WO2023071601A1

WO2023071601A1 - Desloratadine derivative, preparation method therefor and application thereof

Info

Publication number: WO2023071601A1
Application number: PCT/CN2022/119480
Authority: WO
Inventors: 姚晨
Original assignee: 天津市昕晨投资发展有限公司
Priority date: 2021-10-28
Filing date: 2022-09-16
Publication date: 2023-05-04
Also published as: CN115385892A

Abstract

Disclosed in the present application is a compound as represented by formula (A), wherein-R is-R' or -Y-(CH₂)_n-R', Y is O or NH, n is 1, 2, 3, 4, 5 or 6, and -R' is diethylamino, pyrrolidinyl, piperazinyl, N-morpholinyl, bis(2-methoxyethyl)amino or 4-methylpiperazinyl. Also disclosed are a synthesis method for the compound shown, and use of the compound shown in the preparation of drugs for relieving or treating or preventing allergy and related symptoms thereof.

Description

Desloratadine derivative, its preparation method and use

technical field

The present application relates to the field of chemical synthesis, and more specifically relates to a desloratadine derivative, its preparation method and its application.

Background technique

Loratadine is a long-acting non-sedative tricyclic second-generation antihistamine. Developed by Schering Plow of the United States, it was first launched in Belgium in March 1988. Loratadine is currently the best-selling H1 receptor antagonist (Histamine H1 Receptor Antagonists) due to its low cardiotoxicity and good curative effect on allergic diseases such as seasonal rhinitis, perennial rhinitis and chronic urticaria. Desloratadine is a tricyclic long-acting third-generation histamine antagonist.

However, although loratadine and desloratadine have been widely used, those skilled in the art are still researching to find alternative drugs, or even similar drugs with better effects.

Contents of the invention

In one aspect, the application provides a compound of formula (A),

Wherein, the -R is selected from at least one of -R' and -Y-(CH ₂ ) _n -R'; the Y is selected from at least one of O and NH, and the n is selected from 1, 2 , 3, 4, 5, and at least one of the group consisting of 6; and said -R' is selected from diethylamino

pyrrolidinyl

Piperazinyl

N-morpholinyl

Bis(2-methoxyethyl)amino

and 4-methylpiperazinyl

at least one of the group consisting of.

In one aspect, the application provides a method for synthesizing the compound of formula (A). Including: contacting desloratadine with X(CH ₂ ) _n YC(=O)Cl to obtain the compound of formula (B); and contacting the compound of formula (B) with compound H–R′ to obtain the compound of formula (A) compound,

Wherein, X is selected from at least one of Cl and Br.

In some embodiments, a method for synthesizing the compound of formula (A) is provided, comprising: reacting compound H—R and desloratadine as reactants to obtain the compound of formula (A).

In one aspect, the application provides the use of the compound of formula (B) in the preparation of the compound of formula (A).

In one aspect, the application provides the use of compound H—R in the preparation of a compound of formula (A).

In one aspect, the application provides the use of the compound of formula (A) in the preparation of a medicament for alleviating or treating or preventing allergy and its related symptoms.

In some embodiments of the present application, through the compound of the present application and its production method, and its related uses, it is possible to obtain a more excellent effect than the loratadine drug of the prior art on the one hand, for example, in The drug absorption rate, especially the transdermal drug absorption rate, has achieved excellent technical results, and it also provides more alternative technical solutions for this type of drug. In some embodiments of the present application, the reaction conditions in each step of the synthesis method are mild, which is suitable for the selection of various -R, Y, n and -R' in the compounds of the above embodiments of the present application.

Description of drawings

Fig. 1 is the NMR spectrum of the compound of formula (B2) in some embodiments of the present application.

2A-2B are LC-MS spectra of the compound of formula (A2) in some embodiments of the present application.

Fig. 2C is the NMR spectrum of the compound of formula (A2) in some embodiments of the present application.

Fig. 3 is the NMR spectrum of the compound of formula (A6) in some embodiments of the present application.

4A-4B are LC-MS spectra of the compound of formula (A12) in some embodiments of the present application.

Fig. 4C is the NMR spectrum of the compound of formula (A12) in some embodiments of the present application.

Fig. 5 is the NMR spectrum of the compound of formula (A18) in some embodiments of the present application.

6A-6B are LC-MS spectra of the compound of formula (A24) in some embodiments of the present application.

Fig. 6C is the NMR spectrum of the compound of formula (A24) in some embodiments of the present application.

7A-7B are LC-MS spectra of the compound of formula (A30) in some embodiments of the present application.

Fig. 7C is the NMR spectrum of the compound of formula (A30) in some embodiments of the present application.

8A-8B are LC-MS spectra of the compound of formula (A36) in some embodiments of the present application.

Fig. 8C is the NMR spectrum of the compound of formula (A36) in some embodiments of the present application.

Fig. 9 is the NMR spectrum of the compound of formula (A42) in some embodiments of the present application.

10A-10B are LC-MS spectra of the compound of formula (A48) in some embodiments of the present application.

Fig. 10C is the NMR spectrum of the compound of formula (A48) in some embodiments of the present application.

Fig. 11 is the NMR spectrum of the compound of formula (A54) in some embodiments of the present application.

12A-12B are LC-MS spectra of the compound of formula (A55) in some embodiments of the present application.

Fig. 12C is the NMR spectrum of the compound of formula (A55) in some embodiments of the present application.

13A-13B are LC-MS spectra of the compound of formula (A60) in some embodiments of the present application.

Figure 13C is the NMR spectrum of the compound of formula (A60) in some embodiments of the present application.

Fig. 14 is the NMR spectrum of the compound of formula (A66) in some embodiments of the present application.

15A-15B are LC-MS spectra of the compound of formula (A72) in some embodiments of the present application.

Figure 15C is the NMR spectrum of the compound of formula (A72) in some embodiments of the present application.

16A-16B are LC-MS spectra of the compound of formula (A74) in some embodiments of the present application.

Figure 16C is the NMR spectrum of the compound of formula (A74) in some embodiments of the present application.

Fig. 17A is the plasma drug-time curve of the compound of formula (A2) and desloratadine after administration in some embodiments of the present application.

Fig. 17B is a skin drug-time curve of the compound of formula (A2) and desloratadine after administration in some embodiments of the present application.

Fig. 17C is a graph of intramuscular drug-time curves of the compound of formula (A2) and desloratadine after administration in some embodiments of the present application.

Fig. 17D is a bone drug-time curve of the compound of formula (A2) and desloratadine after administration in some embodiments of the present application.

Figure 18 is a graph of the percent drug absorption of the compound of formula (A2) in some embodiments of the present application.

Figures 19A-19N are respectively in some embodiments of the present application, the compound of formula (A6), the compound of formula (A12), the compound of formula (A18), the compound of formula (A24), the compound of formula (A30), the compound of formula (A36), Drug absorption of compounds of formula (A42), compounds of formula (A48), compounds of formula (A54), compounds of formula (A55), compounds of formula (A60), compounds of formula (A66), compounds of formula (A72) and compounds of formula (A74) Percentage graph.

Fig. 20 is a picture of rats with obvious blue spots on their backs due to allergic reactions in some embodiments of the present application.

Fig. 21A to Fig. 21D are the diagrams of blue spots appearing or not appearing on the back of mice in blank group, model group, loratadine group and compound group of formula (A2) in some embodiments of the present application.

Figure 22 is a compound of formula (A).

Detailed ways

In order to further explain the technical means and functions adopted by this application in order to achieve the intended purpose, the specific implementation, structure, features and functions according to this application will be described in detail below in conjunction with the accompanying drawings and preferred embodiments.

In some embodiments, there is provided a compound of formula (A),

The compound of formula (A) is shown in Figure 22.

In some embodiments, the -R is at least one selected from the group consisting of -Y-(CH ₂ ) _n -R' and -R'. is -Y-(CH ₂ ) _n -R′. In some embodiments, the -R is -Y-(CH ₂ ) _n -R′. In some embodiments, the -R is -R'. In some embodiments, the Y is at least one selected from the group consisting of O and NH. In some embodiments, the n is at least one selected from the group consisting of 1, 2, 3, 4, 5, and 6.

In some embodiments, the -R is -Y-(CH ₂ ) _n -R', the Y is at least one selected from the group consisting of O and NH, and the n is selected from 1, 2, At least one of the group consisting of 3, 4, 5, and 6, that is, the compound of formula (A) is a compound of formula (A'),

In some embodiments, the -R is -R', that is, the compound of formula (A) is the compound of formula (A"),

In some embodiments, the -R' is selected from the group consisting of diethylamino, pyrrolidinyl, piperazinyl, N-morpholinyl, bis(2-methoxyethyl)amino, and 4-methylpiper At least one of the group consisting of azinyl.

In some embodiments, the Y is O. In some embodiments, the Y is NH. In some embodiments, the n is 1. In some embodiments, the n is 2. In some embodiments, the n is 3. In some embodiments, the n is 4. In some embodiments, the n is 5. In some embodiments, the n is 6. In some embodiments, said Y is a covalent bond, and said n is 0.

In some embodiments, the n is 1 or 2. In some embodiments, the n is 1, 2 or 3. In some embodiments, the n is 1, 2, 3 or 4. In some embodiments, the n is 1, 2, 3, 4 or 5. In some embodiments, the n is at least one selected from the group consisting of 1-3. In some embodiments, the n is at least one selected from the group consisting of 1-4. In some embodiments, the n is at least one selected from the group consisting of 1-5.

In some embodiments, the -R' is diethylamino. In some embodiments, the -R' is pyrrolidinyl. In some embodiments, the -R' is piperazinyl. In some embodiments, the -R' is N-morpholinyl. In some embodiments, the -R' is bis(2-methoxyethyl)amino. In some embodiments, the -R' is 4-methylpiperazinyl.

In some embodiments, the compound of formula (A) is at least one selected from the group consisting of compounds of formula (A1) to compound of formula (A78):

In some embodiments, the compound of formula (A) is at least one selected from the group consisting of compounds of formula (A1) to compound of formula (A72). In some embodiments, the compound of formula (A) is at least one selected from the group consisting of compounds of formula (A73) to compound of formula (A78).

In some embodiments, there is provided a method for synthesizing a compound of formula (A), especially at least one compound selected from the group consisting of a compound of formula (A1) to a compound of formula (A72), comprising: Loratadine is contacted with X(CH ₂ ) _n YC(=O)Cl to obtain a compound of formula (B); and the compound of formula (B) is contacted with compound H–R′ to obtain a compound of formula (A),

In some embodiments, a method for synthesizing a compound of formula (A) is provided, and its reaction formula is as follows:

In some embodiments, X is selected from at least one of Cl and Br. In some embodiments, X is Cl. In some embodiments, X is Br.

In some embodiments, the compound of formula (B) is at least one selected from the group consisting of compounds of formula (B1) to formula (B12):

In some embodiments, contacting desloratadine with X( _CH2 ) _nYC (=O)Cl is under a basic environment. In some embodiments, desloratadine is contacted with X(CH ₂ ) _n YC(=O)Cl in the presence of N,N-diisopropylethylamine, triethylamine and 2,2,6 , in the presence of at least one of 6-tetramethylpiperidine, or in the presence of potassium carbonate and potassium iodide. In some embodiments, desloratadine is contacted with X( _CH2 ) _nYC (=O)Cl in the presence of N,N-diisopropylethylamine. In some embodiments, desloratadine is contacted with X( _CH2 ) _nYC (=O)Cl in the presence of potassium carbonate and potassium iodide. In some embodiments, contacting desloratadine with X(CH ₂ ) _n YC(=O)Cl uses at least one of dichloromethane, tetrahydrofuran, and acetonitrile as a solvent. In some embodiments, desloratadine is contacted with X(CH ₂ ) _n YC(=O)Cl using dichloromethane as the solvent. In some embodiments, desloratadine is contacted with X(CH ₂ ) _n YC(=O)Cl using tetrahydrofuran as a solvent. In some embodiments, desloratadine is contacted with X(CH ₂ ) _n YC(=O)Cl at room temperature or in an ice bath. In some embodiments, contacting desloratadine with X( _CH2 ) _nYC (=O)Cl is at a temperature of 0°C to 20°C. In some embodiments, contacting desloratadine with X( _CH2 ) _nYC (=O)Cl is at a temperature of 0°C to 10°C. In some embodiments, contacting desloratadine with X( _CH2 ) _nYC (=O)Cl is at a temperature of 5°C.

In some embodiments, contacting a compound of formula (B) with compound H—R' is under a basic environment. In some embodiments, the compound of formula (B) is contacted with compound H–R′ in the presence of N,N-diisopropylethylamine, triethylamine and 2,2,6,6-tetramethylpiperone In the presence of at least one of pyridine, or in the presence of potassium carbonate and potassium iodide. In some embodiments, the compound of formula (B) is contacted with compound H—R' in the presence of N,N-diisopropylethylamine. In some embodiments, the compound of formula (B) is contacted with compound H—R' in the presence of potassium carbonate and potassium iodide. In some embodiments, the compound of formula (B) is contacted with compound H—R′ using at least one of dichloromethane, tetrahydrofuran, and acetonitrile as a solvent. In some embodiments, the compound of formula (B) is contacted with compound H—R' using acetonitrile as solvent. In some embodiments, the compound of formula (B) is contacted with compound H—R' at room temperature or with heating. In some embodiments, the compound of formula (B) is contacted with compound H—R' under heating to reflux. In some embodiments, contacting the compound of formula (B) with compound H—R' is at a temperature of 50°C to 80°C. In some embodiments, contacting the compound of formula (B) with compound H—R' is at a temperature of 60°C to 70°C. In some embodiments, contacting the compound of formula (B) with compound H—R' is at a temperature of 65°C.

In some embodiments, the application provides the use of the compound of formula (B) in the preparation of the compound of formula (A). In some embodiments, the application provides the use of X(CH ₂ ) _n YC(=O)Cl in the preparation of the compound of formula (A). In some embodiments, the application provides the use of compound H—R' in the preparation of a compound of formula (A). In some embodiments, the application provides compounds of formula (B) for use in the preparation of compounds of formula (A). In some embodiments, the application provides X(CH ₂ ) _n YC(=O)Cl for use in the preparation of compounds of formula (A). In some embodiments, the application provides compounds H—R' for use in the preparation of compounds of formula (A).

In some embodiments, there is provided a method for synthesizing a compound of formula (A), especially at least one compound selected from the group consisting of a compound of formula (A1) to a compound of formula (A72), comprising: using the compound H–R reacts with desloratadine as a reactant to obtain a compound of formula (A).

In some embodiments, the compound H—R is at least one selected from the group consisting of compound H—R′ and compound H—Y—(CH ₂ ) _n —R′. In some embodiments, the compound H—R is compound H—Y—(CH ₂ ) _n —R′. In some embodiments, the compound H—R is the compound H—Y—(CH ₂ ) _n —R′, and the Y is O. In some embodiments, the compound H—R is the compound H—Y—(CH ₂ ) _n —R′, and the Y is NH. In some embodiments, the n is 1. In some embodiments, the n is 2. In some embodiments, the n is 3. In some embodiments, the n is 4. In some embodiments, the n is 5. In some embodiments, the n is 6. In some embodiments, the compound H-R is compound H-R'. In some embodiments, the -R' is diethylamino. In some embodiments, the -R' is pyrrolidinyl. In some embodiments, the -R' is piperazinyl. In some embodiments, the -R' is N-morpholinyl. In some embodiments, the -R' is bis(2-methoxyethyl)amino. In some embodiments, the -R' is 4-methylpiperazinyl.

In some embodiments, compound H-R is at least one selected from the group consisting of compounds of formula (C1) to formula (C78):

In some embodiments, compound H-R is at least one selected from the group consisting of compounds of formula (C1) to formula (C72). In some embodiments, compound H—R is at least one selected from the group consisting of compounds of formula (C73) to formula (C78).

In some embodiments, the —R is —Y—(CH ₂ ) _n —R′ and the Y is O, and the compound H—R and desloratadine are reacted as reactants, including: using the compound contacting H—R (ie compound HO—(CH ₂ ) _n —R′) with N,N′-carbonyldiimidazole to obtain a first compound; and contacting the first compound with desloratadine.

In some embodiments, the first compound comprises or consists of a compound of formula (Ca),

In some embodiments, the —R is —Y—(CH ₂ ) _n —R′ and the Y is NH, and the compound H—R and desloratadine are reacted as reactants, including: using the compound contacting H—R (ie compound H ₂ N—(CH ₂ ) _n —R′) with phosgene and/or triphosgene to obtain a second compound; and contacting the second compound with desloratadine.

In some embodiments, the second compound comprises or consists of a compound of formula (Cb),

In some embodiments, the -R is -R', and the compound H-R and desloratadine are reacted as reactants, including: desloratadine and p-nitrobenzyl chloroformate, N , contacting N′-carbonyldiimidazole and/or triphosgene to obtain a third compound; and contacting the third compound with compound H–R (ie, compound H–R′).

In some embodiments, the third compound comprises or consists of a compound of formula (Cc),

In some embodiments, there is provided Compound H-R wherein -R is -Y-(CH ₂ ) _n -R′ and Y is O (i.e., compound HO—(CH ₂ ) _n -R′) The preparation method comprises contacting compound H–R′ with HO(CH ₂ ) _n X′. In some embodiments, contacting HR' with HO( _CH2 ) _nX ' is under basic conditions, more particularly in the presence of potassium carbonate. In some embodiments, contacting HR' with HO( _CH2 ) _nX ' is in tetrahydrofuran. In some embodiments, X' is Br.

In some embodiments, there is provided a compound H-R wherein -R is -Y-(CH ₂ ) _n -R′ and said Y is NH (i.e., compound H ₂ N-(CH ₂ ) _n -R ') preparation method, comprising contacting phthalimide salt, especially potassium phthalimide, with X"(CH ₂ ) _n X" to obtain the fourth compound; contacting compound H—R' to give a fifth compound; and contacting the fifth compound with hydrazine. In some embodiments, X" is Br.

In some embodiments, the fourth compound comprises or consists of a compound of formula (C"),

In some embodiments, the fifth compound comprises or consists of a compound of formula (C'),

In some embodiments, the present application provides the use of the compound of formula (A) in the preparation of a medicament for alleviating or treating or preventing allergy and its related symptoms. In some embodiments, the application provides a compound of formula (A) for alleviating or treating or preventing allergy. In some embodiments, the present application provides a method for alleviating or treating or preventing allergy, comprising administering a compound of formula (A). In some embodiments, the present application provides the use of the compound of formula (A) in alleviating or treating or preventing allergy. In some embodiments, the allergy and its related symptoms are at least one selected from the group consisting of skin allergy, atopic dermatitis, urticaria, eczema, rhinitis and asthma. In some embodiments, the allergy and its related symptoms are selected from at least one of chronic urticaria, perennial rhinitis and seasonal rhinitis. In some embodiments, the allergy and its associated symptoms comprise passive cutaneous anaphylaxis (PCA). In some embodiments, the dosage form of the drug for alleviating or treating or preventing allergy and its related symptoms is selected from the group consisting of spray, patch, dressing, gel, ointment, cream, injection, and oral drug at least one of the In some embodiments, the medicament for relieving or treating or preventing allergy and its related symptoms is administered by at least one of the group consisting of spraying, smearing, sticking, application, injection and oral administration.

In some embodiments, the compound of formula (A) is a compound of formula (A2) and the compound of formula (B) is a compound of formula (B2).

Preparation of Desloratadine Derivatives (Formula (A) Compound)

Synthesize the compound of formula (A2) by synthesizing the compound of formula (B2) (-R is -Y-(CH ₂ ) _n -R', -R' is diethylamino, n=2, Y is O)

[Preparation of formula (B2) compound]

Desloratadine (3g, 1eq) and diisopropylethylamine (1.1eq) were dissolved in dichloromethane (30mL), cooled in an ice bath, and chloroethyl chloroformate (1eq) was added dropwise at 5°C. After the dropwise addition, the reaction was continued for 2 hours.

Add 30 mL of water to quench the reaction, and extract 3 times with 60 mL of dichloromethane. Dichloromethane was combined, washed with water, dried, filtered and concentrated to obtain the product: compound of formula (B2) (4g).

The NMR spectrum of the compound of formula (B2) is shown in Figure 1.

[Preparation of formula (A2) compound]

The compound of formula (B2) (4g, 0.359mmol), diethylamine (10eq), potassium iodide (10eq) and potassium carbonate (10eq) were put into a reaction flask, and after nitrogen replacement, acetonitrile (30mL) was added. The reaction system was heated to 65°C for 18 hours. Subsequently, the reaction was continued for 10 hours until the end of the reaction.

After cooling, 30 mL of water was added to quench the reaction, and 60 mL of dichloromethane was extracted three times. Dichloromethane was combined, washed with water, dried, filtered, concentrated and then column chromatographed to obtain the product formula (A2) compound (2.1g).

The LC-MS spectrum of the compound of formula (A2) is shown in Figures 2A and 2B; its NMR spectrum is shown in Figure 2C.

Synthesize the compound of formula (A6) by synthesizing the compound of formula (C6) (-R is -Y-(CH ₂ ) _n -R', -R' is diethylamino, n=6, Y is O)

[Preparation of formula (C6) compound]

Bromohexanol (1.0eq) and diethylamine (1.5eq) were dissolved in an appropriate amount of tetrahydrofuran at room temperature, potassium carbonate (3.0eq) was added to the system, stirred at room temperature for 3 to 6 hours, and the reaction was monitored by thin-layer chromatography.

After the reaction was completed, water was added to quench the reaction, extracted twice with an appropriate amount of ethyl acetate, and the organic phases were combined. The organic phase was dried by adding anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column, and the eluent was methanol/dichloromethane. A compound of formula (C6) is obtained.

[Preparation of formula (A6) compound]

Dissolve the compound of formula (C6) (1.0eq) in N,N,-dimethylformamide (DMF), add N,N'-carbonyldiimidazole (CDI) (1.0eq), stir at room temperature for 1 hour, thin Layer chromatographic monitoring ensures that the basic reaction of CDI is complete.

Then add desloratadine to the reaction, and heat to 80° C. to react overnight.

After the reaction was completed, water was added to quench the reaction, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain an oily crude product. The crude product was separated and purified by silica gel column, and the eluent was methanol/dichloromethane. The compound of formula (A6) is obtained.

The NMR spectrum of the compound of formula (A6) is shown in Figure 3.

Synthesize the compound of formula (A12) by synthesizing the compound of formula (C12) (-R is -Y-(CH ₂ ) _n -R', -R' is diethylamino, n=6, Y is N)

【Preparation of Formula (C12) Compound】

Potassium phthalimide (1.0eq) and 1,6-dibromohexane (5.0eq) were dissolved in 5V (double volume) of DMF, and stirred at 100°C for about 12 hours. Then distilled under reduced pressure to remove excess 1,6-dibromohexane and DMF. The crude product was separated and purified by silica gel column, and the eluent was ethyl acetate/petroleum ether. This gives N-(6-bromohexyl)phthalimide.

Dissolve N-(6-bromohexyl)phthalimide (1.0eq) and diethylamine (4.0eq) in 50V acetonitrile, add 3.0eq potassium carbonate, and stir for about 24 hours. The solvent was removed by concentration under reduced pressure to obtain a residue. The residue was dissolved in 25V sodium bicarbonate solution. Extract twice with ethyl acetate and combine the organic phases. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Purified by column chromatography. A compound of formula (C12') is obtained.

The compound of formula (C12') was dissolved in methanol, and hydrazine monohydrate (0.8 mL, 16 mmol) was added dropwise. The mixture was refluxed for about 4 hours. The reaction mixture was cooled to room temperature, insoluble phthalohydrazide was filtered off, and the filtrate was evaporated under reduced pressure. The obtained oil was dissolved in chloroform and filtered to remove excess phthalohydrazide. The filtrate is concentrated to give the product, compound of formula (C12).

[Preparation of formula (A12) compound]

The compound of formula (C12) (1.0eq) and diisopropylethylamine (2.0eq) were dissolved in 50V dichloromethane, and a solution of triphosgene (0.3eq) in dichloromethane was added under stirring. The resulting mixture was stirred at 0°C for about 3 hours, then desloratadine (1.0 eq) was added. The reaction mixture was allowed to warm to room temperature overnight. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography. The product obtained is a compound of formula (A12).

The LC-MS spectrum of the compound of formula (A12) is shown in Figures 4A-4B; its NMR spectrum is shown in Figure 4C.

Synthesize the compound of formula (A18) by synthesizing the compound of formula (C18) (-R is -Y-(CH ₂ ) _n -R', -R' is piperazinyl, n=6, Y is O)

【Preparation of Formula (C18) Compound】

Bromohexanol (1.0eq) and piperazine (1.5eq) were dissolved in an appropriate amount of tetrahydrofuran at room temperature, potassium carbonate (3.0eq) was added to the system, stirred at room temperature for 3 to 6 hours, and the reaction was monitored by thin-layer chromatography. After the reaction was completed, water was added to quench the reaction, extracted twice with an appropriate amount of ethyl acetate, the organic phases were combined, dried by adding anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column, and the eluent was methanol/dichloromethane. 1-Piperazine hexanol (compound of formula (C18)) is obtained.

[Preparation of formula (A18) compound]

1-Piperazine hexanol (compound of formula (C18)) (1.0 eq) was dissolved in DMF, CDI (1.0 eq) was added, stirred at room temperature for 1 hour, TLC monitoring ensured that the basic reaction of CDI was complete. Then add desloratadine to the reaction, and heat to 80° C. to react overnight. After the reaction was completed, water was added to quench the reaction, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain an oily crude product. The crude product was separated and purified by silica gel column, and the eluent was methanol/dichloromethane. The compound of formula (A18) was obtained with a purity of 97.85%.

The NMR spectrum of the compound of formula (A18) is shown in Figure 5.

Synthesize the compound of formula (A24) by synthesizing the compound of formula (C24) (-R is -Y-(CH ₂ ) _n -R', -R' is piperazinyl, n=6, Y is N)

【Preparation of Formula (C24) Compound】

Potassium phthalimide (1.0eq) and 1,6-dibromohexane (5.0eq) were dissolved in 5V DMF, and stirred at 100°C for about 12 hours. Then distilled under reduced pressure to remove excess 1,6-dibromohexane and DMF. The crude product was separated and purified by silica gel column, and the eluent was ethyl acetate/petroleum ether. This gives N-(6-bromohexyl)phthalimide.

Dissolve N-(6-bromohexyl)phthalimide (1.0eq) and piperazine (4.0eq) in 50V acetonitrile, add 3.0eq potassium carbonate, and stir for about 24 hours. The solvent was removed by concentration under reduced pressure to obtain a residue. The residue was dissolved in 25V sodium bicarbonate solution. Extract twice with ethyl acetate and combine the organic phases. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Purified by column chromatography with n-hexane/ethyl acetate as eluent. A compound of formula (C24') is obtained.

The compound of formula (C24') was dissolved in methanol, and hydrazine monohydrate (0.8 mL, 16 mmol) was added dropwise. The mixture was refluxed for about 4 hours. The reaction mixture was cooled to room temperature, insoluble phthalohydrazide was filtered off, and the filtrate was evaporated under reduced pressure. The obtained oil was dissolved in chloroform and filtered to remove excess phthalohydrazide. The filtrate is concentrated to give the product, compound of formula (C24).

[Preparation of formula (A24) compound]

The compound of formula (C24) (1.0eq) and diisopropylethylamine (2.0eq) were dissolved in 50V dichloromethane, and a solution of triphosgene (0.3eq) in dichloromethane was added under stirring. The resulting mixture was stirred at 0°C for about 3 hours, then desloratadine (1.0 eq) was added. The reaction mixture was allowed to warm to room temperature overnight. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to a residue, which was purified by silica gel column chromatography. The compound of formula (A24) is obtained.

The LC-MS spectrum of the compound of formula (A24) is shown in Figures 6A-6B; its NMR spectrum is shown in Figure 6C.

Synthesize the compound of formula (A30) by synthesizing the compound of formula (C30) (-R is -Y-(CH ₂ ) _n -R', -R' is two (2-methoxyethyl) amino, n=6, Y for O)

【Preparation of Formula (C30) Compound】

Dissolve bromohexanol (1.0eq) and bis(2-methoxyethyl)amine (1.5eq) in an appropriate amount of tetrahydrofuran at room temperature, add potassium carbonate (3.0eq) to the system, and stir at room temperature for 4-6h , the reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, extracted twice with an appropriate amount of ethyl acetate, the organic phases were combined, dried by adding anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column, and the eluent was methanol/dichloromethane. 6-(Bis(2-methoxyethyl)amino)hexan-1-ol (compound of formula (C30)) is obtained.

[Preparation of formula (A30) compound]

Dissolve 6-(bis(2-methoxyethyl)amino)hexan-1-ol (compound of formula (C30)) (1.0eq) in DMF, add CDI (1.0eq), stir at room temperature for 1 hour, thin layer Chromatographic monitoring ensures that the CDI is substantially complete. Then add desloratadine to the reaction, and heat to 80° C. to react overnight. After the reaction was completed, water was added to quench the reaction, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain an oily crude product. The crude product was separated and purified by silica gel column, and the eluent was methanol/dichloromethane. A compound of formula (A30) is obtained.

The LC-MS spectrum of the compound of formula (A30) is shown in Figures 7A-7B; its NMR spectrum is shown in Figure 7C.

Synthesize the compound of formula (A36) by synthesizing the compound of formula (C36) (-R is -Y-(CH ₂ ) _n -R', -R' is two (2-methoxyethyl) amino, n=6, Y for N)

【Preparation of Formula (C36) Compound】

Potassium phthalimide (1.0eq) and 1,6-dibromohexane (5.0eq) were dissolved in an appropriate amount of DMF, and stirred at 100°C for about 12 hours. Then distilled under reduced pressure to remove excess 1,6-dibromohexane and DMF. The crude product was separated and purified by silica gel column, and the eluent was ethyl acetate:petroleum ether=1:40. This gives N-(6-bromohexyl)phthalimide.

Dissolve N-(6-bromohexyl)phthalimide (1.0eq) and bis(2-methoxyethyl)amine (4.0eq) in 50V acetonitrile, add 3.0eq potassium carbonate, and stir for about 24 hours. The solvent was removed by concentration under reduced pressure to obtain a residue. The residue was dissolved in 25V sodium bicarbonate solution. Extract twice with ethyl acetate and combine the organic phases. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Purified by column chromatography, the eluent was n-hexane:ethyl acetate:triethylamine=5:5:1. A compound of formula (C36') is obtained.

The compound of formula (C36') was dissolved in methanol, and hydrazine monohydrate (0.8 mL, 16 mmol) was added dropwise. The mixture was refluxed for about 4 hours. The reaction mixture was cooled to room temperature, insoluble phthalohydrazide was filtered off, and the filtrate was evaporated under reduced pressure. The obtained oil was dissolved in chloroform and filtered to remove excess phthalohydrazide. The filtrate is concentrated to give the product, compound of formula (C36).

[Preparation of formula (A36) compound]

The compound of formula (C36) (1.0eq) and diisopropylethylamine (2.0eq) were dissolved in 50V dichloromethane, and a solution of triphosgene (0.3eq) in dichloromethane was added under stirring. The resulting mixture was stirred at 0°C for about 3 hours, then desloratadine (1.0 eq) was added. The reaction mixture was allowed to warm to room temperature overnight. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to a residue which was purified by silica gel column. The compound of formula (A36) is obtained.

The LC-MS spectrum of the compound of formula (A36) is shown in Figure 8A-8B; its NMR spectrum is shown in Figure 8C.

Synthesize the compound of formula (A42) by synthesizing the compound of formula (C42) (-R is -Y-(CH ₂ ) _n -R', -R' is pyrrolidinyl, n=6, Y is O)

【Preparation of compound of formula (C42)】

Bromohexanol (1.0eq) and pyrrole (1.5eq) were dissolved in an appropriate amount of tetrahydrofuran at room temperature, potassium carbonate (3.0eq) was added to the system, stirred at room temperature for 3 to 6 hours, and the reaction was monitored by thin-layer chromatography. After the reaction was completed, water was added to quench the reaction, extracted twice with an appropriate amount of ethyl acetate, the organic phases were combined, dried by adding anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column, and the eluent was methanol/dichloromethane. 6-(Pyrrolidin-1-yl)-hexan-1-ol (compound of formula (C42)) is obtained.

[Preparation of formula (A42) compound]

Dissolve 6-(pyrrolidin-1-yl)-hexan-1-ol (compound of formula (C42)) (1.0eq) in DMF, add CDI (1.0eq), stir at room temperature for 1 hour, and monitor by TLC to ensure that CDI The basic response is complete. Then add desloratadine to the reaction, and heat to 80° C. to react overnight. After the reaction was completed, water was added to quench the reaction, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column, and the eluent was methanol/dichloromethane. The compound of formula (A42) is obtained.

The NMR spectrum of the compound of formula (A42) is shown in Figure 9.

Synthesize the compound of formula (A48) by synthesizing the compound of formula (C48) (-R is -Y-(CH ₂ ) _n -R', -R' is pyrrolidinyl, n=6, Y is N)

[Preparation of formula (C48) compound]

Potassium phthalimide (1.0eq) and 1,6-dibromohexane (5.0eq) were dissolved in an appropriate amount of DMF, and stirred at 100°C for about 12 hours. Then distilled under reduced pressure to remove excess 1,6-dibromohexane and DMF. The crude product was separated and purified by silica gel column, and the eluent was ethyl acetate/petroleum ether. This gives N-(6-bromohexyl)phthalimide.

Dissolve N-(6-bromohexyl)phthalimide (1.0eq) and pyrrole (4.0eq) in 50V acetonitrile, add 3.0eq potassium carbonate, and stir for about 24 hours. The solvent was removed by concentration under reduced pressure to obtain a residue. The residue was dissolved in 25V sodium bicarbonate solution. Extract twice with ethyl acetate and combine the organic phases. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Through column chromatography, the eluent was n-hexane:ethyl acetate:triethylamine=5:5:1. A compound of formula (C48') is obtained.

The compound of formula (C48') was dissolved in methanol, and hydrazine monohydrate (0.8 mL, 16 mmol) was added dropwise. The mixture was refluxed for about 4 hours. The reaction mixture was cooled to room temperature, insoluble phthalohydrazide was filtered off, and the filtrate was evaporated under reduced pressure. The obtained oil was dissolved in chloroform and filtered to remove excess phthalohydrazide. The filtrate is concentrated to give the product, compound of formula (C48).

[Preparation of formula (A48) compound]

The compound of formula (C48) (1.0eq) and diisopropylethylamine (2.0eq) were dissolved in 50V dichloromethane, and a solution of triphosgene (0.3eq) in dichloromethane was added under stirring. The resulting mixture was stirred at 0°C for about 3 hours, then desloratadine (1.0 eq) was added. The reaction mixture was allowed to warm to room temperature overnight. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to a residue which was purified by silica gel column. The compound of formula (A48) is obtained.

The LC-MS spectrum of the compound of formula (A48) is shown in Figures 10A-10B; its NMR spectrum is shown in Figure 10C.

Synthesize the compound of formula (A54) by synthesizing the compound of formula (C54) (-R is -Y-(CH ₂ ) _n -R', -R' is N-morpholinyl, n=6, Y is O)

【Preparation of Formula (C54) Compound】

Bromohexanol (1.0eq) and morpholine (1.5eq) were dissolved in an appropriate amount of tetrahydrofuran at room temperature, potassium carbonate (3.0eq) was added to the system, stirred at room temperature for 3 to 6 hours, and the reaction was monitored by thin-layer chromatography. After the reaction was completed, water was added to quench the reaction, extracted twice with an appropriate amount of ethyl acetate, the organic phases were combined, dried by adding anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column, and the eluent was methanol/dichloromethane. 6-(Morpholinyl)-hexan-1-ol (compound of formula (C54)) is obtained.

[Preparation of formula (A54) compound]

Dissolve 6-(morpholinyl)-hexan-1-ol (compound of formula (C54)) (1.0eq) in DMF, add CDI (1.0eq), stir at room temperature for 1 hour, and monitor by TLC to ensure that the basic reaction of CDI is complete . Then add desloratadine to the reaction, and heat to 80° C. to react overnight. After the reaction was completed, water was added to quench the reaction, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain an oily crude product. The crude product was separated and purified by silica gel column, and the eluent was methanol/dichloromethane. The compound of formula (A54) is obtained.

The NMR spectrum of the compound of formula (A54) is shown in Figure 11.

Synthesize the compound of formula (A55) by synthesizing the compound of formula (C55) (-R is -Y-(CH ₂ ) _n -R', -R' is N-morpholinyl, n=1, Y is N)

【Preparation of Formula (C55) Compound】

The starting material was dissolved in methanol and hydrazine monohydrate (0.8 mL, 16 mmol) was added dropwise. The mixture was refluxed for about 4 hours. The reaction mixture was cooled to room temperature, insoluble phthalohydrazide was filtered off, and the filtrate was evaporated under reduced pressure. The obtained oil was dissolved in chloroform and filtered to remove excess phthalohydrazide. The filtrate was concentrated to give the product (compound of formula (C55)), which was directly used in the next step.

[Preparation of formula (A55) compound]

The compound of formula (C55) (1.0eq) and diisopropylethylamine (2.0eq) were dissolved in 50V dichloromethane, and a solution of triphosgene (0.3eq) in dichloromethane was added under stirring. The resulting mixture was stirred at 0°C for about 3 hours, then desloratadine (1.0 eq) was added. The reaction mixture was allowed to warm to room temperature overnight. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to a residue which was purified by silica gel column. The compound of formula (A55) is obtained.

The LC-MS spectrum of the compound of formula (A55) is shown in Figures 12A-12B; its NMR spectrum is shown in Figure 12C.

Synthesize the compound of formula (A60) by synthesizing the compound of formula (C60) (-R is -Y-(CH ₂ ) _n -R', -R' is N-morpholinyl, n=6, Y is N)

【Preparation of Formula (C60) Compound】

Dissolve N-(6-bromohexyl)phthalimide (1.0eq) and morpholine (4.0eq) in 50V acetonitrile, add 3.0eq potassium carbonate, and stir for about 24 hours. The solvent was removed by concentration under reduced pressure to obtain a residue. The residue was dissolved in 25V sodium bicarbonate solution. Extract twice with ethyl acetate and combine the organic phases. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Purified by column chromatography with n-hexane/ethyl acetate as eluent. A compound of formula (C60') is obtained.

The compound of formula (C60') was dissolved in methanol, and hydrazine monohydrate (0.8 mL, 16 mmol) was added dropwise. The mixture was refluxed for about 4 hours. The reaction mixture was cooled to room temperature, insoluble phthalohydrazide was filtered off, and the filtrate was evaporated under reduced pressure. The obtained oil was dissolved in chloroform and filtered to remove excess phthalohydrazide. The filtrate is concentrated to give the product, compound of formula (C60).

[Preparation of formula (A60) compound]

The compound of formula (C60) (1.0eq) and diisopropylethylamine (2.0eq) were dissolved in 50V dichloromethane, and a solution of triphosgene (0.3eq) in dichloromethane was added under stirring. The resulting mixture was stirred at 0°C for about 3 hours, then desloratadine (1.0 eq) was added. The reaction mixture was allowed to warm to room temperature overnight. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to a residue which was purified by silica gel column. A compound of formula (A60) is obtained.

The LC-MS spectrum of the compound of formula (A60) is shown in Figures 13A-13B; its NMR spectrum is shown in Figure 13C.

Synthesize the compound of formula (A66) by synthesizing the compound of formula (C66) (-R is -Y-(CH ₂ ) _n -R', -R' is 4-methylpiperazinyl, n=6, Y is O)

【Preparation of Formula (C66) Compound】

Dissolve bromohexanol (1.0eq) and N-methylmorpholine (1.5eq) in an appropriate amount of tetrahydrofuran at room temperature, add potassium carbonate (3.0eq) to the system, stir at room temperature for 3 to 6 hours, and thin-layer chromatography Monitor the response. After the reaction was completed, water was added to quench the reaction, extracted twice with an appropriate amount of ethyl acetate, the organic phases were combined, dried by adding anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column, and the eluent was methanol/dichloromethane. 6-(4-Methylpiperazin-1-yl)hexan-1-ol (compound of formula (C66)) is obtained.

[Preparation of formula (A66) compound]

Dissolve 6-(4-methylpiperazin-1-yl)hexan-1-ol (1.0eq) in DMF, add CDI (1.0eq), stir at room temperature for 1 hour, and monitor by TLC to ensure that the basic reaction of CDI is complete. Then add desloratadine to the reaction, and heat to 80° C. to react overnight. After the reaction was completed, water was added to quench the reaction, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain an oily crude product. The crude product was separated and purified by silica gel column, and the eluent was methanol/dichloromethane. The compound of formula (A66) is obtained.

The NMR spectrum of the compound of formula (A55) is shown in Figure 14.

Synthesize the compound of formula (A72) by synthesizing the compound of formula (C72) (-R is -Y-(CH ₂ ) _n -R', -R' is 4-methylpiperazinyl, n=6, Y is N)

【Preparation of Formula (C72) Compound】

Dissolve N-(6-bromohexyl)phthalimide (1.0eq) and N-methylpiperazine (4.0eq) in 50V acetonitrile, add 3.0eq potassium carbonate, and stir for about 24 hours. The solvent was removed by concentration under reduced pressure to obtain a residue. The residue was dissolved in 25V sodium bicarbonate solution. Extract twice with ethyl acetate and combine the organic phases. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Purified by column chromatography with n-hexane/ethyl acetate as eluent. A compound of formula (C72') is obtained.

The compound of formula (C72') was dissolved in methanol, and hydrazine monohydrate (0.8 mL, 16 mmol) was added dropwise. The mixture was refluxed for about 4 hours. The reaction mixture was cooled to room temperature, insoluble phthalohydrazide was filtered off, and the filtrate was evaporated under reduced pressure. The obtained oil was dissolved in chloroform and filtered to remove excess phthalohydrazide. The filtrate is concentrated to give the product, compound of formula (C72).

[Preparation of formula (A72) compound]

The compound of formula (C72) (1.0eq) and diisopropylethylamine (2.0eq) were dissolved in 50V dichloromethane, and a solution of triphosgene (0.3eq) in dichloromethane was added under stirring. The resulting mixture was stirred at 0°C for about 3 hours, then desloratadine (1.0 eq) was added. The reaction mixture was allowed to warm to room temperature overnight. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to a residue which was purified by silica gel column. The compound of formula (A72) is obtained.

The LC-MS spectrum of the compound of formula (A72) is shown in Figures 15A-15B; its NMR spectrum is shown in Figure 15C.

Synthetic formula (A74) compound (-R is-R',-R' is piperazinyl)

Dissolve desloratadine (1.0eq) in DMF, add p-nitrobenzyl chloroformate (1.2eq), stir at room temperature for about 3 to 4 hours, and monitor by thin-layer chromatography to ensure that the basic reaction of the raw materials is complete.

Then piperazine was added to the reaction, and heated to 80° C. to react overnight. After the reaction was completed, water was added to quench the reaction, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain an oily crude product. The crude product was separated and purified by silica gel column, and the eluent was methanol/dichloromethane. The compound of formula (A74) is obtained.

The LC-MS spectrum of the compound of formula (A74) is shown in Figures 16A-16B; its NMR spectrum is shown in Figure 16C.

Pharmacokinetic studies

In this experiment, after administration of various formula (A) compounds to rat skin, the skin and plasma exposure of various formula (A) compounds and their metabolites and the residual drug loading of various formula (A) compounds were evaluated. Absorption efficiency of skin administration.

In the experiment, 32 male SD rats with similar body weight were selected, and the dose was 1 mg/rat, and the skin was smeared for a single administration. After administration, the animals in each group collected blood and the skin, muscle, and bone of the administration site at different time points. LC-MS/MS analysis method was used to detect the content of various formula (A) compounds, desloratadine and 3-OH desloratadine in plasma, skin, muscle and bone tissue.

Statistical plasma concentration data, using non-compartmental model (NCA) to calculate pharmacokinetic parameters.

Experiments have shown that after the SD rats are given the formula (A) compound aqueous solution through the skin, the pharmacokinetic behavior is in line with the basic pharmacokinetic behavior trend.

Test article preparation

An aqueous solution of each compound of formula (A) with a final concentration of 16.7 mg/mL was prepared. The final formulation was a clear solution.

Experimental Animals and Drug Administration

36 male SD rats were selected for the experiment. Fasted overnight before administration, fasted for at least 16 hours, and resumed feed supply after 4 hours. 6–8 weeks old at the time of dosing. The body weight of the animals was measured before administration, and healthy animals with similar body weight were selected to be included in the experiment, weighing 186–207 g, of which 32 were in the treatment group and 4 were in the blank group.

Each experimental animal was given a single administration of 1 mg/only of the test product (16.7 mg/mL aqueous solution of the compound of formula (A)). The administration route is smearing on the skin, removing the hair on the back skin near the neck, ^and absorbing the aqueous ^solution of the compound of formula (A) with a 200 μL pipette. After administration, the animals were reared in single cages in metabolic cages.

Experimental animal sample collection and preparation

The 32 mice in the administration group were equally divided into eight groups, and 8 mL of blood samples were collected intravenously or in other ways at 0.5 hour, 1 hour, 2 hours, 3 hours, 5 hours, 8 hours, 12 hours, and 24 hours after administration. And euthanized. After euthanasia, the skin at the administration site, muscle and bone at the administration site were collected.

After the blood sample is collected, put it into an EP tube containing heparin sodium (anticoagulant), put it in crushed ice immediately, and then centrifuge it at 4500rpm at low temperature (4°C) for 5min, take the supernatant plasma, and put it in dry ice , transfer to ultra-low temperature freezer as soon as possible. After the skin at the administration site and the muscle and bone at the administration site are collected, the skin, muscle and bone tissue should be placed in a homogenization tube immediately after sampling, placed in dry ice, and transferred to an ultra-low temperature refrigerator for freezing as soon as possible.

Standard curve and quality control sample preparation

Using 80% aqueous methanol as a diluting solvent, the standard curve working solution and the quality control working solution of the compound of formula (A), desloratadine and 3-OH desloratadine were prepared.

Take 5 μL of the working solution and mix it with 45 μL blank plasma to prepare plasma standard curve and quality control samples. Take 5 μL of working solution and mix with 45 μL blank homogenate (tissue: homogenate = 1 g: 5 mL methanol) to prepare tissue standard curve and quality control samples.

Liquid Chromatography-Mass Spectrometry Sample Preparation

[Compound of formula (A2), desloratadine]

Experimental animal plasma samples, plasma standard curve and quality control samples were thawed at room temperature, 50 μL was taken, and 400 μL of internal standard working solution (10 ng/mL terfenadine in acetonitrile solution) was added, vortexed for 1 min, and 4 Centrifuge at 15400g for 10min. The supernatant was sampled for analysis.

After thawing the experimental animal tissue samples, tissue standard curve and quality control samples at room temperature, take 50 μL, add 400 μL/500 μL internal standard working solution (10 ng/mL terfenadine in acetonitrile solution), vortex and mix for 1 min , 4°C, centrifuged at 15400g for 10min. The supernatant was sampled for analysis.

[Formula (A6) compound, formula (A12) compound, formula (A18) compound, formula (A24) compound, formula (A30) compound, formula (A36) compound, formula (A42) compound, formula (A48) compound, formula (A54) compound, formula (A55) compound, formula (A60) compound, formula (A66) compound, formula (A72) compound, formula (A74) compound]

Take 100 μL of sample (plasma sample, plasma standard curve or quality control sample, or tissue sample, tissue standard curve or quality control sample), add 1500 μL methanol, and mix well. Take 20 μL from it, add 1500 μL internal standard working solution (200 ng/mL terfenadine + 10 μg/mL hesperetin + 5 μg/mL tolbutamide in acetonitrile solution), vortex and mix for 1 min, 4 ° C, 15400 g Centrifuge for 10 min under conditions. The supernatant was sampled for analysis.

Liquid chromatography conditions and mass spectrometry conditions

[Formula (A2) compound, desloratadine] HPLC: LC-20A, SHIMADZU; Liquid phase pump: LC-20AD _XR ; Column thermostat: CTO-20AC; Autosampler: SIL-20AC _XR ; Controller : CBM-20A; Degasser: DGU-20A _5R ; Chromatographic column: ZORBAX Eclipse Plus C18 2.1*50mm, 3.5μm, Agilent; Pre-column: Security Guard Cartridges C18 4*2.00mm, Phenomenex; Column temperature: room temperature; automatic Needle wash solution for the injector: 80% acetonitrile water; needle wash program for the autosampler: Rinse Mode: Before and after aspiration; temperature for the autosampler: 4°C.

In the mobile phase, phase A is an aqueous solution of 0.1% formic acid and 5 mM ammonium acetate, and phase B is acetonitrile. The flow rate was 0.70 mL/min, and the sample injection volume was 2 μL. For detecting the compound of formula (A2), the mobile phase gradient is 80% phase A+20% phase B at 0.30 min, 20% phase A+80% phase B at 0.80 min, and 20% phase A at 1.60 min +80% Phase B, at 1.90min it is 80% Phase A+20% Phase B, and the operation stops at 2.50min. For detecting desloratadine and 3-OH desloratadine, the mobile phase gradient is 80% phase A+20% phase B at 0.30 min, and 20% phase A+80% phase B at 0.80 min, At 1.60 min, it was 20% A phase + 80% B phase, at 1.90 min it was 80% A phase + 20% B phase, and the operation stopped at 2.50 min.

The mass spectrometer adopts a SHIMADZU API 4000 mass spectrometer with an ESI source, and uses positive ion MRM scanning. The ion source is Turbo spray.

Source parameters: CAD = 10 psi; CUR = 30 psi; Gas1 = 55 psi; Gas2 = 55 psi; IS = 5500V;

Compound parameters are listed in Table 1A.

Table 1A

【Compound of formula (A6), compound of formula (A18)】

HPLC: SHIMADZU LC0A; Column: BR-C18

2.1*50mm, 3μm, Sepax; column temperature: room temperature.

In the mobile phase, phase A is an aqueous solution of 0.1% formic acid and 5 mM ammonium acetate, and phase B is acetonitrile. The flow rate was 0.70 mL/min, and the sample injection volume was 0.5 μL. The mobile phase gradient is 70% Phase A + 30% Phase B at 0.30min, 20% Phase A + 80% Phase B at 0.90min, 20% Phase A + 80% Phase B at 1.70min, and Phase A at 1.90 Min is 70% A phase + 30% B phase, and the operation stops at 2.50 min.

The mass spectrometer adopts a SHIMADZU API 4000 mass spectrometer with an ESI source, and uses positive ion MRM scanning.

Compound parameters are listed in Table 1B.

Table 1B

【Compound of formula (A42), compound of formula (A54), compound of formula (A66)】

HPLC: SHIMADZU LC0A; Column: BR-C18

2.1*50mm, 3μm, Sepax; column temperature: room temperature.

In the mobile phase, phase A is an aqueous solution of 0.1% formic acid and 5 mM ammonium acetate, and phase B is acetonitrile. The flow rate was 0.70 mL/min, and the sample injection volume was 0.5 μL. The mobile phase gradient is 70% phase A + 30% phase B at 0.30 min, 20% phase A + 80% phase B at 0.90 min, 20% phase A + 80% phase B at 1.70 min, and phase A at 1.90 Min is 70% A phase + 30% B phase, and the operation stops at 2.50 min.

Compound parameters are listed in Table 1C.

Table 1C

【Compound of formula (A12), compound of formula (A60)】

HPLC: SHIMADZU LC0A; Column: BR-C18

2.1*50mm, 3μm, Sepax; column temperature: room temperature.

Compound parameters are listed in Table 1D.

Table 1D

【Compound of formula (A36), compound of formula (A72)】

HPLC: SHIMADZU LC0A; Column: BR-C18

2.1*50mm, 3μm, Sepax; column temperature: room temperature.

In the mobile phase, phase A is an aqueous solution of 0.1% formic acid and 5 mM ammonium acetate, and phase B is acetonitrile. The flow rate was 0.70 mL/min, and the sample injection volume was 0.5 μL. The mobile phase gradient is 75% Phase A + 25% Phase B at 0.30min, 20% Phase A + 80% Phase B at 1.20min, 20% Phase A + 80% Phase B at 1.70min, and Phase A at 1.90 Min is 75% A phase + 25% B phase, and the operation stops at 2.50 min.

Compound parameters are listed in Table 1E.

Table 1E

【Compound of formula (A24), compound of formula (A30), compound of formula (A48)】

HPLC: SHIMADZU LC0A; Column: BR-C18

2.1*50mm, 3μm, Sepax; column temperature: room temperature.

Compound parameters are listed in Table 1F.

Table 1F

【Compound of formula (A55), compound of formula (A74)】

HPLC: SHIMADZU LC0A; Column: BR-C18

2.1*50mm, 3μm, Sepax; column temperature: room temperature.

In the mobile phase, phase A is an aqueous solution of 0.1% formic acid and 5 mM ammonium acetate, and phase B is acetonitrile. The flow rate was 0.70 mL/min, and the sample injection volume was 0.5 μL. The mobile phase gradient is 80% Phase A + 20% Phase B at 0.30min, 15% Phase A + 85% Phase B at 0.80min, 16% Phase A + 85% Phase B at 1.60min, and Phase A at 1.70 Min is 80% A phase + 20% B phase, and the operation stops at 2.50 min.

Compound parameters are listed in Table 1G.

Table 1G

result

After administration, the plasma, skin, muscle and bone drug-time curves of the compound of formula (A2) and desloratadine are shown in Figures 17A, 17B, 17C and 17D. 3-OH desloratadine had no effective detectable mean concentration or drug loading in each group.

The percentage curve of drug absorption of the compound of formula (A2) is shown in FIG. 18 . The main pharmacokinetic parameters (plasma) in SD rats are shown in Table 2A.

Table 2A

Formula (A6) compound, formula (A12) compound, formula (A18) compound, formula (A24) compound, formula (A30) compound, formula (A36) compound, formula (A42) compound, formula (A48) compound, formula ( A54) compound, formula (A55) compound, formula (A60) compound, formula (A66) compound, formula (A72) compound, formula (A74) compound The percentage curves of transdermal drug absorption are shown in Figures 19A-19N and Table 2B.

Table 2B

From Figures 17A-17D, Figure 18, and Figures 19A-19N, it can be seen that except for the compound of formula (A60), the drug absorption rate of the other compounds after 24 hours is much higher than that of desloratadine. Especially in the case where Y is -NH-, and the -R' is selected from N-morpholinyl, although the compound of formula (A60) with n=6 is not much higher than desloratadine, but in the corresponding In the case of n=1, that is, the compound of formula (A55), the 24-hour transdermal drug absorption rate is as high as 83.0%. The transdermal drug absorption rate of the compound of formula (A55) is also significantly higher than that of the compound of formula (A) with n=6 where -R' is selected from other groups. At the same time, the transdermal drug absorption rate of the compound of formula (A2) is higher than that of the compound of formula (A6) to some extent.

Preliminarily, in the examples, n is selected from 1 to 5, especially the compound where n is 1 or 2, or Y is -O-, obtains an excellent effect on transdermal drug absorption rate; and even in n=6, also in most of –R', such as diethylamino, pyrrolidinyl, piperazinyl, bis(2-methoxyethyl)amino or 4-methylpiperazinyl, in drug Absorption rate, such as transdermal drug absorption rate, has achieved excellent results.

pharmacodynamic research

The effect of the compound of formula (A2) on the passive cutaneous anaphylaxis (PCA) of SD rats was investigated by means of single smear administration.

drug preparation

Mixed emulsion of ovalbumin and Freund's complete adjuvant: Accurately weigh 250mg of ovalbumin powder in a volumetric flask, dilute to 25mL of sterile water and stir to dissolve, then add 25ml of complete Freund's adjuvant and vortex to form an emulsion.

Mixture of Evans blue dye and ovalbumin: Accurately weigh 250mg of ovalbumin powder in a volumetric flask, dilute to 25mL sterile water and stir to dissolve, then add 25ml of 1% Evans blue dye and vortex mix.

Preparation of loratadine drug (positive drug): Accurately weigh 7 mg of loratadine, add 14 mL of normal saline, and dilute to a final concentration of 0.5 mg/mL.

Formula (A2) compound drug (test sample) preparation: Accurately weigh 7 mg of the formula (A2) compound, add 7 mL of normal saline, and dilute to a final concentration of 1 mg/mL.

Sensitized serum preparation

After the adaptation period of 13 male SD animals, the mixed emulsion of ovalbumin and Freund's complete adjuvant was intraperitoneally injected every other day, 5.0 mg ovalbumin per animal, and the administration volume was 1 mL each (containing 0.5 mL ovalbumin, Freund's complete adjuvant 0.5 mL), a total of 3 times of sensitization. Blood was collected 12 days after the last sensitization to prepare sensitized serum.

Preliminary Experiment of Passive Skin Allergic Response in Rats

Six male SD rats were taken for pre-experiment, and 0.1 mL of sensitized serum in gradient dilutions (1 times, 1/4 times and 1/16 times) were injected intradermally after hair removal on the back. After 0.5 hour and 1 hour, the same dose of ovalbumin (5.0 mg) as the sensitization dose plus an equal volume of 1% Evans blue dye (1 mL) was administered intravenously. Rats were euthanized 30 minutes after the challenge injection, and the blue spots on the skin were measured, and those with a diameter > 5mm were positive.

The results are shown in Figure 20. Rats were subcutaneously injected with concentrations of 1 times ("1:0" in Figure 20), 1/4 times ("1:4" in Figure 20) and 1/16 times (Figure 20 In "1:16") sensitized serum 0.5 hours and 1 hour after the tail injection of ovalbumin and 1% Evans blue dye 0.5 hours later, the back appeared obvious blue spots, compared with the control group, 1:16 concentration The diameter of the blue spots stimulated by the sensitized serum was less than 5mm, while the diameters of the blue spots stimulated by the sensitized serum at 1 times and 1/4 concentrations were both greater than 5mm, which were 9.92±0.32mm and 7.33±0.44mm respectively; in addition, There was no significant difference in the diameter of the blue spots between the sensitized serum for 0.5 hour and 1 hour.

In the formal experiment, SD rats were sensitized with 1-fold and 1/4-fold concentration of sensitized serum and injected with 1 mL of ovalbumin and 1% Evans blue solution 0.5 hours later to construct a rat passive skin allergy model.

Effect of formula (A2) compound on passive skin allergic reaction in rats

Get 24 male SD rats, be divided into 4 groups at random, be respectively blank group, model group, loratadine group (positive drug group) and formula (A2) compound group (test sample group), as shown in table 3 Show.

table 3

The loratadine group was intragastrically administered 5 mg/kg of loratadine 2 hours before the challenge, and the formula (A2) compound group was given 1.0 mg/only the compound of the formula (A2) by topical application 2 hours before the challenge. After hair removal on the back, 0.1 mL of sensitized serum with gradient dilution (1-fold and 1/4-fold) was injected intradermally. 0.5 hours later, the same dose of ovalbumin (5.0 mg) as the sensitization dose plus an equal volume of 1% Evans blue dye (1 mL in total) was administered intravenously. Blue spots in the skin were measured 0.5 hours after challenge injection,

Calculate the blue spot diameter for each group. Compare whether there is a statistically significant difference between the compound group of formula (A2) and the model group.

Figure 21A to Figure 21D respectively show the pictures of blue spots appearing or not appearing on the back of mice in blank group, model group, loratadine group, and compound group of formula (A2).

As shown in FIG. 21A , blue spots did not appear in the subcutaneous back of SD rats in the blank group.

As shown in Figure 21B, SD rats were subcutaneously injected with 1-fold and 1/4-fold sensitized serum in the back for 0.5 hours, and then injected ovalbumin and 1% Evans blue dye into the tail vein for 0.5 hours, and then the back appeared obviously blue. The spots, with diameters of 9.92±0.32mm and 7.33±0.44mm, respectively, indicated that the rat passive skin allergy model was successfully constructed.

As shown in Figure 21C, after loratadine was intragastrically administered 2 hours before sensitization, the blue spot diameters were 8.83±0.44mm and 7.09±0.64mm respectively. Compared with the model group, the loratadine group The diameter of blue spots stimulated by 1-fold concentration of sensitized serum was significantly reduced (p<0.01), while the diameter of blue spots stimulated by 1/4 concentration of sensitized serum in the loratadine group also decreased, but there was no statistically significant difference. Significant differences in learning.

As shown in Figure 21D, after the compound of formula (A2) was applied topically and administered 2 hours before sensitization, the blue spot diameters were 7.61±0.63mm and 6.45±0.70mm respectively, compared with the model group, 1 times and 1 /4 times the diameter of the blue spots stimulated by the sensitized serum were significantly reduced (p<0.01, p<0.01). In addition, the diameter of blue spots in the compound group of formula (A2) was significantly lower than that of the loratadine group under 1-fold concentration of serum sensitization.

Diameter of blue spots on the back of rats in each group after a single dose of sensitization

As in Table 4.

Table 4

^## p<0.01vs. blank group; *p<0.05vs. model group, **p<0.01vs. model group;

p<0.01vs. Loratadine group: 5mg/kg

Conclusion: Oral administration of 5 mg/kg loratadine 2 hours before sensitized serum stimulation to SD rats can significantly improve the passive skin allergic reaction of rats; Significantly improved the passive skin allergic reaction of rats, and the effect was better than that of loratadine.

The above-mentioned implementation mode is only the preferred implementation mode of the present application, which cannot limit the protection scope of the present application. Scope of protection claimed.

Claims

A kind of compound is characterized in that, is formula (A) compound,

in,

The -R is at least one selected from the group consisting of -R' and -Y-(CH 2 ) n -R';

said Y is at least one selected from the group consisting of O and NH, and said n is at least one selected from the group consisting of 1, 2, 3, 4, 5, and 6; and

The -R' is selected from the group consisting of diethylamino, pyrrolidinyl, piperazinyl, N-morpholinyl, bis(2-methoxyethyl)amino, and 4-methylpiperazinyl at least one of the
The compound of claim 1, wherein,

The -R is -Y-(CH 2 ) n -R';

Preferably, the compound of formula (A) is at least one selected from the group consisting of compounds of formula (A1) to formula (A72):

Preferably, said n is selected from 1 to 5;

Preferably, said n is selected from 1 to 4;

Preferably, said n is selected from 1 to 3;

Preferably, said n is 1 or 2;

Preferably, the Y is O;

Preferably, said Y is NH;

Preferably, the -R' is diethylamino;

Preferably, the -R' is pyrrolidinyl;

Preferably, the -R' is piperazinyl;

Preferably, the -R' is N-morpholinyl;

Preferably, the -R' is bis(2-methoxyethyl)amino; preferably, the -R' is 4-methylpiperazinyl.
The compound as claimed in claim 1 or 2, characterized in that,

said Y is O; and/or

Said n is selected from 1 to 5, preferably selected from 1 to 4, preferably selected from 1 to 3, preferably 1 or 2; and/or

The -R' is at least one selected from the group consisting of diethylamino, pyrrolidinyl, piperazinyl, bis(2-methoxyethyl)amino, and 4-methylpiperazinyl.
The compound of claim 1, wherein,

said -R is said -R';

Preferably, the compound of formula (A) is at least one selected from the group consisting of compounds of formula (A73) to formula (A78),

Preferably, the -R' is diethylamino;

Preferably, the -R' is pyrrolidinyl;

Preferably, the -R' is piperazinyl;

Preferably, the -R' is N-morpholinyl;

Preferably, the -R' is bis(2-methoxyethyl)amino;

Preferably, the -R' is 4-methylpiperazinyl.
A method for synthesizing the compound described in any one of claims 1 to 4, comprising:

contacting desloratadine with X(CH 2 ) n YC(=O)Cl to obtain a compound of formula (B); and

contacting the compound of formula (B) with compound H-R',

in,

The X is selected from at least one of Cl and Br;

Preferably, the contacting of desloratadine with X(CH 2 ) n YC(=O)Cl is under alkaline environment;

Preferably, the contacting of desloratadine with X(CH 2 ) n YC(=O)Cl is in the presence of N,N-diisopropylethylamine, triethylamine and 2,2,6 , in the presence of at least one of 6-tetramethylpiperidine;

Preferably, the contacting of desloratadine with X(CH 2 ) n YC(=O)Cl uses dichloromethane as a solvent;

Preferably, said contacting desloratadine with X(CH 2 ) n YC(=O)Cl is at a temperature from 0°C to 20°C;

Preferably, the contacting of the compound of formula (B) with the compound H-R' is under an alkaline environment;

Preferably, said compound of formula (B) is contacted with compound H-R' in the presence of potassium carbonate and potassium iodide;

Preferably, said contacting the compound of formula (B) with compound H-R' uses acetonitrile as solvent;

Preferably, said contacting the compound of formula (B) with the compound H—R' is at a temperature of 50°C to 80°C.
A method for synthesizing the compound described in any one of claims 1 to 4, comprising:

React with compound H-R and desloratadine as a reactant to obtain a compound of formula (A);

Preferably, the -R is -Y-(CH 2 ) n -R' and the Y is O, and the reaction with the compound H-R and desloratadine as reactants includes: using the compound H—R is contacted with N,N'-carbonyldiimidazole to obtain a first compound; and contacting said first compound with desloratadine,

Preferably, said first compound comprises or consists of a compound of formula (Ca),

Preferably, the -R is -Y-(CH 2 ) n -R' and the Y is NH, and the reaction with the compound H-R and desloratadine as reactants includes: using the compound contacting H-R with phosgene and/or triphosgene to obtain a second compound; and contacting said second compound with desloratadine,

Preferably, said second compound comprises or consists of a compound of formula (Cb),

Preferably, the -R is -R', and the reaction with the compound H-R and desloratadine includes: desloratadine and p-nitrobenzyl chloroformate, N , N′-carbonyldiimidazole and/or triphosgene are contacted to obtain a third compound; and the third compound is contacted with compound H–R,

Preferably, said third compound comprises or consists of a compound of formula (Cc),
The compound according to any one of claims 1 to 4, which is prepared by the method according to any one of claims 5 to 6.
Use of a compound of formula (B) or compound H-R in the preparation of a compound according to any one of claims 1 to 4.
Use of the compound as described in any one of claims 1 to 4 in the preparation of medicines for alleviating or treating or preventing allergy and its related symptoms.
purposes as claimed in claim 9, is characterized in that,

The allergy is at least one selected from the group consisting of skin allergy, atopic dermatitis, urticaria, eczema, rhinitis and asthma; and/or

The dosage form of the medicine is at least one selected from the group consisting of spray, patch, dressing, gel, injection and oral medicine.