WO2023045377A1 - 新型氘代peg脂质化合物、其制备方法、组合物和应用 - Google Patents
新型氘代peg脂质化合物、其制备方法、组合物和应用 Download PDFInfo
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- WO2023045377A1 WO2023045377A1 PCT/CN2022/095095 CN2022095095W WO2023045377A1 WO 2023045377 A1 WO2023045377 A1 WO 2023045377A1 CN 2022095095 W CN2022095095 W CN 2022095095W WO 2023045377 A1 WO2023045377 A1 WO 2023045377A1
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- Prior art keywords
- deuterated
- compound
- general formula
- dpeg
- composition
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
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Definitions
- the present invention provides novel deuterated polymer-conjugated lipids that can be used in combination with other lipid components such as neutral lipids, steroids, and cationic lipids to form a nucleic acid mRNA lipid nanoparticle composition
- Methods of delivering one or more therapeutic and/or prophylactic agents to mammalian cells or organs and/or producing polypeptides in mammalian cells or organs may also include in specific ratios one or more deuterated polymer-conjugated lipids, neutral lipids including polyunsaturated lipids, substances, cationic lipids, steroids, and/or therapeutic and/or prophylactic agents.
- nucleic acids Efficient targeted delivery of bioactive substances such as small molecule drugs, proteins and nucleic acids presents a persistent medical problem. Specifically, delivery of nucleic acids to cells is made difficult by the relative instability and low cell permeability of these species. Accordingly, there is a need to develop methods and compositions that facilitate the delivery of therapeutic and/or prophylactic agents, such as nucleic acids, to cells.
- compositions generally comprise one or more polymer-conjugated lipids, neutral lipids (such as phospholipids), including polyunsaturated lipids, structured lipids (such as steroids), and/or cation-containing lipids.
- neutral lipids such as phospholipids
- structured lipids such as steroids
- RNA nanoparticles formed from PEGylated deuterated lipids with other lipid components such as neutral lipids, cholesterol, cationic lipids, and oligonucleotides have been used to prevent RNA degradation in plasma and promote Cellular uptake of oligonucleotides and deuterated polymer-conjugated lipids has not been reported.
- lipid compounds and lipid nanoparticles would improve physicochemical properties, provide optimized drug delivery, protect nucleic acids from degradation and clearance in serum, be suitable for systemic or local delivery, and provide intracellular delivery of nucleic acids.
- these preferred lipid-nucleic acid particles should be well tolerated and provide a sufficient therapeutic index such that treatment of a patient at an effective dose of the nucleic acid does not create unacceptable toxicity and/or risk to the patient.
- the present invention provides these and related advantages.
- the present invention provides the following novel polyethylene glycol lipid compounds (such as the following formula A and formula B) and the preparation methods, compositions and applications of these compounds.
- the functional PEGylated deuterated lipids provided by the present invention can realize Better physical and chemical properties - water solubility, stability, and better nucleic acid delivery efficiency in cells.
- the present invention relates to deuterated polyethylene glycol lipid compound (A):
- R1, R2, and R3 are each independently a combination of DDD, DDH, DHH, HHH, DD, DH, HH, D, and H;
- R1, R2, and R3 are all independent. When both R1 and R2 are “HHH”, R3 cannot be “HH”. When R3 is a combination of "HH”, one of R1 and R2 cannot be a combination of "HHH";
- n 40-50, more preferably 45.
- the present invention relates to deuterated polyethylene glycol lipid compound (B):
- R1, R2, R3, R4, R5 are each independently a combination of DDD, DDH, DHH, HHH, DD, DH, HH, D, H;
- R1, R2, R3, R4, and R5 are all independent.
- R1 and R2 are both “HHH” and R4 is “H”
- R3 and R5 cannot be “HH” at the same time
- R3 and R5 are both "HH” HH” combination
- R4 is "H” combination
- R1 and R2 cannot be "HHH” combination at the same time
- R1 and R2 are both "HHH” combination
- R3 and R5 are both "HH” combination
- R4 cannot be "H” "combination
- R1, R2, R3, R4, and R5 are each independently a combination of "DDD”, “DD”, and "D";
- n 40-50, more preferably 45.
- the compound has one of the structures shown in Table 1 below
- compositions comprising any one or more of the deuterated compounds of formulas (A) and (B) and a therapeutic and/or prophylactic agent are provided.
- compositions comprising any one or more of the compounds of structures (A) and (B) and a therapeutic and/or prophylactic agent.
- the composition comprises any one of compounds of structure (A) and (B) and a therapeutic and/or prophylactic agent and one or more compounds selected from neutral lipids, steroids, and cationic lipid excipients.
- Other pharmaceutically acceptable excipients and/or carriers are also included in various embodiments of the compositions.
- the neutral lipid is selected from 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine Alkaline (DPPC), 1,2-Dimyristyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palm Acyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), sphingomyelin (SM) and mixtures thereof.
- the preferred neutral lipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC).
- the steroid is selected from the group consisting of cholesterol, fecal sterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, alpha-tocopherol, and mixtures thereof .
- the preferred steroid is cholesterol.
- the cationic lipid is selected from the group consisting of 4-(N,N-dimethylamino)butanol (6Z,9Z,28Z,31Z)-heptatriodeca-6,9,28,31-tetraene -19-yl ester (DLin-MC3-DMA), heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((decyloxy)hexyl)amino)octyl ester (SM-102), ((4-hydroxybutyl)aza-ethyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (ALC-0315), 4 -(N-2-(N,N-bis(2-hydroxydodecyl)ethylamino)-1-N(2-N(2-ethylamino-(2-(N,N-bis(2 -Hydr
- the cationic lipid is preferably selected from ((4-hydroxybutyl)aza-ethyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (ALC- 0315) deuterated analogue, heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((decyloxy)hexyl)amino)octanoate (SM-102 ) deuterated analogs.
- the cationic lipid in the composition of the present invention has the following structure (formula I):
- R1 and R2 are each independently C6-C24 alkyl or C6-C24 alkenyl, and the hydrocarbon chains are optionally connected by one or more ester bonds or ether bonds;
- R3 and R4 are each independently C1-C12 alkyl Or C1-C12 alkenyl, or R3 and R4 are combined with each other to form a 4 to 10-membered heterocyclic ring, the heteroatoms include one or more heteroatoms in N, O, S, and the heterocyclic ring is optionally replaced by 1 -6 heteroatom substitutions;
- X is C, N, O, S, -S-S-; M is C1-C12 alkyl or C1-C12 alkenyl; x is 0, 1 or 2.
- the ratio of the composition ranges from about 1-10 mol% of the compound, about 0-30 mol% neutral lipid, about 10-55 mol% steroid, and about 30-60 mol% cationic lipid.
- the therapeutic and/or prophylactic agent comprises a nucleic acid.
- the nucleic acid is RNA, which is selected from the following composition: siRNA, aiRNA, miRNA, dsRNA, shRNA, mRNA and mixtures thereof.
- the RNA is selected from mRNA.
- the present invention relates to methods of administering therapeutic and/or prophylactic agents to a subject in need thereof, the method comprising preparing or providing any of the compositions described above and administering the composition to the subject combination.
- the compounds of the invention can be administered as a drug substance, or can be formulated as a pharmaceutical composition.
- the pharmaceutical compositions of the present invention comprise compounds of structures (A) and (B) and one or more pharmaceutically acceptable carriers, diluents or excipients.
- Compounds of structures (A) and (B) are effective to form lipid nanoparticles and deliver therapeutic and/or prophylactic agents. Appropriate concentrations and dosages can be readily determined by those skilled in the art.
- compositions of the present invention may be by any of the acceptable modes of administration for agents of similar utility.
- the pharmaceutical composition of the present invention can be formulated into preparations in solid, semi-solid, liquid or gaseous form, such as tablets, capsules, powders, granules, ointments, solutions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
- Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal and intranasal routes.
- parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intradermal, intrasternal injection or infusion techniques.
- the pharmaceutical compositions of the invention are formulated so as to allow the active ingredient contained therein to be bioavailable upon administration of the composition to a subject.
- Compositions to be administered to a subject or patient are in the form of one or more dosage units, where a tablet may be a single dosage unit and a container of the compound in aerosol form of the invention may hold multiple dosage units. Current methods for the preparation of such dosage forms are known, or will be apparent, to those skilled in the art.
- the composition to be administered will contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treating the associated disease or condition in accordance with the teachings of the invention.
- compositions of the present invention may be in solid or liquid form.
- the carrier is particulate, such that the composition is in tablet or powder form.
- the carrier can be a liquid in which case the composition is an oral syrup or an injectable liquid or an aerosol suitable for administration by inhalation.
- the pharmaceutical composition When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, where forms considered solid or liquid herein include semi-solid, semi-liquid, suspension and gel forms.
- the pharmaceutical compositions can be formulated in the form of powders, granules, compressed tablets, pills, capsules, chewing gums, flakes and the like.
- Such solid compositions will generally contain one or more inert diluents or edible carriers.
- binders such as gelatin, cellulose, etc.
- excipients such as lactose, etc.
- disintegrants such as alginic acid, etc.
- lubricants such as magnesium stearate, etc.
- Glidants such as silica gel, etc.
- sweeteners such as sucrose or saccharin
- flavoring agents such as mint
- coloring agents such as sucrose or saccharin
- liquid carriers other than materials of the above type, such as polyethylene glycol or oil.
- compositions may be in liquid form, such as syrups, solutions, emulsions or suspensions.
- Liquids can be used for oral administration or for injectable delivery, as two examples.
- the compositions of Urim contain, in addition to the compounds of the present invention, one or more of sweetening agents, preservatives, dyeing/coloring agents and darkening agents.
- one or more of surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffers, stabilizers and isotonic agents may be included.
- the liquid pharmaceutical composition of the present invention may include one or more of the following adjuvants: sterile diluents, such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride; fixed oils such as synthetic mono- or diglycerides, polyethylene glycol, glycerol, propylene glycol, or other solvents that may be used as a solvent or suspending medium; antibacterial agents , such as methylparaben, etc.; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenedipic acid; buffering agents, such as acetate, clematine, or phosphate; Reagents for tonicity, such as sodium chloride or glucose; reagents used as cryoprotectants, such as sucrose or trehalose.
- the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose via
- compositions of the invention may consist of dosage units which can be administered as an aerosol.
- aerosol is used to denote systems ranging from those of a colloidal nature to those consisting of pressurized packs. Delivery may be by liquefied or compressed gas, or by a suitable pump system which dispenses the active ingredient. Aerosols of the compounds of the invention may be delivered as single-phase, bi-phasic or triphasic systems to deliver the active ingredient. Aerosol delivery includes the necessary containers, activators, valves, sub-containers, etc., which together may form a kit. Preferred aerosols can be determined by those skilled in the art without undue experimentation.
- compositions of the present invention can be prepared by methods well known in the field of pharmacy.
- Pharmaceutical compositions intended to be administered by injection can be prepared by combining the lipid nanoparticles of the present invention with sterile distilled water or other carriers into a solution.
- Surfactants can be added to promote the formation of a uniform solution or suspension.
- Surfactants are compounds that interact non-covalently with the compounds of the invention in order to facilitate dissolution or uniform suspension of the compounds in aqueous delivery systems.
- composition of the present invention is administered in a therapeutically effective amount, which will vary depending on a number of factors, including the activity of the particular therapeutic agent used; the metabolic stability and duration of action of the therapeutic agent; The patient's age, weight, general health, sex, and diet; mode and timing of administration; rate of excretion; drug combination; severity of the specific case, etc.
- compositions of the invention may also be administered concurrently with, before or after administration of one or more other therapeutic agents.
- combination therapy includes administration of a single pharmaceutical dosage formulation of a composition of the invention and one or more additional active agents, as well as administration of a composition of the invention and each active agent in its own separate pharmaceutical dosage formulation.
- compositions of the invention and other active agents may be administered to a subject together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.
- the compound of the invention and the one or more additional active agents may be administered at substantially the same time, or sequentially at times staggered from each other; it is understood that combination therapy includes all such dosing regimens.
- the structural modification and design of the above deuterated PEGylated deuterated lipid compounds have achieved more advantageous physical and chemical properties, including more suitable pKa and better chemical stability, for mRNA nanoliposome compositions, which can achieve The combination and delivery of ionic nucleic acid drugs is more effective, and its chemical structure is more stable, which is convenient for synthesis and beneficial for development as pharmaceutical excipients.
- all compounds of the present invention that exist in free base or free acid form can be converted to their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid according to methods known to those skilled in the art. Salts of compounds of the present invention may be converted to their free base or acid forms by standard techniques.
- LiAlH 4 lithium aluminum hydride
- PEG polyethylene glycol
- PE petroleum ether (60-90)
- 1,1,2,3,3-3D-3-methylpolyethylene glycol-1,2-propylene oxide (39.2g, 18.9mmol) was dissolved in 500ml tetrahydrofuran, and 2M sodium hydroxide solution (1.13 g, 28.35mmol, 14.16ml), heated up to 50°C and stirred for 6 hours. After the reaction of the raw materials was detected, the temperature was lowered to room temperature, extracted once with EA, washed once with saturated sodium chloride, mixed with silica gel in the organic phase, and purified by column chromatography (EA ) to obtain white solid 38.7g, yield 97.7%.
- EA column chromatography
- a syringe pump mix the ethanolic lipid solution with the aqueous mRNA solution at a ratio of about 1:5 to 1:3 (vol/vol) at a total flow rate of 10 ml/min or more. Ethanol was then removed and the external buffer was replaced by PBS by dialysis. Finally, filter the lipid nanoparticles through a sterile filter with a pore size of 0.2 ⁇ m.
- the particle size of the lipid nanoparticles as determined by quasi-elastic light scattering using a Malvern Zetasizer Nano ZS, is approximately 65-105 nm in diameter, and in some cases, approximately 75-100 nm in diameter.
- R 1 , R 2 , R 3 , R4, R 5 , R 6 , R 7 , and R8 are all independently two "hydrogen" isotopes (including hydrogen and deuterium), specifically expressed
- R 1 , R 2 , R 3 , R4, R 5 , R 6 , R 7 , and R8 are all independently two "hydrogen” isotopes (including hydrogen and deuterium), specifically expressed as “HH", “HD”, and The combination of "DD”.
- liver tissue approximately 50 mg was cut for analysis in 2 mL FastPrep tubes (MP Biomedicals, Solon OH). 1/4" ceramic balls (MP Biomedicals) were added to each tube, and 500 ⁇ L of Glo Lysis Buffer-GLB (Promega, Madison WI) equilibrated to room temperature was added to the liver tissue.
- the FastPrep24 instrument MP Biomedicals
- the Liver tissue was homogenized at 2 ⁇ 6.0 m/s for 15 s. The homogenate was incubated at room temperature for 5 min, then diluted 1:4 in GLB and evaluated using the SteadyGlo luciferase assay system (Promega).
- FLuc mRNA (L-6107) from Trilink Biotechnologies will express the luciferase protein, which was originally isolated from the firefly (Photinus pyralis). Fluc is commonly used in mammalian cell culture to measure gene expression and cell viability. It emits bioluminescence in the presence of the substrate luciferin. This capped and polyadenylated mRNA is completely replaced by 5-methylcytidine and pseudouridine.
- the pKa of the formulated cationic lipid correlates with the effectiveness of the LNP for delivery of nucleic acids.
- the preferred pKa range is 5-7.
- the pKa of each cationic lipid was determined in lipid nanoparticles using an assay based on the fluorescence of 2-(p-toluidino)-6-phthanesulfonic acid (TNS).
- TNS 2-(p-toluidino)-6-phthanesulfonic acid
- the vesicles were diluted to contain 24 ⁇ M lipid in 2 mL of a buffer solution containing 10 mM HEPES, 10 mM MES, 10 mM sodium acetate, 130 mM NaCl, wherein the pH value was 2.5-11. Aliquots of TNS solution were added to give a final concentration of 1 ⁇ M, and after vortex mixing, fluorescence intensity was measured in a SLM Aminco Series 2 Luminescence Spectrophotometer at room temperature using excitation and emission wavelengths of 321 nm and 445 nm. Sigmoid best-fit analysis was applied to the fluorescence data, and pKa was measured as the pH that yielded half the maximum fluorescence intensity.
- lipid nanoparticles containing FLuc mRNA were also used to formulate lipid nanoparticles containing FLuc mRNA (L-6107) using the ordered mixing method as described in Example 83.
- Lipid nanoparticles were formulated using the following molar ratios: 50% cationic lipid/10% distearoylphosphatidylcholine (DSPC)/38% cholesterol/2% deuterated PEG lipid.
- Relative activity was determined by measuring luciferase expression in the liver 5 hours after administration via tail vein injection as described in Example 83. The activities were compared at doses of 0.3 and 1.0 mg mRNA/kg and expressed as ng luciferase/g liver measured 5 hours after administration as described in Example 83.
- the results of Examples 83 and 84 are shown in Table 2.
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Abstract
本发明涉及一种新型氘代PEG脂质化合物、其制备方法、组合物和应用,具体公开了一种如式A和式B所示的新型氘代脂质化合物,或其药学可接受的盐、或其异构体。还公开了上述PEG脂质化合物的制备方法、组合物及应用。该类化合物作为功能性PEG脂质,适用于核酸递送的药物组合物,可实现更优的稳定性、水溶性和药物细胞内的递送效率。其中式A和式B的结构如下。
Description
本发明提供新型氘代聚合物缀合脂质,其可用于与其他脂质组分(如中性脂质、类固醇和阳离子的脂质)结合,以便形成一种核酸mRNA脂质纳米粒子组合物将一种或多种治疗剂和/或预防剂递送至哺乳动物细胞或器官和/或在哺乳动物细胞或器官中产生多肽的方法。除新型氘代脂质外,本发明的脂质纳米粒子组合物还可以包括呈特定比例的一种或多种氘代聚合物缀合脂质、包括多不饱和脂质在内的中性脂质、阳离子脂质、类固醇、和/或治疗剂和/或预防剂。
生物活性物质如小分子药物、蛋白质和核酸的有效靶向递送提出了一个持久的医学难题。确切地说,将核酸递送至细胞因这些物种的相对不稳定性和低细胞渗透性而变得困难。因此,需要开发有助于将治疗剂和/或预防剂如核酸递送至细胞的方法和组合物。
经研究证明,利用含脂质的纳米颗粒组合物、脂质体和脂质体复合物作运输媒介,可有效地将生物活性物质如小分子药物、蛋白质和核酸运送至细胞和/或细胞内隔室中。这些组合物一般包含一种或多种聚合物缀合的脂质,包括多不饱和脂质在内的中性脂质(如磷脂)、结构性脂质(如类固醇)和/或含阳离子的脂质。
然而,在治疗环境中使用寡核苷酸目前面临着两个问题。第一,游离的RNA易于在血浆中核酸酶消化。第二,游离RNA进入存在相关翻译机制的细胞内隔室的能力受限。由PEG化的氘代脂质与其他脂质组分(如中性脂质、胆固醇、阳离子脂质和寡核苷酸)形成的脂质纳米颗粒已用于阻止RNA在血浆中的降解并促进寡核苷酸的细胞摄取,而氘代的聚合物缀合脂质未有报道。
所以,仍然有必要改进的用于递送寡核苷酸的氘代聚乙二醇化的脂质和脂质纳米颗粒。改进的脂质化合物和脂质纳米颗粒会改进理化性质,提供优化的药物递送,保护核酸不在血清中被降解和清除,其适于全身或局部递送,并且提供核酸的细胞内递送。另外,这些优选的脂质-核酸颗粒应当是耐受良好的,并且提供足够的治疗指数,使得在有效剂量的核酸下的患者治疗不会对患者产生不可接受的毒性和/或风险。本发明提供这些优点和相关的优点。
发明内容
本发明提供以下新型聚乙二醇脂质化合物(如下列式A和式B)和这些化合物的制备方法、组合物及其应用,本发明提供的该类功能性PEG化氘代脂质可实现更优的理化性质-水溶性、稳定性,并实现更优的核酸在细胞内递送效率。
1、本发明涉及氘代聚乙二醇脂质化合物(A):
或其药物可接受的盐、互变异构体或立体异构体,其中:
R1、R2、R3各自独立地为DDD、DDH、DHH、HHH、DD、DH、HH、D、H的组合;
R1、R2、R3均有独立性,当R1和R2均为“HHH”时,R3不能为“HH”,当R3为“HH” 组合时,R1、R2其中一个不能为”HHH”组合;
R1、R2、各自独立地为”DDD”组合,R3独自地为”DD”组合;
n的平均值为40~50,更优的为45。
2、本发明涉及氘代聚乙二醇脂质化合物(B):
或其药物可接受的盐、互变异构体或立体异构体,其中:
R1、R2、R3、R4、R5各自独立地为DDD、DDH、DHH、HHH、DD、DH、HH、D、H的组合;
R1、R2、R3、R4、R5均有独立性,当R1、R2均为“HHH”组合,R4为“H”组合时,R3、R5不能同时为“HH”;当R3、R5均为“HH”组合,R4为“H”组合时,R1、R2不能同时为“HHH”组合;当R1、R2均为“HHH”组合,R3、R5均为“HH”组合时、R4不能为“H”组合;
R1、R2、R3、R4、R5各自独立地为”DDD”、”DD”、”D”的组合;
n的平均值为40~50,更优的为45。
在各个不同的实施方案中,所述化合物具有以下表1中所示的结构之一
表1 代表性新型PEG脂质化合物
在一些实施方案中,提供了包含结构式(A)和(B)的氘代化合物中的任一种或多种和治疗剂和/或预防剂的组合物。
在一些实施方案中,提供了包含结构(A)和(B)的化合物中的任一种或多种和治疗剂和/或预防剂的组合物。在一些实施方案中,所述组合物包含结构(A)和(B)的化合物中的任一种和治疗剂和/或预防剂以及一种或多种选自中性脂质、类固醇和阳离子的脂质的赋形剂。其他药物可接受的赋形剂和/或载体也包括在组合物的各种实施方案内。
在一些实施方案中,中性脂质选自1,2-二硬脂酰基-sn-甘油-3-磷酸胆碱(DSPC)、1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱(DPPC)、1,2-二肉豆寇基-sn-甘油-磷酸胆碱(DMPC)、1,2-二油酰基-sn-甘油-3-磷酸胆碱(DOPC)、1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱(POPC)、1, 2-二油酰基-sn-甘油-3-磷酸乙醇胺(DOPE)、鞘磷脂(SM)和其混合。在一些实施方案中,优选中性脂质为1,2-二硬脂酰基-sn-甘油-3-磷酸胆碱(DSPC)。
在一些实施方案中,类固醇选自胆固醇、粪固醇、谷固醇、麦角固醇、菜油固醇、豆固醇、菜籽固醇、番茄碱、熊果酸、α-生育酚和其混合。在一些实施方案中,优选类固醇为胆固醇。在一些实施方案中,阳离子脂质选自4-(N,N-二甲基氨基)丁醇(6Z,9Z,28Z,31Z)-庚三十碳-6,9,28,31-四烯-19-基酯(DLin-MC3-DMA)、十七烷-9-基-8-((2-羟乙基)(6-氧代-6-((癸氧基)己基)氨基)辛酸酯(SM-102)、((4-羟基丁基)氮杂-乙基)双(己烷-6,1-二基)双(2-己基癸酸酯)(ALC-0315),4-(N-2-(N,N-二(2-羟基十二基)乙胺基)-1-N(2-N(2-乙胺基-(2-(N,N-二(2-羟基十二基))-2羟基十二基)乙胺基哌嗪(C12-200)、吡咯烷类新型脂质化合物。
在一些实施方案中,阳离子脂质优选自为((4-羟基丁基)氮杂-乙基)双(己烷-6,1-二基)双(2-己基癸酸酯)(ALC-0315)氘代类似物、十七烷-9-基-8-((2-羟乙基)(6-氧代-6-((癸氧基)己基)氨基)辛酸酯(SM-102)的氘代类似物。
本发明所述的组合物中阳离子脂质具有以下结构(式I):
其中:
L1选自以下结构:-C-、-O(C=O)-、-(C=O)O-、-C(=O)-、-O-、-S(O)X-、-S-S-、-C(=O)S-、-SC(=O)-、-N-C(=O)-、-C(=O)-N-,L2选自以下结构:-C-、-(C=O)O-、-C(=O)-、-S(O)X-、-C(=O)S-、-C(=O)-N-;
R1和R2各自独立地为C6-C24烷基或C6-C24烯基,所述的烃基链任意的被一个或多个酯键或醚键连接;R3和R4各自独立地为C1-C12烷基或C1-C12烯基,或R3和R4彼此结合形成4至10元杂环,所述杂原子包括N、O、S中的一种或多种杂原子,所述杂环任选地被1-6个杂原子取代;
X为C、N、O、S、-S-S-;M为C1-C12烷基或C1-C12烯基;x为0、1或2。
本发明所述的组合物中的阳离子脂质化合物,优选以下专利申请号中公开的所有阳离子脂质化合物:CN2021109304214、CN2021109693918、CN2021109698790、CN2021109700095、CN202110970112X、CN2021109787347、CN2021110306263、CN2021110307694、CN2021110439195、CN2021110310644、CN2021110311986、CN2021111108325、CN2021111057272。
在一些实施方案中,所述组合物比例以下范围:约1-10mol%所述化合物、约0~30mol%中性脂质、约10~55mol%类固醇和约30-60mol%阳离子的脂质。
在一些前述组合物的实施方案中,治疗剂和/或预防剂包括核酸。其中核酸为RNA,其选自以下组成:siRNA、aiRNA、miRNA、dsRNA、shRNA、mRNA以及其混合物。在一些实施方案中,所述RNA选自mRNA。
在其他不同的实施方案中,本发明涉及向有需要的受试者施用治疗剂和/或预防剂的方法,该方法包括制备或提供上述组合物中的任一种并向受试者施用该组合物。
出于施用的目的,本发明的化合物(通常是脂质纳米颗粒与治疗剂和/或预防剂结合的形式)可以以原料药施用,或者可以配制为药物组合物。本发明的药物组合物包含结构(A)和(B)的化合物和一种或多种药物可接受的载体、稀释剂或赋形剂。结构(A)和(B)的化合物以有效形成脂质纳米颗粒并递送治疗剂和/或预防剂。本领域技术人员可以容易地确定适当的浓度和剂量。
本发明组合物的施用可以通过任何用于类似效用的试剂的可接受施用方式来进行。本发明的药物组合物可以配制成固体、半固体、液体或气体形式的制剂,例如片剂、胶囊、粉末、颗粒、软膏、溶液、悬浮液、栓剂、注射剂、吸入剂、凝胶、微球和气溶胶。施用这类药物组合物的典型途径包括,但不限于,口服、局部、经皮、吸入、胃肠外、舌下、口含、直肠、阴道和鼻内途径。本文使用的术语胃肠外包括皮下注射,静脉内、肌内、皮内、胸骨内注射或输注技术。配制本发明的药物组合物以便允许经过对受试者施用该组合物后其中含有的活性成分是生物可利用的。待向对象或患者施用的组合物是一个或多个剂量单位的形式,其中,片剂可以是单剂量单位,而本发明气溶胶形式的化合物的容器可以容纳多个剂量单位。制备这些剂型的现行的方法是己知的,或者对于本领域技术人员是显而易见的。在任何情况下,待施用的组合物将会含有治疗有效量的本发明化合物或其药物可接受的盐,以便根据本发明的教导治疗相关的疾病或病况。
本发明的药物组合物可以是固体或液体的形式。一方面,载体是微粒,使得组合物是片剂或粉末形式。载体可以是液体,此时组合物是口服糖浆或可注射液体或气溶胶,所述气溶胶适用于吸入施用。
当意图用于口服施用时,药物组合物优选为固体或液体形式,其中本文认为是固体或液体的形式包括半固体、半液体、悬浮液和凝胶形式。
作为用于口服施用的固体组合物,药物组合物可以配制成粉末、颗粒、压缩的片剂、丸剂、胶囊、咀嚼胶、薄片等形式。这类固体组合物通常将含有一种或多种惰性稀释剂或可食用载体。另外,可以存在以下的一种或多种:粘合剂,如明胶、纤维素等;赋形剂,如乳糖等;崩解剂,如海藻酸等;润滑剂,如硬脂酸镁等;助流剂,如硅胶等;甜味剂,如蔗糖或糖精;调昧剂,如薄荷等;以及着色剂。
当药物组合物是胶囊形式时,其可以含有上述类型材料之外的液体载体,如聚乙二醇或油。
药物组合物可以是液体的形式,如糖浆、溶液、乳液或悬浮液。作为两种实例,液体可以用于口服施用或用于注射递送。当意图用于口服施用时,优边的组合物含有,除本发明化合物之外的,甜味剂、防腐剂、染色/着色剂和增昧剂中的一种或多种。在通过注射施用的组合物中,可以包括表面活性剂、防腐剂、润湿剂、分散剂、悬浮剂、缓冲剂、稳定剂和等渗剂中的一种或多种。
本发明的液体药物组合物,不论其为溶液、悬浮液还是其他类似的形式,可以包括以下佐剂中的一种或多种:无菌稀释剂,如注射用水、盐水溶液、优选生理盐水、林格氏溶液、等渗氯化钠;不挥发性油类,如可用作溶剂或悬浮介质的合成的单甘酯或双甘酯,聚乙二醇、甘油、丙二醇或其他溶剂;抗菌剂,如尼泊金甲醋等;抗氧化剂,如抗坏血酸或亚硫酸氢钠;螯合剂,如乙二肢四乙酸;缓冲剂,如乙酸盐、拧棱酸盐或磷酸盐;以及用于调节张力的试剂,如氯化钠或葡萄糖;用作冷冻保护剂的试剂,如蔗糖或海藻糖。胃肠外制剂可以封装在玻璃或塑料制作的安瓿、一次性注射器或多剂量瓶中。生理盐水是优选的佐剂。可注射的药物组合物优选为无菌的。
本发明的药物组合物可以由可作为气溶胶施用的剂量单位组成。术语气溶胶用于表示从胶体性质的系统到由加压包装组成的系统的各种系统。可以通过液化气或压缩气来递送,或者通过分散活性成分的适合的泵系统来递送。本发明化合物的气溶胶可以以单相、双相系统或三相系统来递送,以便递送活性成分。气溶胶的递送包括必要的容器、活化剂、阀、子容器等,其在一起可以形成试剂盒。本领域技术人员不需过度实验即可确定优选的气溶胶。
本发明的药物组合物可以通过制药领域熟知的方法来制备。意图通过注射施用的药物组合物可以通过将本发明的脂质纳米颗粒与无菌的蒸馏水或其他载体结合成溶液来制备。可以加入表面活性剂以促进形成均匀的溶液或悬浮液。表面活性剂是与本发明化合物非共价地相互作用,以便促进所述化合物在水性递送系统中溶解或均匀悬浮的化合物。
本发明的组合物或其药物可接受的盐以治疗有效量施用,所述量将会根据多种因素变化,包括使用的具体治疗剂的活性;治疗剂的代谢稳定性和作用时长;受试者的年龄、体重、一般健康状况、性别和饮食;施用的方式和时间;排泄速率;药物组合;具体病例的严重性等。
本发明的组合物也可以在施用一种或多种其他治疗剂的同时、之前或之后施用。这类组合治疗包括施用本发明组合物和一种或多种另外的活性剂的单一药物剂量制剂,以及施用本发明组合物和各个在其自身单独药物剂量制剂中的活性剂。例如,本发明组合物和其他活性剂可以以单一口服剂量组合物(如片剂或胶囊)一起向受试者施用,或者各个试剂以不同的口服剂量制剂施用。当使用不同的剂量制剂时,本发明化合物和一种或多种另外的活性剂可以在基本同一时间施用,或者在相互交错的时间依次施用;应理解组合治疗包括所有的这些给药方案。
上述氘代PEG化氘代脂质化合物的结构修饰和设计,实现了更有优势的理化性质,包括更合适的pKa和更好的化学稳定性,用于mRNA纳米脂质体组合物,可实现对离子类核酸药物更有效结合并递送,同时其化学结构更稳定,便于合成和有利开发为药用辅料。
上述化合物和组合物的制备方法在下文描述,和/或在本领域已知。
本领域的技术人员将会认识到,在本文描述的方法中,原料和中间体的官能团包括环氧、羟基、氨基和酰胺。会使用到取代,还原,缩合等方法,适合于酰胺还原制备胺的方法,主要有金属氢化物还原法、硼烷四氢呋喃络合物还原法、催化加氢还原法、硼氢化钠-路易斯酸体系还原法等。酰胺的制备方法主要有氨酯交换法、脂肪胺与酯交换法、酸酐为原料法、酰卤为原料法、有机磷类缩合剂法以及鎓盐类缩合剂法等。环氧开环主要有酸性催化和碱性催化,方法可以根据底物性质进行选择,所述标准技术是本领域技术人员已知的本文中描述的。
本领域技术人员还将认识到,虽然本发明化合物的这类经还原和缩合的衍生物可能不由此具有药物活性,但其可以对哺乳动物施用并且之后在体内代谢形成具有药理活性的本发明化合物。这类衍生物因此可以被描述为“前药”。所以本发明化合物的前药包括在本发明的范围内。
此外,所有以游离碱或游离酸形式存在的本发明化合物可以根据本领域技术人员已知的方法用适当的无机或有机的碱或酸处理来转化为其药物可接受的盐。本发明化合物的盐可以通过标准技术转化为其游离碱或酸形成。
提供了以下实施例,其目的在于举例展示,并非限定。
以下实施例,除非另外指出,否则使用的所有溶剂和试剂都是商购得到并且以原样使用。
以下描述的程序可用于合成化合物A和B。
本文采用了以下缩写:
DCM:二氯甲烷
THF:四氢呋喃
MeOH:甲醇
HBTU:2-(苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯
DIEA:二异丙基乙胺
DMF:N,N-二甲基甲酰胺
LiAlH
4:四氢化铝锂
NaOH:氢氧化钠
PEG:聚乙二醇
DMSO-d6:氘代二甲基亚砜
EA:乙酸乙酯
PE:石油醚(60-90)
EDCI:1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐
DMAP:N,N-二甲基吡啶。
实施例1
代表性路线
化合物A:N,N-二(14,14,14-D3-十四烷基)-2,2-2D-2-甲基聚乙二醇乙酰胺的合成
1)14,14,14-D3-十四烷酰胺(dPEG-A-3)的合成
分子式:C
14H
26D
3NO
分子量:230.40
在室温下向14,14,14-D3-十四烷酸(dPEG-A-1)(6g,25.9mmo1)的甲苯(50mL)溶液加入草酰氯(38.85mmo1,4.93g)。将得到的混合物在70℃下加热2h后,将混合物浓缩。将残余物溶于甲苯并再次浓缩。在10℃下,通过注射器将残余的油状物加入浓缩的氨溶液(20m)。将反应混合物过滤,并用水洗涤。将白色固体在真空中干燥。获得所需产物14,14,14-D3-十四烷酰胺(dPEG-A-3),为白色固体(3.58g,60%)。
APCI-MS:m/z 231[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 6.8(s,2H),2.28(t,2H,J=7.2Hz),1.80(m,2H),1.35(m,2H),1.24(m,18H)。
2)14,14,14-D3-十四胺(dPEG-A-4)的合成
分子式:C
14H
28D
3N
分子量:216.40
在室温下,经30min的时间,向14,14,14-D3-十四烷酰胺(3.58g,15.54mm01)在THF(70mL)中的悬浮液分批加入氢化铝锂(1.14g,30mmol)。然后将混合物缓慢加热至回流(65℃油浴)过夜。将混合物冷却至5℃,并加入硫酸钠水合物。将混合物搅拌2h,通过硅藻土层过滤,用含15%MeOH的DCM(200m)洗涤。将滤液和洗液合并,并浓缩。将残余的固体在真空中干爍。获得14,14,14-D3-十四胺(dPEG-A-4),为白色固体(2.86,85.1%)。
APCI-MS:m/z 217[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 3.7(s,2H),2.72(m,2H),1.65(m,2H),1.35(m,2H),1.24(m,20H)。
3)14,14,14-D3-十四烷基-14,14,14-D3-十四酰胺(dPEG-A-5)的合成
分子式:C
29H
53D
6NO
分子量:443.82
在室温下,向14,14,14-D3-肉豆蔻酸(1g,4.3mmol)在苯(10mL)和DMF(1滴)中的溶液加入草酰氯(0.82g,6.45mmol),将混合物在室温下搅拌3h。60℃浓缩除去甲苯,将残余的油状物溶于5mL的苯,降温到10℃后,将其加入14,14,14-D3-十四胺(0.97g,4.5mol)和三乙胺(0.65g,6.45mmol)在苯(5ml)中的溶液。加料完毕,反应液在室温下搅拌过夜。确认反应完后,加水,水稀释,并用1.7M HCl调节至pH5-6,有固体析出,室温搅拌5小时,过滤,用水洗涤。得到灰白色湿品,湿品用5ml甲醇升温到58℃溶清,降温到室温搅拌8小时,过滤,用1ml甲醇淋洗,所得固体在55℃下鼓风干燥10小时,即得到目标化合物14,14,14-D3-十四烷基14,14,14-D3-十四酰胺,为淡白色固体(1.77g,93%)。
APCI-MS:m/z 444[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 8.13(s,1H),3.86(m,2H),2.66(m,2H),1.58(m,4H),1.35(m,4H),1.24(m,30H)。
4)N,N-二(14,14,14-D3-十四烷基)胺(dPEG-A-6)的合成
分子式:C
29H
55D
6N
分子量:429.84
在室温下,向14,14,14-D3-十四烷基-14,14,14-D3-十四酰胺(2g,4.5mo1)在THF(20mL)中的悬浮液分批加入氢化铝锂(0.51g,13.5mmo1)。升温到68℃回流过夜。检测反应完后,将混合物冷却至0℃,并加入氢氧化钠水溶液搅拌2h,通过硅藻土和硅胶的垫过滤,用乙醚洗涤。滤液变为浑浊并形成沉淀,搅拌5min,过滤得到白色固体。
白色固体转到20ml双口瓶中,加入5ml甲醇,升温到60℃溶清,30min后降温到25℃搅拌析晶10小时,过滤,用1ml甲醇淋洗,固体在55℃下干燥10小时,得到N,N-二(14,14,14-D3-十四烷基)胺(dPEG-A-6),为白色固体(1.45g,75.01%)。
APCI-MS:m/z 430[M+H]+
1H-NMR(300MHz,DMSO-d6):δppm 3.45(s,1H),2.66(m,4H),1.58(m,4H),1.35(m,4H),1.24(m,44H)。
5)N,N-二(14,14,14-D3-十四烷基)-2,2-2D-2-甲基聚乙二醇乙酰胺(dPEG-A)的合成
分子式:C
117H
231D
8NO
47
分子量:2485
50ml双口瓶中加入向N,N-二(14,14,14-D3-十四烷基)胺(2g,4.65mmol)和三乙胺(0.71g,6.98mmol)在DCM(40mL)中的溶液加入甲基聚乙二醇琥珀酰亚胺乙酸酯(mPEG-NHS,4.65mml,10.1g,PEG MW约2,000,n=约45)的DCM(50m)溶液。室温3搅拌24h,加入水(30mL),用DCM(100mLx2)将水相萃取两次。合并DCM萃取物,用1M HCl(30mL)洗涤。有机相经硫酸钠干燥,过滤,浓缩有机相剩余约30m1后,将其降温至-20℃搅拌8小时,过滤,用3mlDCM淋洗,得到白色固体(0.9g,未反应的起始的胺),向过滤物加入三乙胺(18.6mmol,)和乙酸酐(1.4mmol,143mg),,10min后,有固体析出,在室温下搅拌5h,然后40℃浓缩至固体,残余的固体通过在硅胶(含0-8%甲醇的DCM)上进行柱层析来纯化,得到N,N-二(14,14,14-D3-十四烷基)-2,2-2D-2-甲基聚乙二醇乙酰胺,为白色固体(5.82g,收率约为50%)。
APCI-MS:m/z 2486[M+H]
+
1H-NMR(300MHz,CDC13):δppm 3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,4H),1.24(m,44H)。
实施例2
代表性合成路线
化合物B 3-(2-2-甲基聚乙二醇基(n=45))-1,2-二基-双(14,14,14-3D-十四羧基)1,1,2,3,3-5D-丙烷
1)1,1,2,3,3-3D-3-甲基聚乙二醇基-1,2-环氧丙烷的合成
分子式:C
94H
183D
5O
47
分子量:2073
聚乙二醇单甲醚(dEG-B-2,68.2g,PEG Mw约2000,n=约45,34.1mmol,1.2eq)的THF(55mL)和DMF(10mL)混合溶液冰浴控温于0-10℃,加入NaH(60%质量分数,1.4g,34.1mmol,1.2eq),保温搅拌0.5hr,再缓慢加入1,1,2,3,3-3D-3-氯代-1,2-环氧丙烷(dEG-B-1,2.8g,28.4mmol,1.0eq)的THF溶液(10mL),加入完毕后自然升温搅拌反应18小时。TLC显示dEG-B-1基本反应完全后,将反应液缓慢倒入饱和氯化铵溶液中。加入THF萃取3次。合并有机相,用饱和氯化钠洗涤一次。有机相硅胶拌样,柱层析纯化(EA:PE=5:1,Rf=0.4)得半油半固体39.2g,收率65%。
APCI-MS:m/z 2074[M+H]
+
1H-NMR(300MHz,CDC13):δppm 3.83-3.46(m,180-200H),3.39(s,3H)。
2)1,1,2,3,3-3D-3-甲基聚乙二醇基-1,2-丙二醇的合成
分子式:C
94H
185D
5O
48
分子量:2091
1,1,2,3,3-3D-3-甲基聚乙二醇基-1,2-环氧丙烷(39.2g,18.9mmol)溶于500ml四氢呋喃中,加入2M氢氧化钠溶液(1.13g,28.35mmol,14.16ml),升温到50℃搅拌6小时,检测原料反应完后,降温到室温,EA萃取1次,饱和氯化钠洗涤一次有机相硅胶拌样,柱层析纯化(EA)得到白色固体38.7g,收率97.7%。
APCI-MS:m/z 2092[M+H]
+
1H-NMR(300MHz,CDC13):δppm 6.10(s,1H),5.08(s,1H),3.83-3.46(m,180-200H),3.39(s,3H)。
3)3-(2-2-甲基聚乙二醇基(n=45))-1,2-二基-双(14,14,14-3D-十四羧基)1,1,2,3,3-5D-丙烷的合成
分子式:C
122H
231D
11O
50
分子量:2517
将38.7g 1,1,2,3,3-3D-3-甲基聚乙二醇基-1,2-丙二醇(dPEG-B-4,18.50mmol)加入到1000ml四口瓶中,加入400ml DMF,加入14,14,14-D3-肉豆蔻酸(8.99g,38.85mmol),加入DIEA(5.62g,55.5mmol)和EDCI(10.64g,55.5mmol),升温到45℃反应5小时,检测反应完后,用EA萃取三次,水洗一次,食盐水洗一次,有机相45℃浓缩后,经柱层析(EA:PE=15:1)纯化得到35.6g白色固体(dPEG-B),收率:76.46%。
APCI-MS:m/z 2518[M+H]
+
1H-NMR(300MHz,CDC
13):δppm 3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,4H),1.26(m,32H)。
通过采用上述技术和已为本领域技术人员所熟知的有关步骤,并且使用合适的氘代试剂,可制备出下述化合物。
实施例3 化合物2的合成
分子式:C117H232D7NO47
分子量:2484
APCI-MS:m/z 2485[M+H]+
1H-NMR(300MHz,DMSO-d6):δppm 4.23(s,1H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,4H),1.24(m,44H)。
实施例4 化合物3的合成
分子式:C
117H
232D
7NO
47
分子量:2484
APCI-MS:m/z 2485[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,5H),1.24(m,44H)。
实施例5 化合物4的合成
分子式:C
117H
233D
6NO
47
分子量:2483
APCI-MS:m/z 2484[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.23(s,2H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,4H),1.24(m,44H)。
分子式:C
117H
233D
6NO
47
分子量:2483
APCI-MS:m/z 2484[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.23(s,1H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,5H),1.24(m,44H)。
实施例7 化合物6的合成
分子式:C
117H
233D
6NO
47
分子量:2483
APCI-MS:m/z 2484[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,6H),1.24(m,44H)。
实施例8 化合物7的合成
分子式:C
117H
234D
5NO
47
分子量:2482
APCI-MS:m/z 2483[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,2H),1.24(m,46H),0.88(m,3H)。
实施例9 化合物8的合成
分子式:C
117H
234D
5NO
47
分子量:2482
APCI-MS:m/z 2483[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.56(s,2H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,5H),1.24(m,44H)。
实施例10 化合物9的合成
分子式:C
117H
234D
5NO
47
分子量:2482
APCI-MS:m/z 2483[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.56(s,1H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,6H),1.24(m,44H)。
实施例11 化合物10的合成
分子式:C
117H
234D
5NO
47
分子量:2482
APCI-MS:m/z 2483[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.56(s,1H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,2H),1.24(m,44H),0.89(m,3H)。
实施例12 化合物11的合成
分子式:C
117H
235D
4NO
47
分子量:2482
APCI-MS:m/z 2482[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.56(s,1H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,6H),1.24(m,44H)。
实施例13 化合物12的合成
分子式:C
117H
235D
4NO
47
分子量:2481
APCI-MS:m/z 2482[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,8H),1.24(m,44H)。
分子式:C
117H
235D
4NO
47
分子量:2481
APCI-MS:m/z 2482[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,3H),1.24(m,46H),0.90(m,3H)。
实施例15 化合物14的合成
分子式:C
117H
236D
3NO
47
分子量:2481
APCI-MS:m/z 2482[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.62(s,2H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,2H),1.24(m,46H),0.90(m,3H)。
实施例16 化合物15的合成
分子式:C
117H
236D
3NO
47
分子量:2481
APCI-MS:m/z 2482[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.62(s,2H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,7H),1.24(m,44H)。
实施例17 化合物16的合成
分子式:C
117H
236D
3NO
47
分子量:2481
APCI-MS:m/z 2482[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.62(s,1H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,3H),1.24(m,46H),0.91(m,3H)。
实施例18 化合物17的合成
分子式:C
117H
236D
3NO
47
分子量:2481
APCI-MS:m/z 2482[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.62(s,1H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,8H),1.24(m,44H)。
实施例19 化合物18的合成
分子式:C
117H
236D
3NO
47
分子量:2481
APCI-MS:m/z 2482[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,4H),1.24(m,46H),0.92(m,3H)。
实施例20 化合物19的合成
分子式:C
117H
237D
2NO
47
分子量:2480
APCI-MS:m/z 2481[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.24(m,48H),0.92(m,6H)。
实施例21 化合物20的合成
分子式:C
117H
237D
2NO
47
分子量:2480
APCI-MS:m/z 2481[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.66(s,1H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.36(m,4H),1.24(m,46H),0.92(m,3H)。
实施例22 化合物21的合成
分子式:C
117H
237D
2NO
47
分子量:2480
APCI-MS:m/z 2481[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.66(s,2H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.36(m,6H),1.24(m,44H)。
实施例23 化合物22的合成
分子式:C
117H
237D
2NO
47
分子量:2480
APCI-MS:m/z 2481[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.66(s,2H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.36(m,3H),1.24(m,46H),0.92(m,3H)。
实施例24 化合物23的合成
分子式:C
117H
238D
1NO
47
分子量:2479
APCI-MS:m/z 2480[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.66(s,1H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.24(m,48H),0.92(m,6H)。
实施例25 化合物24的合成
分子式:C
117H
238D
1NO
47
分子量:2479
APCI-MS:m/z 2480[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.66(s,2H),3.83-3.465(m,180-200H),3.39(s,3H),3.28(m,4H),1.58(m,4H),1.35(m,4H),1.24(m,46H),0.92(m,3H)。
实施例26 化合物26的合成
分子式:C
122H
232D
10O
50
分子量:2516
APCI-MS:m/z 2517[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,5H),1.26(m,32H)。
实施例27 化合物27的合成
分子式:C
122H
232D
10O
50
分子量:2516
APCI-MS:m/z 2517[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,5H),1.31(m,4H),1.26(m,32H)。
实施例28 化合物28的合成
分子式:C
122H
232D
10O
50
分子量:2516
APCI-MS:m/z 2517[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 5.6(s,1H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,4H),1.26(m,32H)。
实施例29 化合物29的合成
分子式:C
122H
232D
10O
50
分子量:2516
APCI-MS:m/z 2517[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 5.6(s,1H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,4H),1.26(m,32H)。
实施例30 化合物30的合成
分子式:C
122H
232D
10O
50
分子量:2516
APCI-MS:m/z 2517[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.65(s,1H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,4H),1.26(m,32H)。
实施例31 化合物31的合成
分子式:C
122H
233D
9O
50
分子量:2515
APCI-MS:m/z 2516[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,6H),1.31(m,4H),1.26(m,32H)。
实施例32 化合物32的合成
分子式:C
122H
233D
9O
50
分子量:2515
APCI-MS:m/z 2516[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,6H),1.31(m,4H),1.26(m,32H)。
实施例33 化合物33的合成
分子式:C
122H
233D
9O
50
分子量:2515
APCI-MS:m/z 2516[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 5.6(s,1H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,5H),1.31(m,4H),1.26(m,32H)。
实施例34 化合物34的合成
分子式:C
122H
233D
9O
50
分子量:2515
APCI-MS:m/z 2516[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 5.6(s,1H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,5H),1.31(m,4H),1.26(m,32H)。
实施例35 化合物35的合成
分子式:C
122H
233D
9O
50
分子量:2515
APCI-MS:m/z 2516[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 4.43(s,1H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,5H),1.31(m,4H),1.26(m,32H)。
实施例36 化合物36的合成
分子式:C
122H
234D
8O
50
分子量:2514
APCI-MS:m/z 2515[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,2H),1.26(m,34H),0.92(m,3H)。
实施例37 化合物37的合成
分子式:C
122H
234D
8O
50
分子量:2514
APCI-MS:m/z 2515[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 5.62(d,1H,J=5.6Hz),5.58(d,1H,J=5.6Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,5H),1.26(m,32H)。
实施例38 化合物38的合成
分子式:C
122H
234D
8O
50
分子量:2514
APCI-MS:m/z 2515[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 5.62(t,1H,J=8.3Hz),5.58(d,2H,J=5.3Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,5H),1.31(m,4H),1.26(m,32H)。
实施例39 化合物39的合成
分子式:C
122H
234D
8O
50
分子量:2514
APCI-MS:m/z 2515[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 5.62(s,2H),5.58(s,1H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,5H),1.31(m,4H),1.26(m,32H)。
实施例40 化合物40的合成
分子式:C
122H
233D
9O
50
分子量:2515
APCI-MS:m/z 2516[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 5.62(s,1H),4.86(s,1H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,4H),1.26(m,32H)。
实施例41 化合物41的合成
分子式:C
122H
235D
7O
50
分子量:2513
APCI-MS:m/z 2514[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,3H),1.26(m,34H),0.92(s,3H)。
实施例42 化合物42的合成
分子式:C
122H
235D
7O
50
分子量:2513
APCI-MS:m/z 2514[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 5.56(s,1H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,5H),1.26(m,32H)。
实施例43 化合物43的合成
分子式:C
122H
235D
7O
50
分子量:2513
APCI-MS:m/z 2514[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 5.56(d,1H,J=5.5Hz),5.49(d,1H,J=5.5Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,6H),1.26(m,32H)。
实施例44 化合物44的合成
分子式:C
122H
235D
7O
50
分子量:2513
APCI-MS:m/z 2514[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 5.56(t,1H,J=8.9Hz),5.49(d,1H,J=5.5Hz),4.87(d,1H,J=4.3Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,5H),1.26(m,32H)。
实施例45 化合物45的合成
分子式:C
122H
235D
7O
50
分子量:2513
APCI-MS:m/z 2514[M+H]
+
1H-NMR(300MHz,DMSO-d6):δppm 5.56(t,1H,J=8.9Hz),5.49(d,1H,J=5.5Hz),4.87(d,1H,J=4.3Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,5H),1.26(m,32H)。
实施例46 化合物46的合成
分子式:C
122H
235D
7O
50
分子量:2513
APCI-MS:m/z 2514[M+H]
+
1H-NMR(300MHz,DMSO-d6):3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,3H),1.26(m,34H),0.93(m,3H)。
实施例47 化合物47的合成
分子式:C
122H
236D
6O
50
分子量:2512
APCI-MS:m/z 2513[M+H]
+
1H-NMR(300MHz,DMSO-d6):3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,4H),1.26(m,34H),0.93(m,3H)。
实施例48 化合物48的合成
分子式:C
122H
236D
6O
50
分子量:2512
APCI-MS:m/z 2513[M+H]
+
1H-NMR(300MHz,DMSO-d6):3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,4H),1.26(m,34H),0.93(m,3H)。
实施例49 化合物49的合成
分子式:C
122H
236D
6O
50
分子量:2512
APCI-MS:m/z 2513[M+H]
+
1H-NMR(300MHz,DMSO-d6):4.65(s,2H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,2H),1.26(m,34H),0.93(m,3H)。
实施例50 化合物50的合成
分子式:C
122H
236D
6O
50
分子量:2512
APCI-MS:m/z 2513[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.62(d,1H,J=6.8Hz),4.65(d,1H,J=3.2Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,2H),1.26(m,34H),0.93(m,3H)。
实施例51 化合物51的合成
分子式:C
122H
236D
6O
50
分子量:2512
APCI-MS:m/z 2513[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.72(d,1H,J=8.9Hz),4.65(d,1H,J=3.2Hz),3.83-3.46(m, 180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,2H),1.26(m,34H),0.93(m,3H)。
实施例52 化合物52的合成
分子式:C
122H
236D
6O
50
分子量:2512
APCI-MS:m/z 2513[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.78(m,1H),5.63(d,2H,J=8.6Hz),4.65(d,2H,J=3.8Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,4H),1.26(m,32H)。
实施例53 化合物53的合成
分子式:C
122H
237D
5O
50
分子量:2511
APCI-MS:m/z 2512[M+H]
+
1H-NMR(300MHz,DMSO-d6):3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.26(m,36H),0.93(m,6H)。
实施例54 化合物54的合成
分子式:C
122H
237D
5O
50
分子量:2511
APCI-MS:m/z 2512[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.62(m,1H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,4H),1.26(m,34H),0.93(m,3H)。
实施例55 化合物55的合成
分子式:C
122H
237D
5O
50
分子量:2511
APCI-MS:m/z 2512[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.62(t,1H,J=7.98Hz),4.68(d,2H,J=3.59Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,2H),1.26(m,34H),0.93(m,3H)。
实施例56 化合物56的合成
分子式:C
122H
237D
5O
50
分子量:2511
APCI-MS:m/z 2512[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.62(d,1H,J=6.5Hz),5.58(d,1H,J=6.3Hz),4.68(d,2H,J=3.59Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,2H),1.26(m,34H),0.93(m,3H)。
实施例57 化合物57的合成
分子式:C
122H
237D
5O
50
分子量:2511
APCI-MS:m/z 2512[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.62(d,1H,J=6.5Hz),4.68(d,2H,J=3.59Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,8H),1.26(m,32H)。
实施例58 化合物58的合成
分子式:C
122H
238D
4O
50
分子量:2510
APCI-MS:m/z 2511[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.62(s,1H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.26(m,36H),0.93(m,6H)。
实施例59 化合物59的合成
分子式:C
122H
238D
4O
50
分子量:2510
APCI-MS:m/z 2511[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.62(d,1H,J=5.2Hz),5.59(d,1H,J=6.6Hz)3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,4H)1.26(m,34H),0.93(m,3H)。
实施例60 化合物60的合成
分子式:C
122H
238D
4O
50
分子量:2510
APCI-MS:m/z 2511[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.62(t,1H,J=8.6Hz),5.59(d,1H,J=6.6Hz)4.86(d,1H,J=3.8Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,8H),1.26(m,32H)。
实施例61 化合物61的合成
分子式:C
122H
238D
4O
50
分子量:2510
APCI-MS:m/z 2511[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.62(m,1H),5.59(d,2H,J=6.6Hz)4.86(d,2H,J=3.8Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,6H),1.26(m,32H)。
实施例62 化合物62的合成
分子式:C
122H
238D
4O
50
分子量:2510
APCI-MS:m/z 2511[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.59(s,2H),4.86(s,2H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,2H),1.26(m,34H),0.94(m,3H)。
实施例63 化合物63的合成
分子式:C
122H
239D
3O
50
分子量:2509
APCI-MS:m/z 2510[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.65(d,1H,J=8.4Hz),4.83(d,1H,J=3.9Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.26(m,36H),0.94(m,6H)。
实施例64 化合物64的合成
分子式:C
122H
239D
3O
50
分子量:2509
APCI-MS:m/z 2510[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.65(m,1H),5.58(d,2H,J=6.9Hz),4.83(d,2H,J=3.9Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,2H),1.26(m,34H),0.94(m,4H)。
实施例65 化合物65的合成
分子式:C
122H
239D
3O
50
分子量:2509
APCI-MS:m/z 2510[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.65(m,1H),5.58(d,2H,J=6.9Hz),4.83(d,2H,J=3.9Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,2H),1.26(m,34H),0.94(m,4H)。
实施例66 化合物66的合成
分子式:C
122H
239D
3O
50
分子量:2509
APCI-MS:m/z 2510[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.65(m,1H),5.58(d,2H,J=6.9Hz),4.83(d,2H,J=3.9Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,7H),1.26(m,32H)。
实施例67 化合物67的合成
分子式:C
122H
238D
4O
50
分子量:2510
APCI-MS:m/z 2511[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.65(m,1H),5.58(d,2H,J=6.9Hz),4.83(d,2H,J=3.9Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,6H),1.26(m,32H)。
实施例69 化合物68的合成
分子式:C
122H
238D
4O
50
分子量:2510
APCI-MS:m/z 2511[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.65(d,1H,J=6.6Hz),4.83(d,2H,J=3.9Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,3H),1.26(m,34H),0.95(m,3H)。
实施例69 化合物69的合成
分子式:C
122H
238D
4O
50
分子量:2510
APCI-MS:m/z 2511[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.68(t,1H,J=8.9Hz),5.65(d,1H,J=6.6Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,3H),1.26(m,34H),0.95(m,3H)。
实施例70 化合物70的合成
分子式:C
122H
238D
4O
50
分子量:2510
APCI-MS:m/z 2511[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.65(s,1H),4.69(s,2H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,4H),1.26(m,34H),0.95(m,3H)。
实施例71 化合物71的合成
分子式:C
122H
238D
4O
50
分子量:2510
APCI-MS:m/z 2511[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.56(s,2H),4.69(s,2H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.31(m,7H),1.26(m,32H)。
实施例72 化合物72的合成
分子式:C
122H
240D
2O
50
分子量:2508
APCI-MS:m/z 2509[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.61(t,1H,J=8.3Hz),4.66(d,2H,J=7.8Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.26(m,36H),0.96(m,6H)。
实施例73 化合物73的合成
分子式:C
122H
240D
2O
50
分子量:2508
APCI-MS:m/z 2509[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.79(m,1H),5.66(d,2H,J=7.6Hz),4.61(d,2H,J=7.3Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.32(m,3H),1.26(m,34H),0.96(m,3H)。
实施例74 化合物74的合成
分子式:C
122H
240D
2O
50
分子量:2508
APCI-MS:m/z 2509[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.79(m,1H),5.66(d,2H,J=7.6Hz),4.61(d,2H,J=7.3Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.32(m,3H),1.26(m,34H),0.96(m,3H)。
实施例75 化合物75的合成
分子式:C
122H
240D
2O
50
分子量:2508
APCI-MS:m/z 2509[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.79(m,1H),5.66(d,2H,J=7.6Hz),4.61(d,2H,J=7.3Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.32(m,8H),1.26(m,32H)。
实施例76 化合物76的合成
分子式:C
122H
240D
2O
50
分子量:2508
APCI-MS:m/z 2509[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.66(s,2H,),4.61(s,2H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.32(m,4H),1.26(m,34H),0.93(m,3H)。
实施例77 化合物77的合成
分子式:C
122H
240D
2O
50
分子量:2508
APCI-MS:m/z 2509[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.70(q,1H,J
1=9.6Hz,J
2=3.8Hz),5.66(d,1H,J=7.3Hz),4.61(d,2H,J=7.3Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.32(m,4H),1.26(m,34H),0.93(m,3H)。
实施例78 化合物78的合成
分子式:C
122H
241D
1O
50
分子量:2507
APCI-MS:m/z 2508[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.70(q,1H,J
1=9.6Hz,J
2=3.8Hz),5.69(d,1H,J=7.3Hz),4.63(d,2H,J=3.9Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.26(m,36H),0.93(m,6H)。
实施例79 化合物79的合成
分子式:C
122H
241D
1O
50
分子量:2507
APCI-MS:m/z 2508[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.69(s,2H),4.63(s,2H),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.26(m,36H),0.93(m,6H)。
实施例80 化合物80的合成
分子式:C
122H
241D
1O
50
分子量:2507
APCI-MS:m/z 2508[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.70(q,1H,J
1=9.1Hz,J
2=42.1Hz),5.69(d,2H,J=5.9Hz),4.63(d,1H,J=3.9Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.26(m,36H),0.93(m,6H)。
实施例81 化合物81的合成
分子式:C
122H
241D
1O
50
分子量:2507
APCI-MS:m/z 2508[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.70(m,1H),5.69(d,2H,J=5.9Hz),4.63(d,1H,J=3.9Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.32(m,3H),1.26(m,34H),0.93(m,6H)。
实施例82 化合物82的合成
分子式:C
122H
241D
1O
50
分子量:2507
APCI-MS:m/z 2508[M+H]
+
1H-NMR(300MHz,DMSO-d6):5.70(m,1H),5.69(d,2H,J=5.9Hz),4.63(d,1H,J=3.9Hz),3.83-3.46(m,180-200H),3.39(s,3H),2.35(m,4H),1.69(m,4H),1.38(m,4H),1.32(m,3H),1.26(m,34H),0.93(m,6H)。
实施例83
利用脂质纳米颗粒组合物的荧光素酶mRNA体内评价
将阳离子脂质、DSPC、胆固醇和氘代PEG-脂质以50:10:38:2或48:10:40:2的摩尔比溶解在乙醇中,其中阳离子脂质如E结构式、F结构式所示。以约10:1至30:1的总脂质与mRNA的重量比制备脂质纳米颗粒(LNP)。简而言之,将mRNA在10ml至50ml柠檬酸盐缓冲液(pH=4)稀释至0.15mg/mL。使用注射器泵,将脂质的乙醇溶液与mRNA水溶液以约1:5至1:3(体积/体积)的比例混合,总流速为10ml/min以上。然后去除乙醇,并通过透析用PBS替代外部的缓冲液。最后,将脂质纳米颗粒通过0.2μm孔径的无菌过滤器过滤。使用Malvern Zetasizer Nano ZS通过准弹性光散射测定的脂质纳米颗粒的粒径为直径大约65-105nm,并且在一些情况下,直径大约75-100nm。
E结构式
R
1,R
2,R
3,R4,R
5,R
6,R
7,R8均独立的为2个”氢”同位素(包括氢、氘),具体表现
F结构式
R
1,R
2,R
3,R4,R
5,R
6,R
7,R8均独立的为2个”氢”同位素(包括氢、氘),具体表现 为”HH”、”HD”、和"DD”的组合。
根据国家科学技术委员会制定的指南,在6-8周龄的雌性C57BL/6小鼠,8-10周龄CD-1小鼠上进行研究。通过尾静脉注射全身性给予不同剂量的mRNA脂质纳米颗粒,并在给药后的特定时间点(例如5小时)将动物安乐死。将肝脏和脾脏收集在预先称重的管中,确定重量,立即在液氮中快速冷冻,并且在-80℃下储存,直至用于分析。
对于肝脏,切割约50mg以便在2mL FastPrep管(MP Biomedicals,Solon OH)中进行分析。向各个管中加入1/4"陶瓷球(MP Biomedicals),并将平衡至室温的500μL的Glo裂解缓冲液-GLB(Promega,Madison WI)加入到肝脏组织中。使用FastPrep24仪器(MP Biomedicals)将肝脏组织在2×6.0m/s下均匀化15秒。将匀浆在室温下孵育5分钟,然后在GLB中进行1:4稀释,并使用SteadyGlo荧光素酶测定系统(Promega)进行评估。具体地,将50μL的稀释的组织匀浆与50μL的SteadyGlo底物反应,摇振10秒,接着孵育5分钟,然后使用SpectraMAX_L化学发光型酶标仪(美谷分子仪器(上海)有限公司)定量。通过使用BCA蛋白质定量试剂盒(上海易色医疗科技有限公司)来确定测定的蛋白质的量。然后将相对发光度单位(RLU)归一化成所测定蛋白质的总μg。为了将RLU转化成μg荧光素酶,用QuantiLum重组荧光素酶(Promega)生成了标准曲线。
来自Trilink Biotechnologies的FLuc mRNA(L-6107)将表达荧光素酶蛋白,其最初从萤火虫(Photinus pyralis)中分离出来。Fluc通常用于哺乳动物细胞培养物中以测量基因表达和细胞活力。其在底物萤光素存在下发射出生物性光。这种加帽并且聚腺昔酸化的mRNA被5-甲基胞苷和假尿苷完全取代。
实施例84
所配制得脂质的pKa的测定
所配制的阳离子脂质的pKa与用于递送核酸的LNP的效果相关。优选的pKa范围是5~7。使用基于2-(对甲苯胺基)-6-荼磺酸(TNS)的荧光的分析,在脂质纳米颗粒中测定各阳离子脂质的pKa。如实施例3中所述,使用有序的方法来制备在PBS中的浓度为0.4mM总脂质的包含阳离子脂质/DSPC/胆固醇/PEG脂质(50/10/38/2mol%)的脂质纳米颗粒。将TNS在蒸馏水中制备成100μM储备溶液。将囊泡稀释成在2mL缓冲溶液中含24μM脂质,所述缓冲溶液含有10mM HEPES、10mM MES、10mM乙酸按、130mM NaCl,其中pH值为2.5~11。加入等份的TNS溶液以产生lμM的终浓度,并且在涡旋混合之后,在室温下使用321nm和445nm的激发波长和发射波长在SLM Aminco Series 2发光分光光度计中测量荧光强度。对荧光数据应用S形最佳拟合分析,并将pKa测量为产生半数最大荧光强度的pH。
实施例85
使用体内荧光素酶mRNA表达的啮齿动物模型测定含有各种阳离子脂质的脂质纳米颗粒制剂的效能
为了比较的目的,如实施例83所述,使用有序混合方法,将这些脂质也用于配制含有FLuc mRNA(L-6107)的脂质纳米颗粒。使用以下摩尔比来配制脂质纳米颗粒:50%阳离子脂质/10%二硬脂酰磷脂酰胆碱(DSPC)/38%胆固醇/2%氘代PEG脂质。如实施例83所述,在经由尾静脉注射施用之后的5小时,通过测量肝脏中的荧光素酶表达来确定相对活性。在0.3和1.0mg mRNA/kg的剂量下比较所述活性,并表达成在如实施例83所述的施用之后5小时测量的ng荧光素酶/g肝脏。实施例83及84结果如表2所示。
表2 包含新型PEG脂质的mRNA组合物的效能研究
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对公开专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (25)
- 如权利要求1所示的氘代聚乙二醇脂质,R 1、R 2、R 3均有独立性,当R 1和R 2均为“HHH”时,R 3不能为“HH”,当R 3为“HH”组合时,R 1、R 2其中一个不能为HHH组合。
- 如权利要求1-2所示的氘代聚乙二醇脂质,R 1、R 2、R 3各自独立地为DDD、DD。
- 如权利要求1所示的氘代聚乙二醇脂质,n的平均值为40~50,更优的为45。
- 如权利要求1-2所述的氘代甲基聚乙二醇类化合物的制备方法,其中包括下列步骤:1)在酰氯试剂的作用下,氘代通式化合物dPEG-A-1先生成酰氯,接着在氨水的作用下,进行酰胺化反应,得到氘代通式中间体dPEG-A-3;2)在还原剂的作用下,氘代通式中间体dPEG-A-3进行还原反应,得到氘代通式中间体dPEG-A-4;3)按照步骤1)的方法,氘代通式中间体dPEG-A-4与通式中间体dPEG-A-1进行酰胺化反应,得到氘代通式中间体dPEG-A-5;4)按照步骤2)的方法,氘代通式中间体dPEG-A-5进行还原反应,得到氘代通式中间体dPEG-A-6;5)有机溶剂中,在碱催化作用下,氘代通式中间体dPEG-A-6与氘代通式化合物dPEG-A-7进行酰胺化反应,得到通式A的氘代聚乙二醇脂质化合 物;通式A的合成路线。
- 如权利要求6所示的氘代聚乙二醇脂质,R 1、R 2、R 3、R4、R5均有独立性,当R 1、R 2均为“HHH”组合,R 4为“H”组合时,R 3、R 5不能同时为“HH”;当R 3、R 5均为“HH”组合,R 4为“H”组合时,R 1、R 2不能同时为“HHH”组合;当R 1、R 2均为“HHH”组合,R 3、R 5均为“HH”组合时、R 4不能为“H”组合。
- 如权利要求6所示的氘代聚乙二醇脂质,R 1、R 2、R 3、R 4、R 5各自独立地为”DDD”、”DD”、”D”的组合。
- 如权利要求6所示的氘代聚乙二醇脂质,n的平均值为40~50,更优的为45。
- 权利要求1~10中任一项所述的化合物和治疗剂和/或预防剂的组合物。
- 如权利要求11所述的组合物,其还包含选自中性脂质、类固醇以及阳离子的脂质中的一种或多种赋形剂。
- 如前述权利要求12所述的组合物,其中所述组分中的中性脂质选自以下的一种或多种物质混合:1,2-二硬脂酰基-sn-甘油-3-磷酸胆碱(DSPC)、1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱(DPPC)、1,2-二肉豆寇基-sn-甘油-磷酸胆碱(DMPC)、1,2-二油酰基-sn-甘油-3-磷酸胆碱(DOPC)、1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱(POPC)、1,2-二油酰基-sn-甘油-3-磷酸乙醇胺(DOPE)和鞘磷脂(SM)。
- 如前述权利要求12所述的组合物,其中所述中性脂质为DSPC。
- 如前述权利要求11-12所述的组合物,其中所述组分中的类固醇选自以下一种或多种物质混合:胆固醇、粪固醇、谷固醇、麦角固醇、菜油固醇、豆 固醇、菜籽固醇、番茄碱、熊果酸、α-生育酚。
- 如前述权利要求15所述的组合物,其中所述类固醇为胆固醇。
- 如前述权利要求11-16所述的组合物,其中所述组分中的阳离子脂质选自以下的一种或多种物质混合:4-(N,N-二甲基氨基)丁醇(6Z,9Z,28Z,31Z)-庚三十碳-6,9,28,31-四烯-19-基酯(DLin-MC3-DMA)、十七烷-9-基-8-((2-羟乙基)(6-氧代-6-((癸氧基)己基)氨基)辛酸酯(SM-102)、((4-羟基丁基)氮杂-乙基)双(己烷-6,1-二基)双(2-己基癸酸酯)(ALC-0315),4-(N-2-(N,N-二(2-羟基十二基)乙胺基)-1-N(2-N(2-乙胺基-(2-(N,N-二(2-羟基十二基))-2羟基十二基)乙胺基哌嗪(C12-200)。
- 如前述权利要求中17所述的组合物,其中所述阳离子脂质为((4-羟基丁基)氮杂-乙基)双(己烷-6,1-二基)双(2-己基癸酸酯)(ALC-0315)、十七烷-9-基-8-((2-羟乙基)(6-氧代-6-((癸氧基)己基)氨基)辛酸酯(SM-102)。
- 如前述权利要求中任一项所述的组合物,其中所述治疗剂和/或预防剂是能够引起免疫响应的疫苗或化合物,其中包括核酸。
- 如前述权利要求11的组合物,其中所述核酸为RNA,其选自以下组成:siRNA、aiRNA、miRNA、dsRNA、shRNA、mRNA以及其混合物。
- 如前述权利要求22的组合物,其中所述RNA为mRNA。
- 向有需要的受试者施用治疗剂和/或预防剂的方法,所述方法包括制备或提供上述权利要求中任一项所述的组合物,并向所述对象施用所述组合物。
- 如前述权利要求中任一项所述的受试者为哺乳动物或人。
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US20210252138A1 (en) * | 2020-02-14 | 2021-08-19 | Merck Sharp & Dohme Corp. | Hpv vaccine |
CN113402405A (zh) * | 2021-04-08 | 2021-09-17 | 厦门赛诺邦格生物科技股份有限公司 | 一种阳离子脂质、含该阳离子脂质的脂质体、含该脂质体的核酸药物组合物及其制剂和应用 |
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CN102245023A (zh) * | 2008-11-14 | 2011-11-16 | 康瑟特制药公司 | 取代的二氧代哌啶基邻苯二甲酰亚胺衍生物 |
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