WO2021104515A1 - 一种取代的间三联苯类化合物及其药物组合物和用途 - Google Patents

一种取代的间三联苯类化合物及其药物组合物和用途 Download PDF

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WO2021104515A1
WO2021104515A1 PCT/CN2020/132676 CN2020132676W WO2021104515A1 WO 2021104515 A1 WO2021104515 A1 WO 2021104515A1 CN 2020132676 W CN2020132676 W CN 2020132676W WO 2021104515 A1 WO2021104515 A1 WO 2021104515A1
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substituted
pharmaceutically acceptable
acne
acceptable salt
group
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French (fr)
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张哲峰
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迪斯凯威（深圳）新药发展有限公司
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Priority to CN202080087268.7A priority Critical patent/CN114929678B/zh
Priority to CN202310822552.XA priority patent/CN117304136A/zh
Publication of WO2021104515A1 publication Critical patent/WO2021104515A1/zh

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P17/08—Antiseborrheics
    • 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
    • A61P17/10—Anti-acne agents
    • 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
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to but not limited to the technical field of medicinal chemistry, in particular to a substituted terphenyl compound and its pharmaceutical composition and application.
  • the French GALDERMA R&D company disclosed a trifarotene that selectively regulates RAR- ⁇ in a patent international application (publication number WO2006066978A1). This compound has been approved by the US FDA for the treatment of acne.
  • the present invention develops a substituted meta-terphenyl compound, which can be used for keratosis-related diseases of cell differentiation or proliferation, and for the treatment or prevention of skin diseases.
  • One aspect of the present invention provides a substituted meta-terphenyl compound as shown in (I), or a pharmaceutically acceptable salt thereof:
  • Y is -(CH 2 ) n -, where n is an integer from 1 to 16;
  • R 1 and R 2 are each independently hydrogen or an unsubstituted C 1 -C 6 alkyl group, or is substituted selected from halogen, hydroxy, or alkynyl group one or more groups C 1 -C 6 alkyl;
  • R 3 is hydrogen or R 5 -C(O)-, where R 5 is an unsubstituted C 1 -C 10 alkyl group, a halogen-substituted C 1 -C 10 alkyl group, or an unsubstituted C 3 -C 6 ring Alkyl substituted C 1 -C 10 alkyl, substituted C 3 -C 6 cycloalkyl substituted C 1 -C 10 alkyl, unsubstituted C 1 -C 10 alkoxy or substituted C 1 -C 10 Alkoxy, the substituted C 3 -C 6 cycloalkyl means substituted by one or more selected from halogen, methyl, trifluoromethyl and difluoromethyl; substituted C 1- C 10 alkoxy means substituted by one or more selected from halogen, methyl, trifluoromethyl and difluoromethyl;
  • R 4 is unsubstituted C 1 -C 4 alkyl or trifluoromethyl.
  • the substituted meta-terphenyl compound provided by the present invention wherein R 4 is tert-butyl.
  • the substituted meta-terphenyl compound provided by the present invention wherein Y is -(CH 2 ) n -, and n is an integer from 1 to 5. In a preferred embodiment, n is 1. , 2 or 3.
  • the substituted meta-terphenyl compound provided by the present invention wherein R 1 and R 2 are each independently a C 1 -C 3 alkyl group; in a preferred embodiment, R 1 and R 2 is each independently a methyl group or an ethyl group.
  • the substituted meta-terphenyl compound provided by the present invention wherein R 3 is hydrogen.
  • the substituted terphenyl compound provided by the present invention wherein R 3 is R 5 -C(O)-, wherein R 5 is a substituted or unsubstituted C 1 -C 4 alkyl group,
  • the substituent is selected from one or more of the following: halogen or C 3 -C 6 cycloalkyl; in a preferred embodiment, R 5 is methyl, ethyl, n-propyl, isopropyl, n-butyl Group, isobutyl, sec-butyl or tert-butyl, more preferably methyl or tert-butyl.
  • the substituted m-terphenyl compound provided by the present invention wherein Y is -(CH 2 ) n -, n is 1, 2 or 3; R 1 and R 2 are independently methyl or ethyl Group; R 3 is hydrogen or R 5 -C(O)-, R 5 is methyl or tert-butyl, R 4 is tert-butyl.
  • the above-mentioned substituted meta-terphenyl compound provided by the present invention is selected from one of the following compounds:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned substituted terphenyl compound and a pharmaceutically acceptable salt thereof.
  • the present invention discloses a pharmaceutical composition, which is composed of the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient or main active ingredient, supplemented by a pharmaceutically acceptable carrier.
  • the present invention also provides a preparation route of substituted terphenyl compounds, which includes the following steps:
  • R 1 , R 2 , R 3 , R 4 and Y are as described in the definition of the corresponding groups in formula (I).
  • R 1 , R 2 , R 3 and Y are as defined for the corresponding groups in the aforementioned formula (I).
  • the substituted meta-terphenyl compound and the pharmaceutically acceptable salt thereof of the present invention can be used for keratosis-related diseases of cell differentiation or proliferation.
  • the present invention also provides the use of the above-mentioned substituted terphenyl compounds and their pharmaceutically acceptable salts in the preparation of drugs for the prevention and/or treatment of skin-related diseases.
  • the present invention also provides the use of the above-mentioned substituted meta-terphenyl compounds and pharmaceutically acceptable salts thereof in the preparation of drugs for the prevention and/or treatment of skin-related diseases.
  • the related diseases of the present invention are skin diseases, and the skin diseases include but are not limited to: acne vulgaris, acne, polymorphonuclear leukocytes, rosacea, nodular cystic acne, acne conglobata, senile acne, solar acne, Acne or occupational acne related to medication; squama, ichthyosis-like conditions, keratosis follicularis, palmoplantar keratosis, leukoplakia and leukoplakia, skin or mucous (oral) lichenopathy ; All forms of psoriasis, whether skin, mucus or nail (toe) psoriasis, and even psoriasis rheumatism, or skin atopic reactivity, such as eczema, or respiratory atopic reactivity, or even gingival hypertrophy; Sjogren; common Warts, flat warts and verrucous epidermal dysplasia, oral or bright red
  • the substituted terphenyl compounds of the present invention can be formulated into pharmaceutical compositions, and administered to patients according to a variety of appropriately selected modes of administration, including systemic such as oral or parenteral, intravenous, intramuscular, and intravenous Skin or subcutaneous etc.
  • Forming part of the present invention are pharmaceutically acceptable salts:
  • a suitable "pharmaceutically acceptable salt” includes the conventional non-toxic salt of the compound of the present invention formed by the reaction of the compound of the present invention with an inorganic acid or an organic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.
  • organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, Tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane Salts of disulfonic acid, oxalic acid, ise
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared by the compound of the present invention with pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, and the like.
  • alkyl means a saturated aliphatic hydrocarbon group of 1-20 carbon atoms, including straight-chain and branched-chain groups (the numerical range mentioned in this application, such as “1-18", refers to this group, In this case, it is an alkyl group, which may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 18 carbon atoms).
  • Alkyl groups can be substituted or unsubstituted. When it is a substituted alkyl group, the substituent is preferably one or more, more preferably 1 to 3, and most preferably 1 or 2 substituents.
  • hydroxyl refers to the -OH group.
  • halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • alkynyl refers to a linear, branched or cyclic non-aromatic hydrocarbon group containing 12 to 18 carbon atoms in the main chain and at least one carbon-carbon triple bond.
  • Alkynyl includes ethynyl, propynyl, butynyl, 3-methylbutynyl and the like.
  • the linear, branched or cyclic part of the alkynyl group may contain a triple bond and this part may be substituted if a substituted alkynyl group is indicated.
  • cycloalkyl means a monocyclic or fused ring of all carbons ("fused" ring means that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system) group, where One or more rings do not have a fully connected ⁇ -electron system.
  • Examples (not limited to) cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, and cyclohexane Ene, cycloheptane and cycloheptatriene. Cycloalkyl groups can be substituted and unsubstituted.
  • alkoxy means -O- (unsubstituted alkyl) and -O- (unsubstituted cycloalkyl).
  • Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • the compounds of the present invention can be used for keratosis-related diseases of cell differentiation or proliferation, and for the treatment or prevention of skin diseases.
  • step 1
  • the reaction mixture was raised to -35°C; 20 mL of 3M H 2 SO 4 was added dropwise; after warming to room temperature, 24 mL of MTBE was added to dilute the organic phase, and the organic phase was separated and collected. The organic phase was washed once with 18.4 ml 3M H 2 SO 4 ; the above organic phase was extracted with 1 M NaOH.
  • Trifarotene 45.96g, 0.1mol
  • N,N-diethylethanolamine 14.06g, 0.12mol
  • 75mL xylene and tetrabutyl titanate 3.40g, 0.01mol
  • the water is distilled out until there is no water, then it is cooled to room temperature, stirred for 1 hour, filtered, washed, and the crude product is recrystallized with ethanol to obtain DSC311.
  • step 1
  • This example illustrates a formulation based on the compound according to the invention.
  • Prescription name Prescription dosage DSC303 5mg Allantoin 0.2g Xanthan gum 0.2g Cyclomethicone 20g Ethanol 15g Medium chain triglycerides 3g Phenoxyethanol 0.5g Propylene Glycol 25g purified water Add to 100g
  • Prescription name Prescription dosage DSC310 10mg glycerin 20g
  • Prescription name Prescription dosage DSC312 30mg glycerin 25g Allantoin 0.1g Glyceryl Monostearate 0.4g Phenoxyethanol 1g Simethicone 5g Tween 80 10g Ethanol 20g purified water Add to 100g
  • Prescription name Prescription dosage DSC311 50mg Propylene Glycol 15g Allantoin 0.2g Glyceryl Monostearate 0.4g Sorbic acid 0.8g Cyclomethicone 15g Carbomer 0.3g Ethanol 30g purified water Add to 100g
  • Example 5 Effect test: Experimental study on the effect of oleic acid-induced acne model in Japanese big-eared rabbits
  • the structural formula of the active ingredient is as follows:
  • the positive control group and the experimental group were made into creams in the same way.
  • 64 healthy Japanese big-eared white rabbits weighing 2.0 to 2.5 kg, are all males.
  • 8 rabbits were randomly selected according to their body weight as normal control group.
  • the remaining 56 white rabbits were 2 ⁇ 2cm2 at 2cm outside the ear canal and coated with coal tar once a day, with a thickness of about 0.5mm (before painting) Heat the coal tar in a water bath to melt, and remove the coke shells of the last applied coal tar before each application of coal tar; the normal control group is coated with olive oil, the method is the same as before)
  • 56 white rabbits were randomly divided into 7 groups according to the severity of the skin lesions, namely the model control group, the positive control group (Trifarotene), the DSC311 group, the DSC312 group, the DSC303 group, the DSC304 group, and the DSC305 group.
  • each dose group continued to apply coal tar in the morning. After removing the coal tar in the afternoon, apply the test drug or the control drug (both 0.01%/10g ointment, 1g ointment/only), once per day. Day, for 2 consecutive weeks (the model control group and the normal control group were coated with the same amount of substrate). Twenty-four hours after the last administration, the animals were killed by air embolism, and the skin (full layer) of the ear administration site was taken, fixed with 4% paraformaldehyde solution, and HE stained for routine pathological observation.
  • the thickness of the rabbit ear epidermis in each experimental group was slightly reduced, but the statistical difference was not significant; compared with the model control group, the size of the sebaceous glands in the rabbit ears of DSC311, DSC312, DSC303, DSC304 and DSC305 were all The reduction is statistically significant. This indicates that these compounds can significantly reduce the degree of sebaceous gland hyperplasia in the experimental rabbit ear acne model.

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Abstract

一种取代的间三联苯类化合物及其药物组合物和用途，所述的取代的间三联苯类化合物如式(I)所示。该化合物可用于治疗或预防皮肤疾病。

Description

一种取代的间三联苯类化合物及其药物组合物和用途 技术领域
本发明涉及但不限于药物化学技术领域，尤其涉及一种取代的间三联苯类化合物及其药物组合物和用途。
背景技术
法国GALDERMA研发公司在专利国际申请(公布号WO2006066978A1)公开了一种选择性调节RAR-γ的trifarotene，该化合物已被美国FDA批准上市，用于治疗痤疮。
发明内容
本发明开发了一种取代的间三联苯类化合物，该化合物可用于细胞分化或增殖的角化病相关疾病，用于治疗或预防皮肤疾病。
本发明一方面提供了一种如(I)所示的取代的间三联苯类化合物，或其药学上可接受的盐：
Figure PCTCN2020132676-appb-000001
式(I)中，Y为-(CH 2) n-，其中，n为1至16的整数；
R 1和R 2各自独立地为氢，或者未取代的C 1-C 6烷基，或者被选自卤素、羟基或炔基中一种或多种的基团所取代的C 1-C 6烷基；
R 3为氢或R 5-C(O)-，其中，R 5为未取代的C 1-C 10烷基、卤素取代的C 1-C 10烷基、未取代的C 3-C 6环烷基取代的C 1-C 10烷基、取代的C 3-C 6环烷基取代的C 1-C 10烷基、未取代C 1-C 10的烷氧基或取代的C 1-C 10烷氧基，所述取代的C 3-C 6环烷基是指被选自卤素、甲基、三氟甲基和二氟甲基中一种或多种所取代；取代的C 1-C 10烷氧基是指被选 自卤素、甲基、三氟甲基和二氟甲基中一种或多种所取代；
R 4为未取代的C 1-C 4烷基或三氟甲基。
在一些实施方案中，本发明提供的取代的间三联苯类化合物，其中，R 4为叔丁基。
在一些实施方案中，本发明提供的取代的间三联苯类化合物，其中，Y为-(CH 2) n-，n为1至5的整数，在一种优选的实施例中，n为1、2或3。
在一些实施方案中，本发明提供的取代的间三联苯类化合物，其中，R 1和R 2各自独立地为C 1-C 3烷基；在一种优选的实施例中，R 1和R 2各自独立地为甲基或乙基。
在一些实施方案中，本发明提供的取代的间三联苯类化合物，其中，R 3为氢。
在一些实施方案中，本发明提供的取代的间三联苯类化合物，其中，R 3为R 5-C(O)-，其中，R 5为取代或未取代的C 1-C 4烷基，取代基选自以下一种或几种：卤素或C 3-C 6环烷基；在一种优选的实施方式中，R 5为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，更优选为甲基或叔丁基。
在一些实施方案中，本发明提供的取代的间三联苯类化合物，其中，Y为-(CH 2) n-，n为1、2或3；R 1和R 2独立的为甲基或乙基；R 3为氢或R 5-C(O)-，R 5为甲基或叔丁基，R 4为叔丁基。
在一些实施方案中，本发明提供的上述取代的间三联苯类化合物，选自下列化合物中的一种：
Figure PCTCN2020132676-appb-000002
Figure PCTCN2020132676-appb-000003
Figure PCTCN2020132676-appb-000004
另一方面，本发明提供了包含上述取代的间三联苯类化合物及其药学上可接受的盐的药物组合物。
本发明公开了一种药物组合物，其以本发明所述的化合物或其药学上可接受的盐为活性成分或主要活性成分，辅以药学上可接受的载体组成。
第三方面，本发明还提供取代的间三联苯类化合物的制备路线，该路线包括如下步骤：
Figure PCTCN2020132676-appb-000005
Figure PCTCN2020132676-appb-000006
其中，R 1、R 2、R 3、R 4和Y的定义如式(I)中相应基团的定义所述。
在一种实施中，本发明式I所示的一些化合物，例如R 4为叔丁基时的如式I-a所示化合物还可以通过Trifarotene进行合成：
Figure PCTCN2020132676-appb-000007
其中，R 1、R 2、R 3和Y的定义如前述式(I)中相应基团的定义所述。
本发明所述取代的间三联苯类化合物及其药学上可接受的盐，可用于细胞分化或增殖的角化病相关疾病。
第三发明，本发明还提供上述取代的间三联苯类化合物及其药学上可接受的盐在用于制备预防和/或治疗皮肤相关疾病药物中的应用。
本发明还提供了上述取代的间三联苯类化合物及其药学上可接受的盐在用于制备 预防和/或治疗皮肤相关疾病的药物中的用途。
本发明所述的相关疾病为皮肤疾病，所述皮肤疾病包括但不限于：寻常痤疮、粉刺、多形核白细胞、红斑痤疮、结节囊肿性痤疮、聚合性痤疮、老年痤疮、日光性痤疮、与药物治疗有关的痤疮或职业性痤疮；鳞癣、鱼鳞癣状的病症、毛囊角化病、掌跖角化病、白斑和白斑状病症、皮肤或粘液的(mucous)(口腔的)苔藓病；所有形式的牛皮癣，无论皮肤、粘液或指(趾)甲的牛皮癣，并且甚至是牛皮癣风湿，或皮肤的特异反应性，如湿疹，或呼吸特异反应性，或甚至齿龈肥大；干燥病；普通的疣、扁平疣和疣状表皮发育不良、口部或鲜红的乳头状瘤、T淋巴瘤、嗜碱细胞和棘细胞上皮瘤、角化棘皮瘤；免疫皮肤病，如红斑狼疮、免疫性大疱疾病和胶原病，如硬皮病；由局部或全身性皮质类甾醇诱导的表皮的斑点和/或皮肤萎缩，或任何其它形式的皮肤萎缩；皮脂溢过多的痤疮或单纯皮脂溢；结瘢病症，或用于预防或修复伸长痕迹，或者用于促进结瘢；色素沉着病症，如色素沉着过度、黑斑病、色素沉着不足或白斑病。
本发明所述取代的间三联苯类化合物可以被配制为药用组合物，按照多种合适选择的给予方式给患者用药，这些途径包括全身例如口服或胃肠外，通过静脉内、肌肉、透皮或皮下等。
定义：
构成本发明的一部分是药学上可接受的盐：
如果本发明化合物为碱性的，则适当的“药学上可接受的盐”包括本发明化合物和无机酸或有机酸反应形成的本发明化合物的常规无毒盐。例如，包括得自无机酸例如盐酸、氢溴酸、硫酸、磷酸、硝酸等的盐，也包括得自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等的盐。
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”是指本发明化合物通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。
术语“烷基”表示1-20个碳原子的饱和的脂烃基，包括直链和支链基团(本申请书中提到的数字范围，例如“1-18”，是指该基团，此时为烷基，可以含1个碳原子、 2个碳原子、3个碳原子等，直至包括18个碳原子)。烷基可以是取代的或未取代的。当是取代的烷基时，该取代基优选是一或多个，更优选1-3个，最优选1或2个取代基。
术语“羟基”表示-OH基团。
术语“卤素”表示氟、氯、溴或碘，优选为氟或氯。
术语“炔基”表示直链、支链或环状的，主链含有12～18个碳原子及至少一个碳碳三键的非芳香烃基。炔基包括乙炔基、丙炔基、丁炔基、3-甲基丁炔基等。炔基的直链、支链或环状部分可含有三键且如果指明了取代的炔基则此部分可被取代。
术语“环烷基”表示全部为碳的单环或稠合的环(“稠合”环意味着系统中的每个环与系统中的其它环共享毗邻的一对碳原子)基团，其中一个或多个环不具有完全连接的π电子系统，环烷基的实例(不局限于)为环丙烷、环丁烷、环戊烷、环戊烯、环己烷、金刚烷、环己二烯、环庚烷和环庚三烯。环烷基可为取代的和未取代的。
术语“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基)。代表性实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
本发明所述的化合物可用于细胞分化或增殖的角化病相关疾病，用于治疗或预防皮肤疾病。
具体实施方式
以下实施例可以使本专业技术人员更全面地理解本发明，但不以任何方式限制本发明，所有化合物的结构均经NMR和MS确定。
实施例1
Figure PCTCN2020132676-appb-000008
Figure PCTCN2020132676-appb-000009
步骤1：
6.83g化合物1和7.8ml硼酸三异丙酯溶解于甲苯20ml和THF18ml中，抽真空/氮气置换，重复3次。将上述溶液置于-78℃低温槽中冷却，向上述混合液滴加入n-BuLi溶液，保持反应液内温不超过-55℃，继续低温搅拌至反应结束。
反应混和液升至-35℃；滴加入20mL 3M H 2SO 4；升至室温后，加入24ml MTBE稀释有机相，分液收集有机相。有机相用18.4ml 3M H 2SO 4洗涤一次；上述有机相使用1M NaOH萃取。上述NaOH溶液用20.6mL异丙醇稀释后，冷却至10℃；维持15～20℃，滴加27.2mL 3M H 2SO 4至pH≈2；滴毕，控温15℃搅拌1h；过滤，用水洗涤滤饼(20ml*2)两次，滤饼在真空50℃干燥48h，得到中间体2，收率：77.2％，MS(ESI -,m/z):227.2M -。
步骤2：
中间体3(22.8g)的甲醇溶液，降温至0℃，向其中分批加入二溴海因(DBDMH)14.3g,保持反应液内温不超过40℃；所得反应混合物继续搅拌3小时直至反应完毕。向反应混合液加入2.5g NaHSO 3，搅拌15min；反应液浓缩除去大部分甲醇；使用139mL水和100mL石油醚稀释继续搅拌5mins；分液收集有机相，有机相再使用143mL水，110mL1M NaOH，143mL水，70mL食盐水洗涤后得到中间体4的PE溶液；Na 2SO 4干燥；上述混合液抽滤，浓缩至干，柱层板得到中间体4纯品。MS(ESI -,m/z):306.1M -。
步骤3：
中间体4(30.7g)加入500ml反应瓶，加入醋酸酐加热回流，滴加33％氢溴酸溶 液100ml，滴毕维持温度18小时。体系浓缩致干，用异丙醇和水结晶得到中间体5。MS(ESI -,m/z):292.1M -。
步骤4：
10.3g K 2CO 3溶解在22.6ml水中；8.3g中间体5、6.92g中间体2、THF 28.5ml加入到Na 2CO 3水溶液中，用氮气鼓泡除氧20min；加入催化剂PdCl 2(DTBPF) 2 0.184g，氮气置换3次；氮气保护下40℃剧烈搅拌38h；
降至室温加入50ml水，50ml PE搅拌15min；有机相用水60ml水洗一次，饱和氯化钠洗一次；加入适量无水硫酸钠搅拌1～2h；有机相快速过约4cm高硅胶柱，用PE:THF＝10:1→5:4约300～400ml洗脱；母液浓缩，残渣用100ml正庚烷溶解，室温搅拌析晶30min，很多固体析出；慢慢降至-15℃，继续析晶4h；过滤，滤饼用冰正庚烷洗涤后45℃干燥12h得到中间体6。MS(ESI -,m/z):414.5M -。
步骤5：
11.76g化合物6溶于DCM中，在氮气保护下，滴入SOCl 2 6.74g的DCM溶液，反应2小时后，体系浓缩至干.加入THF适量，滴加化合物II 8.68g，反应5小时。体系浓缩至干，柱层板纯化得到化合物7,MS(ESI +,m/z):515.7M +。
步骤6：
14.75g化合物7溶于THF中降温至0℃，在氮气保护下，滴入LDA溶液，反应2小时后，通入过量环氧乙烷，并反应5小时。体系加水淬灭，浓缩至干，柱层板纯化得到化合物DSC303。MS(ESI +,m/z):559.7M +， 1H NMR(DMSO-D 6,400MHz)1.43(s,9H)；1.78-1.86(m,4H)；1.9(bs,4H)；2.5(s,6H)；2.76(t,2H)3.04(bs,4H)；3.77(t,2H)；4.18(t,2H)；4.43(t,2H)；4.7(s,1H)；7.11(d,J＝8.6Hz,1H)；7.4(d,J＝9.9Hz,1H)；7.45(d,J＝8.2Hz,1H)；7.55(s,1H)；7.63(s,1H)；7.67(d,J＝7.34Hz,1H)；7.80(d,J＝8.45Hz,2H)；7.97(d,J＝8.4Hz,2H)。
步骤7：
5.59g中间体8与乙酸酐混合，加热回流5小时，体系浓缩至干,柱层析得到化合物DSC304。MS(ESI +,m/z):601.9M +， 1H NMR(DMSO-D 6,400MHz)1.43(s,9H)；1.78-1.86(m,4H)；1.9(bs,4H)；2.05(s,3H)；2.47(s,6H)；2.78(t,2H)3.06(bs,4H)；4.17(t,2H)；4.38(t,2H)；4.41(t,2H)；7.12(d,J＝8.6Hz,1H)；7.4(d,J＝9.9Hz,1H)；7.45(d,J＝8.2Hz,1H)；7.55(s,1H)；7.62(s,1H)；7.68(d,J＝7.34Hz,1H)；7.80(d,J＝8.45Hz,2H)；7.97(d,J＝8.4Hz,2H)。
5.59g中间体9溶于THF中，在氮气保护下加入特戊酰氯1.81g，体系加热回流5 小时，体系浓缩至干,柱层析得到化合物DSC305。MS(ESI +,m/z):643.9M +， 1H NMR(DMSO-D 6,400MHz)1.33(s,9H)；1.44(s,9H)；1.78-1.86(m,4H)；1.9(bs,4H)；2.47(s,6H)；2.78(t,2H)3.05(bs,4H)；4.18(t,2H)；4.36(t,2H)；4.40(t,2H)；7.11(d,J＝8.6Hz,1H)；7.38(d,J＝9.9Hz,1H)；7.45(d,J＝8.2Hz,1H)；7.56(s,1H)；7.62(s,1H)；7.68(d,J＝7.34Hz,1H)；7.82(d,J＝8.45Hz,2H)；7.98(d,J＝8.4Hz,2H)。
实施例2 由Trifarotene制备DSC311
Figure PCTCN2020132676-appb-000010
将Trifarotene(45.96g，0.1mol)，N,N-二乙基乙醇胺(14.06g，0.12mol)，75mL二甲苯及钛酸四丁酯(3.40g，0.01mol)加入反应瓶中，加热回流分水，至无水分馏出，降至室温，搅拌1小时，过滤，洗涤，粗品用乙醇重结晶得DSC311。MS(ESI +,m/z):558.8M +， 1H NMR(DMSO-D 6,400MHz)1.05(2s,6H)；1.43(s,9H)；1.9(bs,4H)；2.58(2d,4H)；2.78(t,2H)3.04(bs,4H)；3.76(t,2H)；4.34(t,2H)；4.43(t,2H)；4.7(s,1H)；7.12(d,J＝8.6Hz,1H)；7.4(d,J＝9.9Hz,1H)；7.45(d,J＝8.2Hz,1H)；7.55(s,1H)；7.63(s,1H)；7.66(d,J＝7.34Hz,1H)；7.78(d,J＝8.45Hz,2H)；7.98(d,J＝8.4Hz,2H)。
实施例3 由Trifarotene制备DSC312
Figure PCTCN2020132676-appb-000011
Figure PCTCN2020132676-appb-000012
步骤1:
于反应瓶中加入Trifarotene 45.96g(0.1mol)、乙腈50ml和吡啶39.55g(0.5mol),将反应混合物加热至35℃，于35～40℃滴加乙酸酐20.42g(0.2mol),滴加完成后于50℃反应4小时，降至室温，往反应混合物中加水100ml，搅拌1小时，过滤，水洗，干燥得Tri-1，MS:501.6[M+H] +。
步骤2：
将Tri-1 50.16g(0.1mol)、N,N-二乙基乙醇胺14.06g(0.12mol),75ml二甲苯和钛酸四丁酯3.40g(0.01mol)加入反应瓶中，加热回流分水，至无水分馏出，降至室温，过滤，洗涤，粗品用乙醇-水重结晶得DSC312。MS(ESI +,m/z):600.8M +， 1H NMR(DMSO-D6,400MHz)1.03(2s,6H)；1.43(s,9H)；1.9(bs,4H)；2.08(s,3H)；2.56(2d,4H)；2.78(t,2H)3.04(bs,4H)；3.77(t,2H)；4.33(t,2H)；4.41(t,2H)；7.10(d,J＝8.6Hz,1H)；7.44(d,J＝9.9Hz,1H)；7.48(d,J＝8.2Hz,1H)；7.55(s,1H)；7.63(s,1H)；7.66(d,J＝7.34Hz,1H)；7.78(d,J＝8.45Hz,2H)；7.97(d,J＝8.4Hz,2H)。
按照与上述实施例同样的方法，使用市售化合物或由市售化合物适当合成的中间体化合物，合成了下列实施例化合物。
Figure PCTCN2020132676-appb-000013
Figure PCTCN2020132676-appb-000014
Figure PCTCN2020132676-appb-000015
实施例4 制剂实施例
本实施例举例说明基于根据本发明的化合物的制剂。
1)0.005％的乳膏剂：
处方名称 处方用量
DSC303 5mg
尿囊素 0.2g
黄原胶 0.2g
环甲基硅酮 20g
乙醇 15g
中链甘油三酸酯 3g
苯氧乙醇 0.5g
丙二醇 25g
纯化水 加至100g
2)0.01％的乳膏剂
处方名称 处方用量
DSC310 10mg
甘油 20g
尿囊素 0.3g
羧甲基纤维素钠 3g
苯氧乙醇 0.8g
环甲基硅酮 15g
吐温80 7g
乙醇 20g
纯化水 加至100g
3)0.03％的乳膏剂
处方名称 处方用量
DSC312 30mg
甘油 25g
尿囊素 0.1g
单硬脂酸甘油酯 0.4g
苯氧乙醇 1g
二甲硅油 5g
吐温80 10g
乙醇 20g
纯化水 加至100g
4)0.05％的乳膏剂
处方名称 处方用量
DSC311 50mg
丙二醇 15g
尿囊素 0.2g
单硬脂酸甘油酯 0.4g
山梨酸 0.8g
环甲基硅酮 15g
卡波姆 0.3g
乙醇 30g
纯化水 加至100g
实施例5 效果实验：对油酸诱发的日本大耳白兔痤疮模型的影响试验研究
1、样品及动物信息
阳性对照Trifarotene，活性成分结构式如下：
Figure PCTCN2020132676-appb-000016
阳性对照组和实验组按照同样的方法制成乳膏。
日本大耳白兔(雄性，体重2.0～2.5kg)
2、实验方法
健康日本大耳白兔64只，体重2.0～2.5kg，全雄性。动物适应性饲养1周后按体重随机选取8只作为正常对照组，剩余56只白兔于耳道口外2cm处2×2cm2范围，每日涂煤焦油一次，厚度约为0.5mm(涂前先将煤焦油水浴加热融化，每次涂煤焦油前先将上次涂的煤焦油焦壳取下；正常对照组涂橄榄油，方法同前)。造模3周后，56只白兔按皮损程度轻重随机分为7组，分别为模型对照组、阳性对照组(Trifarotene)、DSC311组、DSC312组、DSC303组、DSC304组、DSC305组，每组8只。分组后，各剂量组每日上午继续涂煤焦油，下午去除煤焦油后在病损局部涂抹受试药物或对照药物(均为0.01％/10g膏，按1g膏/只涂抹)，1次/日，连续2周(模型对照组和正常对照组涂等量基质)。末次给药后24小时，空气栓塞处死动物，取耳部给药处皮肤(全层)，4％多聚甲醛溶液固定，HE染色，进行常规病理观察。
3、实验结果
3.1对实验性兔耳痤疮模型毛囊内角化物的影响
Figure PCTCN2020132676-appb-000017
*表示与模型对照组相比，P<0.05； **表示与模型对照组相比，P<0.01；
由上表可知，与模型对照组相比，DSC311、DSC312、DSC303、DSC304、DSC305各组兔耳毛囊内角化物均有所减小，但统计差异不显著。
3.2对实验性兔耳痤疮模型炎细胞浸润程度的影响
Figure PCTCN2020132676-appb-000018
**表示与模型对照组相比，P<0.01；
由上表可知，与模型对照组相比，DSC311、DSC312、DSC303、DSC304、DSC305各组兔耳炎细胞浸润程度有所改善，但统计差异不显著。
3.3对实验性兔耳痤疮模型角质层、表皮及皮脂腺增生的影响
Figure PCTCN2020132676-appb-000019
Figure PCTCN2020132676-appb-000020
Figure PCTCN2020132676-appb-000021
*表示与模型对照组相比，P<0.05； **表示与模型对照组相比，P<0.01；
由上表可知，与模型对照组相比，各实验组兔耳角质层厚度均有一个程度的减小，统计差异显著；
与模型对照组相比，各实验组兔耳表皮层厚度略有减小，但统计差异不显著；与模型对照组相比，DSC311、DSC312、DSC303、DSC304、DSC305各组兔耳皮脂腺大小均有所减小，统计学差异显著。这表明该类化合物可显著减轻实验性兔耳痤疮模型皮脂腺增生程度。

Claims (10)

  1. 一种如(I)所示的取代的间三联苯类化合物，或其药学上可接受的盐：
    Figure PCTCN2020132676-appb-100001
    式(I)中，Y为-(CH 2) n-，其中，n为1至16的整数；
    R 1和R 2各自独立地为氢，或者未取代的C 1-C 6烷基，或者被选自卤素、羟基或炔基中一种或多种的基团所取代的C 1-C 6烷基；
    R 3为氢或R 5-C(O)-，其中，R 5为未取代的C 1-C 10烷基、卤素取代的C 1-C 10烷基、未取代的C 3-C 6环烷基取代的C 1-C 10烷基、取代的C 3-C 6环烷基取代的C 1-C 10烷基、未取代C 1-C 10的烷氧基或取代的C 1-C 10烷氧基，所述取代的C 3-C 6环烷基是指被选自卤素、甲基、三氟甲基和二氟甲基中一种或多种所取代；取代的C 1-C 10烷氧基是指被选自卤素、甲基、三氟甲基和二氟甲基中一种或多种所取代；
    R 4为未取代的C 1-C 4烷基或三氟甲基。
  2. 根据权利要求1所述的取代的间三联苯类化合物，或其药学上可接受的盐，其特征在于，R 4为叔丁基。
  3. 根据权利要求1所述的取代的间三联苯类化合物，或其药学上可接受的盐，其特征在于，Y为-(CH 2) n-，n为1至5的整数，优选的，n为1、2或3。
  4. 根据权利要求1所述的取代的间三联苯类化合物，或其药学上可接受的盐，其特征在于，R 1和R 2各自独立地为C 1-C 3烷基；优选的，R 1和R 2各自独立地为乙基。
  5. 根据权利要求1所述的取代的间三联苯类化合物，或其药学上可接受的盐，其特征在于，R 3为氢。
  6. 根据权利要求1所述的取代的间三联苯类化合物，或其药学上可接受的盐，其特征 在于，R 3为R 5-C(O)-，其中，R 5为取代或未取代的C 1-C 4烷基，取代基选自以下一种或几种：卤素或C 3-C 6环烷基；在一种优选的实施方式中，R 5为甲基或乙基或叔丁基，更优选为甲基或叔丁基。
  7. 根据权利要求1所述的取代的间三联苯类化合物，或其药学上可接受的盐，其特征在于，选自下列化合物中的一种：
    Figure PCTCN2020132676-appb-100002
    Figure PCTCN2020132676-appb-100003
  8. 一种药物组合物，其以权利要求1～7任一项所述的化合物或其药学上可接受的盐为活性成分或主要活性成分，辅以药学上可接受的载体组成。
  9. 一种权利要求1～7任一项所述的化合物或其药学上可接受的盐的制备方法，
    Figure PCTCN2020132676-appb-100004
    其中，R 1、R 2、R 3、R 4和Y的定义如权利要求1所述。
  10. 权利要求1～7任一项所述的化合物或其药学上可接受的盐在用于制备预防和/或治疗皮肤疾病，所述皮肤疾病包括但不限于：寻常痤疮、粉刺、多形核白细胞、红斑痤疮、结节囊肿性痤疮、聚合性痤疮、老年痤疮、日光性痤疮、与药物治疗有关的痤疮或职业性痤疮；鳞癣、鱼鳞癣状的病症、毛囊角化病、掌跖角化病、白斑和白斑状病症、皮肤或粘液的(mucous)(口腔的)苔藓病；所有形式的牛皮癣，无论皮肤、粘液或指(趾)甲的牛皮癣，并且甚至是牛皮癣风湿，或皮肤的特异反应性，如湿疹，或呼吸特异反应性，或甚至齿龈肥大；干燥病；普通的疣、扁平疣和疣状表皮发育不良、口部或鲜红的乳头状瘤、T淋巴瘤、嗜碱细胞和棘细胞上皮瘤、角化棘皮瘤；免疫皮肤病，如红斑狼疮、免疫性大疱疾病和胶原病，如硬皮病；由局部或全身性皮质类甾醇诱导的表皮的斑点和/或皮肤萎缩，或任何其它形式的皮肤萎缩；皮脂 溢过多的痤疮或单纯皮脂溢；结瘢病症，或用于预防或修复伸长痕迹，或者用于促进结瘢；色素沉着病症，如色素沉着过度、黑斑病、色素沉着不足或白斑病。
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