WO2023173846A1 - Composé stéroïde, son procédé de préparation et son utilisation - Google Patents

Composé stéroïde, son procédé de préparation et son utilisation Download PDF

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WO2023173846A1
WO2023173846A1 PCT/CN2022/138627 CN2022138627W WO2023173846A1 WO 2023173846 A1 WO2023173846 A1 WO 2023173846A1 CN 2022138627 W CN2022138627 W CN 2022138627W WO 2023173846 A1 WO2023173846 A1 WO 2023173846A1
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formula
compound represented
szy1906
pharmaceutically acceptable
acceptable salt
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PCT/CN2022/138627
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English (en)
Chinese (zh)
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刘国强
刘伟
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广州润尔眼科生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a steroid compound and its preparation method and application.
  • Lanosterol also known as isocholesterol, is a white, odorless powder with a variety of important biological activities and extensive pharmacological effects, such as anti-cancer, lowering blood pressure, treating leukemia, lowering blood sugar, and alleviating cataracts in experimental animals (experimental rabbits and experimental dogs) illness, etc.
  • Lanosterol is an intermediate in the biosynthesis of sterols. It has important physiological effects and is an important raw material in the cosmetics, medicine, and chemical industries.
  • Lanosterol is also an endogenous substance in eye tissue and has a basic concentration in each tissue. There are reports of using lanosterol to treat cataracts. However, during the experiment, it was found that local administration of lanosterol to the eye did not increase the amount of eye tissue. The concentration of lanosterol in various parts, especially the lens, shows that lanosterol is poorly absorbed after topical administration to the eye.
  • the object of the present invention is to provide a steroid compound and a pharmaceutically acceptable salt thereof.
  • the steroid compound of the present invention has a structural formula as shown in formula I':
  • R is dimethylamino, methylamino, amino or hydroxyl
  • R is dimethylamino, methylamino, amino or hydroxyl
  • Formula I' or pharmaceutically acceptable salts of compounds represented by Formula I include, but are not limited to, the following salts: citrate, fumarate, salicylate, L-tartrate, fumarate, sodium Salt, potassium salt, calcium salt, hydrochloride, acetate, nitrate, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, acetate, oxalate, lactate, lysine salt, Aspartate, etc.
  • the present invention also provides a method for preparing the compound represented by the above formula I'.
  • the method for preparing the compound represented by formula I' provided by the present invention includes the following steps: esterifying the compound represented by formula II and the compound represented by formula III to obtain the compound represented by formula I';
  • R is dimethylamino, methylamino, amino or hydroxyl.
  • the molar ratio of the compound represented by formula II to the compound represented by formula III can be 1:1-2;
  • the esterification reaction is carried out under the catalysis of carbodiimide; the carbodiimide can specifically be EDCI;
  • the esterification reaction is carried out under alkaline conditions, and the alkaline conditions can be provided by DMAP (4-dimethylaminopyridine).
  • DMAP 4-dimethylaminopyridine
  • the molar ratio of the amount of DMAP to the compound represented by Formula II can be 0.1-0.3, specifically Such as 0.2.
  • the esterification reaction is carried out in an organic solvent, and the organic solvent can specifically be methylene chloride;
  • the temperature of the esterification reaction can be 20-60°C, specifically 25°C;
  • the time of the esterification reaction may be 8-15 h, specifically 12 h.
  • Another object of the present invention is to provide the application of the above-mentioned formula I' or the compound represented by formula I.
  • the application provided by the present invention is the use of formula I' or a compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of medicaments for preventing and/or treating cataracts in ocular tissue.
  • the drug can be administered topically to the eye tissue via eye drops.
  • one or more pharmaceutically acceptable carriers can be added to the above-mentioned drugs.
  • the carrier includes conventional solvents, bacteriostatic agents, etc. in the pharmaceutical field.
  • the present invention also provides a drug or pharmaceutical composition for preventing and/or treating cataracts, the active ingredient of which includes formula I' or a compound represented by formula I or a pharmaceutically acceptable salt thereof.
  • the above-mentioned medicine or pharmaceutical composition can be prepared into liquid preparations, such as eye drops and other dosage forms according to conventional methods known to those skilled in the art.
  • the invention also protects an eye drop for preventing and/or treating cataracts.
  • the active ingredients of the eye drops for preventing and/or treating cataracts provided by the present invention include Formula I' or a compound represented by Formula I or a pharmaceutically acceptable salt thereof.
  • the eye drops also include a solvent, which is composed of polyethylene glycol 400 and a methylated- ⁇ -cyclodextrin physiological saline solution with a mass concentration of 10%.
  • a solvent which is composed of polyethylene glycol 400 and a methylated- ⁇ -cyclodextrin physiological saline solution with a mass concentration of 10%.
  • the volume ratio of the two is 2%:98%. .
  • the preparation method of the methylated- ⁇ -cyclodextrin physiological saline solution with a mass concentration of 10% is as follows: weigh 3.0012g of methylated- ⁇ -cyclodextrin, add 30 mL of physiological saline, and shake until the solution Clarity and transparency.
  • the mass content of the compound represented by formula I or its pharmaceutically acceptable salt is 0.01%-5%, specifically 0.03%.
  • the compound represented by formula I of the present invention has suitable permeability, is easy to absorb, and is relatively stable under storage conditions.
  • Pharmacokinetic experiments have shown that lanosterol can be detected in eye tissue, and is distributed in the cornea, conjunctiva, and aqueous humor. Reaching a higher drug concentration, the intended clinical indication of SZY1906-P22 is cataract, and the drug's target is the lens. After 0.0300% SZY1906-P22 was administered into the eyes of New Zealand rabbits for 30 minutes, the lanosterol content was 4948.0 ⁇ 959.2ng/g, which was approximately 1.83 times that of the SZY1906-P20 group for 30 minutes (2704.5 ⁇ 342.7ng/g) (see Table 8).
  • SZY1906-P22 is an excellent lanosterol prodrug from the perspective of pharmacokinetics. Comparing the lanosterol concentration in various parts of the eye tissue after administration of the following compounds, the lanosterol content in the lens of SZY1906-P21, SZY1906-P20 and the blank control group is close (lanosterol is an endogenous substance and has a basal concentration in the body, Comparable to the blank group, indicating very little absorption at this site), different concentrations of lanosterol were observed in different groups after administration in various tissues of the eye, reflecting the different absorption distributions of compounds with different structures.
  • Figure 1 shows the changes in lens opacity before and after administration of (SZY1906-P22) and (SZY1906-P20) eye drops detected by slit lamp.
  • Figure 2 The average drug concentration of lanosterol in various eye tissues after 30 minutes of administration of 0.0300% SZY1906-P22, 0.0293% SZY1906-P21, and 0.0286% SZY1906-P20 to the eyes of New Zealand rabbits.
  • Figure 3 shows the average drug concentration of lanosterol in various eye tissues after 60 minutes of administration of 0.0300% SZY1906-P22, 0.0293% SZY1906-P21, and 0.0286% SZY1906-P20 to the eyes of New Zealand rabbits.
  • CDP-Y120-1 (2.0g) to a 100ml round bottom flask, add 50ml DCM to dissolve, add DMAP (110mg) and stir for half an hour, then add EDCI (1.8g) and anthranilic acid (770mg), stir for reaction 12h.
  • the reaction solution was washed with 500ml of water, extracted with 200ml*3 of DCM, dried and evaporated, and purified by column chromatography to obtain about 0.68g of white solid compound I-1.
  • Test purpose To detect the effects of (SZY1906-P20) and (SZY1906-P22) eye drops on spontaneous cataracts in elderly New Zealand rabbits, and to observe the pharmacodynamic effects of (SZY1906-P20) and (SZY1906-P22) eye drops.
  • Test substance 0.03% (SZY1906-P20) and (SZY1906-P22) eye drops
  • Preparation method Weigh about 0.00311g of SZY1906-P20 and SZY1906-P22 respectively, first add 200 ⁇ L of polyethylene glycol 400, then add 9.8 ml of 10% methylated- ⁇ -cyclodextrin physiological saline, and sonicate until the solution is Clarity and transparency. Physical and chemical properties: This product is a colorless, clear liquid. Preliminarily determine the storage conditions: protect from light and store at 2-8°C.
  • Both groups of 0.03% eye drops and blank vehicle eye drops were administered to both eyes, 100 ⁇ l/eye/time, 3 times/day, with an interval of about 4 hours, and continuous administration for 7 weeks.
  • Detection method Take slit lamp photography to observe the changes in lens turbidity before and after administration.
  • Figure 1 shows the changes in lens opacity before and after administration of (SZY1906-P22) and (SZY1906-P20) eye drops detected by slit lamp.
  • the test results show that: (SZY1906-P22) lens opacity can be seen to decrease after 2 weeks of administration of eye drops. As the administration time increases, the lens opacity further decreases by 7 weeks of administration. However, the change in lens opacity in the (SZY1906-P20) group was not obvious. The results suggest that (SZY1906-P22) eye drops can effectively reduce lens opacity in New Zealand rabbits with senile spontaneous cataracts.
  • (SZY1906-P22) eye drops reduce lens opacity in New Zealand rabbits with spontaneous senile cataracts. This can provide certain animal test basis for the clinical application of (SZY1906-P22) eye drops in the treatment of spontaneous senile cataracts.
  • Polyethylene glycol 400 Solarbio Life Sciences Company, batch number: 722Y013, valid until April 13, 2020 (expired can still be used).
  • Adaptive feeding Newly received animals are kept adaptively for 1 day. During this period, the animals' drinking water, food intake and health status were observed, as well as whether there were signs of disease and death.
  • Adoption standards Technical guiding principles for drug non-clinical pharmacokinetic research promulgated by the State Food and Drug Administration.
  • the test product is administered in equimolar doses, and the dosage is set to 0.157 ⁇ mol/New Zealand rabbit, that is, the dosage of SZY1906-P20 is 0.0859 mg/New Zealand rabbit, and the dosage of SZY1906-P21 is 0.157 ⁇ mol/New Zealand rabbit.
  • the drug dosage is 0.0880mg/New Zealand rabbit, and the dosage of SZY1906-P22 is 0.0900mg/New Zealand rabbit.
  • a blank control group is needed to compare PK data. The specific grouping and dosage are shown in Table 1.
  • the method of administration is consistent with clinical medication, that is, ocular administration, and administration to the left and right eyes of rabbits is carried out simultaneously.
  • SZY1906-P20 eye drops Weigh 0.00286g of SZY1906-P20, first add 200 ⁇ L of polyethylene glycol 400, then add 9.8 mL of 10% methylated- ⁇ -cyclodextrin physiological saline solution, and ultrasound The solution is clear and transparent.
  • SZY1906-P21 eye drops Weigh 0.00293g of SZY1906-P21, first add 200 ⁇ L of polyethylene glycol 400, then add 9.8 mL of 10% methylated- ⁇ -cyclodextrin physiological saline solution, and ultrasound The solution is clear and transparent.
  • 0.0300% SZY1906-P22 eye drops Weigh 0.00300g of SZY1906-P22, first add 200 ⁇ L of polyethylene glycol 400, then add 9.8 mL of 10% methylated- ⁇ -cyclodextrin physiological saline solution, and ultrasound The solution is clear and transparent.
  • the drug was administered to the left and right eyes of the rabbit at the same time, and the administration volume was 50 ⁇ L for each eye.
  • Use a pipette to accurately administer the drug gently pull the rabbit eyelid down into a cup shape, accurately draw 50 ⁇ L of eye drops into the eyelid with the pipette, and passively close the rabbit eye for 10 seconds.
  • the eye drop concentration of SZY1906-P20 is 0.286 mg/mL
  • the eye drop concentration of SZY1906-P21 is 0.293 mg/mL
  • the eye drop concentration of SZY1906-P22 is 0.300 mg/mL. Therefore, a frequency administration method was adopted, with administration once every 5 minutes and a total of 3 administrations within 10 minutes. The blank group was not given any drugs.
  • aqueous humor, cornea, conjunctiva, iris-ciliary body, lens, and vitreous body were collected at 30 min and 60 min after the completion of three administrations.
  • Collection of aqueous humor After killing the animal, use a 1mL syringe to extract about 200 ⁇ L of aqueous humor from the junction of the pupil and iris (note that the cut surface of the syringe needle is facing downward when extracting aqueous humor to prevent the aqueous humor from spraying out).
  • Collection of cornea, iris and ciliary body fix the eyeball with tweezers, cut the cornea and iris with curved scissors, cut the cornea along the junction of the two, and then take out the iris and ciliary body. After the removed cornea, iris and ciliary body were washed with ultrapure water, the surface liquid was dried with filter paper, weighed accurately, and stored frozen.
  • Collection of the lens and vitreous body Use tweezers to pick up the vitreous body and lens, cut them along the boundary with scissors, and store them separately.
  • Preparation of cornea/conjunctiva/iris-ciliary body/lens homogenate First use small scissors to cut the cornea/conjunctiva/iris-ciliary body/lens of the left and right eyes into small pieces, then add 50% ethanol aqueous solution (mass to volume ratio 1 :10), use a grinder to grind (the program is to cycle grind 4 times, each cycle grinds at 6500 rpm for 30 seconds and waits for 20 seconds), use a low-speed centrifuge to centrifuge at 4000 rpm for 10 minutes, absorb the supernatant, and freeze it for testing.
  • vitreous homogenate Take the vitreous, put it into a grinding vial, grind it with a grinder (the program is 4 cycles of grinding, each cycle grinds at 6500 rpm for 30 seconds and waits for 20 seconds), absorb the homogenate, and freeze it for testing.
  • Aqueous humor/vitreous body sample Take 50 ⁇ L of aqueous humor/vitreous body, add 200 ⁇ L of methanol solution, vortex and mix for 5 minutes, and centrifuge at 12,000 rpm for 10 minutes with a high-speed centrifuge; put the supernatant into an automatic sample vial, and inject 5 ⁇ L of the sample.
  • UHPLC/MS/MS analysis record chromatogram.
  • Cornea, conjunctiva, iris-ciliary body, and lens samples Take 50 ⁇ L of the homogenized supernatant, add 200 ⁇ L of methanol solution, vortex for 5 minutes, and centrifuge for 10 minutes at 12,000 rpm with a high-speed centrifuge; take the supernatant and put it into the automatic Inject 5 ⁇ L into the vial for UHPLC/MS/MS analysis, and record the chromatogram.
  • Liquid-liquid mass spectrometer AB SCIEX Exion LC/Triple Quad 5500 liquid mass spectrometer, equipped with electrospray ionization source (APCI source) (AB SCIEX company).
  • APCI source electrospray ionization source
  • test results show that the concentration deviation of at least 75% of the standard samples for each batch is within ⁇ 15% of the labeled value, and the correlation coefficient R of the batch is greater than 0.99; for each batch of QC, at least 2/3 of the concentration deviation Within ⁇ 15%.
  • the lanosterol content in the lens of SZY1906-P21, SZY1906-P20 and the blank control group is close. Different lanosterol concentrations were observed in different groups after administration in various tissues of the eye, reflecting the absorption distribution of compounds with different structures. There is a difference.
  • SZY1906-P22 is cataract, and the drug's target is the lens.
  • the lanosterol content was 4948.0 ⁇ 959.2ng/g, which was approximately 1.83 times that of the SZY1906-P20 group (2704.5 ⁇ 342.7ng/g) for 30 minutes.
  • the concentration of lanosterol in the -P20 and SZY1906-P21 groups at 30 minutes was close to that of the blank control group.
  • SZY1906-P22 is an excellent lanosterol prodrug from the perspective of pharmacokinetics.
  • Table 4 The average drug concentration of lanosterol in the aqueous humor (ng/mL) after the eyes of New Zealand rabbits were administered 0.0300% SZY1906-P22, 0.0293% SZY1906-P21, and 0.0286% SZY1906-P20 respectively.
  • Table 9 The average drug concentration of lanosterol in the vitreous body (ng/mL) after 0.0300% SZY1906-P22, 0.0293% SZY1906-P21, and 0.0286% SZY1906-P20 were administered to the eyes of New Zealand rabbits respectively.

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  • Organic Chemistry (AREA)
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  • Ophthalmology & Optometry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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Abstract

L'invention concerne un composé stéroïde et un sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et son utilisation. La formule structurale du composé stéroïde est telle que représentée dans la formule I', dans laquelle R est diméthylamino ou méthylamino. Les gouttes oculaires faisant appel à un composé (SZY1906-P22) avec R étant diméthylamino en tant que principe actif peuvent réduire la turbidité du cristallin du Néo-Zélandais liée à la cataracte sénile spontanée.
PCT/CN2022/138627 2022-03-14 2022-12-13 Composé stéroïde, son procédé de préparation et son utilisation WO2023173846A1 (fr)

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CA3228646A1 (fr) * 2021-08-18 2023-02-23 Yandong Wang Application d'un compose steroide dans la preparation d'un medicament pour la prevention et/ou le traitement de corps flottants oculaires
JP2024530742A (ja) * 2021-08-31 2024-08-23 コアンチョウ オキュサン オフサルミック バイオテクノロジー カンパニー リミテッド ステロイド系化合物、その調製方法及びその使用
CN114591389B (zh) * 2022-03-14 2024-06-25 广州润尔眼科生物科技有限公司 一种甾体化合物及其制备方法与应用

Citations (4)

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WO2018137683A1 (fr) * 2017-01-25 2018-08-02 中山大学中山眼科中心 Composé promédicament à base de lanostérol, procédé de préparation et utilisation associés
WO2019097434A1 (fr) * 2017-11-17 2019-05-23 Mahmood Piraee Combinaisons de lanostérol ou de 25-hydroxycholestérol comprenant des dérivés de ceux-ci utiles dans le traitement de troubles du cristallin
CN114129575A (zh) * 2020-09-03 2022-03-04 广州润尔眼科生物科技有限公司 一种药物组合物的制备方法和应用
CN114591389A (zh) * 2022-03-14 2022-06-07 上海英诺富成生物科技有限公司 一种甾体化合物及其制备方法与应用

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US20200384003A1 (en) * 2017-12-29 2020-12-10 Shanghai Lanmu Chemicals Co., Ltd. Triterpenoid-containing pharmaceutical composition and use thereof
CN114129574A (zh) * 2020-09-03 2022-03-04 广州润尔眼科生物科技有限公司 一种甾体化合物的应用、含其的组合物及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018137683A1 (fr) * 2017-01-25 2018-08-02 中山大学中山眼科中心 Composé promédicament à base de lanostérol, procédé de préparation et utilisation associés
WO2019097434A1 (fr) * 2017-11-17 2019-05-23 Mahmood Piraee Combinaisons de lanostérol ou de 25-hydroxycholestérol comprenant des dérivés de ceux-ci utiles dans le traitement de troubles du cristallin
CN114129575A (zh) * 2020-09-03 2022-03-04 广州润尔眼科生物科技有限公司 一种药物组合物的制备方法和应用
CN114591389A (zh) * 2022-03-14 2022-06-07 上海英诺富成生物科技有限公司 一种甾体化合物及其制备方法与应用

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