbing rays over nearly entire regions of UV-A and UV-B, excellent in terms of light stability, exhibiting long-term decomposition resistance and degradation resistance due to both an ultraviolet absorption function and a matrix metal proteinase (MMP) inhibition activity function inherent in the compound, and usable as a hybrid material for doubly protecting skin from aging damages and effective components of skin external preparations useful as MMP inhibitors and having scarce side effects.SOLUTION: The provided 2-(2,4-dihydroxyphenyl)-2H-benzotriazole derivative is expressed by the following general formula 1.

Description

  The present invention relates to a novel benzotriazole compound which is a 2- (2,4-dihydroxyphenyl) -2H-benzotriazole derivative having both an ultraviolet absorption effect and an MMP inhibitory activity, and a cosmetic ultraviolet absorber using the same and a skin external application. It relates to the agent.

In cosmetics, an ultraviolet absorber is blended in order to increase the light stability of the components of the cosmetics themselves or to protect the human skin. For example, in addition to skin external preparations such as sun care cosmetics (sunscreen and sunscreen cosmetics), they are used in various applications such as deodorants, fragrances, hair care, body care and other toiletries. In industrial applications, they are also required for resins, paints, electronic component materials, etc.
The ultraviolet region is divided into a UV-A region (320 to 400 nm), a UV-B region (290 to 320 nm), and a UV-C region (up to 290 nm). Never reach the ground. In addition, UV rays in the UV-A region (320 to 400 nm) invade the skin blackly, but it is not considered to cause sunburn like the UV-B region (290 to 320 nm) and promote skin aging. It was.

  However, in recent years, ultraviolet rays in the UV-B region stay relatively on the surface of the skin, whereas ultraviolet rays in the UV-A region reach the deep part of the skin, and induce skin cancer as well as skin aging. It has been found to be the cause.

  Cosmetic UV absorbers used to date are classified into 1) benzoic acid derivatives, 2) cinnamic acid derivatives, 3) benzophenone derivatives, 4) dibenzoylmethane derivatives, 5) salicylic acid derivatives, etc. There are 2) and 4) as ultraviolet absorbers which are often used in recent years.

However, the above-mentioned ultraviolet absorbers have their respective problems from a practical viewpoint.
In 1), for example, p-dimethylaminobenzoic acid-2-ethylhexyl ester is liquid and transparent and has the advantages of being easy to handle. However, these derivatives have been suspected of causing carcinogenicity and have not been used in recent years. Absent. Further, the maximum absorption wavelength is in the vicinity of 290 nm, and absorbs ultraviolet rays only in the UV-B region.
In 2), p-methoxycinnamic acid-2-ethylhexyl ester is the most commonly used UV absorber for suncare cosmetics currently on the market, but the maximum absorption wavelength is around 310 nm, and the absorption range is UV. -It does not reach the A area.
In 3), for example, 2-hydroxy-4-methoxybenzophenone absorbs over the UV-A and UV-B regions and has relatively good solubility in cosmetic bases, but the maximum absorption wavelength is slightly in the UV-B region. It is close and the absorbance is not very high. In recent years, a basic skeleton structure (benzophenone) has been pointed out as an environmental hormone.
As the compound 4), 4-tert-butoxy-4-methoxydibenzoylmethane is often used. The maximum absorption is in the vicinity of 360 nm, the absorbance is large, and it is excellent as an ultraviolet absorber in the UV-A region. However, absorption in the UV-B region is small, and it is said that there is a problem in light stability. There is also a problem in that the compatibility with the decorative base material is poor and the blending amount is limited.
In the salicylic acid derivative 5), octyl salicylate is used. It has a maximum absorption wavelength in the UV-B region, is oily, and is excellent in compatibility with paraffin oil or the like, but is not practically used because of its low absorbance.

  For this reason, 2) p-methoxycinnamic acid-2-ethylhexyl ester is used for UV-B region UV absorption purposes, whereas 4) 4-tert- for UV-A region UV absorption purposes. Butoxy-4-methoxydibenzoylmethane is often used. And when it is necessary to cover the whole area, both are often used together.

  Particularly in the UV-A region, as a UV absorber for cosmetic use, a good UV absorber other than 4-tert-butoxy-4-methoxydibenzoylmethane (trade name “Parsol 1789”) described above is practically used. Therefore, a UV absorbent that is particularly excellent in UV-A region UV-absorbing ability, has excellent compatibility, is excellent in light stability, and is difficult to decompose and deteriorate over a long period of time. It has been demanded. In addition, when a UV absorber is blended in a topical skin preparation, it must be a highly safe compound without sensitization to the skin. Furthermore, it is important that the compound itself has a so-called light-resistant stability that is not decomposed by exposure to sunlight.

  By the way, it is known that the skin leads to so-called skin aging such as wrinkles and sagging due to various factors such as the loss of oil and collagen in addition to the influence of ultraviolet rays. The structure of the skin is divided into three layers of “epidermis”, “dermis” and “subcutaneous tissue” from the top layer. The “stratum corneum” at the top of the epidermis is on the outermost side of the skin and is exposed to various external stimuli such as outside air and ultraviolet rays.

  In each layer, the skin protects and keeps the skin healthy and has a function of protecting the living body through immune information. However, aging reduces immunity, changes in external environment such as temperature, ultraviolet rays・ Skin health functions decline due to various factors such as external irritation, excessive intake of foreign substances, and skin troubles such as wrinkles, stains, kusumi, tarmi, and rough skin, and aging phenomena appear.

  In recent years, research has progressed and it has become clear that the cause of wrinkle formation is due to fiber reduction and degeneration of the dermal matrix such as collagen and elastin. As a factor for inducing this, the involvement of matrix metalloprotease (Japanese name: matrix metalloproteinase, hereinafter referred to as “MMPs”) has been pointed out.

  MMPs is a general term for extracellular matrix degrading enzymes having zinc (II) ions in the active site. Further, MMPs are known to have subfamilies such as collagenase (MMP-1), gelatinase (MMP-2 and 9), stromelysin (MMP-3 and 10) due to differences in structure and substrate specificity. Collagenase (MMP-1) and gelatinase (MMP-2) are multifunctions of gelatin, type IV collagen (basement membrane), type V collagen, fibronectin (soft cross-linked macromolecules present in soft connective tissue and basement membrane) It is known to denature glycoproteins) and elastin (structural proteins that form a special component of elastic tissues such as arteries, tendons and skin).

  Among MMPs, MMP-1 is an enzyme that degrades collagen, which is a main component of the dermal matrix of the skin, and is an inflammatory cytokine called IL-1β in epidermal cells damaged by ultraviolet irradiation (UV-B). Is released into the dermis, and IL-1β migrates to dermal cells to produce MMP-1, which is one of the causes of collagen loss and degeneration, and is considered to be one major factor in wrinkle formation (patent) Reference 1).

  MMPs are substances that play a central role in the degradation of extracellular matrix in various pathologies such as cancer (cancer) disease, ulceration, rheumatoid arthritis, osteoporosis, periodontitis, gingivitis (non-) Patent Document 1). Since MMPs whose activity is enhanced by external stimuli such as ultraviolet rays decompose components important for maintaining the structure of the skin, MMPs also have an aspect as a skin aging promoting factor activated by ultraviolet rays.

However, when a compound having MMP inhibitory activity is considered from a medical standpoint, its side effects become a problem. As an example, as a mechanism for losing the activity of MMPs, the zinc ion that is the active center can be chelated. In general, MMP inhibitors have zinc chelating sites (ZBGs) in their structure, and hydroxamic acid, carboxylic acid, phosphoric acid, thiol, and the like have been used. These are very strong in chelating action of ZBGs and efficiently inhibit MMPs, but other metalloproteases that should not be inhibited are also chelated and inactivated, causing side effects, phase 3 test The clinical trial has not progressed until recently, and has not yet been put into practical use (see Non-Patent Document 2).
In quasi-drug use as a skin external preparation including cosmetic use, it is necessary to assume that it is taken into the metabolic pathway in the body even when used in the correct way of use, and thus there is a concern about safety. That is a big problem. Therefore, it is necessary to use a compound having an MMP inhibitory activity that does not have a strong chelating action on the metalloprotease and does not adversely affect the body like the ZBGs raised above. Accordingly, the advent of hybrid materials and MMP inhibitors that have both an ultraviolet absorption action and an MMP inhibitory activity action that has a low risk to the human body and that double protects against aging due to skin damage is desired.

  However, even if such a hybrid material is designed, researched and developed, the synthesis method is very difficult, and the structure is too complex, which requires a lot of labor and cost in actual production. Then it doesn't make sense. It is important that the existing equipment can be easily produced by existing equipment without investing in new equipment with the same labor and cost as the production of conventional UV absorbers, and it is important to supply it to users stably.

JP 2011-225550 A

JP 2006-282561 A

JP-A-2005-290240

JP 2005-206473 A

JP-A-3-139589

Nakata, Okada, "Respiration", 18, 4, pp. 365-371 (1999)

Rao, B.A. G. Curr. Pharm. Design, 2005, 11, 295-322.

  In view of the above situation, the problem to be solved by the present invention is a low melting point, excellent compatibility with various cosmetic base materials, having absorption in almost all regions of UV-A, UV-B, and Ultraviolet absorber with excellent photostability and the compound itself is not easily decomposed or deteriorated over a long period of time, or a hybrid material that has both UV absorption and MMP inhibitory activity, and double protects against aging due to skin damage, and MMP inhibition It is to provide a novel compound that can be used as an active ingredient of a skin external preparation useful as a medicine with few side effects.

The main feature of the present invention is that it is a benzotriazole compound which is a 2- (2,4-dihydroxyphenyl) -2H-benzotriazole derivative represented by the following general formula 1.
General formula 1:

一般式３：

Especially, it is a benzotriazole compound shown by the following general formula 2 or the following general formula 3.
General formula 2:

General formula 3:

  According to the benzotriazole compound of the present invention, it is possible to provide a good yield easily and industrially at low cost without using a complicated synthesis process and using existing equipment. Further, by using this benzotriazole compound as a cosmetic ultraviolet absorber, it is possible to solve the following problems, which are disadvantages of the conventional cosmetic ultraviolet absorber, and to combine various secondary effects.

-Conventional cosmetic UV absorbers are inferior in stability of the compound itself and have a problem in durability of UV absorption effect, but benzotriazole derivatives are excellent in stability.

-Since it also has an inhibitory activity against MMP-1, MMP-2, and MMP-9, it not only protects against damage caused by ultraviolet rays, but also promotes skin aging by amplifying production by ultraviolet rays. Can be inhibited.

-Although it is excellent in stability as a compound, it has a low ClogP value and a partitioning ability with respect to water, so it is considered that biodegradability is also excellent.

It is a graph which shows the inhibition rate in 100 micromol density | concentration with respect to each compound of MMP-1, MMP-2, and MMP-9 which is an Example. It is an ultraviolet absorption spectrum before and after sunlight irradiation of the compound (a) of an Example. It is an ultraviolet absorption spectrum before and behind sunlight irradiation of the compound (b) of an Example. It is an ultraviolet absorption spectrum before and after sunlight irradiation of the compound (c) of an Example. It is an ultraviolet absorption spectrum before and after sunlight irradiation of the compound (d) of an Example. It is an ultraviolet absorption spectrum before and behind sunlight irradiation of the compound (e) of an Example. It is an ultraviolet absorption spectrum before and behind sunlight irradiation of the compound (f) of an Example. It is an ultraviolet absorption spectrum before and after sunlight irradiation of the compound (g) of an Example. It is an ultraviolet absorption spectrum before and behind sunlight irradiation of the compound (h) of an Example. It is an ultraviolet absorption spectrum before and after sunlight irradiation of the compound (i) of an Example. It is an ultraviolet absorption spectrum before and after sunlight irradiation of the compound (j) of an Example. It is an ultraviolet absorption spectrum before and behind sunlight irradiation of the compound (k) of an Example. It is an ultraviolet absorption spectrum of the comparative example 3 which is a general ultraviolet absorber. It is an ultraviolet absorption spectrum before and after the sunlight irradiation of the comparative example 1.

In the present invention, the benzotriazole compound is a 2- (2,4-dihydroxyphenyl) -2H-benzotriazole derivative, which is represented by the following general formula 1.
General formula 1:

一般式３：

More specifically, they are represented by the following general formulas 2 and 3.
General formula 2:

General formula 3:

  Here, A in the general formulas 1, 2, and 3 represents a nitrogen atom as a ring constituent atom. An alicyclic ring which may contain an oxygen atom and / or a sulfur atom, or an alkyloxy group or an alkylamino group having the alicyclic ring at its end, and B in the general formula 1 has 3 carbon atoms bonded to A at the α-position A carbonyl group or an ester group of -6, and R1 in the general formulas 1 and 3 is a hydrogen atom or a chlorine atom.

  By providing an alicyclic ring or an alkyloxy group or alkylamino group having an alicyclic end in the structure, the benzene nucleus can be attached while ensuring the same lipophilicity as when a chain alkyl group is introduced. The effect which strengthens an inorganic property like the compound which has many in a molecule | numerator can be acquired. Further, since the structure of the compound can be given a slight stericity, it is considered that the crystallization of the compound in the preparation, which is a disadvantage in the planar structure, can be suppressed. As a result, it is easy to become familiar with the skin when used in applications such as cosmetic UV absorbers and external preparations for skin, and it can be expected to improve biodegradability in nature by having the ability to distribute water. In order to ensure the biodegradability of the compound, if the value of ClogP (C: concentration, P: acid dissociation constant) is approximately 5 or less, the BCF value (= chemical substance concentration in fish body / chemical substance concentration in water) is It is considered to be 5000 times or less. In the Chemical Substances Control Law guidelines, if the LogP value is 3.5 or less, it is considered that the BCF value is 5000 or less and it is not highly concentrated, and the concentration test using fish is exempted. In addition, since all of the compounds synthesized and evaluated by the inventors this time have LogP values 1 to 2 lower than the ClogP values, many compounds satisfy this Chemical Substances Control Law requirement. Further, it has been reported that a compound having a three-dimensional structure generally has a lower concentration than a planar structure. Based on the above, it is considered that the compound is sufficiently considered for the human body and the environment.

  Specific examples of the alicyclic ring which may contain a nitrogen atom, an oxygen atom and / or a sulfur atom as a ring constituent atom include pyrrolidine, pyrrolidone, imidazolidine, hydantoin, pyrazolidine, piperidine, piperazine, oxazolidine, oxazolidinone, morpholine, 2-thio Examples thereof include 5- to 6-membered heterocycles such as hydantoin, thiazolidine, thiazolidinone and sulfolane, and terpene compounds such as adamantane and bornene.

化合物ｂ：Ａｄａｍａｎｔａｎｅ−１−ｃａｒｂｏｘｙｌｉｃ ａｃｉｄ ２−［４−（２Ｈ−ｂｅｎｚｏｔｒｉａｚｏｌ−２−ｙｌ）−３−ｈｙｄｒｏｘｙ−ｐｈｅｎｏｘｙ］−ｅｔｈｙｌ ｅｓｔｅｒ

Specific compounds of the above general formula 2 include the following compounds a and b.
Compound a: Morpholine-4-carboxylic acid 2- [4- (2H-benzotriazol-2-yl) -3-hydroxy-phenoxy] -ethyl ester

Compound b: Adamantane-1-carboxylic acid 2- [4- (2H-benzotriazol-2-yl) -3-hydroxy-phenoxy] -ethyl ester

まず、特許文献３および４に記載などの合成例を参考に、４−ベンゾトリアゾール−２−イルベンゼン−１，３−ジオール体から常法にて２−ベンゾトリアゾール−２−イル−５−（２−ヒドロキシエトキシ）フェノール（Ｍ−１）を合成する。次にトルエン溶媒下、メタンスルホン酸などの酸性触媒を使用して還流脱水により、目的物である（Ｇ−１）を得ることができる。As a synthesis method of the benzotriazole compound represented by the general formula 2, it can be synthesized by the synthesis method of the following formula.

First, with reference to synthesis examples described in Patent Documents 3 and 4, 2-benzotriazol-2-ylbenzene-1,3-diol is synthesized from 2-benzotriazol-2-yl-5- ( 2-hydroxyethoxy) phenol (M-1) is synthesized. Next, the desired product (G-1) can be obtained by reflux dehydration using an acidic catalyst such as methanesulfonic acid in a toluene solvent.

化合物ｄ：１−｛４−［４−（２Ｈ−Ｂｅｎｚｏｔｒｉａｚｏｌ−２−ｙｌ）−３−ｈｙｄｒｏｘｙ−ｐｈｅｎｏｘｙ］−ｂｕｔｙｒｙｌ｝−ｐｙｒｒｏｌｉｄｉｎ−２−ｏｎｅ

化合物ｅ：４−［４−（２Ｈ−Ｂｅｎｚｏｔｒｉａｚｏｌ−２−ｙｌ）−３−ｈｙｄｒｏｘｙ−ｐｈｅｎｏｘｙ］−ｂｕｔｙｒｉｃ ａｃｉｄ ａｄａｍａｎｔａｎ−１−ｙｌ ｅｓｔｅｒ

化合物ｆ：４−［４−（２Ｈ−Ｂｅｎｚｏｔｒｉａｚｏｌ−２−ｙｌ）−３−ｈｙｄｒｏｘｙ−ｐｈｅｎｏｘｙ］−ｂｕｔｙｒｉｃ ａｃｉｄ ２−ｍｏｒｐｈｏｌｉｎ−４−ｙｌ−ｅｔｈｙｌ ｅｓｔｅｒ

化合物ｇ：４−［４−（２Ｈ−Ｂｅｎｚｏｔｒｉａｚｏｌ−２−ｙｌ）−３−ｈｙｄｒｏｘｙ−ｐｈｅｎｏｘｙ］−ｂｕｔｙｒｉｃ ａｃｉｄ ２−ｐｉｐｅｒｉｄｉｎ−１−ｙｌ−ｅｔｈｙｌ ｅｓｔｅｒ

化合物ｈ：４−［４−（２Ｈ−Ｂｅｎｚｏｔｒｉａｚｏｌ−２−ｙｌ）−３−ｈｙｄｒｏｘｙ−ｐｈｅｎｏｘｙ］−Ｎ−（２−ｍｏｒｐｈｏｌｉｎ−４−ｙｌ−ｅｔｈｙｌ）−ｂｕｔｙｒａｍｉｄｅ

化合物ｉ：４−｛４−［５−Ｃｈｌｏｒｏ−（２Ｈ−ｂｅｎｚｏｔｒｉａｚｏｌ−２−ｙｌ）］−３−ｈｙｄｒｏｘｙ−ｐｈｅｎｏｘｙ｝−ｂｕｔｙｒｉｃ ａｃｉｄ ２−ｐｉｐｅｒｉｄｉｎ−１−ｙｌ−ｅｔｈｙｌ ｅｓｔｅｒ

化合物ｊ：４−｛４−［５−Ｃｈｌｏｒｏ−（２Ｈ−ｂｅｎｚｏｔｒｉａｚｏｌ−２−ｙｌ）］−３−ｈｙｄｒｏｘｙ−ｐｈｅｎｏｘｙ｝−ｂｕｔｙｒｉｃ ａｃｉｄ ２−ｍｏｒｐｈｏｌｉｎ−４−ｙｌ−ｅｔｈｙｌ ｅｓｔｅｒ

化合物ｋ：４−｛４−［５−Ｃｈｌｏｒｏ−（２Ｈ−ｂｅｎｚｏｔｒｉａｚｏｌ−２−ｙｌ）］−３−ｈｙｄｒｏｘｙ−ｐｈｅｎｏｘｙ｝−Ｎ−（２−ｍｏｒｐｈｏｌｉｎ−４−ｙｌ−ｅｔｈｙｌ）−ｂｕｔｙｒａｍｉｄｅ

Specific compounds of the general formula 3 include the following compound c, compound d, compound e, compound f, compound g, compound h, compound i, compound j, and compound k.
Compound c: 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -1-morpholin-4-yl-butan-1-one

Compound d: 1- {4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -butyryl} -pyrrolidin-2-one

Compound e: 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -butyric acid adamantan-1-yl ester

Compound f: 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -butyric acid 2-morpholin-4-yl-ethyl ester

Compound g: 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -butyric acid 2-piperidin-1-yl-ethyl ester

Compound h: 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -N- (2-morpholin-4-yl-ethyl) -butyramide

Compound i: 4- {4- [5-Chloro- (2H-benzotriazol-2-yl)]-3-hydroxy-phenoxy} -butyric acid 2-piperidin-1-yl-ethyl ester

Compound j: 4- {4- [5-Chloro- (2H-benzotriazol-2-yl)]-3-hydroxy-phenoxy} -butyric acid 2-morpholin-4-yl-ethyl ester

Compound k: 4- {4- [5-Chloro- (2H-benzotriazol-2-yl)]-3-hydroxy-phenoxy} -N- (2-morpholin-4-yl-ethyl) -butyramide

まず、特許文献５に記載の合成例などを参考に、〔化１５〕の合成でも使用した４−ベンゾトリアゾール−２−イルベンゼン−１，３−ジオール体とγ−ブチロラクトンを強アルカリ触媒下で、１８０℃以上にて開環、付加反応により、中間体化合物Ｍ−２である４−（４−ベンゾトリアゾール−２−イル−３−ヒドロキシフェノキシ）ブチリックアシド誘導体（Ｍ−２）を得る。次いで、〔化１５〕同様にトルエン溶媒下、メタンスルホン酸などの酸性触媒を使用して還流脱水による縮合反応を利用して、目的物である（Ｇ−３）を得ることができる。As a synthesis method of the benzotriazole compound represented by the general formula 3, it can be synthesized by the synthesis method of the following formula.

First, referring to the synthesis example described in Patent Document 5, 4-benzotriazol-2-ylbenzene-1,3-diol and γ-butyrolactone used in the synthesis of [Chemical Formula 15] are used in a strong alkali catalyst. The ring-opening and addition reaction at 180 ° C. or higher gives the intermediate compound M-2, 4- (4-benzotriazol-2-yl-3-hydroxyphenoxy) butyric acid derivative (M-2). Next, similarly to [Chemical Formula 15], the target product (G-3) can be obtained by utilizing a condensation reaction by reflux dehydration using an acidic catalyst such as methanesulfonic acid in a toluene solvent.

EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited only to the modes of these examples. Each synthesized compound was subjected to measurements such as HPLC purity, melting point, ¹ H-NMR, FT-IR, C, H, and N elemental analysis to confirm the structure.
In the examples, analysis conditions, definitions, and names of devices used for measurement are shown below.

<Absorbance measurement conditions>
Measuring device: UV-2450 (manufactured by Shimadzu Corporation)
Measurement wavelength: 250-500 nm
Sample concentration: 10 ppm / chloroform

<HPLC surface 100 purity measurement conditions>
Measuring device: LC-6A (manufactured by Shimadzu Corporation)
Column: SUMPAX ODS-A-212 6 μm, 6 mm × 15 cm
Column temperature: 40 ° C
Mobile phase: methanol: water = 95: 5
Measurement wavelength: 254 nm

<FTIR measurement conditions>
Apparatus: FTIR-8400S (manufactured by Shimadzu Corporation)
Sample: 1/200 (KBr)

^<1 H-NMR measurement conditions>
Apparatus: Varian Mercury-300 (300 MHz) SC-NMR spectrometer
Resonance frequency: 300 MHz ( ¹ H-NMR)
Solvent: DMSO-d6
Tetramethylsilane was used as an internal standard substance for ¹ H-NMR, the chemical shift value was represented by δ value (ppm), and the coupling constant was represented by Hertz. Also, s is a singlet, d is a doublet, t is a triplet, q is a quartet, dd is a doublet doublet, br is a short singlet, and m is an abbreviation of multiplet.

<CHN elemental analysis>
The measurement was performed using a Perkin Elmer 2400 II apparatus.

(Synthesis example)
(Compound a)
Example of Synthesis of Morpholine-4-carboxylic acid 2- [4- (2H-benzotriazol-2-yl) -3-hydroxy-phenoxy] -ethyl ester

  A 200 mL four-necked flask is equipped with a thermometer, a reflux condenser, and a dropping funnel, and 8.14 g (0.03 mol) of 2-benzotriazol-2-yl-5- (2-hydroxyethyl) phenol and 50 mL of dimethylacetamide are added. The mixture was cooled to 0 ° C. with stirring. 2.40 g (0.06 mol) of sodium hydride (in mineral oil 40%) was thoroughly washed with N-hexane, dried, suspended in 50 mL of dimethylacetamide and added little by little at 10 to 20 ° C. Next, 4.71 g (0.032 mol) of Morpholine-4-carbonyl chloride was added dropwise over a period of 0.5 hr in the range of 5 to 10 ° C., and stirred overnight at 20 ° C., then poured into cold water, neutralized with acetic acid, methyl After extraction with isobutyl ketone and filtration, the precipitated crystals were filtered off. Of the 9.71 g of crude crystals obtained by washing and drying, 5.0 g was recrystallized with dimethylacetamide to obtain 4.6 g of white powdery crystals as the target product.

The analysis result of the obtained crystal is as follows.
Mp: 194-195 ° C; HPLC 99.2%; white powder; yield: 77.5% (based on 2-Benzotriazol-2-yl-5- (2-hydroxyethoxy) phenol).
1H-NMR (300 MHz, DMSO-d6) δ: 10.7, (br s, 1H, OH), 8.05-7.98 (m, 2H, benzotriazole-H), 7.73 (d, 1H, J = 9 Hz, phenol-H), 7.55-7.49 (m, 2H, benzotriazol-H), 6.69 (dd, 1H, J = 9 Hz, J = 2.7 Hz, J = 2.4 Hz, phenol-H), 6.63 (d, 1H, J = 2.7 Hz, phenol), 4.37 (t, 2H, J = 8.1 Hz, CH2-OC = OH), 4.27. (T, 2H, J = 9 Hz, PhO—CH 2 —H), 3.55 (b, 4 H, CH 2 —O—CH 2 (Morpholin) -H), 3.37 (b, 4 H, CH 2 —N—CH 2 ( Morpholin) -H).
FT-IR (KBr) cm-1; 3080, 2960 (C-H), 1710 (C = O), 1630, 1600 (C = C), 1520 (C = N), 1460, 1450, 1430 (C = C), 1360 (CN), 1280 (Ph-O), 1190 (CN),.
Anal. Calcd for C19H20N4O5: C, 59.37; H, 5.24; N, 14.58. Found: C, 59.51; H, 5.18; N, 14.63

(Compound b)
Example of synthesis of Adamantane-1-carboxylic acid 2- [4- (2H-benzotriazol-2-yl) -3-hydroxy-phenoxy] -ethyl ester

  A 200 mL four-necked flask was equipped with a thermometer, a reflux condenser, and a water separator, and 2-benzotriazol-2-yl-5- (2-hydroxyethyl) phenol 8.14 g (0.03 mol), Adamantane-1-carboxylic Acid 8.12 g (0.045 mol), toluene 150 mL, anisole 20 mL and methanesulfonic acid 1.0 g were added, and dehydration was performed at 117 to 118 ° C. for 35 hours. After confirming that the theoretical amount of reaction water had distilled, 150 mL of warm water was added and stirred, the lower layer water was separated at 80 ° C., and washed twice with 50 mL of warm water in the same manner. After dehydration with anhydrous magnesium sulfate, filtration through a 1 μm membrane filter, toluene-anisole was collected under reduced pressure, 150 mL of methanol was added and cooled, and the precipitated crystals were filtered off through a membrane filter, washed and dried. 11.4 g of a certain white powdery crystal was obtained.

The analysis result of the obtained crystal is as follows.
Mp: 125-127 ° C; HPLC 99.3%; white powder; yield: 87.4% (based on 2-Benzotriazole-2-yl-5- (2-hydroxyethoxy) phenol).
1H-NMR (300 MHz, CDCl3) δ: 11.4, (br s, 1H, OH), 8.31 (d, 1H, J = 9 Hz, phenol-H), 7.92 (dd, 2H, J = 6.6 Hz, J = 3 Hz, J = 3 Hz, benzotriazole-H), 7.47 (dd, 2H, J = 6.6 Hz, J = 3 Hz, J = 3 Hz, benzotriazole-H), 6.72 (d, 1H, J = 2.7 Hz, phenol-H), 6.64 (dd, 1H, J = 9 Hz, J = 2.7 Hz, J = 2.7 Hz, phenol), 4.43 (t, 2H, J = 9.6 Hz, CH2-OC = O-H), 4.23 (t, 2H, J = 9.6 Hz, PhO-C-CH2-H), 2.01 (brs, 3H, adamantan-H) ), 1.95-1.91 (m, 6H, ad mantan-H), 1.71-1.67 (m, 6H, adamantan-H) ,.
FT-IR (KBr) cm-1; 3230 (OH), 2910 (C-H), 1720 (C = O), 1620, 1600 (C = C), 1530 (C = N), 1450, 1420 (C = C), 1340 (CN), 1240 (Ph-O),.
Anal. Calcd for C25H27N3O4: C, 69.27; H, 6.28; N, 9.69. Found: C, 69.53; H, 6.21; N, 9.73

(Compound c)
Synthesis example of 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -1-morpholin-4-yl-butan-1-one

  A 300 mL four-necked flask was equipped with a reflux condenser and a thermometer. 9.40 g (0.03 mol) of 4- (4-benzotriazol-2-yl-3-hydroxyphenoxy) butyric acid, and 5.23 g (0.06 mol) of morpholine ), Toluene (100 mL), anisole (20 mL), and methanesulfonic acid (1.0 g) were added, and the mixture was reflux-dehydrated at 117 to 118 ° C. for 35 hours. After confirming that the theoretical amount of reaction water had distilled off, 150 mL of warm water was added and stirred, the lower layer water was separated at 80 ° C., and similarly washed twice with 50 mL of warm water. After dehydration with anhydrous magnesium sulfate, filtration through a 1 μm membrane filter, toluene-anisole was recovered under reduced pressure, 50 mL of isopropyl alcohol was added and cooled, and the precipitated crystals were filtered out through a membrane filter to give 5.23 g of tan crystals Got. Recrystallization of 5.1 g of this crystal with toluene gave 4.32 g of the desired product as a fine brown powdery crystal.

The analysis result of the obtained crystal is as follows.
Mp: 146-148 ° C; HPLC 99.5%; light brownish powder; yield: 38.6% (based on 4- (4-Benzotriazol-2-yl-3-hydroxyphenoxy) butyric acid)).
1H-NMR (300 MHz, CDCl3) δ: 11.4, (brs, 1H, OH), 8.29 (d, 1H, J = 9.2 Hz, phenol-H), 7.93-7.90. (M, 2H, benzotriazol-H), 7.50-7.45 (m, 2H, benzotriazol-H), 6.69 (d, 1H, J = 2.7 Hz, phenol-H), 6.61 ( dd, 1H, J = 9.2 Hz, J = 3.0 Hz, 2.7 Hz, phenol), 4.10 (t, 2H, J = 11.7 Hz, PhO—CH 2 —H), 3.67-3. 52 (m, 8H, morpholine-H), 2.58-2.53 (m, 2H, NCOCH2-H), 2.20-2.16 (m, 2H, C-CH2-CH),.
FT-IR (KBr) cm-1; 3090, 2960 (C-H), 1650 (C = O), 1630, 1600, (C = C), 1510 (C = N), 1420 (C = C), 1380, 1190 (CN), 1260 (Ph-O),.
Anal. Calcd for C20H22N4O4: C, 62.82; H, 5.80; N, 14.65. Found: C, 62.93; H, 5.61; N, 14.60.

(Compound d)
Synthesis example of 1- {4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -butyryl} -pyrrolidin-2-one

4- (4-Benzotriazol-2-yl-3-hydroxyphenoxy) butyric acid 9.40 g (0.03 mol), pyrrolidin-2-one 5.11 g (0.06 mol), toluene 100 mL, anisole 20 mL, and methanesulfonic acid 2 0.0 g was added and the same procedure as in the synthesis of Compound c was performed.
The unreacted raw material was removed by filtration through a membrane filter, and then recrystallized twice with isopropanol to obtain 0.88 g of the objective product as a fine brown white powdery crystal.

The analysis result of the obtained crystal is as follows.
Mp: 121-123 ° C; HPLC 98.9%; bright brownish white powder; yield: 9.85% (based on 4- (4-Benzotriazol-2-yl-3-hydroxyphenoxy) butyric acid).
1H-NMR (300 MHz, CDCl3) δ: 11.4, (brs, 1H, OH), 8.28 (d, 1H, J = 9.0 Hz, phenol-H), 7.94-7.89 ( m, 2H, benzotriazol-H), 7.50-7.44 (m, 2H, benzotriazol-H), 6.68 (d, 1H, J = 2.4 Hz, phenol-H), 6.61 (dd , 1H, J = 9.0 Hz, J = 2.7 Hz, 2.4 Hz, phenol), 4.10 (t, 2H, J = 12.3 Hz, O-CH2-H), 3.84 (t, 2H) , J = 14.4 Hz, pyrrolidoneone-H), 3.18-3.11 (m, 2H, pyrrolidoneone-H), 2.61 (t, 2H, J = 16.2 Hz, NCOCH2-H), 2. 25-2.10 ( , 2H, C-CH2-C-H), 2.08-1.61 (m, 2H, pyrrolidinone-H) ,.
FT-IR (KBr) cm-1; 3080, 2960 (C-H), 1740, 1690 (C = O), 1690, 1630, 1600 (C = C), 1520 (C = N), 1470, 1440 ( C = C), 1370 (CN), 1260 (Ph-O), 1180 (CN),.
Anal. Calcd for C20H20N4O4: C, 63.15; H, 5.30; N, 14.73. Found: C, 63.21; H, 5.24; N, 14.55.

(Compound e)
Synthesis example of 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -butyric acid adamantan-1-yl ester

4- (4-Benzotriazol-2-yl-3-hydroxyphenoxy) butyric acid 9.40 g (0.03 mol), Adamantan-1-ol 9.13 g (0.06 mol), toluene 100 mL, and methanesulfonic acid 1.0 g In the same manner as the synthesis of compound c.
The obtained crude crystals were dissolved in 10 times the amount of toluene to remove insoluble matters, and then purified by recrystallization to obtain 9.41 g of the desired product as fine grayish white powder crystals.

The analysis result of the obtained crystal is as follows.
Mp: 125-135 ° C. (Sintering); HPLC 99.5%; light grayish white powder; yield: 70.1% (based on 4- (4-Benzotriazol-2-yl-3-hydroxyphenoxy) butyricac) .
1H-NMR (300 MHz, CDCl3) δ: 11.4, (brs, 1H, OH), 8.29 (dd, 1H, J = 9 Hz, J = 1 Hz, phenol-H), 7.95-7. 88 (m, 2H, benzotriazol-H), 7.50-7.26 (m, 2H, benzotriazol-H), 6.67 (dd, 1H, J = 9 Hz, J = 2.7 Hz, phenol-H) 6.61 (dd, 1H, J = 9 Hz, J = 2.7 Hz, phenol), 4.11-4.03 (m, 2H, Ar—O—CH 2 —H), 2.70-2.35. (M, 2H, O-C = O-CH2-H), 2.17-2.07 (m, 6H, adamantan-H, 1H, adamantan-H, 2H, C-CH2-C-H), 1 79-1.66 (m, 6H, adama tan-H, 2H, adamantan-H) ,.
FT-IR (KBr) cm-1; 3150, 3060, 2960 (C-H), 1730 (C = O), 1620, 1600 (C = C), 1510 (C = N), 1420 (C = C) , 1390 (CN), 1290 (Ph-O).
Anal. Calcd for C26H29N3O4: C, 69.78: H, 6.53; N, 9.39. Found: C, 69.72; H, 6.34; N, 9.53.

(Compound f)
Synthesis of 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -butyric acid 2-morpholin-4-yl-ethyl ester

4- (4-Benzotriazol-2-yl-3-hydroxyphenoxy) butyric acid 9.40 g (0.03 mol), 2-Morpholin-4-yl-ethanol 7.87 g (0.06 mol), toluene 100 mL, and methanesulfone It carried out similarly to the synthesis | combination of the compound c by adding the acid 1.8g.
Unreacted raw materials were removed by filtration through a membrane filter, and then recrystallized twice with isopropanol to obtain 10.15 g of the desired product as fine brown powder crystals.

The analysis result of the obtained crystal is as follows.
Mp: 71-78 ° C, HPLC 99.7%; bright brownish white powder; yield: 69.1% (based on 4- (4-Benzotriazol-2-yl-3-hydroxyphenoxy) butyric acid).
1H-NMR (300 MHz, CDCl 3) δ: 11.4, (br s, 1H, OH), 8.29 (d, 1H, J = 9 Hz, phenol-H), 7.95-7.89 (m, 2H, benzotriazole-H), 7.50-7.44 (m, 2H, benzotriazol-H), 6.68 (d, 1H, J = 2.7 Hz, phenol-H), 6.60 (dd, 1H) , J = 9 Hz, J = 2.7 Hz, 2.7 Hz, phenol), 4.40-4.20 (m, 2H, CH2-OC = O-H), 4.08 (t, 2H, J = 12). .3 Hz, PhOCH2-H), 3.95-3.10 (m, 4H, CH2-O-CH2 (Morpholin) -H), 2.66-2.55 (m, 2H, CH2-C = O- H, m, 2H, N-CH2-H, m, 4H, C 2-N-CH2 (Morpholin) -H), 2.20-2.11 (m, 2H, C-CH2-C-H) ,.
FT-IR (KBr) cm-1; 3310 (OH), 3070, 2960 (C-H), 1640 (C = O), 1600, 1530 (C = C), 1510 (C = N), 1390 (C -N), 1270 (Ph-O), 1190 (CN),.
Anal. Calcd for C22H26N4O5: C, 61.96; H, 6.15; N, 13.14, Found: C, 62.19; H, 6.09; N, 13.16.

(Compound g)
Synthesis example of 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -butyric acid 2-piperidin-1-yl-ethyl ester

4- (4-Benzotriazol-2-yl-3-hydroxyphenoxy) butyric acid 9.40 g (0.03 mol), 2-Piperidin-1-yl-ethanol 7.75 g (0.06 mol), toluene 100 mL, anisole 20 mL, Then, 1.5 g of methanesulfonic acid was added and the same procedure as in the synthesis of compound c was performed.
Unreacted raw materials were removed by filtration through a membrane filter, and then recrystallized twice with isopropanol to obtain 5.15 g of the desired product as fine grayish white powder crystals.

The analysis result of the obtained crystal is as follows.
Mp: 79-80 ° C; HPLC 98.6%; light grayish white powder; yield: 33.3% (based on 4- (4-Benzotriazol-2-yl-3-hydroxyphenoxy) butyric acid).
1H-NMR (300 MHz, CDCl 3) δ: 11.4, (br s, 1H, OH), 8.29 (d, 1H, J = 9 Hz, phenol-H), 7.95-7.89 (m, 2H, benzotriazole-H), 7.50-7.45 (m, 2H, benzotriazol-H), 6.68 (d, 1H, J = 2.7 Hz, phenol-H), 6.65 (dd, 1H , J = 9 Hz, J = 2.7 Hz, 2.4 Hz, phenol), 4.60-4.40 (m, 2H, CH2-OC = OH), 4.08 (t, 2H.J = 12. .0Hz, PhOCH2-H), 2.95-2.57 (m, 2H, CH2-C = OH, m, 2H, N-CH2-H), 2.24-2.11 (m, 2H) , C-CH2-CH), 2.05-1.20 (m, 10H, pi eridine-H) ,.
FT-IR (KBr) cm-1; 3060, 2940 (C-H), 1730 (C = O), 1630, 1590 (C = C), 1520 (C = N), 1470, 1420 (C = C) , 1300 (CN), 1260 (Ph-O), 1190-1180 (CN),.
Anal. Calcd for C23H28N4O4: C, 65.08; H, 6.65; N, 13.20. Found: C, 65.18; H, 6.60; N, 13.21.

(Compound h)
Synthesis example of 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -N- (2-morpholin-4-yl-ethyl) -butyramide

4- (4-Benzotriazol-2-yl-3-hydroxyphenoxy) butyric acid 9.40 g (0.03 mol), 2-Morpholin-4-yl-ethylamine 7.81 g (0.06 mol), toluene 100 mL, and methanesulfone It carried out similarly to the synthesis | combination of the compound C by adding 2.0g of acids.
The obtained crude crystals were dissolved in 20 times the amount of dichloromethane to remove insoluble matters, and then purified by recrystallization to obtain 8.4 g of the desired product as fine grayish white powder crystals.

Mp: 177-178 ° C: HPLC 99.6%; light gray white powder; yield: 66.0% (based on 4- (4-Benzotriazol-2-yl-3-hydroxyphenoxy) butyric acid).
1H-NMR (300 MHz, CDCl3) δ: 11.4, (s, 1H, OH), 8.29 (d, 1H, J = 9.0 Hz, phenol-H), 7.92 (dd, 2H, J = 6.6 Hz, J = 3.0 Hz, benzotriazole-H), 7.47 (dd, 2H, J = 6.6 Hz, J = 3.0 Hz, J = 2.7 Hz, benzotriazol-H), 6.69. (D, 1H, J = 2.7 Hz, phenol-H), 6.61 (dd, 1H, J = 9.0 Hz, J = 2.7 Hz, phenol), 4.07 (t, 2H, PhOCH2-H) ), 3.74 (br, s, 4H, CH2-O-CH2 (Morpholin) -H)), 3.45-3.39 (m, 2H, O = CN-CH2-H), 2. 52-2.42 (m, 4H, CH2-N-CH2 ( orpholin) -H, 2H, N-CH2-H, 2H, CH2-C = O-H), 2.22-2.13 (m, 2H, C-CH2-C-H) ,.
FT-IR (KBr) cm-1; 3160 (NH), 2950, 2850 (C-H), 1720 (C = O), 1620, 1600 (C = C), 1510 (C = N), 1470, 1450 , 1440 (C = C), 1320 (CN), 1270 (Ph-O), 1180 (CN).
Anal. Calcd for C22H27N5O4: C, 62.1; H, 6.40; N, 16.46. Found: C, 62.24; H, 6.31; N, 16.56.

Synthesis example of 4- {4- [5-Chloro- (2H-benzotriazol-2-yl)]-3-hydroxy-phenoxy} -butyric acid-2-piperidin-1-yl-ethyl ester (Compound i)

4- [4- (5-Chloro-benzotriazol-2-yl) -3-hydroxy-phenoxy] -butylic acid 10.43 g (0.03 mol), 2-Piperidin-1-yl-ethanol 7.75 g (0.7. 06 mol), toluene (100 mL), and methanesulfonic acid (2.0 g) were added to carry out in the same manner as in the synthesis of Compound c.
The obtained crude crystals were dissolved in 10 times the amount of toluene to remove insoluble matters, and then purified by recrystallization to obtain 11.04 g of the desired product as fine grayish white powder crystals.

Mp: 101-103 ° C; HPLC 99.5%; bright gray white powder; yield: 80.2% (based on 4- (4-Benzotriazol-2-yl-3-hydroxyphenoxy) butyric acid)).
1H-NMR (300 MHz, CDCl3) δ: 11.2, (brs, 1H, OH), 8.25 (d, 1H, J = 9 Hz, Benzotriazole-H), 7.91 (dd, 1H, J = 1.8 Hz, J = 0.9 Hz, J = 0.6 Hz, Benzotriazol-H), 7.86 (dd, 1H, J = 9 Hz, J = 0.6 Hz, 0.6 Hz, Benzotriazole-H), 7. 42 (dd, 1H, J = 9 Hz, J = 2 Hz, Phenol-H), 6.67 (d, 1H, J = 2.7 Hz, Phenol-H), 6.60 (dd, 1H, J = 9 Hz, J = 2.7 Hz, J = 2.7 Hz, Phenol-H), 4.32-4.05 (m, 2H, CH2-OC = OH, 2H, CH2C = OH), 2.72- 2.55 (m, 2H, Ar-O-C 2-H, 4H, Piperidin-H), 2.17-2.13 (m, 2H, N-CH2-H), 1.6-1.46 (m, 2H, C-CH2-CH, 6H, Piperidin-H),.
FT-IR (KBr) cm-1; 3100, 2940 (C-H), 1730 (C = O), 1630, 1600 (C = C), 1530 (C = N), 1470 (C = C), 1390 (CN), 1260 (Ph-O), 1170 (CN),.
Anal. Calcd for C23H27ClN4O4: C, 60.19; H, 5.93; N, 12.21. Found: C, 60.22; H, 5.98; N, 12.22.

(Compound j)
Synthesis example of 4- {4- [5-Chloro- (2H-benzotriazol-2-yl)]-3-hydroxy-phenoxy} -butyric acid-2-morpholin-4-yl-ethyl ester

4- [4- (5-Chloro-benzotriazol-2-yl) -3-hydroxy-phenoxy] -butyric acid 6.96 g (0.02 mol), 2-Morpholin-4-yl-ethanol 6.96 g (0. 02 mol), 70 mL of toluene, and 0.7 g of methanesulfonic acid were added to carry out in the same manner as the synthesis of compound c.
The obtained crude crystals were dissolved in 10 times the amount of toluene to remove insoluble matters, and then purified by recrystallization to obtain 6.19 g of the desired product as fine grayish white powder crystals.

Mp: 122-125 ° C; HPLC 99.2%; light yellowish white powder; yield: 96.9% (based on 4- [4- (5-Chloro-benzotriol-2-yl) -3-hydroxy-phenoxy] -Butyric acid).
1H-NMR (300 MHz, CDCl3) δ: 11.2, (brs, 1H, OH), 8.25 (d, 1H, J = 6.9 Hz, Benzotriazol-H), 7.91 (dd, 1H, J = 1.5 Hz, J = 0.6 Hz, J = 0.6 Hz, Benzotriazol-H), 7.88 (d, 1H, J = 6.9 Hz, Benzotriazol-H), 7.42 (dd, 1H, J = 6.9 Hz, J = 1.5 Hz, Phenol-H), 6.67 (d, 1H, J = 2 Hz, Phenol-H), 6.60 (dd, 1H, J = 6.9 Hz, J = 2 Hz, J = 2 Hz, Phenol-H), 4.25 (t, 2H, J = 8.7 Hz, CH2-OC = O-H, 2H), 4.07 (t, 2H, J = 9.3 Hz, Ph-O-CH2-H), 3.71-3.6 (M, 4H, CH2-O-CH2 (Morpholin) -H), 2.65-2.50 (m, 4H, CH2-N-CH2 (Morpholin) -H, 2H, N-CH2-H, 2H, CH2-C = O-H), 2.15 (quintet, 2H, J = 9.6 Hz, C-CH2-C-H).
FT-IR (KBr) cm-1; 3160, 2950, (C-H), 1720 (C = O), 1620, 1600 (C = C), 1510 (C = N), 1470, 1450, 1440 (C = C), 1320 (CN), 1270 (Ph-O), 1180 (CN),.
Anal. Calcd for C22H25ClN4O5: C, 57.33; H, 5.47; N, 12.16. Found: C, 57.24; H, 5.28; N, 12.04.

(Compound k)
Synthesis example of 4- {4- [5-Chloro- (2H-benzotriazol-2-yl)]-3-hydroxy-phenoxy} -N- (2-morpholin-4-yl-ethyl) -Butylamide

4- [4- (5-Chloro-benzotriazol-2-yl) -3-hydroxy-phenoxy] -butyric acid 10.43 g (0.03 mol), 2-Morpholin-4-yl-ethylamine 7.81 g (0. 06 mol), 100 mL of toluene, and 3.0 g of methanesulfonic acid were added to carry out in the same manner as the synthesis of compound c.
The obtained crude crystals were dissolved in 10 times the amount of toluene to remove insoluble matters, and then purified by recrystallization to obtain 13.37 g of the desired product as fine grayish white powder crystals.

Mp: 181-183 ° C .; HPLC 99.1%; light yellowish white powder; yield: 96.9% (based on 4- [4- (5-Chloro-benzotriol-2-yl) -3-hydroxy-phenoxy] -Butyric acid).
1H-NMR (300 MHz, CDCl3) δ: 11.2, (brs, 1H, OH), 8.25 (d, 1H, J = 6.9 Hz, Benzotriazol-H), 7.91 (dd, 1H, J = 1.2 Hz, J = 0.6 Hz, J = 0.3 Hz, Benzotriazol-H), 7.88 (dd, 1H, J = 6.9 Hz, J = 0.6 Hz, 0.6 Hz, Benzotriazol-H ), 7.42 (dd, 1H, J = 6.6 Hz, J = 2 Hz, Phenol-H), 6.68 (d, 1H, J = 2 Hz, Phenol-H), 6.62 (dd, 1H, J = 9 Hz, J = 2.1 Hz, J = 2.1 Hz, Phenol-H), 4.07 (t, 2H, J = 9.0 Hz, Ph—O—CH 2 —H, 2H), 3.69 ( br s, 4H, CH2-O-CH2 (M orpholin) -H), 3.39 (brs, 2H, O = CN-CH2-H), 2.45-2.42 (m, 4H, CH2-N-CH2 (Morpholin) -H, 2H , N-CH2-H, 2H, CH2-C = O-H), 2.21-2.14 (m, 2H, C-CH2-C-H).
FT-IR (KBr) cm-1; 3290 (NH), 3090, 2960, 2830 (C-H), 1730 (C = O), 1640, 1600 (C = C), 1520 (C = N), 1460 , 1440, (C = C), 1380 (CN), 1260 (Ph-O), 1190 (CN). .
Anal. Calcd for C22H26ClN5O4: C, 57.45; H, 5.70; N, 15.23. Found: C, 57.59; H, 5.65; N, 15.11.

[Evaluation]
(Dissolution characteristics in cosmetic base material)
Among the benzotriazole derivatives synthesized above, compounds a, b, c, d, f, g, and h were dissolved in the following cosmetic base materials, and the solubility was measured. In addition, as a comparative example, 4-tert-butoxy-4-methoxydibenzoylmethane (trade name “parsol 1789”), which is substantially the only commercially available UV-A absorber for cosmetic applications at present, is compared. As Example 1, the solubility was measured in the same manner.

・ Substrate used Silicone oil: Wako Pure Chemical Reagents LS-8620
Squalane: A product of SQUATECH Super Squalane Liquid paraffin: A product of Kaneda High Coal K-230
CIO: Nippon Seikatsu Co., Ltd. product Cetyl isooctanoate IOTG: Nihon Seika Co., Ltd. product Isooctanoic acid triglyceride

-Method It melt | dissolved at 20 degreeC, preserve | saved for 120 days in a cool dark place (5 degreeC), and investigated the presence or absence of precipitation of the said added benzotriazole derivative, the odor after dissolution, and coloring. The results are shown in Table 1.

None of the compounds dissolved in the above dissolution amount was precipitated as crystals or oily components were separated. Further, the dissolved colors were all slightly yellow and transparent, and no odor was felt.
In addition, the dissolution amount shown with respect to the liquid paraffin of compound a, CIO of compound g, and IOTG is not an upper limit. In addition, the compounds b, f, g, etc. showed solubility close to the solubility of Comparative Example 1 which is a commercial compound of UV-A absorber, and it was found that the compound b, f, g and the like can be sufficiently blended in a cosmetic base material.

(UV absorption characteristics)
The UV absorption region of the synthesized compounds a to k and the compound of Comparative Example 1 (4-tert-butoxy-4-methoxydibenzoylmethane) was measured. Furthermore, the UV absorption range after exposure of these compounds to sunlight for about 150 hours was also measured. These ultraviolet absorption spectra are shown in FIGS. For comparison, FIG. 13 shows an ultraviolet absorption spectrum of p-methoxycinnamic acid-2-ethylhexyl ester (trade name “Parsol MCX”) used in a commercially available sunscreen agent as Comparative Example 3. In Comparative Example 3, absorption was mainly observed in the UV-B region, and slight UV absorption in the UV-A region at 320 to 350 nm close to the UV-B region was observed, but in particular, UV of 350 to 400 nm was observed. It can be seen that there is no absorption in the ultraviolet region important as -A. Further, FIG. 14 shows the ultraviolet absorption spectrum before and after the sunlight irradiation of Comparative Example 1. Comparative Example 2 is 2- (2H-benzotriazol-2-yl-5-octyloxyphenol (trade name “SEESORB707”; manufactured by Cypro Kasei Co., Ltd.) used as a comparative object of the benzotriazole derivative. Regarding light irradiation, the test was conducted by exposing to natural light from 10:00 am to 16:00 pm from late July to late August.

Table 2 shows the maximum absorption wavelength (λmax) and the maximum molar extinction coefficient (ε) of each compound.
Table 2 also shows the HPLC purity and melting point of each compound.

  It can be seen that the synthesized compounds a to k all show higher light resistance than Comparative Example 1. In Comparative Example 1, it has been transformed into a strong reddish viscous crystal body, a large change is observed in the UV absorption wavelength region, and the weight is reduced by 3.7% after UV irradiation. Therefore, there is a high possibility that decomposition and alteration of the compound itself are progressing. Therefore, it is considered that there is a problem in the stability of the compound of Comparative Example 1 itself. On the other hand, since the weight loss after UV irradiation of the synthesized compounds a to k is approximately 0.5% or less, it can be said that the stability of the compound itself is excellent.

  The synthesized compounds a to k are almost the same in terms of the initial maximum absorption wavelength (λmax) and molar extinction coefficient (ε) even when compared with the commercially successful Comparative Example 1. There is no color. In addition, the CLogP value is often 5.0 or less, and it has a stable structure of 2H-benzotriazole derivative, has a partitioning ability to water, and is considered to be excellent in biodegradability.

(MMP inhibitory activity characteristics)
The synthesized compounds a to k were examined for inhibitory activity against MMP-1, MMP-2, and MMP-9. For the activity evaluation, a commercially available MMP Inhibitor Profiling Kit, “Fluorometric” (manufactured by BIOMOL) was used. The work procedure is as follows.

(1) Thaw frozen measurement buffer, N-isobutyl-N- (4-methoxyphenylsulfonyl) glycol hydroxamic acid (hereinafter referred to as “NNGH”) in a vial, and add 1 μL of NNGH. In contrast, 200 μL of the measurement buffer is added to make a diluted solution in another container.
(2) Add 99 μL of assay buffer to 3 wells for assay in 96-well plate, add 79 μL to control well, 59 μL to NNGH well, and add remaining well at the concentration evaluated for the compound to be evaluated The amount of buffer varies.
(3) After thawing MMP, dilute at the ratio shown below.
MMP-1: 1/40 MMP-9: 1/60
MMP-2: 1/70 MMP-10: 1/100
MMP-3: 1/70 MMP-12: 1/285
MMP-7: 1/70 MMP-13: 1/50
MMP-8: 1/100 MMP-14: 1/100
(4) Add 20 μL of the enzyme diluted in (3) above to control, NNGH, and the well of the compound to be evaluated.
(5) Add only the NNGH well to the NNGH solution diluted in (1) above.
(6) Add 5 μL of DMSO only to control wells.
(7) A solution calculated so that the compound to be evaluated has a concentration to be evaluated is added to a predetermined well.
(8) Incubate at 37 ° C. for 1 hour to react the enzyme with the evaluation compound.
(9) After 1 hour, first, 1 μL of the fluorescent peptide substrate is added to 3 wells for the assay, and Ex / Em = 328/420 with a Fluoroskan Ascent (manufactured by Thermo Fisher Scientific) fluorescence / microplate reader. Measure the fluorescence intensity and measure until the value is constant. Use this value as a blank.
(10) After the blank measurement is completed, 1 μL of the fluorescent peptide substrate is added to all remaining wells, and the fluorescence is measured. Measure every 2 minutes and take 10 points.
(11) The points are plotted with respect to time and fluorescence, and the slope when a straight line is drawn is determined for each of control, NNGH, and the compound to be evaluated.
(12) The inhibition rate is calculated using the obtained slope. The calculation formula is obtained by the following [Formula 1].
[1- (Slope of compound to be evaluated) / (Slope of control)] × 100 (%) [Formula 1]

  When the MMP inhibitory activity of the compound synthesized according to the Kit procedure was measured, the inhibitory activity was observed in all the compounds. These results are shown graphically in FIG.

  These compounds were further measured at different concentrations, and 50% inhibitory concentration (IC50) was measured and calculated. Table 3 shows the results.

  In compound g, an inhibitory activity of about 200 μM was observed in all of MMP-1, MMP-2, and MMP-9. In addition, the compound i into which chlorine was introduced also had comparable inhibitory activity with MMP-2 and MMP-9. In the derivative in which adamantane was introduced instead of piperidine, a similar inhibitory activity was observed in compound e. In other compounds, except for compounds j and k, although they were weak, inhibitory activity was observed in any of MMP-1, MMP-2 and MMP-9.

  The above evaluations are shown in Table 4 together with ◎ to ×. The evaluation criteria are as follows (however, ND is not measured).

UV absorption, initial value ◎: 30,000 ≦ ε
○: 26,000 ≦ ε <30,000
Δ: 22,000 ≦ ε <26,000
×: ε <22,000

Light resistance ◎: 80% ≦ ε persistence ○: 70% ≦ ε persistence <80%
Δ: 40% ≦ ε persistence <70%
×: ε persistence <40%

・ Distribution to water ◎: ClogP <5
○: 5 ≦ ClogP <6
Δ: 6 ≦ ClogP <7.5
×: 7.5 ≦ ClogP

・ Solubility in cosmetic base material Solvents with 28 ° C solubility of 1 wt / wt% or more ◎: 4 types or more ○: 2-3 types △: 1 type ×: None

・ NMP activity NMP 50% inhibitory activity concentration (IC50): ◎: Three types of 1,000 μM or less ○: One or two types of 1,000 μM or less △: Except ◎ ○, those with 2,000 μM or less 1 or more ×: Not applicable to any of the above

  From the above results, the benzotriazole compound of the present invention can provide a hybrid material having a large ultraviolet absorption effect in the UVA region, and having both necessary and sufficient solubility in a cosmetic base material and MMP inhibitory activity. . In addition, in view of the fact that the ClogP value is low and the biodegradability is considered to be excellent while being excellent in stability as a compound, as a sun care cosmetic product having higher ability than conventional UV absorbers Available. _

Claims (9)

A benzotriazole compound which is a 2- (2,4-dihydroxyphenyl) -2H-benzotriazole derivative represented by the following general formula 1.
General formula 1:

(A is an alicyclic ring which may contain a nitrogen atom, an oxygen atom and / or a sulfur atom as a ring constituent atom, or an alkyloxy group or an alkylamino group having the alicyclic end as a terminal, and B is bonded to A at the α-position. A carbonyl group or ester group having 3 to 6 carbon atoms, R1 is a hydrogen atom or a chlorine atom) A benzotriazole compound which is a 2- (2,4-dihydroxyphenyl) -2H-benzotriazole derivative represented by the following general formula 1.
General formula 1:

(A is an alkyloxy group or alkylamino group having an alicyclic ring which may contain a nitrogen atom and / or an oxygen atom as a ring constituent atom, and B is a carbonyl group having 3 to 6 carbon atoms bonded to A at the α-position. Or ester group, R1 is hydrogen atom or chlorine atom) A benzotriazole compound which is a 2- (2,4-dihydroxyphenyl) -2H-benzotriazole derivative represented by the following general formula 2 among the benzotriazole compounds represented by the general formula 1 according to claim 1.
General formula 2:

(A is an alicyclic ring which may contain a nitrogen atom, an oxygen atom and / or a sulfur atom as a ring constituent atom, or an alkyloxy group or an alkylamino group having the alicyclic end as a terminal) A benzotriazole compound which is a 2- (2,4-dihydroxyphenyl) -2H-benzotriazole derivative represented by the following general formula 3 among the benzotriazole compounds represented by the general formula 1 according to claim 1.
General formula 3:

(A is an alicyclic ring which may contain a nitrogen atom, an oxygen atom and / or a sulfur atom as a ring constituent atom, or an alkyloxy group or an alkylamino group having the alicyclic end as a terminal, and R1 is a hydrogen atom or a chlorine atom) Among the benzotriazole compounds represented by the general formula 2 according to claim 3, a benzotriazole compound represented by the following compound a or compound b.
Compound a: Morpholine-4-carboxylic acid 2- [4- (2H-benzotriazol-2-yl) -3-hydroxy-phenoxy] -ethyl ester

Compound b: Adamantane-1-carboxylic acid 2- [4- (2H-benzotriazol-2-yl) -3-hydroxy-phenoxy] -ethyl ester

Among the benzotriazole compounds represented by the general formula 3 according to claim 4, any one of the following compound c, compound d, compound e, compound f, compound g, compound h, compound i, compound j or compound k Benzotriazole compounds shown.
Compound c: 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -1-morpholin-4-yl-butan-1-one

Compound d: 1- {4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -butyryl} -pyrrolidin-2-one

Compound e: 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -butyric acidadamantan-1-yl ester

Compound f: 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -butyric acid 2-morpholin-4-yl-ethyl ester

Compound g: 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -butyric acid 2-piperidin-1-yl-ethyl ester

Compound h: 4- [4- (2H-Benzotriazol-2-yl) -3-hydroxy-phenoxy] -N- (2-morpholin-4-yl-ethyl) -butyramide

Compound i: 4- {4- [5-Chloro- (2H-benzotriazol-2-yl)]-3-hydroxy-phenoxy} -butylic-acid 2-piperidin-1-yl-ethyl ester

Compound j: 4- {4- [5-Chloro- (2H-benzotriazol-2-yl)]-3-hydroxy-phenoxy} -butyricacid 2-morpholin-4-yl-ethyl ester

Compound k: 4- {4- [5-Chloro- (2H-benzotriazol-2-yl)]-3-hydroxy-phenoxy} -N- (2-mor-pholin-4-yl-ethyl) -butyramide

  The ultraviolet absorber which contains the benzotriazole compound in any one of Claims 1-6 as the component.   A cosmetic ultraviolet absorber comprising the benzotriazole compound according to any one of claims 1 to 6 as its component.   The skin external preparation which contains the benzotriazole compound in any one of Claims 1-6 as the component.

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