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CN115710193A - Novel cationic lipid compounds - Google Patents

Novel cationic lipid compounds Download PDF

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CN115710193A
CN115710193A CN202110970112.XA CN202110970112A CN115710193A CN 115710193 A CN115710193 A CN 115710193A CN 202110970112 A CN202110970112 A CN 202110970112A CN 115710193 A CN115710193 A CN 115710193A
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黄才古
黄铁强
王帅
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Guangzhou Anovent Pharmaceutical Co Ltd
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Guangzhou Anovent Pharmaceutical Co Ltd
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Abstract

The present invention relates to lipid compounds that can be used alone or in combination with other lipid components, such as neutral lipids, dotted lipids, steroids and/or their analogs, and/or polymer-conjugated lipids, to form lipid nanoparticles for the delivery of therapeutic and/or prophylactic agents. In some examples, lipid nanoparticles are used to deliver nucleic acids, such as messenger RNA and/or anti-mrnaAnd (3) sense RNA. Also provided are methods of using such lipid nanoparticles for the treatment and/or prevention of various diseases, wherein the compounds have the following structural formula I:
Figure RE-RE-DDA0003300734440000011
or a salt or isomer thereof or an N-oxide thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 And R 8 As defined herein.

Description

Novel cationic lipid compounds
Technical Field
The present invention provides novel cationic lipids that can be used in combination with other lipid components (such as neutral lipids, steroids, and polymer-conjugated lipids) to form a nucleic acid mRNA lipid nanoparticle composition for delivering one or more therapeutic and/or prophylactic agents to mammalian cells or organs and/or for producing polypeptides in mammalian cells or organs. In addition to the novel lipids, the lipid nanoparticle compositions of the present invention may include one or more cationic and/or ionizable amino lipids, neutral lipids including polyunsaturated lipids, polymer-conjugated lipids, steroids, and/or therapeutic and/or prophylactic agents in a specific ratio.
Background
Effective targeted delivery of biologically active substances such as small molecule drugs, proteins and nucleic acids presents a long-standing medical challenge. In particular, 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.
Studies have shown that bioactive substances such as small molecule drugs, proteins and nucleic acids can be efficiently delivered to cells and/or intracellular compartments using lipid-containing nanoparticle compositions, liposomes and liposome complexes as delivery vehicles. These compositions generally comprise one or more "cationic" lipids, neutral lipids (e.g., phospholipids), structural lipids (e.g., steroids), and/or polyethylene glycol-containing lipids (polymer-conjugated lipids) including polyunsaturated lipids. Cationic lipids include, for example, amine-containing lipids that can be easily protonated.
However, the use of oligonucleotides in a therapeutic setting currently faces two problems. First, free RNA is susceptible to nuclease digestion in plasma. Second, the ability of free RNA to enter intracellular compartments where relevant translation mechanisms exist is limited. Lipid nanoparticles formed from cationic lipids with other lipid components (such as neutral lipids, cholesterol, PEG, pegylated lipids, and oligonucleotides) have been used to prevent degradation of RNA in plasma and to promote cellular uptake of oligonucleotides.
There remains a need for improved cationic lipids and lipid nanoparticles for delivering oligonucleotides. The improved lipid nanoparticles would 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. In addition, these preferred lipid-nucleic acid particles should be well-tolerated and provide a sufficient therapeutic index such that patient treatment at an effective dose of the nucleic acid does not result in unacceptable toxicity and/or risk to the patient. The present invention provides these and related advantages.
BRIEF SUMMARY OF THE PRESENT DISCLOSURE
The present invention provides the following novel compounds and methods involving these compounds:
in a first aspect, the present invention relates to compounds of the following structural formula (I):
Figure BDA0003225633210000021
or an N-oxide thereof, or a salt or isomer thereof.
Wherein R in the structural formula "I 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 And R 8 Combinations of 2 "hydrogen" isotopes (including isotopes "protium" and "deuterium") each independently, as embodied in combinations of "HH", "HD" and "DD";
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 All have independence, but can not be simultaneously 'HH', i.e., a combination containing at least one 'HD', and the specific combination cases are divided into 14 cases, including a combination containing 1 'D', a combination containing 2 'D', a combination containing 3 'D', a combination containing 4 'D', a combination containing 5 'D', a combination containing 6 'D', a combination containing 7 'D', a combination containing 8 'D', a combination containing 9 'D', a combination containing 10 'D', a combination containing 11 'D', a combination containing 12 'D', a combination containing 13 'D' and a combination containing 14 'D'.
In various embodiments, the compound has one of the structures shown in table 1 below
Representative compounds of Table 1
Figure BDA0003225633210000022
Figure BDA0003225633210000031
Figure BDA0003225633210000041
Figure BDA0003225633210000051
Figure BDA0003225633210000061
Figure BDA0003225633210000071
Figure BDA0003225633210000081
Figure BDA0003225633210000091
Figure BDA0003225633210000101
Figure BDA0003225633210000111
Figure BDA0003225633210000121
Figure BDA0003225633210000131
Figure BDA0003225633210000141
Figure BDA0003225633210000151
In some embodiments, compositions are provided comprising any one or more of the compounds of structural formula (I) and a therapeutic and/or prophylactic agent.
In some embodiments, compositions are provided comprising any one or more of the compounds of structure (I) and a therapeutic and/or prophylactic agent. In some embodiments, the composition comprises any one of the compounds of structure (I) and a therapeutic and/or prophylactic agent and one or more excipients selected from the group consisting of neutral lipids, steroids, and polymer-conjugated lipids. Other pharmaceutically acceptable excipients and/or carriers are also included in various embodiments of the compositions.
In some embodiments, the neutral lipid is selected from 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1, 2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), sphingomyelin (SM), and mixtures thereof. In some embodiments, it is preferred that the neutral lipid is 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC).
In some embodiments, the steroid is selected from the group consisting of cholesterol, coprosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, alpha-tocopherol, and mixtures thereof. In some embodiments, it is preferred that the steroid is cholesterol.
In some embodiments, the pegylated lipid is 1, 2-dimyristoyl-sn-glyceromethoxypolyethylene glycol (PEG-DMG)
In some embodiments, the composition ratio ranges are as follows: about 10-60 mol% of the compound, about 0-30 mol% of a neutral lipid, about 10-55 mol% of a steroid, and about 0-10 mol% of a polymer-conjugated lipid.
In some embodiments of the foregoing composition, the therapeutic and/or prophylactic agent comprises a nucleic acid. Wherein the nucleic acid is RNA selected from the group consisting of: siRNA, airRNA, miRNA, dsRNA, shRNA, mRNA and mixtures thereof. In some embodiments, the RNA is selected from mRNA.
In other various embodiments, the invention relates to a method of administering a therapeutic and/or prophylactic agent to a subject in need thereof, the method comprising preparing or providing any of the above compositions and administering the composition to the subject.
For administration purposes, the compounds of the invention (typically in the form of lipid nanoparticles in combination with a therapeutic and/or prophylactic agent) may be administered as the drug substance or may be formulated as a pharmaceutical composition. The pharmaceutical compositions of the present invention comprise a compound of structure (I) and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of structure (I) 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.
Administration of the compositions of the present invention may be by any acceptable manner of administration of the agents for similar utility. The pharmaceutical composition of the present invention may 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. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intradermal, intrasternal injection or infusion techniques. The pharmaceutical compositions of the present invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a subject. The composition to be administered to a subject or patient is in the form of one or more dosage units, wherein a tablet may be a single dosage unit and a container of a compound of the invention in aerosol form may contain a plurality of dosage units. Current methods of preparing such dosage forms are known or will be apparent to those skilled in the art. In any event, the composition to be administered will contain a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, in order to treat the relevant disease or condition in accordance with the teachings of the present invention.
The pharmaceutical compositions of the present invention may be in solid or liquid form. In one aspect, the carrier is a microparticle, such that the composition is in the form of a tablet or powder. The carrier may be a liquid, in which case the composition is an oral syrup or an injectable liquid or aerosol, which is suitable for administration by inhalation.
When intended for oral administration, the pharmaceutical composition is preferably in solid or liquid form, wherein forms considered herein to be solid or liquid include semi-solid, semi-liquid, suspension, and gel forms.
As solid compositions for oral administration, the pharmaceutical compositions may be formulated into the form of powders, granules, compressed tablets, pills, capsules, chewing gums, wafers, and the like. Such solid compositions will typically contain one or more inert diluents or edible carriers. Additionally, one or more of a binder, such as gelatin, cellulose, and the like; excipients, such as lactose and the like; disintegrating agents such as alginic acid and the like; lubricants, such as magnesium stearate and the like; glidants such as silicone gel and the like; sweetening agents, such as sucrose or saccharin; flavoring agents such as herba Menthae; and a colorant.
When the pharmaceutical composition is in the form of a capsule, it may contain a liquid carrier other than the above-mentioned types of materials, such as polyethylene glycol or oil.
The pharmaceutical composition may be in the form of a liquid, such as a syrup, solution, emulsion or suspension. As two examples, the liquid may be for oral administration or for injection delivery. When intended for oral administration, the compositions of the present invention contain, in addition to the compounds of the present invention, one or more of sweetening agents, preserving agents, coloring/colorizing agents and taste-enhancing agents. In compositions for administration by injection, one or more of surfactants, preservatives, wetting agents, dispersing agents, suspending agents, buffers, stabilizers, and isotonic agents may be included.
The liquid pharmaceutical compositions of the present invention, whether in solution, suspension or other similar form, may include one or more of the following adjuvants, such as sterile diluents, e.g., water for injection, saline solution, preferably normal saline, ringer's solution, isotonic sodium chloride; non-volatile oils such as synthetic monoglycerides or diglycerides which may be used as a solvent or suspending medium, polyethylene glycols, glycerol, propylene glycol or other solvents; antibacterial agents such as methyl paraben vinegar; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers such as acetates, squarates or phosphates; and agents for regulating tonicity, such as sodium chloride or dextrose; agents used as cryoprotectants, such as sucrose or trehalose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. The injectable pharmaceutical composition is preferably sterile.
The pharmaceutical compositions of the invention may be intended for topical administration, in which case the carrier may suitably comprise a solution base, an emulsion base, an ointment base or a hydrocolloid base. The matrix may comprise one or more of: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. The thickening agent may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may comprise a transdermal patch or an iontophoretic device.
The pharmaceutical compositions of the present invention may include various materials that modify the physical form of the solid or liquid dosage unit. The composition may include a material that forms a shell around the active ingredient. The material forming the coating is generally inert and may be, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredient may be encapsulated in a gelatin capsule.
Pharmaceutical compositions of the invention in solid or liquid form may include agents that bind to the compounds of the invention and thereby facilitate delivery of the compounds. Suitable agents that can function with this capability include monoclonal or polyclonal antibodies or proteins.
The pharmaceutical compositions of the present invention may be comprised of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from systems of a colloidal nature to systems consisting of pressurized packaging. Delivery may be by liquefied or compressed gas, or by a suitable pump system for dispersing the active ingredient. Aerosols of the compounds of the invention may be delivered as a single phase, biphasic system, or triphasic system for delivery of the active ingredient. The delivery of the aerosol includes the necessary containers, activators, valves, sub-containers, etc., which together may form a kit. One skilled in the art can determine the preferred aerosol without undue experimentation.
The pharmaceutical compositions of the present invention may be prepared by methods well known in the pharmaceutical art. Pharmaceutical compositions intended for administration by injection may be prepared by combining the lipid nanoparticles of the present invention in solution with sterile distilled water or other carrier. Surfactants may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that interact non-covalently with the compounds of the present invention in order to facilitate dissolution or uniform suspension of the compounds in an aqueous delivery system.
The compositions of the present invention, or pharmaceutically acceptable salts thereof, are administered in therapeutically effective amounts, which will vary depending on a variety of factors, including the activity of the particular therapeutic agent employed; metabolic stability and length of action of the therapeutic agent; the age, weight, general health, sex, and diet of the subject; the mode and time of administration; the rate of excretion; a pharmaceutical composition; severity of the particular case, etc.
The compositions of the present invention may also be administered simultaneously with, before or after the administration of one or more other therapeutic agents. Such combination therapies include the administration of a single pharmaceutical dosage formulation of a composition of the present invention and one or more additional active agents, as well as the administration of a composition of the present invention and each active agent in its own separate pharmaceutical dosage formulation. For example, the compositions of the invention and other active agents can be administered to a subject together in a single oral dosage composition (e.g., a tablet or capsule), or each agent can be administered in a different oral dosage formulation. When different dosage formulations are employed, the compound of the invention and one or more additional active agents may be administered at substantially the same time, or sequentially at staggered times; it is understood that combination therapy encompasses all of these dosing regimens.
The structure modification and design of the novel deuterated cationic lipid compound realize more advantageous physicochemical properties including more appropriate pKa and better chemical stability, and the novel deuterated cationic lipid compound is used for mRNA nanoliposome compositions, can realize more effective combination and delivery of ionic nucleic acid drugs, has more stable chemical structure, is convenient to synthesize and is beneficial to development as a pharmaceutical adjuvant.
Methods for preparing the above compounds and compositions are described below, and/or are known in the art.
One skilled in the art will recognize that in the methods described herein, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, and carboxylic acid. Suitable protecting groups for hydroxyl include trialkylsilyl or diarylalkylsilyl, tetrahydrofuranyl, benzyl, and the like. Suitable protecting groups for amino include tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acids include hydrocarbyl, aryl or arylalkyl esters. Protecting groups may be added or removed according to standard techniques known to those skilled in the art and described herein.
One skilled in the art will also recognize that while such protected derivatives of the compounds of the present invention may not be pharmaceutically active thereby, they may be administered to a mammal and thereafter metabolized in vivo to form the compounds of the present invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Prodrugs of the compounds of the invention are therefore included within the scope of the invention.
Furthermore, all compounds of the invention in free base or free acid form can be converted into their pharmaceutically acceptable salts by treatment with a suitable inorganic or organic base or acid according to methods known to those skilled in the art. Salts of the compounds of the present invention may be formed by conversion to their free base or acid by standard techniques.
The following examples are provided for the purpose of illustration and not limitation.
The following examples, unless otherwise indicated, all solvents and reagents used were commercially available and used as received.
The procedure described below can be used to synthesize compound I in table 1.
The following abbreviations are used herein:
Figure BDA0003225633210000201
Detailed Description
Example 1:
representative routes
Synthesis of Compound 24
Figure BDA0003225633210000211
1) Synthesis of Compound 24-3
Figure BDA0003225633210000212
Chemical formula C 22 H 40 D 3 BrO 2
Molecular weight 422.51
In sequence to 2-d 1 Hexyl decanoic acid (3.86g, 15.0 mmol) and 1-d 1 Bromo-n-hexanol-5-d 1 EDC.HCl (EDC.HCl) (10.0 mmol) is added to the DCM mixture2.08g, 11.0mmol), DIEA (5.30 ml, 30.0mmol), DMAP (0.18g, 1.5mmol). After 24 hours of reaction at room temperature, the reaction mixture was diluted with DCM, washed with a saturated aqueous sodium bicarbonate solution and a diluted aqueous hydrochloric acid solution in this order, dried over magnesium sulfate, filtered and concentrated, and the residue obtained was purified by a silica gel column (0 to 15% ethyl acetate/n-hexane). Compound 24-3 (3.16g, 75%) was obtained.
2) Synthesis of Compound 24-5
Figure BDA0003225633210000221
The chemical formula is as follows: c 26 H 49 D 4 NO 3
Molecular weight: 431.74
Mixing compound 24-3 (4.22g, 10.0mmol) with 10ml of ethanol, adding 4-d 4 2-aminobutanol (2.71g, 30.0 mmol), and reacted at room temperature for 4 hours. Vacuum concentrating system, adding ethyl acetate and water to the residue, separating the organic phase, drying with anhydrous sodium sulfate, vacuum concentrating, passing the residue through silica gel column (0-100% (1% NH) 4 OH, 20% meoh in dichloromethane) purification. Compound 24-5 (2.96g, 69%) was obtained.
3) Synthesis of Compound 24-6
Figure BDA0003225633210000222
The chemical formula is as follows: c 22 H 42 DBrO 2
Molecular weight: 420.49
The compound 24-6 can be prepared according to the synthesis method of 24-3.
4) Synthesis of Compound 24
Figure BDA0003225633210000223
The chemical formula is as follows: c 48 H 90 D 5 NO 5
Molecular weight: 771.32
To a mixture of the compounds 24-5 (0.43g, 1.0 mmol) and 24-6 (0.63g, 1.5 mmol) in acetonitrile in this order was added K 2 CO 3 (0.27g, 2.0 mmol) and potassium iodide were heated to 65 ℃ and stirred for 24 hours, the solvent was concentrated under reduced temperature and pressure, the residue was dissolved in ethyl acetate, and the organic phase was washed with a saturated aqueous salt solution. After drying over anhydrous sodium sulfate, it was concentrated in vacuo. The residue was passed through a silica gel column (0-100% (1% 4 OH, 20% MeOH in dichloromethane) to yield compound 24 (0.69g, 89%). C 48 H 90 D 5 NO 5 ,Ms m/z:[M+H + ]771.6； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.60(t, 2H)，4.14～3.78(t,3H)，2.55～2.13(br.m,5H)，1.72～1.40(m,18H)，1.37～1.23 (m,50H)，0.87(m,12H)。
Example 2:
synthesis of Compound 1
Figure BDA0003225633210000231
The chemical formula is as follows: c 48 H 94 DNO 5
Molecular weight: 767.30
Compound 1 can be synthesized according to the representative route described in example 1.
C 48 H 94 DNO 5 ,Ms m/z:[M+H + ]767.6； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.14 (t,1H)，4.10～3.45(t,5H)，3.01～2.13(br.m,8H)，1.60～1.40(m,18H)，1.37～1.23 (m,50H)，0.87(m,12H)。
Example 3:
synthesis of Compound 2
Figure BDA0003225633210000241
The chemical formula is as follows: c 48 H 94 DNO 5
Molecular weight: 767.30
Compound 1 can be synthesized according to the representative route described in example 1.
C 48 H 94 DNO 5 ,Ms m/z:[M+H + ]767.6； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.14 (t,1H)，4.10～3.45(t,6H)，3.01～2.13(br.m,7H)，1.60～1.40(m,18H)，1.37～1.23 (m,50H)，0.87(m,12H)。
Example 4:
synthesis of Compound 3
Figure BDA0003225633210000242
The chemical formula is as follows: c 48 H 94 DNO 5
Molecular weight: 767.30
Compound 1 can be synthesized according to the representative route described in example 1.
C 48 H 94 DNO 5 ,Ms m/z:[M+H + ]767.6； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.14 (t,1H)，4.13～3.43(t,6H)，3.00～2.10(br.m,7H)，1.60～1.40(m,18H)，1.37～1.23 (m,50H)，0.87(m,12H)。
Example 5:
synthesis of Compound 4
Figure BDA0003225633210000251
The chemical formula is as follows: c 48 H 94 DNO 5
Molecular weight: 767.30
Compound 1 can be synthesized according to the representative route described in example 1.
C 48 H 94 DNO 5 ,Ms m/z:[M+H + ]767.6； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.14 (t,1H)，4.10～3.45(t,5H)，3.01～2.13(br.m,8H)，1.60～1.40(m,18H)，1.37～1.23 (m,50H)，0.87(m,12H)。
Implementation 6:
synthesis of Compound 5
Figure BDA0003225633210000252
The chemical formula is as follows: c 48 H 94 DNO 5
Molecular weight: 767.30
Compound 1 can be synthesized according to the representative route described in example 1.
C 48 H 94 DNO 5 ,Ms m/z:[M+H + ]767.6； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.14 (t,1H)，4.10～3.35(t,6H)，3.13～2.13(br.m,7H)，1.60～1.40(m,18H)，1.37～1.23 (m,50H)，0.87(m,12H)。
Example 7:
synthesis of Compound 6
Figure BDA0003225633210000261
The chemical formula is as follows: c 48 H 93 D 2 NO 5
Molecular weight: 768.30
Compound 1 can be synthesized according to the representative route described in example 1.
C 48 H 93 D 2 NO 5 ,Ms m/z:[M+H + ]768.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.14 (t,1H)，4.12～3.38(t,4H)，3.22～2.20(br.m,8H)，1.60～1.40(m,18H)，1.37～1.23 (m,50H)，0.87(m,12H)。
Example 8:
synthesis of Compound 7
Figure BDA0003225633210000262
The chemical formula is as follows: c 48 H 93 D 2 NO 5
Molecular weight: 768.30
Compound 1 can be synthesized according to the representative route described in example 1.
C 48 H 93 D 2 NO 5 ,Ms m/z:[M+H + ]768.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.24 (t,1H)，4.22～3.42(t,6H)，3.22～2.20(br.m,6H)，1.65～1.45(m,18H)，1.37～1.23 (m,50H)，0.87(m,12H)。
Example 9:
synthesis of Compound 8
Figure BDA0003225633210000271
The chemical formula is as follows: c 48 H 93 D 2 NO 5
Molecular weight: 768.30
Compound 1 can be synthesized according to the representative route described in example 1.
C 48 H 93 D 2 NO 5 ,Ms m/z:[M+H + ]768.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.33 (t,1H)，4.12～3.32(t,5H)，3.13～2.13(br.m,7H)，1.65～1.45(m,18H)，1.37～1.23 (m，50H)，0.87(m，12H)。
Example 10:
synthesis of Compound 9
Figure BDA0003225633210000272
The chemical formula is as follows: c 48 H 93 D 2 NO 5
Molecular weight: 768.30
Compound 1 can be synthesized according to the representative route described in example 1.
C 48 H 93 D 2 NO 5 ,Ms m/z:[M+H + ]768.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.23 (t,1H)，4.15～3.35(t,6H)，3.16～2.16(br.m,6H)，1.65～1.45(m,18H)，1.37～1.23 (m,50H)，0.87(m,12H)。
Example 11:
Figure BDA0003225633210000281
the chemical formula is as follows: c 48 H 92 D 3 NO 5
Molecular weight: 769.30
Compound 1 can be synthesized according to the representative route described in example 1.
C 48 H 92 D 3 NO 5 ,Ms m/z:[M+H + ]769.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.33 (t,1H)，4.13～3.35(t,4H)，3.13～2.13(br.m,7H)，1.65～1.45(m,18H)，1.37～1.23 (m,50H)，0.87(m,12H)。
Example 12:
synthesis of Compound 11
Figure BDA0003225633210000291
The chemical formula is as follows: c 48 H 92 D 3 NO 5
Molecular weight: 769.30
Compound 1 can be synthesized according to the representative route described in example 1.
C 48 H 92 D 3 NO 5 ,Ms m/z:[M+H + ]769.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.33 (t,1H)，4.11～3.32(t,6H)，3.11～2.11(br.m,5H)，1.65～1.45(m,18H)，1.37～1.23 (m,50H)，0.87(m,12H)。
Example 13:
synthesis of Compound 12
Figure BDA0003225633210000292
The chemical formula is as follows: c 48 H 92 D 3 NO 5
Molecular weight: 769.30
Compound 12 can be synthesized according to the representative route described in example 1.
C 48 H 92 D 3 NO 5 ,Ms m/z:[M+H + ]769.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.33 (t,1H)，4.02～3.29(t,5H)，3.14～2.14(br.m,6H)，1.65～1.45(m,18H)，1.37～1.23 (m,50H)，0.87(m,12H)。
Example 14:
synthesis of Compound 13
Figure BDA0003225633210000301
The chemical formula is as follows: c 48 H 92 D 3 NO 5
Molecular weight: 769.30
Compound 13 can be synthesized according to the representative route described in example 1.
C 48 H 92 D 3 NO 5 ,Ms m/z:[M+H + ]769.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.23 (t,1H)，4.02～3.29(t,4H)，3.14～2.14(br.m,7H)，1.65～1.45(m,18H)，1.37～1.23 (m,50H)，0.87(m,12H)。
Example 15:
synthesis of Compound 14
Figure BDA0003225633210000302
The chemical formula is as follows: c 48 H 92 D 3 NO 5
Molecular weight: 769.30
Compound 14 can be synthesized according to the representative route described in example 1.
C 48 H 92 D 3 NO 5 ,Ms m/z:[M+H + ]769.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.23 (t,1H)，4.12～3.33(t,4H)，3.24～2.24(br.m,7H)，1.65～1.45(m,18H)，1.37～1.23 (m,50H)，0.87(m,12H)。
Example 16:
synthesis of Compound 15
Figure BDA0003225633210000311
The chemical formula is as follows: c 48 H 92 D 3 NO 5
Molecular weight: 769.30
Compound 15 can be synthesized according to the representative route described in example 1.
C 48 H 92 D 3 NO 5 ,Ms m/z:[M+H + ]769.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.23 (t,1H)，4.12～3.33(t,5H)，3.24～2.24(br.m,6H)，1.64～1.44(m,18H)，1.36～1.26 (m,50H)，0.87(m,12H)。
Example 17:
synthesis of Compound 16
Figure BDA0003225633210000312
The chemical formula is as follows: c 48 H 91 D 4 NO 5
Molecular weight: 770.30
Compound 16 can be synthesized according to the representative route described in example 1.
C 48 H 91 D 4 NO 5 ,Ms m/z:[M+H + ]770.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.23 (t,1H)，4.12～3.23(t,4H)，3.11～2.11(br.m,6H)，1.64～1.44(m,18H)，1.35～1.25 (m,50H)，0.87(m,12H)。
Example 18:
synthesis of Compound 17
Figure BDA0003225633210000321
The chemical formula is as follows: c 48 H 91 D 4 NO 5
Molecular weight: 770.30
Compound 17 can be synthesized according to the representative route described in example 1.
C 48 H 91 D 4 NO 5 ,Ms m/z:[M+H + ]770.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.23 (t,1H)，4.16～3.26(t,5H)，3.11～2.11(br.m,5H)，1.63～1.40(m,18H)，1.35～1.25 (m,50H)，0.87(m,12H)。
Example 19:
synthesis of Compound 18
Figure BDA0003225633210000322
The chemical formula is as follows: c 48 H 91 D 4 NO 5
Molecular weight: 770.30
Compound 18 can be synthesized according to the representative route described in example 1.
C 48 H 91 D 4 NO 5 ,Ms m/z:[M+H + ]770.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.23 (t,1H)，4.16～3.22(t,4H)，3.12～2.12(br.m,6H)，1.63～1.41(m,18H)，1.35～1.25 (m,50H)，0.87(m,12H)。
Example 20:
synthesis of Compound 19
Figure BDA0003225633210000331
The chemical formula is as follows: c 48 H 91 D 4 NO 5
Molecular weight: 770.30
Compound 19 can be synthesized according to the representative route described in example 1.
C 48 H 91 D 4 NO 5 ,Ms m/z:[M+H + ]770.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.23 (t,1H)，4.16～3.22(t,3H)，3.12～2.11(br.m,7H)，1.63～1.40(m,18H)，1.35～1.21 (m,50H)，0.87(m,12H)。
Example 21:
synthesis of Compound 20
Figure BDA0003225633210000341
The chemical formula is as follows: c 48 H 91 D 4 NO 5
Molecular weight: 770.30
Compound 20 can be synthesized according to the representative route described in example 1.
C 48 H 91 D 4 NO 5 ,Ms m/z:[M+H + ]770.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.21 (t,1H)，4.18～3.24(t,4H)，3.13～2.13(br.m,6H)，1.62～1.42(m,18H)，1.36～1.26 (m,50H)，0.88(m,12H)。
Example 22:
synthesis of Compound 21
Figure BDA0003225633210000342
The chemical formula is as follows: c 48 H 91 D 4 NO 5
Molecular weight: 770.30
Compound 21 can be synthesized according to the representative route described in example 1.
C 48 H 91 D 4 NO 5 ,Ms m/z:[M+H + ]770.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.23 (t,1H)，4.15～3.21(t,3H)，3.09～2.11(br.m,7H)，1.61～1.41(m,18H)，1.33～1.23 (m,50H)，0.88(m,12H)。
Example 23:
synthesis of Compound 22
Figure BDA0003225633210000351
The chemical formula is as follows: c 48 H 91 D 4 NO 5
Molecular weight: 770.30
Compound 22 can be synthesized according to the representative route described in example 1.
C 48 H 91 D 4 NO 5 ,Ms m/z:[M+H + ]770.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.23 (t,1H)，4.15～3.20(t,3H)，3.08～2.10(br.m,7H)，1.62～1.42(m,18H)，1.33～1.23 (m,50H)，0.88(m,12H)。
Example 24:
synthesis of Compound 23
Figure BDA0003225633210000352
The chemical formula is as follows: c 48 H 9l D 4 NO 5
Molecular weight: 770.30
Compound 23 can be synthesized according to the representative route described in example 1.
C 48 H 91 D 4 NO 5 ,Ms m/z:[M+H + ]770.7； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.23 (t,1H)，4.17～3.21(t,5H)，3.15～2.12(br.m,5H)，1.63～1.42(m,18H)，1.33～1.23 (m,50H)，0.88(m,12H)。
Example 25:
synthesis of Compound 25
Figure BDA0003225633210000361
The chemical formula is as follows: c 48 H 90 D 5 NO 5
Molecular weight: 771.30
Compound 25 can be synthesized according to the representative route described in example 1.
C 48 H 90 D 5 NO 5 ,Ms m/z:[M+H + ]771.8； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.22 (t,1H)，4.15～3.21(t,3H)，3.12～2.13(br.m,6H)，1.60～1.40(m,18H)，1.32～1.23 (m,50H)，0.88(m,12H)。
Example 26:
synthesis of Compound 26
Figure BDA0003225633210000362
Molecular weight: 771.30
Compound 26 can be synthesized according to the representative route described in example 1.
C 48 H 90 D 5 NO 5 ,Ms m/z:[M+H + ]771.8； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.22 (t,1H)，4.15～3.22(t,4H)，3.14～2.13(br.m,5H)，1.60～1.40(m,18H)，1.32～1.23 (m,50H)，0.88(m,12H)。
Example 27:
synthesis of Compound 27
Figure BDA0003225633210000371
The chemical formula is as follows: c 48 H 90 D 5 NO 5
Molecular weight: 771.30
Compound 27 can be synthesized according to the representative route described in example 1.
C 48 H 90 D 5 NO 5 ,Ms m/z:[M+H+]771.8；1H-NMR(300MHz,CDCl3)δ:ppm 4.22(t,1H)，4.14～3.21(t,3H)，3.11～2.13(br.m,6H)，1.60～1.40(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 28:
synthesis of Compound 28
Figure BDA0003225633210000372
The chemical formula is as follows: c 48 H 90 D 5 NO 5
Molecular weight: 771.30
Compound 28 can be synthesized according to the representative route described in example 1.
C 48 H 90 D 5 NO 5 ,Ms m/z:[M+H+]771.8；1H-NMR(300MHz,CDCl3)δ:ppm 4.22(t,1H)，4.14～3.20(t,3H)，3.11～2.11(br.m,6H)，1.61～1.41(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 29:
synthesis of Compound 29
Figure BDA0003225633210000381
The chemical formula is as follows: c 48 H 90 D 5 NO 5
Molecular weight: 771.30
Compound 29 can be synthesized according to the representative route described in example 1.
C 48 H 90 D 5 NO 5 ,Ms m/z:[M+H + ]771.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.22(t,1H)，4.16～3.21(t,4H)，3.12～2.11(br.m,5H)，1.61～1.41(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 30:
synthesis of Compound 30
Figure BDA0003225633210000382
The chemical formula is as follows: c 48 H 90 D 5 NO 5
Molecular weight: 771.30
Compound 30 can be synthesized according to the representative route described in example 1.
C 48 H 90 D 5 NO 5 ,Ms m/z:[M+H + ]771.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.22(t,1H)，4.16～3.21(t,5H)，3.12～2.11(br.m,4H)，1.61～1.41(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 31:
synthesis of Compound 31
Figure BDA0003225633210000391
The chemical formula is as follows: c 48 H 90 D 5 NO 5
Molecular weight: 771.30
Compound 31 can be synthesized according to the representative route described in example 1.
C 48 H 90 D 5 NO 5 ,Ms m/z:[M+H + ]771.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.22(t,1H)，4.15～3.22(t,3H)，3.11～2.10(br.m,6H)，1.60～1.40(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 32:
synthesis of Compound 32
Figure BDA0003225633210000392
Molecular weight: 771.30
Compound 32 can be synthesized according to the representative route described in example 1.
C 48 H 90 D 5 NO 5 ,Ms m/z:[M+H + ]771.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.22(t,1H)，4.14～3.22(t,6H)，3.13～2.12(br.m,3H)，1.60～1.40(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 33:
synthesis of Compound 33
Figure BDA0003225633210000401
The chemical formula is as follows: c 48 H 90 D 5 NO 5
Molecular weight: 771.30
Compound 33 can be synthesized according to the representative route described in example 1.
C 48 H 90 D 5 NO 5 ,Ms m/z:[M+H + ]771.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.22(t,1H)，4.14～3.19(t,6H)，3.13～2.13(br.m,3H)，1.61～1.41(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 34:
synthesis of Compound 34
Figure BDA0003225633210000402
The chemical formula is as follows: c 48 H 89 D 6 NO 5
Molecular weight: 772.30
Compound 34 can be synthesized according to the representative route described in example 1.
C 48 H 89 D 6 NO 5 ,Ms m/z:[M+H + ]772.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.22(t,1H)，4.16～3.22(t,5H)，3.15～2.14(br.m,3H)，1.60～1.39(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 35:
synthesis of Compound 35
Figure BDA0003225633210000411
The chemical formula is as follows: c 48 H 89 D 6 NO 5
Molecular weight: 772.30
Compound 35 can be synthesized according to the representative route described in example 1.
C 48 H 89 D 6 NO 5 ,Ms m/z:[M+H + ]772.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.22(t,1H)，4.15～3.21(t,4H)，3.14～2.14(br.m,4H)，1.61～1.39(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 36:
synthesis of Compound 36
Figure BDA0003225633210000412
Molecular weight: 771.30
Compound 36 can be synthesized according to the representative route described in example 1.
C 48 H 90 D 5 NO 5 ,Ms m/z:[M+H + ]771.8； 1 H-NMR (300MHz, CDCl3). Delta.ppm 4.21 (t, 1H), 4.16-3.21 (t, 5H), 3.15-2.12 (br.m, 4H), 1.60-1.39 (m, 18H), 1.32-1.23 (m, 50H), 0.88 (m, 12H). Example 37:
synthesis of Compound 37
Figure BDA0003225633210000421
The chemical formula is as follows: c 48 H 89 D 6 NO 5
Molecular weight: 772.30
Compound 35 can be synthesized according to the representative route described in example 1.
C 48 H 89 D 6 NO 5 ,Ms m/z:[M+H + ]772.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.21(t,1H)，4.15～3.22(t,4H)，3.14～2.14(br.m,4H)，1.61～1.38(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 38:
synthesis of Compound 38
Figure BDA0003225633210000422
The chemical formula is as follows: c 48 H 89 D 6 NO 5
Molecular weight: 772.30
Compound 38 can be synthesized according to the representative route described in example 1.
C 48 H 89 D 6 NO 5 ,Ms m/z:[M+H + ]772.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.21(t,1H)，4.14～3.21(t,3H)，3.12～2.12(br.m,5H)，1.61～1.38(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 39:
synthesis of Compound 39
Figure BDA0003225633210000431
The chemical formula is as follows: c 48 H 89 D 6 NO 5
Molecular weight: 772.30
Compound 39 can be synthesized according to the representative route described in example 1.
C 48 H 89 D 6 NO 5 ,Ms m/z:[M+H + ]772.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.23(t,1H)，4.18～3.23(t,4H)，3.14～2.14(br.m,4H)，1.60～1.38(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 40:
synthesis of Compound 40
Figure BDA0003225633210000432
The chemical formula is as follows: c 48 H 89 D 6 NO 5
Molecular weight: 772.30
Compound 40 can be synthesized according to the representative route described in example 1.
C 48 H 89 D 6 NO 5 ,Ms m/z:[M+H + ]772.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.21(t,1H)，4.16～3.20(t,2H)，3.15～2.13(br.m,6H)，1.61～1.40(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 41:
synthesis of Compound 41
Figure BDA0003225633210000441
The chemical formula is as follows: c 48 H 89 D 6 NO 5
Molecular weight: 772.30
Compound 41 can be synthesized according to the representative route described in example 1.
C 48 H 89 D 6 NO 5 ,Ms m/z:[M+H + ]772.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.25(t,1H)，4.13～3.20(t,2H)，3.11～2.11(br.m,6H)，1.61～1.38(m,18H)， 1.32～1.21(m,50H)，0.87(m,12H)。
Example 42:
synthesis of Compound 42
Figure BDA0003225633210000442
Molecular weight: 772.30
Compound 42 can be synthesized according to the representative route described in example 1.
C 48 H 89 D 6 NO 5 ,Ms m/z:[M+H + ]772.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.20(t,1H)，4.13～3.21(t,4H)，3.12～2.11(br.m,4H)，1.60～1.39(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 43:
synthesis of Compound 43
Figure BDA0003225633210000451
The chemical formula is as follows: c 48 H 89 D 6 NO 5
Molecular weight: 772.30
Compound 43 can be synthesized according to the representative route described in example 1.
C 48 H 89 D 6 NO 5 ,Ms m/z:[M+H + ]772.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～3.21(t,2H)，3.12～2.12(br.m,6H)，1.61～1.38(m,18H)， 1.32～1.21(m,50H)，0.88(m,12H)。
Example 44:
synthesis of Compound 44
Figure BDA0003225633210000452
The chemical formula is as follows: c 48 H 89 D 6 NO 5
Molecular weight: 772.30
Compound 44 can be synthesized according to the representative route described in example 1.
C 48 H 89 D 6 NO 5 ,Ms m/z:[M+H + ]772.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～3.21(t,2H)，3.13～2.13(br.m,6H)，1.60～1.40(m,18H)， 1.32～1.21(m,50H)，0.88(m,12H)。
Example 45:
synthesis of Compound 45
Figure BDA0003225633210000461
The chemical formula is as follows: c 48 H 89 D 6 NO 5
Molecular weight: 772.30
Compound 45 can be synthesized according to the representative route described in example 1.
C 48 H 89 D 6 NO 5 ,Ms m/z:[M+H + ]772.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.07(t,1H)，3.13～2.13(br.m,7H)，1.62～1.41(m,18H)，1.32～1.21 (m,50H)，0.88(m,12H)。
Example 46:
synthesis of Compound 46
Figure BDA0003225633210000462
The chemical formula is as follows: c 48 H 89 D 6 NO 5
Molecular weight: 772.30
Compound 46 can be synthesized according to the representative route described in example 1.
C 48 H 89 D 6 NO 5 ,Ms m/z:[M+H + ]772.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～3.22(t,3H)，3.15～2.13(br.m,5H)，1.61～1.40(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 47:
synthesis of Compound 47
Figure BDA0003225633210000471
The chemical formula is as follows: c 48 H 89 D 6 NO 5
Molecular weight: 772.30
Compound 47 can be synthesized according to the representative route described in example 1.
C 48 H 89 D 6 NO 5 ,Ms m/z:[M+H + ]772.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～3.20(t,5H)，3.13～2.13(br.m,3H)，1.60～1.41(m,18H)， 1.31～1.20(m,50H)，0.88(m,12H)。
Example 48:
synthesis of Compound 48
Figure BDA0003225633210000472
Molecular weight: 772.30
Compound 48 can be synthesized according to the representative route described in example 1.
C 48 H 89 D 6 NO 5 ,Ms m/z:[M+H + ]772.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.20(t,1H)，4.12～3.20(t,6H)，3.13～2.13(br.m,2H)，1.60～1.41(m,18H)， 1.32～1.22(m,50H)，0.88(m,12H)。
Example 49:
synthesis of Compound 49
Figure BDA0003225633210000481
The chemical formula is as follows: c 48 H 88 D 7 NO 5
Molecular weight: 773.33
Compound 49 can be synthesized according to the representative route described in example 1.
C 48 H 88 D 7 NO 5 ,Ms m/z:[M+H + ]773.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～3.20(t,3H)，3.13～2.13(br.m,4H)，1.60～1.40(m,18H)， 1.32～1.21(m,50H)，0.88(m,12H)。
Example 50:
synthesis of Compound 50
Figure BDA0003225633210000482
The chemical formula is as follows: c 48 H 88 D 7 NO 5
Molecular weight: 773.33
Compound 50 can be synthesized according to the representative route described in example 1.
C 48 H 88 D 7 NO 5 ,Ms m/z:[M+H + ]773.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.11～4.08(t,2H)，3.13～2.13(br.m,5H)，1.60～1.40(m,18H)， 1.32～1.21(m,50H)，0.88(m,12H)。
Example 51:
synthesis of Compound 51
Figure BDA0003225633210000491
The chemical formula is as follows: c 48 H 88 D 7 NO 5
Molecular weight: 773.33
Compound 51 can be synthesized according to the representative route described in example 1.
C 48 H 88 D 7 NO 5 ,Ms m/z:[M+H + ]773.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～4.08(t,2H)，3.14～2.12(br.m,5H)，1.61～1.40(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 52:
synthesis of Compound 52
Figure BDA0003225633210000492
The chemical formula is as follows: c 48 H 88 D 7 NO 5
Molecular weight: 773.33
Compound 52 can be synthesized according to the representative route described in example 1.
C 48 H 88 D 7 NO 5 ,Ms m/z:[M+H + ]773.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～4.09(t,2H)，3.12～2.13(br.m,5H)，1.61～1.40(m,18H)，1.32～1.21(m,50H)，0.88(m,12H)。
Example 53:
synthesis of Compound 53
Figure BDA0003225633210000501
The chemical formula is as follows: c 48 H 88 D 7 NO 5
Molecular weight: 773.33
Compound 53 can be synthesized according to the representative route described in example 1.
C 48 H 88 D 7 NO 5 ,Ms m/z:[M+H + ]773.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～4.08(t,2H)，3.14～2.13(br.m,5H)，1.61～1.40(m,18H)， 1.32～1.21(m,50H)，0.88(m,12H)。
Example 54:
synthesis of Compound 54
Figure BDA0003225633210000502
The chemical formula is as follows: c 48 H 88 D 7 NO 5
Molecular weight: 773.33
Compound 54 can be synthesized according to the representative route described in example 1.
C 48 H 88 D 7 NO 5 ,Ms m/z:[M+H + ]773.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～4.08(t,2H)，3.13～2.12(br.m,5H)，1.61～1.40(m,18H)， 1.32～1.22(m,50H)，0.88(m,12H)。
Example 55:
synthesis of Compound 55
Figure BDA0003225633210000511
The chemical formula is as follows: c 48 H 88 D 7 NO 5
Molecular weight: 773.33
Compound 55 can be synthesized according to the representative route described in example 1.
C 48 H 88 D 7 NO 5 ,Ms m/z:[M+H + ]773.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～4.09(t,2H)，3.14～2.13(br.m,5H)，1.61～1.40(m,18H)， 1.32～1.23(m,50H)，0.88(m,12H)。
Example 56:
synthesis of Compound 56
Figure BDA0003225633210000512
The chemical formula is as follows: c 48 H 87 D 8 NO 5
Molecular weight: 774.34
Compound 56 can be synthesized according to the representative route described in example 1.
C 48 H 87 D 8 NO 5 ,Ms m/z:[M+H + ]774.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～4.10(t,2H)，3.13～2.13(br.m,4H)，1.62～1.39(m,18H)， 1.32～1.21(m,50H)，0.88(m,12H)。
Example 57:
synthesis of Compound 57
Figure BDA0003225633210000521
The chemical formula is as follows: c 48 H 87 D 8 NO 5
Molecular weight: 774.34
Compound 57 can be synthesized according to the representative route described in example 1.
C 48 H 87 D 8 NO 5 ,Ms m/z:[M+H + ]774.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～4.10(t,4H)，2.23～2.13(m,2H)，1.62～1.39(m,18H)， 1.32～1.21(m,50H)，0.88(m,12H)。
Example 58:
synthesis of Compound 58
Figure BDA0003225633210000531
The chemical formula is as follows: c 48 H 86 D 9 NO 5
Molecular weight: 775.34
Compound 58 can be synthesized according to the representative route described in example 1.
C 48 H 86 D 9 NO 5 ,Ms m/z:[M+H + ]775.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～3.37(t,3H)，2.23～2.13(m,2H)，1.62～1.37(m,18H)， 1.32～1.22(m,50H)，0.88(m,12H)。
Example 59:
synthesis of Compound 59
Figure BDA0003225633210000532
The chemical formula is as follows: c 48 H 85 D 10 NO 5
Molecular weight: 776.35
Compound 59 can be synthesized according to the representative route described in example 1.
C 48 H 85 D 10 NO 5 ,Ms m/z:[M+H + ]776.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～3.37(t,3H)，2.15～2.13(m,1H)，1.62～1.38(m,18H)， 1.32～1.22(m,50H)，0.88(m,12H)。
Example 60:
synthesis of Compound 60
Figure BDA0003225633210000541
The chemical formula is as follows: c 48 H 85 D 10 NO 5
Molecular weight: 776.35
Compound 60 can be synthesized according to the representative route described in example 1.
C 48 H 85 D 10 NO 5 ,Ms m/z:[M+H + ]776.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～4.08(t,2H)，2.15～2.12(m,2H)，1.61～1.39(m,18H)， 1.32～1.21(m,50H)，0.88(m,12H)。
Example 61:
synthesis of Compound 61
Figure BDA0003225633210000542
The chemical formula is as follows: c 48 H 84 D 11 NO 5
Molecular weight: 777.36
Compound 61 can be synthesized according to the representative route described in example 1.
C 48 H 84 D 11 NO 5 ,Ms m/z:[M+H + ]777.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～4.10(t,2H)，2.15～2.13(m,1H)，1.61～1.38(m,18H)， 1.32～1.22(m,50H)，0.88(m,12H)。
Example 62:
synthesis of Compound 62
Figure BDA0003225633210000551
The chemical formula is as follows: c 48 H 84 D 11 NO 5
Molecular weight: 777.36
Compound 62 can be synthesized according to the representative route described in example 1.
C 48 H 84 D 11 NO 5 ,Ms m/z:[M+H + ]777.8； 1 H-NMR(300MHz,CDCl3)δ:ppm 4.19(t,1H)，4.12～4.10(t,2H)，2.16～2.14(m,1H)，1.61～1.39(m,18H)， 1.32～1.21(m,50H)，0.88(m,12H)。
Example 63:
synthesis of Compound 63
Figure BDA0003225633210000552
The chemical formula is as follows: c 48 H 83 D 12 NO 5
Molecular weight: 778.36
Compound 63 can be synthesized according to the representative route described in example 1.
C 48 H 83 D 12 NO 5 ,Ms m/z:[M+H + ]778.8； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.19(t,1H)，4.12～4.10(t,1H)，2.15～2.13(m,1H)，1.61～1.40(m,18H)， 1.32～1.22(m,50H)，0.88(m,12H)。
Example 64:
synthesis of Compound 64
Figure BDA0003225633210000561
The chemical formula is as follows: c 48 H 82 D 13 NO 5
Molecular weight: 779.37
Compound 64 can be synthesized according to the representative route described in example 1.
C 48 H 82 D 13 NO 5 ,Ms m/z:[M+H + ]779.8； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.19(t,1H)，2.15～2.13(m,1H)，1.61～1.41(m,18H)，1.31～1.21(m,50H)， 0.88(m,12H)。
Example 65:
synthesis of Compound 65
Figure BDA0003225633210000562
The chemical formula is as follows: c 48 H 81 D 14 NO 5
Molecular weight: 780.38
Compound 65 can be synthesized according to the representative route described in example 1.
C 48 H 81 D 14 NO 5 ,Ms m/z:[M+H + ]780.9； 1 H-NMR(300MHz,CDCl 3 )δ:ppm 4.19(t,1H)，1.61～1.38(m,18H)，1.32～1.20(m,50H)，0.88(m,12H)。
Example 66
Luciferase mRNA in vivo evaluation using lipid nanoparticle composition
The cationic lipid, DSPC, cholesterol and PEG-lipid were dissolved in ethanol at a molar ratio of 50. Lipid Nanoparticles (LNPs) were prepared at a weight ratio of total lipid to mRNA of about 10. Briefly, mRNA was diluted to 0.15 mg/ml in 10ml to 50ml citrate buffer (pH = 4). The lipid ethanol solution and the mRNA aqueous solution were mixed using a syringe pump at a ratio of about 1. The ethanol was then removed and the external buffer was replaced by PBS by dialysis. Finally, the lipid nanoparticles were filtered through a sterile filter of 0.2um pore size. The particle size of the lipid nanoparticles as determined by quasielastic light scattering using a Malvern Zetasizer Nano ZS was approximately 65-105nm in diameter, and in some cases approximately 75-100 nm in diameter.
The study was carried out on 6-8 week old female C57BL/6 mice, 8-10 week old CD-1 mice, according to the guidelines set by the national institute of science and technology. Various doses of mRNA lipid nanoparticles were administered systemically by tail vein injection and animals were euthanized at specific time points (e.g., 5 hours) post-administration. Liver and spleen were collected in pre-weighed tubes, weighed, immediately snap frozen in liquid nitrogen, and stored at-80 ℃ until used for analysis.
For the liver, approximately 50mg was cut for analysis in 2mL FastPrep tubes (MP Biomedicals, solon OH). 1/4 "ceramic spheres (MP Biomedicals) were added to each tube, and 500. Mu.L of Glo lysis buffer-GLB (Promega, madison Wis.) equilibrated to room temperature was added to the liver tissue. Liver tissue was homogenized at 2x6.0m/s for 15 seconds using a FastPrep24 instrument (MP Biomedicals). The homogenate was incubated at room temperature for 5 min, then diluted 1. Specifically, 50uL of the diluted tissue homogenate was reacted with 50uL of SteadyGlo substrate, shaken for 10 seconds, followed by incubation for 5 minutes, and then quantified using a SpectraMAX _ L chemiluminescence-type microplate reader (Meigu Mole Co., ltd.). The amount of the protein determined was determined by using BCA protein quantification kit (shanghai chromophil medical science and technology ltd). The Relative Luminescence Units (RLU) were then normalized to the total ug of protein assayed. To convert RLU to μ g luciferase, a standard curve was generated with QuantiLum recombinant luciferase (Promega).
Fluciferase protein will be expressed by Fluuc mRNA from Trilink Biotechnologies (L-6107), which was originally isolated from fireflies (Photinus pyralis). Fluc is commonly used in mammalian cell cultures to measure gene expression and cell viability. Which emits bioluminescence in the presence of the substrate luciferin. This capped and polyadenylated mRNA was completely replaced by 5-methylcytidine and pseudouridine.
Example 67
Determination of pKa of the prepared lipid
The pKa of the formulated cationic lipid correlates with the effect of the LNP used to deliver the nucleic acid. The preferred pKa range is from 5 to 7. The pKa of each cationic lipid was determined in lipid nanoparticles using an assay based on the fluorescence of 2- (p-toluidinyl) -6-naphthalenesulfonic acid (TNS). Lipid nanoparticles comprising cationic lipids/DSPC/cholesterol/PEG lipids (50/10/38/2 mol%) at a concentration of 0.4mM total lipid in PBS were prepared using an ordered method as described in example 64. TNS was prepared as a 100uM stock solution in distilled water. The vesicles were diluted to 24uM lipid in 2mL of buffer containing 10mM HEPES, 10mM MES, 10mM acetic acid, 130mM NaCl, pH 2.5-11. Aliquots of the TNS solution were added to give a final concentration of l uM, 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 321nm and 445 nm. Sigmoidal best fit analysis was applied to the fluorescence data and pKa was measured as the pH yielding half the maximum fluorescence intensity.
Example 68
Determination of the efficacy of lipid nanoparticle formulations containing various cationic lipids using rodent models of luciferase mRNA expression in vivo
For comparison purposes, these lipids were also used to formulate lipid nanoparticles containing FLuc mRNA (L-6107) using an ordered mixing method, as described in example 66. Lipid nanoparticles were formulated using a molar ratio of 50% cationic lipid/10% Distearoylphosphatidylcholine (DSPC)/38% cholesterol/2% PEG lipid ("PEG-DMG", i.e., (1- (monomethoxy-polyethylene glycol) -2, 3-dimyristoyl glycerol, average PEG molecular weight 2000.) the relative activity was determined by measuring luciferase expression in liver 5 hours after administration via tail vein injection as described in example 66. The activities were compared at doses of 0.3 and 1.0mg mRNA/kg and expressed as ng luciferase/g liver measured 5 hours after administration as described in example 66. Examples 67 and 68 results are shown in Table 2.
Table 2 comparison of lipids exhibiting Activity with mRNA
Figure BDA0003225633210000591
Figure BDA0003225633210000601
Figure BDA0003225633210000611
Figure BDA0003225633210000621
Figure BDA0003225633210000631
Figure BDA0003225633210000641
Figure BDA0003225633210000651
Figure BDA0003225633210000661
Figure BDA0003225633210000671
Figure BDA0003225633210000681
Figure BDA0003225633210000691
Figure BDA0003225633210000701
Figure BDA0003225633210000711
Figure BDA0003225633210000721
Figure BDA0003225633210000731
Figure BDA0003225633210000741
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the patent disclosure. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent should be subject to the appended claims.

Claims (15)

1. A compound of formula "I":
Figure FDA0003225633200000011
or an N-oxide thereof, or a salt or isomer thereof.
Wherein R in the structural formula "I 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 And R 8 All are independent combinations of 2 "hydrogen" isotopes (including the isotopes "protium" and "deuterium"), embodied as combinations of "HH", "HD" and "DD";
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 All have independence, but can not be simultaneously 'HH', i.e., a combination containing at least one 'HD', and the specific combination cases are divided into 14 cases, including a combination containing 1 'D', a combination containing 2 'D', a combination containing 3 'D', a combination containing 4 'D', a combination containing 5 'D', a combination containing 6 'D', a combination containing 7 'D', a combination containing 8 'D', a combination containing 9 'D', a combination containing 10 'D', a combination containing 11 'D', a combination containing 12 'D', a combination containing 13 'D' and a combination containing 14 'D'.
2. A compound selected from the compounds in table 1.
3. A composition comprising a compound according to any one of claims 1 to 2 and a therapeutic and/or prophylactic agent.
4. The composition of claim 3, further comprising one or more excipients selected from the group consisting of neutral lipids, steroids, and polymer-conjugated lipids.
5. A composition as claimed in claim 4, wherein the neutral lipids of the component are selected from a mixture of one or more of: 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1, 2-dimyristyl-sn-glycero-phosphocholine (DMPC), 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and Sphingomyelin (SM).
6. The composition of claim 5, wherein the neutral lipid is DSPC.
7. A composition as claimed in any one of claims 4 to 6, wherein the steroid in the component is selected from a mixture of one or more of: cholesterol, coprosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, alpha-tocopherol.
8. The composition of claim 7, wherein the steroid is cholesterol.
9. The composition of claims 4-8, wherein the polymer-conjugated lipid in the component is a pegylated lipid.
10. The composition of claim 9, wherein the pegylated lipid is 1, 2-dimyristoyl-sn-glyceromethoxypolyethylene glycol (PEG-DMG)
11. The composition of any one of the preceding claims, wherein the therapeutic and/or prophylactic agent is a vaccine or compound capable of eliciting an immune response, including nucleic acids.
12. The composition of claim 11, wherein the nucleic acid is RNA selected from the group consisting of: siRNA, airRNA, miRNA, dsRNA, shRNA, mRNA and mixtures thereof.
13. The composition of claim 12, wherein the RNA is mRNA.
14. A method of administering a therapeutic and/or prophylactic agent to a subject in need thereof, the method comprising preparing or providing the composition of any one of the preceding claims, and administering the composition to the subject.
15. The subject of any one of the preceding claims is a mammal or a human.
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