WO2023221665A1 - 一种二酚类化合物及其制备方法和应用 - Google Patents

一种二酚类化合物及其制备方法和应用 Download PDF

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WO2023221665A1
WO2023221665A1 PCT/CN2023/085442 CN2023085442W WO2023221665A1 WO 2023221665 A1 WO2023221665 A1 WO 2023221665A1 CN 2023085442 W CN2023085442 W CN 2023085442W WO 2023221665 A1 WO2023221665 A1 WO 2023221665A1
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compound
optionally substituted
formula
group
acid
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PCT/CN2023/085442
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French (fr)
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邢文龙
焦体
李生学
王志会
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帕潘纳(北京)科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/347—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/08—Oxygen atoms
    • C07D223/10—Oxygen atoms attached in position 2

Definitions

  • the present invention relates to a class of diphenolic compounds, their preparation methods, pharmaceutical compositions or cosmetic compositions containing such compounds, and their use in pharmaceutical applications and cosmetics, in particular for inhibiting pigmentation and treating pigments.
  • the use of excessive composure is a class of diphenolic compounds, their preparation methods, pharmaceutical compositions or cosmetic compositions containing such compounds, and their use in pharmaceutical applications and cosmetics, in particular for inhibiting pigmentation and treating pigments. The use of excessive composure.
  • Melanin present in melanocytes and produced by the tyrosinase-catalyzed conversion of tyrosine, is the pigment responsible for skin coloration. Overproduction of melanin can cause hyperpigmentation of the skin due to factors such as excessive sun exposure, hormonal imbalances, melasma, illness, injuries from medications, scarring, age spots due to aging, and more.
  • Human skin color is primarily determined by the amount of melanin in the basal layer of the skin.
  • Melanin which is usually brown to black, is formed in the melanin-forming cells of the skin, where it is transferred to the stratum corneum of the skin and gives the skin or hair its color.
  • brown-black eumelanin is mainly formed from hydroxyl-substituted aromatic amino acids such as L-tyrosine and L-DOPA, and yellow to red pseudomelanin is formed from sulfur-containing molecules.
  • L-DOPA L-3,4-dihydroxyphenylalanine
  • Hyperpigmentation may also occur due to exposure to sunlight or due to different inflammatory stimuli. Increased melanin production is often accompanied by melasma, melasma or solar pigmentation (age spots), freckles, and keratosis pigmentosum. Melasma is a general term describing dull skin. Melasma is often used to describe skin discoloration caused by hormones. These hormonal changes are often due to pregnancy, birth control pills, or estrogen replacement therapy.
  • Solar pigmentation refers to dark spots on the skin caused by sunlight. These spots are common in adults with a history of long-term unprotected sun exposure. Although skin damage such as scars, wounds, or rashes can also cause hyperpigmentation, the most common cause of darkened areas, brown spots, or discolored areas of skin is unprotected sun exposure.
  • the prior art discloses methods of treating hyperpigmentation through the use of skin lightening agents.
  • Representative compounds commonly used as skin lighteners include hydroquinone and vitamin C.
  • hydroquinone and vitamin C.
  • One way these agents work is by inhibiting the enzyme tyrosinase involved in melanin production to lighten the skin.
  • the most popular ingredients used for skin lightening, skin bleaching, or skin whitening include hydroquinone, arbutin, kojic acid, licorice extract, niacinamide, and more.
  • Hydroquinone is one of the most effective depigmenting agents. Although its efficacy has been proven, in the early 2000s, hydroquinone began to be removed or its use in cosmetics was limited due to its potential dermatological and systemic side effects.
  • Arbutin (a natural product extracted from plants) is a glycosylated derivative of hydroquinone and is a more stable and less toxic potent tyrosinase inhibitor than hydroquinone. However, despite its great potential, arbutin is still unstable and undergoes hydrolysis under different conditions, leading to the release of hydroquinone.
  • resorcinol compound which can be used as a tyrosinase inhibitor, especially for cosmetic or pharmaceutical applications, and more particularly as a depigmenting agent, whitening agent, Bleaching agents or whitening agents and are used to treat pigmentation disorders or for cosmetic purposes to slow or ameliorate hyperpigmentation.
  • the present invention provides a type of resorcinol formula that can affect the pigmentation of the skin area caused by sunlight, especially ultraviolet and visible light, and especially prevent, treat and/or reduce the pigmentation of the skin area or skin part.
  • Compound A the structure of compound A is as follows:
  • R 1 is selected from H, optionally substituted alkyl and optionally substituted arylalkyl;
  • R 2 and R 6 may be the same or different, and each is independently selected from optionally substituted aryl and heteroaryl groups, optionally substituted alkyl groups, optionally substituted amide groups, optionally substituted ester groups, R 3 , R 4 , R 7 , and R 8 may be the same or different, and each may be independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted amido. R 3 and R 4 may be the same as them.
  • R 7 and R 8 can be connected to their commonly connected carbon atoms to form a ring; or their cosmetically or pharmaceutically acceptable salts, stereoisomers or stereoisomers in any ratio mixtures, in particular enantiomers or mixtures of enantiomers, more particularly racemic mixtures.
  • compound A is a compound of formula (I),
  • R 1 to R 4 are as defined above.
  • compound A is a compound of formula (Ia), Wherein, R 1 to R 3 are as defined above, Z 1 and Z 2 may be the same or different, each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted amide Groups, Z 1 and Z 2 can be connected to the carbon atoms they are jointly connected to form a ring, and the ring can be substituted.
  • compound A is a compound of formula (V),
  • R 1 to R 4 are as defined above.
  • compound A is a compound of formula (Va), Wherein, R 1 to R 3 are as defined above, Z 1 and Z 2 may be the same or different, each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted amide group, Z 1 and Z 2 can be connected to the carbon atoms they are connected together to form a ring, and the ring can be substituted.
  • compound A is a compound of formula (VI), Among them, R 1 to R 4 and R 6 to R 8 are as defined above.
  • compound A is (VIa), Among them, R 1 to R 4 and R 6 to R 7 are as defined above, Z 1 and Z 2 can be the same or different, and each is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optional If a substituted amide group is selected, Z 1 and Z 2 can be connected to the carbon atoms they are jointly connected to form a ring, and the ring can be substituted.
  • the invention also provides a preparation method of compound A.
  • the present invention also provides pharmaceutical compositions containing compounds of the present invention or pharmaceutically acceptable salts thereof.
  • the present invention also provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, preventing and/or alleviating hyperpigmentation.
  • the invention also discloses non-therapeutic, cosmetic uses containing compounds of the invention or salts thereof for the treatment, prevention and/or reduction of hyperpigmentation.
  • the invention also discloses a cosmetic composition containing the compound of the invention or a salt thereof.
  • “Hyperpigmentation” as used herein means hyperpigmentation caused by sunlight, more particularly visible light.
  • cosmetically or pharmaceutically acceptable means that it can be used in the preparation of cosmetics or pharmaceutical compositions, usually for pharmaceuticals. It is non-toxic, safe and acceptable for chemical and cosmetic uses.
  • a "cosmetically or pharmaceutically acceptable salt” is a cosmetically or pharmaceutically acceptable salt as defined herein, and which has the pharmaceutical and cosmetic properties and activities of the original compound.
  • Such salts may be: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids, The organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2- Hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., but are not limited thereto.
  • Acceptable inorganic bases include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • stereoisomer refers to configurational stereoisomers, which includes geometric and optical isomers, as well as conformational isomers.
  • Geometric isomers also known as E/Z isomers or cis-trans isomers
  • Optical isomers result from substituents on an atom (such as a carbon atom or a sulfur atom) that contain four different substituents (potentially including lone pairs of electrons) or from different positions in space of the lone pair of electrons. Therefore, this atom represents a chiral or asymmetric center. Therefore, optical isomers that are not mirror images of each other are called “diastereomers” and optical isomers that are non-superimposable mirror images of each other are called “enantiomers.”
  • racemic mixture An equimolar mixture of two enantiomers of a chiral compound is called a racemic mixture.
  • Halogen in the present invention means in all cases fluorine, chlorine, bromine and iodine.
  • alkyl as used herein (and in other groups containing alkyl groups, for example, the alkyl moiety of alkoxy, the alkyl moiety of arylalkyl) means in each case generally 1 to 20 Carbon atoms, often 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, especially straight-chain or branched alkyl groups of 1 to 3 carbon atoms.
  • Examples of C 1 -C 4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl) ), 1,1-dimethylethyl (tert-butyl).
  • C 1 -C 6 alkyl groups in addition to the groups mentioned for C 1 -C 4 alkyl groups, include n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl base, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2- Methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2 ,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-tri Methylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl
  • C 1 -C 10 alkyl groups in addition to the groups mentioned for C 1 -C 6 alkyl groups, include n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 1- Ethylhexyl, 2-ethylhexyl, 1,2-dimethylhexyl, 1-propylpentyl, 2-propyl Pentyl, nonyl, decyl, 2-propylheptyl and 3-propylheptyl, but not limited thereto.
  • the alkyl group may be substituted by halogen, cyano group, nitro group, aryl group, cycloalkyl group, heterocyclyl group, amido group, ester group, etc., but is not limited thereto.
  • aryl refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group with 6 to 10 ring atoms, such as phenyl or naphthyl, especially naphthyl, but is not limited thereto.
  • the aryl group may be substituted by an alkyl group, halogen, cyano group, nitro group, cycloalkyl group, heterocyclyl group, amido group, ester group, etc., but is not limited thereto.
  • ring refers to “cycloalkyl” or “heterocyclyl”
  • cycloalkyl refers to a monocyclic monovalent hydrocarbon group of three to six carbon atoms, which can be saturated or contain a double bond.
  • the cycloalkyl group may be unsubstituted or substituted by one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxyl or cyano, but is not limited thereto.
  • Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocycloprop-1-yl, 1-cyanomethylcycloprop-1-yl, 3-fluorocyclohexyl, etc. , but not limited to this.
  • a cycloalkyl group contains a double bond, it may be referred to herein as a cycloalkenyl group.
  • Heterocyclyl refers to a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms, one or two of which are heteroatoms selected from N, O or S(O) p , where p is an integer from 0 to 2, and the remaining ring atoms are C.
  • one or two ring carbon atoms in the heterocyclyl ring may optionally be replaced by a -CO- group.
  • heterocyclyl includes, but is not limited to, azetidinyl, oxetanyl, pyrrolidinyl, piperidino, homopiperidinyl, 2-oxopyrrolidine group, 2-oxopiperidinyl, morpholinyl, piperazino (piperazino), tetrahydropyranyl, thiomorpholinyl, etc., but are not limited thereto.
  • the cycloalkyl group, heterocyclic group, etc. may be substituted by an alkyl group, halogen, cyano group, nitro group, aryl group, amido group, ester group, etc., but are not limited thereto.
  • the substituent may be alkyl, halogen, cyano, nitro, cycloalkyl, heterocyclyl, amido, ester, alkoxy, halogen, etc., but is not limited thereto.
  • a haloalkyl group is formed, but is not limited thereto.
  • Alkoxy refers to the -OR group, where R is an alkyl group as defined above, for example, methoxy, ethoxy, propoxy, or 2-propoxy, n-butoxy, isobutoxy group or tert-butoxy group, etc., but are not limited to this.
  • amide group in the present invention refers to the group containing "-NHCO-" or group, the amide group, for example, -NHCOCH 3 , -NHCOH, -NHCOCH 2 CH 3 , -NHCOCH 2 CH 2 CH 3 , -NHCOCH(CH 3 ) 2 , -NHCOCH(CH 2 ) 2 , -N(COCH 3 ) 2 , -CONH 2 , -CON(CH 3 ) 2 , -CONHCH 3 , -CONHCH 2 CH 3 , -CON(CH 2 CH 3 ) 2 , -CONHCH(CH 3 ) 2 , -CONHCH 2 CH 2 CH 3 , -CONHCH 2 CH 2 CH 3 , -CONHCH 2 CH 2 CH 3 , -CONHCH 2 CH 2 CH 3 , phthalimide group, succinimide group, glutarimide group, maleimide group,
  • R 9 is selected from optionally substituted alkyl or
  • n is selected from a natural number of 1-6, preferably 1, 2, and 3. But not limited to this.
  • ester group in the present invention means that the group contains "-COO-".
  • the ester group is, for example, -COOCH 3 , -COOCH 2 CH 3 , -COOCH(CH 3 ) 2 , -COOCH 2 CH 2 CH 3. -COOCH 2 CH 2 CH 2 CH 3 , but not limited to this.
  • Heteroaryl in the present invention covers: 5 to 10 membered aromatic monocyclic rings, aromatic fused rings, wherein the aromatic monocyclic ring contains one or more (such as 1 to 4, or in some embodiments 1 to 3 ) heteroatoms selected from N, O, and S and the remaining atoms are carbon; aromatic fused rings containing one or more (such as 1 to 4, or in certain embodiments 1 to 3) selected Heteroatoms from N, O and S and the remaining ring atoms are carbon, and at least one of the heteroatoms is present in the aromatic ring.
  • heteroaryl includes a 5 to 10 membered heterocycloalkyl aromatic ring fused to a 5 to 10 membered cycloalkyl or heterocycloalkyl ring.
  • bicyclic heteroaromatic ring systems in which only one ring contains one or more heteroatoms, the point of attachment can be on either ring.
  • the total number of S and O atoms in a heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heteroaryl group does not exceed 2.
  • the total number of S and O atoms in the aromatic heterocycle does not exceed 1.
  • heteroaryl groups include, but are not limited to (numbered from attachment position 1) 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyridazinyl, 3,4-pyridinyl Azinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiazolinyl Thiadiazolinyl, tetrazolyl, thienyl, benzothiophenyl, furanyl, benzofuranyl, benzimidazolinyl, indolinyl, pyrazinyl , triazolyl, quinolyl, pyrazolyl and 5,6,7,8-tetrahydroisoquinolyl.
  • Heteroaryl does not encompass or overlap with aryl, cycloalkyl or heterocycloalkyl, as defined herein.
  • Arylalkyl refers to a residue in which the aryl moiety is attached to the parent structure through an alkyl residue. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl, and the like.
  • Heteroaralkyl refers to a residue in which the heteroaryl moiety is attached to the parent structure through an alkyl residue. Examples include furylmethyl, pyridylmethyl, pyrimidinylethyl, and the like.
  • the present invention provides a resorcinol compound of formula A,
  • R 1 is selected from H, optionally substituted alkyl and optionally substituted arylalkyl;
  • R 2 and R 6 may be the same or different, and each is independently selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl,
  • R 3 , R 4 , R 7 , R 8 may be the same or different, each independently selected from hydrogen, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted amide group, R 3 and R 4 can be connected to the carbon atoms they are jointly connected to form a ring, R 7 and R 8 can be connected to the carbon atoms they are jointly connected to form a ring, wherein the amide group
  • the groups are preferably -NHCOCH 3 , -NHCOH, -NHCOCH 2 CH 3 , -NHCOCH 2 CH 2 CH 3 , -NHCOCH(CH 3 ) 2 , -NHCOCH(CH 2 ) 2 , -N(COCH 3 ) 2 ,
  • stereoisomers or mixtures of stereoisomers in any proportion, in particular enantiomers or mixtures of enantiomers, more particularly racemates mixture.
  • the present invention provides a compound of formula (I) or a salt thereof:
  • R 1 is selected from H, optionally substituted alkyl and optionally substituted arylalkyl;
  • R 2 is selected from an optionally substituted aryl group, an optionally substituted alkyl group, an optionally substituted amide group, an optionally substituted ester group, and an optionally substituted five- to ten-membered heteroaryl group (the heteroaryl group includes 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur), preferably optionally substituted alkyl,
  • R 9 is selected from optionally substituted alkyl or aryl groups, carboxyl or salts thereof, cyano groups, optionally substituted amide groups, optionally substituted ester groups,
  • n is selected from natural numbers from 1 to 6, preferably 1, 2, 3;
  • R 3 and R 4 can be the same or different, each independently selected from hydrogen, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted amide group, R 3 and R 4 can be with The carbon atoms they share are linked together to form a ring.
  • R 1 is selected from H and C 1 -C 6 alkyl, with H and methyl being particularly preferred;
  • R 2 is selected from, wherein n is 1, 2 or 3.
  • R 2 is selected from.
  • R 2 is selected from phenyl.
  • R 3 is selected from H and C 1 -C 6 alkyl, particularly preferably one of H, methyl, ethyl, propyl and butyl;
  • R 4 is selected from H and C 1 -C 6 alkyl, particularly preferably one of H, methyl, ethyl, propyl and butyl;
  • the present invention preferably provides compounds of formula (I) as follows: compounds of formulas (I-1), (I-2) and (I-3):
  • R 1 is selected from H and C 1 -C 6 alkyl, particularly preferably H and methyl
  • R 2 is selected from phenyl
  • R 3 is selected from H and C 1 -C 6 Alkyl, particularly preferably one of H, methyl, ethyl, propyl and butyl
  • R 4 is selected from H and C 1 -C 6 alkyl, especially Particularly preferably one of H, methyl, ethyl, propyl and butyl
  • R 10 is selected from C 1 -C 18 alkyl, preferably n-dodecyl, n-tetradecyl and n-hexadecyl
  • n Choose from 1, 2 and 3.
  • the compound of formula A of the present invention is the preferred compound of formula (Ia), wherein, R 1 is selected from H, optionally substituted alkyl and optionally substituted arylalkyl; R 2 is selected from optionally substituted aryl, optionally substituted five to ten-membered heteroaryl (the five-membered heteroaryl The ten-membered heteroaryl group includes 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur), optionally substituted alkyl and optionally substituted amide groups; R 3 is selected from hydrogen, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted amide group; Z 1 and Z 2 can be the same or different, each independently selected from hydrogen, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkyl group, If a substituted amide group is selected, Z 1 and Z 2 can be connected to the carbon atoms they are jointly connected to form a
  • R 1 is selected from H and C 1 -C 6 alkyl, with H and methyl being particularly preferred;
  • R 2 is selected from one of (where n is a natural number from 1 to 6), and phenyl.
  • the compound of formula (Ia) of the present invention is preferably the following compound of formula Ia-1 and Ia-2:
  • R 1 is selected from H and C 1 -C 6 alkyl, preferably H and methyl;
  • Z 1 and Z 2 are each independently selected from H and C 1 -C 6 alkyl, preferably one of H, methyl, ethyl, propyl and butyl; or Z 1 and Z 2 together with the attached carbon atom
  • C 3 -C 6 cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
  • the preferred radicals are ethylene oxide, azetidinyl, oxetanyl, pyrrolidinyl, piperidino, homopiperidinyl, 2-oxopyrrolidinyl, and 2-oxopiperidinyl.
  • n is selected from a natural number of 1-6, preferably 1, 2 and 3.
  • compound A of the present invention is preferably a compound of formula (V),
  • R 1 is selected from H, optionally substituted alkyl and optionally substituted arylalkyl;
  • R 2 is selected from an optionally substituted aryl group, an optionally substituted alkyl group, and an optionally substituted amide group.
  • the amide group is preferably -NHCOCH 3 , -NHCOH, -NHCOCH 2 CH 3 , -NHCOCH 2 CH 2 CH 3 , -NHCOCH(CH 3 ) 2 , -NHCOCH(CH 2 ) 2 , -N(COCH 3 ) 2 , -CONH 2 , -CON(CH 3 ) 2 , -CONHCH 3 , -CONHCH 2 CH 3 , - CON(CH 2 CH 3 ) 2 , -CONHCH(CH 3 ) 2 , -CONHCH 2 CH 2 CH 3 , -CON(CH 2 CH 3 ) 2 , -CONHCH(CH 3 ) 2 , -CONHCH 2 CH 2 CH 3 , -CONHCH 2 CH 2 CH 3 , phthalimide group, succinimide group,
  • the compound of formula (V) is a compound of formula (Va),
  • R 1 is selected from H, optionally substituted alkyl and optionally substituted arylalkyl;
  • R 2 is selected from an optionally substituted aryl group, an optionally substituted alkyl group, and an optionally substituted amide group.
  • the amide group is preferably -NHCOCH 3 , -NHCOH, -NHCOCH 2 CH 3 , -NHCOCH 2 CH 2 CH 3 , -NHCOCH(CH 3 ) 2 , -NHCOCH(CH 2 ) 2 , -N(COCH 3 ) 2 , -CONH 2 , -CON(CH 3 ) 2 , -CONHCH 3 , -CONHCH 2 CH 3 , - CON(CH 2 CH 3 ) 2 , -CONHCH(CH 3 ) 2 , -CONHCH 2 CH 2 CH 3 , -CON(CH 2 CH 3 ) 2 , -CONHCH(CH 3 ) 2 , -CONHCH 2 CH 2 CH 3 , -CONHCH 2 CH 2 CH 3 , phthalimide group, succinimide group,
  • the compound of formula A is preferably compound (VI),
  • R 1 is selected from H, optionally substituted alkyl and optionally substituted arylalkyl;
  • R 2 and R 6 can be the same or different, and each is independently selected from optionally substituted aryl, five to ten-membered aryl groups.
  • Heteroaryl (the five- to ten-membered heteroaryl contains 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur), optionally substituted alkyl, optionally substituted ester group, optionally substituted Amide group, wherein the amide group is preferably -NHCOCH 3 , -NHCOH, -NHCOCH 2 CH 3 , -NHCOCH 2 CH 2 CH 3 , -NHCOCH(CH 3 ) 2 , -NHCOCH(CH 2 ) 2 , -N (COCH 3 ) 2 , -CONH 2 , -CON(CH 3 ) 2 , -CONHCH 3 , -CONHCH 2 CH 3 , -CON(CH 2 CH 3 ) 2 , -CONHCH(CH 3 ) 2 , -CONHCH 2 CH 2 CH 3 , -CONHCH(CH 3 ) 2 , -CONHCH 2 CH 2 CH 3 , -CONHCH 2 CH 2 CH 3 ,
  • R 2 and R 6 are selected from, and n is a natural number from 1 to 6.
  • R 2 and R 6 are selected from phenyl.
  • formula (VI) of the present invention preferably provides compounds of the following formulas (VI-1) and (VI-2):
  • R 1 is selected from H and C 1 -C 6 alkyl, preferably H and methyl
  • R 3 is selected from H and C 1 -C 6 alkyl, preferably H, methyl, ethyl, propyl and butyl
  • R 4 is selected from H and C 1 -C 6 alkyl, preferably one of H, methyl, ethyl, propyl and butyl
  • R 7 is selected from H and C 1 -C 6 alkyl, Preferably H, methyl, ethyl, propyl and butyl
  • R 8 is selected from H and C 1 -C 6 alkyl, preferably methyl, ethyl, propyl and butyl
  • n is selected from 1, 2 and 3
  • m is selected from 1, 2 and 3.
  • formula (VI) is preferably formula (VIa), Among them, R 1 is selected from H, optionally substituted alkyl and optionally substituted arylalkyl; R 2 and R 6 can be the same or different, and each is independently selected from optionally substituted aryl, five to ten-membered heterogeneous groups.
  • Aryl group (the five- to ten-membered heteroaryl group contains 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur), optionally substituted alkyl group, optionally substituted ester group, optionally substituted amide group, wherein the amide group is preferably -NHCOCH 3 , -NHCOH, -NHCOCH 2 CH 3 , -NHCOCH 2 CH 2 CH 3 , -NHCOCH(CH 3 ) 2 , -NHCOCH(CH 2 ) 2 , -N(COCH 3 ) 2 , -CONH 2 , -CON(CH 3 ) 2 , -CONHCH 3 , -CONHCH 2 CH 3 , -CON(CH 2 CH 3 ) 2 , -CONHCH(CH 3 ) 2 , -CONHCH 2 CH 2 CH 3 , -CONHCH(CH 3 ) 2 , -CONHCH 2 CH 2 CH 3 , -CONHCH 2 CH 2 CH 3 ,
  • the carbon atoms are connected to form a ring;
  • Z 1 and Z 2 can be the same or different, each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted amide group, Z 1 , Z 2
  • the carbon atoms to which they are bonded may be connected to form a ring, and the ring may be substituted.
  • the compounds of the present invention are selected from the following compounds:
  • the present invention also provides a method for preparing the compound of formula (I) above.
  • the synthesis route is as follows: R 1 , R 2 , R 3 and R 4 are as defined above, R 5 is selected from a leaving group, and the leaving group is selected from OH, H 2 O, OTs, OMs, Cl, Br , one of I;
  • reaction temperature is 40-110 degrees, preferably 70-90 degrees;
  • the molar ratio of formula II to formula IVa is 1:1-1.5, preferably 1:1.01-1.05;
  • the above reaction is carried out in a solvent, and the solvent is selected from toluene, capronitrile, dioxane, DMF, DMAc, DMSO, NMP, DMI, ethyl acetate, isopropyl acetate, dichloroethane, etc. or Several combinations, preferably toluene.
  • the above reaction can be carried out under the promotion of a catalyst, which is a protonic acid or a Lewis acid, selected from hydrochloric acid, HBr, HI, HF, sulfuric acid, phosphoric acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boric acid, benzenesulfonic acid , p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.
  • a catalyst which is a protonic acid or a Lewis acid, selected from hydrochloric acid, HBr, HI, HF, sulfuric acid, phosphoric acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boric acid, benzenesulfonic acid , p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.
  • the present invention also provides a method for preparing the compound of formula (Ia).
  • the synthesis route is as follows: Wherein R 1 , R 2 and R 3 are as defined above, Z 1 and Z 2 may be the same or different, each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted Of the amide group, Z 1 and Z 2 can be connected to the carbon atoms they are jointly connected to form a ring;
  • reaction temperature is 40-110 degrees, preferably 70-90 degrees;
  • the molar ratio of formula II to formula IIIa is 1:1-1.5, preferably 1:1.01-1.05;
  • the above reaction is carried out in a solvent, and the solvent is selected from toluene, capronitrile, dioxane, DMF, DMAc, DMSO, NMP, DMI, ethyl acetate, isopropyl acetate, dichloroethane, etc. or Several combinations, preferably toluene.
  • the above reaction can be carried out under the promotion of a catalyst, which is a protonic acid or a Lewis acid, selected from hydrochloric acid, HBr, HI, HF, sulfuric acid, phosphoric acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boric acid, benzenesulfonic acid , p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.
  • a catalyst which is a protonic acid or a Lewis acid, selected from hydrochloric acid, HBr, HI, HF, sulfuric acid, phosphoric acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boric acid, benzenesulfonic acid , p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.
  • the invention also provides a method for preparing the compound of formula (V).
  • the synthesis route is as follows:
  • R 1 , R 2 , R 3 and R 4 are as defined above, wherein R 5 is selected from a leaving group, and the leaving group is selected from OH, H 2 O, OTs, OMs, Cl , Br, I, etc.
  • reaction temperature is 40-110 degrees, preferably 70-90 degrees;
  • the molar ratio of formula II to formula IVa is 1:2.0-3.0, preferably 1:2.01-2.10;
  • the above reaction is carried out in a solvent, and the solvent is selected from toluene, capronitrile, dioxane, DMF, DMAc, DMSO, NMP, DMI, ethyl acetate, isopropyl acetate, dichloroethane, etc. or Several combinations, preferably toluene.
  • the above reaction can be carried out under the promotion of a catalyst, which is a protonic acid or a Lewis acid, selected from hydrochloric acid, HBr, HI, HF, sulfuric acid, phosphoric acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boric acid, benzenesulfonic acid , p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.
  • a catalyst which is a protonic acid or a Lewis acid, selected from hydrochloric acid, HBr, HI, HF, sulfuric acid, phosphoric acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boric acid, benzenesulfonic acid , p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.
  • the invention also provides a method for preparing the compound of formula (Va).
  • the synthesis route is as follows:
  • R 1 , R 2 and R 3 are as defined above, Z 1 and Z 2 can be the same or different, and each is independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl, Select a substituted amide group, and Z 1 and Z 2 can be connected to the carbon atoms they are jointly connected to form a ring;
  • reaction temperature is 40-110 degrees, preferably 70-90 degrees;
  • the molar ratio of formula II to formula IIIa is 1:2.0-3.0, preferably 1:2.01-2.10;
  • the above reaction is carried out in a solvent, and the solvent is selected from toluene, capronitrile, dioxane, DMF, DMAc, DMSO, NMP, DMI, ethyl acetate, isopropyl acetate, dichloroethane, etc. or Several combinations, preferably toluene.
  • the above reaction can be carried out under the promotion of a catalyst, which is a protonic acid or a Lewis acid, selected from hydrochloric acid, HBr, HI, HF, sulfuric acid, phosphoric acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boric acid, benzenesulfonic acid , p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.
  • a catalyst which is a protonic acid or a Lewis acid, selected from hydrochloric acid, HBr, HI, HF, sulfuric acid, phosphoric acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boric acid, benzenesulfonic acid , p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.
  • the invention also provides a method for preparing the compound of formula (VI).
  • the synthesis route is as follows:
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as defined above, wherein R 5 is selected from a leaving group, and the leaving group is selected from OH, H 2 O, OTs, OMs, Cl, Br, I, etc.
  • reaction temperature is 40-110 degrees, preferably 70-90 degrees;
  • reaction feed molar ratio of formula I and formula IVb is 1:1-1.5, preferably 1:1.01-1.05;
  • the above reaction is carried out in a solvent, and the solvent is selected from toluene, capronitrile, dioxane, DMF, DMAc, DMSO, NMP, DMI, ethyl acetate, isopropyl acetate, dichloroethane, etc. or Several combinations, preferably toluene.
  • the above reaction can be carried out under the promotion of a catalyst, which is a protonic acid or a Lewis acid, selected from hydrochloric acid, HBr, HI, HF, sulfuric acid, phosphoric acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boric acid, benzenesulfonic acid , p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.
  • a catalyst which is a protonic acid or a Lewis acid, selected from hydrochloric acid, HBr, HI, HF, sulfuric acid, phosphoric acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boric acid, benzenesulfonic acid , p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.
  • the invention also provides a method for preparing the compound of formula (VIa).
  • the synthesis route is as follows:
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , Z 1 and Z 2 are as defined above.
  • reaction temperature is 40-110 degrees, preferably 70-90 degrees;
  • the molar ratio of formula I to formula IIIb reaction is 1:1-1.5, preferably 1:1.01-1.05;
  • the above reaction is carried out in a solvent, and the solvent is selected from toluene, capronitrile, dioxane, DMF, DMAc, DMSO, NMP, DMI, ethyl acetate, isopropyl acetate, dichloroethane, etc. or Several combinations, preferably toluene.
  • the above reaction can be carried out under the promotion of a catalyst, which is a protonic acid or a Lewis acid, selected from hydrochloric acid, HBr, HI, HF, sulfuric acid, phosphoric acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boric acid, benzenesulfonic acid , p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.
  • a catalyst which is a protonic acid or a Lewis acid, selected from hydrochloric acid, HBr, HI, HF, sulfuric acid, phosphoric acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, boric acid, benzenesulfonic acid , p-toluenesulfonic acid, etc., preferably p-toluenesulfonic acid.
  • the compounds of the present invention can be used in the preparation of drugs or cosmetics for treating, preventing and/or alleviating hyperpigmentation.
  • the stated should Use is particularly by topical application to skin, such as human skin.
  • the present invention also provides a cosmetic composition or pharmaceutical composition containing the compound of formula (A) of the present invention or a salt thereof.
  • the above-mentioned cosmetic composition can be made into suitable forms such as cream, emulsion, ointment, capsule, lotion, foam, gel, dispersant, suspension, spray, essence, facial mask, etc.
  • the pharmaceutical/cosmetic composition of the present invention may also contain one or more additives, such as antioxidants, emollients, humectants, thickeners, fragrances, preservatives, pigments or colorants, or opacifiers. These additives are routine to the person skilled in the art.
  • Antioxidants can be used to protect the ingredients of the composition against oxidizing agents that are contained in the composition or that come into contact with the composition.
  • antioxidants include ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, potassium propyl gallate, octyl gallate, dodecyl gallate, phenyl-alpha-naphthylamine, and Tocopherols such as alpha-tocopherol.
  • Emollients are agents that soften and smooth the skin.
  • emollients include oils and waxes (eg, microcrystalline wax, polyethylene), triglycerides (eg, castor oil, cocoa butter, safflower oil, corn oil, olive oil, cod liver oil, almond oil, palm oil, peanut oil). Soybean oil), squalene, acetylated monoglycerides, ethoxylated glycerides, fatty acids, alkyl esters of fatty acids, alkenyl esters of fatty acids, fatty alcohols, fatty alcohol ethers, ether-esters, lanolin and wool Lipid derivatives, polyol esters, wax esters (e.g.
  • beeswax vegetable waxes
  • phospholipids and sterols isopropyl palmitate or glyceryl stearate, especially almond oil or fatty alcohols (e.g. cetyl alcohol, stearyl alcohol and / or myristol).
  • Silicones are particularly preferred emollient agents. Silicones that can be used in the present invention include, but are not limited to, dimethicone, methylcyclosiloxane, phenyltrimethicone, phenyldimethicone, cetyl dimethylsiloxane, stearyldimethylsiloxane, amino-terminated dimethylsiloxane, C 30-45 alkyldimethylsiloxane, C 30-45 alkylmethylsiloxane oxane, cetearyl methylsiloxane, dimethicone copolyol, cyclopentylsiloxane, cyclohexylsiloxane or any combination thereof. In particular, amino-terminated dimethicone can be used as an emollient in the present invention.
  • Moisturizers are used to increase and maintain moisture in the skin.
  • humectants include propylene glycol, butylene glycol, polyethylene glycol (PEG) (such as PEG-4 to PEG-32), glycerol (also known as glycerin), sorbitol, xylitol, maltitol, Mannitol, polydextrose, hyaluronic acid and its salts (such as sodium salt or potassium salt), urea, aloe juice, honey, etc.
  • Thickeners are used to increase the viscosity and consistency of compositions.
  • thickeners include lipid thickeners such as cetyl alcohol, stearyl alcohol, myristyl alcohol, carnauba wax or stearic acid; naturally derived thickeners such as cellulose derivatives such as hydroxyethyl cellulose Vegetarian, guar gum, locust bean gum, xanthan gum or gelatin; mineral thickeners such as silica, bentonite or magnesium aluminum silicate; synthetic thickeners such as carbomer; ionic thickeners such as NaCl.
  • aromatics or fragrances examples include peppermint, rose oil, rose water, aloe vera juice, clove oil, menthol, camphor, eucalyptus oil, and other plant extracts.
  • masking agents may be used.
  • Preservatives can be used to protect the composition from degradation.
  • preservatives include phenoxyethanol, methylparaben, benzalkonium chloride, benzethonium chloride, propylparaben, benzoic acid, benzyl alcohol, and mixtures thereof. In particular, it may be phenoxyethanol, methylparaben or mixtures thereof.
  • Pigments or colorants are used to change the color of the composition.
  • insoluble photoprotective dyes especially finely divided Metal oxides or salts are also suitable for this purpose.
  • titanium dioxide can be selected.
  • Use opacifiers such as titanium oxide in clear or transparent compositions to render them opaque.
  • particularly suitable metal oxides are also zinc oxide, iron, zirconium, silicon, manganese, aluminum and cerium oxides and mixtures thereof.
  • Silicates (talc), barium sulfate or zinc stearate can be used as examples of suitable salts.
  • Oxides and salts are used in the form of pigments used in skin care and skin protection lotions and decorative cosmetics.
  • the particles should have an average diameter of less than 100 nm, preferably between 5 and 50 nm, particularly preferably between 15 and 30 nm. They can be spherical, but it is also possible to use particles with an elliptical shape or other shapes than spherical. Pigments can also be surface treated, i.e. hydrophilized or hydrophobicized. A typical example is coated titanium dioxide. Suitable hydrophobic coating agents in this case are primarily silicones, in particular trialkoxyoctylsilanes or trimosiloxanes. So-called micro- or nanodyes are preferably used in sunscreen preparations, preferably micronized zinc oxide is used.
  • the photoprotective dye is selected from the group consisting of finely divided titanium dioxide, zinc oxide, and finely divided zinc oxide.
  • titanium dioxide is selected as photoprotective dye, it is advantageous if its total amount is from 0.1 to 10.0% by weight of the formulation.
  • zinc oxide is selected as the photoprotective dye, it is advantageous that the total amount is 0.1 to 10.0% by weight of the formulation, and when one or more triazine organic pigments are selected, it is advantageous that the total amount is 0.1 to 10.0% by weight of the formulation. %, based on total dosage.
  • the pharmaceutical or cosmetic composition according to the invention also contains at least one skin lightening agent, for example, sclareolactone.
  • the present invention also relates to the cosmetic use of the compounds of formula (A) according to the invention, in particular as depigmenting agents, whitening agents, bleaching agents or whitening agents, more particularly on skin, such as human skin.
  • the present invention also relates to the cosmetic use of a cosmetic composition according to the invention, in particular as a depigmenting, whitening, bleaching or whitening agent composition, more particularly intended for topical application to skin, such as human skin.
  • the invention also relates to the use of a compound of formula (A) according to the invention for the preparation of a cosmetic composition intended in particular for depigmenting, whitening, bleaching or whitening skin, such as human skin.
  • the invention also relates to a compound of formula (A) according to the invention for its use as a depigmenting agent, whitening agent, bleaching agent or whitening agent, more particularly for skin, such as human skin.
  • the present invention also relates to a method for depigmenting, whitening, bleaching or whitening skin, such as human skin, by applying to the skin an effective amount of a compound according to the invention or a cosmetic composition according to the invention to a human in need thereof.
  • the invention also relates to a compound according to the invention for its use as a medicament, especially in the treatment of pigmentation disorders, more particularly by topical application to skin, such as human skin.
  • the invention also relates to a pharmaceutical composition, in particular a dermatological composition, according to the invention, for use as a medicament, especially in the treatment of pigmentation diseases, more particularly by topical application to skin, such as human skin.
  • the invention also relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition, in particular a dermatological composition, intended in particular for the treatment of pigmentation diseases, moreover In particular by topical application to skin, such as human skin.
  • the invention also relates to the use of a compound according to the invention for the treatment of pigmentation disorders, more particularly by topical application to skin, such as human skin.
  • the present invention also relates to a method for administering to the skin of a person in need thereof an effective amount of a compound according to the present invention or a compound according to the present invention.
  • Pharmaceutical compositions in particular dermatological compositions, methods of treating pigmentation diseases of skin, such as human skin.
  • the pigmentation disease will more particularly be hyperpigmentation, including nevus, melasma, freckles, post-inflammatory hyperpigmentation and hyperpigmentation caused by drugs, chemicals or sunlight.
  • the invention also relates to the use of a compound according to the invention as an antioxidant, in particular to inhibit or reduce oxidative stress, especially oxidative stress due to UV, more particularly oxidative stress in the skin.
  • the invention also relates to a method for inhibiting or reducing oxidative stress, in particular oxidative stress due to UV, more particularly in the skin, comprising administration to a person in need thereof, in particular topical application An effective amount of a compound according to the invention.
  • the combination of the compounds of the present invention and UV filters is well tolerated, does not cause redness, whitening or browning of the skin, is non-irritating, does not dry the skin, and does not form Moist, scaly, powdery or sticky film that does not crack the skin.
  • These UV filters can be UV-A filters, UV-B filters, photoprotective dyes or mixtures thereof.
  • the UV filter substance refers to, for example, an organic substance (light filter substance) that is liquid or crystalline at room temperature, and can absorb ultraviolet radiation and release the absorbed energy in the form of long-wave radiation such as heat.
  • the content of UV filter substance is from 0.05% to 50% by weight, preferably from 0.5% to 40% by weight.
  • UV filter materials can be oil-soluble or water-soluble.
  • Suitable oil-soluble materials include:
  • ⁇ Esters of cinnamic acid preferably 2-ethylhexyl 4-methoxycinnamate, propyl 4-methoxycinnamate, isoamyl 4-methoxycinnamate, and 2-cyano-3,3 -2-ethylhexyl diphenylacrylate (octocrylene);
  • ⁇ Esters of salicylic acid preferably 2-ethylhexyl salicylate, homosalate, and menthyl salicylate;
  • ⁇ Benzophenone derivatives preferably 2,2'-dihydroxy-4,4'-dimethoxybenzophenone, 2-hydroxy-4-methoxy-benzophenone, 2,2' -Dihydroxy-4-methoxybenzophenone;
  • Benzylmalonate preferably 4-methoxybenzylmalonate bis-2-ethylhexyl
  • Triazine derivatives such as 2,4,6-tris(p-2-ethylhexylaniline)-1,3,5-triazine and dioctylbutylamidotriazinone;
  • ⁇ Benzoylmethane derivatives preferably 4-tert-butyl-4’-methoxydibenzoylmethane
  • ⁇ Carbonyl-containing polycyclic compounds such as ketone tricyclic (5.2.1.0) decane derivatives, etc.
  • Suitable water-soluble materials include:
  • UV-A light filtering substances include derivatives of benzoylmethane, such as 4-tert-butyl-4′-methoxy-dibenzoylmethane, 2-(4-diethylamino -2-Hydroxybenzoyl)-hexyl benzoate, 1-phenyl-3-(4′-isopropylphenyl)propane-1,3-dione, and enamine compounds.
  • benzoylmethane such as 4-tert-butyl-4′-methoxy-dibenzoylmethane, 2-(4-diethylamino -2-Hydroxybenzoyl)-hexyl benzoate, 1-phenyl-3-(4′-isopropylphenyl)propane-1,3-dione, and enamine compounds.
  • UV-A and UV-B filter substances can also be mixed, for example, composed of diphenylmethane derivatives and/or benzoylmethane derivatives 4-tert-butyl-4′-methoxy-dibenzoyl Combination of methane and cinnamic acid derivatives
  • the cinnamic acid derivative is preferably 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene) and/or 4-methoxycinnamic acid 2 - Ethylhexyl ester and/or isoamyl 4-methoxycinnamate and/or propyl 4-methoxycinnamate.
  • the cinnamate derivatives of this combination can also be replaced by water-soluble filter substances such as 2-phenylbenzimidazole-5-sulfonic acid and its alkali metals, alkaline earth metals, ammonium, alkylammonium, alkanols, and glucoammonium. Salts and/or 4-(2-oxo-3-bornylidenemethyl)benzenesulfonic acid and 2-methyl-5-(2-oxo-3-bornylidenemethyl)sulfonic acid and their alkali metals, Alkaline earth metals, ammonium, alkylammonium, alkanols, glucoammonium salts.
  • water-soluble filter substances such as 2-phenylbenzimidazole-5-sulfonic acid and its alkali metals, alkaline earth metals, ammonium, alkylammonium, alkanols, and glucoammonium salts.
  • the (cosmetic or pharmaceutical) preparation according to the invention contains at least one additional UV-absorbing substance selected from the group consisting of:
  • compositions of the present invention when applied to human skin, can be used concurrently with skin lightening agents to enhance the alleviation of hyperpigmentation.
  • suitable skin lightening agents for use in the present invention include: kojic acid derivatives (preferably kojic acid dipalmitate), arbutin, ascorbic acid and ascorbic acid derivatives (preferably magnesium ascorbyl phosphate), hydroquinone and hydroquinone derivatives, Sperillalide, amino acids (preferably cyclohexyl carbamates, N-acetyltyrosine and its derivatives, undecylenoylphenylalanine), sulfur-containing molecules (preferably glutathione , cysteine, thiourea derivatives, lipoic acid), ⁇ -hydroxy acids (preferably citric acid, lactic acid, malic acid, their salts and esters), glucose Acids, chromone derivatives (aloe picrin is preferred), 1-aminoethylphosphinic acid, flavonoids, ellagic
  • Conversion rate (moles of raw materials input - moles of raw materials remaining in the product)/moles of raw materials input ⁇ 100%.
  • Test method A Use the absorbance method to test the inhibitory activity of the sample against tyrosinase
  • the compounds of the present invention were prepared into solutions with five concentrations: 5 ⁇ g/mL, 3 ⁇ g/mL, 1 ⁇ g/mL, 0.5 ⁇ g/mL, and 0.01 ⁇ g/mL.
  • the positive control kojic acid was prepared into solutions with concentrations of 25, 20, 10, 7.5, 5, and 2.5 ⁇ g/mL respectively.
  • Take 50 ⁇ L of each of the above five concentration solutions use 950 ⁇ L of phosphate buffer solution with a pH value of 6.8 to make 1 mL, add 1 mL of 0.1 mg/mL tyrosine, and then add phosphate buffer solution with a pH value of 6.8.
  • Enzyme activity inhibition rate [(A2-A1)-(B2-B1)]/(A2-A1) ⁇ 100%
  • A1 is the absorption value without inhibitors at 0 minutes;
  • A2 is the absorption value without inhibitors after 20 minutes;
  • the test results show that the compound of the present invention has a good inhibitory effect on inhibiting tyrosinase when the IC50 is 10 ⁇ M.
  • the compounds of the present invention have strong tyrosinase inhibition Activity; the present invention can be used as a tyrosinase inhibitor alone or mixed for the inhibition of enzymatic browning of fruits and vegetables, for whitening in whitening cosmetics, and for the prevention and treatment of human pigmentation diseases caused by excess melanin. , melanoma, and other conditions requiring inhibition of tyrosinase activity.
  • Cell seeding seed cells into a 96-well plate at a seeding density of 1 ⁇ 10 4 cells/well, and incubate overnight in an incubator (37°C, 5% CO 2 ).
  • the experiment is set up as zeroing group, control group, positive control group and sample group.
  • sample group different concentration gradients are set for each sample, and 3 replicate wells are set under each concentration gradient.
  • Liquid preparation Prepare sample working solutions of different concentrations according to the test concentration setting table.
  • Administration will be performed when the cell plating rate in the 96-well plate reaches 40% to 60%.
  • 200 ⁇ L of culture medium containing 10% PBS (Gibco) was added to each well; in the positive control group, 200 ⁇ L of culture medium containing 10% DMSO was added to each well; in the sample group, 200 ⁇ L of culture medium containing samples of corresponding concentrations was added to each well; in the zeroing group, no For cell seeding, add only 200 ⁇ L of cell culture medium.
  • the 96-well plate was placed in an incubator (37°C, 5% CO 2 ) for culture.
  • a cell melanin synthesis inhibition test was performed within the allowable range of cytotoxicity.
  • the samples were grouped according to different concentrations, the detection index was melanin content, the detection model was melanocytes, and the colorimetric method was used for detection.
  • PC sample is kojic acid.
  • test results show that the compounds Ia, Id, Ie, If, Ig, Ih, Va, Vb, and Vc of the present invention perform better at lower concentrations (not exceeding More than 0.10% g/ml) has a cytomelanin synthesis inhibitory effect.
  • Selected Ia, Id, and Va all show better cytomelanin synthesis inhibitory effects than kojic acid, and can inhibit cytomelanin even at extremely low concentrations. synthesis.
  • the compounds of the present invention have strong tyrosinase inhibitory activity; the compounds of the present invention can be used alone or mixed as tyrosinase inhibitors for whitening in whitening cosmetics, and for the prevention and treatment of excessive melanin.
  • Various formulations of drugs for human pigmentation disorders, melanoma, and other conditions requiring inhibition of tyrosinase activity are also useful.

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Abstract

本发明提供一类式A所示间苯二酚衍生化合物，该化合物可以用于制备抑制色素沉着过度的药物，以及处理色素沉着过度的化妆、非治疗用途。本发明化合物对于抑制紫外和/或可见光辐射导致的色素沉积，以及皮肤抗衰老等方面具有显著作用。其中W为T为H、或 R1至R8的定义如说明书所定义。

Description

一种二酚类化合物及其制备方法和应用 技术领域
本发明涉及一类二酚类化合物，其制备方法，含有这种化合物的药物组合物或化妆品组合物，以及其用于药物应用和化妆品的用途，特别是用于抑制色素沉着方面，以及处理色素沉着过度的用途。
背景技术
存在于黑素细胞中，并通过酪氨酸酶催化转化酪氨酸产生的黑色素是负责皮肤着色的色素。由于过度的日光暴露、激素失调、黄褐斑、疾病、药物治疗受伤、疤痕、衰老导致的老年斑等因素，黑色素的过度产生会引起皮肤的色素沉着过度。
人类皮肤颜色主要由皮肤基底层中黑色素的量决定。黑色素，其通常为棕至黑色，在皮肤的黑素形成细胞中形成，其被转移至皮肤角质层并赋予皮肤或毛发其颜色。在哺乳动物中，棕黑色的真黑素主要由羟基取代的芳香族氨基酸如L-酪氨酸和L-DOPA形成，此外黄至红色的假黑素由含硫分子形成。由L-酪氨酸开始，L-3,4-二羟苯丙氨酸(L-DOPA)通过酪氨酸酶形成并通过酪氨酸酶转换为多巴色素，后续通过各种酶的一系列催化步骤，最终被氧化形成黑色素。
当过多的黑色素浓缩在一个区域或部分皮肤时，皮肤表现为过度色素沉着。由于暴露于日光或由于不同的炎症刺激也可能出现色素沉着过度。增多的黑色素产生通常伴随着黑斑病、黄褐斑或日光性着色斑(老年斑)、雀斑和着色角化症这些表现。黑斑病是描述皮肤暗沉的一般术语。黄褐斑通常用于描述由激素引起的皮肤变色。这些激素变化通常是由于怀孕、避孕药或雌激素替代疗法这些原因。日光性着色斑是指由于阳光导致的皮肤上的深色斑。这些斑常见于有长期无保护的阳光照射历史的成年人。尽管皮肤损伤，如疤痕、伤口或皮疹也能导致色素沉着过度，但皮肤变暗区域、棕色斑或变色区域的最通常原因是无保护的阳光照射。
现有技术公开了通过使用亮肤剂处理色素沉着过度的方法。常用的亮肤剂的代表性化合物包括氢醌和维生素C。这类制剂一个作用途径为通过抑制参与黑色素生成的酪氨酸酶来提亮皮肤。用于皮肤美白、皮肤漂白或皮肤增白的最受欢迎的成分包括氢醌、熊果苷、曲酸、甘草提取物、烟酰胺等。氢醌是最有效的脱色剂之一。虽然其功效已经被证实，但在21世纪初，由于其潜在的皮肤病学和全身性副作用，氢醌开始在化妆品中被去除或者其在化妆品中的使用受到限制。熊果苷(从植物中提取的天然产物)是一种氢醌的糖基化衍生物，并且是一种比氢醌更稳定且毒性更低的有效的酪氨酸酶抑制剂。然而，尽管其有巨大的潜力，熊果苷仍然是不稳定的，并且在不同的条件下经历水解，导致氢醌的释放。
研发更安全、更有效地改善皮肤色素沉着的化合物是人们一直追求的目标。通过研究酪氨酸酶的作用机制，模拟黑色素形成过程中的中间产物L-DOPA，从而开发间苯二酚型酪氨酸酶抑制剂，这 条研究思路越来越受到皮肤美白相关研发人员的重视。4-丁基间苯二酚、4-己基间苯二酚、二甲氧基甲苯基-4-丙基间苯二酚(WO2012/129260)、苯乙基间苯二酚(WO2018/001485)以及异丁酰胺基噻唑基间苯二酚(WO2015/090850)，这一系列的间苯二酚衍生物都被证明对于皮肤色素沉着具有显著效用。这些结果表明间苯二酚类化合物对于抑制酪氨酸酶的活性具有很好的潜力。因此，开发新型具有间苯二酚结构的化合物结构，探索其作为酪氨酸酶抑制剂的生物学功能，这对于开发新型、高效的酪氨酸酶抑制剂，进而开发新型治疗或改善皮肤色素沉着过度的化合物组合具有重要意义。
发明内容
本发明人经过研究，开发了一种新的间苯二酚类化合物，其可用作酪氨酸酶抑制剂，特别是用于化妆品或药物应用，并且更特别地作为脱色剂、美白剂、漂白剂或增白剂，并且用于治疗色素沉着类疾病，或者用于减缓或改善色素沉着过度的化妆品用途。
特别的，本发明提供一类能够影响日光导致的，特别是紫外、可见光导致的皮肤区域色素沉着，特别是预防、治疗和/或减轻皮肤区域或皮肤部分的色素沉着的间苯二酚类式A化合物，式A化合物结构如下：
其中W为T为H、
其中，R1选自H、任选取代的烷基和任选取代芳基烷基；
R2、R6可以相同或不同，各自独立地选自任选取代的芳基和杂芳基、任选取代的烷基、任选取代的酰胺基、任选取代的酯基，R3、R4、R7、R8可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，R3、R4可与它们共同连接的碳原子连接成环，R7、R8可与它们共同连接的碳原子连接成环；或其化妆品上或药学上可接受的盐、立体异构体或任何比例的立体异构体的混合物，特别是对映异构体或对映异构体的混合物，更特别是外消旋体混合物。
进一步的，化合物A为式(I)化合物，其中R1至R4的定义如上述所定义。
进一步的，化合A物为式(Ia)化合物，其中，R1至R3的定义如上述定义，Z1、Z2可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，Z1、Z2可与它们共同连接的碳原子连接成环，所述的环可以被取代。
进一步的，化合物A为式(V)化合物，
其中，R1至R4的定义如上。
进一步的，化合物A为式(Va)化合物，其中，R1至R3的定义如上，Z1、Z2可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，Z1、Z2可与它们共同连接的碳原子连接成环，所述的环可以被取代。
进一步的，化合物A为式(VI)化合物，其中，R1至R4及R6至R8的定义如上。
进一步的，化合物A为(VIa)，其中，R1至R4及R6至R7的定义如上，Z1、Z2可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，Z1、Z2可与它们共同连接的碳原子连接成环，所述的环可以被取代。
本发明还提供了化合物A的制备方法。
本发明还提供了含有本发明化合物或其药学上可接受的盐的药物组合物。
本发明还提供了含有本发明化合物或其药学上可接受的盐在制备治疗、预防和/或减轻色素沉着过度的药物中的用途。
本发明还公开了含有本发明化合物或其盐用于处理、防止和/或减轻色素沉着过度的非治疗、化妆用途。
本发明还公开了一种化妆组合物，含有本发明化合物或其盐。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。除非另有其它明确表示，否则在整个说明书和权利要求书中，术语“包括”或其变换如“包含”或“包括有”等等将被理解为包括所陈述的成分或步骤，而并未排除其它物质成分或步骤。
另外，为了更好的说明本发明，在下文的具体实施方式中给出了众多的具体细节。
本领域技术人员应当理解，没有某些具体细节，本发明同样可以实施。在一些实施例中，对于本领域技术人员熟知的原料、方法、手段等未作详细描述，以便于凸显本发明的主旨。
在本文中所披露的范围的端点和任何值都不限于该精确的范围或值，这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说，各个范围的端点值之间、各个范围的端点值和单独的点值之间，以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围，这些数值范围应被视为在本文中具体公开。
在本发明中“色素沉着过度”是指日光导致，更特别是可见光导致的色素沉着过度。
本发明中，“化妆品上或药学上可接受的”是指可用于化妆品或药物组合物的制备，通常对于药 物和化妆品用途是无毒的、安全的并且可接受的。
本发明中，“化妆品上或药学上可接受的盐”是如本文所定义的化妆品上或药学上可接受的盐，并且其具有原始化合物的药物和化妆品性质和活性。这种盐可以为：(1)与无机酸形成的酸式加成盐，所述无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等；或者与有机酸形成的酸式加成盐，所述有机酸如乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡庚糖酸、葡萄糖酸、谷氨酸、乙醇酸、羟基萘甲酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘康酸、2-萘磺酸、丙酸、水杨酸、琥珀酸、二苯甲酰基-L-酒石酸、酒石酸、对甲苯磺酸、三甲基乙酸、三氟乙酸等，但不限于此，和(2)当母体化合物中存在的酸质子被金属离子，例如碱金属离子(例如Na+、K+或Li+)、碱土金属离子(如Ca2+或Mg2+)或铝离子替代时形成的盐；或者当母体化合物中存在的酸质子与有机碱或无机碱配位时形成的盐。可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等，但不限于此。可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠，但不限于此。
在本发明中使用的术语“立体异构体”是指构型立体异构体，其包括几何异构体和光学异构体，以及构象异构体。
几何异构体(也被称为E/Z异构体或顺-反异构体)是由C＝C双键上的取代基的不同位置导致的，其可以具有Z或E构型，也被称为顺式或反式构型。
光学异构体是由包含四个不同的取代基(潜在地包括孤对电子)的原子(如碳原子或硫原子)上的取代基或孤对电子在空间中的不同位置导致的。因此，该原子代表手性或非对称中心。因此，彼此不为镜像的光学异构体被称作“非对映异构体”，而彼此为不可重叠的镜像的光学异构体被称作“对映异构体”。
手性化合物的两种对映异构体的等摩尔混合物被称作外消旋混合物。
本发明中卤素在所有情况下表示氟、氯、溴和碘。
本文所用的术语“烷基”(以及在包含烷基的其它基团，例如烷氧基的烷基结构部分，芳基烷基的烷基部分)在每种情况下表示通常具有1-20个碳原子，常常为1-6个碳原子，优选1-4个碳原子，尤其是1-3个碳原子的直链或支化烷基。C1-C4烷基的示例如甲基、乙基、正丙基、异丙基、正丁基、1-甲基丙基(仲丁基)、2-甲基丙基(异丁基)、1,1-二甲基乙基(叔丁基)。C1-C6烷基的示例除C1-C4烷基所提到的基团外，还有正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、2,2-二甲基丙基、1-乙基丙基、1,1-二甲基丙基、1,2-二甲基丙基、己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、1-乙基丁基、2-乙基丁基、1,1,2-三甲基丙基、1,2,2-三甲基丙基、1-乙基-1-甲基丙基或1-乙基-2-甲基丙基。C1-C10烷基的示例除C1-C6烷基所提到基团外，还有正庚基、1-甲基己基、2-甲基己基、3-甲基己基、1-乙基己基、2-乙基己基、1,2-二甲基己基、1-丙基戊基、2-丙基 戊基、壬基、癸基、2-丙基庚基和3-丙基庚基，但不限于此。烷基可以被卤素、氰基、硝基、芳基、环烷基、杂环基、酰氨基、酯基等取代，但不限于此。
本发明中“芳基”是指6至10个环原子的一价单环或双环芳香烃基团，如，苯基或萘基，尤其是萘基，但不限于此。芳基可以被烷基、卤素、氰基、硝基、环烷基、杂环基、酰氨基、酯基等取代，但不限于此。
本发明中“环”是指“环烷基”或“杂环基”，“环烷基”是指三至六个碳原子的单环单价烃基，其可以是饱和的或含有一个双键。环烷基可以未被取代或被一个或两个独立地选自烷基、卤素、烷氧基、羟基或氰基的取代基取代，但不限于此。实例包括但不限于环丙基、环丁基、环戊基、环己基、1-氰基环丙-1-基、1-氰基甲基环丙-1-基、3-氟环己基等，但不限于此。当环烷基含有双键时，它在本文中可称为环烯基。“杂环基”是指4至8个环原子的饱和或不饱和一价单环基团，其中一个或两个环原子为选自N、O或S(O)p的杂原子，其中p为整数0至2，剩余的环原子为C。此外，杂环基环中一个或两个环碳原子可任选被-CO-基团代替。更具体地，术语杂环基包括，但不限于，氮杂环丁烷基、氧杂环丁烷基、吡咯烷子基、哌啶子基、高哌啶子基、2-氧代吡咯烷基、2-氧代哌啶基、吗啉基、哌嗪基(piperazino)、四氢吡喃基、硫吗啉基等，但不限于此。当环烷基、杂环基等被取代时，可以被烷基、卤素、氰基、硝基、芳基、酰氨基、酯基等取代，但不限于此。
术语“任选取代”指相关基团可以被取代基取代，也可不被取代。
当基团被取代时，所述的取代基可以为烷基、卤素、氰基、硝基、环烷基、杂环基、酰氨基、酯基、烷氧基和卤素等，但不限于此，例如，烷基被卤素取代时，形成卤代烷基，但不限于此。
“烷氧基”是指-OR基团，其中R为如上定义的烷基，例如，甲氧基、乙氧基、丙氧基、或2-丙氧基、正丁氧基、异丁氧基或叔丁氧基等，但不限于此。
本发明的“酰胺基”指基团中含有“-NHCO-”或的基团，所述的酰胺基团，例如，-NHCOCH3、-NHCOH、-NHCOCH2CH3、-NHCOCH2CH2CH3、-NHCOCH(CH3)2、-NHCOCH(CH2)2、-N(COCH3)2、-CONH2、-CON(CH3)2、-CONHCH3、-CONHCH2CH3、-CON(CH2CH3)2、-CONHCH(CH3)2、-CONHCH2CH2CH3、-CONHCH2CH2CH2CH3、邻苯二甲酰亚胺基、琥珀酰亚胺基、戊二酰亚胺基、马来酰亚胺基、其中，R9选自任选取代的烷基或芳基、羧基或其盐、氰基、任选取代的酰胺基、任选取代的酯基，n选自1-6的自然数，所述的酯基优选-COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOCH2CH2CH3、-COOCH2CH2CH2CH3；
n选自1-6的自然数，优选1、2、3。但不限于此。
本发明的“酯基”是指基团中含有“-COO-”，所述的酯基例如，-COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOCH2CH2CH3、-COOCH2CH2CH2CH3，但不限于此。
本发明中“杂芳基”涵盖：5至10元芳香单环、芳香稠环，其中，芳香单环含一个或多个(如1至4个，或在某些实施方案中是1至3个)选自于N、O和S的杂原子且其余原子是碳；芳香稠环，其包含一个或多个(如1至4个，或在某些实施方案中是1至3个)选自于N、O和S的杂原子且其余环原子是碳，且其中至少一个杂原子存在于芳环中。例如，杂芳基包括与5至10元环烷基或杂环烷基环稠合的5至10元杂环烷基芳环。对于其中只有一个环包含一个或多个杂原子的所述融合，双环的杂芳环体系，连接点可以在任一环上。当杂芳基基团中S和O原子的总数超过1时，这些杂原子彼此不相邻。在某些实施方案中，杂芳基基团中S和O原子的总数不超过2。在某些实施方案中，芳香杂环中S和O原子的总数不超过1。杂芳基基团的实例包括但不限于(自定为1位的连接位置编号)2-吡啶基、3-吡啶基、4-吡啶基、2，3-哒嗪基、3，4-哒嗪基、2，4-嘧啶基、3，5-嘧啶基、2，3-吡唑啉基、2，4-咪唑啉基、异噁唑啉基、噁唑啉基、噻唑啉基、噻二唑啉基(thiadiazolinyl)、四唑基、噻吩基、苯并硫代苯基(benzothiophenyl)、呋喃基(furanyl)、苯并呋喃基、苯并咪唑啉基、吲哚啉基、吡嗪基、三唑基、喹啉基、吡唑基和5，6，7，8-四氢异喹啉基。从名称以“基”结尾的一价杂芳基基团中具有自由价的碳上去除一个氢原子而衍生出的二价基团通过在相应的一价基团的名称上加上“亚”命名，如具有两个连接点的吡啶基基团是吡啶亚基。杂芳基不涵盖芳基、环烷基或杂环烷基或不与芳基、环烷基或杂环烷基重叠，其如本文所定义。
“芳基烷基”是指其中芳基部分通过烷基残基与母体结构连接的残基。实例包括苄基、苯乙基、苯基乙烯基、苯基烯丙基等。“杂芳烷基”是指其中杂芳基部分通过烷基残基与母体结构连接的残基。实例包括呋喃基甲基、吡啶基甲基、嘧啶基乙基等。
下面关于式(A)化合物的变量的及变量的优选实施方案、本发明的用途和方法的特征以及本发明组合物的特征所作描述无论是其自身还是优选相互组合都是有效的。
总体而言，本发明提供一种间苯二酚类式A化合物，
其中W为T为H、
其中，R1选自H、任选取代的烷基和任选取代的芳基烷基；
R2、R6可以相同或不同，各自独立地选自任选取代的芳基和任选取代的杂芳基、任选取代的烷基、 任选取代的酰胺基、任选取代的酯基，R3、R4、R7、R8可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，R3、R4可与它们共同连接的碳原子连接成环，R7、R8可与它们共同连接的碳原子连接成环，其中，所述的酰胺基团优选为-NHCOCH3、-NHCOH、-NHCOCH2CH3、-NHCOCH2CH2CH3、-NHCOCH(CH3)2、-NHCOCH(CH2)2、-N(COCH3)2、-CONH2、-CON(CH3)2、-CONHCH3、-CONHCH2CH3、-CON(CH2CH3)2、-CONHCH(CH3)2、-CONHCH2CH2CH3、-CONHCH2CH2CH2CH3、邻苯二甲酰亚胺基、琥珀酰亚胺基、戊二酰亚胺基、马来酰亚胺基、其中，R9选自任选取代的烷基或任选取代的芳基、羧基或其盐、氰基、任选取代的酰胺基、任选取代的酯基，n选自1-6的自然数，所述的酯基优选-COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOCH2CH2CH3、-COOCH2CH2CH2CH3中一种；
或其化妆品上或药学上可接受的盐、立体异构体或任何比例的立体异构体的混合物，特别是对映异构体或对映异构体的混合物，更特别是外消旋体混合物。
进一步地，本发明供一种式A为式(I)化合物或其盐：
其中，R1选自H、任选取代的烷基和任选取代的芳基烷基；
R2选自任选取代的芳基、任选取代的烷基、任选取代的酰胺基、任选取代的酯基、任选取代的五至十元杂芳基(所述杂芳基包含1至4个独立选自氮、氧或硫的杂原子)，优选任选取代的烷基、其中，R9选自任选取代的烷基或芳基、羧基或其盐、氰基、任选取代的酰胺基、任选取代的酯基，n选自1-6的自然数，优选1、2、3；R3、R4可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，R3、R4可与它们共同连接的碳原子连接成环。
进一步的，在一些式(I)实施方式中，R1选自H和C1-C6烷基，特别优选H和甲基；
进一步的，在一些式(I)实施方式中，R2选自，其中n为1、2或3。
进一步的，在另一些式(I)实施方式中，R2选自。
进一步的，在一些式(I)实施方式中，R2选自苯基。
在一些式(I)实施方式中，优选地，R3选自H和C1-C6烷基，特别优选H、甲基、乙基、丙基和丁基中一种；
在一些式(I)实施方式中，优选地，R4选自H和C1-C6烷基，特别优选H、甲基、乙基、丙基和丁基中一种；
更进一步的，本发明优选提供式(I)化合物如下式(I-1)、(I-2)和(I-3)化合物：
其中，R1选自H和C1-C6烷基，特别优选H和甲基；R2选自苯基；在一些实施方式中，优选地，R3选自H和C1-C6烷基，特别优选H、甲基、乙基、丙基和丁基中一种；R4选自H和C1-C6烷基，特 别优选H、甲基、乙基、丙基和丁基中一种；R10选自C1-C18烷基，优选正十二烷基、正十四烷基和正十六烷基；n选自1、2和3。
进一步的，提供本发明式A化合物为优选式(Ia)化合物，其中，R1选自H、任选取代的烷基和任选取代的芳基烷基；R2选自任选取代的芳基、任选取代的五至十元杂芳基(所述五至十元杂芳基包括含1至4个独立选自氮、氧或硫的杂原子)、任选取代的烷基和任选取代的酰胺基；R3选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基；Z1、Z2可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，Z1、Z2可与它们共同连接的碳原子连接成环，所述的环可以被取代基取代。
进一步地，式(Ia)化合物中，R1选自H和C1-C6烷基，特别优选H和甲基；
进一步的，在一些式(Ia)化合物实施方式中，R2选自(其中n为1-6的自然数)、和苯基中一种。
更进一步的，本发明式(Ia)化合物优选如下式Ia-1和Ia-2化合物：
其中，R1选自H和C1-C6烷基，优选H和甲基；
Z1和Z2各种独立选自H和C1-C6烷基，优选H、甲基、乙基、丙基和丁基中一种；或Z1和Z2与连接的碳原子一起形成C3-C6环烷基、3-6元的杂环基；C3-C6环烷基优选环丙基、环丁基、环戊基、环己基；3-6元的杂环基优选环氧乙烷、氮杂环丁烷基、氧杂环丁烷基、吡咯烷子基、哌啶子基、高哌啶子基、2-氧代吡咯烷基、2-氧代哌啶基、吗啉基、哌嗪基、四氢吡喃基、硫吗啉基；
n选自1-6的自然数，优选1、2和3。
进一步的，一些实施方案中本发明化合物A优选为式(V)化合物，
其中，R1选自H、任选取代的烷基和任选取代的芳基烷基；
R2选自任选取代的芳基、任选取代的烷基、任选取代的酰胺基，所述酰胺基团优选为-NHCOCH3、-NHCOH、-NHCOCH2CH3、-NHCOCH2CH2CH3、-NHCOCH(CH3)2、-NHCOCH(CH2)2、-N(COCH3)2、-CONH2、-CON(CH3)2、-CONHCH3、-CONHCH2CH3、-CON(CH2CH3)2、-CONHCH(CH3)2、-CONHCH2CH2CH3、-CONHCH2CH2CH2CH3、邻苯二甲酰亚胺基、琥珀酰亚胺基、戊二酰亚胺基、马来酰亚胺基、中一种，其中，R9选自任选取代的烷基或芳基、羧基或其盐、任选取代的酯基(所述的酯基优选-COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOCH2CH2CH3、-COOCH2CH2CH2CH3中一种)、氰基、任选取代的酰胺基，n选自1-6的自然数；R3、R4可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，R3、R4可与它们共同连接的碳原子连接成环。
进一步的，一些实施方案中式(V)化合物为式(Va)化合物，
其中，R1选自H、任选取代的烷基和任选取代芳基烷基；
R2选自任选取代的芳基、任选取代的烷基、任选取代的酰胺基，所述酰胺基团优选为-NHCOCH3、-NHCOH、-NHCOCH2CH3、-NHCOCH2CH2CH3、-NHCOCH(CH3)2、-NHCOCH(CH2)2、-N(COCH3)2、-CONH2、-CON(CH3)2、-CONHCH3、-CONHCH2CH3、-CON(CH2CH3)2、-CONHCH(CH3)2、-CONHCH2CH2CH3、-CONHCH2CH2CH2CH3、邻苯二甲酰亚胺基、琥珀酰亚胺基、戊二酰亚胺基、马来酰亚胺基、中一种，其中，R9选自任选取代的烷基或芳基、羧基或其盐、任选取代的酯基(所述的酯基优选-COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOCH2CH2CH3、-COOCH2CH2CH2CH3中一种)、氰基、任选取代的酰胺基，n选自1-6的自然数；R3选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基；Z1、Z2可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，Z1、Z2可与它们共同连接的碳原子连接成环，所述的环可以被取代。
进一步的，本发明一些实施例方案中提供式A化合物优选为(VI)化合物，
其中，R1选自H、任选取代的烷基和任选取代的芳基烷基；R2、R6可以相同或不同，各自独立地选自任选取代的芳基、五至十元杂芳基(所述的五至十元杂芳基包含1至4个独立选自氮、氧或硫的杂原子)、任选取代的烷基、任选取代的酯基、任选取代的酰胺基，其中，所述的酰胺基优选-NHCOCH3、-NHCOH、-NHCOCH2CH3、-NHCOCH2CH2CH3、-NHCOCH(CH3)2、-NHCOCH(CH2)2、-N(COCH3)2、-CONH2、-CON(CH3)2、-CONHCH3、-CONHCH2CH3、-CON(CH2CH3)2、-CONHCH(CH3)2、-CONHCH2CH2CH3、-CONHCH2CH2CH2CH3、邻苯二甲酰亚胺基、琥珀酰亚胺基、戊二酰亚胺基、马来酰亚胺基、中一种，其中，R9选自任选取代的烷基或芳基、羧基或其盐、任选取代的酯基(所述的酯基优选-COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOCH2CH2CH3、-COOCH2CH2CH2CH3中一种)、氰基、任选取代的酰胺基，n选自1-6的自然数；R3、R4、R7、R8可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取 代的酰胺基，R3、R4可与它们共同连接的碳原子连接成环，R7、R8可与它们共同连接的碳原子连接成环，所述的环可以被取代。
进一步的，在一些式(VI)实施方式中，R2和R6选自，n为1-6的自然数。
进一步的，在一些式(VI)实施方式中，R2和R6选自苯基。
更进一步的，本发明式(VI)优选提供如下式(VI-1)和(VI-2)化合物：
其中，R1选自H和C1-C6烷基，优选H和甲基；R3选自H和C1-C6烷基，优选H、甲基、乙基、丙基和丁基中一种；R4选自H和C1-C6烷基，优选H、甲基、乙基、丙基和丁基中一种；R7选自H和C1-C6烷基，优选H、甲基、乙基、丙基和丁基；R8选自H和C1-C6烷基，优选甲基、乙基、丙基和丁基；n选自1、2和3，m选自1、2和3。
进一步的，本发明一些实施方案中式(VI)优选为式(VIa)，其中，R1选自H、任选取代的烷基和任选取代芳基烷基；R2、R6可以相同或不同，各自独立地选自任选取代的芳基、五至十元杂芳基(所述的五至十元杂芳基包含1至4个独立选自氮、氧或硫的杂原子)、任选取代的烷基、任选取代的酯基、任选取代的酰胺基，其中，酰胺基优选-NHCOCH3、-NHCOH、-NHCOCH2CH3、-NHCOCH2CH2CH3、-NHCOCH(CH3)2、-NHCOCH(CH2)2、-N(COCH3)2、-CONH2、 -CON(CH3)2、-CONHCH3、-CONHCH2CH3、-CON(CH2CH3)2、-CONHCH(CH3)2、-CONHCH2CH2CH3、-CONHCH2CH2CH2CH3、邻苯二甲酰亚胺基、琥珀酰亚胺基、戊二酰亚胺基、马来酰亚胺基、中一种，其中，R9选自任选取代的烷基或芳基、羧基或其盐、任选取代的酯基(所述的酯基优选-COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOCH2CH2CH3、-COOCH2CH2CH2CH3中一种)、氰基、任选取代的酰胺基，n选自1-6的自然数；R3、R4、R7可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，R3、R4可与它们共同连接的碳原子连接成环；Z1、Z2可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，Z1、Z2可与它们共同连接的碳原子连接成环，所述的环可以被取代。
特别优选的，本发明化合物选自下列化合物：
N-(1-(2,4-二羟基苯基)乙基)-2-吡咯烷酮；
N-(1-(2,4-二羟基苯基)丙基)-2-吡咯烷酮；
N-(1-(2,4-二羟基苯基)乙基)-2-哌啶酮；
N-(1-(2,4-二羟基苯基)丙基)-2-哌啶酮；
N-(1-(2,4-二羟基苯基)乙基)-2-环己亚胺酮；
N-(1-(2,4-二羟基苯基)丙基)-2-环己亚胺酮；
1,1'-((4,6-二羟基-1,3-苯叉基)双(乙-1,1-叉基))双(吡咯烷-2-酮)；
1,1'-((4,6-二羟基-1,3-苯叉基)双(丙-1,1-叉基))双(吡咯烷-2-酮)；
1,1'-((4,6-二羟基-1,3-苯叉基)双(乙-1,1-叉基))双(哌啶烷-2-酮)；
1,1'-((4,6-二羟基-1,3-苯叉基)双(丙-1,1-叉基))双(哌啶烷-2-酮)；
1,1'-((4,6-二羟基-1,3-苯叉基)双(乙-1,1-叉基))双(环己亚胺-2-酮)；
1,1'-((4,6-二羟基-1,3-苯叉基)双(丙-1,1-叉基))双(环己亚胺-2-酮)；
4,6-双(1-苯基乙基)-1,3-苯二酚。
本发明还提供一种上述式(I)化合物的制备方法，合成路线如下：其中R1、R2、R3和R4的定义如上述定义，其中R5选自离去基团，所述的离去基团选自OH、H2O、OTs、OMs、Cl、Br、I中一种；
上述反应中，反应温度为40-110度，优选为70-90度；
上述反应中，式Ⅱ与式IVa反应投料摩尔比为1:1-1.5，优选为1:1.01-1.05；
上述反应在溶剂中进行，所述的溶剂选自甲苯、已腈、二氧六环、DMF、DMAc、DMSO、NMP、DMI、乙酸乙酯、乙酸异丙酯、二氯乙烷等一种或几种组合，优选为甲苯。
上述反应可在催化剂促进下进行，所述催化剂为质子酸或路易斯酸，选自盐酸、HBr、HI、HF、硫酸、磷酸、草酸、甲磺酸、三氟甲磺酸、硼酸、苯磺酸、对甲苯磺酸等，优选为对甲苯磺酸。
本发明还提供一种上述式(Ia)化合物的制备方法，合成路线如下：其中R1、R2、R3的定义如上述定义，Z1、Z2可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，Z1、Z2可与它们共同连接的碳原子连接成环；
上述反应中，反应温度为40-110度，优选为70-90度；
上述反应中，式Ⅱ与式Ⅲa反应投料摩尔比为1:1-1.5，优选为1:1.01-1.05；
上述反应在溶剂中进行，所述的溶剂选自甲苯、已腈、二氧六环、DMF、DMAc、DMSO、NMP、DMI、乙酸乙酯、乙酸异丙酯、二氯乙烷等一种或几种组合，优选为甲苯。
上述反应可在催化剂促进下进行，所述催化剂为质子酸或路易斯酸，选自盐酸、HBr、HI、HF、硫酸、磷酸、草酸、甲磺酸、三氟甲磺酸、硼酸、苯磺酸、对甲苯磺酸等，优选为对甲苯磺酸。
本发明还提供了一种式(V)化合物的制备方法，合成路线如下：
其中，R1、R2、R3、R4的定义如上述所定义，其中R5选自离去基团，所述的离去基团选自OH、H2O、OTs、OMs、Cl、Br、I等。
上述反应中，反应温度为40-110度，优选为70-90度；
上述反应中，式Ⅱ与式IVa反应投料摩尔比为1:2.0-3.0，优选为1:2.01-2.10；
上述反应在溶剂中进行，所述的溶剂选自甲苯、已腈、二氧六环、DMF、DMAc、DMSO、NMP、DMI、乙酸乙酯、乙酸异丙酯、二氯乙烷等一种或几种组合，优选为甲苯。
上述反应可在催化剂促进下进行，所述催化剂为质子酸或路易斯酸，选自盐酸、HBr、HI、HF、硫酸、磷酸、草酸、甲磺酸、三氟甲磺酸、硼酸、苯磺酸、对甲苯磺酸等，优选为对甲苯磺酸。
本发明还提供了一种式(Va)化合物的制备方法，合成路线如下：
其中，R1、R2、R3的定义如上述所定义，Z1、Z2可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，Z1、Z2可与它们共同连接的碳原子连接成环；
上述反应中，反应温度为40-110度，优选为70-90度；
上述反应中，式Ⅱ与式Ⅲa反应投料摩尔比为1:2.0-3.0，优选为1:2.01-2.10；
上述反应在溶剂中进行，所述的溶剂选自甲苯、已腈、二氧六环、DMF、DMAc、DMSO、NMP、DMI、乙酸乙酯、乙酸异丙酯、二氯乙烷等一种或几种组合，优选为甲苯。
上述反应可在催化剂促进下进行，所述催化剂为质子酸或路易斯酸，选自盐酸、HBr、HI、HF、硫酸、磷酸、草酸、甲磺酸、三氟甲磺酸、硼酸、苯磺酸、对甲苯磺酸等，优选为对甲苯磺酸。
本发明还提供了一种式(VI)化合物的制备方法，合成路线如下：
其中，R1、R2、R3、R4、R6、R7和R8的定义如上述所定义，其中R5选自离去基团，所述的离去基团选自OH、H2O、OTs、OMs、Cl、Br、I等。
上述反应中，反应温度为40-110度，优选为70-90度；
上述反应中，式I与式IVb反应投料摩尔比为1:1-1.5，优选为1:1.01-1.05；
上述反应在溶剂中进行，所述的溶剂选自甲苯、已腈、二氧六环、DMF、DMAc、DMSO、NMP、DMI、乙酸乙酯、乙酸异丙酯、二氯乙烷等一种或几种组合，优选为甲苯。
上述反应可在催化剂促进下进行，所述催化剂为质子酸或路易斯酸，选自盐酸、HBr、HI、HF、硫酸、磷酸、草酸、甲磺酸、三氟甲磺酸、硼酸、苯磺酸、对甲苯磺酸等，优选为对甲苯磺酸。
本发明还提供了一种式(VIa)化合物的制备方法，合成路线如下：
，其中，R1、R2、R3、R4、R6、R7、Z1和Z2的定义如上述所定义。
上述反应中，反应温度为40-110度，优选为70-90度；
上述反应中，式I与式Ⅲb反应投料摩尔比为1:1-1.5，优选为1:1.01-1.05；
上述反应在溶剂中进行，所述的溶剂选自甲苯、已腈、二氧六环、DMF、DMAc、DMSO、NMP、DMI、乙酸乙酯、乙酸异丙酯、二氯乙烷等一种或几种组合，优选为甲苯。
上述反应可在催化剂促进下进行，所述催化剂为质子酸或路易斯酸，选自盐酸、HBr、HI、HF、硫酸、磷酸、草酸、甲磺酸、三氟甲磺酸、硼酸、苯磺酸、对甲苯磺酸等，优选为对甲苯磺酸。
本发明化合物可以用于制备治疗、预防和/或减轻色素沉着过度药物或化妆品中应用。所述的应 用特别是通过局部用至皮肤，例如人的皮肤。
本发明还提供一种含有本发明式(A)化合物或其盐的化妆组合物或药物组合物。
进一步的，上述化妆品组合物可以制成霜剂、乳液、膏剂、胶囊剂、洗剂、泡沫剂、凝胶剂、分散剂、混悬剂、喷雾剂、精华素、面膜等合适的形式。
进一步的，本发明的药物/化妆品组合物还可以包含一种或多种添加剂，如抗氧化剂、润肤剂、保湿剂、增稠剂、芳香剂、防腐剂、颜料或着色剂或遮光剂。这些添加剂对于本领域技术人员是常规的。
可以使用抗氧化剂以保护组合物的成分对抗包含在组合物中的或将与组合物接触的氧化剂。抗氧化剂的示例包括抗坏血酸棕榈酸酯、丁基化羟基苯甲醚、丁基化羟基甲苯、没食子酸丙酯钾、没食子酸辛酯、没食子酸十二烷酯、苯基-α-萘基胺和生育酚如α-生育酚。
润肤剂为软化和平滑皮肤的试剂。润肤剂的示例包括油和蜡(如微晶蜡，聚乙烯)，甘油三酸酯(如蓖麻油、可可脂、红花油、玉米油、橄榄油、鱼肝油、杏仁油、棕榈油、大豆油)，角鲨烯，乙酰化单酸甘油酯，乙氧基化甘油酯，脂肪酸，脂肪酸的烷基酯，脂肪酸的烯基酯，脂肪醇，脂肪醇醚，醚-酯，羊毛脂和羊毛脂衍生物，多元醇酯，蜡酯(如蜂蜡、植物蜡)，磷脂和甾醇，棕榈酸异丙酯或硬脂酸甘油酯，特别是杏仁油或脂肪醇(如鲸蜡醇、硬脂醇和/或肉豆蔻醇)。
硅氧烷是特别优选的润肤剂。在本发明中可以使用的硅氧烷包括但不限于二甲基硅氧烷、甲基环硅氧烷、苯基聚三甲基硅氧烷、苯基聚二甲基硅氧烷、鲸蜡基二甲基硅氧烷、硬脂基二甲基硅氧烷、氨基封端二甲基硅氧烷、C30-45烷基二甲基硅氧烷、C30-45烷基甲基硅氧烷、鲸蜡硬脂基甲基硅氧烷、二甲基硅氧烷共聚醇(dimethicone copolyol)、环戊基硅氧烷、环己基硅氧烷或其任何组合。特别地，在本发明中可以使用氨基封端二甲基硅氧烷作为润肤剂。
保湿剂用于增加和保持皮肤的水分。保湿剂的示例包括丙二醇、丁二醇、聚乙二醇(PEG)(如PEG-4至PEG-32)、丙三醇(也被称为甘油)、山梨醇、木糖醇、麦芽糖醇、甘露糖醇、聚右旋糖、透明质酸及其盐(如钠盐或钾盐)、尿素、芦荟汁、蜂蜜等。
增稠剂用于增加组合物的粘度和稠度。增稠剂的示例包括脂质增稠剂如鲸蜡醇、硬脂醇、肉豆蔻醇、巴西棕榈蜡或硬脂酸；天然衍生的增稠剂，如纤维素衍生物，如羟乙基纤维素、瓜尔胶、槐豆胶、黄原胶或明胶；矿物增稠剂如二氧化硅、膨润土或硅酸铝镁；合成增稠剂如卡波姆；离子增稠剂如NaCl。
芳香剂或香料的示例包括胡椒薄荷、玫瑰油、玫瑰水、芦荟汁、丁香油、薄荷脑、樟脑、桉树油和其他植物提取物。为了消除组合物的某些气味，可以使用掩蔽剂。
防腐剂可以用于保护组合物免受降解。防腐剂的示例包括苯氧乙醇、对羟基苯甲酸甲酯、苯扎氯铵、苄索氯铵、对羟基苯甲酸丙酯、苯甲酸、苯甲醇，及其混合物。特别地，其可以为苯氧乙醇、对羟基苯甲酸甲酯或其混合物。
颜料或着色剂用于改变组合物的颜色。除了上述可溶性物质，不溶性光保护染料，特别是细分散 的金属氧化物或盐，也适用于此目的。如获得白色的组合物，可以选二氧化钛。在澄清或透明的组合物中使用遮光剂如氧化钛，以使其不透明。特别适当的金属氧化物实例还有氧化锌、铁、锆、硅、锰、铝和铈氧化物及其混合物。硅酸盐(滑石)、硫酸钡或硬脂酸锌可以用作适当盐的实例。氧化物和盐以用于护肤和皮肤保护乳液和装饰性化妆品的颜料的形式使用。在这种情况下，颗粒应该具有小于100nm，优选在5到50nm之间，特别优选在15和30nm之间的平均直径。它们可以是球形的，但是也可以使用具有椭圆形状或不是球形的其他形状的颗粒。颜料也可进行表面处理，即亲水化或疏水化。典型的实例是包覆的二氧化钛。在这种情况下适当的疏水涂层剂首先是有机硅，特别是三烷氧基辛基硅烷或三聚硅氧烷。所谓的微或纳米染料优选在防晒制剂中使用，优选使用微粉化氧化锌。
优选实施方案中，光保护染料选自微细二氧化钛、氧化锌、微细氧化锌。当选择二氧化钛作为光保护染料时，有利的是其总量为制剂的0.1至10.0重量％。当选择氧化锌作为光保护染料时，有利的是其总量为制剂的0.1至10.0重量％，并且当选择一种或多种三嗪有机颜料时，有利的是其总量为0.1至10.0重量％，基于制剂总量计。在一个优选实施方案中，根据本发明的药物或化妆品组合物还含有至少一种亮肤剂，例如，香紫苏内酯。
本发明还涉及根据本发明的式(A)的化合物的化妆品用途，特别地作为脱色剂、美白剂、漂白剂或增白剂，更特别地用于皮肤如人的皮肤的化妆品用途。
本发明还涉及根据本发明的化妆品组合物的化妆品用途，特别地作为脱色剂、美白剂、漂白剂或增白剂组合物，更特别地旨在局部应用至皮肤如人的皮肤的化妆品用途。
本发明还涉及根据本发明的式(A)的化合物用于制备化妆品组合物的用途，所述化妆品组合物尤其旨在用于使皮肤如人的皮肤脱色、美白、漂白或增白。
本发明还涉及一种根据本发明的式(A)的化合物，其作为脱色剂、美白剂、漂白剂或增白剂，更特别地用于皮肤如人的皮肤的用途。
本发明还涉及一种通过向有需要的人在皮肤上应用有效量的根据本发明的化合物或根据本发明的化妆品组合物，使皮肤如人的皮肤脱色、美白、漂白或增白的方法。
本发明还涉及一种根据本发明的化合物，其作为药物，尤其在治疗色素沉着疾病中的用途，更特别地通过局部应用至皮肤如人的皮肤。
本发明还涉及一种根据本发明的药物组合物，特别是皮肤病学组合物，其作为药物，尤其在治疗色素沉着疾病中的用途，更特别地通过局部应用至皮肤如人的皮肤。
本发明还涉及根据本发明的化合物用于制备药物组合物，特别是皮肤病学组合物的用途，所述药物组合物，特别是皮肤病学组合物尤其旨在用于治疗色素沉着疾病，更特别地通过局部应用至皮肤如人的皮肤。
本发明还涉及根据本发明化合物用于治疗色素沉着疾病的用途，更特别地通过局部应用至皮肤如人的皮肤。
本发明还涉及一种通过向有需要的人在皮肤上应用有效量的根据本发明的化合物或根据本发明 的药物组合物特别是皮肤病学组合物，治疗皮肤如人的皮肤的色素沉着疾病的方法。
所述色素沉着疾病将更特别地为色素沉着过度，包括小痣、黑斑病、雀斑、炎症后色素沉着过度和由药物、化学物质或日光引起的色素沉着过度。
本发明还涉及一种根据本发明的化合物，其作为抗氧化剂，特别地抑制或减少氧化应激，尤其是由于UV的氧化应激，更特别地在皮肤中的氧化应激的用途。
本发明还涉及一种用于抑制或减少氧化应激，尤其是由于UV的氧化应激，更特别地在皮肤中的氧化应激的方法，其包括向有需要的人施用，特别是局部施用有效量的根据本发明的化合物。
本发明组合物当施用至人类皮肤时，本发明化合物和UV过滤物质的结合被良好耐受，不会引起皮肤发红、变白或变褐，无刺激、不会使皮肤干燥、不会形成潮湿、鳞片状、粉状或粘性膜、并且不会使皮肤皴裂。这些UV过滤物质可以是UV-A过滤物质、UV-B过滤物质、光保护染料或其混合物。其中，UV过滤物质是指例如在室温下为液态或晶体的有机物质(光过滤物质)，能够吸收紫外辐射并以长波辐射如热的形式释放吸收的能量。通常，UV过滤物质的含量为0.05重量％至50重量％，优选0.5重量％至40重量％。
UV过滤物质可以是油溶或水溶的。
适当的油溶物质包括：
·3-亚苄基樟脑及其衍生物，如3-(4-甲基亚苄基)樟脑；
·4-氨基苯甲酸衍生物，优选4-(二甲氨基)苯甲酸2-乙基己酯、4-(二甲氨基)苯甲酸2-辛酯和4-(二甲氨基)苯甲酸戊酯；
·肉桂酸的酯，优选4-甲氧基肉桂酸2-乙基己酯、4-甲氧基肉桂酸丙酯、4-甲氧基肉桂酸异戊酯、2-氰基-3,3-二苯基丙烯酸2-乙基己酯(奥克立林)；
·水杨酸的酯，优选水杨酸2-乙基己酯、胡莫柳酯、水杨酸薄荷酯；
·二苯甲酮衍生物，优选2，2’-二羟基-4,4’-二甲氧基二苯甲酮、2-羟基-4-甲氧基-二苯甲酮、2,2’-二羟基-4-甲氧基二苯甲酮；
·苄基丙二酸酯，优选4-甲氧基苄基丙二酸双-2-乙基己酯、
·三嗪衍生物，例如，2,4,6-三(对-2-乙基己基苯胺)-1,3,5-三嗪和双辛基丁酰胺三嗪酮；
·苯甲酰甲烷衍生物，优选4-叔丁基-4’-甲氧基二苯甲酰甲烷；
·含羰基多环类化合物，如酮基三环(5.2.1.0)癸烷衍生物等。
适当的水溶性物质实施例包括：
·2-苯基苯并咪唑-5-磺酸及其碱金属、碱土金属、铵、烷基铵、烷醇、葡糖铵盐；
·2,2’-双-(1,4-亚苯基)1H-苯并咪唑-4,6-二磺酸的二钠盐；
·二苯甲酮的磺酸衍生物，优选2-羟基-4-甲氧基二苯甲酮-5-磺酸及其盐；
·3-亚苄基樟脑的磺酸衍生物，优选亚苄基樟脑磺酸和2-甲基-5-(2-氧代-3-亚冰片基)磺酸及其盐。
特别适合的UV-A光过滤物质典型实例，包括苯甲酰甲烷的衍生物，例如4-叔丁基-4′-甲氧基-二苯甲酰甲烷、2-(4-二乙基氨基-2-羟基苯甲酰基)-苯甲酸己酯、1-苯基-3-(4′-异丙基苯基)丙烷-1,3-二酮，以及烯胺类化合物。当然UV-A和UV-B过滤物质也可以混合使用，比如，由二苯基甲烷衍生物和/或苯甲酰甲烷衍生物4-叔丁基-4′-甲氧基-二苯甲酰甲烷和肉桂酸衍生物的组合，肉桂酸衍生物优选2-氰基-3,3-二苯基丙烯酸2-乙基己酯(奥克立林)和/或4-甲氧基肉桂酸2-乙基己酯和/或4-甲氧基肉桂酸异戊酯和/或4-甲氧基肉桂酸丙酯。这类组合的肉桂酸酯衍生物也可换为水溶性过滤物质如2-苯基苯并咪唑-5-磺酸及其碱金属、碱土金属、铵、烷基铵、烷醇、葡糖铵盐和/或4-(2-氧代-3-亚冰片基甲基)苯磺酸和2-甲基-5-(2-氧代-3-亚冰片基)磺酸及其碱金属、碱土金属、铵、烷基铵、烷醇、葡糖铵盐。
在一个优选实施方案中，本发明的(化妆或药物)制剂含有至少一种额外的UV吸收物质，选自组包括：
·樟脑苯扎铵甲基硫酸盐
·对苯二亚甲基-二莰烷磺酸和盐
·水杨酸高薄荷醇酯
·亚苄基樟脑磺酸和盐
·2-氰基-3,3-二苯基丙烯酸-2-乙基己酯
·对氨基苯甲酸乙酯
·对甲氧基肉桂酸异戊酯
·2-苯基苯并咪唑磺酸及其盐
·2,4,6-三(对-2-乙基己基苯胺)-1,3,5-三嗪
·2-(2H-苯并三唑-2-基)-4-甲基-6-(2-甲基-3-(1,3,3,3-四甲基-1-(三甲基硅基-氧)-二硅氧烷基)-丙基)苯酚
·亚甲基双-苯并三唑基四甲基丁基酚
·4,4’-[(6-[4-(1,1-二甲基)-氨基羰基]苯基氨基)-1,3,5-三嗪-2,4-二基]二亚氨基]-二-(苯甲酸2-乙基己基酯)
·3-(4′-甲基亚苄基)-D,L-樟脑
·3-亚苄基樟脑
·水杨酸-2-乙基己酯
·4-二甲基氨基苯甲酸-2-乙基己酯
·4-羟基-4-甲氧基二苯甲酮-5-磺酸及其盐
·亚苄基丙二酸酯-聚硅氧烷
·邻氨基苯甲酸薄荷醇酯
·聚丙烯酰胺甲基亚苄基樟脑
·对甲氧基肉桂酸2-乙基己酯
或其混合物。
本发明组合物当施用至人类皮肤时，可和亮肤剂同时使用，以增强对色素沉着过度的减缓作用。用于本发明的适当的亮肤剂包括：曲酸衍生物(优选曲酸二棕榈酸酯)、熊果苷、抗坏血酸及抗坏血酸衍生物(优选抗坏血酸磷酸镁)、氢醌及氢醌衍生物、香紫苏内酯、氨基酸类(优选环己基氨基甲酸酯类、N-乙酰基酪氨酸及其衍生物、十一碳烯酰基苯基丙氨酸)、含硫分子(优选谷胱甘肽、半胱氨酸、硫脲衍生物、硫辛酸)、α-羟基酸类(优选柠檬酸、乳酸、苹果酸，其盐类和酯类)、葡萄糖 酸、色酮衍生物(优选芦荟苦素)、1-氨基乙基次膦酸、黄酮类化合物、鞣花酸、烟酰胺、崖柏素及其衍生物、三萜类(优选山楂酸)、甾醇类(优选地麦角甾醇)、苯并呋喃酮类(优选川芎内酯)、4-乙烯基愈创木酚、4-乙基愈创木酚、锌盐类(优选氯化锌或葡萄糖酸锌)、二酸类(优选十八烯二酸和/或壬二酸)、氮氧化物合成抑制剂(优选地L-硝基精氨酸及其衍生物、2,7-二硝基吲唑或硫代-L-瓜氨酸)、金属螯合剂(优选α-羟基脂肪酸类、植酸、胆酸、胆汁提取物、腐殖酸、EGTA、EDTA及其衍生物)、豆奶及其提取物、维甲酸类化合物、丝氨酸蛋白酶抑制剂、其他合成或提取的天然活性成分(优选以植物提取物的形式使用，例如，熊果提取物、葡萄提取物、桑果提取物、凉薯提取物、大米提取物、番木瓜提取物、姜黄提取物、香附提取物、甘草根提取物(优选光甘草定或甘草查尔酮A)、桂木提取物、酸模属提取物、松属(松树)的提取物、葡萄属提取物或者从其中分离或浓缩的茋类衍生物、虎耳草提取物、黄芩提取物、微藻提取物(优选四肩突四鞭藻提取物)、人参提取物。
以下将通过实施例对本发明进行详细描述。但是，可以理解的是相关实施例并不是对保护范围进行任何限定。
以下实施例中：
反应物和产物的量通过液相色谱(Agilent HPLC 1260)测得。
反应的转化率和选择性通过以下公式计算：
转化率＝(原料投入摩尔量-产物中残留的原料摩尔量)/原料投入摩尔量×100％。
选择性＝目标产物的实际摩尔量/目标产物的理论摩尔量×100％
在没有特别说明的情况下，所用原料均采用市售产品，所述室温为25±5℃。
实施例1
在1000ml四口瓶中加入甲苯250g，催化剂对甲苯磺酸1.0g，间苯二酚110g，式N-乙烯基哌啶酮125g，加热，90℃下反应10小时，液相检测反应完毕，减压脱出溶剂后，加入乙酸乙酯/石油醚混合溶剂重结晶得到产物，收率90％，纯度99％。
实施例2
在1000ml四口瓶中加入甲苯250g，催化剂对甲苯磺酸1.0g，间苯二酚110g，6-甲氧基-2-萘基乙醇202g，加热，90℃下反应10小时，液相检测反应完毕，减压脱出溶剂后，加入乙酸乙酯/石油醚混合溶剂重结晶得到产物，收率92％，纯度99％。
实施例3
在1000ml四口瓶中加入甲苯250g，催化剂对甲苯磺酸1.0g，间苯二酚110g，式N-乙烯基吡咯烷酮222g，加热，90℃下反应10小时，液相检测反应完毕，减压脱出溶剂后，加入乙酸乙酯/石油醚混合溶剂重结晶得到产品，收率85％，纯度96％。
实施例4
在1000ml四口瓶中加入甲苯250g，催化剂对甲苯磺酸1.0g，间苯二酚110g，1-苯基乙醇244g，加热，90℃下反应10小时，液相检测反应完毕，减压脱出溶剂后，通过硅胶柱进行分离纯化(乙酸乙酯/石油醚混合溶剂淋洗)，浓缩除去溶剂后得到产品，收率82％，纯度97％。
实施例5
在1000ml四口瓶中加入甲苯150g，催化剂对甲苯磺酸0.50g，间苯二酚吡咯烷酮衍生物110g，式N-乙烯基吡咯烷酮56g，加热，90℃下反应10小时，液相检测反应完毕，减压脱出溶剂后，加入乙酸乙酯/石油醚混合溶剂重结晶得到产品，收率84％，纯度97％。
实施例6
在1000ml四口瓶中加入甲苯250g，催化剂对甲苯磺酸1.0g，间苯二酚苯取代乙基衍生物214g，1-苯基乙醇122g，加热，90℃下反应10小时，液相检测反应完毕，减压脱出溶剂后，通过硅胶柱进行分离纯化(乙酸乙酯/石油醚混合溶剂淋洗)，浓缩除去溶剂后得到产品，收率80％，纯度95％。
参照上述实施例方法制备得到下列表1-3中化合物。
表1:结构I型化合物


表2:结构VI型化合物

表3:化合物I-a至I-g核磁共振数据


应用测试例：酪氨酸酶抑制活性评价
1.1测试方法A：采用吸光法测试样品对酪氨酸酶的抑制活性
将本发明化合物分别配成5μg/mL、3μg/mL、1μg/mL、0.5μg/mL、0.01μg/mL这5个浓度的溶液。阳性对照曲酸分别配成25、20、10、7.5、5、2.5μg/mL浓度的溶液。取上述五种浓度溶液各50μL，用950μL的pH值为6.8磷酸盐缓冲溶液配成1mL，加进0.1mg/mL的酪氨酸1mL，然后加入由pH值6.8的磷酸盐缓冲溶液配成的1mL酪氨酸酶(200U/mL)，在37℃下孵育20min，于490nm处测定吸光值。
酶活性抑制率＝[(A2-A1)-(B2-B1)]/(A2-A1)×100％
A1为0min时候未加抑制剂的吸收值；A2为20min后未加抑制剂的吸收值；
B1为0min时候加抑制剂的吸收值；B2为20min后加了抑制剂的吸收值。
测试结果显示：本发明化合物IC50为10μM下对抑制酪氨酸酶具有较好的抑制效果，优选的化合物I-a、I-b、I-c、I-d、I-e、I-f、I-g、I-h、V-a、V-b和V-c在0.05μM-1μM下就有较好的抑制效果，对照样品曲酸的IC50为47.0μM。上述结果说明：本发明化合物均有很强的酪氨酸酶抑制 活性；本发明可以单独或混合作为酪氨酸酶抑制剂用于果蔬的酶促褐变的抑制，用于美白化妆品中美白，以及制备用于预防和治疗黑色素过多导致的人体色素沉着性疾病、黑色素瘤以及其他需要抑制酪氨酸酶活性的病症药物的各种制剂。
1.3测试方法B：
1.3.1细胞毒性测试
1)细胞接种:按1×104个/孔的接种密度接种细胞至96孔板，培养箱(37℃、5％CO2)中孵育过夜。
2)实验分组:实验设置调零组、对照组、阳性对照组与样品组。样品组中，每个样品设置不同浓度梯度，每个浓度梯度下设置3个重复孔。
3)配液:按测试浓度设定表配制不同浓度的样品工作液。
4)给药:待96孔板中细胞铺板率达到40％～60％时进行给药。对照组每孔加入200μL含10％PBS(Gibco)的培养液；阳性对照组每孔加入200μL含10％DMSO的培养液；样品组每孔加入200μL含有相应浓度样品的培养液；调零组无细胞接种，仅加入200μL细胞培养液。给药完成后将96孔板放置在培养箱(37℃、5％CO2)中培养。
5)检测:细胞孵育培养24h后，弃掉上清，加入MTT工作液(0.5mg/mL)，37℃避光孵育4h，孵育结束后，弃掉上清，每孔加100μL DMSO，在490nm处读取OD值。
6)细胞相对活力计算:
细胞活率测试数据示例：
*对照样品为：苯乙基间苯二酚
细胞活率数据表明，本发明化合物结构具有较低的细胞毒性。
1.3.2细胞黑素合成抑制试验
根据细胞毒性测试数据，在细胞毒性允许的范围内进行细胞黑素合成抑制试验。将样品按照不同浓度进行分组，检测指标为黑色素含量，检测模型为黑色素细胞，采用显色法进行检测。收集对数生长期细胞，细胞密度为2×105个/瓶接种至24孔板，在培养箱(37℃，5％CO2)中培养24h后，根据细胞毒性结果，按照浓度要求加入药物，以未处理细胞作为空白对照，每组设置3个平行。加药后在培养箱(37℃，5％CO2)中继续培养48h，弃去上清，加入1mL含10％DMSO的1M NaOH，放入60℃恒温烘箱中孵育1h，恢复室温后每孔转移200μL至96孔板，以含10％DMSO的1M NaOH作为空白对照，于405nm下读取吸光度值并计算细胞黑素相对抑制率。
细胞黑素合成抑制率结果
*注：PC样为曲酸。
测试结果表明，本发明化合物I-a、I-d、I-e、I-f、I-g、I-h、V-a、V-b、V-c在较低浓度下(不超 过0.10％g/ml)具有细胞黑素合成抑制效果，精选的I-a、I-d、V-a都表现出优于曲酸的细胞黑素合成抑制效果，甚至在极低浓度下都可以抑制细胞黑素合成。
上述结果说明：本发明化合物均有很强的酪氨酸酶抑制活性；本发明可以单独或混合作为酪氨酸酶抑制剂用于美白化妆品中美白，以及制备用于预防和治疗黑色素过多导致的人体色素沉着性疾病、黑色素瘤以及其他需要抑制酪氨酸酶活性的病症药物的各种制剂。
虽然本发明已以较佳实施例公开如上，但其并非用以限定本发明，任何熟悉此技术的人，在不脱离本发明的精神和范围内，都可做各种的改动与修饰，因此本发明的保护范围应该以权利要求书所界定的为准。

Claims (18)

  1. 式A化合物，
    其中W为T为H、
    其中，R1选自H、任选取代的烷基和任选取代的芳基烷基；
    R2、R6可以相同或不同，各自独立地选自任选取代的芳基和任选取代的杂芳基、任选取代的烷基、任选取代的酰胺基、任选取代的酯基，R3、R4、R7、R8可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，R3、R4可与它们共同连接的碳原子连接成环，R7、R8可与它们共同连接的碳原子连接成环，其中，所述的酰胺基团优选为-NHCOCH3、-NHCOH、-NHCOCH2CH3、-NHCOCH2CH2CH3、-NHCOCH(CH3)2、-NHCOCH(CH2)2、-N(COCH3)2、-CONH2、-CON(CH3)2、-CONHCH3、-CONHCH2CH3、-CON(CH2CH3)2、-CONHCH(CH3)2、-CONHCH2CH2CH3、-CONHCH2CH2CH2CH3、邻苯二甲酰亚胺基、琥珀酰亚胺基、戊二酰亚胺基、马来酰亚胺基、其中，R9选自任选取代的烷基或任选取代的芳基、羧基或其盐、氰基、任选取代的酰胺基、任选取代的酯基，n选自1-6的自然数，所述的酯基优选-COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOCH2CH2CH3、-COOCH2CH2CH2CH3；
    或其化妆品上或药学上可接受的盐、立体异构体或任何比例的立体异构体的混合物，特别是对映异构体或对映异构体的混合物，更特别是外消旋体混合物。
  2. 根据权利要求1所述的化合物，其特征在于，化合物A为式(I)化合物， 其中R1至R4的定义如权利要求1所定义。
  3. 根据权利要求1或2所述的化合物，其特征在于，化合物A为式(Ia)化合物， 其中，R1至R3的定义如权利要求1或2所定义，Z1、Z2可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，Z1、Z2可与它们共同连接的碳原子连接成环，所述的环可以被取代。
  4. 根据权利要求1所述的化合物，其特征在于，化合物A为式(V)化合物，
    其中，R1至R4的定义如权利要求1所定义。
  5. 根据权利要求4所述的化合物，其特征在于，化合物A为式(Va)化合物， 其中，R1至R3的定义如权利要求4所定义，Z1、Z2可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，Z1、Z2可与它们共同连接的碳原子连接成环，所述的环可以被取代。
  6. 根据权利要求1所述的化合物，其特征在于，化合物A为式(VI)化合物， 其中，R1至R4及R6至R8的定义如权利要求1所定义。
  7. 根据权利要求6所述的化合物，其特征在于，化合物A为(VIa)，其中，R1至R4及R6至R7的定义如权利要求1所定义，Z1、Z2可以相同或不同，各自独立地选自氢、任选取代的烷基、任选取代的环烷基、任选取代的酰胺基，Z1、Z2可与它们共同连接的碳原子连接成环，所述的环可以被取代。
  8. 根据权利要求1-7任意一项所述的化合物，其特征在于，选自下列化合物：
    N-(1-(2,4-二羟基苯基)乙基)-2-吡咯烷酮；
    N-(1-(2,4-二羟基苯基)丙基)-2-吡咯烷酮；
    N-(1-(2,4-二羟基苯基)乙基)-2-哌啶酮；
    N-(1-(2,4-二羟基苯基)丙基)-2-哌啶酮；
    N-(1-(2,4-二羟基苯基)乙基)-2-环己亚胺酮；
    N-(1-(2,4-二羟基苯基)丙基)-2-环己亚胺酮；
    1,1'-((4,6-二羟基-1,3-苯叉基)双(乙-1,1-叉基))双(吡咯烷-2-酮)；
    1,1'-((4,6-二羟基-1,3-苯叉基)双(丙-1,1-叉基))双(吡咯烷-2-酮)；
    1,1'-((4,6-二羟基-1,3-苯叉基)双(乙-1,1-叉基))双(哌啶烷-2-酮)；
    1,1'-((4,6-二羟基-1,3-苯叉基)双(丙-1,1-叉基))双(哌啶烷-2-酮)；
    1,1'-((4,6-二羟基-1,3-苯叉基)双(乙-1,1-叉基))双(环己亚胺-2-酮)；
    1,1'-((4,6-二羟基-1,3-苯叉基)双(丙-1,1-叉基))双(环己亚胺-2-酮)；
    4,6-双(1-苯基乙基)-1,3-苯二酚。
  9. 一种制备式(I)化合物的制备方法，其特征在于，式(II)化合物与式(IVa)化合物反应，合成路线如下：
    其中，R1、R2、R3和R4的定义如权利要求1所定义，其中R5选自离去基团，所述的离去基团优选OH、H2O、OTs、OMs、Cl、Br、I中一种。
  10. 一种制备式(Ia)化合物的制备方法，其特征在于，式(II)化合物与式(IIIa)化合物反应，合 成路线如下：其中，R1、R2、R3的定义如权利要求1所定义，Z1、Z2如权利要求3所定义。
  11. 一种制备式(V)化合物的制备方法，其特征在于，式(II)化合物与式(IVa)化合物反应，合成路线如下：其中，R1、R2、R3、R4的定义如权利要求1所定义，其中R5选自离去基团，所述的离去基团优选OH、H2O、OTs、OMs、Cl、Br、I中一种。
  12. 一种制备式(Va)化合物的制备方法，其特征在于，式(II)化合物与式(IIIa)化合物反应，合成路线如下：
    其中，R1、R2、R3、Z1和Z2的定义如权利要求5所定义。
  13. 一种制备式(VI)化合物的制备方法，其特征在于，式(I)化合物与式(IVb)化合物反应，合成路线如下：
    其中，R1、R2、R3、R4、R6、R7和R8的定义如权利要求1所定义，其中R5选自离去基团，所述的离去基团选自OH、H2O、OTs、OMs、Cl、Br、I中一种。
  14. 一种制备(VIa)化合物的制备方法，其特征在于，式(I)化合物与式(IIIb)化合物反应，合成路线如下：
    ，其中，R1、R2、R3、R4、R6、R7的定义如权利要求1所定义，Z1和Z2的定义如权利要求7所定义。
  15. 一种药物组合物，含有权利要求1-8任一项所述化合物或其药学上可接受的盐。
  16. 权利要求1-8任一项所述化合物在制备治疗、预防和/或减轻色素沉着过度中药物中的用途。
  17. 权利要求1-8任一项所述化合物或其盐用于处理、防止和/或减轻色素沉着过度的非治疗、化妆用途。
  18. 一种化妆组合物，含有权利要求1-8任一项所述化合物或其盐。
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