WO2021038637A1 - Novel vitamin a derivative and method for producing same - Google Patents

Abstract

Provided are: a novel vitamin A derivative which is useful as a medicinal drug and a cosmetic and which comprises a compound represented by formula (I) or formula (II) (in the formulae, R¹ and R² each independently denote a hydrogen atom, an alkyl group having 1-12 carbon atoms, an alkenyl group having 2-10 carbon atoms, an alkynyl group having 2-10 carbon atoms or an acyl group having 2-30 carbon atoms), or a salt thereof; and a method for producing same.

Description

New vitamin A derivative and its manufacturing method

The present invention relates to a novel vitamin A derivative and a method for producing the same.

Retinoids or vitamin A derivatives are used in various fields, especially in the fields of medicine, cosmetics and agricultural foods, and many synthetic methods are known. They bind to retinoid receptors in vivo and are used in the treatment of skin diseases such as acne, photoaging, and certain malignant tumors, and are also incorporated into cosmetics mainly for the purpose of beauty. Pharmaceuticals include tretinoin and adapalene, and cosmetics include retinol and retinol palmitate, which have been approved for the indication of wrinkle-improving action. Tretinoin is an all-trans retinoic acid isomer (ATRA) in which all retinoic acid double bonds are trans-type. This tretinoin is marketed as besanoid, which is a therapeutic agent for acute promyelocytic leukemia, and orsenone ointment, which is an external medicine suitable for pressure ulcers and skin ulcers (burn ulcer, diabetic ulcer, leg ulcer).

In general, cancer cells to be treated acquire autonomous growth due to some gene mutation and continue to grow indefinitely. The promyelocytic leukemia cell line, the HL60 cell line, is a model cell line used for screening for apoptosis-inducing substances and differentiation-inducing substances. When the HL60 cell line is induced to differentiate, its proliferation is suppressed and the tumorigenic effect is lost by the final differentiation (decancerous state). In the treatment of cancer, induction of apoptosis and induction of differentiation are considered as effective means, and certain anticancer agents and retinoic acid derivatives have already been clinically applied.

Tretinoin is said to have about 100 times the pharmacological action of retinol, but is known to have serious side effects such as teratogenicity and dyspnea. In addition, retinoic acid and its analogs are vulnerable to ultraviolet rays and are unstable. For this reason, 7-hydroxyretinoic acid, which has higher photostability than conventional retinoic acid and its derivatives, has been isolated from certain cyanobacteria (for example, Non-Patent Document 1 and Patent Documents). 1). However, the amount of 7-hydroxyretinoic acid extracted from blue-green algae is extremely small, and it becomes a mixture of four isomers in the process of purifying this, so the carboxy group of 7-hydroxyretinoic acid is reduced. It is difficult to obtain 7-hydroxyretinol. Therefore, retinol having a hydroxy group or an oxo group at the 7-position or a derivative thereof is not yet known.

Japanese Unexamined Patent Publication No. 2011-251942

An object of the present invention is to provide a novel vitamin A derivative and a method for producing the same, which are useful as pharmaceuticals and cosmetics.

In one embodiment of the present invention, the following formula (I):

Or formula (II):

(In the formula, R ¹ and R ² are independent of each other, a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, or 2 carbon atoms. A compound represented by (30) acyl groups or a salt thereof is provided.
In the compound of the above formula (I) or (II), it is preferable that both ^{R 1} and R ^{2 are hydrogen atoms.} Further, ^{it is further that R 1} is a hydrogen atom and R ² is an acyl group represented by the formula (III): −CO (CH ₂ ) _n CH ₃ (n is an integer of 0 to 28). Preferably, R ² is an acetyl group, even more preferably.

In another embodiment of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any of the above or a salt thereof.
This pharmaceutical composition is used to treat night blindness, rickets, psoriasis, leukemia or dry eye inflammation, or to impart resistance to infection and promote body growth and bone and / or tooth development. It is preferable to do so.

In still another embodiment of the present invention, there is provided a skin turnover promoter for preventing abnormal dryness and pigmentation of the skin, which contains the compound described in any of the above or a salt thereof as an active ingredient. ..

In another aspect, the invention provides resistance to the treatment of night blindness, rickets, psoriasis, leukemia or dry eye inflammation, or imparts resistance to body growth and bone and / or tooth development. To provide a method comprising administering to a subject in need thereof an effective amount of any of the above compounds or salts thereof.

In yet another aspect of the present invention, the following equation (IV):

(In the formula, PG indicates a hydroxy group protecting group.)
The aldehyde represented by the following formula (V):

(In the formula, R ⁴ represents an alkyl group having 1 to 12 carbon atoms, R ⁵ represents an aryl group, and X represents a halogen atom.) A phosphonium salt represented by the formula, or the following formula (VI). :

(In the formula, R ³ and R ⁴ represent alkyl groups having 1 to 12 carbon atoms independently of each other.)
The Wittig reaction or the Horner-Wadsworth-Emmons reaction with the phosphonate represented by the following formula (VII):

The process of obtaining the ester represented by
The ester represented by the formula (VII) is reduced and acylated, and the protecting group PG is further deprotected to obtain the following formula (VIII):

(In the formula, R ² has the same meaning as described above.) And the step of obtaining the compound represented by
By oxidizing the compound represented by the formula (VII), the following formula (II):

Provided is a method for producing a vitamin A derivative, which comprises a step of obtaining a compound represented by.

According to the present invention, a novel vitamin A derivative and a method for producing the same, which are useful as pharmaceuticals and cosmetics, are provided.

FIG. 1 shows the quantification result of the NBT-positive cell rate using HL-60 cells for the compound of the present invention.

Next, preferred embodiments of the present invention will be described in the order of the following items.
(1) New Vitamin A Derivative (2) Method for Producing New Vitamin A Derivative (3) Pharmaceutical Composition and Therapeutic Use (4) Other Uses The embodiments described below are inventions according to claims. It is not limited, and not all of the elements and combinations thereof described in the embodiments are essential to the solution of the present invention. Also, the disclosures of all patent and non-patent documents cited herein are incorporated herein by reference in their entirety.

(1) Novel Vitamin A Derivative The novel vitamin A derivative according to the embodiment of the present invention is represented by the following formula (I):

Or formula (II):

(In the formula, R ¹ and R ² are independent of each other, a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, or 2 carbon atoms. It is a compound represented by (30) acyl groups or a salt thereof.

As used herein, the term "alkyl group having 1 to 12 carbon atoms" means a monovalent linear or branched saturated hydrocarbon group consisting of only carbon atoms and hydrogen atoms and having 1 to 12 carbon atoms. .. For example, methyl group, ethyl group, propyl group, 1-methylethyl group, butyl group, 2-methylpropyl group, 1-methylpropyl group, 1,1-dimethylethyl group, pentyl group, 3-methylbutyl group, 2- Methylbutyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group Group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, heptyl group, 1-methylhexyl group, 1-ethylpentyl group, octyl Groups include 1-methylheptyl groups, 2-ethylhexyl groups, nonyl groups, or decyl groups. An alkyl group having 1 to 6 carbon atoms is preferable, and an alkyl group having 1 to 4 carbon atoms is more preferable.

The "alkenyl group having 2 to 10 carbon atoms" includes a linear or branched alkenyl group having 2 to 10 carbon atoms containing at least one double bond. Specifically, an ethenyl group, a propenyl group, a 1-methylethenyl group, a butenyl group, a 2-methylpropenyl group, a 1-methylpropenyl group, a pentenyl group, a 3-methylbutenyl group, a 2-methylbutenyl group, a 1-ethylpropenyl group, Hexenyl group, 4-methylpentenyl group, 3-methylpentenyl group, 2-methylpentenyl group, 1-methylpentenyl group, 3,3-dimethylbutenyl group, 1,2-dimethylbutenyl group, heptenyl group, 1- Examples thereof include a methylhexenyl group, a 1-ethylpentenyl group, an octenyl group, a 1-methylheptenyl group, a 2-ethylhexenyl group, a nonenyl group, or a decenyl group. An alkenyl group having 2 to 6 carbon atoms is preferable, and an alkenyl group having 2 to 4 carbon atoms is more preferable.

The "alkynyl group having 2 to 10 carbon atoms" includes a linear or branched alkynyl group having 2 to 10 carbon atoms containing at least one triple bond. Specifically, ethynyl group, propynyl group, butynyl group, pentynyl group, 3-methylbutynyl group, hexynyl group, 4-methylpentynyl group, 3-methylpentynyl group, 3,3-dimethylbutynyl group, heptynyl group. , Octinyl group, 3-methylheptinyl group, 3-ethylhexynyl group, noninyl group, or decynyl group. Preferably, an alkynyl group having 2 to 6 carbon atoms is mentioned, and more preferably, an alkynyl group having 2 to 4 carbon atoms is mentioned.

Further, the "acyl group having 2 to 30 carbon atoms" means the group R'-CO-, where R'is a linear or linear group having 1 to 29 carbon atoms which may have an unsaturated bond. Represents a branched alkyl group, an aryl group such as phenyl or naphthyl, or a heteroaryl group such as pyridyl, imidazolyl, thienyl, or frill containing a hetero atom selected from a nitrogen atom, a sulfur atom, and an oxygen atom as a ring member. .. These groups may have a functional group such as an amino group. Specific examples of the "acyl group having 2 to 30 carbon atoms" include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, a hexanoyl group, a lauroyl group, a palmitoyl group, and an oleoyl group. , Especially desirable to be an acetyl group. Such a compound of formula (I) or formula (II) in which R is an acyl group having 2 to 30 carbon atoms can be synthesized by using a method already known for acylating a retinol compound. For example, 7-hydroxyretinol can be easily obtained by carrying out a monoacylation reaction with a lipase in the presence of an acylating agent (see JP-A-10-036301 and JP-A-2007-143561).

Various conventional alkyl acylates and alkenyl acylates such as methyl acetate, ethyl acetate, butyl acetate, vinyl acetate, allyl acetate, isopropenyl acetate, ethyl propionate, ethyl butyrate and vinyl propionate and esters of long chain fatty acids such as Vinyl laurate can also be used as an acylating agent. Ethyl acetate, butyl acetate or vinyl acetate is used for acetylation. Vinyl esters of the corresponding fatty acids are also suitable for the production of long chain asherahs. The amount of acylating agent used can be 1 molar equivalent or several times higher, but is particularly excessive when the acylating agent is used as a solvent at the same time, in the case of alkyl and alkenyl acylates. May be applicable.

The compound represented by the formula (I) or the formula (II) may be in the form of an isomer or a salt. Examples of the acid addition salt include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate and other inorganic acid salts, oxalate, malonate, and succinic acid. Salt, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethane Examples include organic acid salts such as sulfonates. Examples of the base salt include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt.

The term "isomer" as used herein means a geometric isomer, an optical isomer or a tautomer. The compounds of this embodiment include all of the above isomers and mixtures thereof in any proportion.

Although not limited to a specific theory, the novel vitamin A derivative of the present embodiment is photostable because the 7-position is hydroxyated or oxo-ized, so that the conjugated system of the conventional retinol and the retinol derivative is blocked. It is thought that the sex is improving. Furthermore, although not limited to a specific theory, the novel vitamin A derivative of the present embodiment may cause tautomerism and contribute to the improvement of photostability by always being present as a mixture.

(2) Method for Producing a New Vitamin A Derivative A method for producing a vitamin A derivative according to another aspect of the present invention is described in the following formula (IV):

(In the formula, PG indicates a hydroxy group protecting group.)
The aldehyde represented by the following formula (V):

(In the formula, R ⁴ represents an alkyl group having 1 to 12 carbon atoms, R ⁵ represents an aryl group, and X represents a halogen atom.) A phosphonium salt represented by the formula, or the following formula (VI). :

(In the formula, R ³ and R ⁴ represent alkyl groups having 1 to 12 carbon atoms independently of each other.)
The Wittig reaction or the Horner-Emmons reaction with the phosphonate represented by the following formula (VII):

(In the formula, R ⁴ represents an alkyl group having 1 to 12 carbon atoms.)
Including the step of obtaining the ester represented by.

In the above step, the aldehyde represented by the formula (IV) can be synthesized by various methods. For example, as described in Scheme 1 and Examples described later, β-cyclocitral (1) is reacted with 4-bromo-3-methyl-2-butenenitrile (2) to produce hydroxynitrile (3). After synthesizing and protecting the hydroxy group at the 7-position with a silyl ether, the nitrile may be partially reduced to an aldehyde using diisobutylaluminum hydride. Examples of the hydroxy group protecting group (indicated by PG in the above formula) include a substituted silyl group (trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, phenyldimethylsilyl group, etc.). Examples thereof include tetrahydropyranyl group, tetrahydrofuranyl group, alkoxyalkyl group (methoxymethyl group, ethoxyethyl group, etc.), benzyloxymethyl group, benzyl group, trityl group, acyl group (formyl group, acetyl group, benzoyl group, etc.). .. The reaction temperature is −50 ° C. to room temperature, preferably −30 ° C. to 0 ° C.

The Wittig reaction is a reaction of an aldehyde or ketone with a triphenylphosphonium ylide to give alkenes and triphenylphosphine oxides (A. Maercker, Org. React. 1965, 14, 270-490; A.W. Carruthers, Some Modern Methods of Organic Synthesis, Cambridge University Press, Cambridge UK1971, pp81-90). The Wittig reaction is the most commonly used reaction for coupling aldehydes and ketones to phosphine ylides substituted alone. Wittig reagent is usually prepared from a phosphonium salt, wherein the phosphonium salts are prepared by the reaction of Ph 3 _P and a halogenated alkyl. To form the Wittig reagent (ylide), was suspended phosphonium salt in a solvent such as Et 2 _O or THF, is added a strong base such as phenyl lithium or n- butyl lithium. With a simple ylide, the product is generally predominantly the Z-isomer, but relatively small amounts of the E-isomer are often formed as well. If the desired product is the E-isomer, a Schlosser modification method may be used. With stabilized ylide (carbanion phosphonate), the product is predominantly the E-isomer. Alternatively, the Horner-Wadsworth-Emmons reaction (BE Maryanoff and AB Reitz, Chem Rev. 1989, 89: 863-927) is used to predominantly produce E-alkenes. A chemical reaction between a stabilized carbanion phosphonate and an aldehyde (or ketone). The Horner-Wadsworth-Emmons reaction (or HWE reaction) is a stabilized condensation reaction of a phosphonate carbanion with an aldehyde (or ketone) to predominantly produce an E-alkene. Carbanions stabilized with phosphonates have higher nucleophilicity and higher basicity to the phosphonium ylide used in the Wittig reaction. These reactions can be carried out at a temperature in the range of usually −78 to 60 ° C., preferably −10 to 25 ° C. for usually 0.5 to 24 hours, preferably about 0.5 to 2 hours.

Next, the ester represented by the above formula (VII) is reduced and acylated, and the protecting group PG is further deprotected to obtain the following formula (VIII):

(In the formula, R ² has the meaning described above.) To obtain the compound represented by.
Suitable reducing agents include, but are not limited to _{, LiAlH 4} , LiBH ₄ , NaBH _{4-LiBr, and DIBAL.} In one embodiment, the reducing agent is LiAlH ₄ . In another embodiment, the reducing agent is LiBH ₄ . In yet another embodiment, the reducing agent LiBH ₄ may be produced in situ, for example _{by joint use of NaBH 4 and LiBr.} The amount of reducing agent is generally 0.8 to 1.6 equivalents, or more specifically 1.0 to 1.4 equivalents.

The obtained terminal alcohol may be acylated with a carboxylic acid anhydride. Further, the protecting group PG of the 7-position hydroxy group can be deprotected by a method known to those skilled in the art. For example, the protection of the hydroxy group by the substituted silyl group can be easily deprotected by using a fluorine anion or the like. it can.

Subsequently, the compound represented by the above formula (VIII) is oxidized to form the following formula (II):

Obtain the compound represented by. In the formula, R ² is as described above.
Oxidation of the 7-position hydroxy group of the compound represented by the above formula (VIII) can be carried out under mild conditions using 2-iodoxybenzoic acid (IBX) or the like.

As the reaction solvent, if necessary, an inert organic solvent (for example, anhydrous tetrahydrofuran, anhydrous dimethyl sulfoxide, etc.) is used. The reaction temperature is 0 to 50 ° C. The product of each of the above steps can be separated and purified from the reaction mixture by a method known per se, for example, silica gel column chromatography, if necessary.

The compound represented by the above formula (II) is a keto-enol tautomer of 7-hydroxyretinol (I), both of which coexist in a solution at a predetermined abundance ratio, but are organic such as chloroform. The proportion of ketoform represented by the formula (II) is high in the solvent.

Scheme 1 below shows one typical method for producing a compound of formula (II). The starting material may be a known compound or may be prepared according to methods known in the art.

(3) Pharmaceutical Compositions and Therapeutic Uses The present invention relates to at least one compound described above, or an individual isomer, a racemic or non-racemic mixture of isomers, or a pharmaceutically acceptable salt or solvent thereof. To treat night blindness, racemic mixture, psoriasis, leukemia or dry ophthalmitis, or containing Japanese products with at least one pharmaceutically acceptable carrier and optionally other therapeutic and / or prophylactic ingredients. Includes pharmaceutical compositions for imparting resistance to infection and promoting body growth and bone and / or tooth growth.

In general, the pharmaceutical composition of this embodiment will be administered by any of the acceptable dosage forms for agents that contain therapeutically effective amounts of the above compounds and provide similar utility. A therapeutically effective amount of a compound is related to the severity of the disease to be treated, the age and relative health of the subject, the efficacy of the compound used, the route and form of administration, the indication to which administration is directed, and. Depending on a number of factors such as physician preference and experience, it is typically 1 to 500 mg per day, preferably 1 to 100 mg per day, and most preferably 1 to 30 mg per day. Those skilled in the art treating such diseases will be able to obtain therapeutically effective amounts of the compounds of the invention for a given disease without undue experimentation and, depending on personal knowledge and disclosure of the present application. You will be able to locate it.

The pharmaceutical composition of the present embodiment is oral (including buccal and sublingual), rectal, intranasal, topical, transpulmonary, transvaginal or parenteral (intramuscular, intraarterial, intrathecal, subcutaneous and venous). It may be administered as a pharmaceutical formulation containing those suitable for administration (including) or in a form suitable for administration by inhalation or aeration. The preferred method of administration is generally oral using a convenient daily dosing regimen that can be adjusted according to the degree of distress.

The pharmaceutically acceptable carrier may be either solid or liquid. Formulations in solid form include powders, tablets, pills, capsules, cashiers, suppositories and dispersible granules. A solid carrier is one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating materials. You can. In powders, the carrier is generally a micronized solid that is a mixture with a micronized active ingredient. In tablets, the active ingredient is generally mixed with a carrier having the required binding capacity in an appropriate proportion and shaped into the desired shape and size. Powders and tablets preferably contain from about 1 to about 70% of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacant, methyl cellulose, sodium carboxymethyl cellulose, low melting point wax, cacao butter and the like. The term "formulation" includes a formulation of an active compound having an encapsulating material as a carrier that provides a capsule in which the active ingredient with or without a carrier is surrounded by a carrier associated thereto. Intended. Similarly, cashiers and lozenges are included. Tablets, powders, capsules, pills, cashiers and lozenges can be in solid form suitable for oral administration.

Other forms suitable for oral administration are intended to be converted to liquid forms of emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or liquid forms just prior to use. Includes solid form formulations. Emulsions can be prepared in liquids, such as aqueous propylene glycol liquids, or can contain emulsifiers such as lecithin, sorbitan monooleate or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding the appropriate colorants, flavoring agents, stabilizers and thickeners. Aqueous suspending agents can be prepared by dispersing the micronized active ingredient in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. it can. Solid form formulations include solutions, suspensions and emulsions, in addition to active ingredients, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers. Etc. can be contained.

The pharmaceutical composition of the present embodiment can be formulated for parenteral administration (eg, by injection, eg, bolus injection or continuous infusion) and is a unit dose of ampoule, prefilled syringe, small volume infusion. It can also be provided in form or in a multi-dose container containing the added preservative. The composition can take the form of a suspension, liquid or emulsion, such as a liquid of aqueous polyethylene glycol, in an oily or aqueous vehicle. Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (eg olive oil), and organic esters for injection (eg ethyloleate), preservatives, wetting agents, etc. It may contain a compounding agent such as an emulsifier or suspending agent, a stabilizer and / or a dispersant. Alternatively, the active ingredient is obtained by aseptic separation of the sterile solid or by lyophilization from the pre-use constitutive solution with a suitable vehicle, eg, sterile pyrogen-free water. It may be in powder form.

The pharmaceutical composition of the present embodiment can be formulated for topical administration to the epidermis as an ointment, cream or lotion, or as a transdermal patch. For example, ointments and creams can also be formulated with an aqueous or oily base with the addition of appropriate thickeners and / or gelling agents. Lotions can be formulated with aqueous or oily bases and will generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or colorants. Formulations suitable for topical oral administration are lozenges containing an active agent in a flavored base, usually sucrose and acacia or tragacanth; active in gelatin and glycerin or inactive bases such as sucrose and acacia. Ingredient-containing sucrose; as well as mouthwash containing the active ingredient in a suitable liquid carrier.

Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Complexe of Pharmacy 1995, E. et al. W. Edited by Martin, Mack Publishing Company, 19th Edition, Easton, Pennsylvania.

(4) Other Uses The novel vitamin A derivative described above can be used as a skin turnover accelerator for preventing abnormal dryness and pigmentation of the skin. Specifically, it is used for prevention and / or improvement of thinning or wrinkle formation of the epidermal viable cell layer, dryness, disordered texture, dullness, dark spots, darkening of spots, etc. due to delayed turnover. be able to.

From yet another viewpoint, a method for promoting epidermal turnover, which comprises applying the above vitamin A derivative to the stratum corneum, is also provided. This method is for cosmetic purposes, not for the prevention or treatment of illness. In addition, the subject of implementation may be a person other than a doctor, and specifically, a person who performs a beauty treatment for another person such as a cosmetics salesperson or an esthetician as a profession. It may also be the person to be treated. The act of instructing and soliciting the person to be treated to implement the method of the present invention is also included in the implementation of the method of the present invention.

Whether or not the turnover of the epidermis is promoted can be evaluated by a known method. For example, a method of evaluating the turnover speed of the epidermis as a time change of the pigment of the epidermis can be mentioned. The dye may be generated by patching an aqueous solution of DHA (dihydroxyacetone) on the medial side of the upper arm and labeling the skin in a tan color. When DHA is applied to the skin, it reacts with the amino acids that make the protein and the protein is altered, and this altered protein turns yellow or brown. Alternatively, it can be evaluated by a method for evaluating epidermal turnover (see JP-A-2007-199053), which is characterized by using the presence position of a stratum corneum protein in the stratum corneum as an index.

Unless otherwise specified, the skin turnover accelerator in the present embodiment is the active ingredient of the vitamin A derivative, and further cosmetics such as diluents, stabilizers, antioxidants, preservatives, or external use on the skin. It may be the one to which an additive that is acceptable as an agent is added. The skin turnover accelerator can be used as a component of cosmetics, external preparations for skin, and pharmaceutical compositions (hereinafter, referred to as "cosmetics and the like"). Cosmetics and the like can contain, for example, 0.00001 to 1% by mass or more of the above vitamin A derivative as a solid content, preferably 0.00001 to 0.1% by mass or more, and 0.0001 to 0.1. It is more preferable to contain by mass% or more.

Cosmetics and the like containing the above-mentioned vitamin A derivative can also be prepared in various dosage forms such as solid preparations, semi-solid preparations and liquid preparations, depending on the purpose of use. More specifically, cosmetics include cleansing, washing pigments, lotions, emulsions, creams, massage products, pack products, beauty liquids / gels, lip care products, etc. as basic cosmetics; foundations, face powders as base makeup cosmetics. , Makeup base, concealer, etc .; As point makeup cosmetics, lipstick, lip gloss liner, teak products, eye shadows, eye liners, mascara, eyebrow products, etc .; Body cosmetics, soap, liquid cleaning agent, sunscreen cream, bathing agent Etc .; As cosmetics for hair or cosmetics for scalp, shampoo, rinse, hair treatment, hair styling product, hair tonic, hair restorer, scalp treatment and the like can be used. Further, it can be a plaster, an ointment, a poultice, a liniment, a lotion, a coating agent, a patch, an aerosol agent (spray agent).

Cosmetics and the like containing the above-mentioned vitamin A derivative can contain various additives that are acceptable as cosmetics or pharmaceuticals, in addition to the agents of the present invention, as long as the effects of the present invention are not impaired. Examples of this are water (purified water, hot spring water, deep ocean water, etc.), surfactants (emulsifiers, solubilizers, suspending agents, stabilizers, etc.), antioxidants, preservatives, gelling agents, alcohols. Classes, film-forming agents, colorants, fragrances, deodorants, salts, pH adjusters, refreshing agents, chelating agents, keratolytic agents, enzymes, vitamins and the like. In addition, the cosmetics and the like of the present embodiment can contain various functional ingredients that are acceptable as additives for cosmetics or external preparations for skin, as long as the effects of the skin turnover accelerator are not impaired. Examples of such ingredients are whitening agents, UV protection agents, antibacterial agents, anti-inflammatory agents, cell activators, reactive oxygen species removers, moisturizers, skin cleansing ingredients, acne and asemo-preventing ingredients.

Next, examples will be given and the present invention will be described in more detail, but the present invention is not limited to these examples. The compound numbers described in the following examples are the numbers shown in the above scheme 1 in parentheses.

(Step 1)
<Step of synthesizing hydroxynitrile (3) from β-cyclocitral (1)>
An anhydrous tetrahydrofuran solution of β-cyclocitral (1) 1.63 g (10.7 mmol) and bromonitrile (2) 2.03 g (12.8 mmol) in 1.26 g (19.3 mmol) of activated zinc in a nitrogen stream. (20 mL) was added, and the mixture was reacted at room temperature for 3 and a half hours under ultrasonic irradiation. The reaction mixture was diluted with ethyl acetate and the insoluble material was filtered off with Celite. The residue obtained by concentrating the filtrate was purified using an ethyl acetate / hexane (1/4 volume ratio) mixed solvent as an elution solvent using silica gel column chromatography, and 1.19 g of a pale yellow oily substance. (3) [Yield 48% with respect to β-cyclocitral (1)] was obtained.

^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 0.97 and 1.11 (each3H, s, gem-Me), 1.43 (2H, m, 2-H ₂ ), 1.57 (2H, m) , 3-H ₂ ), 1.85 (3H, s, 5-Me), 1.95 (2H, m, 4-H ₂ ), 2.15 (3H, d, J = 1Hz, 9-Me) , 2.30 (1H, ddd, J = 1,2.5 and 14.5Hz, 8-H), 2.80 (1H, ddd, J = 1,10.5 and 14.5Hz, 8-H) , 4.45 (1H, dd, J = 2.5 and 10.5Hz, 7-H), 5.27 (1H, sext, J = 1Hz, 10-H).
IR _Vmax (CHCl ₃ ) cm ^-1 : 3610 and 3480 (OH), 2220 (CN).
HRMSm / z: 256.1674 [(M + Na) ⁺ , C ₁₅ H ₂₃ ONNa requires 256.1672].

(Step 2)
<Step of synthesizing siloxynitrile (4) from hydroxynitrile (3)>
In a nitrogen stream, in an anhydrous 6-chloromethane solution (10 mL) of hydroxynitrile (3) 410 mg (1.76 mmol), triethylamine 1.23 mL (8.80 mmol) and N, N-dimethylaminopyridine 43 mg (0.35 mmol). After adding 0.59 mL (3.5 mmol) of chlorotriethylsilane at 0 ° C. and reacting at room temperature for 16 hours, a saturated aqueous solution of ammonium chloride was added to stop the reaction. The organic matter was extracted with diethyl ether, the organic layer was washed with saturated brine, dried, and the solvent was evaporated. The resulting residue was purified using a mixed solvent of ethyl acetate / hexane (1/9 volume ratio) as an elution solvent using silica gel column chromatography, and a colorless oily substance of 590 mg (4) [hydroxynitrile (hydroxynitrile). Yield 97% with respect to 3)] was obtained.

^{1 1} H-NMR (300MHz, CDCl ₃ ) δ: 0.56 (6H, q, J = 7.5Hz, SiC ₂ CH ₃ × 3), 0.93 (9H, t, J = 7.5Hz, SiC ₂₎ CH ₃ × 3), 0.93 and 1.12 (6H, s, gem-Me), 1.42 (2H, m, 2-H ₂ ), 1.55 (2H, m, 3-H ₂ ) , 1.82 (3H, br s, 5-Me), 1.91, (2H, m, 4-H ₂ ), 2.11 (3H, d, J = 1Hz, 9-Me), 2.28 (1H, dd, J = 2 and 13.5Hz, 8-H), 2.65 (1H, ddd, J = 0.5, 10 and 13.5Hz, 8-H), 4.36 (1H, br) d-like, J = 7.5Hz, 7-H), 5.15 (1H, d-like, J = 1Hz, 10-H).
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 5.06 (C × 3), 6.72 (C × 3), 19.15, 21.11.25, 28.38, 29.59, 34.11, 34.55, 40.26, 47.24, 69.71, 97.21, 117.07, 132.29, 138.12, 163.15.
IR _Vmax (CHCl ₃ ) cm ^-1 : 2219 (CN).
HRMSm / z: 370.2536 [(M + Na) ⁺ , C ₂₁ H ₃₇ ONNaSi requires 370.2537].

(Step 3)
<Step of synthesizing siloxyaldehyde (5) from siloxynitrile (4)>
3.46 mL (3.46 mmol) of a 1.0 M hexane solution of diisobutylaluminum hydride in an anhydrous diethyl ether solution (50 mL) of 1.00 g (2.88 mmol) of silica gel (4) in a nitrogen stream at -30 ° C. In addition, after reacting at −30 ° C. for 30 minutes, silica gel containing water was added to stop the reaction. The insoluble matter precipitated with Celite was filtered off, and the residue obtained by concentrating the filtrate was used as a solvent for elution with a mixed solvent of diethyl ether / hexane (15/85 volume ratio) using silica gel column chromatography. 843 mg (5) of a colorless oily substance [yield 84% with respect to silica gel (4)] was obtained.

^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 0.54 (6H, q, J = 7.5 Hz, SiC ₂ CH ₃ × 3), 0.89 (9 H, t, J = 7.5 Hz, SiC H ₂₎ CH ₃ × 3), 1.01 and 1.13 (each 3H, s, gem-Me), 1.42 (2H, m, 2-H ₂ ), 1.55 (2H, m, 3-H ₂₎ ), 1.84 (3H, br s, 5-Me), 1.92 (2H, m, 4-H ₂ ), 2.24 (3H, d, J = 1.5Hz, 9-Me), 2 .35 (2H, dd, J = 2 and 13Hz, 8-H), 2.67 (1H, dd, J = 10 and 13Hz, 8-H), 4.43 (1H, br d-like, J = 8.5Hz, 7-H), 5.94 (1H, br d, J = 8.5Hz, 10-H), 10.00 (1H, d, J = 8.5Hz, CHO).
IR _Vmax (CHCl ₃ ) cm ^-1 : 1665 (conj.CO), 1630 and 1607 (C = C).
HRMSm / z: 373.2534 [(M + Na) ⁺ , C ₂₁ H ₃₈ O ₂ NaSi oxygen 373.2534].

(Step 4)
<Step of synthesizing siloxyester (7) from siloxyaldehyde (5)>
N-Butyllithium in anhydrous tetrahydrofuran solution (10 mL) of phosphonate (6) 0.99 mL (4.08 mmol) and N, N'-dimethylpropylene urea 1.48 mL (12.3 mmol) in a nitrogen stream at -30 ° C. 2.57 mL (4.08 mmol) of the 1.59 M hexane solution was added and reacted at −30 ° C. for 15 minutes to prepare an anhydrous tetrahydrofuran solution containing the lithium salt of phosphonate (6). To this solution, add 715 mg (2.04 mmol) of syroxyaldehyde (5) in anhydrous tetrahydrofuran (10 mL) at -30 ° C, react at -30 ° C for 30 minutes, and then add saturated aqueous ammonium chloride solution to stop the reaction. It was. The organic matter was extracted with diethyl ether, the organic layer was washed with saturated brine, dried, and the solvent was evaporated. The residue thus obtained was purified using a mixed solvent of diethyl ether / hexane (8/92 volume ratio) as an elution solvent using silica gel column chromatography, and the colorless oily substance 909 mg (7) [siloxynitrile (syroxynitrile). Yield 97% with respect to 5)] was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.50 (6 H, m, SiC ₂ CH ₃ × 3), 0.88 (9 H, t, J = 8 Hz, SiC ₂ CH ₃ × 3), 1. 00 and 1.12 (each 3H, br s, gem-Me), 1.29 (3H, t, J = 7Hz, OCH ₂ CH ₃ ), 1.41 (2H, m, 2-H2), 1. 55 (2H, m, 3-H2), 1.85 (3H, br s, 5-Me), 1.90 (3H, s, 9-Me), 1.93 (2H, m, 4-H2) , 2.22 (1H, br d, J = 13.5 Hz, 8-H), 2.34 (3H, d, J = 1.5 Hz, 13-Me), 2.57 (2H, dd, J = 10 and 13.5 Hz, 8-H), 4.17 (2H, q, J = 7 Hz, OCH ₂ CH ₃ ), 4.34 (1H, br d-like, J = 9 Hz, 7- H), 5.75 (1H, br s, 14-H), 5.99 (1H, br d, J = 11 Hz, 10-H), 6.18 (1H, d, J = 15.5 Hz, 12-H), 6.83 (1H, dd, J = 11 and 15.5Hz, 11-H).
IR _Vmax (CHCl ₃ ) cm ^-1 : 1701 (conj.CO), 1635 and 1602 (C = C).
HRMS m / z: 461.3446 (MH ⁺ , C ₂₈ H ₄₉ O ₃ Si requires 462.3446).

(Step 5)
<Step of synthesizing hydroxy ester (8) from siloxy ester (7)>
In a nitrogen stream, add 2.14 mL (2.14 mmol) of a 1.0 M tetrahydrofuran solution of tetra-n-butylammonium fluoride to an anhydrous tetrahydrofuran solution (10 mL) of 658 mg (1.43 mmol) of siloxyester (7) at 0 ° C. In addition, after the reaction was carried out at room temperature for 1 hour, a saturated aqueous solution of ammonium chloride was added to stop the reaction. The organic matter was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried, and the solvent was evaporated. The residue thus obtained was purified using a mixed solvent of ethyl acetate / hexane (15/85 volume ratio) as an elution solvent using silica gel column chromatography, and 381 mg (8) of a yellow oily substance [siloxy ester (siloxy ester). Yield 77% with respect to 7)] was obtained.

^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 and 1.12 (each 3H, s, gem-Me), 1.29 (3H, t, J = 7 Hz, OCH ₂ CH ₃ ), 1. 44 (2H, m, 2-H ₂ ), 1.56 (2H, m, 3-H ₂ ), 1.88 (3H, s, 5-Me), 1.95 (3H, s, 9-Me) ), 1.95 (2H, overlapped, 4-H ₂ ), 2.29 (1H, br d, J = 14Hz, 8-H), 2.33 (3H, d, J = 1Hz, 13-Me) , 2.71 (1H, dd, J = 10.5 and 14Hz, 8-H), 4.17 (2H, q, J = 7Hz, OCH ₂ CH ₃ ), 4.44 (1H, dd, J = 2.5 and 10.5Hz, 7-H), 5.76 (1H, br s, 14-H), 6.09 (1H, br d, J = 11Hz, 10-H), 6.24 (1H) , D, J = 15.5Hz, 12-H), 6.86 (1H, dd, J = 11 and 15Hz, 11-H).
IR _Vmax (CHCl ₃ ) cm ^-1 : 3609 (OH), 1701 (conj.CO), 1604 (C = C).
HRMSm / z: 347.2578 (MH ⁺ , C ₂₂ H ₃₅ O ₃ requires 347.2581).

(Step 6)
<Step of synthesizing hydroxycarboxylic acid (9) from hydroxy ester (8)>
In a nitrogen stream, 6.7 mL (12 mmol) of a 10% aqueous sodium hydroxide solution was added to an ethanol solution (11 mL) of 307 mg (0.89 mmol) of hydroxyester (8), reacted at 50 ° C. for 2 hours, and then saturated chloride. Aqueous ammonium chloride was added to stop the reaction. The organic matter was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried, and the solvent was evaporated. The resulting residue was purified using silica gel column chromatography using a methanol / dichloromethane (8/92 volume ratio) mixed solvent as the elution solvent, and the yellow solid was 156 mg (9) [siloxyester (7)). Yield 55%] was obtained.

^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 and 1.11 (each 3H, s, gem-Me), 1.44 (2H, m, 2-H ₂ ), 1.57 (2H, m, 3-H ₂ ), 1.88 (3H, s, 5-Me), 1.96 (3H, s, 9-Me), 1.96 (2H, overlapped, 4-H ₂ ), 2. 30 (1H, br d, J = 14Hz, 8-H), 2.34 (3H, d, J = 1Hz, 13-Me), 2.72 (1H, dd, J = 10.5 and 14Hz, 8) -H), 4.45 (1H, dd, J = 2.5 and 10.5Hz, 7-H), 5.78 (1H, br s, 14-H), 6.11 (1H, br d, J = 11Hz, 10-H), 6.26 (1H, d, J = 15Hz, 12-H), 6.91 (1H, dd, J = 11 and 15Hz, 11-H).
IR _Vmax (CHCl ₃ ) cm ^-1 : 3605 and 3529 (OH), 1681 (conj.CO), 1600 (C = C).
HRMSm / z: 341.2089 [(M + Na) ⁺ , C ₂₀ H ₃₀ O ₃ Na requires 341.2087].

(Step 7)
<Step of synthesizing oxocarboxylic acid (10) from hydroxycarboxylic acid (9)>
In a nitrogen stream, add 410 mg (1.46 mmol) of 2-iodoxybenzoic acid in several portions to a mixed solution of 156 mg (0.49 mmol) of hydroxycarboxylic acid (9) in 3 mL of anhydrous tetrahydrofuran and 3 mL of anhydrous dimethyl sulfoxide at room temperature. After reacting at room temperature for 45 minutes, water was added to stop the reaction. The organic matter was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried, and the solvent was evaporated. The resulting residue was purified using silica gel column chromatography using an acetone / dichloromethane (1/4 volume ratio) mixed solvent as the elution solvent, and the yellow solid 141 mg (10) [hydroxycarboxylic acid (9). ) Was obtained.

^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (6H, s, gem-Me), 1.44 (2H, m, 2-H ₂ ), 1.61 (3H, s, 5-Me) ), 1.66 (2H, m, 3-H ₂ ), 1.96 (3H, s, 9-Me), 1.96 (2H, overlapped, 4-H ₂ ), 2.34 (3H, s) , 13-Me), 3.37 (2H, s, 8-H ₂ ), 5.78 (1H, br s, 14-H), 5.98 (1H, br d, J = 11 Hz, 10- H), 6.24 (1H, d, J = 15.5Hz, 12-H), 6.91 (1H, dd, J = 11 and 15.5Hz, 11-H).
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 14.00, 18.10, 18.80, 21.000, 28.77 (C × 2), 31.16, 33.33, 38.89, 56 .28, 117.85, 128.85, 129.54, 131.11, 134.65, 137.09, 143.21, 155.15, 171.98, 208.33.
IR _Vmax (CHCl ₃ ) cm ^-1 : 1686 (conj.CO), 1600 (C = C).
HRMS m / z: 317.2114 (MH ⁺ , C ₂₀ H ₂₉ O ₃ requires 317.2111).

(Step 8)
<Step of synthesizing hydroxyacetate (11) from siloxy ester (7)>
In a nitrogen stream, 490 mg (1.06 mmol) of siloxyester (7) in anhydrous diethyl ether solution (5 mL) was added to 41 mg (1.06 mmol) of lithium aluminum hydride in anhydrous diethyl ether suspension (15 mL) at 0 ° C. After reacting at 0 ° C. for 10 minutes, water was added little by little to stop the reaction. After the diethyl ether layer was dried, the solvent was distilled off and the obtained crude product was dissolved in 8 mL of anhydrous dichloromethane, and triethylamine 0.45 mL (3.2 mmol) and acetic anhydride 0.15 mL (1) were dissolved in a nitrogen stream at room temperature. .6 mmol) and 5 mg (0.04 mmol) of N, N-dimethylaminopyridine were added and reacted at room temperature for 30 minutes, and then water was added to stop the reaction. The organic matter was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried, and the solvent was evaporated. The crude product thus obtained was dissolved in anhydrous tetrahydrofuran mL, and 2.66 mL (2.66 mmol) of a 1.0 M tetrahydrofuran solution of tetra-n-butylammonium fluoride was added at room temperature in a nitrogen stream to 35. After reacting at ° C. for one and a half hours, a saturated aqueous solution of ammonium chloride was added to stop the reaction. The organic matter was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried, and the solvent was evaporated. The residue thus obtained was purified using an ethyl acetate / hexane (1/4 volume ratio) mixed solvent as an elution solvent using silica gel column chromatography, and a colorless oily substance of 338 mg (12) [siloxyester (siloxyester). Yield 92% with respect to 7)] was obtained.

^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 0.99 and 1.12 (each 3H, s, gem-Me), 1.42 (2H, m, 2-H ₂ ), 1.56 (2H, 2H, m, 3-H ₂ ), 1.87 (6H, s, 5-Me and 13-Me), 1.90 (3H, s, 9-Me), 1.95 (2H, brt, J = 6) .5Hz, 4-H ₂ ), 2.07 (3H, s, OAc), 2.27 (1H, br d, J = 14Hz, 8-H), 2.66 (1H, dd, J = 10. 5 and 14Hz, 8-H), 4.72 (2H, d, J = 7Hz, 15-H ₂ ), 5.59 (1H, brt, J = 7Hz, 14-H), 6.03 (1H) , Br d, J = 11Hz, 10-H), 6.23 (1H, d, J = 15.5Hz, 12-H), 6.50 (1H, dd, J = 11 and 15.5Hz, 11- H).
IR _Vmax (CHCl ₃ ) cm ^-1 : 3609 and 3550 (OH), 1735 (OAc).
HRMS m / z: 369.2403 [(M + Na) ⁺ , C ₂₂ H ₃₄ O ₃ Na requires 369.2400].

(Step 9)
<Step of synthesizing oxoacetate (12) from hydroxyacetate (11)>
In a nitrogen stream, 517 mg (1.85 mmol) of 2-iodoxybenzoic acid was added in several portions to a mixed solution of 320 mg (0.92 mmol) of hydrochiacetate (11) in 6 mL of anhydrous tetrahydrofuran and 3 mL of anhydrous dimethyl sulfoxide at room temperature. After reacting at room temperature for 40 minutes, water was added to stop the reaction. The organic matter was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried, and the solvent was evaporated. The resulting residue was purified using a mixed solvent of ethyl acetate / hexane (12/88 volume ratio) as an elution solvent using silica gel column chromatography, and 254 mg (12) [hydrochiacetate (hydrochiacetate), a colorless oily substance. Yield 90% with respect to 11)] was obtained.

^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 1.08 (6H, s, gem-Me), 1.44 (2H, m, 2-H ₂ ), 1.60 (3H, s, 5-Me) ), 1.67 (2H, m, 3-H ₂ ), 1.87 (3H, s, 13-Me), 1.91 (3H, d, J = 1Hz, 9-Me), 1.96 ( 2H, brt, J = 6.5Hz, 4-H ₂ ), 2.06 (3H, s, OAc), 3.33 (2H, s, 8-H ₂ ), 4.72 (2H, d, J = 7Hz, 15-H ₂ ), 5.58 (1H, br t, J = 7Hz, 14-H), 5.91 (1H, br d, J = 11Hz, 10-H), 6.20 ( 1H, d, J = 15.5Hz, 12-H), 6.51 (1H, dd, J = 11 and 15.5Hz, 11-H).
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 12.67, 17.75, 18.78, 21.00 (C × 2), 28.74 (C × 2), 31.12.33.26, 38.84, 56.19, 61.23, 124.25, 125.15, 129.18, 129.29, 132.75, 135.27, 138.93, 143.19, 171.00, 208. 87.
IR _Vmax (CHCl ₃ ) cm ^-1 : 1734 (OAc), 1688 (conj.CO).
HRMS m / z: 367.2245 [(M + Na) ⁺ , C ₂₂ H ₃₂ O ₃ Na requires 367.2244].

(Step 10)
<Step of synthesizing diol (13) from siloxy ester (7)>
In a nitrogen stream, to an anhydrous diethyl ether suspension (15 mL) of 42 mg (1.11 mmol) of lithium aluminum hydride, 510 mg (1.11 mmol) of siloxyester (7) anhydrous diethyl ether solution (5 mL) was added at 0 ° C. After reacting at 0 ° C. for 10 minutes, water was added little by little to stop the reaction. After drying the diethyl ether layer, the solvent was distilled off, and the obtained crude product was dissolved in 10 mL of anhydrous tetrahydrofuran, and 1.44 mL of a 1.0 M tetrahydrofuran solution of tetra-n-butylammonium fluoride at room temperature in a nitrogen stream. (1.44 mmol) was added and the reaction was carried out at 35 ° C. for 1 and a half hours, and then saturated aqueous ammonium chloride solution was added to stop the reaction. The organic matter was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried, and the solvent was evaporated. The residue thus obtained was purified using an ethyl acetate / hexane (1/3 volume ratio) mixed solvent as an elution solvent using silica gel column chromatography, and 281 mg (13) of a colorless oily substance [siloxy ester (siloxy ester). A yield of 83% with respect to 7) was obtained.

^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 and 1.11 (each 3H, s, gem-Me), 1.43 (2H, m, 2-H ₂ ), 1.56 (2H, m, 3-H ₂ ), 1.85 (3H, s, 13-Me), 1.87 (3H, s, 5-Me), 1.90 (3H, s, 9-Me), 1.95 (2H, br t, J = 6.5Hz, 4-H ₂ ), 2.27 (1H, br d, J = 14Hz, 8-H), 2.66 (1H, dd, J = 10.5 and 14Hz, 8-H), 4.30 (2H, br d, J = 6Hz, 15-H ₂ ), 4.41 (1H, br d, J = 10.5Hz, 7-H), 5.67 ( 1H, br t, J = 7Hz, 14-H), 6.04 (1H, br d, J = 11Hz, 10-H), 6.24 (1H, d, J = 15.5Hz, 12-H) , 6.48 (1H, d, J = 11 and 15.5Hz, 11-H).

(Step 11)
<Step of synthesizing oxo alcohol (14) from diol (13)>
In a nitrogen stream, 0.17 mL (1.0 mmol) of chlorotriethylsilane was added to an anhydrous dichloromethane solution (8 mL) of 281 mg (0.92 mmol) of diol (13) and 0.39 mL (2.8 mmol) of triethylamine at 0 ° C. After reacting at 0 ° C. for 5 minutes, water was added to stop the reaction. The organic substance is extracted with ethyl acetate, the organic layer is washed with saturated brine, dried, and the solvent is distilled off. The obtained residue is subjected to ethyl acetate / hexane (1/3 volume) using silica gel column chromatography. Ratio) Purification was performed using a mixed solvent as an elution solvent. 353 mg (0.84 mmol) of the resulting monosilyl ether was dissolved in 6 mL of anhydrous tetrahydrofuran and 3 mL of anhydrous dimethyl sulfoxide, and 472 mg (3.57 mmol) of 2-iodoxybenzoic acid was added in several portions in a nitrogen stream at room temperature. After reacting at room temperature for 30 minutes, water was added to stop the reaction. The organic material was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried, and the solvent was evaporated. The obtained residue was subjected to ethyl acetate / hexane (5/95 volume) using silica gel column chromatography. Ratio) Purification was performed using a mixed solvent as an elution solvent. 238 mg (0.57 mmol) of the oxosilyl ether thus obtained was dissolved in 7 mL of anhydrous tetrahydrofuran, and 0.69 mL (0.69 mmol) of a 1.0 M tetrahydrofuran solution of acetic acid and tetra-n fluoride in a nitrogen stream at 0 ° C. -0.69 mL (0.69 mmol) of a 1.0 M tetrahydrofuran solution of butylammonium was added and reacted at room temperature for 30 minutes, and then water was added to stop the reaction. The organic matter was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried, and the solvent was evaporated. The resulting residue was purified using an ethyl acetate / hexane (1/2 volume ratio) mixed solvent as an elution solvent using silica gel column chromatography, and the yellow oily substance 92 mg (14) [diol (13). ) Was obtained.

^{1 1} H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (6H, s, gem-Me), 1.44 (2H, m, 2-H ₂ ), 1.60 (3H, s, 5-Me) ), 1.67 (2H, m, 3-H ₂ ), 1.84 (3H, s, 13-Me), 1.91 (3H, d, J = 1Hz, 9-Me), 1.96 ( 2H, br t, J = 6.5Hz, 4-H ₂ ), 3.33 (2H, s, 8-H ₂ ), 4.30 (2H, br dd, J = 4 and 6.5Hz, 15- _{H 2), 5.66 (1H,} br t, J = 6.5Hz, 14-H), 5.91 (1H, br d, J = 11Hz, 10-H), 6.20 (1H, d, J = 15.5Hz, 12-H), 6.48 (1H, dd, J = 11 and 15.5Hz, 11-H).
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 12.59, 17.75, 18.80, 21.01, 28.77 (C × 2), 31.13, 33.28, 38.87, 56 .22, 59.48, 124.60, 129.32 (C × 2), 129.75, 132.29, 135.27, 136.76, 143.22, 209.01.
IR _Vmax (CHCl ₃ ) cm ^-1 : 3606 and 3474 (OH), 1688 (conj.CO).
HRMS m / z: 325.2139 [(M + Na) ⁺ , C ₂₀ H ₃₀ O ₂ Na requires 325.2138]

(Measurement of leukemia cell differentiation inducing ability)
It is known that leukemia cells have the ability to differentiate and are induced to differentiate into monocytes, granulocytes, erythrocytes, lymphocytes, etc. by the action of differentiation-inducing factors. HL-60 cells are a cell line derived from acute promyelocytic leukemia, and when they differentiate into granulocytes (neutrophils) by the action of differentiation-inducing factors, their ability to generate active oxygen that reduces NBT (nitro blue terrazolium) increases. To do. Therefore, by investigating the NBT reducing ability, the effect of the compound of the present invention on the induction of differentiation of leukemia cells was investigated. The NBT reducing ability was measured by treating the cells with NBT to cause formazan precipitation and counting the cells stained in blue.

The compounds (12) and (14) produced in the above steps 9 and 11 (hereinafter, referred to as acetyl forms of 7-hydroxyretinol and 7-hydroxyretinol, respectively) are dissolved in ethanol and concentrated in ethanol at a predetermined concentration. Diluted to: This solution was added in an amount of 1/500 to the medium to prepare a medium containing a test substance having a concentration twice the target final concentration. As a solvent control, 1/500 amount of ethanol was added to the medium to prepare a double solvent control medium (final ethanol concentration 0.2%). These were prepared at the time of use.

HL-60 cells were awakened using medium and _{suspended cultured in a CO 2} incubator (37 ° C, 5% CO ₂ , wet, and so on). Subcultured and expanded cultures were used for testing. Next, 50 μL of double test substance-added medium and double solvent-added medium were added to each well of the 96-well plate, and then HL-60 cells were ^{seeded in each well at 2 × 10 4} cells / 50 μL, and 1 At a double solvent control concentration (EtOH final concentration 0.1%), the _{cells were cultured in a CO 2} incubator for 5 days and treated with the test substance. 100 μL of NBT solution and 2 μL of TPA solution were added to each well and incubated at 37 ° C. for 30 minutes. The cells were then centrifuged at 1,200 rpm for 5 minutes and the cells were resuspended in 200 μL DPBS. Transfer 50 μL of the cell suspension to a new 96-well plate, centrifuge at 1,200 rpm for 1 minute, and then take a bright-field image of each well with KEYENCE BZ-X710 to count the total number of cells in the field and the number of NBT-positive cells. , NBT positive cell rate (number of NBT positive cells / total number of cells × 100) was calculated. Granulocytes were stained by NBT staining, and the NBT positive rate (granulocyte differentiation rate) was quantified.

The results are shown in Table 1 and FIG. The NBT-positive cell rate of HL-60 cells was found to increase dose-dependently for each of the acetyl forms of 7-hydroxyretinol and 7-hydroxyretinol.

Since 7-hydroxyretinol and its derivatives according to the present invention have at least the ability to induce the differentiation of leukemia cells, they have the same physiological activity as retinol, and for example, night blindness, scab, psoriasis, leukemia or dryness. It can be used in pharmaceutical applications to treat ophthalmia or to impart resistance to infection and promote body growth and bone and / or tooth growth. The 7-hydroxyretinol and its derivatives of the present invention have improved photostability as compared with retinol because the 7-position is hydroxy or oxo, and are suitable for use as cosmetics, especially as an external preparation for skin. Conceivable.

Claims (9)

1. The following formula (I):
   

   

   Or formula (II):
   

   

   (In the formula, R ¹ and R ² are independent of each other, a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, or 2 carbon atoms. A compound represented by (showing 30 acyl groups) or a salt thereof.
2. The compound according to claim 1, wherein R ¹ and R ² are both hydrogen atoms, or a salt thereof.
3. The ^{first aspect} of the present invention, wherein ^{R 1 is a hydrogen atom and R 2} is an acyl group represented by the formula (III): -CO (CH ₂ ) _n CH ₃ (n is an integer of 0 to 28). Compound or salt thereof.
4. The compound according to claim 3 or a salt thereof, wherein R ^{2 is an acetyl group.}
5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to any one of claims 1 to 4 or a salt thereof.
6. The fifth aspect of claim 5, for treating night blindness, rickets, psoriasis, leukemia or dry eye inflammation, or for imparting resistance to infection and promoting body growth and bone and / or tooth growth. Pharmaceutical composition.
7. A skin turnover accelerator for preventing abnormal dryness and pigmentation of the skin, which contains the compound according to any one of claims 1 to 4 or a salt thereof as an active ingredient.
8. A method for treating night blindness, rickets, psoriasis, leukemia or dry eye inflammation, or for imparting resistance to infection and promoting body growth and bone and / or tooth growth.
   A method comprising administering an effective amount of the compound according to any one of claims 1 to 4 or a salt thereof to a subject in need thereof.
9. The following formula (IV):
   

   

   (In the formula, PG indicates a hydroxy group protecting group.)
   The aldehyde represented by the following formula (V):
   

   

   (In the formula, R ⁴ represents an alkyl group having 1 to 12 carbon atoms, R ⁵ represents an aryl group, and X represents a halogen atom.) A phosphonium salt represented by the formula, or the following formula (VI). :
   

   

   (In the formula, R ³ and R ⁴ represent alkyl groups having 1 to 12 carbon atoms independently of each other.)
   The Wittig reaction or the Horner-Emmons reaction with the phosphonate represented by the following formula (VII):
   

   

   (In the formula, R ⁴ represents an alkyl group having 1 to 12 carbon atoms.)
   The process of obtaining the ester represented by
   The ester represented by the formula (VII) is reduced and acylated, and the protecting group PG is further deprotected to obtain the following formula (VIII):
   

   

   (In the formula, R ² has the meaning according to claim 1), and the step of obtaining the compound represented by the above.
   The compound represented by the formula (VII) is oxidized to form the following formula (II):
   

   

   The process of obtaining the compound represented by
   A method for producing a vitamin A derivative, which comprises.
   
   

Images