JP6696060B1 - Novel vitamin A derivative and method for producing the same - Google Patents

Abstract

Formula (I): or Formula (II): (In the formula, R1 and R2 are each independently a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, or 2 carbon atoms. The present invention provides a novel vitamin A derivative comprising a compound represented by an alkynyl group of 10 to 10 or an acyl group of 2 to 30 carbon atoms) or a salt thereof, which is useful as a medicine and cosmetics, and a method for producing the same.

Description

  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. These bind to retinoid receptors in the living body and are used for treatment of skin diseases such as acne, photoaging, and specific 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 their wrinkle-improving effect. Tretinoin is an all-trans retinoic acid isomer (ATRA) in which all double bonds of retinoic acid are in the trans form. This tretinoin is marketed as a drug for treating acute promyelocytic leukemia, or as an external medicine orsenone ointment for the treatment of pressure sores and skin ulcers (burn ulcer, diabetic ulcer, leg ulcer).

  In general, a cancer cell that is a therapeutic target acquires autonomous growth by some gene mutation and continues to grow indefinitely. The HL60 cell line, which is a promyelocytic leukemia cell line, is a model cell line used for screening for apoptosis inducers and differentiation inducers. When the HL60 cell line is induced to differentiate, the growth is suppressed, and the tumorigenic activity is lost due to terminal differentiation (decellularized state). In cancer therapy, 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 a pharmacological action about 100 times that of retinol, but it is known to have serious side effects such as teratogenicity and dyspnea. Also, retinoic acid and its analogs are weak and unstable to ultraviolet light. Therefore, 7-hydroxyretinoic acid, which has higher photostability as compared with conventional retinoic acid and its derivatives, has been isolated from certain cyanobacteria (for example, Non-Patent Document 1 and Patent Document 1). 1). However, the amount of 7-hydroxyretinoic acid obtained by extraction from cyanobacteria is extremely small, and since it becomes a mixture of four isomers in the process of purifying it, the carboxy group of 7-hydroxyretinoic acid is reduced to cope with it. It is difficult to obtain 7-hydroxyretinol. Therefore, retinol or a derivative thereof having a hydroxy group or an oxo group at the 7-position has not yet been known.

Kaya K. Other 3 persons, A novel retinoic acid analogoue, 7-hydroxy retinioic acid, isolated from cyanobacteria. Biochim Biophys Acta. 1810 (2011) 414-419.

JP, 2011-251942, A

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

The present invention in one embodiment is represented by the following formula (I):
Or formula (II):

(In the formula, R ¹ and R ² are each independently 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 the formula (1) to an acyl group of 30) or a salt thereof.
In the compound of the above formula (I) or (II), it is preferable that both R ¹ and R ² are hydrogen atoms. Further, ^{R 1} is hydrogen atom, ^{R 2} is Formula _{(III): - CO (CH} 2) n CH 3 (n is an integer of 0 to 28.) Further it is an acyl group represented by Even more preferably, R ² is an acetyl group.

In another embodiment of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound or salt thereof described in any of the above.
This pharmaceutical composition is used 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 development. Preferably.

  In still another embodiment of the present invention, there is provided a skin turnover accelerator for preventing abnormal dryness and pigmentation of the skin, which comprises the compound or salt thereof according to any one of the above as an active ingredient. ..

  In another aspect, the present invention is for treating night blindness, rickets, psoriasis, leukemia or dry eye inflammation or imparting resistance to infection and promoting body growth and bone and / or tooth development. A method for the administration of a compound according to any one of the above or a salt thereof to a subject in need thereof.

In still another aspect of the present invention, the following formula (IV):
(In the formula, PG represents a hydroxy-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.), Or a phosphonium salt represented by the following formula (VI). :

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

A step of obtaining an ester represented by
The ester represented by the formula (VII) is reduced and acylated, and the protecting group PG is deprotected to give the following formula (VIII):

(Wherein R ² has the same meaning as described above), and
By oxidizing the compound represented by the formula (VII), the following formula (II):

A method for producing a vitamin A derivative, comprising the 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 quantitative results of 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 following item order.
(1) Novel vitamin A derivative (2) Manufacturing method of novel vitamin A derivative (3) Pharmaceutical composition and therapeutic use (4) Other uses In addition, the embodiments described below are the inventions according to claims. The elements and combinations thereof described in the embodiments are not limited to all, and are not necessarily essential to the solution means of the present invention. Further, the disclosures of all patent documents 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 one embodiment of the present invention has the following formula (I):
Or formula (II):

(In the formula, R ¹ and R ² are each independently 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. To 30 acyl groups) or a salt thereof.

  In the present specification, the “alkyl group having 1 to 12 carbon atoms” means a monovalent straight chain or branched chain 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 group Group, 1-methylheptyl group, 2-ethylhexyl group, nonyl group, or decyl group. Preferred is an alkyl group having 1 to 6 carbon atoms, and more preferred is an alkyl group having 1 to 4 carbon atoms.

  Examples of the "alkenyl group having 2 to 10 carbon atoms" include linear or branched alkenyl groups having 2 to 10 carbon atoms and containing at least one double bond. Specifically, ethenyl group, propenyl group, 1-methylethenyl group, butenyl group, 2-methylpropenyl group, 1-methylpropenyl group, pentenyl group, 3-methylbutenyl group, 2-methylbutenyl group, 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, and 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.

  Examples of the "alkynyl group having 2 to 10 carbon atoms" include a linear or branched alkynyl group having 2 to 10 carbon atoms and 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. , An octynyl group, a 3-methylheptinyl group, a 3-ethylhexynyl group, a nonynyl group, or a decynyl group. Preferred is an alkynyl group having 2 to 6 carbon atoms, and more preferred is an alkynyl group having 2 to 4 carbon atoms.

  The "acyl group having 2 to 30 carbon atoms" means a group R'-CO-, wherein R'is a straight chain having 1 to 29 carbon atoms which may have an unsaturated bond or Represents a branched alkyl group, or an aryl group such as phenyl and naphthyl, or a heteroaryl group such as pyridyl, imidazolyl, thienyl, and furyl 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 acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, hexanoyl group, lauroyl group, palmitoyl group and oleoyl group. Particularly preferably an acetyl group. The compound of formula (I) or formula (II) in which R is an acyl group having 2 to 30 carbon atoms can be synthesized by a method already known as acylation of a retinol compound. For example, 7-hydroxyretinol can be easily obtained by carrying out a monoacylation reaction with lipase in the presence of an acylating agent (see JP-A-10-036301 and JP-A-2007-143561).

  Various conventional alkyl 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. For acetylation, ethyl acetate, butyl acetate or vinyl acetate is used. The corresponding vinyl esters of fatty acids are also suitable for the production of long-chain acylates. The amount of the acylating agent used can be 1 molar equivalent or several times larger than that, but when the acylating agent serves as a solvent at the same time, it is used in an excessive amount, which is the case in the case of alkyl and alkenyl acylates. Can be true.

  The compound represented by formula (I) or formula (II) may be in the form of an isomer or a salt. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate and phosphate, oxalate, malonate and succinic acid. Salt, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethane Examples thereof include organic acid salts such as sulfonic acid salts. 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 refers to geometric isomers, optical isomers or tautomers. The compound of this embodiment includes all of the above isomers and a mixture thereof in any ratio.

  Although not limited to a particular theory, in the novel vitamin A derivative of the present embodiment, since the 7-position is hydroxylated or oxolated, the conjugated system possessed by conventional retinol and retinol derivatives is blocked, and the photostability is improved. It is thought that the sexuality has improved. Furthermore, although not limited to a particular theory, the novel vitamin A derivative of the present embodiment may cause tautomerism and always exist as a mixture to contribute to the improvement of photostability.

(2) Method for producing novel vitamin A derivative A method for producing a vitamin A derivative according to another aspect of the present invention is represented by the following formula (IV):
(In the formula, PG represents a hydroxy-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.), Or a phosphonium salt represented by the following formula (VI). :

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

(In the formula, R ⁴ represents an alkyl group having 1 to 12 carbon atoms.)
The step of obtaining an 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 give hydroxynitrile (3). After synthesis and protection of the hydroxy group at the 7-position with a silyl ether, the nitrile may be partially reduced using diisobutylaluminum hydride to convert it into an aldehyde. 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.), 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 to 0 ° C.

The Wittig reaction is the reaction of an aldehyde or ketone with 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 UK 1971, pp 81-90). The Wittig reaction is the most commonly used reaction for coupling aldehydes and ketones to singly substituted phosphine ylides. Wittig reagents are typically prepared from phosphonium salts, where phosphonium salts are prepared by the reaction of Ph ₃ P with an alkyl halide. 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 simple ylides, the product is typically predominantly the Z-isomer, but relatively small amounts of the E-isomer are also often formed. If the desired product is the E-isomer, a modified Schlosser procedure may be used. With the stabilized ylide (carbanion phosphonate), the product is predominantly the E-isomer. Alternatively, the Horner-Wadsworth-Emmons reaction (BE Maryyanoff and AB Reitz, Chem Rev. 1989, 89: 863-927) is used to predominantly produce an E-alkene. It is a chemical reaction of a stabilized carbanion phosphonate with an aldehyde (or ketone). The Horner-Wadsworth-Emmons reaction (or HWE reaction) is a condensation reaction of a stabilized carbanion phosphonate with an aldehyde (or ketone) to predominantly produce an E-alkene. For the phosphonium ylide used in the Wittig reaction, phosphonate-stabilized carbanions have higher nucleophilicity and higher basicity. These reactions can be carried out at a temperature in the range of usually -78 to 60 ° C, preferably -10 to 25 ° C, usually for 0.5 to 24 hours, preferably for 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 give the following formula (VIII):
(Wherein R ² has the meaning described above).
Suitable reducing _{agents, LiAlH 4, LiBH 4, NaBH} 4 -LiBr, and DIBAL including without being limited thereto. 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 generated in situ, for example by the 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 resulting terminal alcohol may be acylated with a carboxylic acid anhydride. Furthermore, the protective group PG for the 7-position hydroxy group can be deprotected by a method known to those skilled in the art. For example, protection of a hydroxy group with a substituted silyl group can be easily deprotected using a fluorine anion or the like. it can.

Then, the compound represented by the above formula (VIII) is oxidized to give the following formula (II):
A compound represented by In the formula, R ² is as described above.
The oxidation of the 7-position hydroxy group of the compound represented by the above formula (VIII) can be carried out using 2-iodoxybenzoic acid (IBX) or the like under mild conditions.

  As a reaction solvent, an inert organic solvent (for example, anhydrous tetrahydrofuran, anhydrous dimethyl sulfoxide, etc.) is used if necessary. The reaction temperature is 0 to 50 ° C. The product of each step described above can be separated and purified from the reaction mixture by a method known per se, for example, a method such as 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 the ketoform represented by the formula (II) is high in the solvent.

Scheme 1 below illustrates one exemplary method for making compounds of formula (II). Starting materials are known compounds or may be prepared according to methods known in the art.

(3) Pharmaceutical composition and therapeutic use The present invention provides 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. A solvate for treating night blindness, rickets, psoriasis, leukemia or ophthalmitis, or comprising at least one pharmaceutically acceptable carrier, and optionally other therapeutic and / or prophylactic ingredients, or It comprises a pharmaceutical composition for imparting resistance to infection and for promoting body growth and bone and / or tooth development.

  In general, the pharmaceutical compositions of this embodiment will be administered by any of the accepted modes of administration for agents that serve a similar utility, containing a therapeutically effective amount of the compounds described above. A therapeutically effective amount of a compound refers to the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication for which it is administered, and Depending on a number of factors such as the physician's preferences and experience, typically 1-500 mg per day, preferably 1-100 mg per day, and most preferably 1-30 mg per day. Those of skill in the art of treating such diseases will, without undue experimentation, and depending on their personal knowledge and disclosure of this application, determine a therapeutically effective amount of a compound of the invention for a given disease. You can find out.

  The pharmaceutical composition of this embodiment is orally (including buccal and sublingual), rectal, intranasal, topical, transpulmonary, vaginal or parenteral (intramuscular, intraarterial, intrathecal, subcutaneous and intravenous). (Including in)) or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the degree of affliction.

  Pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier is one or more substances that can also serve as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. You may. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain from about 1 to about 70% active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, cocoa butter and the like. The term "formulation" is meant to include formulations of active compounds with encapsulating materials as carriers, which provide capsules in which the active ingredient, with or without a carrier, is surrounded by the carrier with which it is associated. Is intended. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be as solid forms suitable for oral administration.

  Other forms suitable for oral administration are intended to be converted into liquid form formulations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or liquid forms just prior to use. Solid form formulations. Emulsions may be prepared in solutions, for example aqueous propylene glycol solutions, or may contain emulsifying agents such as lecithin, sorbitan monooleate or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickening agents. Aqueous suspensions may be prepared by dispersing the finely divided active ingredient in water with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose and other well known suspending agents. it can. Solid form preparations include solutions, suspensions and emulsions, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers. Etc. can be included.

  The pharmaceutical compositions of this embodiment can be formulated for parenteral administration (eg, by injection, eg, bolus injection or continuous infusion), ampoules, prefilled syringes, unit doses of small volume infusion. It can also be provided in form or in a multi-dose container with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (eg olive oil), and injectable organic esters (eg ethyl oleate), preservatives, wetting agents, Compounding agents such as emulsifiers or suspending agents, stabilizers and / or dispersants may be included. Alternatively, the active ingredient may be obtained by aseptic separation of sterile solids, or by lyophilization from constitutional solutions prior to use with a suitable vehicle, eg sterile pyrogen-free water. It may be in powder form.

  The pharmaceutical composition of this 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 be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the oral cavity include lozenges containing the active agent in a flavored base, which is usually sucrose and acacia or tragacanth; gelatin and glycerin or active in an inert base such as sucrose and acacia. Pastilles containing the ingredients; as well as mouth rinses containing the active ingredient in a suitable liquid carrier.

  Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, ed. W. Martin Editing, Mack Publishing Company, 19th Edition, Easton, Pennsylvania.

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

  In still another aspect, there is also provided a method for promoting epidermal turnover, which comprises applying the vitamin A derivative to the stratum corneum. This method is performed for the purpose of beauty and not for prevention or treatment of diseases. Further, the subject of the implementation may be a person other than a doctor, and specifically, a person who professionally performs an operation for the purpose of beauty for others such as a cosmetics salesperson or an esthetician. Further, the person to be treated may be the person himself / herself. The act of instructing or soliciting a subject to perform 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 the time change of the pigment of the epidermis can be mentioned. The dye may be generated by patching an aqueous DHA (dihydroxyacetone) solution on the medial side of the upper arm and marking the skin a tan color. When DHA is applied to the skin, it reacts with the amino acids that make up the protein, causing the protein to deteriorate, and the altered protein becomes yellow or brown. Alternatively, it can also be evaluated by a method for evaluating epidermal turnover (see Japanese Patent Application Laid-Open No. 2007-199053), which is characterized by using the position of the horny layer protein in the horny layer as an index.

  Unless otherwise specified, the skin turnover accelerator in the present embodiment is a cosmetic composition such as a diluent, a stabilizer, an antioxidant, an antiseptic agent or the like for external use on the skin, in addition to the above-mentioned vitamin A derivative which is an active ingredient. In some cases, additives acceptable as agents are added. The skin turnover promoter can be used as a component of cosmetics, skin external preparations, and pharmaceutical compositions (hereinafter referred to as "cosmetics and the like"). Cosmetics etc. can contain the above-mentioned vitamin A derivative as solid content, for example, 0.00001 to 1 mass% or more, preferably 0.00001 to 0.1 mass% or more, and 0.0001 to 0.1 It is more preferable that the content is at least mass%.

  Cosmetics and the like containing the above vitamin A derivative can also be prepared in various dosage forms such as solid agents, semi-solid agents and liquid agents depending on the purpose of use. More specifically, cosmetics include basic cosmetics such as cleansing, facial cleanser, lotion, emulsion, cream, massage product, pack product, beauty essence / gel, lip care product, etc .; base makeup cosmetics such as foundation and face powder. , Makeup base, concealer, etc .; Point make-up cosmetics such as lipsticks, lip gloss liners, cheek products, eye shadows, eye liners, mascaras, eyebrow products, etc .; Body cosmetics such as soaps, liquid cleansers, sunscreens, bath salts Etc. As hair cosmetics or scalp cosmetics, shampoo, conditioner, hair treatment, hair styling agent, 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, a patch, and an aerosol (spray).

  The cosmetics and the like containing the vitamin A derivative may contain various cosmetically or pharmaceutically acceptable additives in addition to the agent 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 sea water, etc.), surfactants (emulsifiers, solubilizers, suspending agents, stabilizers, etc.), antioxidants, preservatives, gelling agents, alcohols. Examples thereof include film forming agents, colorants, fragrances, deodorants, salts, pH adjusting agents, cooling agents, chelating agents, keratolytic agents, enzymes and vitamins. In addition, the cosmetic or the like of the present embodiment may contain various functional components that are acceptable as an additive to the cosmetic or the external preparation for the skin, as long as the effect of the skin turnover accelerator is not impaired. Examples of such ingredients are whitening agents, UV protectants, antibacterial agents, anti-inflammatory agents, cell activating agents, active oxygen scavengers, moisturizers, skin cleansing ingredients, acne, and asemostatic ingredients.

  Next, the present invention will be described in more detail with reference to examples, 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.

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

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 = 1 Hz, 9-Me). , 2.30 (1H, ddd, J = 1, 2.5 and 14.5 Hz, 8-H), 2.80 (1H, ddd, J = 1, 10.5 and 14.5 Hz, 8-H) , 4.45 (1H, dd, J = 2.5 and 10.5 Hz, 7-H), 5.27 (1H, sext, J = 1 Hz, 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].

(Process 2)
<Step of synthesizing siloxynitrile (4) from hydroxynitrile (3)>
In a nitrogen stream, 410 mg (1.76 mmol) of hydroxynitrile (3), 1.23 mL (8.80 mmol) of triethylamine and 43 mg (0.35 mmol) of N, N-dimethylaminopyridine in anhydrous 6chloromethane solution (10 mL) were added, Chlorotriethylsilane (0.59 mL, 3.5 mmol) was added at 0 ° C. and reacted at room temperature for 16 hours, and then saturated ammonium chloride aqueous solution 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 residue thus obtained was purified by silica gel column chromatography using a mixed solvent of ethyl acetate / hexane (1/9 volume ratio) as an elution solvent, and 590 mg (4) of colorless oily substance [hydroxynitrile ( 3% yield] was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.56 (6H, q, J = 7.5 Hz, SiCH ₂ CH ₃ × 3), 0.93 (9H, t, J = 7.5 Hz, SiCH ₂ CH ₃ × _3), 0.93 and 1.12 (6H, s, gem- Me), 1.42 (2H, m, 2H 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 13.5 Hz, 8-H), 2.65 (1H, ddd, J = 0.5, 10 and 13.5 Hz, 8-H), 4.36 (1H, br) d-like, J = 7.5 Hz, 7-H), 5.15 (1H, d-like, J = 1 Hz, 10-H).
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 5.06 (C × 3), 6.72 (C × 3), 19.15, 21.11, 12.50, 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).
HRMS m / z: 370.2536 [(M + Na) ⁺ , C ₂₁ H ₃₇ ONNaSi requires 370.2537].

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

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.54 (6H, q, J = 7.5 Hz, SiCH ₂ CH ₃ × 3), 0.89 (9H, t, J = 7.5 Hz, SiCH 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 13 Hz, 8-H), 2.67 (1H, dd, J = 10 and 13 Hz, 8-H), 4.43 (1H, br d-like, J = 8.5 Hz, 7-H), 5.94 (1H, br d, J = 8.5 Hz, 10-H), 10.00 (1H, d, J = 8. 5 Hz, 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 requires 373.2534].

(Process 4)
<Step of synthesizing siloxy ester (7) from siloxy aldehyde (5)>
In a stream of nitrogen, 0.99 mL (4.08 mmol) of phosphonate (6) and 1.48 mL (12.3 mmol) of N, N′-dimethylpropyleneurea in anhydrous tetrahydrofuran (10 mL) were added to n-butyllithium at −30 ° C. 1.59 M hexane solution (2.57 mL, 4.08 mmol) was added and reacted at -30 ° C for 15 minutes to prepare an anhydrous tetrahydrofuran solution containing a lithium salt of phosphonate (6). Anhydrous tetrahydrofuran solution (10 mL) of 715 mg (2.04 mmol) of siloxy aldehyde (5) was added to this solution at -30 ° C, and the mixture was reacted at -30 ° C for 30 minutes, and then saturated ammonium chloride aqueous solution was added 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 by silica gel column chromatography using a mixed solvent of diethyl ether / hexane (8/92 volume ratio) as an elution solvent, and a colorless oily substance 909 mg (7) [siloxynitrile ( 5% yield] was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.50 (6 H, m, SiCH ₂ CH ₃ × 3), 0.88 (9 H, t, J = 8 Hz, SiCH 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, brs, 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 _{13.5Hz, 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, brs, 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).

(Process 5)
<Step of synthesizing hydroxy ester (8) from siloxy ester (7)>
In a stream of nitrogen, to a solution of 658 mg (1.43 mmol) of siloxy ester (7) in anhydrous tetrahydrofuran (10 mL) was added 2.14 mL (2.14 mmol) of 1.0 M tetrahydrofuran solution of tetra-n-butylammonium fluoride at 0 ° C. In addition, after reacting for 1 hour at room temperature, saturated ammonium chloride aqueous 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 by silica gel column chromatography using a mixed solvent of ethyl acetate / hexane (15/85 volume ratio) as an elution solvent, and yellow oily substance 381 mg (8) [siloxy ester ( The yield was 77% based on 7).

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, 2H 2} ), 1.56 (2H, m, 3H 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 = 14 Hz, 8-H), 2.33 (3H, d, J = 1 Hz, 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 10.5 Hz, 7-H), 5.76 (1 H, br s, 14-H), 6.09 (1 H, br d, J = 11 Hz, 10-H), 6.24 (1 H , D, J = 15.5 Hz, 12-H), 6.86 (1H, dd, J = 11 and 15 Hz, 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).

(Process 6)
<Step of synthesizing hydroxycarboxylic acid (9) from hydroxy ester (8)>
In a nitrogen stream, 6.7 mg (12 mmol) of a 10% sodium hydroxide aqueous solution was added to an ethanol solution (11 mL) of 307 mg (0.89 mmol) of hydroxy ester (8), and the mixture was reacted at 50 ° C. for 2 hours and then saturated chlorination. The reaction was stopped by adding an aqueous ammonium solution. 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 by silica gel column chromatography using a mixed solvent of methanol / dichloromethane (8/92 volume ratio) as an elution solvent to give 156 mg (9) of a yellow solid [siloxy ester (7). 55%] was obtained.

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, 3H 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 10.5 Hz, 7-H), 5.78 (1H, brs, 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].

(Process 7)
<Step of synthesizing oxocarboxylic acid (10) from hydroxycarboxylic acid (9)>
In a nitrogen stream, 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, 410 mg (1.46 mmol) of 2-iodoxybenzoic acid was added in several portions at room temperature. After reacting for 45 minutes at room temperature, 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 residue thus obtained was purified by silica gel column chromatography using an acetone / dichloromethane (1/4 volume ratio) mixed solvent as an elution solvent to obtain 141 mg (10) of a yellow solid [hydroxycarboxylic acid (9 Yield of 91%] was obtained.

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, 21.00, 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).

(Process 8)
<Step of synthesizing hydroxyacetate (11) from siloxy ester (7)>
In a nitrogen stream, to an anhydrous diethyl ether suspension (15 mL) of 41 mg (1.06 mmol) of lithium aluminum hydride, a solution of 490 mg (1.06 mmol) of siloxy ester (7) in anhydrous diethyl ether (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 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 0.45 mL (3.2 mmol) of triethylamine and 0.15 mL of acetic anhydride (1 .6 mmol) and N, N-dimethylaminopyridine (5 mg, 0.04 mmol) 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 in a nitrogen stream was added at room temperature to give 35. After reacting for 1 hour and a half at 0 ° C., 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 by silica gel column chromatography using a mixed solvent of ethyl acetate / hexane (1/4 volume ratio) as an elution solvent, and 338 mg (12) of colorless oily substance [siloxy ester ( Yield 92% based on 7)] was obtained.

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, _{m, 3H 2), 1.87 (} 6H, s, 5-Me and 13-Me), 1.90 (3H , s, 9-Me), 1.95 (2H, br t, 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, br t, J = 7Hz, 14-H), 6.03 (1H , Br d, J = 11 Hz, 10-H), 6.23 (1H, d, J = 15.5 Hz, 12-H), 6.50 (1H, dd, J = 1 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].

(Process 9)
<Step of synthesizing oxoacetate (12) from hydroxyacetate (11)>
To a mixed solution of 320 mg (0.92 mmol) of hydroxyacetate (11) in 6 mL of anhydrous tetrahydrofuran and 3 mL of anhydrous dimethylsulfoxide in a nitrogen stream, 517 mg (1.85 mmol) of 2-iodoxybenzoic acid was added at several times at room temperature, After reacting for 40 minutes at room temperature, 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 residue thus obtained was purified by silica gel column chromatography using a mixed solvent of ethyl acetate / hexane (12/88 volume ratio) as an elution solvent to obtain 254 mg (12) of colorless oily substance [hydroxyacetate ( 90% yield relative to 11) was obtained.

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 = 1 Hz, 9-Me), 1.96 ( 2H, br t, J = 6.5 Hz, 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].

(Process 10)
<Step of synthesizing diol (13) from siloxy ester (7)>
To a suspension of lithium aluminum hydride (42 mg, 1.11 mmol) in anhydrous diethyl ether (15 mL) at 0 ° C., 510 mg (1.11 mmol) of siloxy ester (7) in anhydrous diethyl ether (5 mL) was added in a nitrogen stream. 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 to obtain a crude product, which was dissolved in 10 mL of anhydrous tetrahydrofuran, and 1.44 mL of a 1.0 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran at room temperature in a nitrogen stream. (1.44 mmol) was added and the mixture was reacted at 35 ° C. for 1 hour and a half, and then saturated ammonium chloride aqueous 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 by silica gel column chromatography using a mixed solvent of ethyl acetate / hexane (1/3 volume ratio) as an elution solvent, and 281 mg (13) of colorless oily substance [siloxy ester ( The yield was 83% based on 7).

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, 3H 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 = 6.5 Hz, 4-H ₂ ), 2.27 (1 H, br d, J = 14 Hz, 8-H), 2.66 (1 H, 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 = 7 Hz, 14-H), 6.04 (1H, br d, J = 11 Hz, 10-H), 6.24 (1H, d, J = 15. Hz, 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, 281 mg (0.92 mmol) of diol (13) and 0.39 mL (2.8 mmol) of triethylamine in anhydrous dichloromethane (8 mL) were added with 0.17 mL (1.0 mmol) of chlorotriethylsilane at 0 ° C. After reacting at 0 ° C. for 5 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 to give a residue, which was purified by silica gel column chromatography using ethyl acetate / hexane (1/3 volume). (Ratio) A mixed solvent was used as an elution solvent for purification. 353 mg (0.84 mmol) of monosilyl ether thus obtained was dissolved in 6 mL of anhydrous tetrahydrofuran and 3 mL of anhydrous dimethylsulfoxide, and 472 mg (3.57 mmol) of 2-iodoxybenzoic acid was added in several portions at room temperature in a nitrogen stream. After reacting for 30 minutes at room temperature, 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 to give a residue, which was purified by silica gel column chromatography using ethyl acetate / hexane (5/95 vol. (Ratio) A mixed solvent was used as an elution solvent for purification. 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 solution of acetic acid in tetrahydrofuran in a stream of nitrogen and tetra-n fluoride. After adding 0.69 mL (0.69 mmol) of a 1.0 M tetrahydrofuran solution of -butylammonium and reacting it at room temperature for 30 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 residue thus obtained was purified by silica gel column chromatography using a mixed solvent of ethyl acetate / hexane (1/2 volume ratio) as an elution solvent, and 92 mg (14) of a yellow oily substance [diol (13 33% yield].

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 = 1 Hz, 9-Me), 1.96 ( 2H, br t, J = 6.5 Hz, 4-H ₂ ), 3.33 (2H, s, 8-H ₂ ), 4.30 (2H, br dd, J = 4 and 6.5 Hz, 15- H ₂ ), 5.66 (1 H, br t, J = 6.5 Hz, 14-H), 5.91 (1 H, br d, J = 11 Hz, 10-H), 6.20 (1 H, d, J = 15.5 Hz, 12-H), 6.48 (1H, dd, J = 11 and 15.5 Hz, 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 differentiation-inducing ability of leukemia cells)
It is known that leukemia cells have a differentiation ability and are induced to be differentiated into monocytes, granulocytes, erythrocytes, lymphocytes and the like by the action of differentiation inducers. HL-60 cells are a cell line derived from acute promyelocytic leukemia, and when differentiated into granulocytes (neutrophils) by the action of a differentiation inducing factor, the ability to generate active oxygen that reduces NBT (nitro blue tetrazolium) is increased. To do. Therefore, the effect of the compound of the present invention on the induction of differentiation of leukemia cells was examined by examining the NBT reducing ability. The NBT reducing ability was measured by treating the cells with NBT to cause formazan precipitation and counting the cells stained blue.

  The compounds (12) and (14) (hereinafter, referred to as 7-hydroxyretinol and acetylated form of 7-hydroxyretinol, respectively) produced in the above Step 9 and Step 11 are dissolved in ethanol, and the ethanol is dissolved in a predetermined concentration. It was diluted so that This solution was added to the medium in an amount of 1/500 to prepare a test substance-added medium 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 2-fold solvent control-added medium (final concentration of ethanol: 0.2%). These were prepared before use.

The HL-60 cells were put to sleep using a medium and suspension-cultured in a CO ₂ incubator (37 ° C., 5% CO ₂ , wet, the same below). Subcultured and expanded, and used for the test. Next, 50 μL of a 2-fold test substance-added medium and a 2-fold solvent control-added medium were added to each well of a 96-well plate, and then HL-60 cells were seeded at 2 × 10 ⁴ cells / 50 μL in each well, and 1 A double solvent control concentration (final EtOH concentration of 0.1%) was used, and the cells were cultured in a CO ₂ incubator for 5 days and treated with a 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. 50 μL of the cell suspension was transferred to a new 96-well plate, centrifuged at 1,200 rpm for 1 minute, and bright-field photographed in each well with KEYENCE BZ-X710 to count the total number of cells and NBT-positive cells in the visual field. , NBT positive cell rate (NBT positive cell number / total cell number × 100) was calculated. Granulocytes were stained with NBT and the NBT positive rate (granulocyte differentiation rate) was quantified.

  The results are shown in Table 1 and FIG. It was found that the NBT-positive cell rate of HL-60 cells increased in a dose-dependent manner for each of 7-hydroxyretinol and the acetylated form of 7-hydroxyretinol.

7-Hydroxyretinol and its derivatives according to the present invention have at least the ability to induce differentiation of leukemia cells, and therefore have the same physiological activity as that of retinol. It can be used in pharmaceutical applications for treating ophthalmitis or for conferring resistance to infection and for promoting body growth and bone and / or tooth development. The 7-hydroxyretinol and the derivative thereof of the present invention have higher photostability than retinol because the 7-position is hydroxylated or oxolated, and are suitable for use as cosmetics, particularly as a skin external preparation. Conceivable.

Claims (8)

Formula (I) below:
Or formula (II):
(Wherein, R ¹ represents a hydrogen atom, R ² is water MotoHara coma others. Showing the acyl group having 2 to 30 carbon atoms) or a salt thereof. The compound or salt thereof according to claim 1, wherein both R ¹ and R ² are hydrogen atoms. R ¹ is a hydrogen atom, ^{R 2} is Formula _{(III): - CO (CH} 2) n CH 3 (n is an integer of 0 to 28.) According to claim 1, wherein the acyl group represented by Or a salt thereof. The compound or salt thereof according to claim 3, wherein R ² is an acetyl group.   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 method according to claim 5, for treating night blindness, rickets, psoriasis, leukemia or dry eye inflammation, or for conferring resistance to infection and promoting body growth and bone and / or tooth development. Pharmaceutical composition.   A skin turnover promoter for preventing abnormal dryness and pigmentation of the skin, which comprises the compound according to any one of claims 1 to 4 or a salt thereof as an active ingredient. Formula (IV) below:
(In the formula, PG represents a hydroxy-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.), Or a phosphonium salt represented by the following formula (VI). :
(In the formula, R ³ and R ⁴ each independently represent an alkyl group having 1 to 12 carbon atoms.)
By the Wittig reaction or the Horner-Emmons reaction with a phosphonate represented by the following formula (VII):
(In the formula, R ⁴ represents an alkyl group having 1 to 12 carbon atoms.)
A step of obtaining an ester represented by
The ester of the formula (VII) is reduced and optionally acylated, and the protecting group PG is deprotected to give the following formula (VIII):
(In the formula, R ² is a hydrogen atom or an acyl group having 2 to 30 carbon atoms .),
By oxidizing the compound represented by the formula (VIII) , the following formula (II):
A step of obtaining a compound represented by
A method for producing a vitamin A derivative, comprising: