WO2022193449A1 - 一种塞来昔布的前体药物及其制备方法与应用 - Google Patents

一种塞来昔布的前体药物及其制备方法与应用 Download PDF

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WO2022193449A1
WO2022193449A1 PCT/CN2021/098759 CN2021098759W WO2022193449A1 WO 2022193449 A1 WO2022193449 A1 WO 2022193449A1 CN 2021098759 W CN2021098759 W CN 2021098759W WO 2022193449 A1 WO2022193449 A1 WO 2022193449A1
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formula
compound
celecoxib
compound represented
szy1907
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PCT/CN2021/098759
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English (en)
French (fr)
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王延东
刘国强
刘伟
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上海英诺富成生物科技有限公司
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Priority to EP21931034.9A priority Critical patent/EP4309675A1/en
Priority to CA3212464A priority patent/CA3212464A1/en
Priority to JP2023556887A priority patent/JP2024509993A/ja
Priority to AU2021433515A priority patent/AU2021433515A1/en
Priority to KR1020237034724A priority patent/KR20230155559A/ko
Publication of WO2022193449A1 publication Critical patent/WO2022193449A1/zh
Priority to ZA2023/09408A priority patent/ZA202309408B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention belongs to the field of medicine, in particular to a prodrug of celecoxib and a preparation method and application thereof.
  • Celecoxib is an anti-inflammatory and analgesic drug that selectively inhibits cyclooxygenase-2, which can inhibit the production of prostaglandins and reduce inflammation, edema and pain. Clinically, it mainly treats joint pain and limited mobility caused by osteoarthritis of the knee joint. It also has a good therapeutic effect on rheumatism and rheumatoid arthritis. It can also effectively relieve acute and chronic pain. Acute pain such as trauma, surgery pain. Chronic pain such as lumbar muscle strain, cervical spondylosis, and epicondylitis of the humerus. The eye drop preparation made directly with celecoxib has a low concentration in the eye tissue.
  • the object of the present invention is to provide a prodrug of celecoxib and a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of the compound shown in formula I refers to, within the scope of reliable medical judgment, suitable for contacting with human and lower animal tissues without excessive toxicity, irritation, allergic reaction, etc., and with reasonable The effect/risk ratio is commensurate with salt.
  • the pharmaceutically acceptable salts of the compound shown in formula I include but are not limited to 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, aspartate, etc.
  • the present invention also provides a method for preparing the compound represented by the above formula I.
  • the preparation method of the compound shown in formula I provided by the present invention comprises the following steps:
  • the molar ratio of the compound represented by the formula II (to the compound represented by the formula III is 1:1.4.
  • step 1) of the above method the reaction is carried out in a solvent, and the solvent may specifically be DCM (dichloromethane).
  • step 1) the reaction is carried out under stirring conditions at room temperature and monitored by TLC until there is no raw material.
  • step 1) the following post-processing steps are also included after the reaction is completed: wash once with 3% dilute hydrochloric acid, wash once with saturated ammonium chloride, wash with saturated sodium chloride until neutral, and use sodium sulfate for the organic phase Dry and spin-dried to obtain a white solid; dissolve the white solid in ethanol, add an equal amount of water, heat up and reflux until it is completely dissolved, cool down slowly, separate out the product, filter with suction, and dry to obtain SZY1907-05.
  • the reaction conditions of the reaction are stirring at room temperature; the solid is gradually precipitated during the reaction process, and TLC is monitored to show that there is no raw material.
  • step 2 after the reaction is finished, the following post-processing steps are also included: spin dry, rinse the solid with ethyl acetate, collect the filter cake, spin dry to constant weight, and obtain the compound shown in the product formula I.
  • Another object of the present invention is to provide the application of the compound represented by the above formula I.
  • the application provided by the present invention is the application of the compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and/or treating ocular tissue inflammation.
  • the medicament for preventing and/or treating ocular tissue inflammation prepared by using the compound represented by formula I as an active ingredient also belongs to the protection scope of the present invention.
  • the drug can be introduced into the body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, spray, nasal instillation, eye instillation, penetration, absorption, physical or chemical mediated methods; or after being mixed or wrapped by other substances. Import the body.
  • the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants and the like conventional in the pharmaceutical field.
  • the present invention also provides a medicament or pharmaceutical composition for preventing and/or treating ocular tissue inflammation, the active ingredients of which include the compound represented by formula I or a pharmaceutically acceptable salt thereof.
  • the above-mentioned drugs or pharmaceutical compositions can be prepared into liquid preparations, such as eye drops and injections, according to conventional methods known to those skilled in the art.
  • the present invention also protects an eye drop for preventing and/or treating inflammation of ocular tissue.
  • the eye drops protected by the present invention contain the following components in every 100ml of the eye drops: 0.1 g of the compound shown in formula I, 0.05 g of Tween 80, 0.45 g of polyoxyethylene 40 hydrogenated castor oil, 0.45 g of sodium chloride 0.9 g, 0.01 g of benzalkonium chloride, the balance being distilled water; the pH value of the eye drops is 5.5-6.5.
  • the compound shown in formula I of the present invention has suitable solubility, is relatively stable under storage conditions, and shows that celecoxib can be detected in ocular tissue through pharmacokinetic experiments, and the cornea, conjunctiva and aqueous humor are all distributed, reaching a relatively high level.
  • the high drug concentration is an excellent prodrug of celecoxib, while the control compound SZY1907-P4 has almost no distribution detected.
  • the compound of formula I has a significant absorption advantage, and the drug concentration in the eye tissue is significantly higher than that of the celecoxib group and the control group SZY1907-P4, which can be prepared into liquid preparations, such as eye drops and injections, etc. in inflammatory response.
  • Figure 1 is the HNMR spectrum of SZY1907-P3.
  • Figure 2 is the LC-MS spectrum of SZY1907-P3.
  • the present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.
  • the methods are conventional methods unless otherwise specified.
  • the raw materials can be obtained from open commercial sources unless otherwise specified.
  • Celecoxib (20.00g, 0.0525mol), DCM (400mL) were added to the three-necked flask, Boc- ⁇ -alanine (0.0735mol), EDCI (0.121mol), triethylamine (0.158mol), DMAP (0.0164 mol); stirred at room temperature and monitored by TLC until no starting material.
  • Post-treatment wash once with 3% dilute hydrochloric acid, wash once with saturated ammonium chloride, wash with saturated sodium chloride until neutral, dry the organic phase with sodium sulfate, spin dry to obtain a white solid; dissolve the white solid in ethanol, add The same amount of water is heated and refluxed until it is completely dissolved, and the temperature is slowly lowered to separate out the product, suction filtration, and drying to obtain SZY1907-05, the yield is about 95%, and the purity is greater than 98%.
  • Post-processing spin dry, rinse the solid with 200 mL of ethyl acetate, collect the filter cake, spin dry to constant weight.
  • the product was obtained with a yield of about 85% and a purity of more than 99%.
  • Embodiment 2 the preparation of different salt forms of SZY1907-P3
  • solubility of the prototype of P3 and its different salts has a strong pH dependence, and the solubility is less than 1 mg/mL at pH ⁇ 4.
  • Celecoxib (1.34g, 3.5mmol) and DCM (26mL) were added to the three-necked flask, followed by N-methyl-Boc- ⁇ -alanine (4.9mmol), EDCI (8.05mmol), triethylamine (10.5 mmol), DMAP (1 mmol); stirring at room temperature, monitoring by TLC, until no starting material.
  • Post-treatment wash once with 3% dilute hydrochloric acid, wash once with saturated ammonium chloride, wash with saturated sodium chloride until neutral, dry the organic phase with sodium sulfate, spin dry to obtain a white solid; Chloromethane/methanol was flushed to 30:1 (v/v) to produce the product, collected and spin-dried to obtain 1.3 g of white solid.
  • Post-processing spin dry to obtain a white solid; dissolve in methanol, add 2 ml of triethylamine, mix the sample and pass through the column, rinse with dichloromethane and methanol to 15:1 (v/v) to obtain the product, collect the organic phase, add 5 ml of ethyl acetate hydrochloride , spin-dried to obtain 0.6g of white solid.
  • SZY1907-P4 white solid, molecular formula: C21H22ClF3N4O3S, molecular weight: 502.9, batch number: 20200801, purity: 98.99%, storage condition: 2 ⁇ 8°C, valid until 2021.07.31.
  • Celecoxib white powdery solid, molecular formula: C17H14F3N3O2S, molecular weight: 381.37, batch number: 20190701, re-examination purity: 99.87%, storage conditions: 2 ⁇ 8 °C, dark, valid until: 2021.06.27.
  • Celecoxib vehicle 2% polyethylene glycol 400 + 98% in 7.5% methylated-beta-cyclodextrin in water.
  • Methylated- ⁇ -cyclodextrin MedChem Express.
  • Polyethylene Glycol 400 Solarbio Life Sciences.
  • Distilled water Guangzhou Watsons Food and Beverage Co., Ltd.
  • Polyoxyethylene 40 Hydrogenated Castor Oil Croda Corporation.
  • Benzalkonium chloride solution (80% concentration): Sinopharm Chemical Reagent Co., Ltd.
  • Diazepam methanol solution provided by the New Drug Evaluation Center of Hebei Yiling Pharmaceutical Research Institute Co., Ltd.
  • Gender and quantity of animals 12 males were purchased, 9 were selected for this experiment, and the remaining 3 were taken as blank tissue samples.
  • Adaptive rearing Newly received animals are reared adaptively for 3-5 days. During this period, the animals were observed for water, food intake and health status, as well as for signs of illness and death.
  • Adoption standard The technical guidelines for non-clinical pharmacokinetic research of drugs issued by the State Food and Drug Administration.
  • Grouping 9 male New Zealand rabbits were randomly divided into 3 groups with 3 rabbits in each group.
  • the administration method adopts the same administration method as clinical medication, namely, ocular administration, and administration to the left and right eyes of rabbits at the same time.
  • 0.1% SZY1907-P3 eye drop preparation Weigh 0.01000g of SZY1907-P3, add 0.00500g of Tween 80 and 0.04500g of polyoxyethylene 40 hydrogenated castor oil, and stir with a glass rod until the solution is milky. Slowly add 5 mL of distilled water while stirring, and use it for later use after dissolving. Weigh 0.09000 g of sodium chloride and 0.00125 g of 80% benzalkonium chloride, add 2 mL of distilled water, and stir to dissolve. Combine the two solutions and make up to 10 mL. Use 1 mol/L NaOH solution to adjust the pH to 5.5-6.5.
  • 0.1% SZY1907-P4 eye drops Weigh 0.01000g of SZY1907-P4, add 0.00500g of Tween 80 and 0.04500g of polyoxyethylene 40 hydrogenated castor oil, stir and inflate with a glass rod until the solution is milky. Slowly add 5 mL of distilled water while stirring, and use it for later use after dissolving. Weigh 0.09000 g of sodium chloride and 0.00125 g of 80% benzalkonium chloride, add 2 mL of distilled water, and stir to dissolve. Combine the two solutions and make up to 10 mL. Use 1 mol/L NaOH solution to adjust the pH to 5.5-6.5.
  • celecoxib eye drops Weigh 0.00750g of celecoxib into a 1.5mL centrifuge tube, add 200 ⁇ L of polyethylene glycol 400, centrifuge at 12000rpm for 60s, and then transfer to a 10mL volumetric flask, Add 7.5% methylated- ⁇ -cyclodextrin aqueous solution to the volume, and shake until the solution is clear and transparent.
  • test article the left and right eyes of the rabbit were administered simultaneously, and the administration volume was 50 ⁇ L in each eye.
  • Precise administration with a pipette Gently pull down the rabbit eyelid to form a cup, and the pipette accurately draws 50 ⁇ L of eye drops into the eyelid, and the rabbit eye is passively closed for 10 seconds.
  • Collection of samples The collection of aqueous humor, cornea and conjunctiva was selected at 1h after administration. Collection of aqueous humor: After the animals were sacrificed, about 200 ⁇ L of aqueous humor was extracted with a 1 mL syringe from the junction of the pupil and iris (pay attention to the cut surface of the syringe needle facing down when extracting aqueous humor to prevent the aqueous humor from spraying out). Cornea collection: fix the eyeball with forceps, cut the cornea and iris with curved scissors, and cut the cornea along the junction of the two.
  • the removed cornea was washed with ultrapure water, and then the surface liquid was blotted with filter paper, accurately weighed, and frozen for storage.
  • Collection of conjunctiva Use forceps to pick up the upper and lower palpebral conjunctiva, and cut them off with scissors.
  • the removed conjunctiva was washed with ultrapure water, and then the surface liquid was blotted dry with filter paper, accurately weighed, and frozen for storage.
  • Preparation of cornea/conjunctiva homogenate first use small scissors to cut the left and right corneas/conjunctiva into small pieces, then add 50% methanol aqueous solution (mass to volume ratio 1:10), and grind with a grinder (program: Circular grinding 4 times, grinding at 6500 rpm for 30 s for each cycle and waiting for 20 s), centrifuging at 4000 rpm for 10 min with a low-speed centrifuge, sucking the supernatant, and refrigerating it for testing.
  • Aqueous humor sample take 50 ⁇ L of aqueous humor, add 200 ⁇ L of internal standard working solution (100 ng/mL diazepam methanol solution), vortex and mix for 5 minutes, and centrifuge at 12,000 rpm for 10 minutes using a high-speed centrifuge; The supernatant was loaded into autosampler vials for testing.
  • internal standard working solution 100 ng/mL diazepam methanol solution
  • Cornea and conjunctiva samples Take 50 ⁇ L of the homogenate supernatant, add 200 ⁇ L of the internal standard working solution (100 ng/mL diazepam in methanol), vortex for 5 minutes, and then centrifuge at 12,000 rpm for 10 minutes using a high-speed centrifuge; take the supernatant The solution is loaded into an autosampler vial for testing.
  • the internal standard working solution 100 ng/mL diazepam in methanol
  • Instrument system liquid mass spectrometer: Waters Xevo TQD/PDA ACQUITY UPLC liquid mass spectrometer, equipped with electrospray ionization source (ESI source) (Waters company).
  • ESI source electrospray ionization source
  • New Zealand rabbits were given 0.1% SZY1907-P3/P4 and 0.075% celecoxib respectively.
  • New Zealand rabbits were given 0.1% SZY1907-P3/P4 and 0.075% celecoxib respectively.
  • New Zealand rabbits were given 0.1% SZY1907-P3/P4 and 0.075% celecoxib respectively, and the average drug concentration of celecoxib in the conjunctiva after 1 h
  • ND means not detected, — means unable to calculate
  • celecoxib can be detected in the eye tissue, and is distributed in the cornea, conjunctiva and aqueous humor, reaching a higher drug concentration, which is an excellent prodrug of celecoxib, while the control compound SZY1907 -P4 has almost no distribution detected, and the concentration of eye drops prepared with celecoxib in the cornea, conjunctiva and aqueous humor is also low.
  • the compound of formula I, SZY1907-P3 has a significant absorption advantage.
  • the drug concentration was significantly higher than that of the celecoxib group and the control group SZY1907-P4, which could be prepared into liquid preparations, such as eye drops and injections, for inflammatory reactions.

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Abstract

本发明公开了一种式I所示塞来昔布的前体药物及其制备方法与应用。该化合物具有适宜的溶解度，储存条件下相对稳定，经过药代实验表明在眼组织中能够检测到塞来昔布，并且角膜、结膜、房水中均有分布，达到较高的药物浓度，为优良的塞来昔布前体药物，而对照化合物SZY1907-P4则几乎未检测到有分布，采用塞来昔布制备的滴眼液在角膜、结膜、房水中的浓度也较低，式I化合物具有显著的吸收优势，在眼组织中的药物浓度显著高于塞来昔布组及对照组SZY1907-P4，能够制备成液体制剂，如滴眼液和注射液等，用于炎症反应。

Description

一种塞来昔布的前体药物及其制备方法与应用 技术领域
本发明属于医药领域，具体涉及塞来昔布的前体药物及其制备方法与应用。
背景技术
塞来昔布是一种选择性的抑制环氧化酶-2的消炎镇痛药物，可以抑制前列腺素的产生，减轻炎症水肿和疼痛。在临床上主要治疗膝关节的骨性关节炎导致的关节疼痛以及活动受限。对于风湿、类风湿性关节炎也有很好的治疗效果。另外也能够有效的缓解急、性慢性疼痛。急性疼痛比如外伤、手术导致的疼痛。慢性疼痛比如腰肌劳损、颈型颈椎病以及肱骨内外髁上炎。直接用塞来昔布做成的滴眼液制剂，在眼组织中的浓度较低。
发明内容
本发明的目的是提供一种塞来昔布的前体药物及其药学上可接受的盐。
所述塞来昔布的前体药物其结构式如式I所示：
Figure PCTCN2021098759-appb-000001
式I所示化合物药学上可接受的盐是指在可靠的医学判断范围内，适合用于与人类和低等动物的组织接触而不出现过度的毒性、刺激、过敏反应等，且与合理的效果/风险比相称的盐。式I所示化合物药学上可接受的盐包括但不限于柠檬酸盐、反丁烯二酸盐、水杨酸盐、L-酒石酸盐、富马酸盐、钠盐、钾盐、钙盐、盐酸盐、醋酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、乙酸盐、草酸盐、乳酸盐、赖氨酸盐、天冬氨酸盐等。
本发明还提供了上述式I所示化合物的制备方法。
本发明所提供的式I所示化合物的制备方法，包括下述步骤：
1)将式Ⅱ所示的化合物(塞来昔布)与式Ⅲ所示的化合物(Boc-β-丙氨酸)在EDCI/DMAP/三乙胺存在下进行反应，得到式Ⅳ所示的化合物(SZY1907-05)；
Figure PCTCN2021098759-appb-000002
2)使式Ⅳ所示的化合物与氯化氢的乙酸乙酯溶液进行反应，得到式I所示化合物。
上述方法步骤1)中，所述式Ⅱ所示的化合物(与式Ⅲ所示的化合物的摩尔比为1：1.4。
上述方法步骤1)中，所述式Ⅱ所示的化合物与EDCI、DMAP、三乙胺的摩尔比依次为2.3：0.32：3
上述方法步骤1)中，所述反应在溶剂中进行，所述溶剂具体可为DCM(二氯甲烷)。
上述方法步骤1)中，所述反应在室温搅拌条件下进行，TLC监测，至无原料。
上述方法步骤1)中，所述反应结束后还包括下述后处理步骤：用3％的稀盐酸洗一次，饱和氯化铵洗一次，饱和氯化钠洗至中性，有机相用硫酸钠干燥，旋干得到白色固体；将白色固体溶于乙醇中，加入等量水，升温回流至完全溶清，缓慢降温，析出产品，抽滤，干燥，得到SZY1907-05。
上述方法步骤2)中，所述式Ⅳ所示的化合物与氯化氢的摩尔比为0.05:1.71
上述方法步骤2)中，所述反应的反应条件为室温搅拌；反应过程逐步析出固体，TLC监测至无原料。
上述方法步骤2)中，所述反应结束后还包括下述后处理步骤：旋干，用乙酸乙酯淋洗固体，收集滤饼，旋干至恒重，得到产品式I所示化合物。
本发明另一个目的是提供上述式I所示化合物的应用。
本发明所提供的应用是式I所示化合物或其药学上可接受的盐在制备预防和/或治疗眼组织炎症药物中的应用。
以式I所示的化合物为活性成分制备的预防和/或治疗眼组织炎症药物也属于本发明的保护范围。
所述药物可通过注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉、粘膜组织；或是被其他物质混合或包裹后导入机体。
需要的时候，在上述药物中还可以加入一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
本发明还提供了一种用于预防和/或治疗眼组织炎症的药物或药物组合物，其活性成分包括式I所示化合物或其药学上可接受的盐。
上述药物或药物组合物可以按照本领域技术人员已知的常规方法制成液体制剂，如滴眼液和注射液等剂型。
本发明还保护一种用于预防和/或治疗眼组织炎症的滴眼液。
本发明所保护的滴眼液，每100ml所述滴眼液中含有下述组分：式I所示化合物0.1g、吐温80 0.05g、聚氧乙烯40氢化蓖麻油0.45g、氯化钠0.9g、苯扎氯铵0.01g，余量为蒸馏水；所述滴眼液的pH值在5.5-6.5。
本发明式I所示的化合物，具有适宜的溶解度，储存条件下相对稳定，经过药代实验表明在眼组织中能够检测到塞来昔布，并且角膜、结膜、房水中均有分布，达到较高的药物浓度，为优良的塞来昔布前体药物，而对照化合物SZY1907-P4则几乎未检测到有分布，采用塞来昔布制备的滴眼液在角膜、结膜、房水中的浓度也较低，式I化合物具有显著的吸收优势，在眼组织中的药物浓度显著高于塞来昔布组及对照组SZY1907-P4，能够制备成液体制剂，如滴眼液和注射液等，用于炎症反应。
附图说明
图1为SZY1907-P3的HNMR谱图。
图2为SZY1907-P3的LC-MS谱图。
具体实施方式
下面结合具体实施例对本发明作进一步阐述，但本发明并不限于以下实施例。所述方法如无特别说明均为常规方法。所述原材料如无特别说明均能从公开商业途径获得。
实施例1、制备式I所示化合物SZY1907-P3
Figure PCTCN2021098759-appb-000003
SZY1907-05制备：
在三口瓶中加入塞来昔布(20.00g，0.0525mol)，DCM(400mL)，依次加入Boc-β-丙氨酸(0.0735mol)、EDCI(0.121mol)、三乙胺(0.158mol)、DMAP(0.0164mol)；室温搅拌，TLC监测，至无原料。
后处理：用3％的稀盐酸洗一次，饱和氯化铵洗一次，饱和氯化钠洗至中性，有机相用硫酸钠干燥，旋干得到白色固体；将白色固体溶于乙醇中，加入等量水，升温回流至完全溶清，缓慢降温，析出产品，抽滤，干燥，得到SZY1907-05，收率约为95％，纯度大于98％。
状态：白色固体。
SZY1907-P3的制备
在三口瓶中加入SZY1907-05(28.00g,0.05mol)，然后加入氯化氢的乙酸乙酯溶液(3.8mol/L，450mL)，反应过程逐步析出固体，TLC监测至无原料。
后处理：旋干，用200mL乙酸乙酯淋洗固体，收集滤饼，旋干至恒重。得到产品，收率约85％，纯度大于99％。
状态：白色固体。
1HNMR H 2Oδ:7.55-7.53(d,J＝7.6Hz,2H),6.83-6.81(d,J＝6.8Hz,2H),6.54-6.46(m,4H),6.15(s,1H),3.05-3.04(m,2H),2.64(m,2H),1.76(m,3H),
LC-MS:m/z＝453.5(M+1).
结构确证结果见图1、2。
实施例2、SZY1907-P3的不同盐型的制备
1：SZY1907-P3的柠檬酸盐制备：
将SZY1907-P3溶于水中，滴加1mol/L氢氧化钠，至有固体析出，抽滤，干燥，取100mg溶于甲醇中，加入42mg柠檬酸，搅拌30分钟至澄清，旋干甲醇，得140mg柠檬酸盐。
2：SZY1907-P3的反丁烯二酸盐制备：
将SZY1907-P3溶于水中，滴加1mol/L氢氧化钠，至有固体析出，抽滤，干燥，取100mg溶于甲醇中，加入26mg反丁烯二酸，搅拌30分钟至澄清，旋干甲醇，得110mg反丁烯二酸盐。
3：SZY1907-P3的水杨酸盐制备：
将SZY1907-P3溶于水中，滴加1mol/L氢氧化钠，至有固体析出，抽滤，干燥，取100mg溶于水杨酸中，加入31mg水杨酸，搅拌30分钟至澄清，旋干甲醇，得120mg水杨酸盐。
4：SZY1907-P3的L-酒石酸盐制备：
将SZY1907-P3溶于水中，滴加1mol/L氢氧化钠，至有固体析出，抽滤，干燥，取100mg溶于甲醇中，加入33mgL-酒石酸，搅拌30分钟至澄清，旋干甲醇，得125mgL-酒石酸盐。
实施例3、ZY1907-P3的溶解性以及稳定性的初步研究
由于SZY1907-P3在初期的溶解性试验中，发现其盐酸盐溶解度与pH值相关，呈现一定的pH依赖性，准备测定其原型及盐型在不同pH值下的溶解度曲线，
目前已经测定了原型、柠檬酸盐，醋酸盐，酒石酸盐等，具体数据如下表1所示。
表1
Figure PCTCN2021098759-appb-000004
可以看出，P3的原型及其不同的盐的溶解性具有很强的pH依赖性，在pH≥4时，溶解度小于1mg/mL。
同时还是测定了其原型在不同pH的稳定性数据，具体见下表2。
表2
Figure PCTCN2021098759-appb-000005
由表2可以看出，放置5d，纯度未见明显变化。
对比例1、制备化合物SZY1907-P4
Figure PCTCN2021098759-appb-000006
SZY1907-06的制备：
在三口瓶中加入塞来昔布(1.34g，3.5mmol)，DCM(26mL)，依次加入N-甲基-Boc-β-丙氨酸(4.9mmol)、EDCI(8.05mmol)、三乙胺(10.5mmol)、DMAP(1mmol)；室温搅拌，TLC监测，至无原料。
后处理：用3％的稀盐酸洗一次，饱和氯化铵洗一次，饱和氯化钠洗至中性，有机相用硫酸钠干燥，旋干得到白色固体；将白色固体拌样过柱，二氯甲烷/甲醇冲至30:1(v/v)出产品，收集旋干，得1.3g白色固体。
状态：白色固体。
SZY1907-P4的制备
在三口瓶中加入SZY1907-04(1.00g,1.77mmol)，然后加入氯化氢的乙酸乙酯溶液(3.8mol/L，30mL)，搅拌反应至TLC监测至无原料。
后处理：旋干得到白色固体；甲醇溶解，加入2ml三乙胺，拌样过柱， 二氯甲烷甲醇冲至15:1(v/v)出产品，收集有机相，加入5ml盐酸乙酸乙酯，旋干，得0.6g白色固体。
状态：白色固体。
1HNMR H 2O
δ:7.56-7.54(d,J＝8.0Hz,2H),6.87-6.84(d,J＝7.6Hz,2H),6.59-6.50(m,4H),6.20(s,1H),3.06-3.03(m,2H),2.63-254(m,5H),1.78(m,3H),
LC-MS:m/z＝467.5(M+1).
实施例4、化合物SZY1907-P3和化合物SZY1907-P4的眼部药代试验
试验目的：比较新西兰兔眼部给药SZY1907-P3、SZY1907-P4、塞来昔布后，眼部各组织中活性化合物塞来昔布的含量，以筛选出药代特征优秀的先导化合物。
实验材料供试品：SZY1907-P3：白色粉末，分子式：C20H20ClF3N4O3S，分子量：488.91，批号：20201106，纯度：99.85％，保存条件：2～8℃，有效期至2021.05.05。
SZY1907-P4：白色固体，分子式：C21H22ClF3N4O3S，分子量：502.9，批号：20200801，纯度：98.99％，保存条件：2～8℃，有效期至2021.07.31。
塞来昔布：白色粉末状固体，分子式：C17H14F3N3O2S，分子量：381.37，批号：20190701，复检纯度：99.87％，保存条件：2～8℃、避光，有效期至：2021.06.27。
溶媒：SZY1907-P3/P4滴眼液组方见表3。
表3溶媒组分及作用
表3溶媒组分(w/v)及作用
Figure PCTCN2021098759-appb-000007
塞来昔布溶媒：2％的聚乙二醇400+98％的7.5％甲基化-β-环糊精水溶液。
工具药及主要试剂：
甲醇(色谱纯)：德国默克。
甲酸(色谱纯)：阿拉丁。
甲基化-β-环糊精：MedChem Express公司。
聚乙二醇400：Solarbio Life Sciences公司。
蒸馏水：广州屈臣氏食品饮料有限公司。
吐温80：VETEC公司。
聚氧乙烯40氢化蓖麻油：Croda公司。
苯扎氯铵溶液(浓度为80％)：国药集团化学试剂有限公司。
氯化钠：VETEC公司。
地西泮甲醇溶液：由河北以岭医药研究院有限公司新药评价中心提供。
实验系统
动物种系：新西兰兔。
动物级别：普通级。
动物性别和数量：购买雄性12只，从中挑选9只用于本试验，剩余3只取空白组织样品。
购买时动物年龄：3～5月龄。
购买时动物体重：1.5～2.0kg。
适应性饲养：新领到的动物适应性饲养3-5天。其间观察动物饮水、摄食和健康状况，以及是否存在疾病和死亡征兆。
标识：耳部标号笔编号。
试验设计依据
采用标准：国家食品药品监督管理局颁布的药物非临床药代动力学研究技术指导原则。
剂量与分组
分组：9只雄性新西兰兔，随机分为3组，每组3只。
剂量：根据广州中山眼科的制剂组方，SZY1907-P3/P4的滴眼液浓度均为0.1％。因此，设置SZY1907-P3/P4的给药剂量为0.100mg/只新西兰兔，塞来昔布给药剂量为0.075mg/只新西兰兔(接近SZY1907-P3/P4的等摩尔剂量)。具体分组与给药剂量见表4。
表4 SZY1907-P3、SZY1907-P4及塞来昔布给药剂量
Figure PCTCN2021098759-appb-000008
给药方法采用与临床用药一致的给药方式，即眼部给药，兔左右眼同时给药。
供试品配制和保存(以下操作可根据实际需要调整配制体积)
0.1％的SZY1907-P3滴眼液制剂：称取0.01000g的SZY1907-P3，加入0.00500g的吐温80和0.04500g的聚氧乙烯40氢化蓖麻油，玻璃棒搅拌通胀至溶液呈乳状。边搅拌边缓慢加入5mL的蒸馏水，溶解后，备用。称取0.09000g的氯化钠和0.00125g的80％苯扎氯铵，加入2mL的蒸馏水，搅拌溶解。合并两溶液，定容至10mL。使用1mol/L的NaOH溶液，调节PH值至5.5-6.5之间。
0.1％的SZY1907-P4滴眼液：称取0.01000g的SZY1907-P4，加入0.00500g的吐温80和0.04500g的聚氧乙烯40氢化蓖麻油，玻璃棒搅拌通胀至溶液呈乳状。边搅拌边缓慢加入5mL的蒸馏水，溶解后，备用。 称取0.09000g的氯化钠和0.00125g的80％苯扎氯铵，加入2mL的蒸馏水，搅拌溶解。合并两溶液，定容至10mL。使用1mol/L的NaOH溶液，调节PH值至5.5-6.5之间。
0.075％塞来昔布滴眼液：称取0.00750g的塞来昔布于1.5mL的离心管中，先加入200μL的聚乙二醇400，12000rpm离心60s，再转移至10mL的容量瓶中，加入7.5％甲基化-β-环糊精水溶液定容，振荡至溶液澄清透明，即得。
供试品的给予：兔左右眼同时给药，给药体积为每只眼睛50μL。采用移液枪精确给药：轻轻将兔眼睑拉低呈杯状，移液枪精确吸取滴眼液50μL滴入眼睑，兔眼被动闭合10秒。
观测的指标、时间和内容：样品的采集：选择给药后1h点进行房水、角膜、结膜的采集。房水的采集：处死的动物，用1mL注射器从瞳孔与虹膜交界处进针抽取房水约200μL(注意抽取房水时注射器针的切面朝下，防止房水喷出)。角膜的采集：用镊子固定眼球，用弯剪剪破角膜与虹膜，沿两者交界处剪下角膜。取下的角膜用超纯水清洗后，再用滤纸吸干表面液体，精密称量，冷冻保存。结膜的采集：用镊子夹起上、下睑结膜，用剪刀剪离。取下的结膜用超纯水清洗后，再用滤纸吸干表面液体，精密称量，冷冻保存。
组织样品的处理：角膜/结膜匀浆液制备：首先使用小剪子把左右眼角膜/结膜剪碎成小块，然后加入50％甲醇水溶液(质量体积比1:10)，使用研磨器研磨(程序为循环研磨4次，每个循环6500rpm研磨30s等待20s)，使用低速离心机4000rpm离心10min，吸取上清液，冷冻保存待测。
样品检测前预处理：房水样品：取50μL的房水，加入200μL的内标工作液(100ng/mL地西泮甲醇溶液)，涡旋混合5min后，使用高速离心机12000rpm下离心10min；取上清液装入自动进样器小瓶待测。
角膜、结膜样品：取50μL的匀浆上清液，加入200μL的内标工作液(100ng/mL地西泮甲醇溶液)，涡旋混合5min后，使用高速离心机12000rpm下离心10min；取上清液装入自动进样器小瓶待测。
仪器系统：液质联用仪：Waters Xevo TQD/PDA ACQUITY UPLC液质联用仪，配有电喷雾离子化源(ESI源)(Waters公司)。
数据系统：Masslynx V4.1(Waters公司)。
数据处理：以样品与内标的峰面积比进行计算。用加权(W＝1/X 2)最小二乘法进行回归计算，求得直线回归方程，将比值代入方程后计算药物浓度。
实验结果：
新西兰兔眼部分别给予0.1％的SZY1907-P3/P4、0.075％的塞来昔布，1h后房水中塞来昔布的平均药物浓度
Figure PCTCN2021098759-appb-000009
新西兰兔眼部分别给予0.1％的SZY1907-P3/P4、0.075％的塞来昔布，1h后角膜中塞来昔布的平均药物浓度
Figure PCTCN2021098759-appb-000010
新西兰兔眼部分别给予0.1％的SZY1907-P3/P4、0.075％的塞来昔布，1h后结膜中塞来昔布的平均药物浓度
Figure PCTCN2021098759-appb-000011
ND表示未检测到，—代表无法计算
由上述结果可知，在眼组织中能够检测到塞来昔布，并且角膜、结膜、房水中均有分布，达到较高的药物浓度，为优良的塞来昔布前体药物，而对照化合物SZY1907-P4则几乎未检测到有分布，采用塞来昔布制备的滴眼液在角膜、结膜、房水中的浓度也较低，式I化合物SZY1907-P3具有显著的吸收优势，在眼组织中的药物浓度显著高于塞来昔布组及对照组SZY1907-P4，能够制备成液体制剂，如滴眼液和注射液等，用于炎症反应。

Claims (10)

  1. 如式I所示化合物或其药学上可接受的盐：
    Figure PCTCN2021098759-appb-100001
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于：所述式I所示化合物药学上可接受的盐包括柠檬酸盐、反丁烯二酸盐、水杨酸盐、L-酒石酸盐、富马酸盐、钠盐、钾盐、钙盐、盐酸盐、醋酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、乙酸盐、草酸盐、乳酸盐、赖氨酸盐、天冬氨酸盐。
  3. 权利要求1所述式I所示化合物的制备方法，包括下述步骤：
    1)将式Ⅱ所示的化合物与式Ⅲ所示的化合物在EDCI/DMAP/三乙胺存在下进行反应，得到式Ⅳ所示的化合物；
    Figure PCTCN2021098759-appb-100002
    2)使式Ⅳ所示的化合物与氯化氢的乙酸乙酯溶液进行反应，得到式I所示化合物。
  4. 根据权利要求3所述的方法，其特征在于：所述步骤1)中，所述式Ⅱ所示化合物与式Ⅲ所示化合物的摩尔比为1：1.4；
    所述步骤1)中，所述式Ⅱ所示化合物与EDCI、DMAP、三乙胺的摩尔比依次为2.3：0.31：3；
    所述步骤1)中，所述反应在溶剂中进行，所述溶剂为DCM；
    所述步骤1)中，所述反应在室温搅拌条件下进行，TLC监测，至无原料。
  5. 根据权利要求3或4所述的方法，其特征在于：所述步骤1)中，所述反应结束后还包括下述后处理步骤：用3％的稀盐酸洗一次，饱和氯化铵洗一次，饱和氯化钠洗至中性，有机相用硫酸钠干燥，旋干得到白色固体；将白色固体溶于乙醇中，加入等量水，升温回流至完全溶清，缓慢降温，析出产品，抽滤，干燥，得到式Ⅳ所示的化合物。
  6. 根据权利要求3-5中任一项所述的方法，其特征在于：所述步骤2)中，所述式Ⅳ所示的化合物与氯化氢的摩尔比为0.05:1.71；
    所述步骤2)中，所述反应的反应条件为室温搅拌；反应过程逐步析出固体，TLC监测至无原料。
  7. 根据权利要求3-6中任一项所述的方法，其特征在于：所述步骤2)中，所述反应结束后还包括下述后处理步骤：旋干，用乙酸乙酯淋洗固体，收集滤饼，旋干至恒重，得到式I所示化合物。
  8. 式I所示化合物或其药学上可接受的盐在制备预防和/或治疗眼组织炎症药物中的应用。
  9. 一种用于预防和/或治疗眼组织炎症的药物或药物组合物，其活性成分包括式I所示化合物或其药学上可接受的盐。
  10. 一种用于预防和/或治疗眼组织炎症的滴眼液，每100ml所述滴眼液中含有下述组分：式I所示化合物0.1g、吐温80 0.05g、聚氧乙烯40氢化蓖麻油0.45g、氯化钠0.9g、苯扎氯铵0.01g，余量为蒸馏水；所述滴眼液的pH值在5.5-6.5。
PCT/CN2021/098759 2021-03-15 2021-06-08 一种塞来昔布的前体药物及其制备方法与应用 WO2022193449A1 (zh)

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