CN116514895A - Ciclesonide analogue, preparation method and application thereof - Google Patents

Ciclesonide analogue, preparation method and application thereof Download PDF

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Publication number
CN116514895A
CN116514895A CN202210079901.9A CN202210079901A CN116514895A CN 116514895 A CN116514895 A CN 116514895A CN 202210079901 A CN202210079901 A CN 202210079901A CN 116514895 A CN116514895 A CN 116514895A
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China
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
prodrug
ciclesonide
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CN202210079901.9A
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Chinese (zh)
Inventor
袁建栋
王晨英
黄仰青
顾家宁
吉超
丁海峰
崔洋洋
韩海冰
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Borui Pharmaceutical Suzhou Co ltd
Brightgene Bio Medical Technology Co Ltd
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Borui Pharmaceutical Suzhou Co ltd
Brightgene Bio Medical Technology Co Ltd
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Priority to CN202210079901.9A priority Critical patent/CN116514895A/en
Publication of CN116514895A publication Critical patent/CN116514895A/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
    • C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pulmonology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a ciclesonide analogue shown in a formula (I), a preparation method and application thereof, wherein the analogue is metabolized into an active ingredient of deisobutyryl ciclesonide (des-CIC) in vivo, the active ingredient is enriched in alveoli more quickly, the effect is faster, and in addition, the analogue has improved absorption and metabolism distribution properties, solubility, drug formation and the like.

Description

Ciclesonide analogue, preparation method and application thereof
Technical Field
The invention relates to the field of medicines, in particular to a corticosteroid compound, a preparation method and application thereof.
Background
Ciclesonide (alvasco) is a new generation of corticosteroid antiasthmatic drugs available for localized activation and inhalation developed by the pharmaceutical companies of sirofine-antomon and alltana in germany, and is mainly used clinically for the treatment of asthma and allergic rhinitis in different degrees in adults and children and adolescents over 4 years. The drug was first approved in australia on 12 months 15 2004.
Ciclesonide is a glucocorticoid with high-efficiency local anti-inflammatory effect, and can enhance the stability of endothelial cells, smooth muscle cells and lysosome membranes, inhibit immune response, reduce antibody synthesis, reduce release and activity of allergic mediums such as histamine, alleviate enzymatic processes triggered by antigen-antibody combination, and inhibit synthesis and release of bronchoconstrictor substances.
Ciclesonide is administered as a precursor compound and activated in the lung by esterases in the airways to the active ingredient, deisobutyryl ciclesonide (des-CIC), exerting anti-inflammatory activity. These active metabolites are extremely lipophilic and can be reversibly bound to fatty acids, and esterification in the cell increases the residence time of these drugs in the airways, thus prolonging the duration of action, but ciclesonide has the problem of poor solubility.
Disclosure of Invention
Technical problem to be solved by the invention
In order to solve the above problems in the prior art, the present invention provides a better ciclesonide analogue with improved absorption and metabolism distribution properties, solubility, drug formation and the like.
Solution for solving the problem
In one aspect, the invention provides a compound of formula i, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof:
further, the pharmaceutically acceptable salt is selected from the group consisting of sodium, potassium, calcium, magnesium and ammonium salts; preferably sodium and potassium salts; more preferably the sodium salt.
The invention provides a pharmaceutical composition, which comprises a compound shown in the formula I or pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label thereof.
The invention provides an application of a compound shown in a formula I or pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label thereof or a pharmaceutical composition in preparation of a medicament for treating and/or preventing asthma.
The invention provides an application of a compound shown in a formula I or pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label thereof or a pharmaceutical composition in preparation of a medicament for treating and/or preventing allergic rhinitis.
The present invention provides a method for treating and/or preventing asthma, comprising the steps of: a therapeutically effective amount of a compound of formula I according to the invention or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition according to the invention, is administered to a patient in need thereof.
The present invention provides a method for the treatment and/or prophylaxis of allergic rhinitis comprising the steps of: a therapeutically effective amount of a compound of formula I according to the invention or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition according to the invention, is administered to a patient in need thereof.
The invention provides a method for preparing a compound shown in a formula I, which comprises the following steps:
and (3) carrying out esterification reaction on the compound 2 to obtain a compound I.
Further, the esterification reaction is carried out in the presence of triethylamine and phosphorus oxychloride.
ADVANTAGEOUS EFFECTS OF INVENTION
(1) The ciclesonide analogue provided by the invention is metabolized into the effective component deisobutyryl ciclesonide (des-CIC) in vivo, and the effective component is enriched in alveoli more quickly, so that the effective blood concentration can be reached more quickly, and the effect is faster.
(2) The ciclesonide analogue has increased water solubility, and can be prepared into a true solution in an aqueous solution.
(3) The ciclesonide analogue provided by the invention can stay in the lung for a long time, is administrated once a day, and has better patient compliance.
(4) The ciclesonide analogue provided by the invention is administered through the lung, so that the first pass effect is avoided, and the toxic and side effects are reduced.
(5) The ciclesonide analogue of the invention is not absorbed in the gastrointestinal tract, and the active ingredients are fully metabolized in the lung and absorbed by the lung, so that the ciclesonide analogue has no side effect basically.
Detailed Description
In order to make the technical scheme and beneficial effects of the present invention more obvious and understandable, the following detailed description is given by way of specific examples (embodiments). Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In one aspect, the invention provides a compound of formula i, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof:
in some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts.
In some embodiments, the pharmaceutically acceptable salt is selected from sodium salt, potassium salt.
In some embodiments, the pharmaceutically acceptable salt is selected from sodium salts.
The invention also provides a preparation method of the compound shown in the formula I,
and (3) carrying out esterification reaction on the compound 2 to obtain a compound I.
In some embodiments, the esterification reaction may be described with reference to methods reported in the prior literature, such as, but not limited to: mild and Chemoselective Phosphorylation of Alcohols Using a ψ -Reagent, org.lett.
In some embodiments, the esterification reaction is performed in the presence of triethylamine and phosphorus oxychloride.
The invention also provides a pharmaceutical composition comprising at least one of the foregoing compounds or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
The present invention also provides a method of treating and/or preventing asthma, comprising the steps of: a therapeutically effective amount of a compound of formula I according to the invention or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition, is administered to a patient in need thereof.
The present invention also provides a method of treating and/or preventing allergic rhinitis comprising the steps of: a therapeutically effective amount of a compound of formula I according to the invention or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition, is administered to a patient in need thereof.
Term interpretation:
unless stated to the contrary, the terms used in the specification and claims have the following meanings.
In the chemical structure of the compounds of the invention, the bondThe configuration is not specified, i.e. bond +.>May beOr at the same time contain->Two configurations. In the chemical structure of the compounds of the invention, the bondThe configuration is not specified, i.e., either the Z configuration or the E configuration, or both configurations are included.
The term "isomers" encompasses all isomeric forms including enantiomers, diastereomers and geometric isomers including cis-trans isomers. Thus, individual stereochemical isomers of the compounds contemplated herein, or mixtures of enantiomers, diastereomers, or geometric isomers (or cis-trans isomers) thereof, are all within the scope of the invention.
The term "isotopic label" may be used to introduce isotopes into any of the compounds of the present invention, where the isotopes may be 2 H， 3 H， 13 C， 14 C， 15 N， 17 O， 18 O， 31 P， 32 P， 35 S， 18 F， 36 The Cl, specific isotopic derivatives, can be prepared by conventional techniques.
The term "pharmaceutically acceptable salts" means that the compounds of the invention are present in the form of their pharmaceutically acceptable salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in pharmaceutically salts, described in S.M. Berge, J.pharmaceutical Sciences (volume 66: pages 1-19, 1977). In the present invention, pharmaceutically acceptable non-toxic acid addition salts refer to salts of the compounds of the present invention with organic or inorganic acids including, but not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid and the like. Pharmaceutically acceptable non-toxic base addition salts represent salts of the compounds of the present invention with organic or inorganic bases, including, but not limited to, alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; salts of organic bases, e.g. ammonium salts formed with organic bases containing N groups or N + (C 1-6 Alkyl group 4 And (3) salt.
The term "pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
The term "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but is capable of achieving the desired effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.
The term "solvate" refers to a physical association of a compound of the invention with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical bond includes a hydrogen bond. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the crystalline solid lattice, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates and isopropanolates. Solvation methods are well known in the art.
The term "prodrug" means a compound that can be converted in vivo under physiological conditions, for example by hydrolysis in the blood, to yield an active prodrug.
The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.
The terms involved in the present invention are defined above, and those skilled in the art can understand the above terms in combination with the prior art, and the following is further described based on the contents of the present invention and the definition of the terms.
The preparation of the compounds, pharmaceutically acceptable salts of the present invention is further described below in connection with the examples, which are not intended to limit the scope of the invention.
The experimental methods in the examples of the present invention, in which specific conditions are not specified, are generally conducted under conventional conditions or under conditions recommended by the manufacturer of the raw materials or goods. The reagents of specific origin are not noted and are commercially available conventional reagents.
Example 1
3.8g of compound 2 is dissolved in a mixed solution of 76mL of THF and 1.40g of triethylamine, the temperature is reduced to minus 15+/-5 ℃, then 380mg of phosphorus oxychloride is added dropwise, the temperature is kept at minus 15+/-5 ℃ for reaction for 5 hours until a thin layer of the material disappears, then 15mL of water and 15mL of ethyl acetate are added for extraction, a water phase is collected, the organic phase is sequentially added with 15mL of water for extraction, the water phase is combined, the pH value of the water phase is adjusted to 7-8 by saturated sodium bicarbonate solution, and 1.5g of white solid target compound I is obtained after high-pressure liquid phase preparation and purification, the purity is 99%, and the ee value is 98.0%.
LCMS:549.10[M-1] - .
HNMR(400M,D 2 O)δ:7.47(d,J＝10.0Hz,1H),6.26(dd,J 1 ＝10.0Hz,J 2 ＝2.0Hz,1H),6.03(s,1H),5.19(d,J＝7.6Hz,1H),4.84(dd,J 1 ＝19.2Hz,J 2 ＝5.6Hz,1H),4.80(m,1H),4.57(dd,J 1 ＝19.2Hz,J 2 ＝5.6Hz,1H),4.41(d,J＝2.8Hz,1H),2.60(m,1H),2.34(m,1H),2.10(m,2H),1.88(m,3H),1.68～1.34(m,11H),1.20～0.80(m,10Hz).
Example 2
The following describes the biological implementation data in detail to further illustrate the technical scheme of the invention.
1. Purpose of test
Ciclesonide, ciclesonide analogs and active metabolites in the alveolar lavage fluid of SD rats were measured to investigate the metabolic status of ciclesonide and ciclesonide analogs in the alveolar lavage fluid of SD rats and the generation status of metabolites.
Ciclesonide analogs:active metabolite: />
2. Test materials
2.1 subject information
Ciclesonide original grinding (HSND): purity/content, 99.89%/NA, source borrelia biomedical (su state) stock, inc;
ciclesonide analog (HSND-L): purity/content, 98.8%/NA, source borrelia biomedical (su state) stock, inc;
active metabolite (HSND-D): purity/content, 90%/NA, source borrelia biomedical (su state) stock, inc.
2.2 blank matrix information
The blank matrix used in this project was SD rat alveolar lavage.
3. Test method
3.1 preparation of working fluid of incubation System
3.2 sample pretreatment procedure
4. Test results
The metabolic conditions of ciclesonide and ciclesonide analogues in the alveolar lavage fluid of the rats and the generation conditions of metabolites thereof are determined by liquid chromatography and mass spectrometry, and the results are shown in Table 1 in detail.
TABLE 1 results of metabolic stability in ciclesonide, ciclesonide analog rat alveolar lavage
Conclusion of experiment: ciclesonide analogs, like ciclesonide, are also metabolized in vivo to active metabolites; in addition, the ciclesonide analogue provided by the invention has higher metabolism speed in vivo and is enriched in alveoli (the concentration of the metabolite generated in vivo is higher in the same incubation time), so that the ciclesonide analogue can be released more quickly and has a faster effect when being prepared into an inhalant.
It should be understood that the above examples (embodiments) are illustrative and are not intended to encompass all possible embodiments encompassed by the claims. Various modifications and changes may be made in the above examples (implementations) without departing from the scope of the invention. Likewise, the individual technical features of the above embodiments (embodiments) may also be combined arbitrarily to form further embodiments (embodiments) of the invention which may not be explicitly described. Therefore, the above examples (embodiments) merely represent several embodiments of the present invention, and do not limit the scope of protection of the present invention.

Claims (9)

1. A compound of formula i or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof:
2. the compound of claim 1, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of sodium, potassium, calcium, magnesium and ammonium salts; preferably sodium and potassium salts; more preferably the sodium salt.
3. A pharmaceutical composition comprising a compound of any one of claims 1-2, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof.
4. Use of a compound according to any one of claims 1-2 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof or a pharmaceutical composition according to claim 3 for the manufacture of a medicament for the treatment and/or prophylaxis of asthma.
5. Use of a compound according to any one of claims 1-2 or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof or a pharmaceutical composition according to claim 3 for the manufacture of a medicament for the treatment and/or prophylaxis of allergic rhinitis.
6. A method of treating and/or preventing asthma comprising the steps of: administering a therapeutically effective amount of a compound having the structure of formula I according to any one of claims 1-2, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition of claim 3, to a patient in need thereof.
7. A method of treating and/or preventing allergic rhinitis comprising the steps of: administering a therapeutically effective amount of a compound having the structure of formula I according to any one of claims 1-2, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotopic label thereof, or a pharmaceutical composition of claim 3, to a patient in need thereof.
8. A process for preparing a compound of formula I according to claim 1, comprising the steps of:
and (3) carrying out esterification reaction on the compound 2 to obtain a compound I.
9. The process of claim 8, wherein the esterification reaction is carried out in the presence of triethylamine and phosphorus oxychloride.
CN202210079901.9A 2022-01-24 2022-01-24 Ciclesonide analogue, preparation method and application thereof Pending CN116514895A (en)

Priority Applications (1)

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CN202210079901.9A CN116514895A (en) 2022-01-24 2022-01-24 Ciclesonide analogue, preparation method and application thereof

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Application Number Priority Date Filing Date Title
CN202210079901.9A CN116514895A (en) 2022-01-24 2022-01-24 Ciclesonide analogue, preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN116514895A true CN116514895A (en) 2023-08-01

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