PEG-modified glucocorticoid drug and application thereof

Abstract

The invention provides a polyethylene glycol (PEG) modified glucocorticoid medicine and application thereof, and relates to the technical field of medicinal chemistry, and the medicine comprises but is not limited to asthma, chronic obstructive pulmonary diseases, bronchitis, rhinitis and the like. The invention relates to a polyethylene glycol modified glucocorticoid drug. The polyethylene glycol modified glucocorticoid drug comprises but is not limited to the following compounds: KYAC-03, KYAC-04, KYAC-08, KYAC-09, KYAC-10, KYAC-11, KYAC-14, KYAC-16, KYAC-17, KYAC-20, KYAC-33 and KYAC-39. An anti-asthma and allergic rhinitis pharmacological experiment shows that the PEG-modified glucocorticoid medicine provided by the invention can remarkably improve disease symptoms and signs of asthma model mice and allergic rhinitis model mice, and remarkably reduces the administration dosage of glucocorticoid, so that the side effects of the whole body are reduced.

Description

PEG-modified glucocorticoid drugs and uses thereof Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry technology, and in particular to a polyethylene glycol (PEG)-modified glucocorticoid drug and its uses, including but not limited to asthma, chronic obstructive pulmonary disease, bronchitis, rhinitis, etc. Background Art

[0002] Glucocorticoids, with their anti-inflammatory properties, are widely used to treat inflammatory disorders or diseases, such as respiratory diseases, rheumatic autoimmune diseases, renal diseases, and skin diseases. They can control symptoms and slow disease progression, with significant clinical efficacy. The primary mechanisms of action of glucocorticoids in treating various inflammatory diseases include inhibiting the migration and activation of inflammatory cells such as eosinophils and neutrophils; inhibiting the production of cytokines such as prostaglandins and leukotrienes; inhibiting the release of inflammatory mediators; and enhancing β2 receptor responsiveness in bronchial smooth muscle cells. Because glucocorticoid receptors are widely distributed within effector cells, the effects of glucocorticoids are closely dose-dependent. At supraphysiological doses, glucocorticoids exhibit a wide range of pharmacological effects, particularly important ones such as anti-inflammatory, immunosuppressive, and anti-shock effects. However, they can also be associated with numerous adverse reactions, such as obesity, moon facies, buffalo hump, edema, spontaneous fractures, osteoporosis and femoral head necrosis, ulcers, acute gastrointestinal bleeding, insomnia, hirsutism, and decreased immunity, which limit their clinical application. In particular, osteoporosis caused by glucocorticoids accounts for 30% to 50% of patients treated with long-term glucocorticoids. There is currently no good treatment method. Once discovered, glucocorticoid drugs can only be discontinued.

[0003] In the treatment of lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and bronchitis, the use of inhalation preparations can directly reach the lesion site, which has its unique advantages over other modes of administration; however, it still faces the problems of large drug loss, small lung deposition, and inability to reach deep lungs. In the prior art, the 21-position succinate of glucocorticoids is coupled and hydrolyzed with oligoethylene glycol monosilyl protection compounds to obtain a compound with a terminal hydroxyl group, which has a short retention time in the lungs and results in poor local efficacy (e.g., control compound 1); in addition, the 21-position hydroxyl group of the glucocorticoid is directly esterified with the terminal carboxyl group of oxidized PEG or the 21-position carbonate of the glucocorticoid is coupled with oligoethylene glycol monoether, and the resulting compound has poor stability and is not suitable for preparing solution preparations (e.g., control compound 2 and control compound 3).

[0004] In view of the shortcomings and deficiencies of the above-mentioned prior art, the present invention provides a novel low-molecular-weight PEG (<5000) covalently modified glucocorticoid drug and its uses, including but not limited to asthma, chronic obstructive pulmonary disease, bronchitis, rhinitis, etc.

[0005] Summary of the Invention

[0006] The main purpose of the present invention is to provide a PEG-modified glucocorticoid drug and its use, in order to at least partially solve at least one of the above-mentioned technical problems.

[0007] As a first aspect of the present invention, the present invention provides a polyethylene glycol (PEG)-modified glucocorticoid drug, characterized in that the structural formula of the compound of formula I is as follows:

[0008] Wherein, A, B, C, R1, R2, R3, R4 and R5 shown in the structural formula of the compound of general formula I are selected independently of each other, and:

[0009] n is an integer from 3 to 100;

[0010] A is selected from C(O) or P(O)(OH);

[0011] B is selected from null, substituted or unsubstituted alkylene containing 1 to 6 carbon atoms, and substituted or unsubstituted arylene containing 6 to 10 carbon atoms;

[0012] C is selected from no group, C(O), S(O)2 or P(O)(OH)O;

[0013] R1 is selected from H or halogen;

[0014] R2 is selected from H, methyl or halogen;

[0015] R3 and R4 are independently selected from H, OH, an alkyl group containing 1 to 6 carbon atoms, OR6, OCOR7,

[0016] Or, R3 and R4 together form That is, C16 and C17 are connected by an oxygen bridge.

[0017] Or, R3 and R4 together form That is, C16 and C17 are connected by an oxazole ring.

[0018] Or, R3 and R4 together form That is, C16 and C17 are connected by epoxy.

[0019] Or, R3 and R4 together form a single bond, i.e., C16 and C17 are also connected by a double bond;

[0020] R5 is selected from substituted or unsubstituted alkyl groups containing 1 to 6 carbon atoms;

[0021] wherein R6 is selected from an alkyl group or a halogenated alkyl group containing 1 to 6 carbon atoms;

[0022] wherein R7 is selected from an alkyl group containing 1 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, an alkynyl group containing 2 to 6 carbon atoms, an aryl group containing 6 to 10 carbon atoms, or a heteroaryl or heterocyclic group containing 4 to 10 carbon atoms;

[0023] wherein R8 and R9 are independently selected from H, an alkyl group (chain alkane or cycloalkane) containing 1-6 carbon atoms, an alkenyl group containing 2-6 carbon atoms, an alkynyl group containing 2-6 carbon atoms, an aryl group containing 6-10 carbon atoms, a heteroaryl group or a heterocyclic group containing 4-10 carbon atoms, or R8 and R9 together form a cycloalkane containing 3-5 carbon atoms;

[0024] Among them, R 10 is selected from H, an alkyl group containing 1 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, an alkynyl group containing 2 to 6 carbon atoms, an aryl group containing 6 to 10 carbon atoms, or a heteroaryl or heterocyclyl group containing 4 to 10 carbon atoms;

[0025] wherein the halogen is selected from F or Cl;

[0026] The dashed lines represent single or double bonds.

[0027] Furthermore, n is an integer of 3-70; preferably an integer of 3-16; more preferably an integer of 5-9; further preferably an integer of 7-9.

[0028] Furthermore, A is selected from C(O).

[0029] Furthermore, B is selected from a null, substituted or unsubstituted alkylene group containing 2-4 carbon atoms; preferably a substituted or unsubstituted alkylene group containing 2-4 carbon atoms; further preferably a substituted or unsubstituted alkylene group containing 2-3 carbon atoms; and further preferably a substituted or unsubstituted ethylene group.

[0030] Furthermore, C is selected from no group or C(O); preferably C(O).

[0031] Furthermore, R2 is selected from H, methyl or halogen; preferably H or halogen.

[0032] Furthermore, R3 and R4 are independently selected from H, OH, an alkyl group containing 1-3 carbon atoms, and OCOR7, wherein R7 is selected from an alkyl group containing 1-3 carbon atoms or a heterocyclic group containing 4-6 carbon atoms; preferably, R3 and R4 are independently selected from H, OH, methyl, and OCOR7, wherein R7 is selected from ethyl and furyl; further preferably, R3 and R4 are independently selected from OH, methyl, and OCOR7, wherein R7 is selected from ethyl and furyl.

[0033] Furthermore, R3 and R4 together form That is, C16 and C17 are also connected by an oxygen bridge, wherein R8 and R9 are independently selected from H, an alkyl group containing 1-6 carbon atoms (chain alkane or cycloalkane), or R8 and R9 together form a cycloalkane containing 3-5 carbon atoms.

[0034] Furthermore, R3 and R4 together form That is, C16 and C17 are connected by an oxazole ring, wherein R 10 Selected from alkyl groups containing 1-3 carbons; preferably R 10 Selected from methyl.

[0035] Furthermore, A, B, C, R1, R2, R3, R4 and R5 shown in the structural formula of the compound of general formula I are selected independently of each other, and:

[0036] n is an integer from 3 to 70;

[0037] A is selected from C(O) or P(O)(OH);

[0038] B is selected from a null, substituted or unsubstituted alkylene group containing 2 to 4 carbon atoms;

[0039] C is selected from no group or C(O);

[0040] R1 is selected from H or halogen;

[0041] R2 is selected from H, methyl or halogen;

[0042] R3 and R4 are independently selected from H, OH, an alkyl group containing 1 to 3 carbon atoms, OCOR7,

[0043] Or, R3 and R4 together form That is, C16 and C17 are connected by an oxygen bridge.

[0044] Or, R3 and R4 together form That is, C16 and C17 are also connected through an oxazole ring;

[0045] R5 is selected from substituted or unsubstituted alkyl groups containing 1 to 3 carbons;

[0046] wherein R7 is selected from an alkyl group containing 1 to 3 carbon atoms or a heterocyclic group containing 4 to 6 carbon atoms;

[0047] wherein R8 and R9 are independently selected from H, an alkyl group containing 1 to 6 carbon atoms (chain alkane or cycloalkane), or R8 and R9 together form a cycloalkane containing 3 to 5 carbon atoms;

[0048] Among them, R 10 Selected from alkyl groups containing 1 to 3 carbons;

[0049] wherein the halogen is selected from F or Cl;

[0050] The dashed lines represent single or double bonds.

[0051] Furthermore, A, B, C, R1, R2, R3, R4 and R5 shown in the structural formula of the compound of general formula I are selected independently of each other, and:

[0052] n is an integer from 3 to 16;

[0053] A is selected from C(O);

[0054] B is selected from an alkylene group containing 2 to 4 carbon atoms;

[0055] C is selected from C(O);

[0056] R1 is selected from H or halogen;

[0057] R2 is selected from H, methyl or halogen;

[0058] R3 and R4 are independently selected from H, OH, an alkyl group containing 1 to 3 carbon atoms, OCOR7,

[0059] Or, R3 and R4 together form That is, C16 and C17 are connected by an oxygen bridge.

[0060] Or, R3 and R4 together form That is, C16 and C17 are also connected through an oxazole ring;

[0061] R5 is selected from substituted or unsubstituted alkyl groups containing 1 to 3 carbons;

[0062] wherein R7 is selected from an alkyl group containing 1 to 3 carbon atoms or a heterocyclic group containing 4 to 6 carbon atoms;

[0063] wherein R8 and R9 are independently selected from H, an alkyl group containing 1 to 6 carbon atoms (chain alkane or cycloalkane), or R8 and R9 together form a cycloalkane containing 3 to 5 carbon atoms;

[0064] Among them, R 10 Selected from alkyl groups containing 1 to 3 carbons;

[0065] wherein the halogen is selected from F or Cl;

[0066] The dashed lines represent single or double bonds.

[0067] Furthermore, A, B, C, R1, R2, R3, R4 and R5 shown in the structural formula of the compound of general formula I are selected independently of each other, and:

[0068] n is an integer from 5 to 9;

[0069] A is selected from C(O);

[0070] B is selected from an alkylene group containing 2-3 carbons;

[0071] C is selected from C(O);

[0072] R1 is selected from H or halogen;

[0073] R2 is selected from H or halogen;

[0074] R3 and R4 are independently selected from H, OH, methyl, OCOR7,

[0075] Or, R3 and R4 together form That is, the C16 and C17 positions are also connected by an oxygen bridge;

[0076] R5 is selected from methyl;

[0077] Wherein, R7 is selected from ethyl, furyl;

[0078] wherein R8 and R9 are independently selected from H, an alkyl group containing 1 to 6 carbon atoms (chain alkane or cycloalkane), or R8 and R9 together form a cycloalkane containing 3 to 5 carbon atoms;

[0079] wherein the halogen is selected from F or Cl;

[0080] The dashed lines represent single or double bonds.

[0081] Furthermore, A, B, C, R1, R2, R3, R4 and R5 shown in the structural formula of the compound of general formula I are selected independently of each other, and:

[0082] n is an integer from 7 to 9;

[0083] A is selected from C(O);

[0084] B is selected from ethylene;

[0085] C is selected from C(O);

[0086] R1 is selected from H or halogen;

[0087] R2 is selected from H or halogen;

[0088] R3 and R4 are independently selected from OH, methyl, OCOR7,

[0089] Or, R3 and R4 together form That is, the C16 and C17 positions are also connected by an oxygen bridge;

[0090] R5 is selected from methyl;

[0091] Wherein, R7 is selected from ethyl, furyl;

[0092] wherein R8 and R9 are independently selected from H, an alkyl group containing 1 to 6 carbon atoms (chain alkane or cycloalkane), or R8 and R9 together form a cycloalkane containing 3 to 5 carbon atoms;

[0093] wherein the halogen is selected from F or Cl;

[0094] The dashed lines represent single or double bonds.

[0095] Furthermore, the compound of general formula I is selected from the following compounds:

[0096] Furthermore, the compound of general formula I is selected from the following compounds:

[0097] Furthermore, the compound of general formula I is selected from the following compounds:

[0098] Furthermore, the compound of general formula I is selected from the following compounds: KYAC-03, KYAC-04, KYAC-08, KYAC-09, KYAC-10, KYAC-11, KYAC-14, KYAC-16, KYAC-17, KYAC-20, KYAC-33, and KYAC-39.

[0099] As a second aspect of the present invention, the present invention provides the use of the above-mentioned PEG-modified glucocorticoid drug in the preparation of a drug for treating glucocorticoid receptor-mediated diseases.

[0100] Furthermore, the disease includes but is not limited to eczema, psoriasis, atopic dermatitis, allergic dermatitis, neurodermatitis, rheumatoid arthritis, rhinitis, nasal polyps, asthma, chronic obstructive pulmonary disease, bronchitis, interstitial lung disease, conjunctivitis, colitis, segmental enteritis or chronic glomerulonephritis; preferably asthma, chronic obstructive pulmonary disease, bronchitis or rhinitis; further preferably asthma, bronchitis or rhinitis; further preferably asthma or bronchitis.

[0101] As a third aspect of the present invention, the present invention provides a pharmaceutical composition comprising the above-mentioned PEG-modified glucocorticoid drug.

[0102] Furthermore, it also includes one or more additional therapeutic agents, which are selected from β2-receptor agonists, anticholinergic drugs or antibacterial drugs.

[0103] Furthermore, the β2-receptor agonist is selected from a short-acting β2-receptor agonist or a long-acting β2-receptor agonist.

[0104] Furthermore, the short-acting β2-receptor agonist is selected from salbutamol, terbutaline or fenoterol; the long-acting β2-receptor agonist is selected from formoterol, arformoterol, salmeterol, procaterol, olodaterol or indacaterol.

[0105] Furthermore, the anticholinergic drug is selected from a short-acting anticholinergic drug or a long-acting anticholinergic drug.

[0106] Furthermore, the short-acting anticholinergic drug is selected from ipratropium bromide; the long-acting anticholinergic drug is selected from tiotropium bromide, glycopyrrolate, oxitropium bromide, umeclidinium bromide, aclidinium bromide or revenacin.

[0107] Furthermore, the antibacterial drug is selected from tobramycin, amikacin, polymyxin E sodium mesylate, levofloxacin or aztreonam lysine.

[0108] Furthermore, the dosage form of the pharmaceutical composition is selected from injection, oral preparation, external preparation or inhalation preparation.

[0109] Furthermore, the dosage form of the pharmaceutical composition is selected from an inhalation preparation.

[0110] As a fourth aspect of the present invention, the present invention provides a method for preparing a PEG-modified glucocorticoid drug, comprising the following steps: reacting a compound of formula II with oligoethylene glycol monomethyl ether in the presence of a catalyst and a condensing agent to obtain a compound of formula I, i.e., a PEG-modified glucocorticoid drug, wherein the reaction formula is as follows:

[0111] Wherein, A, B, C, R1, R2, R3, R4 and R5 shown in the structural formula of the compound of formula I and the compound of formula II are selected independently of each other, and:

[0112] n is an integer from 3 to 100;

[0113] A is selected from C(O) or P(O)(OH);

[0114] B is selected from null, substituted or unsubstituted alkylene containing 1 to 6 carbon atoms, and substituted or unsubstituted arylene containing 6 to 10 carbon atoms;

[0115] C is selected from no group, C(O), S(O)2 or P(O)(OH)O;

[0116] R1 is selected from H or halogen;

[0117] R2 is selected from H, methyl or halogen;

[0118] R3 and R4 are independently selected from H, OH, an alkyl group containing 1 to 6 carbon atoms, OR6, OCOR7,

[0119] Or, R3 and R4 together form That is, C16 and C17 are connected by an oxygen bridge.

[0120] Or, R3 and R4 together form That is, C16 and C17 are connected by an oxazole ring.

[0121] Or, R3 and R4 together form That is, C16 and C17 are connected by epoxy.

[0122] Or, R3 and R4 together form a single bond, i.e., C16 and C17 are also connected by a double bond;

[0123] R5 is selected from substituted or unsubstituted alkyl groups containing 1 to 6 carbon atoms;

[0124] wherein R6 is selected from H or an alkyl or halogenated alkyl group containing 1 to 6 carbon atoms;

[0125] wherein R7 is selected from an alkyl group containing 1 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, an alkynyl group containing 2 to 6 carbon atoms, an aryl group containing 6 to 10 carbon atoms, or a heteroaryl or heterocyclic group containing 4 to 10 carbon atoms;

[0126] wherein R8 and R9 are independently selected from H, an alkyl group (chain alkane or cycloalkane) containing 1-6 carbon atoms, an alkenyl group containing 2-6 carbon atoms, an alkynyl group containing 2-6 carbon atoms, an aryl group containing 6-10 carbon atoms, a heteroaryl group or a heterocyclic group containing 4-10 carbon atoms, or R8 and R9 together form a cycloalkane containing 3-5 carbon atoms;

[0127] Among them, R 10 is selected from H, an alkyl group containing 1 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, an alkynyl group containing 2 to 6 carbon atoms, an aryl group containing 6 to 10 carbon atoms, or a heteroaryl or heterocyclyl group containing 4 to 10 carbon atoms;

[0128] wherein the halogen is selected from F or Cl;

[0129] The dashed lines represent single or double bonds.

[0130] Furthermore, n is an integer of 3-70; preferably an integer of 3-16; more preferably an integer of 5-9; further preferably an integer of 7-9.

[0131] Furthermore, A is selected from C(O).

[0132] Furthermore, B is selected from a group consisting of an unsubstituted, substituted or unsubstituted alkylene group containing 1 to 6 carbon atoms; preferably, an unsubstituted, substituted or unsubstituted alkylene group containing 2 to 4 carbon atoms; further preferably, a substituted or unsubstituted alkylene group containing 2 to 4 carbon atoms; further preferably, a substituted or unsubstituted alkylene group containing 2 to 3 carbon atoms; and most preferably, a substituted or unsubstituted ethylene group.

[0133] Furthermore, C is selected from no group or C(O); preferably C(O).

[0134] Furthermore, R2 is selected from H, methyl or halogen; preferably H or halogen.

[0135] Furthermore, R3 and R4 are independently selected from H, OH, an alkyl group containing 1-3 carbon atoms, and OCOR7, wherein R7 is selected from an alkyl group containing 1-3 carbon atoms or a heterocyclic group containing 4-6 carbon atoms; preferably, R3 and R4 are independently selected from H, OH, methyl, and OCOR7, wherein R7 is selected from ethyl and furyl; further preferably, R3 and R4 are independently selected from OH, methyl, and OCOR7, wherein R7 is selected from ethyl and furyl.

[0136] Furthermore, R3 and R4 together form That is, C16 and C17 are also connected by an oxygen bridge, wherein R8 and R9 are independently selected from H, an alkyl group containing 1 to 6 carbon atoms, or R8 and R9 together form a cycloalkane containing 3 to 5 carbon atoms.

[0137] Furthermore, R3 and R4 together form That is, C16 and C17 are connected by an oxazole ring, wherein R 10 Selected from alkyl groups containing 1-3 carbons; preferably R 10 Selected from methyl.

[0138] Furthermore, the catalyst is selected from 4-dimethylaminopyridine (DMAP) or 4-pyrrolidinylpyridine; preferably 4-dimethylaminopyridine (DMAP).

[0139] Furthermore, the condensing agent is selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI); preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI).

[0140] Furthermore, the degree of polymerization of the oligoethylene glycol monomethyl ether is 3-100; preferably, the degree of polymerization is 3-70; more preferably, the degree of polymerization is 3-16; further preferably, the degree of polymerization is 5-9; and most preferably, the degree of polymerization is 7-9.

[0141] Furthermore, the compound of formula II is obtained by reacting the compound of formula III with an acylating agent, and the reaction formula is as follows:

[0142] Wherein, R1, R2, R3, and R4 shown in the structural formula of the compound of general formula III are the same as R1, R2, R3, and R4 shown in the structural formula of the compound of general formula II.

[0143] Furthermore, the acylating agent is selected from carboxylic acid, acid anhydride, acyl chloride, phosphorus oxychloride, and chlorosulfonic acid.

[0144] Furthermore, the carboxylic acid is selected from substituted or unsubstituted malonic acid, succinic acid, glutaric acid, adipic acid, and pimelic acid; the acid anhydride is selected from substituted or unsubstituted succinic anhydride, glutaric anhydride, adipic anhydride, and pimelic anhydride; the acyl chloride is selected from oxalyl chloride, substituted or unsubstituted malonic chloride, succinic chloride, glutaric chloride, adipic chloride, and pimelic chloride; and the phosphorus oxychloride is selected from phosphorus oxychloride and pyrophosphorus oxychloride.

[0145] Furthermore, the carboxylic acid is selected from substituted or unsubstituted succinic acid, glutaric acid or adipic acid; the acid anhydride is selected from substituted or unsubstituted succinic anhydride, glutaric anhydride or adipic anhydride; the acid chloride is selected from substituted or unsubstituted succinyl chloride, glutaryl chloride or adipic chloride; and the phosphorus oxychloride is selected from pyrophosphorus oxychloride.

[0146] Compared with the prior art, the present invention has the following beneficial effects:

[0147] The present invention derives a glucocorticoid drug from oligoethylene glycol monomethyl ether via a linker moiety (including but not limited to carboxylate or phosphate) to obtain a PEG-modified glucocorticoid drug. The drug has significantly improved solubility and can form micellar self-assemblies in aqueous solutions and buffer salt systems. The PEG-modified glucocorticoid drug provided by the present invention can improve the drug delivery efficiency to the lungs during pulmonary administration. It can also penetrate the mucus layer on the airway surface in the form of hydrophilic micelles to reach the lung epithelial cells and be metabolized in the lung tissue to release glucocorticoid active molecules, avoiding clearance by ciliary tissue, improving drug efficacy, reducing the hormone dosage, and thus reducing the systemic toxic side effects caused by long-term use of glucocorticoid drugs.

[0148] The PEG-modified glucocorticoid drug provided by the present invention can significantly reduce the agonist activity on the GR receptor and has a lower GR receptor agonist activity before being converted into active metabolites by endogenous esterases, thereby reducing the oropharyngeal adverse reactions caused by aerosol inhalation administration and the side effects caused by systemic absorption.

[0149] Anti-asthma and allergic rhinitis efficacy experiments show that the PEG-modified glucocorticoid drug provided by the present invention can significantly improve the disease symptoms and signs of asthma model mice and allergic rhinitis model mice, and significantly reduce the dosage of glucocorticoid, thereby reducing systemic side effects.

[0150] Compared with the method of coupling and hydrolyzing the 21-position succinate of glucocorticoid with oligoethylene glycol monosilyl protection compounds to obtain a compound with a terminal hydroxyl group, the present invention can form a micellar solution with a long retention time in the lungs, thereby prolonging the duration of local drug effect.

[0151] Compared with compounds obtained by directly esterifying the 21-hydroxyl group of a glucocorticoid with the terminal carboxyl group of oxidized PEG or coupling the 21-carbonate of a glucocorticoid with an oligoethylene glycol monoether, the present invention has better stability in a buffer salt system (weak acid or weak base), avoids degradation reactions of the ester bond, and is more suitable for the preparation of pharmaceutical solution preparations.

[0152] Figures in the specification

[0153] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0154] Figure 1 shows the distribution of the deposition amounts of KYAC-03 solution and budesonide suspension at various sites on the NGI. DETAILED DESCRIPTION

[0155] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are intended only to illustrate the present invention and should not be construed as limiting the scope of the present invention. Where specific conditions are not specified in the examples, conventional conditions were used. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0156] The glucocorticoid conversion in the present invention is based on the molecular weight ratio of the compound before conversion (PEG-modified glucocorticoid drug) to the compound after conversion (glucocorticoid prototype drug with a hydroxyl group at position 21). For example, in Experimental Example 6, compound KYAC-02 is converted according to the molecular weight ratio of compound KYAC-02 to budesonide.

[0157] Example 1-1: Synthesis of compound KYAC-01

[0158] Budesonide (20 g, 46 mmol) was dissolved in dichloromethane (120 mL), followed by the addition of succinic anhydride (6 g, 60 mmol) and DMAP (7.4 g, 60 mmol). The reaction was allowed to proceed at room temperature and monitored by TLC until no budesonide was present. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution and the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate budesonide succinate (20 g, 81% yield). MS m / z (ESI): 553.4 [M+Na] + .

[0159] Budesonide succinate (5.4 g, 10 mmol), triethylene glycol monomethyl ether (2.0 g, 12 mmol), DMAP (0.25 g, 2 mmol), and EDCI (2.9 g, 15 mmol) were dissolved in dichloromethane (85 mL) and reacted at room temperature. TLC monitoring indicated the absence of budesonide succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. Purification by silica gel column chromatography (dichloromethane (DCM) / methanol (MeOH) = 50:1) and concentration in vacuo afforded KYAC-01 (2.1 g, 31% yield) as a colorless oil. 1 H NMR (400MHz, d6-DMSO): δ7.29(d,J=9.2Hz,1H),6.27(d,J=7.9Hz,1H),4.56-4.44(m,3H),4.26-4.13(m ,2H),4.11-4.09(m,2H),3.57-3.54(m,2H),3.51-3.43(m,6H),3.39-3.36(m,2H),3.17(s,3H),2.68-2 .63(m,2H),2.54-2.48(m,2H),2.34(d,J=5.9Hz,2H),2.33-1.95(m,2H),1.93-1.47(m,3H),1.78-1.74 (m,1H),1.64-1.52(m,5H),1.52-1.23(m,3H),1.31-1.25(m,2H),0.93-0.80(m,5H),0.92-0.88(m,3H). MS m / z(ESI):677.3[M+H] + .

[0160] Example 1-2: Synthesis of compound KYAC-02

[0161] Budesonide succinate (4 g, 7.5 mmol), pentaethylene glycol monomethyl ether (2.3 g, 9 mmol), DMAP (0.18 g, 1.5 mmol), and EDCI (1.7 g, 9 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of budesonide succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 50:1) and concentrated in vacuo to afford KYAC-02 (3.2 g, 46% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ7.30(dd,J=10.1,3.7Hz,1H),6.15(dt,J=10.1,1.8Hz,1H),5.91(t,J=1.6Hz,1H),5.18(t,J=4.9Hz,1H),5.08-4.96(m, 2H), 4.84 (t, J=4.3Hz, 1H), 4.82-4.73 (m, 1H), 4.73-4.59 (m, 1H), 4.28 (dt, J=7.8, 3.6Hz, 1H), 4.12 (dd, J=6. 1,3.6Hz,2H),3.59(dd,J=5.3,4.2Hz,2H),3.56-3.46(m,14H),3.46-3.37(m,2H),3.22(s,3H),2.67(dd,J=8. 0,5.8Hz,2H),2.59(dd,J=7.0,4.9Hz,2H),2.32-2.24(m,1H),1.98(d,J=10.4Hz,2H),1.84-1.69(m,2H),1.63 -1.54(m,4H),1.57-1.51(m,1H),1.54-1.38(m,1H),1.38-1.20(m,5H),1.02-0.88(m,1H),0.90-0.80(m,6H). MS m / z(ESI):765.4[M+H] + .

[0162] Example 1-3: Synthesis of compound KYAC-03

[0163] Budesonide succinate (4 g, 7.5 mmol), heptaethylene glycol monomethyl ether (3.1 g, 9 mmol), DMAP (0.18 g, 1.5 mmol), and EDCI (1.7 g, 9 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of budesonide succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-03 (3.6 g, 46% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ7.30(dd,J=10.1,3.7Hz,1H),6.15(dt,J=10.1,1.8Hz,1H),5.91(d,J=1.6Hz,1H),5.18(t,J=4.9Hz,1H),5.0 8-4.96(m,2H),4.84(t,J=4.3Hz,1H),4.82-4.73(m,1H),4.73-4.59(m,1H),4.28(dt,J=7.8,3.7Hz,1H),4.12(dd,J=6.1,3.7Hz,2H), 3.59(d,J=4.7Hz,2H),3.60-3.46(m,22H),3.41(dd,J=5.9,3.6Hz,2H),3.22(s,3H),2.67(dd,J=7.1,4.8Hz,2H),2.63-2.50(m,2H), 2.32-2.24(m,1H),2.01-1.91(m,2H),1.84-1.67(m,2H),1.63-1.47(m,5H),1.40-1.21(m,6H),1.03-0.88(m,1H),0.90-0.80(m,6H). MS m / z(ESI):853.4[M+H] + .

[0164] Example 1-4: Synthesis of compound KYAC-04

[0165] Budesonide succinate (4 g, 7.5 mmol), nonaethylene glycol monomethyl ether (3.9 g, 9 mmol), DMAP (0.18 g, 1.5 mmol), and EDCI (1.7 g, 9 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature. TLC monitoring indicated the absence of budesonide succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 20:1) and concentrated in vacuo to afford KYAC-04 (3.9 g, 55% yield) as a colorless oil. 1 H NMR (400MHz, d6-DMSO): δ7.30 (dd, J=10.1, 3.7Hz, 1H), 6.15 (dt, J=10.1, 1.8Hz, 1H), 5.91 (d, J=1.6Hz, 1H), 5.18 (t, J=4.9Hz, 1H), 5.08-4. 97(m,2H),4.84(t,J=4.3Hz,1H),4.82-4.75(m,1H),4.73-4.59(m,1H),4.28(dt,J=7.8,3.7Hz,1H),4.12(dd,J=6.1,3.7Hz,2H),3.59(d,J= 4.7Hz,2H),3.60-3.46(m,30H),3.50-3.42(m,2H),3.34(s,3H),2.58-2.54(m,2H),2.51-2.45(m,2H),2.41(d,J=5.8Hz,1H),2.27-1.94(m ,2H),1.91-1.58(m,2H),1.73-1.65(m,1H),1.61-1.56(m,5H),1.52- 1.37(m,3H),1.30-1.25(m,2H),1.03-0.90(m,1H),0.90-0.80(m,6H). MS m / z(ESI):941.5[M+H] + .

[0166] Example 1-5: Synthesis of compound KYAC-05

[0167] Budesonide succinate (4 g, 7 mmol), hexadecanediol monomethyl ether (6.6 g, 9 mmol), DMAP (0.18 g, 1 mmol), and EDCI (1.7 g, 9 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of budesonide succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-05 (2.6 g, 30% yield) as a colorless oil. 1 H NMR (400MHz, d6-DMSO): δ7.32(d,J=9.8Hz,1H),6.49(d,J=7.9Hz,1H),4.71-4.55(m,3H),4.47-4.35(m ,2H),4.28-4.16(m,2H),3.89-3.64(m,2H),3.60-3.50(m,58H),3.44-3.39(m,2H),3.31(s,3H),2.62-2 .53(m,2H),2.48-2.41(m,2H),2.39(d,J=5.9Hz,2H),2.30-2.15(m,2H),1.95-1.55(m,3H),1.75-1.65 (m,1H),1.60-1.54(m,5H),1.50-1.32(m,3H),1.30-1.21(m,2H),0.99-0.87(m,5H),0.95-0.87(m,3H). MS m / z(ESI):1249.8[M+H] +

[0168] Example 1-6: Synthesis of compound KYAC-06

[0169] Deisobutyl ciclesonide (20 g, 42 mmol) was dissolved in pyridine (160 mL), and succinic anhydride (17 g, 170 mmol) was added. The reaction was allowed to proceed at room temperature, and TLC was monitored until deisobutyl ciclesonide was eliminated. The reaction solution was then poured into 0.2 N hydrochloric acid solution (2 L), resulting in the formation of a large amount of white precipitate. After filtration, the product was rinsed three times with water to obtain the intermediate deisobutyl ciclesonide succinate (20 g, 82% yield). MS m / z (ESI): 593.3 [M+Na] + .

[0170] Desisobutyl ciclesonide succinate (4 g, 7 mmol), triethylene glycol monomethyl ether (1.4 g, 8.4 mmol), DMAP (0.17 g, 1.4 mmol), and EDCI (1.6 g, 8.4 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of desisobutyl ciclesonide succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 50:1) and concentrated in vacuo to afford KYAC-06 (2.1 g, 42% yield) as a colorless oil. 1 H NMR (400MHz, d6-DMSO) δ7.31(d,J=9.8Hz,1H),6.15(d,J=8.2Hz,1H),5.89(s,1H),4.78-4.70(m,2H),4.39-4.25( m,2H),4.23(d,J=8.3Hz,1H),4.15(d,J=8.9Hz,1H),4.12-4.10(m,2H),3.58-3.56(m,2H),3.50-3.45(m,6H),3.4 0-3.38(m,2H),3.19(s,3H),2.66-2.62(m,2H),2.58-2.54(m,2H),2.57-2.50(m,1H),2.33-2.22(m,1H),2.11-2. 02(m,1H),2.02-1.92(m,1H),1.81-1.67(m,2H),1.67-1.42(m,9H),1.36(s,3H),1.17-0.85(m,7H),0.79(s,3H). MS m / z(ESI):717.4[M+H] + .

[0171] Example 1-7: Synthesis of compound KYAC-07

[0172] Desisobutyl ciclesonide succinate (4 g, 7 mmol), pentaethylene glycol monomethyl ether (2.1 g, 8.4 mmol), DMAP (0.17 g, 1.4 mmol), and EDCI (1.6 g, 8.4 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of desisobutyl ciclesonide succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 50:1) and concentrated in vacuo to afford KYAC-07 (2.8 g, 56% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.32(d,J=10Hz,1H),6.17(d,J=8.4Hz,1H),5.92(s,1H),4.80-4.73(m,2H),4.42-4.28(m ,2H),4.25(d,J=8.5Hz,1H),4.17(d,J=9.1Hz,1H),4.13-4.11(m,2H),3.60-3.58(m,2H),3.53-3.48(m,14H),3.4 2-3.40(m,2H),3.22(s,3H),2.69-2.65(m,2H),2.61-2.57(m,2H),2.60-2.52(m,1H),2.36-2.25(m,1H),2.14-2. 05(m,1H),2.05-1.95(m,1H),1.84-1.70(m,2H),1.70-1.45(m,9H),1.39(s,3H),1.20-0.88(m,7H),0.82(s,3H). MS m / z(ESI):805.4[M+H] + .

[0173] Example 1-8: Synthesis of compound KYAC-08

[0174] Desisobutyl ciclesonide succinate (4 g, 7 mmol), heptaethylene glycol monomethyl ether (2.9 g, 8.4 mmol), DMAP (0.17 g, 1.4 mmol), and EDCI (1.6 g, 8.4 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of desisobutyl ciclesonide succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-08 (3.0 g, 48% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.35(d,J=10.3Hz,1H),6.20(d,J=8.7Hz,1H),5.95(s,1H),4.83-4.76(m,2H),4.45-4.31 (m,2H),4.28(d,J=8.8Hz,1H),4.20(d,J=9.4Hz,1H),4.16-4.14(m,2H),3.63-3.61(m,2H),3.56-3.51(m,22H),3. 45-3.43(m,2H),3.25(s,3H),2.72-2.68(m,2H),2.64-2.60(m,2H),2.63-2.55(m,1H),2.39-2.28(m,1H),2.17-2 .08(m,1H),2.08-1.98(m,1H),1.87-1.73(m,2H),1.73-1.48(m,9H),1.42(s,3H),1.23-0.91(m,7H),0.85(s,3H). MS m / z(ESI):893.5[M+H] + .

[0175] Example 1-9: Synthesis of compound KYAC-09

[0176] Desisobutyl ciclesonide succinate (4 g, 7 mmol), nonaethylene glycol monomethyl ether (3.6 g, 8.4 mmol), DMAP (0.17 g, 1.4 mmol), and EDCI (1.6 g, 8.4 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature. TLC monitoring indicated the absence of desisobutyl ciclesonide succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 20:1) and concentrated in vacuo to afford KYAC-09 (3.7 g, 54% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.37(d,J=10.5Hz,1H),6.22(d,J=8.5Hz,1H),5.97(s,1H),4.85-4.78(m,2H),4.47-4.33 (m,2H),4.30(d,J=8.2Hz,1H),4.22(d,J=9.1Hz,1H),4.18-4.16(m,2H),3.65-3.63(m,2H),3.58-3.53(m,30H),3. 47-3.45(m,2H),3.27(s,3H),2.74-2.70(m,2H),2.66-2.62(m,2H),2.65-2.57(m,1H),2.41-2.30(m,1H),2.19-2 .10(m,1H),2.10-2.00(m,1H),1.89-1.75(m,2H),1.75-1.50(m,9H),1.44(s,3H),1.25-0.93(m,7H),0.87(s,3H). MS m / z(ESI):981.5[M+H] + .

[0177] Example 1-10: Synthesis of compound KYAC-10

[0178] 17-Beclomethasone propionate (10 g, 22 mmol) was dissolved in dichloromethane (60 mL), followed by the addition of succinic anhydride (2.6 g, 26 mmol) and DMAP (3.1 g, 26 mmol). The reaction was allowed to proceed at room temperature and monitored by TLC until no 17-beclomethasone propionate was present. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution and the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate 17-beclomethasone propionate succinate (9.6 g, 79% yield). MS m / z (ESI): 587.2 [M+Na] + .

[0179] Beclomethasone 17-propionate succinate (4 g, 7 mmol), heptaethylene glycol monomethyl ether (2.9 g, 8.4 mmol), DMAP (0.17 g, 1.4 mmol), and EDCI (1.6 g, 8.4 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of beclomethasone 17-propionate succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-10 (2.8 g, 45% yield) as a colorless oil. 1H NMR (400MHz, d6-DMSO) δ7.29(d,J=9.9Hz,1H),6.22(d,J=8.0Hz,1H),5.98(s,1H),5.48-4.43(m,1H),5.02-4.95(m,1H),4.80(s ,1H),4.35(s,1H),4.13-4.11(m,2H),3.60-3.58(m,2H),3.53-3.48(m,22H),3.42-3.40(m,2H),3.22(s,3H),2.69-2.65(m,2H) ,2.61-2.57(m,2H),2.55-2.50(m,2H),2.49-2.45(m,1H),2.42-2.38(m,2H),2.37-2.31(m,1H),2.27-2.19(m,1H),2.16-2.08( m,1H),1.93-1.85(m,1H),1.84-1.76(m,1H),1.61(s,3H),1.58-1.50(m,1H),1.45-1.40(m,1H),1.11-1.00(m,7H),0.93(s,3H). MS m / z(ESI):887.3[M+H] + .

[0180] Example 1-11: Synthesis of compound KYAC-11

[0181] Beclomethasone 17-propionate succinate (4 g, 7 mmol), nonaethylene glycol monomethyl ether (3.6 g, 8.4 mmol), DMAP (0.17 g, 1.4 mmol), and EDCI (1.6 g, 8.4 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature. TLC monitoring indicated the absence of beclomethasone 17-propionate succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 20:1) and concentrated in vacuo to afford KYAC-11 (3.2 g, 46% yield) as a colorless oil. 1H NMR(400MHz,d6-DMSO)δ7.31(d,J=9.8Hz,1H),6.24(d,J=8.0Hz,1H),5.99(s,1H),5.52-5.42(m,1H ),4.82-4.72(m,2H),4.37(s,1H),4.15-4.13(m,2H),3.62-3.60(m,2H),3.55-3.50(m,30H),3.44- 3.42(m,2H),3.24(s,3H),2.71-2.67(m,2H),2.63-2.59(m,2H),2.58-2.52(m,2H),2.51-2.47(m,1 H),2.44-2.40(m,2H),2.39-2.33(m,1H),2.29-2.21(m,1H),2.18-2.10(m,1H),1.95-1.87(m,1H), 1.86-1.78(m,1H),1.63(s,3H),1.60-1.52(m,1H),1.47-1.41(m,1H),1.13-1.02(m,7H),0.95(s,3H). MS m / z(ESI):975.5[M+H] + .

[0182] Example 1-12: Synthesis of compound KYAC-12

[0183] Beclomethasone 17-propionate succinate (1 g, 1.9 mmol), polyethylene glycol monomethyl ether PEG1500 (3.4 g, 2.3 mmol), DMAP (0.05 g, 0.4 mmol), and EDCI (0.43 g, 2.3 mmol) were dissolved in dichloromethane (60 mL) and reacted at room temperature. TLC monitoring was performed until the absence of beclomethasone 17-propionate succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude oil. Purification was performed on an LH-20 column and concentrated in vacuo to obtain the target product, KYAC-12 (2.0 g, 53% yield). 1H NMR(400MHz,d6-DMSO)δ7.30(d,J=10.2Hz,1H),6.26(d,J=8.0Hz,1H),6.02(s,1H),5.55-5.41(m,1H),4.85-4.71(m ,2H),4.44(s,1H),4.17-4.12(m,2H),3.65-3.58(m,2H),3.54-3.48(m,122H),3.44-3.38(m,2H),3.21(s,3H),2.72 -2.69(m,2H),2.63-2.51(m,4H),2.50-2.47(m,1H),2.44-2.41(m,2H),2.39-2.32(m,1H),2.28-2.21(m,1H),2.18- 2.11(m,1H),1.97-1.78(m,2H),1.65(s,3H),1.60-1.51(m,1H),1.48-1.40(m,1H),1.15-1.05(m,7H),0.97(s,3H).

[0184] Example 1-13: Synthesis of compound KYAC-13

[0185] Beclomethasone 17-furoate (10 g, 20 mmol) was dissolved in dichloromethane (60 mL), followed by the addition of succinic anhydride (2.4 g, 24 mmol) and DMAP (2.9 g, 24 mmol). The reaction was allowed to proceed at room temperature, and TLC was monitored until the absence of beclomethasone 17-furoate. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution, the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate beclomethasone 17-furoate succinate (9.8 g, 82% yield). MS m / z (ESI): 625.2 [M+Na] + .

[0186] Beclomethasone 17-furoate succinate (4 g, 6.6 mmol), heptaethylene glycol monomethyl ether (2.7 g, 8 mmol), DMAP (0.16 g, 1.3 mmol), and EDCI (1.5 g, 8 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of beclomethasone 17-furoate succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-13 (2.0 g, 33% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.62(s,1H),7.29(d,J=9.8Hz,1H),7.24(s,1H),6.54(s,1H),6.22(d,J=8.0Hz,1H),5.98(s,1H),5.52-5.42 (m,1H),5.02-4.95(m,1H),4.80(s,1H),4.35(s,1H),4.13-4.11(m,2H),3.60-3.58(m,2H),3.53-3.48(m,22H),3.42-3.40(m,2H),3. 22(s,3H),2.69-2.65(m,2H),2.61-2.57(m,2H),2.55-2.50(m,2H),2.49-2.45(m,1H),2.37-2.31(m,1H),2.27-2.19(m,1H),2.16-2 .08(m,1H),1.93-1.85(m,1H),1.84-1.76(m,1H),1.61(s,3H),1.58-1.50(m,1H),1.45-1.40(m,1H),1.11-1.06(m,4H),0.93(s,3H). MS m / z(ESI):925.3[M+H] + .

[0187] Example 1-14: Synthesis of compound KYAC-14

[0188] Beclomethasone 17-furoate succinate (5 g, 8.3 mmol), nonaethylene glycol monomethyl ether (4.2 g, 9.9 mmol), DMAP (0.20 g, 1.6 mmol), and EDCI (1.9 g, 9.9 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature. TLC monitoring indicated the absence of beclomethasone 17-furoate succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-14 (3.0 g, 36% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.67(s,1H),7.41(d,J=9.8Hz,1H),7.35(s,1H),6.83(s,1H),6.24(d,J=8.0Hz,1H),5.61(s,1H),5.44-5.42(m,1 H),4.66-4.63(m,1H),4.60(s,1H),4.25(s,1H),4.11-4.09(m,2H),3.58-3.56(m,2H),3.51-3.46(m,30H),3.40-3.38(m,2H),3.20(s,3H) ,2.67-2.63(m,2H),2.59-2.55(m,2H),2.52-2.49(m,2H),2.47-2.43(m,1H),2.35-2.29(m,1H),2.25-2.17(m,1H),2.14-2.06(m,1H),1. 91-1.83(m,1H),1.82-1.74(m,1H),1.59(s,3H),1.57-1.49(m,1H),1 .45-1.43(m,1H),1.21-1.17(m,1H),1.11-1.07(m,3H),0.98(s,3H). MS m / z(ESI):1013.4[M+H] + .

[0189] Example 1-15: Synthesis of compound KYAC-15

[0190] 17-Dexamethasone furoate (10 g, 21 mmol) was dissolved in dichloromethane (60 mL), followed by the addition of succinic anhydride (2.5 g, 25 mmol) and DMAP (3 g, 25 mmol). The reaction was allowed to proceed at room temperature, and TLC was monitored until the 17-dexamethasone furoate disappeared. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution, the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate 17-dexamethasone furoate succinate (9 g, 75% yield). MS m / z (ESI): 609.3 [M+Na] + .

[0191] Dexamethasone 17-furoate succinate (4 g, 6.8 mmol), heptaethylene glycol monomethyl ether (2.8 g, 8.2 mmol), DMAP (0.17 g, 1.4 mmol), and EDCI (1.6 g, 8.2 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of 17-furoate succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-15 (2.2 g, 35% yield) as a colorless oil. 1H NMR(400MHz,d6-DMSO)δ7.60(s,1H),7.24(d,J=9.9Hz,1H),7.18(s,1H),6.52(s,1H),6.19(d,J=8.2Hz,1H),5.87(s,1H),5.32-5.30(m,1 H),4.57-4.55(m,1H),4.43(s,1H),4.31(s,1H),4.09-4.01(m,2H),3.46-3.32(m,2H),3.30-3.28(m,22H),3.26-3.24(m,2H),3.20(s,3H) ,2.67-2.63(m,2H),2.58-2.55(m,2H),2.53-2.43(m,2H),2.41-2.35(m,1H),2.33-2.29(m,1H),2.25-2.17(m,1H),2.14-2.07(m,1H),1. 97-1.80(m,1H),1.79-1.71(m,1H),1.67(s,3H),1.63-1.52(m,1H),1 .48-1.46(m,1H),1.21-1.04(m,1H),1.03-1.00(m,3H),0.83(s,3H). MS m / z(ESI):909.3[M+H] + .

[0192] Example 1-16: Synthesis of compound KYAC-16

[0193] Dexamethasone 17-furoate succinate (5 g, 8.5 mmol), nonaethylene glycol monomethyl ether (4.4 g, 10.2 mmol), DMAP (0.21 g, 1.7 mmol), and EDCI (2.0 g, 10.2 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature. TLC monitoring indicated the absence of dexamethasone 17-furoate succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-16 (3.2 g, 38% yield) as a colorless oil. 1H NMR(400MHz,d6-DMSO)δ7.61(s,1H),7.22(d,J=9.9Hz,1H),7.13(s,1H),6.47(s,1H),6.29(d ,J=8.1Hz,1H),5.81(s,1H),5.42-5.40(m,1H),4.56-4.52(m,1H),4.46(s,1H),4.35(s,1H), 4.24-4.01(m,2H),3.34-3.30(m,2H),3.29-3.23(m,30H),3.23-3.17(m,2H),3.12(s,3H),2. 72-2.65(m,2H),2.61-2.57(m,2H),2.52-2.47(m,2H),2.45-2.37(m,1H),2.35-2.27(m,1H), 2.26-2.15(m,1H),2.13-2.05(m,1H),1.92-1.83(m,1H),1.76-1.68(m,1H),1.57(s,3H), 1.56-1.49(m,1H),1.48-1.44(m,1H),1.32-1.14(m,1H),1.07-1.05(m,3H),0.89(s,3H). MS m / z(ESI):997.5[M+H] + .

[0194] Example 1-17: Synthesis of compound KYAC-17

[0195] Flumethasone acetate (20 g, 44 mmol) was dissolved in dichloromethane (300 mL), followed by the addition of DMAP (16 g, 0.13 mol). Furoyl chloride (6.6 mL, 66 mmol) was slowly added dropwise and allowed to react at room temperature. TLC monitoring was performed until no flumethasone acetate was present. Dichloromethane was added to the reaction solution, which was then washed sequentially with water, dilute hydrochloric acid, and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The intermediate 17-furoyl flumethasone acetate (8.4 g, yield: 35%) was obtained by separation and purification via silica gel column chromatography (dichloromethane / acetone = 4 / 1). MS m / z (ESI): 547.2 [M+H] + .

[0196] Dissolve 17-furoyl flumethasone acetate (8 g, 15 mmol) in acetonitrile (80 mL), then add perchloric acid (6.5 mL, 58 mmol) and react at room temperature. TLC monitoring indicates the absence of 17-furoyl flumethasone acetate. The reaction solution is concentrated in vacuo, and dichloromethane is added. The organic phase is washed with water until neutral, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purify by silica gel column chromatography (dichloromethane / acetone = 4:1) and concentrate in vacuo to obtain the intermediate 17-furoyl flumethasone acetate (6.3 g, yield: 85%). MS m / z (ESI): 505.3 [M+H] + .

[0197] 17-Fluometasone furoate (10 g, 20 mmol) was dissolved in dichloromethane (60 mL), followed by the addition of succinic anhydride (2.4 g, 24 mmol) and DMAP (2.9 g, 24 mmol). The reaction was allowed to proceed at room temperature, and TLC was monitored until the absence of 17-Fluometasone furoate. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution, the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate 17-Fluometasone furoate succinate (9.7 g, 81% yield). MS m / z (ESI): 627.3 [M+Na] + .

[0198] Flumethasone 17-furoate succinate (4 g, 6.6 mmol), heptaethylene glycol monomethyl ether (2.7 g, 7.9 mmol), DMAP (0.16 g, 1.3 mmol), and EDCI (1.5 g, 7.9 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of flumethasone 17-furoate succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-17 (2.0 g, 33% yield) as a colorless oil. 1H NMR(400MHz,d6-DMSO)δ7.59(s,1H),7.27(d,J=10.2Hz,1H),7.15(s,1H),6.49(s,1H),6.29(dd,J=10.1,2.7Hz,1H),6 .11(s,1H),5.77-5.46(m,1H),5.43-5.30(m,1H),4.50-4.46(m,1H),4.21-4.12(m,1H),4.08-3.98(m,3H),3.47-3.35( m,2H),3.32-3.28(m,22H),3.26-3.22(m,2H),3.20(s,3H),3.08-2.89(m,1H),2.69-2.63(m,2H),2.59-2.54(m,2H),2. 50-2.39(m,1H),2.29-2.07(m,3H),1.66-1.61(m,1H),1.59-1.37(m,5H),1.19-1.02(m,1H),0.86(s,3H),0.80(s,3H). MS m / z(ESI):927.4[M+H] + .

[0199] Example 1-18: Synthesis of compound KYAC-18

[0200] Flumethasone 17-furoate succinate (5 g, 8.3 mmol), nonaethylene glycol monomethyl ether (4.2 g, 9.9 mmol), DMAP (0.20 g, 1.6 mmol), and EDCI (1.9 g, 9.9 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature. TLC monitoring indicated the absence of flumethasone 17-furoate succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-18 (2.9 g, 35% yield) as a colorless oil. 1H NMR(400MHz,d6-DMSO)δ7.61(s,1H),7.28(d,J=10.2Hz,1H),7.16(s,1H),6.50(s,1H),6.31(dd,J=10.1,2.7Hz,1H),6 .12(s,1H),5.78-5.45(m,1H),5.43-5.31(m,1H),4.52-4.48(m,1H),4.22-4.11(m,1H),4.08-3.95(m,3H),3.48-3.34( m,2H),3.32-3.28(m,30H),3.26-3.22(m,2H),3.21(s,3H),3.09-2.88(m,1H),2.69-2.65(m,2H),2.59-2.55(m,2H),2. 50-2.41(m,1H),2.32-2.08(m,3H),1.67-1.62(m,1H),1.58-1.36(m,5H),1.18-1.01(m,1H),0.87(s,3H),0.81(s,3H). MS m / z(ESI):1015.7[M+H] + .

[0201] Example 1-19: Synthesis of compound KYAC-19

[0202] Fluorothiazolinone (10 g, 23 mmol) was dissolved in dichloromethane (60 mL), followed by the addition of succinic anhydride (2.8 g, 27 mmol) and DMAP (3.4 g, 27 mmol). The reaction was allowed to proceed at room temperature and monitored by TLC until no fluorothiazolinone was present. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution and the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate fluorothiazolinone succinate (10 g, 83% yield). MS m / z (ESI): 559.3 [M+Na] + .

[0203] Fluorothiazolinone succinate (4 g, 7.5 mmol), heptaethylene glycol monomethyl ether (3.1 g, 9 mmol), DMAP (0.18 g, 1.5 mmol), and EDCI (1.7 g, 9 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of fluorothiazolinone succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-19 (2.7 g, 42% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ6.06(s,1H),4.85-4.78(m,1H),4.53(d,J=18Hz,1H),4.50-4.42(m,1H),4.27(s,1H),4.18-4.12(m,3H), 3.92-3.83(m,1H),3.65-3.60(m,2H),3.55-3.51(m,22H),3.46-3.43(m,2H),3.26(s,3H),2.75-2.66(m,2H),2.62-2.58(m,2H), 2.56-2.42(m,1H),2.38-2.32(m,1H),2.25-2.18(m,1H),2.15-2.09(m,1H),2.05-1.92(m,2H),1.89-1.79(m,2H),1.74-1.62(m, 1H), 1.50 (dd, J = 14.0, 2.4Hz, 1H), 1.49-1.44 (m, 2H), 1.42 (s, 3H), 1.35 (s, 3H), 1.09 (s, 3H), 1.05 (d, J = 3.2Hz, 1H), 0.92 (s, 3H). MS m / z(ESI):859.6[M+H] + .

[0204] Example 1-20: Synthesis of compound KYAC-20

[0205] Fluorothiazolinone succinate (3.5 g, 6.5 mmol), nonaethylene glycol monomethyl ether (3.3 g, 7.8 mmol), DMAP (0.16 g, 1.3 mmol), and EDCI (1.5 g, 7.8 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of fluorothiazolinone succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-20 (2.2 g, 35% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ6.07(s,1H),4.86-4.78(m,1H),4.52(d,J=18Hz,1H),4.50-4.40(m,1H),4.28(s,1H),4.19-4.11(m,3H), 3.95-3.81(m,1H),3.66-3.61(m,2H),3.56-3.51(m,30H),3.47-3.42(m,2H),3.27(s,3H),2.78-2.67(m,2H),2.62-2.59(m,2H), 2.56-2.40(m,1H),2.38-2.30(m,1H),2.26-2.19(m,1H),2.15-2.08(m,1H),2.04-1.91(m,2H),1.89-1.78(m,2H),1.75-1.61(m, 1H), 1.52 (dd, J = 14.0, 2.4Hz, 1H), 1.49-1.44 (m, 2H), 1.40 (s, 3H), 1.34 (s, 3H), 1.10 (s, 3H), 1.04 (d, J = 3.2Hz, 1H), 0.91 (s, 3H). MS m / z(ESI):947.7[M+H] + .

[0206] Example 1-21: Synthesis of compound KYAC-21

[0207] Fluocinolone acetonide (5g, 11mmol) was dissolved in tetrahydrofuran (50mL), and then pyrophosphoryl chloride (4.6mL, 33mmol) was dissolved in tetrahydrofuran (5mL). The tetrahydrofuran solution of pyrophosphoryl chloride was slowly added dropwise to the system at -40°C and reacted at -40°C. TLC was monitored until no fluocinolone acetonide was produced. The reaction solution was then poured into a saturated sodium bicarbonate solution and the pH was adjusted to 8-9. 1N hydrochloric acid solution was then added to the system to adjust the pH to 2-3. The aqueous phase was then extracted with ethyl acetate (100mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the intermediate fluocinolone acetonide phosphate (5g, yield 85%). MS m / z (ESI): 533.2[M+H] + .

[0208] Fluocinolone phosphate (1 g, 1.9 mmol), polyethylene glycol monomethyl ether PEG3000 (6.8 g, 2.3 mmol), DMAP (0.05 g, 0.4 mmol), and EDCI (0.44 g, 2.3 mmol) were dissolved in dichloromethane (85 mL) and reacted at room temperature. TLC monitoring was performed until no fluocinolone phosphate was present. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude oil. Purification was performed on an LH-20 column and concentrated in vacuo to obtain the target product, KYAC-21 (2.1 g, 30% yield). 1 H NMR(400MHz,d6-DMSO)δ7.25(d,J=10.2Hz,1H),6.29(dd,J=10.1,1.6Hz,1H),6.11(s,1H),5.72-5.57(m,1H ),5.47-5.38(m,1H),4.92-4.85(m,1H),4.5-4.43(m,1H),4.25-4.20(m,1H),4.19-4.15(m,3H),4.06-3.98 (m,1H),3.65-3.61(m,2H),3.58-3.52(m,254H),3.45-3.43(m,2H),3.24(s,3H),2.66-2.54(m,1H),2.31-2 .22(m,1H),2.05-1.96(m,2H),1.63-1.53(m,3H),1.52-1.43(m,4H),1.33(s,3H),1.08(s,3H),0.79(s,3H).

[0209] Example 1-22: Synthesis of compound KYAC-22

[0210] Budesonide (5 g, 12 mmol) was dissolved in tetrahydrofuran (50 mL), and then pyrophosphoryl chloride (4.8 mL, 35 mmol) was dissolved in tetrahydrofuran (10 mL). The tetrahydrofuran solution of pyrophosphoryl chloride was slowly added dropwise to the system at -40 ° C. The reaction was carried out at -40 ° C. TLC was monitored until no budesonide was present. The reaction solution was then poured into a saturated sodium bicarbonate solution and the pH was adjusted to 8-9. 1N hydrochloric acid solution was then added to the system to adjust the pH to 2-3. The aqueous phase was then extracted with ethyl acetate (100 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the intermediate budesonide phosphate (5 g, yield 84%). MS m / z (ESI): 511.2 [M+H] + .

[0211] Budesonide phosphate (1 g, 2 mmol), polyethylene glycol monomethyl ether PEG3000 (7.0 g, 2.4 mmol), DMAP (0.05 g, 0.4 mmol), and EDCI (0.46 g, 2.4 mmol) were dissolved in dichloromethane (85 mL) and reacted at room temperature. TLC monitoring was performed until the budesonide phosphate was eliminated. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude oil. Purification was performed on an LH-20 column and concentrated in vacuo to obtain the target product, KYAC-22 (2.1 g, 30% yield). 1 H NMR (400MHz, d6-DMSO): δ7.32 (d, J = 9.8 Hz, 1H), 6.47 (d, J = 7.9 Hz, 1H), 4.72-4.58 (m, 3H), 4.47-4. 35(m,2H),4.29-4.18(m,2H),4.21-4.17(m,1H),3.88-3.64(m,2H),3.61-3.52(m,256H),3.45-3. 35(m,2H),3.31(s,3H),2.36(d,J=6Hz,2H),2.31-2.18(m,2H),1.94-1.82(m,3H),1.75-1.62(m,1 H),1.60-1.52(m,5H),1.48-1.32(m,3H),1.30-1.20(m,2H),0.99-0.85(m,5H),0.95-0.85(m,3H).

[0212] Example 1-23: Synthesis of compound KYAC-23

[0213] Budesonide (10 g, 23 mmol) was dissolved in dichloromethane (120 mL), followed by the addition of glutaric anhydride (3.2 g, 28 mmol) and DMAP (3.4 g, 28 mmol). The reaction was allowed to proceed at room temperature and monitored by TLC until no budesonide was present. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution, the pH adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (120 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate budesonide glutarate (9 g, 71% yield). MS m / z (ESI): 567.4 [M+Na] + .

[0214] Budesonide glutarate (4.1 g, 7.6 mmol), heptaethylene glycol monomethyl ether (3.1 g, 9.1 mmol), DMAP (0.18 g, 1.5 mmol), and EDCI (1.7 g, 9.1 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of budesonide glutarate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-23 (1.6 g, 25% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.24(d,J=9.4Hz,1H),6.50(d,J=7.7Hz,1H),4.65-4.50(m,3H),4.30-4.25(m,2H), 4.18-4.14(m,2H),3.60-3.48(m,2H),3.42-3.36(m,22H),3.32-3.26(m,2H),3.22(s,3H),2.55-2.50(m,2H) ,2.48-2.40(m,2H),2.35-2.32(m,2H),2.30(d,J=5.80Hz,2H),2.28-1.95(m,2H),1.90-1.75(m,3H),1.70- 1.66(m,1H),1.62-1.52(m,5H),1.50-1.25(m,3H),1.22-1.18(m,2H),0.98-0.80(m,5H),0.86-0.82(m,3H). MS m / z(ESI):867.5[M+H] + .

[0215] Example 1-24: Synthesis of compound KYAC-24

[0216] Budesonide glutarate (5.9 g, 10.8 mmol), nonaethylene glycol monomethyl ether (5.6 g, 13 mmol), DMAP (0.27 g, 2.2 mmol), and EDCI (2.5 g, 13 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature. TLC monitoring was performed until the budesonide glutarate disappeared. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to obtain KYAC-24 (3.8 g, 37% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.26(d,J=9.4Hz,1H),6.50(d,J=7.7Hz,1H),4.73-4.58(m,3H),4.40-4.32(m,2H), 4.28-4.18(m,2H),3.87-3.66(m,2H),3.60-3.48(m,30H),3.45-3.40(m,2H),3.36(s,3H),2.50-2.45(m,2H) ,2.42-2.38(m,2H),2.35(d,J=5.8Hz,2H),2.25-2.18(m,2H),2.15-1.90(m,2H),1.87-1.65(m,3H),1.63-1 .56(m,1H),1.58-1.44(m,5H),1.46-1.35(m,3H),1.30-1.24(m,2H),1.06-1.02(m,5H,),0.98-0.95(m,3H). MS m / z(ESI):955.6[M+H] + .

[0217] Example 1-25: Synthesis of compound KYAC-25

[0218] Budesonide (12 g, 28 mmol) was dissolved in dichloromethane (120 mL), followed by the addition of adipic anhydride (4.3 g, 33 mmol) and DMAP (4.1 g, 33 mmol). The reaction was allowed to proceed at room temperature, and TLC was monitored until no budesonide was present. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution, the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate budesonide adipate (11 g, 72% yield). MS m / z (ESI): 581.4 [M+Na] + .

[0219] Budesonide adipate (3.6 g, 6.5 mmol), heptaethylene glycol monomethyl ether (2.7 g, 7.8 mmol), DMAP (0.16 g, 1.3 mmol), and EDCI (1.5 g, 7.8 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of budesonide adipate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-25 (1.4 g, 25% yield) as a colorless oil. 1 H NMR (400MHz, d6-DMSO) δ7.25 (d, J = 9.4 Hz,1H),6.54(d,J=7.6Hz,1H),4.70-4.58(m,3H),4.38-4.32(m,2H),4.20-4.16(m,2H),3.65-3.54(m, 2H),3.48-3.40(m,22H),3.35-3.28(m,2H),3.25(s,3H),2.60-2.54(m,2H),2.52-2.46(m,2H),2.38(d, J=5.82Hz,2H),2.30-2.07(m,2H),2.04-1.87(m,3H),1.84-1.76(m,1H),1.75-1.65(m,5H),1.63-1.61 (m,2H),1.60-1.58(m,2H),1.54-1.40(m,3H),1.32-1.28(m,2H),0.99-0.87(m,5H),0.85-0.83(m,3H). MS m / z(ESI):881.6[M+H]+ .

[0220] Example 1-26: Synthesis of compound KYAC-26

[0221] Budesonide adipate (5.1 g, 9.2 mmol), nonaethylene glycol monomethyl ether (4.7 g, 11 mmol), DMAP (0.22 g, 1.8 mmol), and EDCI (2.1 g, 11 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature. TLC monitoring was performed until the budesonide adipate disappeared. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to obtain KYAC-26 (3.8 g, 43% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.27(d,J=9.4Hz,1H),6.52(d,J=7.6Hz,1H),4.70-4.55(m,3H),4.35-4.26(m,2H),4.24 -4.14(m,2H),3.88-3.65(m,2H),3.60-3.45(m,30H),3.42-3.37(m,2H),3.29(s,3H),2.50-2.46(m,2H),2.42-2 .38(m,2H),2.35(d,J=5.8Hz,2H),2.23-2.16(m,2H),2.13-1.90(m,2H),1.85-1.65(m,3H),1.63-1.55(m,1H),1 .53-1.50(m,2H),1.48-1.44(m,5H),1.42-1.35(m,3H),1.32-1.28(m,2H),0.98-0.90(m,5H),0.90-0.87(m,3H). MS m / z(ESI):969.6[M+H] + .

[0222] Example 1-27: Synthesis of compound KYAC-27

[0223] Methylprednisolone (10 g, 27 mmol) was dissolved in dichloromethane (100 mL), followed by the addition of succinic anhydride (3.2 g, 32 mmol) and DMAP (3.9 g, 32 mmol). The reaction was allowed to proceed at room temperature, and TLC was monitored until the methylprednisolone was removed. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution, the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate methylprednisolone succinate (13 g, 73% yield). MS m / z (ESI): 497.3 [M+Na] + .

[0224] Methylprednisolone succinate (3.3 g, 7 mmol), nonaethylene glycol monomethyl ether (3.6 g, 8.4 mmol), DMAP (0.17 g, 1.4 mmol), and EDCI (1.6 g, 8.4 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature. TLC monitoring indicated the absence of methylprednisolone succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-27 (2.9 g, 47% yield) as a colorless oil. 1H NMR(400MHz,d6-DMSO)δ7.26(d,J=10.3Hz,1H),6.30(d,J=10.1Hz,1H),6.05(s,1H),5.46-5.39(m,1H),5.04(s,1H),4 .46(s,1H),4.30(d,J=20Hz,2H),4.19-4.08(m,2H),3.65-3.52(m,2H),3.49-3.21(m,30H),3.29-3.21(m,2H),3.15(s ,3H),2.77-2.65(m,3H),2.56-2.45(m,2H),2.24-2.18(m,2H),2.14-2.11(m,1H),2.07-2.00(m,1H),1.82-1.73(m,1H) ),1.70-1.65(m,1H),1.57-1.53(m,2H),1.49-1.45(m,1H),1.41(s,3H),1.12-1.08(m,2H),1.09(s,3H),0.95(s,3H). MS m / z(ESI):885.5[M+H] + .

[0225] Example 1-28: Synthesis of compound KYAC-28

[0226] Betamethasone (13 g, 33 mmol) was dissolved in dichloromethane (130 mL), followed by the addition of succinic anhydride (4.0 g, 40 mmol) and DMAP (4.9 g, 40 mmol). The reaction was allowed to proceed at room temperature and monitored by TLC until the absence of betamethasone. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution and the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate betamethasone succinate (13 g, 80% yield). MS m / z (ESI): 515.3 [M+Na] + .

[0227] Betamethasone succinate (4.5 g, 9.1 mmol), nonaethylene glycol monomethyl ether (4.7 g, 11 mmol), DMAP (0.22 g, 1.8 mmol), and EDCI (2.1 g, 11 mmol) were dissolved in dichloromethane (110 mL) and reacted at room temperature. TLC monitoring indicated the absence of betamethasone succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-28 (3.5 g, 42% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.27(d,J=10.2Hz,1H),6.21(dd,J=10.1,1.8Hz,1H),6.01(s,1H),5.23(s,1H),5.12(s,1 H),4.36-4.28(m,2H),4.18-4.11(m,3H),3.75-3.64(m,2H),3.54-3.45(m,30H),3.37-3.30(m,2H),3.19(s,3H),2 .62-2.58(m,3H),2.51-2.43(m,3H),2.36-2.30(m,1H),2.12-2.03(m,2H),2.00-1.93(m,1H),1.92-1.87(m,1H),1 .86-1.78(m,1H),1.49(s,3H),1.44-1.35(m,1H),1.34-1.28(m,1H),1.09-1.00(m,1H),1.03(s,3H),0.96(s,3H). MS m / z(ESI):903.7[M+H] + .

[0228] Example 1-29: Synthesis of compound KYAC-29

[0229] Diflucortolone (11 g, 28 mmol) was dissolved in dichloromethane (110 mL), followed by the addition of succinic anhydride (3.4 g, 33 mmol) and DMAP (4.1 g, 33 mmol). The reaction was allowed to proceed at room temperature, and the reaction was monitored by TLC until the diflucortolone was eliminated. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution, the pH adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate diflucortolone succinate (11 g, 80% yield). MS m / z (ESI): 517.3 [M+Na] + .

[0230] Diflucortolone succinate (5.0 g, 10 mmol), nonaethylene glycol monomethyl ether (5.2 g, 12 mmol), DMAP (0.25 g, 2 mmol), and EDCI (2.3 g, 12 mmol) were dissolved in dichloromethane (120 mL) and reacted at room temperature. TLC monitoring indicated the absence of diflucortolone succinate. Dichloromethane (120 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (120 mL), saturated sodium bicarbonate solution (120 mL), and water (120 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 20:1) and concentrated in vacuo to afford KYAC-29 (4.3 g, 47% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.27(d,J=10.1Hz,1H),6.29(dd,J=10.0,2.1Hz,1H),6.11(s,1H),5.7 9-5.54(m,1H),5.44-5.36(m,1H),4.20-4.15(m,3H),3.67-3.57(m,4H),3.54-3.47(m,30H),3. 37-3.32(m,2H),3.19(s,3H),2.70-2.65(m,3H),2.58-2.48(m,3H),2.30-2.18(m,2H),1.92-1 .86(m,1H),1.80-1.60(m,3H),1.56-1.41(m,4H),1.27-1.16(m,1H),0.89(s,3H),0.84(s,3H). MS m / z(ESI):905.6[M+H] + .

[0231] Example 1-30: Synthesis of compound KYAC-30

[0232] Diflucortolone succinate (5.0 g, 10 mmol), hexadecanediol monomethyl ether (8.8 g, 12 mmol), DMAP (0.20 g, 1.6 mmol), and EDCI (1.9 g, 9.9 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature. TLC monitoring indicated the absence of diflucortolone succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 20:1) and concentrated in vacuo to afford KYAC-30 (5.1 g, 42% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.26(d,J=10.1Hz,1H),6.30(dd,J=10.0,2.1Hz,1H),6.12(s,1H),5.79-5.55(m,1H),5.44-5.37(m,1H), 4.21-4.15(m,3H),3.57-3.68(m,4H),3.55-3.47(m,58H),3.36-3.32(m,2H),3.19(s,3H),2.71-2.64(m,3H),2.58-2.45(m,3 H),2.32-2.18(m,2H),1.92-1.86(m,1H),1.81-1.60(m,3H),1.57-1.41(m,4H),1.28-1.16(m,1H),0.89(s,3H),0.84(s,3H). MS m / z(ESI):1213.5[M+H] + .

[0233] Example 1-31: Synthesis of compound KYAC-31

[0234] Deacetylfoscot (8 g, 20 mmol) was dissolved in dichloromethane (80 mL), followed by the addition of succinic anhydride (2.4 g, 24 mmol) and DMAP (2.9 g, 24 mmol). The reaction was allowed to proceed at room temperature, and TLC was monitored until the deacetylfoscot was eliminated. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution, the pH adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (80 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate deacetylfoscot succinate (8.2 g, 82% yield). MS m / z (ESI): 522.3 [M+Na] + .

[0235] Deacetylfoscotate succinate (4.0 g, 8 mmol), heptaethylene glycol monomethyl ether (4.3 g, 9.6 mmol), DMAP (0.20 g, 1.6 mmol), and EDCI (1.8 g, 9.6 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature. TLC monitoring indicated the absence of deacetylfoscotate succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 20:1) and concentrated in vacuo to afford KYAC-31 (2.8 g, 42% yield) as a colorless oil. 1H NMR(400MHz,d6-DMSO)δ7.28(d,J=10.1Hz,1H),6.14(dd,J=10.2,1.7Hz,1H),5.91(s,1H),5.21-5.12(m,1H),4.73-4.66(m ,1H),4.37-4.30(m,1H),4.28-4.21(m,1H),4.11-4.08(m,3H),3.57-3.53(m,2H),3.50-3.41(m,22H),3.39-3.36(m,2H),3. 17(s,3H),2.68-2.63(m,2H),2.54-2.48(m,3H),2.32-2.25(m,1H),2.09-2.01(m,1H),2.00-1.94(m,1H),1.90-1.82(m,4H ),1.79-1.75(m,1H),1.73-1.61(m,2H),1.39(s,3H),1.15-1.06(m,1H),1.06-0.98(m,1H),0.96-0.91(m,1H),0.85(s,3H). MS m / z(ESI):822.5[M+H] + .

[0236] Example 1-32: Synthesis of compound KYAC-32

[0237] Deacetylfoscotate succinate (4.0 g, 8 mmol), nonaethylene glycol monomethyl ether (4.1 g, 9.6 mmol), DMAP (0.20 g, 1.6 mmol), and EDCI (1.8 g, 9.6 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature. TLC monitoring indicated the absence of deacetylfoscotate succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 20:1) and concentrated in vacuo to afford KYAC-32 (3.1 g, 42% yield) as a colorless oil. 1H NMR(400MHz,d6-DMSO)δ7.29(d,J=10.1Hz,1H),6.15(dd,J=10.2,1.7Hz,1H),5.91(s,1H),5.21-5.12(m,1H),4.73-4.65(m ,1H),4.37-4.30(m,1H),4.28-4.22(m,1H),4.11-4.09(m,3H),3.57-3.54(m,2H),3.51-3.43(m,30H),3.39-3.36(m,2H),3. 17(s,3H),2.68-2.63(m,2H),2.54-2.48(m,3H),2.32-2.25(m,1H),2.09-2.01(m,1H),2.00-1.94(m,1H),1.91-1.82(m,4H ),1.78-1.75(m,1H),1.73-1.61(m,2H),1.38(s,3H),1.15-1.06(m,1H),1.06-0.98(m,1H),0.95-0.90(m,1H),0.86(s,3H). MS m / z(ESI):910.7[M+H] + .

[0238] Example 1-33: Synthesis of compound KYAC-33

[0239] Amcinonide (14 g, 30 mmol) was dissolved in dichloromethane (140 mL), followed by the addition of succinic anhydride (3.6 g, 36 mmol) and DMAP (4.5 g, 36 mmol), and the reaction was allowed to proceed at room temperature. TLC monitoring was performed until amcinonide was absent. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution, the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (140 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate amcinonide succinate (14.5 g, 85% yield). MS m / z (ESI): 583.3 [M+Na] + .

[0240] Amcinonide succinate (3.8 g, 7.1 mmol), heptaethylene glycol monomethyl ether (2.9 g, 8.5 mmol), DMAP (0.17 g, 1.4 mmol), and EDCI (1.6 g, 8.5 mmol) were dissolved in dichloromethane (110 mL) and reacted at room temperature. TLC monitoring indicated the absence of amcinonide succinate. Dichloromethane (110 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (110 mL), saturated sodium bicarbonate solution (110 mL), and water (110 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 20:1) and concentrated in vacuo to afford KYAC-33 (2.7 g, 43% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.37(d,J=10.2Hz,1H),6.25(d,J=8.5Hz,1H),5.93(s,1H),4.93-4.85(m,2H), 4.48-4.34(m,2H),4.22(d,J=8.9Hz,1H),4.20-4.15(m,2H),3.71-3.64(m,2H),3.58-3.49(m,22H),3.4 7-3.43(m,2H),3.25(s,3H),2.75-2.67(m,2H),2.65-2.56(m,3H),2.45-2.40(m,1H),2.35-2.31(m,1H) ,2.20-2.09(m,1H),1.90-1.80(m,2H),1.74-1.55(m,6H),1.39(s,3H),1.30-0.96(m,6H),0.85(s,3H). MS m / z(ESI):883.5[M+H] + .

[0241] Example 1-34: Synthesis of compound KYAC-34

[0242] Amcinonide succinate (4.8 g, 9.4 mmol), nonaethylene glycol monomethyl ether (4.8 g, 11.3 mmol), DMAP (0.23 g, 1.9 mmol), and EDCI (2.2 g, 11.3 mmol) were dissolved in dichloromethane (110 mL) and reacted at room temperature. TLC monitoring indicated the absence of amcinonide succinate. Dichloromethane (110 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (110 mL), saturated sodium bicarbonate solution (110 mL), and water (110 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 20:1) and concentrated in vacuo to afford KYAC-34 (4.1 g, 45% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.35(d,J=10.2Hz,1H),6.20(d,J=8.5Hz,1H),5.95(s,1H),4.89-4.82(m,2H), 4.52-4.36(m,2H),4.20(d,J=8.9Hz,1H),4.18-4.14(m,2H),3.68-3.62(m,2H),3.56-3.50(m,30H),3.4 7-3.41(m,2H),3.24(s,3H),2.78-2.71(m,2H),2.68-2.56(m,3H),2.46-2.42(m,1H),2.40-2.31(m,1H) ,2.22-2.11(m,1H),1.95-1.81(m,2H),1.75-1.55(m,6H),1.41(s,3H),1.31-0.97(m,6H),0.85(s,3H). MS m / z(ESI):971.6[M+H] + .

[0243] Example 1-35: Synthesis of compound KYAC-35

[0244] Amcinonide succinate (5.0 g, 8.9 mmol), hexadecanediol monomethyl ether (7.9 g, 10.7 mmol), DMAP (0.22 g, 1.8 mmol), and EDCI (2.0 g, 10.7 mmol) were dissolved in dichloromethane (120 mL) and reacted at room temperature. TLC monitoring indicated the absence of amcinonide succinate. Dichloromethane (120 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (120 mL), saturated sodium bicarbonate solution (120 mL), and water (120 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 20:1) and concentrated in vacuo to afford KYAC-35 (6 g, 53% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.37(d,J=10.1Hz,1H),6.23(d,J=8.3Hz,1H),5.95(s,1H),4.90-4.87(m,2H), 4.50-4.35(m,2H),4.20(d,J=9.0Hz,1H),4.18-4.15(m,2H),3.75-3.68(m,2H),3.56-3.43(m,58H),3.4 5-3.40(m,2H),3.25(s,3H),2.80-2.72(m,2H),2.66-2.56(m,3H),2.45-2.38(m,1H),2.40-2.33(m,1H) ,2.20-2.11(m,1H),1.96-1.83(m,2H),1.77-1.58(m,6H),1.40(s,3H),1.33-0.95(m,6H),0.83(s,3H). MS m / z(ESI):1279.8[M+H] + .

[0245] Example 1-36: Synthesis of compound KYAC-36

[0246] Chlorocortolone (12 g, 29 mmol) was dissolved in dichloromethane (120 mL), followed by the addition of succinic anhydride (3.5 g, 35 mmol) and DMAP (4.3 g, 35 mmol). The reaction was allowed to proceed at room temperature, and the reaction was monitored by TLC until the chlorocortolone was eliminated. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution, the pH adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (120 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate chlorocortolone succinate (12 g, 81% yield). MS m / z (ESI): 533.3 [M+Na] + .

[0247] Clocortolone succinate (3.6 g, 7 mmol), heptaethylene glycol monomethyl ether (2.9 g, 8.4 mmol), DMAP (0.17 g, 1.4 mmol), and EDCI (1.6 g, 8.4 mmol) were dissolved in dichloromethane (70 mL) and reacted at room temperature. TLC monitoring indicated the absence of clocortolone succinate. Dichloromethane (70 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (70 mL), saturated sodium bicarbonate solution (70 mL), and water (70 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. Purification by silica gel column chromatography (DCM / MeOH = 20:1) and concentration in vacuo afforded KYAC-36 (2.9 g, 49% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.30(d,J=10.2Hz,1H),6.32(dd,J=10.1,2.2Hz,1H),6.13(s,1H),5.80-5. 62(m,1H),5.46-5.38(m,1H),4.23-4.12(m,1H),4.09-3.89(m,4H),3.77-3.64(m,2H),3.59-3.48(m ,22H),3.43-3.36(m,2H),3.27(s,3H),3.18-2.83(m,3H),2.74-2.58(m,3H),2.30-2.12(m,2H),1. 95-1.84(m,1H),1.81-1.62(m,3H),1.48-1.32(m,4H),1.20-1.09(m,1H),0.92(s,3H),0.82(s,3H). MS m / z(ESI):833.8[M+H] + .

[0248] Example 1-37: Synthesis of compound KYAC-37

[0249] Desonide (9 g, 21 mmol) was dissolved in dichloromethane (90 mL), followed by the addition of succinic anhydride (2.5 g, 25 mmol) and DMAP (3.1 g, 25 mmol). The reaction was allowed to proceed at room temperature, and the desonide residue was monitored by TLC until it was free. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution, and the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (90 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate desonide succinate (9.5 g, 85% yield). MS m / z (ESI): 539.2 [M+Na] + .

[0250] Desonide succinate (4.7 g, 8.8 mmol), nonaethylene glycol monomethyl ether (4.5 g, 10.6 mmol), DMAP (0.22 g, 1.8 mmol), and EDCI (2.0 g, 10.6 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature. TLC monitoring indicated the absence of desonide succinate. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 15:1) and concentrated in vacuo to afford KYAC-37 (3.7 g, 44% yield) as a colorless oil. 1H NMR(400MHz,d6-DMSO)δ7.21(d,J=10.2Hz,1H),6.32(d,J=10.1Hz,1H),6.08(s,1H),5.10(s,1H),4.95-4.81 (m,1H),4.52(s,1H),4.32(d,J=19.5Hz,2H),4.28-4.19(m,2H),3.87-3.64(m,2H),3.59-3.48(m,30H),3.41- 3.35(m,2H),3.27(s,3H),2.88-2.73(m,2H),2.64-2.53(m,3H),2.42-2.31(m,1H),2.17-2.12(m,1H),2.13- 2.05(m,2H),1.72-1.61(m,2H),1.56-1.47(m,2H),1.43(s,3H),1.30(s,3H),1.15-1.07(m,5H),0.83(s,3H). MS m / z(ESI):927.7[M+H] + .

[0251] Example 1-38: Synthesis of compound KYAC-38

[0252] Desoximetasone (8 g, 21 mmol) was dissolved in dichloromethane (80 mL), followed by the addition of succinic anhydride (2.5 g, 25 mmol) and DMAP (3.1 g, 25 mmol). The reaction was allowed to proceed at room temperature and monitored by TLC until the absence of desoximetasone. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution and the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (80 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate desoximetasone succinate (8.3 g, 82% yield). MS m / z (ESI): 499.2 [M+Na] + .

[0253] Desoximetasone succinate (4.1 g, 8.6 mmol), heptaethylene glycol monomethyl ether (3.5 g, 10.3 mmol), DMAP (0.21 g, 1.7 mmol), and EDCI (2.0 g, 10.3 mmol) were dissolved in dichloromethane (90 mL) and reacted at room temperature. TLC monitoring indicated the absence of desoximetasone succinate. Dichloromethane (90 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (90 mL), saturated sodium bicarbonate solution (90 mL), and water (90 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 25:1) and concentrated in vacuo to afford KYAC-38 (3.1 g, 45% yield) as a colorless oil. 1 H NMR (400MHz, d6-DMSO) δ7.31 (d, J=10.3Hz, 1H), 6.27 (dd, J=10.0, 2.1Hz, 1H), 6.08 (s, 1H), 5.42-5. 32(m,1H),4.22-4.12(m,1H),4.09-4.04(m,4H),3.54-3.51(m,2H),3.53-3.41(m,22H),3.36-3.32( m,2H),3.15(s,3H),2.63-2.60(m,4H),2.54-2.51(m,2H),2.50-2.38(m,1H),2.32-2.20(m,2H),1. 95-1.82(m,2H),1.78-1.62(m,3H),1.54-1.40(m,4H),1.25-1.18(m,1H),0.87(s,3H),0.73(s,3H). MS m / z(ESI):799.2[M+H] + .

[0254] Example 1-39: Synthesis of compound KYAC-39

[0255] Diflorasone (9.5 g, 23 mmol) was dissolved in dichloromethane (95 mL), and then succinic anhydride (2.8 g, 28 mmol) and DMAP (3.4 g, 28 mmol) were added. The reaction was allowed to proceed at room temperature and monitored by TLC until no diflorasone was present. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution and the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (95 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate diflorasone succinate (9.8 g, 83% yield). MS m / z (ESI): 533.2 [M+Na] + .

[0256] Diflorasone succinate (3.9 g, 7.6 mmol), nonaethylene glycol monomethyl ether (3.9 g, 9.2 mmol), DMAP (0.19 g, 1.5 mmol), and EDCI (1.8 g, 9.2 mmol) were dissolved in dichloromethane (85 mL) and reacted at room temperature. TLC monitoring indicated the absence of diflorasone succinate. Dichloromethane (85 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (85 mL), saturated sodium bicarbonate solution (85 mL), and water (85 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-39 (3.2 g, 46% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.31(d,J=10.1Hz,1H),6.23(dd,J=10.1,1.8Hz,1H),6.05(s,1H),5.80-5.62(m,1H),5 .25(s,1H),5.15(s,1H),4.44-4.36(m,2H),4.20-4.13(m,1H),4.11-4.09(m,2H),3.54-3.51(m,2H),3.49-3.4 0(m,30H),3.36-3.31(m,2H),3.17(s,3H),2.65-2.60(m,2H),2.52-2.42(m,3H),2.15-2.05(m,3H),2.00-1.93 (m,1H),1.87-1.80(m,1H),1.65-1.57(m,1H),1.52(s,3H),1.36-1.25(m,1H),1.12-1.00(m,4H),0.96(s,3H). MS m / z(ESI):921.6[M+H] +.

[0257] Example 1-40: Synthesis of compound KYAC-40

[0258] Diflorasone (12 g, 29 mmol) was dissolved in dichloromethane (120 mL), followed by the addition of adipic anhydride (4.5 g, 35 mmol) and DMAP (4.3 g, 35 mmol). The reaction was allowed to proceed at room temperature and monitored by TLC until diflorasone was eliminated. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH adjusted to 2-3, and the organic phase extracted. The organic phase was poured into a 0.2 N sodium carbonate solution, the pH adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (120 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate diflorasone adipate (12.9 g, 82% yield). MS m / z (ESI): 561.3 [M+Na] + .

[0259] Diflorasone adipate (6.5 g, 12 mmol), heptaethylene glycol monomethyl ether (5.1 g, 15 mmol), DMAP (0.31 g, 2.5 mmol), and EDCI (2.9 g, 15 mmol) were dissolved in dichloromethane (120 mL) and reacted at room temperature. TLC monitoring indicated the absence of diflorasone adipate. Dichloromethane (120 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (120 mL), saturated sodium bicarbonate solution (120 mL), and water (120 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 15:1) and concentrated in vacuo to afford KYAC-40 (5.1 g, 49% yield) as a colorless oil. 1H NMR(400MHz,d6-DMSO)δ7.35(d,J=10.1Hz,1H),6.25(dd,J=10.1,1.8Hz,1H),5.95(s,1H),5.82-5.65(m,1H),5.25( s,1H),5.18(s,1H),4.45-4.35(m,2H),4.20-4.10(m,1H),4.05-4.00(m,2H),3.55-3.50(m,2H),3.45-3.35(m,22H) ,3.33-3.31(m,2H),3.15(s,3H),2.66-2.62(m,2H),2.60-2.55(m,3H),2.35-2.25(m,3H),2.20-2.15(m,1H),2.05- 1.99(m,1H),1.80-1.73(m,4H),1.70-1.66(m,1H),1.58(s,3H),1.45-1.38(m,1H),1.18-1.05(m,4H),0.98(s,3H). MS m / z(ESI):861.6[M+H] + .

[0260] Example 1-41: Synthesis of compound KYAC-41

[0261] Flumethasone (8 g, 19 mmol) was dissolved in dichloromethane (80 mL), and then succinic anhydride (2.3 g, 23 mmol) and DMAP (2.9 g, 23 mmol) were added and reacted at room temperature. TLC was monitored until there was no flumethasone. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution and the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (80 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the intermediate flumethasone succinate (7.9 g, yield 79%). MS m / z (ESI): 533.3 [M+Na] + .

[0262] Flumethasone succinate (3.5 g, 6.8 mmol), nonaethylene glycol monomethyl ether (3.5 g, 8.2 mmol), DMAP (0.17 g, 1.4 mmol), and EDCI (1.6 g, 8.2 mmol) were dissolved in dichloromethane (80 mL) and reacted at room temperature. TLC monitoring indicated the absence of flumethasone succinate. Dichloromethane (80 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (80 mL), saturated sodium bicarbonate solution (80 mL), and water (80 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 30:1) and concentrated in vacuo to afford KYAC-41 (3.5 g, 48% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.27(d,J=10.1Hz,1H),6.29(dd,J=10.0,2.1Hz,1H),6.11(s,1H),5.79-5.54(m ,1H),5.44-5.36(m,1H),4.18-4.09(m,3H),4.03-3.82(m,2H),3.65-3.63(m,2H),3.58-3.53(m,30H),3. 47-3.45(m,2H),3.27(s,3H),2.74-2.70(m,2H),2.69-2.55(m,3H),2.50-2.36(m,1H),2.30-2.18(m,2H ),1.92-1.86(m,1H),1.80-1.60(m,3H),1.56-1.41(m,4H),1.27-1.16(m,1H),0.89(s,3H),0.84(s,3H). MS m / z(ESI):921.6[M+H] + .

[0263] Example 1-42: Synthesis of compound KYAC-42

[0264] Flunisolide (9.5 g, 21 mmol) was dissolved in dichloromethane (95 mL), followed by the addition of succinic anhydride (2.5 g, 25 mmol) and DMAP (3.1 g, 25 mmol). The reaction was allowed to proceed at room temperature and monitored by TLC until the absence of flunisolide. The reaction solution was then poured into a 0.2 N hydrochloric acid solution, the pH was adjusted to 2-3, and the organic phase was extracted. The organic phase was poured into a 0.2 N sodium carbonate solution and the pH was adjusted to 9-10. The aqueous phase was extracted twice with dichloromethane, and then 12 N concentrated hydrochloric acid was added to the aqueous phase to adjust the pH to 2-3. The aqueous phase was then extracted with dichloromethane (95 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the intermediate flunisolide succinate (9.8 g, 84% yield). MS m / z (ESI): 557.3 [M+Na] + .

[0265] Flunisolide succinate (4.6 g, 8.4 mmol), heptaethylene glycol monomethyl ether (3.4 g, 10 mmol), DMAP (0.20 g, 1.7 mmol), and EDCI (1.9 g, 10 mmol) were dissolved in dichloromethane (90 mL) and reacted at room temperature. TLC monitoring indicated the absence of flunisolide succinate. Dichloromethane (90 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (90 mL), saturated sodium bicarbonate solution (90 mL), and water (90 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 20:1) and concentrated in vacuo to afford KYAC-42 (2.8 g, 44% yield) as a colorless oil. 1 H NMR(400MHz,d6-DMSO)δ7.28(d,J=10.2Hz,1H),6.32(dd,J=10.1,1.6Hz,1H),6.12(s,1H),5.78-5.62(m,1H),5. 53-5.36(m,1H),4.88-4.72(m,1H),4.61-4.52(m,1H),4.20-4.11(m,1H),4.13-4.07(m,3H),3.55-3.53(m,2H), 3.50-3.44(m,22H),3.37-3.34(m,2H),3.14(s,3H),2.63-2.60(m,3H),2.51-2.44(m,2H),2.30-2.21(m,1H),2. 05-1.90(m,2H),1.68-1.55(m,3H),1.52-1.40(m,4H),1.12-1.07(m,1H),1.28(s,3H),1.01(s,3H),0.78(s,3H). MS m / z(ESI):857.4[M+H]+ .

[0266] Comparative Example 1-1: Synthesis of Control Compound 1

[0267] Nonaethylene glycol (5 g, 12 mmol), imidazole (1.6 g, 24 mmol), and tert-butyldimethylsilyl chloride (3.6 g, 24 mmol) were dissolved in dichloromethane and reacted at room temperature. TLC monitoring was performed until the nonaethylene glycol disappeared. Dichloromethane (50 mL) was then added to the reaction solution, which was then washed with water (80 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 40:1) and concentrated in vacuo to obtain the nonaethylene glycol monosilyl protected compound (2.7 g, 42% yield).

[0268] Budesonide succinate (2 g, 4 mmol), nonaglycol monosilyl protected compound (2.4 g, 4.5 mmol), DMAP (0.1 g, 0.8 mmol), and EDCI (1 g, 5.7 mmol) were dissolved in dichloromethane (50 mL) and reacted at room temperature. TLC monitoring indicated the absence of budesonide succinate. Dichloromethane (80 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (80 mL), saturated sodium bicarbonate solution (80 mL), and water (80 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to yield a crude oil. Purification by silica gel column chromatography (DCM / MeOH = 50:1) and vacuum concentration afforded the nonaglycol monosilyl protected compound (2 g, 52% yield) as a colorless oil. MS m / z (ESI): 1041.7 [M+H] + .

[0269] Budesonide succinate nonaglycol silyl protected compound (2 g, 2 mmol) and a 1 M tetrabutylammonium fluoride tetrahydrofuran solution (4 mL, 4 mmol) were dissolved in tetrahydrofuran (40 mL) and reacted at room temperature. TLC monitoring indicated the absence of budesonide succinate nonaglycol silyl protected compound. The reaction solution was concentrated in vacuo, dichloromethane (50 mL) was added, and the mixture was washed with water (80 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude oil. The crude product was purified by silica gel column chromatography (DCM / MeOH = 50:1) and concentrated in vacuo to obtain reference compound 1 (1.5 g, 84% yield) as an oil. 1H NMR (400MHz, d6-DMSO): δ7.29(d,J=9.2Hz,1H),6.27(d,J=7.9Hz,1H),4.56-4.44(m,3H),4.26-4.1 3(m,2H),4.11-4.09(m,2H),3.57-3.54(m,2H),3.51-3.43(m,30H),3.39-3.36(m,2H),2.68-2.63(m ,2H),2.54-2.48(m,2H),2.34(d,J=5.9Hz,2H),2.33-1.95(m,2H),1.93-1.47(m,3H),1.78-1.74(m, 1H),1.64-1.52(m,5H),1.52-1.23(m,3H),1.31-1.25(m,2H),0.93-0.80(m,5H),0.92-0.88(m,3H). MS m / z(ESI):927.6[M+H] + .

[0270] Comparative Example 1-2: Synthesis of Control Compound 2

[0271] Budesonide (5 g, 12 mmol), mPEG9-COOH (6.6 g, 14 mmol), DMAP (0.3 g, 2 mmol), and EDCI (3.3 g, 17 mmol) were dissolved in dichloromethane (100 mL) and reacted at room temperature. TLC monitoring was performed until the budesonide was eliminated. Dichloromethane (100 mL) was then added to the reaction solution, which was then washed sequentially with 10% citric acid solution (100 mL), saturated sodium bicarbonate solution (100 mL), and water (100 mL). The product was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 50:1) and concentrated in vacuo to obtain the reference compound 2 (4.6 g, 45% yield) as an oil. 1H NMR (400MHz, d6-DMSO): δ7.29(d,J=9.2Hz,1H), 6.27(d,J=7.9Hz,1H), 4.56-4.44(m,3H),4.26-4.13(m,2H),4.11-4.09(m,2H),3.51-3.43(m,30H),3. 39-3.36(m,2H),3.17(s,3H),2.68-2.63(m,2H),2.54-2.48(m,2H),2.34(d,J=5. 9Hz,2H),2.33-1.95(m,2H),1.93-1.47(m,3H),1.78-1.74(m,1H),1.64-1.52(m, 5H),1.52-1.23(m,3H),1.31-1.25(m,2H),0.93-0.80(m,5H),0.92-0.88(m,3H). MS m / z(ESI):855.6[M+H] + .

[0272] Comparative Examples 1-3: Synthesis of Comparative Compound 3

[0273] Budesonide (5 g, 12 mol) was dissolved in dichloromethane (60 mL), followed by the addition of di(p-nitrobenzene) carbonate (4 g, 14 mmol) and diisopropylethylamine (DIEA) (3 mL, 17 mmol). The reaction was allowed to proceed at room temperature, and TLC monitoring was performed until the budesonide was eliminated. Dichloromethane (50 mL) was then added to the reaction solution, which was then washed with water (80 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to yield a crude oil. Purification by silica gel column chromatography (DCM / MeOH = 50:1) afforded the intermediate budesonide carbonate (5.4 g, 78% yield). MS m / z (ESI): 596.3 [M+H] + .

[0274] Budesonide carbonate (5 g, 8 mmol), nonaglycone monomethyl ether (4 g, 10 mmol), and DIEA (2 mL, 12 mmol) were dissolved in dichloromethane (85 mL) and reacted at room temperature. TLC monitoring was performed until the budesonide carbonate disappeared. Dichloromethane (50 mL) was then added to the reaction solution, which was then washed with water (80 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude oil. The product was purified by silica gel column chromatography (DCM / MeOH = 50:1) and concentrated in vacuo to obtain the reference compound 3 (5 g, 65% yield) as an oil. 1H NMR (400MHz, d6-DMSO): δ7.27(d,J=9.4Hz,1H),6.52(d,J=7.7Hz,1H),4.73-4.57(m,3H),4.4 1-4.31(m,2H),3.65-3.52(m,30H),3.50-3.42(m,2H),3.34(s,3H),2.59-2.54(m,2H),2.51-2 .45(m,2H),2.41(d,J=5.8Hz,2H),2.27-1.94(m,2H),1.91-1.58(m,3H),1.73-1.65(m,1H),1. 61-1.56(m,5H),1.52-1.37(m,3H),1.31-1.25(m,2H),1.00-0.85(m,5H,),0.96-0.92(m,3H). MS m / z(ESI):919.6[M+H] + .

[0275] Experimental Example 1 Solubility Evaluation of PEG-Modified Glucocorticoid Drugs

[0276] 2 mg of each compound of Example 1-42 was weighed and placed in a glass bottle. 50 μl of secondary purified water was added each time. The sample was ultrasonicated at room temperature (25±3° C.) for 10 minutes to observe whether it was completely dissolved. The solubility test results are shown in Table 1.

[0277] Table 1 Solubility test results (25±3℃)

[0278] The results show that compared with budesonide, ciclesonide, fluticasone propionate, beclomethasone dipropionate and beclomethasone 17-propionate, the solubility of the PEG-modified glucocorticoid drug provided by the present invention is increased by tens to thousands of times.

[0279] Experimental Example 2 Characterization of PEG-modified glucocorticoid drug micelles

[0280] Dynamic light scattering (DLS) was used to measure the Brownian motion of particles in the sample. The average particle size distribution and polydispersity coefficient of the micelle particles were obtained by fitting the raw data. The critical micelle concentration (CMC) was determined by plotting the ratio of light scattering intensity to the PEG-modified glucocorticoid concentration. The results of the micelle characterization experiments are shown in Table 2.

[0281] 2.1 Preparation of test solution

[0282] The KYAC-02, KYAC-03, KYAC-04, KYAC-08, KYAC-09, KYAC-11, KYAC-14, and KYAC-33 compounds in the examples, as well as budesonide and reference compound 1, were dissolved in a pH 4.5 citrate buffer solution to prepare a 1 mg / ml test solution. An appropriate amount of the 1 mg / ml test solution was diluted stepwise by adding citrate buffer solution to prepare 0.5 mg / ml, 0.25 mg / ml, 0.125 mg / ml, 0.025 mg / ml, and 0.005 mg / ml test solutions, respectively, and the light scattering intensities thereof were measured.

[0283] 2.2 Results

[0284] Table 2 Results of micelle characterization experiments

[0285] The results show that: budesonide and control compound 1 are both unable to form micellar solutions; while the PEG-modified glucocorticoid drug provided by the present invention can form micelles with an average particle size in the range of 400-1000nm. The critical micelle concentration (CMC) of different compounds is obtained by plotting the ratio of light scattering intensity to the concentration of PEG-modified glucocorticoid drug, and the CMC concentration distribution is between 0.125 and 0.5mg / ml. The micelles formed by these low molecular weight PEG-modified glucocorticoid drugs have the characteristics of small particle size, surface electrical neutrality and good hydrophilicity. When administered to the lungs, the outer hydrophilic PEG micelles can pass through the mucus barrier on the surface of the respiratory tract to prevent adhesion and clearance, and can be better deposited in the lungs, thereby improving the local absorption of drug molecules in the lungs and reducing the safety risks brought by systemic absorption. The present invention can form a micellar solution, and its residence time in the lungs will be significantly increased, thereby prolonging the duration of local drug effect.

[0286] Experimental Example 3 Delivery Efficiency of PEG-Modified Glucocorticoid Drugs for Pulmonary Administration

[0287] 3.1 Preparation of test solution

[0288] Accurately weigh KYAC-02, KYAC-03, KYAC-04, KYAC-09, KYAC-11, KYAC-14, and KYAC-33 compounds in the examples and place them in a beaker. Dissolve them in a small amount of water for injection. Then weigh sodium chloride, anhydrous citric acid, and sodium citrate dihydrate in a beaker. Add water for injection to 100 g, stir and mix, and sonicate for 20 minutes to prepare a 0.5 mg / ml buffered saline solution (pH 4.5).

[0289] 3.2 Experimental methods

[0290] (1) The sample volume for each group was 2 mL, and there were three groups in total. The diluent was a 1:1 solution of ethanol and water. A PARI TurboBOY nebulizer and nebulizer cup were used, and the adult mode was selected to conduct a respiratory simulation test.

[0291] (2) The amount of material extracted from the first collection membrane after nebulization for 1 min using the diluent is the delivery rate;

[0292] (3) After replacing the second collection membrane, continue atomization for 9 minutes. Stop the machine and extract the adapter, device, and second collection membrane with diluent. The total amount of substance extracted and the amount of substance delivered at the delivery rate divided by the amount of substance consumed is the total amount delivered. The results of the respiratory simulation experiment are shown in Table 3.

[0293] 3.3 Results

[0294] Table 3 Breathing simulation test results

[0295] The results showed that compared with budesonide suspension, the total delivery amount of KYAC-02, KYAC-03, KYAC-04, KYAC-08, KYAC-09, KYAC-11, KYAC-14, and KYAC-33 compounds in the respiratory simulation experiment increased by nearly 1 times, and were significantly better than control compounds 1, 2, and 3, thereby reducing the residue of inhaled glucocorticoid drugs in the oropharynx and increasing the delivery and deposition of drugs in the lungs.

[0296] Test Example 4 Determination of the Dosage of PEG-Modified Glucocorticoid Drug Microparticles

[0297] 4.1 Preparation of test solution

[0298] Accurately weigh the KYAC-03 compound in the example and place it in a beaker. Dissolve it in a small amount of water for injection. Then weigh sodium chloride, anhydrous citric acid, and sodium citrate dihydrate in a beaker. Add water for injection to 100 g, stir and mix, and sonicate for 20 minutes to prepare a 0.5 mg / ml buffered saline solution (pH 4.5).

[0299] 4.2 Experimental methods

[0300] The next-generation pharmaceutical impactor (NGI) was placed in a cooling cabinet. After the cabinet temperature dropped to 4°C, the experiment began. The NGI was connected to a low-flow vacuum pump and a flow meter, and the flow rate was adjusted to 15 L / min (±5%). 2 ml of KYAC-03 solution (0.5 mg / ml in buffered saline) was added to the nebulizer cup. The nebulizer cup was connected to a compressor. The low-flow vacuum pump was first turned on, followed by the compressor. Atomization was performed using the compressed air generated by the compressor. After 16 minutes (nebulization was complete), the compressor was turned off, the nebulizer cup was removed, and the low-flow vacuum pump was turned off again. Remove and disassemble the NGI and nebulizer cup to which the sample was added. Rinse the nebulizer cup with a mixture of deionized water and methanol (60:40) to recover the residual drug solution into a 100ml volumetric flask. Use the mixture to clean the throat and transfer it to a 50ml volumetric flask. Use the mixture to clean and recover the first, second, third, fourth, fifth, sixth, and seventh collection layers, as well as the MOC collection layer with filter paper, into corresponding 50ml volumetric flasks. Repeat the measurement three times. The test solution in the MOC collection layer is filtered through a 0.45μm filter membrane. The filtrate is used as the test solution for the MOC collection layer. Other test solutions can be directly injected.

[0301] The above experimental method was repeated to determine the fine particle dosage of budesonide suspension (0.5 mg / ml). The results of the fine particle dosage experiment are shown in Table 4.

[0302] 4.3 Results

[0303] Table 4 Fine particle dosage experimental results

[0304] The results showed that the FPD (fine particle dose) of the KYAC-03 solution was 515.9 μg, significantly higher than the 134.8 μg of the budesonide suspension solution; the FPF (fine particle effective deposition rate) of the KYAC-03 solution was 52.3%, significantly higher than the 33.2% of the budesonide suspension solution; and the MMAD (mass median aerodynamic diameter) of the KYAC-03 solution was 4.6 μm, less than the 6.4 μm of the budesonide suspension solution. The PEG-modified glucocorticoid drug provided by the present invention has a higher delivery efficiency than the budesonide suspension solution. Figure 1 shows that the deposition amount of the PEG-modified glucocorticoid drug provided by the present invention in the 5th to 7th levels and the MOC layer is significantly higher than that of the budesonide suspension solution, and is significantly better than that of the control compound 1, control compound 2, and control compound 3, indicating that the PEG-modified glucocorticoid drug provided by the present invention can be more effectively delivered to the deep lung.

[0305] The compounds KYAC-04, KYAC-08, KYAC-09, etc. in this application have similar performance to KYAC-03 and will not be described in detail here.

[0306] Test Example 5 Glucocorticoid Receptor (GR) Agonist Activity Assay

[0307] 5.1 Preparation of stock solution for drug delivery

[0308] Test compound: Accurately weigh the test compound, dissolve it in DMSO, prepare a stock solution with a concentration of 20 mM, and store it at -20°C.

[0309] Positive control: Accurately weigh the dexamethasone control, dissolve it in DMSO, prepare a stock solution with a concentration of 10 mM, and store it at -20°C.

[0310] 5.2 Basis for concentration selection

[0311] The positive control was diluted 3-fold starting at 1 μM, serially diluted to 10 concentrations, for a total of two groups. The test compound was diluted 4-fold starting at 10 μM, serially diluted to 10 concentrations, for a total of two groups. The blank control was 0.1% DMSO.

[0312] 5.3 Cell culture

[0313] HEK293 cells were cultured in DMEM + 10% FBS + 200 μg / ml Hygromycin B at 37°C in a 5% CO2 incubator. The old culture medium was removed and washed once with phosphate buffered saline (PBS), and then 1 mL of TrypLE TM Express enzyme and incubate at 37°C for approximately 2 minutes. When cells detach from the bottom of the dish, add approximately 5 mL of complete culture medium preheated at 37°C. Gently pipette the cell suspension to dissociate aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes to collect cells for use in experiments or subculture.

[0314] 5.4 Determination of the inhibitory activity of compounds on GR receptors

[0315] HEK293 cells were digested and inoculated into 6 cm culture dishes. The pBIND-GR plasmid was transfected into HEK293 cells using a transfection reagent to obtain HEK293 cells successfully transfected with the pBIND-GR plasmid. The cells were resuspended in phenol red-free DMEM medium containing 5% carbon-adsorbed serum, counted, and inoculated into 96-well plates. The test compound or positive control was added and then incubated in an incubator. The luminescence signal value was read using a multi-function microplate reader according to the instructions of the luciferase assay kit, and the EC of each test compound was calculated using the GraphPad nonlinear fitting formula. 50 The glucocorticoid receptor agonist activity is shown in Table 5.

[0316] 5.5 Results

[0317] Table 5 Glucocorticoid receptor agonist activity

[0318] Results indicate that the PEG-modified glucocorticoid drugs provided by the present invention can significantly reduce their agonist activity on the GR receptor, exhibiting low GR receptor agonist activity before conversion to active metabolites by endogenous esterases. These less active glucocorticoid prodrugs can reduce oropharyngeal adverse reactions caused by aerosol inhalation administration, as well as side effects associated with systemic absorption.

[0319] Test Example 6 Anti-asthma pharmacodynamics experiment

[0320] 6.1 Model preparation

[0321] 190 female BALB / c mice were acclimated to the condition. After one week, 180 qualified mice were selected for testing. Ten mice were randomly selected as blank controls. 170 mice were used to establish an asthma model, with 10 mice in each group. Model mice were sensitized with 0.2 mL of a sensitizing solution containing 50 μg OVA(IV) and 2 mg AL(OH)3 via intraperitoneal injection on days 0, 7, and 14. A control group received an equal volume of saline. On days 21-25 of sensitization, mice in the model and treatment groups were challenged with 5% OVA(II) via oronasal exposure, while mice in the control group received saline nebulization for the same duration.

[0322] 6.2 Grouping and Dosing

[0323] The corresponding drug was administered by nebulization for 60 minutes 1 hour before each challenge, and the drug administration and challenge were continued for 5 consecutive days. The animal groups and dosages are shown in Table 6. AstraZeneca's Pulmicort Respules (0.5 mg / mL) was used as budesonide suspension.

[0324] Table 6 Animal grouping and dosage

[0325] 6.3 Airway Hyperresponsiveness Measurement

[0326] Airway reactivity was measured in each group of mice after the final challenge. Mice were placed in a nebulizer and baseline expiratory pause (Penh) values ​​were measured. Then, they were challenged with nebulized methacholine at concentrations ranging from 0, 6.25, and 12.5 mg / mL, with a nebulized dose of 100 μL per session for 60 seconds. After each concentration, the mice were observed for signs of hypoxia, such as shortness of breath, head scratching, and irritability. Penh values ​​were recorded for 3 minutes, and the average values ​​were used to compare airway reactivity among the groups. The effects on the expiratory pause (Penh) values ​​of mice are shown in Table 7.

[0327] 6.4 Sample Collection and Bronchoalveolar Lavage Fluid Cell Count

[0328] After the airway hyperresponsiveness test, mice were sacrificed after overdose of anesthesia and fixed on a dissecting tray. The abdomen and thoracic cavity were opened, and the neck skin and excess tissue were trimmed to expose the trachea. A small incision was made transversely along the trachea with small scissors. A pre-treated 1 mL syringe needle was inserted and secured with surgical suture. 0.4 mL of pre-chilled phosphate-buffered saline (PBS) was drawn into the lungs of the mice using a 1 mL syringe and slowly injected into the lungs, followed by slow aspiration. Each mouse was lavaged once, collecting approximately 0.3 mL of lavage fluid. The alveolar lavage fluid was centrifuged at 3000 rpm for 5 minutes. After centrifugation, the supernatant was aliquoted and stored at -20°C. The cell pellet was resuspended in 1 mL of pre-chilled PBS and counted using a cell analyzer. Cells analyzed included white blood cells and lymphocytes. The effects on the number of inflammatory cells in the alveolar lavage fluid of mice are shown in Table 8.

[0329] 6.5 Statistics

[0330] SPSS software was used for statistical analysis. The measurement data were expressed as mean ± standard deviation. One-way ANOVA was used for comparison between groups. LSD test was used for homogeneous variances, and Dunnett-t test was used for unequal variances. P < 0.05 was considered statistically significant.

[0331] 6.6 Results

[0332] 6.6.1 Effects on Airway Hyperresponsiveness in Mice

[0333] Table 7 Effects on the expiratory pause (Penh) value of mice

[0334] Note: Compared with the blank control group: ## P<0.01, ### P<0.001; compared with the model control group: * P<0.05, ** P<0.01, *** P<0.001; compared with the budesonide suspension group: Δ P<0.05, ΔΔ P<0.01.

[0335] The results showed that when mice were sensitized with 50 μg OVA+2 mg AL(OH)3 for 3 weeks and then challenged with 5% OVA for 5 consecutive days, and then challenged with 6.25 mg / mL and 12.5 mg / mL methacholine, the expiratory pause (Penh) value was significantly increased compared with the blank control group (P<0.01 or P<0.001), indicating that the mouse asthma model was successfully established; when the model mice were pre-nebulized with 0.5 mg / ml budesonide suspension before challenge, the Penh value was significantly decreased compared with the model control group (P<0.01), indicating that the positive control drug budesonide suspension had significant anti-asthma activity; the model mice had a significant effect on the asthma control group after challenge. After pre-nebulization administration of 0.25 mg / ml of the example compounds, the Penh value was extremely significantly reduced compared with the model control group (P<0.001). Among them, the inhibitory activity of 0.25 mg / ml compounds KYAC-03, KYAC-04, KYAC-08, KYAC-09, KYAC-10, KYAC-11, KYAC-14, KYAC-16, KYAC-17, KYAC-20, KYAC-33, and KYAC-39 were all better than that of the 0.5 mg / ml budesonide suspension control group, with statistically significant differences (P<0.05).

[0336] 6.6.2 Effect on the number of inflammatory cells in mouse bronchoalveolar lavage fluid

[0337] Table 8 Effects on the number of inflammatory cells in the alveolar lavage fluid of mice

[0338] Note: Compared with the blank control group: ### P<0.001; compared with the model control group: * P<0.05, ** P<0.01, *** P<0.001; compared with the budesonide suspension group: Δ P<0.05, ΔΔ P<0.01.

[0339] The results showed that after mice were sensitized with 50 μg OVA+2 g AL(OH)3 for 3 weeks and then challenged with 5% OVA for 5 consecutive days, the white blood cell and lymphocyte counts in the alveolar lavage fluid were significantly increased compared with the blank control group (P<0.001), indicating that the mouse asthma model was successfully established; after the model mice were pre-administered with 0.5 mg / ml budesonide suspension by aerosol before challenge, the white blood cell and lymphocyte counts in the alveolar lavage fluid were significantly decreased compared with the model control group (P<0.05), indicating that the positive control drug budesonide suspension had significant anti-inflammatory activity; the model mice were pre-administered with 0. After administration of 25 mg / ml of the example compounds, the white blood cell and lymphocyte counts in the alveolar lavage fluid were significantly reduced compared with the model control group (P<0.01). Among them, the anti-inflammatory activities of 0.25 mg / ml compounds KYAC-03, KYAC-04, KYAC-08, KYAC-09, KYAC-10, KYAC-11, KYAC-14, KYAC-16, KYAC-17, KYAC-33, and KYAC-39 were superior to those of the 0.5 mg / ml budesonide suspension control group, with statistically significant differences (P<0.05).

[0340] Test Example 7 Anti-allergic rhinitis pharmacodynamics experiment

[0341] 7.1 Model preparation

[0342] Seventy female BALB / c mice were adaptively fed, and after one week, 60 qualified mice were selected for the experiment. Ten mice were randomly selected as the blank control group and 50 mice were selected to prepare an allergic rhinitis model, with 10 mice in each group. The modeled mice were sensitized by intraperitoneal injection of 0.2 mL of sensitizing solution on days 0, 7, and 14, respectively. Each mL of sensitizing solution contained 0.25 mg OVA (IV) and 5 mg Al (OH) 3. The normal group was injected with an equal volume of normal saline.

[0343] 7.2 Grouping and Dosing

[0344] On days 21-27 after sensitization, the sensitized mice were challenged bilaterally with OVA (IV) saline. After the allergic rhinitis model developed, the mice were divided into a model control group, a budesonide nasal spray group (Ranocort, AstraZeneca Pharmaceuticals Co., Ltd.), a KYAC-04 group, a KYAC-09 group, and a KYAC-11 group. Nasal administration was performed using a microinjector: the blank and model controls received 20 μl of saline, while the positive control group received 10 μl of budesonide nasal spray (1.28 mg / ml). The drug-treated groups received 20 μl of 0.25 mg / ml KYAC-04, KYAC-09, and KYAC-11 solutions, respectively. Each group received drug administration for 7 consecutive days. Thirty minutes after the last dose, 20 μl of 5% OVA (IV) in normal saline was dripped into the nasal cavity of each group of mice for challenge. The mice were closely observed for signs and symptoms of allergic rhinitis within 30 minutes of challenge. Blood was collected from the orbital vein of each group of mice at the end of the experiment for eosinophil counts. After centrifugation, serum was collected for IgE antibody analysis, and the results were statistically analyzed between groups. The animal groups and dosages are shown in Table 9. The effects on the symptoms and signs of allergic rhinitis in mice are shown in Table 10. The effects on IgE antibodies and eosinophils in the blood of mice with allergic rhinitis are shown in Table 11.

[0345] Table 9 Animal grouping and dosage

[0346] 7.3 Results

[0347] 7.3.1 Results of the preventive effect on the symptoms and signs of allergic rhinitis in mice

[0348] Table 10 Effects on symptoms and signs of allergic rhinitis in mice (x±s, n=10)

[0349] Note: Compared with the blank control group: # P<0.05, ## P < 0.01, ### P<0.001; compared with the model control group: * P<0.5, ＊＊ P<0.01.

[0350] The results showed that the model control group developed significant symptoms and signs of nasal itching, including scratching, sneezing, and runny nose, after model establishment, with highly significant and extremely significant differences compared to the blank control group, indicating that the allergic rhinitis model was successfully established. The symptoms and signs of scratching, sneezing, and runny nose in the budesonide nasal spray, KYAC-04, KYAC-09, and KYAC-11 groups were alleviated to varying degrees compared to the model control group, with significant differences in all quantitative indicators. This indicates that budesonide nasal spray, KYAC-04, KYAC-09, and KYAC-11 significantly improved the symptoms and signs of scratching, sneezing, and runny nose in rats with allergic rhinitis.

[0351] 7.3.2 Inhibitory Effects on IgE Antibodies and Eosinophils in Allergic Rhinitis in Mice

[0352] Table 11 Effects on IgE antibodies and eosinophils in the blood of mice with allergic rhinitis (x±s, n=10)

[0353] Note: Compared with the blank control group: # P<0.05, ## P < 0.01, ### P<0.001; compared with the model control group: * P<0.5, ＊＊ P < 0.01, ＊＊＊ P<0.001.

[0354] The results showed that the model control group showed increased eosinophil counts and increased IgE antibody levels in the blood after modeling, with highly significant differences compared to the normal control group, indicating that the allergic rhinitis model was successfully established. The budesonide nasal spray, KYAC-04, KYAC-09, and KYAC-11 groups showed significant reductions in eosinophil counts and IgE antibody levels in the blood, with varying degrees of significant differences compared to the model control group. This indicates that budesonide nasal spray, KYAC-04, KYAC-09, and KYAC-11 can significantly reduce the levels of eosinophils and IgE antibodies in the blood of rats with allergic rhinitis.

[0355] Experimental studies on allergic rhinitis have shown that KYAC-04, KYAC-09, and KYAC-11 at a concentration of 0.25 mg / ml have similar pharmacodynamic activity to budesonide nasal spray at a concentration of 1.28 mg / ml. They can significantly improve the symptoms and signs of allergic rhinitis, such as scratching, sneezing, and runny nose, and significantly reduce the levels of eosinophils and IgE antibodies in the blood of rats with allergic rhinitis. It is speculated that this may be one of the mechanisms by which they improve nasal symptoms.

[0356] The compounds KYAC-03 and KYAC-08 of the present invention have similar performances to KYAC-04, KYAC-09, and KYAC-11, and are not described in detail here.

[0357] Test Example 8 Stability Study

[0358] 8.1 Preparation of test solution

[0359] KYAC-04, Reference Compound 2, and Reference Compound 3 from the Examples were dissolved in pH 4.5 citrate buffer to prepare 0.5 mg / ml test solutions. Appropriate amounts of these test solutions were then taken to investigate their stability under various storage conditions. Stability results are shown in Tables 12 and 13.

[0360] 8.2 Results

[0361] Table 12 Stability results (25°C / 60% relative humidity)

[0362] Table 13 Stability results (40°C / 75% relative humidity)

[0363] The results showed that compared with the initial values, the content and total impurities of KYAC-04 did not change significantly after storage at 25°C / 60% relative humidity for 6 months, meeting the stability requirements of the solution; while the control compounds 2 and 3 underwent significant degradation at 25°C / 60% relative humidity and 40°C / 75% relative humidity, indicating that the solution stability of the control compound 2 directly coupled with the carboxyl group and the control compound 3 coupled with the carbonate was poor and could not meet the stability requirements of the nebulized inhalation solution.

[0364] The compounds KYAC-03, KYAC-08, KYAC-09, KYAC-10, KYAC-11, KYAC-14, KYAC-16, KYAC-17, KYAC-20, KYAC-33, and KYAC-39 of the present invention have similar performance to KYAC-04 and are not described in detail here.

[0365] In summary, the PEG-modified glucocorticoid drug provided by the present invention can greatly improve the solubility of the glucocorticoid drug, and form micellar self-assemblies with an average particle size in the range of 400-1000 nm in aqueous solution and buffer salt systems. The PEG-modified glucocorticoid drug provided by the present invention can improve the delivery efficiency of the drug to the lungs when administered to the lungs, and can pass through the mucus layer on the surface of the airway to reach the lung epithelial cells in the form of hydrophilic micelles, and be metabolized in the lung tissue to release glucocorticoid active molecules, avoiding clearance by ciliary tissue, thereby improving drug efficacy. The PEG-modified glucocorticoid drug provided by the present invention can significantly reduce the agonist activity on the GR receptor, and has a lower GR receptor agonist activity before being converted into active metabolites by endogenous esterases, thereby reducing the oropharyngeal adverse reactions caused by aerosol inhalation administration, and the side effects caused by systemic absorption. Anti-asthma efficacy experiments show that compared with the positive control drug budesonide suspension, the PEG-modified glucocorticoid drug provided by the present invention has better anti-asthma efficacy at a 1 / 4 administration concentration (calculated according to the glucocorticoid molecules contained), significantly reducing the airway reactivity index Penh value and the number of inflammatory cells in the alveolar lavage fluid of asthma model mice (P<0.05), greatly reducing the dosage, and reducing the risk of systemic toxicity and side effects. Anti-allergic rhinitis experimental studies have shown that the PEG-modified glucocorticoid drug provided by the present invention has similar pharmacodynamic activity to budesonide nasal spray at a 1 / 5 administration concentration (calculated according to the glucocorticoid molecules contained), and can significantly improve the symptoms and signs of allergic rhinitis such as scratching, sneezing and runny nose, and significantly reduce the eosinophil and IgE antibody levels in the blood of rats with allergic rhinitis. Stability experiments show that the PEG-modified glucocorticoid drug provided by the present invention has good stability and can meet the stability requirements of aerosol inhalation solution.

[0366] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A PEG-modified glucocorticoid drug, characterized in that: The structural formula of the compound of general formula I is as follows: Wherein, A, B, C, R1, R2, R3, R4 and R5 shown in the structural formula of the compound of general formula I are selected independently of each other, and: n is an integer from 3 to 100; A is selected from C(O) or P(O)(OH); B is selected from null, substituted or unsubstituted alkylene containing 1 to 6 carbon atoms, and substituted or unsubstituted arylene containing 6 to 10 carbon atoms; C is selected from no group, C(O), S(O)2 or P(O)(OH)O; R1 is selected from H or halogen; R2 is selected from H, methyl or halogen; R3 and R4 are independently selected from H, OH, an alkyl group containing 1 to 6 carbon atoms, OR6, OCOR7, Or, R3 and R4 together form That is, C16 and C17 are connected by an oxygen bridge. Or, R3 and R4 together form That is, C16 and C17 are connected by an oxazole ring. Or, R3 and R4 together form That is, C16 and C17 are connected by epoxy. Or, R3 and R4 together form a single bond, i.e., C16 and C17 are also connected by a double bond; R5 is selected from substituted or unsubstituted alkyl groups containing 1 to 6 carbon atoms; wherein R6 is selected from an alkyl group or a halogenated alkyl group containing 1 to 6 carbon atoms; wherein R7 is selected from an alkyl group containing 1 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, an alkynyl group containing 2 to 6 carbon atoms, an aryl group containing 6 to 10 carbon atoms, or a heteroaryl or heterocyclic group containing 4 to 10 carbon atoms; wherein R8 and R9 are independently selected from H, an alkyl group containing 1-6 carbon atoms, an alkenyl group containing 2-6 carbon atoms, an alkynyl group containing 2-6 carbon atoms, an aryl group containing 6-10 carbon atoms, a heteroaryl group or a heterocyclic group containing 4-10 carbon atoms, or R8 and R9 together form a cycloalkane containing 3-5 carbon atoms; Among them, R 10 is selected from H, an alkyl group containing 1 to 6 carbon atoms, an alkenyl group containing 2 to 6 carbon atoms, an alkynyl group containing 2 to 6 carbon atoms, an aryl group containing 6 to 10 carbon atoms, or a heteroaryl or heterocyclyl group containing 4 to 10 carbon atoms; wherein the halogen is selected from F or Cl; The dashed lines represent single or double bonds.

2. The PEG-modified glucocorticoid drug according to claim 1, wherein in, A, B, C, R1, R2, R3, R4 and R5 shown in the structural formula of the compound of general formula I are selected independently of each other, and: n is an integer from 3 to 70; A is selected from C(O) or P(O)(OH); B is selected from a null, substituted or unsubstituted alkylene group containing 2 to 4 carbon atoms; C is selected from no group or C(O); R1 is selected from H or halogen; R2 is selected from H, methyl or halogen; R3 and R4 are independently selected from H, OH, an alkyl group containing 1 to 3 carbon atoms, OCOR7, Or, R3 and R4 together form That is, C16 and C17 are connected by an oxygen bridge. Or, R3 and R4 together form That is, C16 and C17 are also connected through an oxazole ring; R5 is selected from substituted or unsubstituted alkyl groups containing 1 to 3 carbons; wherein R7 is selected from an alkyl group containing 1 to 3 carbon atoms or a heterocyclic group containing 4 to 6 carbon atoms; wherein R8 and R9 are independently selected from H, an alkyl group containing 1 to 6 carbon atoms, or R8 and R9 together form a cycloalkane containing 3 to 5 carbon atoms; Among them, R 10 Selected from alkyl groups containing 1 to 3 carbons; wherein the halogen is selected from F or Cl; The dashed lines represent single or double bonds.

3. The PEG-modified glucocorticoid drug according to claim 1, wherein in, A, B, C, R1, R2, R3, R4 and R5 shown in the structural formula of the compound of general formula I are selected independently of each other, and: n is an integer from 3 to 16; A is selected from C(O); B is selected from an alkylene group containing 2 to 4 carbon atoms; C is selected from C(O); R1 is selected from H or halogen; R2 is selected from H, methyl or halogen; R3 and R4 are independently selected from H, OH, an alkyl group containing 1 to 3 carbon atoms, OCOR7, Or, R3 and R4 together form That is, C16 and C17 are connected by an oxygen bridge. Or, R3 and R4 together form That is, C16 and C17 are also connected through an oxazole ring; R5 is selected from substituted or unsubstituted alkyl groups containing 1 to 3 carbons; wherein R7 is selected from an alkyl group containing 1 to 3 carbon atoms or a heterocyclic group containing 4 to 6 carbon atoms; wherein R8 and R9 are independently selected from H, an alkyl group containing 1 to 6 carbon atoms, or R8 and R9 together form a cycloalkane containing 3 to 5 carbon atoms; Among them, R 10 Selected from alkyl groups containing 1 to 3 carbons; wherein the halogen is selected from F or Cl; The dashed lines represent single or double bonds.

4. The PEG-modified glucocorticoid drug according to any one of claims 1 to 3, characterized in that in, A, B, C, R1, R2, R3, R4 and R5 shown in the structural formula of the compound of general formula I are selected independently of each other, and: n is an integer from 5 to 9; A is selected from C(O); B is selected from an alkylene group containing 2-3 carbons; C is selected from C(O); R1 is selected from H or halogen; R2 is selected from H or halogen; R3 and R4 are independently selected from H, OH, methyl, OCOR7, Or, R3 and R4 together form That is, the C16 and C17 positions are also connected by an oxygen bridge; R5 is selected from methyl; Wherein, R7 is selected from ethyl, furyl; wherein R8 and R9 are independently selected from H, an alkyl group containing 1 to 6 carbon atoms, or R8 and R9 together form a cycloalkane containing 3 to 5 carbon atoms; wherein the halogen is selected from F or Cl; The dashed lines represent single or double bonds.

5. The PEG-modified glucocorticoid drug according to claim 4, wherein in, A, B, C, R1, R2, R3, R4 and R5 shown in the structural formula of the compound of general formula I are selected independently of each other, and: n is an integer from 7 to 9; A is selected from C(O); B is selected from ethylene; C is selected from C(O); R1 is selected from H or halogen; R2 is selected from H or halogen; R3 and R4 are independently selected from OH, methyl, OCOR7, Or, R3 and R4 together form That is, the C16 and C17 positions are also connected by an oxygen bridge; R5 is selected from methyl; Wherein, R7 is selected from ethyl, furyl; wherein R8 and R9 are independently selected from H, an alkyl group containing 1 to 6 carbon atoms, or R8 and R9 together form a cycloalkane containing 3 to 5 carbon atoms; wherein the halogen is selected from F or Cl; The dashed lines represent single or double bonds.

6. The PEG-modified glucocorticoid drug according to claim 1 or 2, characterized in that The compound of general formula I is selected from the following compounds:

7. The PEG-modified glucocorticoid drug according to any one of claims 1 to 3, characterized in that The compound of general formula I is selected from the following compounds:

8. The PEG-modified glucocorticoid drug according to claim 4, wherein The compound of general formula I is selected from the following compounds:

9. The use of a PEG-modified glucocorticoid drug according to any one of claims 1 to 8 in the preparation of a medicament for treating a glucocorticoid receptor-mediated disease, wherein the disease is selected from eczema, psoriasis, atopic dermatitis, allergic dermatitis, neurodermatitis, rheumatoid arthritis, rhinitis, nasal polyps, asthma, chronic obstructive pulmonary disease, bronchitis, interstitial lung disease, conjunctivitis, colitis, Crohn's disease, or chronic glomerulonephritis.

10. A pharmaceutical composition, characterized in that A glucocorticoid drug comprising the PEG modification of any one of claims 1 to 8.

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