A substituted m-terphenyl compound, pharmaceutical composition thereof and use thereof

Abstract

The application discloses a substituted meta-triphenyl compound, a pharmaceutical composition thereof and application, and the substituted meta-triphenyl compound is shown as formula (I). The compound can be used for treating or preventing skin diseases.

Description

[0001] This application is a divisional application of the application with the application number 202080087268.7, the application date of November 30, 2020, and the title of "A substituted m-triphenyl compound and its pharmaceutical composition and use". TECHNICAL FIELD

[0002] The present application relates to, but not limited to, the technical field of pharmaceutical chemistry, and particularly relates to a substituted m-triphenyl compound and its pharmaceutical composition and use. BACKGROUND

[0003] The French GALDERMA Research and Development Company discloses a trifarotene for selectively regulating RAR-gamma in the patent international application (publication number WO2006066978A1), and the compound has been approved by the US FDA for marketing for treating acne. SUMMARY

[0004] The present application develops a substituted m-triphenyl compound, which can be used for cell differentiation or proliferation of keratinization disease related diseases, and for treating or preventing skin diseases.

[0005] In one aspect, the present application provides a substituted m-triphenyl compound as shown in formula (I), or a pharmaceutically acceptable salt thereof:

[0006]

[0007] In formula (I), Y is -(CH2) n , wherein n is an integer from 1 to 16;

[0008] R1 and R2 are each independently hydrogen, or unsubstituted C1-C6 alkyl, or C1-C6 alkyl substituted with one or more groups selected from halogen, hydroxyl or alkynyl;

[0009] R3 is hydrogen or R5-C(O)-, wherein R5 is unsubstituted C1-C 10 alkyl, halogen-substituted C1-C 10 alkyl, unsubstituted C3-C6 cycloalkyl-substituted C1-C 10 alkyl, substituted C3-C6 cycloalkyl-substituted C1-C 10 alkyl, unsubstituted C1-C 10 alkoxy or substituted C1-C 10 alkoxy, the substituted C3-C6 cycloalkyl refers to being substituted with one or more groups selected from halogen, methyl, trifluoromethyl and difluoromethyl; the substituted C1-C 10 alkoxy refers to being substituted with one or more groups selected from halogen, methyl, trifluoromethyl and difluoromethyl;

[0010] R4 is unsubstituted C1-C4 alkyl or trifluoromethyl.

[0011] In some embodiments, the application provides substituted meta-terphenyl compounds, wherein R4 is t-butyl.

[0012] In some embodiments, the application provides substituted meta-terphenyl compounds, wherein Y is -(CH2)n- and n is an integer from 1 to 5, in a preferred embodiment n is 1, 2 or 3. n In some embodiments, the application provides substituted meta-terphenyl compounds, wherein Y is -(CH2)n- and n is an integer from 1 to 5, in a preferred embodiment n is 1, 2 or 3.

[0013] In some embodiments, the application provides substituted meta-terphenyl compounds, wherein R1 and R2 are each independently C1-C3 alkyl; in a preferred embodiment R1 and R2 are each independently methyl or ethyl.

[0014] In some embodiments, the application provides substituted meta-terphenyl compounds, wherein R3 is hydrogen.

[0015] In some embodiments, the application provides substituted meta-terphenyl compounds, wherein R3 is R5-C(O)-, wherein R5 is substituted or unsubstituted C1-C4 alkyl, the substituents being selected from one or more of halogen or C3-C6 cycloalkyl; in a preferred embodiment R5 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl, more preferably methyl or t-butyl.

[0016] In some embodiments, the application provides substituted meta-terphenyl compounds, wherein Y is -(CH2)n- and n is an integer from 1 to 5, in a preferred embodiment n is 1, 2 or 3. n In some embodiments, the application provides substituted meta-terphenyl compounds, wherein Y is -(CH2)n- and n is an integer from 1 to 5, in a preferred embodiment n is 1, 2 or 3; R1 and R2 are independently methyl or ethyl; R3 is hydrogen or R5-C(O)-, R5 is methyl or t-butyl, and R4 is t-butyl.

[0017] In some embodiments, the application provides substituted meta-terphenyl compounds as described above, selected from one of the following compounds:

[0018]

[0019]

[0020]

[0021] In another aspect, the application provides pharmaceutical compositions comprising the above-mentioned substituted meta-terphenyl compounds and pharmaceutically acceptable salts thereof.

[0022] The present application discloses a pharmaceutical composition, which comprises a compound or a pharmaceutically acceptable salt thereof as an active ingredient or a main active ingredient, and a pharmaceutically acceptable carrier.

[0023] In a third aspect, the present application provides a preparation route of the substituted m-triphenyl compounds, which comprises the following steps:

[0024]

[0025]

[0026] wherein R1, R2, R3, R4 and Y are defined as the corresponding groups in formula (I).

[0027] In one embodiment, some compounds of formula I, such as the compound of formula I-a, wherein R4 is tert-butyl, can be synthesized by Trifarotene:

[0028]

[0029] wherein R1, R2, R3 and Y are defined as the corresponding groups in formula (I).

[0030] The substituted m-triphenyl compounds and the pharmaceutically acceptable salts thereof can be used for the treatment of keratinization-related diseases associated with cell differentiation or proliferation.

[0031] In a third aspect, the present application provides a preparation route of the substituted m-triphenyl compounds, which comprises the following steps:

[0032] The present application also provides the use of the substituted m-triphenyl compounds and the pharmaceutically acceptable salts thereof in the preparation of a medicament for preventing and / or treating skin-related diseases.

[0033] The diseases related to the present application are skin diseases, including but not limited to: acne vulgaris, comedones, polymorphonuclear leukocytes, rosacea, nodulocystic acne, conglobata acne, senile acne, solar acne, acne related to medication or occupational acne; ichthyosis, ichthyosiform conditions, Darier's disease, palmoplantar keratoderma, leukoplakia and leukoplakiform conditions, cutaneous or mucous (buccal) lichen; all forms of psoriasis, whether cutaneous, mucous or ungual, and even psoriatic rheumatism, or cutaneous atopy, such as eczema, or respiratory atopy, or even gingival hypertrophy; xeroderma; common warts, flat warts and verruciform epidermodysplasia, oral or erythroplastic papillomas, T lymphomas, baso- and spinocellular epitheliomas, keratoacanthomas; immunocutaneous diseases, such as lupus erythematosus, immunobullous diseases and collagen diseases, such as scleroderma; cutaneous macules and / or atrophy of the epidermis induced by topical or systemic corticosteroids, or any other form of cutaneous atrophy; hyperseborrhoeic acne or simple seborrhoea; cicatrization disorders, or for preventing or repairing stretch marks, or for promoting cicatrization; pigmentation disorders, such as hyperpigmentation, melasma, hypopigmentation or vitiligo.

[0034] The substituted m-triphenyls of the present application can be formulated into pharmaceutical compositions and administered to a patient in a variety of suitable chosen modes of administration, including systemic, e.g., orally or parenterally, by intravenous, intramuscular, transdermal or subcutaneous injection, etc.

[0035] Definitions:

[0036] Included as a part of the present application are pharmaceutically acceptable salts:

[0037] If the compounds of the present application are basic, suitable "pharmaceutically acceptable salts" include conventional nontoxic salts of the compounds of the present application which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and 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, sulfanilic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid and the like.

[0038] If the compounds of the present application are acidic, suitable "pharmaceutically acceptable salts" refers to the salts of the compounds of the present application with pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from organic bases include salts of primary, secondary, and tertiary amines, substituted amines with straight chain alkyl groups of 1 to 6 carbon atoms, branched alkyl groups of 3 to 6 carbon atoms, cyclic alkyl groups of 3 to 6 carbon atoms, as well as aryl groups, such as benzyl, substituted benzyl, phenyl and the like.

[0039] The term "alkyl" denotes a saturated aliphatic radical of 1 to 20 carbon atoms, including straight chain and branched groups (the numerical ranges referred to in this application, for example "1 to 18", mean that the group, in this case alkyl, can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on, up to and including 18 carbon atoms). The alkyl group can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably 1 to 3, most preferably 1 or 2 substituents.

[0040] The term "hydroxy" denotes an -OH group.

[0041] The term "halogen" denotes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0042] The term "alkynyl" denotes a straight chain, branched or cyclic, non-aromatic hydrocarbon group having 12 to 18 carbon atoms in the main chain and at least one carbon-carbon triple bond. Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl and the like. The straight chain, branched or cyclic portion of the alkynyl group can contain the triple bond and, if a substituted alkynyl group is specified, this portion can be substituted.

[0043] The term "cycloalkyl" denotes a monocyclic or fused ring ("fused" ring means that each ring in the system shares a pair of adjacent carbon atoms with another ring in the system) group of all carbon, in which one or more rings do not have a fully conjugated pi-electron system, examples of cycloalkyl groups (without limitation) are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane and cycloheptatriene. Cycloalkyl groups can be substituted and unsubstituted.

[0044] The term "alkoxy" denotes -O-(unsubstituted alkyl) and -O-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy and the like.

[0045] The compounds described in the present application can be used for keratinization-related diseases of cell differentiation or proliferation, for the treatment or prevention of skin diseases. DETAILED DESCRIPTION

[0046] The following examples can enable a person skilled in the art to more fully understand the present application, but in no way limit the present application, and the structures of all compounds are determined by NMR and MS.

[0047] Example 1

[0048]

[0049]

[0050] Step 1:

[0051] 6.83g of Compound 1 and 7.8ml of boronate triisopropyl ester were dissolved in 20ml of toluene and 18ml of THF, vacuum / nitrogen was replaced for 3 times. The solution was cooled in a -78°C low temperature bath, n-BuLi solution was added dropwise into the mixture, the temperature of the reaction solution was kept below -55°C, and the low temperature stirring was continued until the reaction was completed.

[0052] The reaction mixture was raised to -35°C; 20ml of 3M H2SO4 was added dropwise; after being raised to room temperature, 24ml of MTBE was added to dilute the organic phase, and the organic phase was collected by liquid separation. The organic phase was washed once with 18.4ml of 3M H2SO4; the organic phase was extracted with 1M NaOH. The NaOH solution was diluted with 20.6ml of isopropyl alcohol, and then cooled to 10°C; 27.2ml of 3M H2SO4 was added dropwise to pH≈2 while maintaining the temperature at 15-20°C; after the dropwise addition was completed, the temperature was controlled at 15°C for 1h of stirring; the filter cake was washed twice with water (20ml*2), and the filter cake was dried in vacuum at 50°C for 48h to obtain the intermediate 2, yield: 77.2%, MS (ESI-, m / z): 227.2M-. - ,m / z):227.2M - .

[0053] Step 2:

[0054] The methanol solution of the intermediate 3 (22.8g) was cooled to 0°C, and DBDMH 14.3g was added portionwise into the solution while keeping the temperature of the reaction solution below 40°C; the obtained reaction mixture was continuously stirred for 3h until the reaction was completed. 2.5g of NaHSO3 was added into the reaction mixture, and stirred for 15min; the reaction solution was concentrated to remove most of the methanol; 139ml of water and 100ml of petroleum ether were used for dilution and continued stirring for 5min; the organic phase was collected by liquid separation, and the organic phase was washed with 143ml of water, 110ml of 1M NaOH, 143ml of water, and 70ml of brine to obtain the PE solution of the intermediate 4; Na2SO4 was used for drying; the mixture was filtered, concentrated to dryness, and column chromatography was used to obtain the pure intermediate 4. MS (ESI-, m / z): 306.1M-.

[0055] Step 3:

[0056] The intermediate 4 (30.7g) was added into a 500ml reaction flask, and acetic anhydride was added for heating reflux, and 100ml of 33% hydrobromic acid solution was added dropwise, and the temperature was maintained for 18h after the dropwise addition was completed. The system was concentrated to dryness, and isopropyl alcohol and water were used for crystallization to obtain the intermediate 5. MS (ESI-, m / z): 292.1M-.

[0057] Step 4:

[0058] 10.3 g K2CO3 was dissolved in 22.6 ml water; 8.3 g of intermediate 5, 6.92 g of intermediate 2, THF 28.5 ml were added to the aqueous Na2CO3 solution, and deoxygenated by bubbling nitrogen for 20 min; 20.184 g of catalyst PdCl2(DTBPF) was added, and replaced by nitrogen for 3 times; under nitrogen protection, the system was stirred vigorously at 40°C for 38 h;

[0059] After cooling to room temperature, 50 ml of water and 50 ml of PE were added, and stirred for 15 min; the organic phase was washed with 60 ml of water once and saturated sodium chloride once; an appropriate amount of anhydrous sodium sulfate was added, and stirred for 1-2 h; the organic phase was quickly passed through a silica gel column about 4 cm high, and eluted with PE:THF=10:1→5:4 about 300-400 ml; the mother liquor was concentrated, and the residue was dissolved with 100 ml of n-heptane, and stirred at room temperature for 30 min to crystallize; a large amount of solid was precipitated; slowly cooled to -15°C, and continue to crystallize for 4 h; filtered, and the filter cake was washed with ice n-heptane, and dried at 45°C for 12 h to obtain intermediate 6. MS (ESI-, m / z): 414.5 M-.

[0060] Step 5:

[0061] 11.76 g of compound 6 was dissolved in DCM, and 6.74 g of SOCl2 in DCM was added dropwise under nitrogen protection; after 2 h of reaction, the system was concentrated to dryness; an appropriate amount of THF was added, and 8.68 g of compound II was added dropwise; after 5 h of reaction, the system was concentrated to dryness, and column chromatography was performed to obtain compound 7. MS (ESI + ,m / z): 515.7 M + .

[0062] Step 6:

[0063] 14.75 g of compound 7 was dissolved in THF and cooled to 0°C; under nitrogen protection, an LDA solution was added dropwise; after 2 h of reaction, excess ethylene oxide was introduced, and reacted for 5 h; the system was quenched with water, and concentrated to dryness; column chromatography was performed to obtain compound DSC303. MS (ESI + ,m / z): 559.7 M + , 1HNMR (DMSO-D6, 400 MHz) 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 = 8.6 Hz, IH); 7.4 (d, J = 9.9 Hz, IH); 7.45 (d, J = 8.2 Hz, IH); 7.55 (s, IH); 7.62 (s, IH); 7.68 (d, J = 7.34 Hz, IH); 7.80 (d, J = 8.45 Hz, 2H); 7.97 (d, J = 8.4 Hz, 2H).

[0064] Step 7:

[0065] 5.59g of intermediate 8 was mixed with acetic anhydride and heated to reflux for 5 hours. The system was concentrated to dryness and column chromatography was used to obtain compound DSC304. MS (ESI + , m / z): 601.9 M + , 1 HNMR (DMSO-D6, 400 MHz) 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 = 8.6 Hz, IH); 7.4 (d, J = 9.9 Hz, IH); 7.45 (d, J = 8.2 Hz, IH); 7.55 (s, IH); 7.62 (s, IH); 7.68 (d, J = 7.34 Hz, IH); 7.80 (d, J = 8.45 Hz, 2H); 7.97 (d, J = 8.4 Hz, 2H).

[0066] 5.59g of intermediate 9 was dissolved in THF and 1.81g of pivaloyl chloride was added under nitrogen protection. The system was heated to reflux for 5 hours. The system was concentrated to dryness and column chromatography was used to obtain compound DSC305. MS (ESI + , m / z): 643.9 M + , 1H NMR (DMSO-D6, 400 MHz) 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 = 8.6 Hz, IH); 7.38 (d, J = 9.9 Hz, IH); 7.45 (d, J = 8.2 Hz, IH); 7.56 (s, IH); 7.62 (s, IH); 7.68 (d, J = 7.34 Hz, IH); 7.82 (d, J = 8.45 Hz, 2H); 7.98 (d, J = 8.4 Hz, 2H).

[0067] Example 2 Preparation of DSC311 from Trifarotene

[0068]

[0069] Trifarotene (45.96 g, 0.1 mol), N,N-diethylethanolamine (14.06 g, 0.12 mol), 75 mL of xylene and tetrabutyl titanate (3.40 g, 0.01 mol) were added to a reaction flask, heated to reflux to remove water, cooled to room temperature, stirred for 1 hour, filtered, washed, and the crude product recrystallized from ethanol to give DSC311. MS (ESI + , m / z): 558.8 M + , 1 H NMR (DMSO-D6, 400 MHz) 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, IH); 7.12 (d, J = 8.6 Hz, IH); 7.4 (d, J = 9.9 Hz, IH); 7.45 (d, J = 8.2 Hz, IH); 7.55 (s, IH); 7.63 (s, IH); 7.66 (d, J = 7.34 Hz, IH); 7.78 (d, J = 8.45 Hz, 2H); 7.98 (d, J = 8.4 Hz, 2H).

[0070] Example 3 Preparation of DSC312 from Trifarotene

[0071]

[0072]

[0073] Step 1:

[0074] Into a reaction flask was added Trifarotene 45.96g (0.1 mol), acetonitrile 50ml and pyridine 39.55g (0.5 mol), the reaction mixture was heated to 35°C, acetic anhydride 20.42g (0.2 mol) was added dropwise at 35-40°C, after the addition was completed, the reaction was carried out at 50°C for 4 hours, it was cooled to room temperature, water 100ml was added to the reaction mixture, stirred for 1 hour, filtered, washed with water, and dried to give Tri-1, MS: 501.6 [M+H] + .

[0075] Step 2:

[0076] Into a reaction flask was added Tri-1 50.16g (0.1 mol), N,N-diethylethanolamine 14.06g (0.12 mol), 75ml xylene and tetrabutyl titanate 3.40g (0.01 mol), heated to reflux and distilled water, until no water distilled out, cooled to room temperature, filtered, washed, and the crude product was recrystallized with ethanol-water to give DSC312. MS (ESI + , m / z): 600.8 M + , 1 HNMR (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 = 8.6 Hz, IH); 7.44 (d, J = 9.9 Hz, IH); 7.48 (d, J = 8.2 Hz, IH); 7.55 (s, IH); 7.63 (s, IH); 7.66 (d, J = 7.34 Hz, IH); 7.78 (d, J = 8.45 Hz, 2H); 7.97 (d, J = 8.4 Hz, 2H).

[0077] The following example compounds were synthesized according to the same method as the above examples, using commercially available compounds or intermediate compounds synthesized appropriately from commercially available compounds.

[0078]

[0079]

[0080]

[0081] Formulation Example of Example 4

[0082] This example illustrates a formulation based on a compound according to the present application.

[0083] 1) 0.005% cream

[0084] Prescription Name Prescription Amount DSC303 5 mg Allantoin 0.2g Xanthan Gum 0.2g Cyclo-methicone 20g Ethanol 15g Medium Chain Triglycerides 3g Phenoxyethanol 0.5g Propylene Glycol 25g Purified Water q.s. 100 g

[0085] 2) 0.01% cream

[0086]

[0087]

[0088] 3) 0.03% cream

[0089] Prescription Name Prescription Amount DSC312 30 mg Glycerin 25g Allantoin 0.1g Glyceryl Monostearate 0.4g Phenoxyethanol 1g Dimethicone 5g Tween 80 10g Ethanol 20g Purified Water q.s. 100 g

[0090] 4) 0.05% cream

[0091] Prescription Name Prescription Amount DSC311 50 mg Propylene Glycol 15g Allantoin 0.2g Glyceryl Monostearate 0.4g Sorbic Acid 0.8g Cyclo-methicone 15g Carbomer 0.3g Ethanol 30g Purified Water q.s. 100 g

[0092] Example 5 Effect Test: Study on the effect on the acne model of Japanese white rabbits induced by oleic acid

[0093] 1. Sample and animal information

[0094] The positive control Trifarotene has the following structure of active ingredient:

[0095]

[0096] The positive control group and the experimental group were prepared into creams according to the same method.

[0097] Japanese white rabbits (male, body weight 2.0-2.5 kg)

[0098] 2. Experimental method

[0099] Healthy Japanese white rabbits, 64, 2.0-2.5 kg, all male. After 1 week of adaptive feeding, 8 were randomly selected as normal control group according to body weight, and the remaining 56 white rabbits were coated with coal tar once a day at 2 cm outside the ear canal, with a thickness of about 0.5 mm (before coating, the coal tar was heated and melted in a water bath, and the coal tar shell was removed before each coating; the normal control group was coated with olive oil, the same as before). After 3 weeks of modeling, 56 white rabbits were randomly divided into 7 groups according to the severity of skin lesions, namely model control group, positive control group (Trifarotene), DSC311 group, DSC312 group, DSC303 group, DSC304 group, DSC305 group, 8 in each group. After grouping, each dose group continued to coat coal tar in the morning, and after removing the coal tar in the afternoon, the test drug or control drug (0.01% / 10 g paste, 1 g paste per rabbit) was applied to the local lesion, 1 time / day, for 2 weeks (the model control group and the normal control group were coated with the same amount of matrix). 24 hours after the last administration, the animals were sacrificed by air embolism, and the ear skin (full-thickness) was taken and fixed with 4% paraformaldehyde solution, stained with HE, and observed by routine pathology.

[0100] 3. Results of the experiment

[0101] 3.1 Effect on the keratinous plugs in the hair follicles of the experimental rabbit ear acne model

[0102]

[0103] * P < 0.05 compared with the model control group; ** P < 0.01 compared with the model control group;

[0104] As can be seen from the above table, compared with the model control group, the keratinous plugs in the hair follicles of the DSC311, DSC312, DSC303, DSC304, and DSC305 groups were reduced, but the statistical difference was not significant.

[0105] 3.2 Effect on the inflammatory cell infiltration degree of the experimental rabbit ear acne model

[0106]

[0107] ** P < 0.01 compared with the model control group;

[0108] As can be seen from the above table, compared with the model control group, the inflammatory cell infiltration degree of the DSC311, DSC312, DSC303, DSC304, and DSC305 groups was improved, but the statistical difference was not significant.

[0109] 3.3 Effects on the hyperplasia of stratum corneum, epidermis and sebaceous glands in the experimental rabbit ear acne model

[0110]

[0111]

[0112] * P < 0.05 compared with the model control group; ** P < 0.01 compared with the model control group;

[0113] From the above table, it can be seen that the stratum corneum thickness of the rabbit ears in each experimental group was reduced to a certain extent, and the statistical difference was significant compared with the model control group; the epidermis thickness of the rabbit ears in each experimental group was slightly reduced compared with the model control group, but the statistical difference was not significant; the size of the sebaceous glands of the rabbit ears in the DSC311, DSC312, DSC303, DSC304 and DSC305 groups was reduced, and the statistical difference was significant compared with the model control group. This indicates that the compounds can significantly reduce the degree of sebaceous gland hyperplasia in the experimental rabbit ear acne model.

Claims

1. A substituted meta-terphenyl compound, or a pharmaceutically acceptable salt thereof, characterized in that, Selected from one of the following compounds:

2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient or a major active ingredient, supplemented by a pharmaceutically acceptable carrier.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 2 in the preparation of a medicament for the prevention and / or treatment of skin diseases.

Images