CN114929678B

CN114929678B - Substituted m-terphenyl compound, and pharmaceutical composition and application thereof

Info

Publication number: CN114929678B
Application number: CN202080087268.7A
Authority: CN
Inventors: 张哲峰
Original assignee: Shijiazhuang Dikaiwei Pharmaceutical Technology Co ltd
Current assignee: Shijiazhuang Dikaiwei Pharmaceutical Technology Co ltd
Priority date: 2019-11-29
Filing date: 2020-11-30
Publication date: 2023-08-15
Anticipated expiration: 2040-11-30
Also published as: WO2021104515A1; CN117304136A; CN114929678A

Abstract

A substituted m-terphenyl compound, a pharmaceutical composition and application thereof are disclosed, wherein the substituted m-terphenyl compound is shown as a formula (I). The compounds are useful for the treatment or prevention of skin disorders.

Description

Substituted m-terphenyl compound, and pharmaceutical composition and application thereof

Technical Field

The application relates to the technical field of pharmaceutical chemistry, in particular to a substituted m-terphenyl compound, a pharmaceutical composition and application thereof.

Background

The French GALDERMA research and development company in International patent application (publication number WO2006066978A 1) discloses a tri-rotene that selectively modulates RAR-gamma, which has been approved by the U.S. FDA for use in the treatment of acne.

Disclosure of Invention

The application develops a substituted m-terphenyl compound which can be used for treating or preventing keratosis related diseases of cell differentiation or proliferation and skin diseases.

In one aspect, the present application provides a substituted meta-terphenyl compound as shown in (I), or a pharmaceutically acceptable salt thereof:

in the formula (I), Y is- (CH) ₂ ) _n -wherein n is an integer from 1 to 16;

R ₁ and R is ₂ Each independently is hydrogen, or unsubstituted C ₁ -C ₆ Alkyl, or C substituted by one or more groups selected from halogen, hydroxy or alkynyl ₁ -C ₆ An alkyl group;

R ₃ is hydrogen or R ₅ -C (O) -, wherein R ₅ Is unsubstituted C ₁ -C ₁₀ Alkyl, halogen substituted C ₁ -C ₁₀ Alkyl, unsubstituted C ₃ -C ₆ Cycloalkyl-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 with one or more selected from halogen, methyl, trifluoromethyl and difluoromethyl; substituted C ₁ -C ₁₀ Alkoxy means substituted with one or more selected from halogen, methyl, trifluoromethyl and difluoromethyl;

R ₄ is unsubstituted C ₁ -C ₄ Alkyl or trifluoromethyl.

In some embodiments, the present application provides substituted m-terphenyl compounds wherein R4 is tert-butyl.

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

In some embodiments, the present application provides substituted meta-terphenyl compounds wherein R ₁ And R is ₂ Each independently is C ₁ -C ₃ An alkyl group; in a preferred embodiment, R ₁ And R is ₂ Each independently is methyl or ethyl.

In some embodiments, the present application provides substituted meta-terphenyl compounds wherein R ₃ Is hydrogen.

In some embodiments, the present application provides substituted meta-terphenyl compounds wherein R ₃ Is R ₅ -C (O) -, wherein R ₅ Is substituted or unsubstituted C ₁ -C ₄ Alkyl, substituent is selected from one or more of the following: halogen or C ₃ -C ₆ Cycloalkyl; in a preferred embodiment, R ₅ Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, more preferably methyl or tert-butyl.

In some embodiments, the present application provides substituted meta-terphenyl compounds wherein Y is- (CH) ₂ ) _n -, n is 1, 2 or 3; r is R ₁ And R is ₂ Independently methyl or ethyl; r is R ₃ Is hydrogen or R ₅ -C(O)-，R ₅ Is methyl or tert-butyl, R ₄ Is tert-butyl.

In some embodiments, the substituted meta-terphenyl compound provided herein is selected from one of the following compounds:

in another aspect, the application provides pharmaceutical compositions comprising the above-described substituted meta-terphenyl compounds and pharmaceutically acceptable salts thereof.

The application discloses a pharmaceutical composition, which is composed of the compound or pharmaceutically acceptable salt thereof as an active ingredient or a main active ingredient and a pharmaceutically acceptable carrier.

In a third aspect, the present application also provides a process for the preparation of a substituted meta-terphenyl compound, the process comprising the steps of:

wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ And Y is as defined for the corresponding groups in formula (I).

In one embodiment, some compounds of formula I of the present application, for example, compounds of formula I-a when R4 is t-butyl, may also be synthesized by Trifarote:

wherein R is ₁ 、R ₂ 、R ₃ And Y is as defined above for the corresponding groups in formula (I).

The substituted m-terphenyl compound and the pharmaceutically acceptable salt thereof can be used for cell differentiation or proliferation of keratosis related diseases.

The application also provides application of the substituted m-terphenyl compound and pharmaceutically acceptable salt thereof in preparing medicaments for preventing and/or treating skin related diseases.

The application also provides application of the substituted m-terphenyl compound and pharmaceutically acceptable salt thereof in preparing medicines for preventing and/or treating skin related diseases.

The related diseases described herein are skin diseases including, but not limited to: acne vulgaris, comedones, polymorphonuclear leukocytes, rosacea, nodulocystic acne, acne conglobata, senile acne, solar acne, acne related to medication or occupational acne; ichthyosis, ichthyosis disorders, follicular keratosis, palmoplantar keratosis, leukoplakia and leukoplakia disorders, lichen (of the oral cavity) of the skin or mucous; all forms of psoriasis, whether psoriasis of the skin, mucous or nails, and even psoriatic rheumatism, or skin atopy, such as eczema, or respiratory atopy, or even gingival hypertrophy; xerosis; common warts, flat warts and epidermodysplasia verrucosa, oral or reddish papillomas, T lymphomas, basophils and acanthocellular epitheliomas, keratoacanthomas; immune skin diseases such as lupus erythematosus, immune bullous diseases, and collagenosis such as scleroderma; spots and/or skin atrophy of the epidermis induced by topical or systemic corticosteroids, or any other form of skin atrophy; acne with excessive seborrhea or simple seborrhea; cicatrization disorders, or for preventing or repairing elongation marks, or for promoting cicatrization; pigmentation disorders such as hyperpigmentation, melasma, hypopigmentation or vitiligo.

The substituted meta-terphenyl compounds of the present application can be formulated as pharmaceutical compositions for administration to patients in a variety of suitably selected modes of administration, including systemic, e.g., oral or parenteral, intravenous, intramuscular, transdermal, subcutaneous, and the like.

Definition:

forms part of the present application are pharmaceutically acceptable salts:

if the compounds of the present application are basic, suitable "pharmaceutically acceptable salts" include the conventional non-toxic salts of the compounds of the present application formed by the reaction of the compounds of the present application with inorganic or organic acids. For example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like are included, as well as salts derived from 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, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid and the like.

If the compounds of the present application are acidic, the appropriate "pharmaceutically acceptable salts" refers to salts of the compounds of the present application prepared by pharmaceutically acceptable non-toxic bases including inorganic 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.

The term "alkyl" means a saturated aliphatic radical of 1 to 20 carbon atoms, including straight and branched chain groups (the numerical ranges mentioned herein, e.g. "1 to 18", refer to such groups, which in this case are alkyl groups, which may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 18 carbon atoms). Alkyl groups may be substituted or unsubstituted. When substituted alkyl, the substituent is preferably one or more, more preferably 1 to 3, most preferably 1 or 2 substituents.

The term "hydroxy" denotes an-OH group.

The term "halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

The term "alkynyl" denotes a straight, branched or cyclic, non-aromatic hydrocarbon radical having a main chain containing from 12 to 18 carbon atoms and at least one carbon-carbon triple bond. Alkynyl includes ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like. The straight, branched or cyclic portion of an alkynyl group may contain a triple bond and this portion may be substituted if a substituted alkynyl group is indicated.

The term "cycloalkyl" means a single or fused ring of all carbons ("fused" ring means that each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system), wherein one or more of the rings does not have a fully attached pi-electron system, examples of cycloalkyl (without limitation) are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cycloheptatriene. Cycloalkyl groups may be substituted and unsubstituted.

The term "alkoxy" means-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.

The compounds of the present application are useful for the treatment or prevention of diseases associated with keratosis of cell differentiation or proliferation, and for the treatment or prevention of skin diseases.

Detailed Description

The following examples will allow one skilled in the art to more fully understand the application, but are not intended to limit the application in any way, the structures of all compounds being determined by NMR and MS.

Example 1

Step 1:

6.83g of Compound 1 and 7.8ml of triisopropyl borate were dissolved in toluene 20ml and THF18ml, and the vacuum/nitrogen substitution was performed 3 times. And (3) cooling the solution in a low-temperature tank at the temperature of minus 78 ℃, dropwise adding n-BuLi solution into the mixed liquid, keeping the internal temperature of the reaction liquid not to exceed minus 55 ℃, and continuing stirring at the low temperature until the reaction is finished.

The reaction mixture is raised to-35 ℃; 20mL of 3M H was added dropwise ₂ SO ₄ The method comprises the steps of carrying out a first treatment on the surface of the After warming to room temperature, 24ml of MTBE was added to dilute the organic phase, which was collected by pipetting. The organic phase was treated with 18.4ml of 3M H ₂ SO ₄ Washing for one time; the organic phase was extracted with 1M NaOH. The NaOH solution is diluted with 20.6mL of isopropanol and then cooled to 10 ℃; maintaining 15-20 ℃, and dropwise adding 27.2mL of 3M H ₂ SO ₄ To a pH of approximately 2; after the dripping is finished, stirring for 1h at 15 ℃ under the control of temperature; filtration, washing the filter cake (20 ml x 2) twice with water, drying the filter cake at 50 ℃ in vacuo for 48h, gives intermediate 2, yield: 77.2%, MS (ESI) ^- ，m/z)：227.2M ^- 。

Step 2:

a methanol solution of the intermediate 3 (22.8 g) is cooled to 0 ℃, 14.3g of dibromohydantoin (DBDMH) is added into the methanol solution in batches, and the internal temperature of the reaction solution is kept to be not more than 40 ℃; the resulting reaction mixture was stirred for 3 hours until the reaction was completed. 2.5g NaHSO was added to the reaction mixture ₃ Stirring for 15min; concentrating the reaction solution to remove most of methanol; stirring was continued for 5mins with 139mL of water and 100mL of petroleum ether dilution; separating and collecting an organic phase, washing the organic phase by using 143mL of water, 110mL1M NaOH,143mL water and 70mL of saline water to obtain a PE solution of the intermediate 4; na (Na) ₂ SO ₄ Drying; filtering the mixed solution, concentrating to dryness, and obtaining the intermediate 4 pure product by a column laminate. MS (ESI) ^- ，m/z)：306.1M ^- 。

Step 3:

intermediate 4 (30.7 g) was added to a 500ml reaction flask, acetic anhydride was added thereto and heated to reflux, 100ml of 33% hydrobromic acid solution was added dropwise, and the temperature was maintained for 18 hours after the addition. The system was concentrated to dryness and crystallized from isopropanol and water to give intermediate 5.MS (ESI) ^- ，m/z)：292.1M ^- 。

Step 4:

10.3g K ₂ CO ₃ dissolved in 22.6ml of water; 8.3g of intermediate 5, 6.92g of intermediate 2, THF 28.5ml were added to Na ₂ CO ₃ Deoxidizing the aqueous solution for 20min by bubbling nitrogen; adding catalyst PdCl ₂ (DTBPF) ₂ 0.184g, nitrogen displacement 3 times; stirring vigorously at 40 ℃ for 38h under the protection of nitrogen;

cooling to room temperature, adding 50ml of water, and stirring 50ml of PE for 15min; the organic phase is washed once with 60ml of water and once with saturated sodium chloride; adding a proper amount of anhydrous sodium sulfate and stirring for 1-2 h; the organic phase is passed rapidly through a column of about 4cm Gao Guijiao and eluted with about 300-400 ml of PE: THF=10:1→5:4; concentrating the mother solution, dissolving the residue with 100ml of n-heptane, stirring at room temperature for crystallization for 30min, and precipitating a lot of solids; slowly reducing the temperature to-15 ℃ and continuing crystallization for 4 hours; the mixture was filtered, and the filter cake was washed with ice n-heptane and dried at 45℃for 12h to give intermediate 6.MS (ESI) ^- ，m/z)：414.5M ^- 。

Step 5:

11.76g of Compound 6 were dissolved in DCMUnder the protection of nitrogen, drop into SOCl ₂ 6.74g of DCM was reacted for 2 hours, and the system was concentrated to dryness, then a suitable amount of THF was added, 8.68g of Compound II was added dropwise, and the reaction was continued for 5 hours. Concentrating the system to dryness, purifying with column chromatography to obtain compound 7, MS (ESI) ⁺ ，m/z)：515.7M ⁺ 。

Step 6:

14.75g of Compound 7 was dissolved in THF, cooled to 0℃and, under nitrogen protection, LDA solution was added dropwise thereto, after 2 hours of reaction, excess ethylene oxide was introduced and the reaction was continued for 5 hours. The system was quenched with water, concentrated to dryness and purified on column plates to give compound DSC303.MS (ESI) ⁺ ，m/z)：559.7M ⁺ ， ¹ H 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)。

Step 7:

5.59g of intermediate 8 was mixed with acetic anhydride, heated under reflux for 5 hours, and the system was concentrated to dryness, followed by column chromatography to give compound DSC304.MS (ESI) ⁺ ，m/z)：601.9M ⁺ ， ¹ H 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 of intermediate 9 was dissolved in THF, 1.81g of pivaloyl chloride was added under nitrogen protection, the system was heated under reflux for 5 hours, the system was concentrated to dryness, and column chromatography gave compound DSC305.MS (ESI) ⁺ ，m/z)：643.9M ⁺ ， ¹ H 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)。

EXAMPLE 2 preparation of DSC311 from Trifarotene

Trifarote (45.96 g,0.1 mol), N, N-diethylethanolamine (14.06 g,0.12 mol), 75mL of xylene and tetrabutyl titanate (3.40 g,0.01 mol) were added to a reaction flask, heated to reflux and split until anhydrous, cooled to room temperature, stirred for 1 hour, filtered, washed, and the crude product recrystallized from ethanol to give DSC311.MS (ESI) ⁺ ，m/z)：558.8M ⁺ ， ¹ H 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)。

EXAMPLE 3 preparation of DSC312 from Trifarotene

Step 1:

trifarote 45.96g (0.1 mol), acetonitrile 50ml and pyridine 39.55g (0.5 mol) are added into a reaction bottle, the reaction mixture is heated to 35 ℃, acetic anhydride 20.42g (0.2 mol) is added dropwise at 35-40 ℃, after the completion of the dropwise addition, the reaction is carried out for 4 hours at 50 ℃, the temperature is reduced to room temperature, water 100ml is added into the reaction mixture, and the mixture is stirred for 1 hourFiltering, washing with water, and drying to obtain Tri-1, MS:501.6[ M+H ]] ⁺ 。

Step 2:

tri-1.16 g (0.1 mol), N-diethyl ethanolamine 14.06g (0.12 mol), 75ml xylene and tetrabutyl titanate 3.40g (0.01 mol) are added into a reaction bottle, water is heated and refluxed until no water is separated out, the temperature is reduced to room temperature, the filtration and the washing are carried out, and the crude product is recrystallized by ethanol-water to obtain DSC312.MS (ESI) ⁺ ，m/z)：600.8M ⁺ ， ¹ H 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)。

The following examples were synthesized in the same manner as in the above examples, using commercially available compounds or intermediate compounds appropriately synthesized from the commercially available compounds.

Example 4 formulation example

This example illustrates a formulation based on a compound according to the application.

1) 0.005% cream:

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	To 100g

2) 0.01% of cream

3) 0.03% of cream

Prescription name	Prescription dosage
		DSC312	30mg
Glycerol	25g
		Allantoin	0.1g
Glyceryl monostearate	0.4g
		Phenoxyethanol	1g
Simethicone	5g
		Tween 80	10g
Ethanol	20g
		Purified water	To 100g

4) 0.05% of cream

Prescription name	Prescription dosage
		DSC311	50mg
Propylene glycol	15g
		Allantoin	0.2g
Glyceryl monostearate	0.4g
		Sorbic acid	0.8g
Cyclomethicone	15g
		Carbomer (carbomer)	0.3g
Ethanol	30g
		Purified water	To 100g

Example 5 effect experiment: experimental study on Effect of oleic acid-induced acne model of Japanese white rabbits

1. Sample and animal information

The positive control Trifarotene has the following structural formula of the active ingredient:

the positive control group and the experimental group were prepared into cream in the same manner.

Japanese big ear white rabbit (Male, weight 2.0-2.5 kg)

2. Experimental method

64 healthy Japanese white rabbits with weight of 2.0-2.5 kg and complete male. After the animals are adaptively raised for 1 week, 8 animals are randomly selected as a normal control group according to the weight, the rest 56 white rabbits are coated with coal tar once a day within a range of 2X 2cm < 2 > at a position which is 2cm outside the auditory meatus, and the thickness is about 0.5mm (the coal tar is heated and melted in a water bath before being coated, the last coated coal tar coke shell is removed before each coal tar coating, and the normal control group is coated with olive oil, and the method is the same as the above). After 3 weeks of molding, 56 white rabbits were randomly divided into 7 groups according to the skin loss degree, namely, a model control group, a positive control group (Trifarote), a DSC311 group, a DSC312 group, a DSC303 group, a DSC304 group and a DSC305 group, and 8 animals each. After grouping, each dose group was continuously coated with coal tar in the morning, and after coal tar removal in the afternoon, the lesion was locally coated with the test drug or the control drug (each 001%/10g of paste, 1g of paste per day), 1 time/day, and 2 weeks continuously (the model control group and the normal control group were coated with the same amount of matrix). 24 hours after the last administration, animals were sacrificed by air embolism, the skin (full layer) at the ear administration site was taken, 4% paraformaldehyde solution was fixed, HE stained, and conventional pathological observation was performed.

3. Experimental results

3.1 Effect on the internal corner of the hair follicle in the Experimental Lagotis acne model

^* P < 0.05 compared with the model control group; ^** p < 0.01 compared with the model control group;

as can be seen from the above table, the number of the follicles of rabbit ears in each of the groups DSC311, DSC312, DSC303, DSC304, and DSC305 was reduced as compared with the model control group, but the statistical difference was not significant.

3.2 Effect on the degree of infiltration of inflammatory cells in the Experimental rabbit ear acne model

^** P < 0.01 compared with the model control group;

as is clear from the above table, the degrees of infiltration of the rabbit earinflammatory cells were improved in each of the DSC311, DSC312, DSC303, DSC304, and DSC305 groups, but the statistical differences were not significant, as compared with the model control group.

3.3 Effect on experimental Lagotis acne model stratum corneum, epidermis and sebaceous gland hyperplasia

as can be seen from the above table, compared with the model control group, the thickness of the stratum corneum of the rabbit ears of each experimental group is reduced to a certain extent, and the statistical difference is obvious;

compared with the model control group, the thickness of the rabbit ear epidermis layer of each experimental group is slightly reduced, but the statistical difference is not obvious; the individual groups of DSC311, DSC312, DSC303, DSC304, and DSC305 all had a reduced sebaceous gland size compared to the model control group, and the statistical differences were significant. This shows that the compounds can significantly reduce the degree of sebaceous gland hyperplasia of experimental rabbit ear acne model.

Claims

1. A method for preparing a substituted m-terphenyl compound shown in (I) or pharmaceutically acceptable salt thereof:

in the formula (I), the formula M-8 and the formula M-7, Y is- (CH) ₂ ) _n -wherein n is an integer from 1 to 16;

in the formula (I), the formula M-8 and the formula M-7, R ₁ And R is ₂ Each independently is hydrogen, or unsubstituted C ₁ -C ₆ Alkyl, or C substituted by one or more groups selected from halogen, hydroxy or alkynyl ₁ -C ₆ An alkyl group;

in the formula (I), R ₃ Is hydrogen or R ₅ -C (O) -, wherein R ₅ Is unsubstituted C ₁ -C ₁₀ Alkyl, halogen substituted C ₁ -C ₁₀ Alkyl, unsubstituted C ₃ -C ₆ Cycloalkyl-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 with one or more selected from halogen, methyl, trifluoromethyl and difluoromethyl; substituted C ₁ -C ₁₀ Alkoxy means substituted with one or more selected from halogen, methyl, trifluoromethyl and difluoromethyl;

in the formula (I), the formula M-1, the formula M-2, the formula M-6 and the formula M-7, R ₄ Is unsubstituted C ₁ -C ₄ Alkyl or trifluoromethyl.

2. The process according to claim 1, wherein R is selected from the group consisting of formula (I), formula M-1, formula M-2, formula M-6 and formula M-7 ₄ Is tert-butyl.

3. The process of claim 1, wherein in formula (I), formula M-8 and formula M-7, Y is- (CH) ₂ ) _n -n is an integer from 1 to 5.

4. The process according to claim 3, wherein in the formulae (I), (M-8) and (M-7), Y is- (CH) ₂ ) _n -n is 1, 2 or 3.

5. The process according to claim 1, wherein R is selected from the group consisting of formula (I), formula M-8 and formula M-7 ₁ And R is ₂ Each independently is C ₁ -C ₃ An alkyl group.

6. The process according to claim 5, wherein R is selected from the group consisting of formula (I), formula M-8 and formula M-7 ₁ And R is ₂ Each independently is ethyl.

7. The process according to claim 1, wherein in formula (I), R ₃ Is hydrogen.

8. The process according to claim 1, wherein in formula (I), R ₃ Is R ₅ -C (O) -, wherein R ₅ Is substituted or unsubstituted C ₁ -C ₄ Alkyl, substituent is selected from one or more of the following: halogen or C ₃ -C ₆ Cycloalkyl groups.

9. The process according to claim 8, wherein in formula (I), R ₃ Is R ₅ -C (O) -, wherein,

R ₅ methyl, ethyl or tert-butyl.

10. The process according to claim 8, wherein in formula (I), R ₃ Is R ₅ -C (O) -, wherein,

R ₅ is methyl or tert-butyl.

11. The process according to claim 1, wherein the compound of formula (I) is selected from one of the following compounds: