CN117486738A - Lipid molecule and composition thereof - Google Patents

Lipid molecule and composition thereof Download PDF

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Publication number
CN117486738A
CN117486738A CN202311345249.1A CN202311345249A CN117486738A CN 117486738 A CN117486738 A CN 117486738A CN 202311345249 A CN202311345249 A CN 202311345249A CN 117486738 A CN117486738 A CN 117486738A
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alkyl
ibmc
lipid
alkyl group
independently selected
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Inventor
谭蔚泓
张鹏晖
李岩
邓旭倩
符婷
谢斯滔
甘绍举
刘湘圣
程明
逯良伟
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Institute Of Basic Medicine And Oncology Chinese Academy Of Sciences Preparatory
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Institute Of Basic Medicine And Oncology Chinese Academy Of Sciences Preparatory
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/14—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
    • A61K48/0033—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being non-polymeric
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
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    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

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Abstract

The present invention discloses lipids for delivering active ingredientsPreparation and application of a plasma molecule and a composition thereof relate to the field of biological medicine. The novel lipid molecules comprise the general formula (I), (II) or (III):can be used to deliver active ingredients (e.g., nucleic acids, polypeptides, proteins) to cells and/or organs. Embodiments of the present invention provide nucleic acid-lipid nanoparticle compositions of a variety of novel lipid molecules, the lipid nanodelivery systems comprised thereof for delivery of mRNA; the DLin-MC3-DMA delivery efficiency of the product on the market at the cellular level and the animal level is superior to that of the product on the market at present, and the DLin-MC3-DMA delivery efficiency can be used as a novel method for delivering nucleic acid medicines, so that the development of the nucleic acid medicines is promoted.

Description

Lipid molecule and composition thereof
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to preparation and application of lipid molecules and compositions thereof for delivering active ingredients.
Background
Following small molecule drugs and antibody drugs, nucleic acid drugs have become the third wave of modern pharmacy. Nucleic acid drugs are usually prepared by introducing specific nucleic acid molecules into target cells or tissues to replace, compensate, block and correct specific genes, so as to achieve the purpose of preventing and treating diseases. Although nucleic acid drugs have obvious advantages, the presence of nuclease in serum can lead to rapid degradation of nucleic acid, and electronegativity of nucleic acid molecules can lead to difficulty in crossing cell membranes, so that the half-life of nucleic acid is extremely short, and the nucleic acid cannot enter cells, so that the therapeutic effect cannot be achieved. Therefore, there is a need to develop specific compounds and delivery systems to improve this situation to facilitate nucleic acid drugs as an important means for disease prevention and treatment.
It has been demonstrated that nanoparticle compositions containing lipid molecules can be used as a safe and efficient vehicle for delivering active ingredients. Such lipid-containing compositions can block RNA degradation in serum and promote cellular uptake of oligonucleotides, and can be effective in delivering small molecule, polypeptide, and protein drugs to target cells and/or organs in addition to delivering nucleic acid molecules. Although a variety of lipid molecule-containing compositions have been disclosed, their safety, efficacy and specificity are still further improved. Thus, there remains a need to design and screen novel lipid molecules and their nanocompositions for delivery of a variety of specific nucleic acid molecules.
Disclosure of Invention
The object of the present invention is to provide a novel lipid molecule and a nanoparticle composition comprising said lipid molecule, which nanoparticle composition is capable of delivering an active ingredient to cells and/or organs according to the related methods of the present invention.
The technical scheme adopted by the invention for achieving the purpose is as follows:
a lipid molecule for delivering an active ingredient comprising: lipid compounds represented by general formulas (I), (II), (III), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non-covalent complexes thereof;
Wherein,
m is selected from benzene ring, cyclobutane, cyclopentyl, cyclohexyl, pyrrole ring, pyridine, piperazine, imidazole, biphenyl, naphthalene ring, anthracene ring, pyrimidine ring or 4-8 membered heterocycle;
G 1 、G’ 1 each independently selected from- (CH) 2 ) x -O(C＝O)-、-(CH 2 ) x -(C＝O)O-、-(CH 2 ) x -(C＝O)S-、-(CH 2 ) x -(C＝O)NH-、-(CH 2 ) x -O-、-(CH 2 ) x -O(C＝O)NH-、-(CH 2 ) x -O(C＝O)O-、-(CH 2 ) x NH (c=o) -wherein x is an integer between 0 and 4;
L 1 、L’ 1 each independently selected from unsubstituted C 1-6 One of the alkyl groups;
G 2 selected from- (CH) 2 ) 0-3 -、-O-(CH 2 ) y -(C＝O)O-、-(CH 2 ) y -(C＝O)O-、-(CH 2 ) y -(C＝O)NH-、-S-
(CH 2 ) y -(C＝O)O-、-(CH 2 ) y One of- (c=o) S-, -O-, wherein y is an integer between 0 and 4;
G 1 、G’ 1 、G 2 each independently linked to any of the M sites, said sites being carbon or nitrogen atoms;
x is selected from carbon or nitrogen atoms; n is selected from integers between 0 and 6;
L 2 selected from H, OH, C 1-3 Alkyl, C 2-3 One of alkenyl groups;
L 3 、L 4 each independently selected from C 0-25 Alkyl, C 2-25 Alkenyl, C 3-25 One of the alkynyl groups;
G 3 、G 4 each independently selected from-CH 2 -one of-O (c=o) -, - (c=o) O-, -O (c=o) O-, -NH (c=o) -, -S (c=o) -, - (c=o) S-, -S-;
L 5 、L 6 each independently selected from C 1-25 Alkyl, C 2-25 Alkenyl, C 3-25 One of the alkynyl groups;
R 1 、R 2 and R'. 1 、R’ 2 Each independently selected from optionally substituted or unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, - (c=o) C 1-3 Alkyl group,Wherein the substituent is 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxy, C 1-3 Alkoxy, - (c=o) OC 1-3 Alkyl, C 1-3 An alkyl group; x is X 1 、X 2 Each independently selected from C 1-3 An alkyl group;
or alternatively
R 1 And R is 2 、R’ 1 And R'. 2 Taken together to form an optionally substituted 4-8 membered heterocyclic ring, pyrimidine ring, purine ring; wherein the substituents are 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxy, C 1-3 Alkoxy, - (c=o) OC 1-3 Alkyl, C 1-3 An alkyl group;
z in formula (II) is selected from H, F, -OH, -SH-, -NH 2 、-CF 3 、-NH-(CH 2 ) r CH 3 、-N(CH 3 )-(CH 2 ) r CH 3 Wherein r is an integer between 0 and 4;
z' in formula (III) is selected from optionally substituted or unsubstituted H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 One of cycloalkynyl, phenyl, 4-8 membered heterocycle, wherein the substituents are 1 or 2 independent OH, SH, C 1-3 Hydroxy, C 1-3 Alkoxy, amino, nitro, cyano, - (c=o) OC 1-3 An alkyl group.
In certain embodiments, the lipid compounds of formula (i) above comprise a structure of formula (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex thereof;
in certain embodiments, the lipid compounds of formula (ii) above comprise a structure of formula (iia), (iib), (iic), (iid), (iie), (iif), (iig) or (ih), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non-covalent complexes thereof;
In certain embodiments, the lipid compounds of the above general formula (iii) comprise a structure of formula (iiia), (iiib) or (iiic), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex thereof;
wherein G is 1 、G’ 1 Each independently selected from- (CH) 2 ) x -O(C＝O)-、-(CH 2 ) x -(C＝O)O-、-(CH 2 ) x -(C＝O)S-、-(CH 2 ) x -(C＝O)NH-、-(CH 2 ) x -O-、-(CH 2 ) x -O(C＝O)NH-、-(CH 2 ) x -O(C＝O)O-、-(CH 2 ) x NH (c=o) -wherein x is an integer between 0 and 4;
L 1 、L’ 1 each independently selected from unsubstituted C 1-6 One of the alkyl groups;
G 1 、G’ 1 each independently linked to an arbitrary site in the benzene ring;
z' is selected from optionally substituted or unsubstituted H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, 4-8 memberedOne of the heterocycles; wherein the substituent groups are 1 or 2 independent OH, SH, C 1-3 Hydroxy, C 1-3 Alkoxy, amino, nitro, cyano, - (c=o) OC 1-3 An alkyl group;
R 1 、R 2 and R'. 1 、R’ 2 Each independently selected from optionally substituted or unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, - (c=o) C 1-3 Alkyl group,Wherein the substituent is 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxy, C 1-3 Alkoxy, - (c=o) OC 1-3 Alkyl, C 1-3 An alkyl group; x is X 1 、X 2 Each independently selected from C 1-3 An alkyl group;
or alternatively
R 1 And R is 2 、R’ 1 And R'. 2 Taken together to form an optionally substituted 4-8 membered heterocyclic ring, pyrimidine ring, purine ring; wherein the substituents are 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxy, C 1-3 Alkoxy, - (c=o) OC 1-3 Alkyl, C 1-3 An alkyl group;
e is selected from oxygen or sulfur atoms;
m is an integer between 0 and 4;
t comprises one of the structures of formula (1) -formula (18):
in certain embodiments, the lipid compounds described above, whereinEach independently selected from one of the structures represented by formulas Y01-Y30:
in certain embodiments, the lipid molecule is selected from one or more of the following compounds:
the invention also provides a nanoparticle composition comprising one or more of the lipid compounds described above.
In certain embodiments, the nanoparticle composition described above further comprises a therapeutic and/or prophylactic agent.
In certain embodiments, the therapeutic and/or prophylactic agents described above are encapsulated within or associated with the nanoparticle.
In certain embodiments, the therapeutic and/or prophylactic agent comprises a nucleic acid, a small molecule compound, a polypeptide, or a protein; the nucleic acid comprises single-stranded DNA, double-stranded DNA, short isomer, agomir, antagomir, antisense molecule, small interfering RNA (siRNA), asymmetric interfering RNA (airRNA), microRNA (miRNA), dicer-substrate
At least one of RNA (dsRNA), small hairpin RNA (shRNA), transfer RNA (tRNA), messenger RNA (mRNA), circular RNA (circRNA), and aptamer (aptamer).
In certain embodiments, the nucleic acid further comprises mRNA.
In certain embodiments, the nanoparticle composition further comprises one or more neutral lipids, one or more steroids, one or more polymer conjugated lipids; wherein the mole percentage of the lipid molecules for delivering the active ingredient is 20-100%; the mole percentage of the steroid is 0-80%; the mole percentage of the neutral lipid is 0-40%; the above polymer conjugated lipid mole percent is 0-20%.
Preferably, the above mentioned lipid molecules for delivering the active ingredient are in a molar percentage of 20-95%; the mole percentage of the steroid is 5-80%; the mole percentage of the neutral lipid is 5-40%; the mole percentage of the polymer conjugated lipid is 10-20%.
In certain embodiments, the neutral lipids comprise 1, 2-distearoyl-sn-glycero-3-phosphorylcholine (DSPC), 1, 2-dipalmitoyl-sn-glycero-3-phosphorylcholine (DPPC), 1, 2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphorylcholine (POPC), 1, 2-dioleoyl-sn-glycero-3-phosphorylcholine (DOPC), 1, 2-dioleoyl-sn-glycero-3-phosphorylethanolamine (DOPE), palmitoyl-phosphatidylethanolamine (POPE), distearoyl-phosphatidylethanolamine (DSPE), dipalmitoyl phosphatidylethanolamine (DPPE), dimyristoyl-phosphoethanolamine (DMPE), 1-stearoyl-2-oleoyl-stearoyl-ethanolamine (SOPE), 1-stearoyl-2-oleoyl-phosphatidylethanolamine (SOPC), ceramide, sphingomyelin (SM), and at least one of the sphingomyelin derivatives thereof.
In certain embodiments, the steroid comprises at least one of cholesterol, fecal sterols, non-sterols, sitosterols, ergosterols, campesterols, stigmasterols, brassicasterol, lycorine, ursolic acid, alpha-tocopherol, corticosteroids, and derivatives thereof.
In certain embodiments, the polymer-conjugated lipids described above comprise at least one of polyethylene glycol modified phosphatidylethanolamine, polyethylene glycol modified phosphatidic acid, polyethylene glycol modified ceramide, polyethylene glycol modified dialkylamine, polyethylene glycol modified diacylglycerol, polyethylene glycol modified dialkylglycerol.
In certain embodiments, the polymer-conjugated lipid comprises DMG-PEG2000 or DMPE-PEG2000.
The invention also discloses a method for delivering nucleic acid to cells and/or organs by using the nanoparticle composition containing the lipid compound.
In certain embodiments, the nanoparticle composition described above is administered by a method including, but not limited to, intravenous, intramuscular, intradermal, subcutaneous, or nasal drip.
The invention also discloses application of the nanoparticle composition in preparation of medicines.
The above drugs include nucleic acid drugs, nucleic acid vaccines, small molecule drugs, polypeptide drugs, protein drugs, and the like.
The present invention provides a novel lipid molecule that can be used to deliver an active ingredient (e.g., nucleic acid, polypeptide, protein) to cells and/or organs. Embodiments of the present invention provide a variety of nucleic acid-lipid nanoparticle compositions comprising the novel lipid molecules described herein, and lipid nanodelivery systems composed thereof for delivery of mRNA. The DLin-MC3-DMA delivery efficiency of the product on the market at the cellular level and the animal level is superior to that of the product on the market at present, and the DLin-MC3-DMA delivery efficiency can be used as a novel method for delivering nucleic acid medicines to promote the development of the nucleic acid medicines.
The lipid compound prepared by the invention can deliver nucleic acid molecules, small molecular compounds, polypeptides or proteins and the like, and the carrier prepared by the lipid compound has high encapsulation efficiency on the nucleic acid molecules, can successfully transport the nucleic acid molecules into cells and/or organs, and can express the nucleic acid molecules with high efficiency; and the nanoparticle composition prepared by the present invention can effectively deliver mRNA in animals and express related proteins at high levels.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of IBMC-001;
FIG. 2 is a nuclear magnetic resonance spectrum of IBMC-002;
FIG. 3 is a nuclear magnetic resonance spectrum of IBMC-003;
FIG. 4 is a nuclear magnetic resonance spectrum of IBMC-004;
FIG. 5 is a nuclear magnetic resonance spectrum of IBMC-005;
FIG. 6 is a nuclear magnetic resonance spectrum of IBMC-006;
FIG. 7 is a nuclear magnetic resonance spectrum of IBMC-007;
FIG. 8 is a nuclear magnetic resonance spectrum of IBMC-011;
FIG. 9 is a nuclear magnetic resonance spectrum of IBMC-012;
FIG. 10 is a nuclear magnetic resonance spectrum of IBMC-015;
FIG. 11 is a nuclear magnetic resonance spectrum of IBMC-018;
FIG. 12 is a nuclear magnetic resonance spectrum of IBMC-019;
FIG. 13 is a nuclear magnetic resonance spectrum of IBMC-020;
FIG. 14 is a nuclear magnetic resonance spectrum of IBMC-023;
FIG. 15 is a nuclear magnetic resonance spectrum of IBMC-024;
FIG. 16 is a nuclear magnetic resonance spectrum of IBMC-025;
FIG. 17 is a nuclear magnetic resonance spectrum of IBMC-028;
FIG. 18 is a nuclear magnetic resonance spectrum of IBMC-029;
FIG. 19 is a nuclear magnetic resonance spectrum of IBMC-030;
FIG. 20 is a nuclear magnetic resonance spectrum of IBMC-031;
FIG. 21 is a nuclear magnetic resonance spectrum of IBMC-034;
FIG. 22 is a nuclear magnetic resonance spectrum of IBMC-035;
FIG. 23 is a nuclear magnetic resonance spectrum of IBMC-036;
FIG. 24 is a nuclear magnetic resonance spectrum of IBMC-037;
FIG. 25 is a nuclear magnetic resonance spectrum of IBMC-040;
FIG. 26 is a nuclear magnetic resonance spectrum of IBMC-041;
FIG. 27 is a nuclear magnetic resonance spectrum of IBMC-042;
FIG. 28 is a nuclear magnetic resonance spectrum of IBMC-043;
FIG. 29 is a nuclear magnetic resonance spectrum of IBMC-044;
FIG. 30 is a nuclear magnetic resonance spectrum of IBMC-048;
FIG. 31 is a nuclear magnetic resonance spectrum of IBMC-051;
FIG. 32 is a nuclear magnetic resonance spectrum of IBMC-052;
FIG. 33 is a nuclear magnetic resonance spectrum of IBMC-053;
FIG. 34 is a nuclear magnetic resonance spectrum of IBMC-054;
FIG. 35 is a nuclear magnetic resonance spectrum of IBMC-055;
FIG. 36 is a nuclear magnetic resonance spectrum of IBMC-056;
FIG. 37 is a nuclear magnetic resonance spectrum of IBMC-057;
FIG. 38 is a nuclear magnetic resonance spectrum of IBMC-058;
FIG. 39 is a nuclear magnetic resonance spectrum of IBMC-059;
FIG. 40 is a nuclear magnetic resonance spectrum of IBMC-060;
FIG. 41 is a nuclear magnetic resonance spectrum of IBMC-061;
FIG. 42 is a nuclear magnetic resonance spectrum of IBMC-062;
FIG. 43 is a nuclear magnetic resonance spectrum of IBMC-066;
FIG. 44 is a graph showing the effect of cell transfection of EGFP mRNA with lipid nanoparticle compositions at different N/Ps;
FIG. 45 shows the effect of Hela cell transfection with lipid nanoparticle compositions;
FIG. 46 is a graph showing the transfection effect of lipid nanoparticle compositions 293T cells;
FIG. 47 is a graph showing results of in vivo delivery level testing of lipid nanoparticle compositions (LNP formulations) by different injection modes;
FIG. 48 is a graph showing results of in vivo delivery level testing of lipid nanoparticle compositions (LNP formulations) at various time points;
FIG. 49 shows in vivo delivery of lipid nanoparticle compositions (LNP formulations) to SARS-CoV2 Spike induces expression levels of S protein in muscle;
FIG. 50 is a graph showing the expression levels of S protein in liver induced by in vivo delivery of SARS-CoV2 Spike from a lipid nanoparticle composition (LNP formulation);
FIG. 51 is a graph showing that in vivo delivery of a lipid nanoparticle composition (LNP formulation) induces expression levels of S protein in blood by SARS-CoV2 Spike.
Detailed Description
The technical scheme of the invention is further described in detail below with reference to the specific embodiments and the attached drawings:
synthesizing lipid molecules represented by the general formulae (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), (IIIc); the lipid molecules can be synthesized in a modularized mode. In the specific examples of the present invention, all starting materials and reagents used were commercially available, unless otherwise indicated, and no further purification was required.
Example 1: the synthetic route for IBMC-001 is shown below:
the specific synthetic procedure for IBMC-001 is as follows: step 1: synthesis of Bi-12: 79mmol of Bi-01 (5-hydroxyisophthalic acid), 160mmol of Xiu and 240mmol of sodium bicarbonate are dissolved in 100mL of DMF and stirred at 40℃for 8h, the reaction is diluted with dichloromethane and washed with saturated sodium bicarbonate, sodium chloride, dried over anhydrous sodium sulfate and spun dry, and purified by a silica gel column to give Bi-12 (14.2 g, 49.58%). 1 H NMR(400MHz,Chloroform-d)δ8.31(s,1H),7.79(d,J＝1.5Hz,2H),7.51–7.29(m,10H),6.41(s,1H),5.37(s,4H)。
Step 2: synthesis of Bi-13: 10mmol of Bi-12, 20mmol of t-butyl bromoacetate and 30mmol of potassium carbonate were dissolved in 100mL of acetonitrile, stirred at 70℃for 8 hours, the reaction solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and then spin-dried, and purified by a silica gel column to give Bi-13 (4.35 g, 90.52%). 1 H NMR(400MHz，Chloroform-d)δ8.39(t,J＝1.4Hz,1H),7.77(d,J＝1.4Hz,2H),7.47–7.32(m,10H),5.37(s,4H),4.58(s,2H),1.47(s,9H)。
Step 3: synthesis of Bi-14: 6mmol of Bi-13 was dissolved in 50mL of a mixed solvent of trifluoroacetic acid/dichloromethane=4/1, stirred at room temperature for 12 hours, the solvent was dried by spin-drying, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and dried by spin-drying, and purified by a silica gel column to give Bi-14 (1.92 g, 77.05%). 1 H NMR(400MHz,Chloroform-d)δ8.40(t,J＝1.4Hz,1H),7.80(d,J＝1.4Hz,2H),7.48–7.30(m,11H),5.37(s,4H),4.75(s,2H)。
Step 4: synthesis of Bi-140013: 1.52mmol Bi-14 and 3.04mmol T-13 was dissolved in 50mL of methylene chloride, 3.04mmol of 4-dimethylaminopyridine, 4.56mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, stirred at room temperature for 8 hours, extracted with methylene chloride, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and spin-dried, and purified on a silica gel column to give Bi-140013 (1.56 g, 83.78%). 1 H NMR(400MHz,Chloroform-d)δ8.39(s,1H),7.80(d,J＝1.4Hz,2H),7.46–7.34(m,10H),5.37(s,4H),5.04–4.97(m,1H),4.69(s,2H),4.05(dt,J＝13.4,6.6Hz,4H),2.30(td,J＝9.0,4.4Hz,2H),1.68–1.19(m,64H),0.87(tt,J＝7.1,2.2Hz,12H)。
Step 5: synthesis of Bi-150013: 1.11mmol of Bi-140013 and 100mg of Pd/C were dissolved in 50mL of methanol, the mixture was stirred at room temperature for 8 hours after being purged with hydrogen, and the filtrate was dried by suction filtration to give Bi-150013 (682 mg, 79.95%). 1 H NMR(400MHz,Chloroform-d)δ8.45(s,1H),7.80(s,2H),5.01(s,1H),4.74(s,2H),4.05(d,J＝7.1Hz,4H),2.31(s,2H),1.67–1.16(m,64H),0.90-0.83(m,12H)。
Step 6: synthesis of IBMC-001: 0.067mmol Bi-150013 and 0.266mmol N-methyldiethanolamine are dissolved in 5mL dichloromethane, 4-dimethylaminopyridine 0.1995mmol, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.3325mmol are added, stirred at room temperature for 8h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and spun dry, and purified by silica gel column to give IBMC-001 (41 mg, 55.79%). 1 H NMR (400 mhz, chloro-d) delta 8.33 (s, 1H), 7.78 (d, j=1.4 hz, 2H), 5.01 (t, j=6.3 hz, 1H), 4.72 (s, 2H), 4.44 (t, j=5.6 hz, 4H), 4.04 (t, j=6.6 hz, 4H), 3.61 (t, j=5.3 hz, 4H), 2.86 (t, j=5.6 hz, 4H), 2.65 (t, j=5.3 hz, 4H), 2.38 (s, 6H), 2.30 (s, 2H), 1.66-1.19 (m, 64H), 0.87 (t, j=6.7 hz, 12H), nuclear magnetic hydrogen spectra are shown in fig. 1.
The T-13 synthesis route is shown below:
the specific synthesis steps of T-13 are as follows:
step 1: synthesis of T-3-3: in a three-necked flask, 48.7mmol of TosMIC was weighed into 150mL of DMSO and 16 was incubated in ice6mmol NaH, 107.2mmol T-3-1 (5-bromopentylacetate) and 9.7mmol TBAI were added to the reaction flask, and after the addition was completed, stirred overnight at room temperature; after completion of the reaction, ice-water was added to the reaction mixture, followed by extraction with methylene chloride, washing with a saturated sodium hydrogencarbonate solution, saturated brine, drying over anhydrous sodium sulfate, and concentration to obtain intermediate T-3-2 (20.9 g, 95%) which was directly subjected to the next step. 20.9g of T-3-2 was dissolved in 250mL of methylene chloride, 50mL of saturated concentrated hydrochloric acid was added dropwise thereto, and after stirring for 1 hour, water was added to the reaction mixture, the mixture was extracted with methylene chloride, washed with a saturated sodium hydrogencarbonate solution, saturated brine, dried over anhydrous sodium sulfate, and concentrated, followed by separation by column chromatography to give T-3-3 (7.5 g, 53.9%). 1 H NMR(400MHz,CDCl 3 )δ4.05(t,J＝6.76Hz,4H),2.42(t,J＝7.44,4H),2.04(s,6H),1.56-1.67(m,8H),1.30-1.39(m,4H)。
Step 2: synthesis of T-3-4: 24.4mmol of T-3-3 was dissolved in 100mL of a methanol/water (4:1) mixture, 73mmol of sodium hydroxide was added, the mixture was stirred at 40℃for 4 hours, methanol was removed by rotary evaporation, extraction was performed with ethyl acetate, and after concentration, column chromatography was performed to obtain T-3-4 (3.5 g, 71%). 1 H NMR(400MHz,CDCl 3 )δ3.65(t,J＝6.50Hz,4H),2.42(t,J＝7.31,4H),1.54-1.64(m,8H),1.30-1.39(m,4H)。
Step 3: synthesis of T-3-5: 17.3mmol of T-3-4 and 51.98mmol of 2-hexyldecanoic acid were dissolved in 100mL of methylene chloride, 34.6mmol of 4-dimethylaminopyridine, 34.6mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and the mixture were added, stirred overnight at room temperature, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and spin-dried and purified on a silica gel column to give T-3-5 (9.5 g, 80.9%). 1 H NMR(400MHz,CDCl 3 )δ(ppm)4.06(t,J＝6.63Hz,4H),2.40(t,J＝7.42Hz,4H),2.27-2.34(m,2H),1.55-1.66(m,16H),1.25-1.28(m,44H),0.87(t,J＝13.38Hz,12H)。
Step 4: synthesis of T-13: 14mmol of T-3-5 was dissolved in 150mL of methanol, 56mmol of sodium borohydride was added, stirred at room temperature for 3 hours, then 50mL of ice water was added for quenching, extraction with methylene chloride, saturated brine washing, drying over anhydrous sodium sulfate, and concentration by evaporation gave T-13 (9.5 g, 99%). 1 H NMR(400MHz,CDCl 3 )δ4.00(t,J＝6.61Hz,4H),3.51-3.52(m,1H),2.20-2.27(m,2H),1.48-1.60(m,8H),1.26-1.42(m,12H),1.18-1.25(s,44H),0.80(t,J＝13.31,12H)。
Example 2: the synthetic route for IBMC-002 is shown below:
the specific synthetic procedure for IBMC-002 differs from that of example 1:
1) The synthesis procedure of Bi-140011 differs from that of Bi-140013: t-11 is adopted to replace T-13;
2) The synthesis procedure of Bi-150011 differs from that of Bi-150013: bi-140011 was used instead of Bi-140013.
Hydrogen spectrum of IBMC-002: 1 h NMR (400 mhz, chloro-d) delta 8.31 (s, 1H), 7.78 (s, 2H), 5.00 (p, j=6.0 hz, 1H), 4.71 (s, 2H), 4.46 (t, j=5.6 hz, 4H), 4.03 (td, j=6.5, 4.4hz, 4H), 3.64 (t, j=5.3 hz, 4H), 2.92 (t, j=5.6 hz, 4H), 2.70 (t, j=5.3 hz, 4H), 2.42 (s, 6H), 2.28 (q, j=7.5, 6.8hz, 3H), 1.64-1.17 (m, 52H), 0.86 (t, j=6.6 hz, 9H), nuclear magnetic hydrogen spectra are shown in fig. 2.
The T-11 synthesis route is shown below:
the specific synthesis steps of T-11 are as follows:
step 1: synthesis of T-3-7: 17.3mmol of T-3-4 and 4.32mmol of 2-hexyldecanoic acid were dissolved in 50mL of methylene chloride, 8.64mmol of 4-dimethylaminopyridine, 8.64mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride were added thereto, stirred overnight at room temperature, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and spun dry, and purified by silica gel column to give T-3-7 (1.7 g, 90%). 1 H NMR(400MHz,CDCl 3 )δ4.06(t,J＝6.63Hz,2H),3.65(t,J＝6.51,2H),2.39-2.43(m,4H),2.27-2.34(m,1H),1.54-1.66(m,10H),1.25-1.44(m,26H),0.87(t,J＝6.67,6H)。
Step 2: synthesis of T-3-8: 3.8mmol of T-3-7, 4.6mmol of nonanoic acid are dissolved in 50mL of dichloromethane, and 7.6mmol of 4-dimethylaminopyridine, 1-ethyl- (3-dimethyl) are addedAmidopropyl) carbodiimide hydrochloride 7.6mmol, stirred overnight at room temperature, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and spin-dried, purified on a silica gel column to give T-3-8 (0.9 g, 90%). 1 H NMR(400MHz,CDCl 3 )δ4.06(td,J＝6.6,2.9Hz,4H),2.40(t,J＝7.4Hz,4H),2.30(q,J＝8.4,7.5Hz,3H),1.67–1.52(m,12H),1.48–1.18(m,36H),0.87(t,J＝6.6Hz,9H)。
Step 3: synthesis of T-11: 1.3mmol of T-3-8 was dissolved in 50mL of methanol, 5.2mmol of sodium borohydride was added, and after stirring at room temperature for 3h, 50mL of ice water was added for quenching, dichloromethane extraction, saturated brine washing, drying over anhydrous sodium sulfate, and concentration by evaporation gave T-11 (0.9 g, 99%). 1 H NMR(400MHz,CDCl 3 )δ4.07(td,J＝6.7,3.2Hz,4H),3.59(dd,J＝7.5,4.0Hz,1H),2.38–2.21(m,3H),1.67–1.56(m,8H),1.48–1.22(m,44H),0.92–0.83(m,9H)。
The specific synthetic procedure for T-3-4 is as in example 1.
Example 3: the synthetic route for IBMC-003 is shown below:
specific synthetic procedure for IBMC-003 differs from example 2: t-08 was used instead of T-11.
Hydrogen spectrum of IBMC-003: 1 H NMR(400MHz,Chloroform-d)δ8.33(t,J＝1.5Hz,1H),7.79(d,J＝
1.5hz, 2H), 5.00 (p, j=6.2 hz, 1H), 4.72 (s, 2H), 4.44 (t, j=5.7 hz, 4H), 3.65-3.59 (m, 4H), 2.87 (t, j=5.6 hz, 4H), 2.70-2.63 (m, 4H), 2.39 (s, 6H), 1.18-1.25 (m, 68H), 0.91-0.85 (m, 6H), and nuclear magnetic hydrogen spectra are shown in fig. 3.
The T-08 synthesis route is shown below:
the specific synthesis steps of T-08 are as follows:
step 1: synthesis of T-1-1: 17.8mmol of T-1-0 (linoleic acid) was dissolved in 50mL of TH in an ice-water bathF was slowly added dropwise to 50mL containing 17.8mmol LiAlH 4 Stirring in tetrahydrofuran of (2), stirring at room temperature for 2h after dripping, and quenching LiAlH by adding ice water after the reaction is completed 4 Suction filtration, spin drying and column chromatography separation gave T-1-1 (4.5 g, 94.7%). 1 H NMR(400MHz,CDCl 3 )δ5.29-5.42(m,4H),3.64(t,J＝6.64Hz,2H),2.77(t,J＝6.64Hz,2H),2.02-2.07(m,4H),1.53-1.60(m,2H),1.25-1.39(m,16H),0.89(t,J＝6.89Hz,3H)。
Step 2: synthesis of T-1-2: under ice-water bath, 16.9mmol of T-1-1 and 17.7mmol of CBr are taken 4 Dissolving in 100mL of dichloromethane, and adding PPh 3 The reaction was carried out for 2 hours, the solvent was dried by spin-drying, and the resultant T-1-2 (5.7 g, 90%) was isolated by column chromatography. 1 H NMR(400MHz,CDCl 3 )δ5.32-5.44(m,4H),3.43(t,J＝6.87Hz,2H),2.79(t,J＝6.49Hz,2H),2.07(dd,J＝6.81Hz,4H),1.87(t,J＝14.74Hz,2H),1.26-1.46(m,16H),0.91(t,J＝6.86Hz,3H)。
Step 3: synthesis of T-08: 18.29mmol of magnesium strip was added to the Schlenk tube and evacuated, ultra-dry THF was added, and finally 6mmol of T-1-2 was dissolved in 5mL of THF, poured into a reaction flask, stirred at room temperature for 1h, then ethyl formate was added and stirred overnight, the reaction was quenched with water, extracted with dichloromethane, concentrated and separated by column chromatography to give T-08 (0.9 g, 28%). 1 HNMR(400MHz,CDCl 3 )δ5.29-5.42(m,8H),3.56-3.59(m,1H),2.77(t,J＝6.41Hz,4H),2.02-2.07(m,8H),1.23-1.47(m,40H),0.89(t,J＝6.89Hz,6H)。
Example 4: the synthetic route for IBMC-004 is shown below:
the specific synthetic procedure for IBMC-004 is as follows: step 1: synthesis of Bi-02: 55mmol of Bi-01 (5-hydroxyisophthalic acid) and 330mmol of borane tetrahydrofuran are dissolved in 100mL of ultra-dry THF and stirred at room temperature for 24h, the reaction is quenched with saturated ammonium chloride, washed with saturated sodium chloride and then with anhydrous NaSO 4 Dried and purified by a silica gel column to give Bi-02 (5.25 g, 61%). 1 H NMR(400MHz,Methanol-d4)δ6.77(q,J＝1.1Hz,1H),6.67(d,J＝1.5Hz,2H),4.49(s,4H)。
Step 2: synthesis of Bi-04: 64.6mmol of Bi-02 and 77.2mmol of methyl bromoacetate were dissolved in 300mL of acetonitrile, 129.8mmol of potassium carbonate was added, the mixture was refluxed at 80℃and reacted for 4 hours, the reaction solution was cooled to room temperature and then filtered, and the filtrate was dried by spin-drying and then purified by silica gel column to obtain Bi-04 (10.97 g, 75%). 1 H NMR(400MHz,Chloroform-d)δ6.99(tt,J＝1.3,0.7Hz,1H),6.85(d,J＝1.4Hz,2H),4.67(d,J＝0.7Hz,4H),4.66(s,2H),3.81(s,3H)。
Step 3: synthesis of Bi-06: 22.1mmol of Bi-04 and 88.4mmol of imidazole are dissolved in 100mL of anhydrous dichloromethane, tert-butyldimethyl chlorosilane is dissolved in 50mL of anhydrous dichloromethane, the mixture is added dropwise to the reaction solution, the reaction is carried out for 4 hours at room temperature, and the target product Bi-06 (7.56 g, 70%) is obtained by spin-drying and column purification. 1 H NMR(400MHz,Chloroform-d)δ6.89(dt,J＝1.9,0.9Hz,1H),6.84–6.72(m,2H),4.75–4.65(m,4H),4.64(s,2H),3.80(s,3H),0.94(s,18H),0.15(s,12H)。
Step 4: synthesis of Bi-07: 11mmol Bi-06 is dissolved in 90mL methanol; 22mmol of sodium hydroxide is dissolved in 30mL of deionized water and added dropwise to a methanol solution for reaction for 2h, the solution is spun to one third and then extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then purified by spin-drying and column purification to obtain the target product Bi-07 (2.9 g, 60%). 1 H NMR(400MHz,Chloroform-d)δ6.94(s,1H),6.75(s,2H),4.67(d,J＝12.8Hz,4H),3.48(d,J＝1.1Hz,2H),0.93(d,J＝7.2Hz,18H),0.08(d,J＝7.1Hz,12H)。
Step 5: synthesis of Bi-0713: 0.227mmol Bi-07 was dissolved in 50mL methylene chloride, and T-130.114mmol, 4-dimethylaminopyridine 0.3411 mmol, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.272mmol, and then stirred at room temperature for 8 hours, washed with sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried and purified with a silica gel column to give the objective product Bi-0713 (2.29 g, 71%). 1 H NMR(400MHz,Chloroform-d)δ6.83(d,J＝6.7Hz,1H),6.73–6.66(m,2H),4.91(td,J＝7.2,3.5Hz,1H),4.62(s,4H),4.54(d,J＝5.8Hz,2H),3.97(t,J＝6.7Hz,4H),2.23(tt,J＝8.8,5.3Hz,2H),1.58–1.07(m,64H),0.87(s,18H),0.83–0.78(m,12H)，0.02(s,12H)。
Step 6: synthesis of Bi-070013: dissolving 0.91mmol Bi-0713After 50mL of methylene chloride was added dropwise with 5mL of saturated concentrated hydrochloric acid and reacted for 8 hours, the resultant was dried by spin-drying and purified by a silica gel column to obtain the target product Bi-070013 (0.71 g, 81%). 1 H NMR(400MHz,Chloroform-d)δ7.04–6.92(m,1H),6.85(d,J＝1.3Hz,2H),5.09–4.93(m,1H),4.66(s,4H),4.64(s,2H),4.03(td,J＝6.8,1.5Hz,4H),2.30(tt,J＝8.9,5.4Hz,2H),1.69–1.16(m,64H),0.94–0.79(m,12H)。
Step 7: synthesis of IBMC-004: 0.08mmol Bi-070013 is dissolved in 8mL methylene dichloride, 0.32mmol of 3- (4-morpholinyl) propionic acid, 0.48mmol of 4-dimethylaminopyridine, 0.38mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride are sequentially added for reaction at room temperature for 12h, saturated sodium chloride solution is washed, anhydrous sodium sulfate is dried and then spun dry, and a silica gel column is used for purification to obtain a target product IBMC-004 (42 mg, 45.38%). 1H NMR (400 MHz, chloroform-d) delta 6.96 (d, J=1.5 Hz, 1H), 6.87 (d, J=1.6 Hz, 2H), 5.09 (s, 4H), 5.01 (q, J=6.0 Hz, 1H), 4.61 (s, 2H), 4.04 (t, J=6.6 Hz, 4H), 3.69 (t, J=4.6 Hz, 8H), 2.71 (s, 4H), 2.57 (s, 4H), 2.47 (s, 8H), 2.33-2.26 (m, 2H), 1.82-1.20 (m, 64H), 0.91-0.83 (m, 12H), nuclear magnetic hydrogen spectra are shown in FIG. 4.
The specific synthetic procedure for T-13 is as in example 1.
Example 5: the synthetic route for IBMC-005 is shown below:
the specific synthetic procedure for IBMC-005 is as follows: step 1: synthesis of Bi-0711: 0.227mmol Bi-07 was dissolved in 5mL methylene chloride, 0.114mmol T-11, 4-dimethylaminopyridine 0.348 mmol, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.227mmol were added sequentially, and the mixture was stirred at room temperature for 12 hours, washed with sodium chloride solution, dried over anhydrous sodium sulfate and spun dry, and purified by silica gel column to give the objective product Bi-0711 (90 mg, 78.95%). 1 H NMR(400MHz,Chloroform-d)δ6.81(d,J＝6.4Hz,1H),6.72–6.63(m,2H),4.89(p,J＝6.0Hz,1H),4.62–4.58(m,4H),4.54(s,1H),4.51(s,1H),3.94(td,J＝6.7,3.6Hz,4H),3.71(s,1H),2.29–2.09(m,2H),1.59–1.06(m,52H),0.85(s,18H),0.82–0.75(m,9H)，0.01(s,12H)。
Step 2: synthesis of Bi-070011: 0.045mmol Bi-0711 was dissolved in 5mL dichloromethane, 0.6mL saturated concentrated hydrochloric acid was added dropwise, reacted for 8h, spin-dried and purified by silica gel column to give the target product Bi-070011 (53 mg, 75%). 1 HNMR(400MHz,Chloroform-d)δ6.98(t,J＝1.4Hz,1H),6.85(d,J＝1.4Hz,2H),5.30(s,2H),5.05–4.94(m,1H),4.65(d,J＝9.0Hz,4H),4.11–3.91(m,4H),2.35–2.19(m,3H),1.74–1.12(m,52H),0.93–0.81(m,9H)。
Step 3: synthesis of IBMC-005: 0.064mmol Bi-070011 is dissolved in 5mL dichloromethane, N-dimethyl-aminobutyrate hydrochloride 0.032mmol, 4-dimethyl-aminopyridine 0.096mmol, 1-ethyl- (3-dimethyl-aminopropyl) carbodiimide hydrochloride 0.096mmol are added sequentially, the reaction is carried out for 12h at room temperature, saturated sodium chloride solution is washed, anhydrous sodium sulfate is dried and then spin-dried, and the target product IBMC-005 (7 mg, 10.1%) is obtained by purifying with a silica gel column. 1 H NMR (400 mhz, chloroform-d) delta 7.01 (s, 1H), 6.83 (dt, j=13.1, 2.3hz, 2H), 5.08 (s, 2H), 4.99 (tt, j=7.2, 3.5hz, 1H), 4.64 (d, j=15.2 hz, 4H), 4.03 (td, j=6.7, 4.1hz, 4H), 2.45 (dt, j=16.9, 7.4hz, 6H), 2.36 (s, 4H), 2.28 (t, j=7.6 hz, 3H), 1.93 (p, j=7.2 hz, 2H), 1.70-1.16 (m, 52H), 0.88 (td, j=6.9, 1.7hz, 9H), nuclear magnetic hydrogen spectra are shown in fig. 5.
The specific synthetic procedure for Bi-07 was as in example 4.
Example 6: the synthetic route for IBMC-006 is shown below:
the specific synthetic procedure for IBMC-006 differs from that of example 5: t-08 was used instead of T-11. Hydrogen spectrum of IBMC-006: 1 H NMR (400 mhz, chloro-d) delta 6.96 (d, j=1.6 hz, 1H), 6.75 (dt, j=12.2, 2.2hz, 2H), 5.36-5.21 (m, 8H), 5.02 (s, 2H), 4.92 (p, j=6.1 hz, 1H), 4.57 (d, j=19.0 hz, 4H), 2.74-2.68 (m, 4H), 2.61 (t, j=7.9 hz, 2H), 2.45 (s, 6H), 2.40 (t, j=6.9 hz, 2H), 1.98 (td, j=7.2, 4.2hz, 8H), 1.53-1.08 (m, 42H), 0.85-0.75 (m, 6H), nuclear magnetic hydrogen spectra are shown in fig. 6.
The specific synthetic procedure for T-08 is as in example 3.
Example 7: specific synthetic procedure for IBMC-007: 0.067mmol Bi-150013 and 0.266mmol N, N-dimethylpropanolamine were dissolved in 5mL of dichloromethane, 4-dimethylaminopyridine 0.1995mmol, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.3325mmol was added, stirred at room temperature for 8h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and spin-dried purified on a silica gel column to give IBMC-007 (41 mg, 55.79%). 1 H NMR (400 mhz, chloro-d) delta 8.30 (t, j=1.4 hz, 1H), 7.76 (d, j=1.4 hz, 2H), 5.04-4.97 (m, 1H), 4.70 (s, 2H), 4.38 (t, j=6.6 hz, 4H), 4.04 (t, j=6.6 hz, 4H), 2.42 (dd, j=7.9, 6.7hz, 4H), 2.29 (ddd, j=8.9, 5.4,3.6hz, 2H), 2.25 (s, 12H), 1.99-1.90 (m, 4H), 1.64-1.19 (m, 64H), 0.86 (td, j=6.8, 1.2hz, 12H), nuclear magnetic hydrogen spectra are shown in fig. 7.
The specific synthetic procedure of Bi-150013 is the same as in example 1.
Example 8: specific synthetic steps of IBMC-011: 0.067mmol Bi-150013 and 0.266mmol morpholinopropanol are dissolved in 5mL dichloromethane, 4-dimethylaminopyridine 0.1995mmol, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.3325mmol are added and stirred at room temperature for 8h, dichloromethane extracted saturated sodium chloride wash, dried over anhydrous sodium sulfate and spin-dried purified on silica gel column to give IBMC-011 (41 mg, 55.79%). 1 H NMR (400 mhz, chloroform-d) delta 8.31-8.29 (m, 1H), 7.77 (d, j=1.5 hz, 2H), 5.05-4.99 (m, 1H), 4.71 (s, 2H), 4.41 (t, j=6.6 hz, 4H), 4.05 (t, j=6.6 hz, 4H), 3.74-3.68 (m, 8H), 2.53-2.42 (m, 12H), 2.30 (tt, j=8.9, 5.3hz, 2H), 1.97 (p, j=6.8 hz, 4H), 1.65-1.19 (m, 64H), 0.90-0.85 (m, 12H), and nuclear magnetic hydrogen spectra are shown in fig. 8.
The specific synthetic procedure of Bi-150013 is the same as in example 1.
Example 9: specific synthetic procedure for IBMC-012: same as in example 8. Hydrogen spectrum of IBMC-012: 1H NMR (400 MHz, chloroform-d) delta 8.33-8.30 (m, 1H), 7.79-7.73 (m, 2H), 5.01 (td, J=7.1, 3.5Hz, 1H), 4.70 (s, 2H), 4.39 (q, J=7.0 Hz, 4H), 4.04 (t, J=6.6 Hz, 4H), 3.71 (t, J=4.6 Hz, 4H), 2.48 (dt, J=10.2, 6.0Hz, 4H), 2.29 (tt, J=8.9, 5.3Hz, 2H), 1.97 (p, J=6.8 Hz, 2H), 1.68-1.16 (m, 64H), 0.90-0.83 (m, 12H), nuclear magnetic hydrogen spectra are shown in FIG. 9.
Example 10: specific synthetic procedure for IBMC-015: specific synthetic procedure for IBMC-015: 0.022mmol Bi-150013, 0.067mmol EDCI and 0.067mmol HOBT are dissolved in 5mL of dichloromethane, after 1h morpholinopropanol 0.088mmol and DIEA 0.088mmol are added thereto, stirred for 8h at room temperature, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column; 0.089mmol of phenethyl alcohol was dissolved in 5mL of dichloromethane, 0.067mmol of 4-dimethylaminopyridine, 0.11mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride were added, stirred at room temperature for 8h, washed with saturated sodium chloride extracted with dichloromethane, dried over anhydrous sodium sulfate, and spin-dried and purified by silica gel column to give IBMC-015 (5 mg, 20.15%). 1 H (400 mhz, chloro form-d) delta 8.26 (t, j=4.8 hz, 1H), 8.03 (s, 1H), 7.76-7.68 (m, 2H), 7.47-7.34 (m, 5H), 5.38 (s, 2H), 5.00 (dq, j=12.4, 6.6,5.9hz, 1H), 4.70 (s, 2H), 4.03 (t, j=6.6 hz, 4H), 3.70 (t, j=4.7 hz, 4H), 3.57 (q, j=5.6 hz, 2H), 2.60-2.44 (m, 6H), 2.29 (tt, j=8.9, 5.3hz, 2H), 1.79 (p, j=6.0 hz, 2H), 1.66-1.17 (m, 64H), 0.90-0.84 (m, 12H), nuclear magnetic spectrum as shown in fig. 10.
Example 11: specific synthetic procedure for IBMC-018: 0.075mmol Bi-150011 and 0.3mmol 1, 4-bis (2-hydroxyethyl) piperazine were dissolved in 5mL dichloromethane, 4-dimethylaminopyridine 0.225mmol, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.375mmol were added, stirred at room temperature for 8h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried purified on a silica gel column to give IBMC-018 (21 mg, 25.3%). 1 H NMR (400 mhz, chloro-d) delta 8.27 (s, 1H), 7.76 (s, 2H), 5.00 (q, j=6.3 hz, 1H), 4.70 (s, 2H), 4.46 (t, j=5.8 hz, 4H), 4.03 (q, j=6.2 hz, 4H), 3.70 (t, j=5.2 hz, 4H), 2.89-2.57 (m, 24H), 2.27 (t, j=7.6 hz, 3H), 1.64-1.18 (m, 52H), 0.86 (t, j=6.6 hz, 9H), nuclear magnetic hydrogen spectra are shown in fig. 11.
The specific synthetic procedure of Bi-150011 is the same as in example 2.
Example 12: specific synthetic procedure for IBMC-019: 0.075mmol Bi-150011 and 0.3mmol morpholinopropanol are dissolved in 5mL dichloromethane, 4-dimethylaminopyridine 0.225mmol, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.375mmol are added and stirred at room temperature for 8h, twoMethyl chloride was extracted, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried and purified on a silica gel column to give IBMC-019 (36 mg, 45.57%). 1 H NMR (400 mhz, chloro-d) delta 8.28 (t, j=1.5 hz, 1H), 7.75 (d, j=1.4 hz, 2H), 5.01 (dt, j=7.1, 5.3hz, 1H), 4.69 (s, 2H), 4.39 (t, j=6.6 hz, 4H), 4.03 (td, j=6.6, 4.6hz, 4H), 3.70 (t, j=4.7 hz, 8H), 2.47 (dt, j=10.0, 6.0hz, 12H), 2.27 (dd, j=9.2, 6.1hz, 3H), 1.96 (q, j=6.9 hz, 4H), 1.65-1.18 (m, 52H), 0.90-0.83 (m, 9H), nuclear magnetic hydrogen spectra are shown in fig. 12.
The specific synthetic procedure of Bi-150011 is the same as in example 2.
Example 13: specific synthetic procedure for IBMC-020: 0.075mmol Bi-150011 and 0.3mmol N, N-dimethylpropanolamine are dissolved in 5mL dichloromethane, 4-dimethylaminopyridine 0.225mmol, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.375mmol are added, stirred at room temperature for 8h, dichloromethane extracted, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried purified over a silica gel column to give IBMC-020 (25 mg, 34.39%). 1 H NMR (400 mhz, chloro-d) delta 8.30 (d, j=1.6 hz, 1H), 7.77 (d, j=1.4 hz, 2H), 5.01 (q, j=6.4 hz, 1H), 4.71 (s, 2H), 4.40 (t, j=6.5 hz, 4H), 4.04 (q, j=6.4 hz, 4H), 2.52 (t, j=7.4 hz, 4H), 2.32 (s, 12H), 2.28 (t, j=7.6 hz, 3H), 2.00 (q, j=6.9 hz, 4H), 1.66-1.18 (m, 52H), 0.91-0.84 (m, 9H), and nuclear magnetic hydrogen spectra are shown in fig. 13.
The specific synthetic procedure of Bi-150011 is the same as in example 2.
Example 14: specific synthetic procedure for IBMC-023: 0.377mmol Bi-070013 is dissolved in 10mL methylene dichloride, N-dimethyl amino butyrate hydrochloride 0.189mmol, 4-dimethyl amino pyridine 0.567mmol, 1-ethyl- (3-dimethyl amino propyl) carbodiimide hydrochloride 0.227mmol are added in sequence, the reaction is carried out for 12h at room temperature, saturated sodium chloride solution is washed, anhydrous sodium sulfate is dried and then spin-dried, and a silica gel column is used for purification, thus obtaining a target product IBMC-023 (100 mg, 53.6%). 1 H NMR(400MHz,Chloroform-d)δ6.95(s,1H),6.82–6.70(m,2H),5.01(s,2H),4.92(td,J＝7.1,3.5Hz,1H),4.57(d,J＝14.0Hz,4H),3.97(t,J＝6.7Hz,4H),2.59(t,J＝7.8Hz,2H),2.43(s,6H),2.39(d,J＝6.9Hz,2H),2.23(tt,J＝8.8,5.3Hz,2H),1.95(q,J＝7.4Hz,2H),1.62–1.08(m,64H),0.80(t, j=6.7 hz,12 h), the nuclear magnetic hydrogen spectrum is shown in fig. 14.
The specific synthetic procedure for Bi-070013 is as in example 4.
Example 15: specific synthetic procedure for IBMC-024: 0.235mmol Bi-070013 is dissolved in 8mL methylene dichloride, 0.118mmol of 3- (4-morpholinyl) propionic acid, 0.353mmol of 4-dimethylaminopyridine, 0.142mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride are sequentially added, the reaction is carried out for 12h at room temperature, the solution is washed with sodium chloride, and after anhydrous sodium sulfate is dried, the spin-drying is carried out and the silica gel column is used for purification, thus obtaining the target product IBMC-024 (62.7 mg, 50.93%). 1 H NMR (400 mhz, chloroform-d) delta 6.90 (s, 1H), 6.79 (dt, j=7.8, 2.3hz, 2H), 5.02 (s, 2H), 4.98-4.87 (m, 1H), 4.58 (d, j=16.4 hz, 4H), 3.96 (t, j=6.6 hz, 4H), 3.67-3.55 (m, 4H), 2.64 (t, j=7.2 hz, 2H), 2.49 (t, j=7.2 hz, 2H), 2.38 (t, j=4.6 hz, 4H), 2.23 (tt, j=8.9, 5.3hz, 2H), 1.66-1.08 (m, 64H), 0.80 (t, j=6.7 hz, 12H), nuclear magnetic hydrogen spectra are shown in fig. 15.
The specific synthetic procedure for Bi-070013 is as in example 4.
Example 16: the synthetic route for IBMC-025 is shown below:
specific synthetic procedure for IBMC-025: step 1: synthesis of 1 OH-02: 65mmol of 1OH-1 (3, 5-dihydroxybenzoic acid), 195mmol of borane tetrahydrofuran are dissolved in 100mL of ultra-dry THF and stirred at room temperature for 24h; the reaction mixture was quenched with saturated ammonium chloride, washed with saturated sodium chloride and then with anhydrous NaSO 4 Drying and purification by silica gel column gave 1OH-02 (5.9 g, 65%). 1 H NMR(400MHz,DMSO-d6)δ9.05(s,2H),6.17(d,J＝2.2Hz,2H),6.05(t,J＝2.2Hz,1H),4.98(t,J＝5.8Hz,1H),4.30(d,J＝5.8Hz,2H)。
Step 2: synthesis of 1 OH-03: 71.4mmol of 1OH-02 and 35.7mmol of benzyl bromoacetate are dissolved in 200mL of acetonitrile, potassium carbonate is added to 71.4mmol of the mixture at 50 ℃ for 4 hours, the reaction solution is cooled to room temperature and filtered, and the filtrate is dried by spin-drying and then purified by a silica gel column to obtain 1OH-03 (3.61 g, 59%). 1 H NMR(400MHz,Chloroform-d)δ7.39–7.27(m,5H),7.13(s,1H),6.44–6.36(m,1H),6.32(dd,J＝2.3,1.2Hz,1H),6.25(t,J＝2.3Hz,1H),5.18(s,2H),4.52(s,2H),4.42(d,J＝2.8Hz,2H)。
Step 3: synthesis of 1 OH-04: 11.1mmol of 1OH-03 and 44.4mmol of imidazole are dissolved in 100mL of anhydrous dichloromethane, tert-butyldimethyl chlorosilane is dissolved in 20mL of anhydrous dichloromethane, the mixture is added dropwise to the reaction solution, the reaction is carried out at room temperature for 4h, and the target product 1OH-04 (5.6 g, 97.7%) is obtained by spin-drying and column purification. 1 H NMR(400MHz,Chloroform-d)δ7.39–7.31(m,5H),6.48(tq,J＝2.1,0.9Hz,2H),6.30(t,J＝2.3Hz,1H),5.24(s,2H),4.63(d,J＝1.7Hz,4H),0.97(s,9H),0.94(s,9H),0.18(s,6H),0.09(s,6H)。
Step 4: synthesis of 1 OH-05: 0.7g of 1OH-04 and 0.07g of Pd/C were dissolved in 20mL of methanol and stirred at room temperature for 1 hour. The spin-dried solvent was filtered and purified on a silica gel column to give 1OH-05 (0.44 g, 76%). 1 H NMR(400MHz,Chloroform-d)δ6.52–6.44(m,2H),6.31(s,1H),4.64(s,2H),4.60(s,2H),0.96(s,9H),0.93(s,9H),0.18(s,6H),0.08(s,6H)。
Step 5: synthesis of 1 OH-06: 3.3mmol of 1OH-05 was dissolved in 50mL of methylene chloride, 4.95mmol of T-13, 14.85mmol of 4-dimethylaminopyridine, 9.9mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride were added in this order, and the mixture was stirred at room temperature for 8 hours, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried and purified by silica gel column to give the objective product 1OH-06 (3.07 g, 86%). 1 H NMR(400MHz,Chloroform-d)δ6.47(ddt,J＝3.4,2.2,1.2Hz,2H),6.28(t,J＝2.3Hz,1H),4.99(qd,J＝7.2,5.2Hz,1H),4.63(s,2H),4.55(s,2H),4.04(t,J＝6.6Hz,4H),2.30(tt,J＝8.9,5.3Hz,2H),1.59(dq,J＝11.2,6.6Hz,12H),1.46–1.38(m,4H),1.33–1.21(m,48H),0.96(s,9H),0.93(s,9H),0.90–0.84(m,12H),0.18(s,6H),0.08(s,6H)。
Step 6: synthesis of 1 OH-07: 0.92mmol of 1OH-06 was dissolved in 50mL of dichloromethane, 1.2mL of saturated concentrated hydrochloric acid was added dropwise, the reaction was carried out for 6h, and after spin-drying, the target product 1OH-07 (0.68 g, 76%) was obtained by purification on a silica gel column. 1 H NMR(400MHz,Chloroform-d)δ6.52(dd,J＝2.2,1.3Hz,1H),6.48(dd,J＝2.2,1.3Hz,1H),6.33(t,J＝2.3Hz,1H),4.99(qd,J＝7.2,5.1Hz,1H),4.58(d,J＝5.3Hz,4H),4.03(t,J＝6.7Hz,4H),2.30(tt,J＝8.9,5.4Hz,2H),1.62–1.52(m,12H),1.46–1.38(m,4H),1.33–1.20(m,48H),0.97(s,9H),0.90–0.84(m,12H),0.19(s,6H)。
Step 7: synthesis of 1 OH-08: 0.21mmol of 1OH-07 was dissolved in 15mL of methylene chloride, and 0.41mmol of N, N-dimethylaminobutyrate hydrochloride, 75.13mmol of 4-dimethylaminopyridine, 94.32mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and then, were added to the solution to react at room temperature for 12 hours, the solution was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and spin-dried, and purified by a silica gel column to give the objective product 1OH-08 (0.16 g, 71.7%). 1 H NMR(400MHz,Chloroform-d)δ6.50(t,J＝1.9Hz,1H),6.45(t,J＝1.8Hz,1H),6.35(t,J＝2.3Hz,1H),5.04–4.94(m,3H),4.56(s,2H),4.04(t,J＝6.6Hz,4H),2.51(t,J＝7.6Hz,2H),2.43(t,J＝7.2Hz,2H),2.38(s,6H),2.29(ddd,J＝8.9,5.4,3.6Hz,2H),1.91(p,J＝7.3Hz,2H),1.63–1.50(m,12H),1.45–1.37(m,4H),1.24(s,48H),0.96(s,9H),0.90–0.83(m,12H),0.18(s,6H)。
Step 8: synthesis of IBMC-025: 0.046mmol of 1OH-08 was dissolved in 8mL of tetrahydrofuran, 1mL of 1M TBAF tetrahydrofuran was added, reacted at room temperature for 2 hours, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and spin-dried, and purified by silica gel column to give the objective product IBMC-025 (20 mg, 44.7%). 1 H NMR (400 mhz, chloroform-d) delta 6.39 (d, j=1.8 hz, 1H), 6.34 (t, j=1.8 hz, 1H), 6.26 (t, j=2.3 hz, 1H), 4.96-4.88 (m, 3H), 4.51 (s, 2H), 3.99 (tt, j=6.7, 3.2hz, 4H), 2.32 (td, j=8.2, 7.7,5.8hz, 4H), 2.27-2.18 (m, 8H), 1.79 (q, j=7.5 hz, 2H), 1.58-1.43 (m, 12H), 1.40-1.33 (m, 4H), 1.18 (d, j=3.5 hz, 48H), 0.80 (t, j=6.7 hz, 12H), nuclear magnetic hydrogen spectra are shown in fig. 16.
Example 17: specific synthetic procedure for IBMC-028: 0.0558mmol of Bi-150013 and 0.223mmol of 1, 4-bis (2-hydroxyethyl) piperazine were dissolved in 5mL of methylene chloride, 0.1674mmol of 4-dimethylaminopyridine, 0.279mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride were added, stirring was performed at room temperature for 8 hours, methylene chloride extraction, washing with saturated sodium chloride, drying over anhydrous sodium sulfate and spin-drying, purification was performed by silica gel column to give IBMC-028 (18 mg, 26.73%). 1 H NMR(400MHz,Chloroform-d)δ8.28(d,J＝1.6Hz,1H),7.76(d,J＝1.4Hz,2H),5.00(td,J＝7.0,3.5Hz,1H),4.70(s,2H) The nuclear magnetic hydrogen spectra are shown in fig. 17, 4.46 (t, j=5.9 hz, 4H), 4.04 (t, j=6.6 hz, 4H), 3.65-3.56 (m, 4H), 2.78 (t, j=5.9 hz, 4H), 2.65-2.52 (m, 16H), 2.34-2.18 (m, 6H), 1.65-1.17 (m, 64H), 0.86 (t, j=6.7 hz, 12H).
The specific synthetic procedure of Bi-150013 is the same as in example 1.
Example 18: the specific synthetic procedure for IBMC-029 is as in example 17. Hydrogen spectrum of IBMC-029: 1 h NMR (400 mhz, chloro-d) delta 8.30 (d, j=1.6 hz, 1H), 7.76 (dt, j=14.5, 2.2hz, 2H), 5.01 (p, j=6.1 hz, 1H), 4.70 (s, 2H), 4.46 (t, j=6.0 hz, 2H), 4.04 (t, j=6.6 hz, 4H), 3.93 (s, 2H), 3.62 (t, j=5.4 hz, 2H), 2.79 (t, j=6.0 hz, 2H), 2.71-2.50 (m, 8H), 2.31 (dt, j=14.3, 5.7hz, 2H), 1.65-1.18 (m, 64H), 0.86 (t, j=6.7 hz), nuclear magnetic hydrogen spectra are shown in fig. 18.
Example 19: specific synthetic procedure for IBMC-030: 0.057mmol Bi-070013 is dissolved in 5mL dichloromethane, 0.229mmol 4- (4-methyl-1-piperazinyl) butanoic acid, 0.348 mmol 4-dimethylaminopyridine, 0.229mmol 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride are added sequentially, reacted for 12h at room temperature, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and spun dry, purified by silica gel column to give the target product IBMC-030 (40 mg, 57.7%). 1H NMR (400 MHz, chloride-d) delta 6.94 (s, 1H), 6.85 (s, 2H), 5.05 (s, 4H), 4.98 (q, J=6.3 Hz, 1H), 4.60 (s, 2H), 4.03 (t, J=6.6 Hz, 4H), 2.68-2.41 (m, 16H), 2.39 (t, J=7.3 Hz, 8H), 2.33 (s, 6H), 1.83 (p, J=7.3 Hz, 4H), 1.56 (dd, J=13.4, 7.0Hz, 12H), 1.45-1.18 (m, 54H), 0.86 (t, J=6.6 Hz, 12H), nuclear magnetic hydrogen spectra are shown in FIG. 19.
The specific synthetic procedure for Bi-070013 is as in example 4.
Example 20: specific synthetic procedures for IBMC-031: 0.171mmol Bi-070013 is dissolved in 8mL methylene chloride, 0.086mmol 4- (4-methyl-1-piperazinyl) butyric acid, 0.258mmol 4-dimethylaminopyridine, 0.103mmol 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride are added in sequence, the reaction is carried out for 12h at room temperature, saturated sodium chloride solution is washed, anhydrous sodium sulfate is dried, and then the mixture is purified by silica gel column to obtain the target product IBMC-031 (89.68 mg, 50.3%). 1 H NMR(400MHz,Chloroform-d)δ6.99(s,1H),6.91–6.77(m,2H),5.07(s,2H),5.06–4.95(m,1H)The nuclear magnetic resonance hydrogen spectrum is shown in fig. 20, 4.64 (d, j=15.0 hz, 4H), 4.04 (t, j=6.7 hz, 4H), 2.69-2.16 (m, 17H), 1.84 (p, j=7.2 hz, 2H), 1.71-1.12 (m, 64H), 0.87 (t, j=6.7 hz, 12H).
The specific synthetic procedure for Bi-070013 is as in example 4.
Example 21: the synthetic route for IBMC-034 is shown below:
specific synthetic procedure for IBMC-034: step 1: synthesis of m 46-02: 0.017mmol of m46-01 and 0.0187mmol of potassium acetate are dissolved in 30mL of DMF and stirred at room temperature for 5h, the reaction is quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride and then with anhydrous NaSO 4 Drying and purification by silica gel column gave m46-02 (1.81 g, 54.7%). 1 H NMR(400MHz,Chloroform-d)δ11.04(d,J＝0.5Hz,1H),9.90(d,J＝0.6Hz,1H),7.60–7.57(m,1H),7.56–7.52(m,1H),7.00(d,J＝8.5Hz,1H),5.08(s,2H),2.10(s,3H)。
Step 2: synthesis of m 46-03: 3.09mmol of M46-02 was dissolved in 20mL of 1M NaOH solution and stirred at room temperature for 5h. The reaction mixture was adjusted to ph=3.5 with 6M hydrochloric acid, extracted with ethyl acetate, washed with saturated sodium chloride and then with anhydrous NaSO 4 Drying and purification by silica gel column gave m46-03 (0.42 g, 89.4%). 1 H NMR(400MHz,Chloroform-d)δ11.00(s,1H),9.90(s,1H),7.58(d,J＝2.2Hz,1H),7.53(dd,J＝8.5,2.3Hz,1H),6.99(d,J＝8.6Hz,1H),4.69(s,2H)。
Step 3: synthesis of m 46-04: 3.16mmol m46-04, 3.79mmol methyl bromoacetate are dissolved in 20mL acetonitrile, 4.75mmol potassium carbonate is added, and the mixture is refluxed at 80℃and reacted for 4h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was dried by spin-drying, followed by purification on a silica gel column to give m46-04 (0.42 g, 59.4%). 1 H NMR(400MHz,Chloroform-d)δ10.54(s,1H),7.84(d,J＝2.4Hz,1H),7.58(dd,J＝8.5,2.4Hz,1H),6.87(d,J＝8.5Hz,1H),4.78(s,2H),4.67(s,2H),3.82(s,3H)。
Step 4: synthesis of m 46-05: 1.16mmol of m46-04, 2.32mmol of imidazole are dissolved in 20mL of anhydrous dichloromethane, tert-butyldimethylAfter the chlorosilane is dissolved in 5mL of anhydrous dichloromethane, the solution is added dropwise to the reaction solution, the reaction is carried out for 4 hours at room temperature, and the target product m46-05 (0.28 g, 71.4%) is obtained after spin-drying and column purification. 1 H NMR(400MHz,Chloroform-d)δ10.55(s,1H),7.83–7.71(m,1H),7.55(ddt,J＝8.5,2.2,0.7Hz,1H),6.84(d,J＝8.6Hz,1H),4.76(s,2H),4.69(d,J＝0.9Hz,2H),3.81(s,3H),0.93(s,9H),0.09(s,6H)。
Step 5: synthesis of m 46-06: 0.83mmol of m46-05 is dissolved in 10mL of methanol, 1.24mmol of sodium hydroxide is dissolved in 20mL of deionized water and added dropwise to the methanol solution for reaction for 2h, the solution is extracted with ethyl acetate after rotating to one third, and after drying over anhydrous sodium sulfate, the target product m46-06 (180 g, 67.2%) is obtained by spin-drying and column purification. 1 H NMR(400MHz,DMSO-d6)δ10.43(s,1H),7.61(d,J＝2.3Hz,1H),7.47(dd,J＝8.6,2.4Hz,1H),6.98(d,J＝8.6Hz,1H),4.64(s,2H),4.41(d,J＝5.2Hz,2H),0.89(s,9H),0.06(s,6H)。
Step 6: synthesis of m 46-07: 1.39mmol of m46-06 was dissolved in 40mL of dichloromethane, 2.78mmol of T-13, 5.56mmol of 4-dimethylaminopyridine, 4.17mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride were added in this order, and the mixture was stirred at room temperature for 8 hours, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried and purified by silica gel column to give the target product m46-07 (0.84 g, 61%). 1 H NMR(400MHz,Chloroform-d)δ10.55(s,1H),7.78(d,J＝2.3Hz,1H),7.57–7.50(m,1H),6.85(d,J＝8.6Hz,1H),4.99(p,J＝6.2Hz,1H),4.74(s,2H),4.69(s,2H),4.04(t,J＝6.7Hz,4H),2.30(tt,J＝8.9,5.3Hz,2H),1.61–1.54(m,12H),1.46–1.39(m,4H),1.25(d,J＝3.6Hz,48H),0.92(s,9H),0.89–0.84(m,12H),0.09(s,6H)。
Step 7: synthesis of m 46-08: 0.22mmol of m46-07 was dissolved in 20mL of dichloromethane, 0.025mL of saturated concentrated hydrochloric acid was added dropwise, stirred at room temperature for 8h, and spin-dried and purified by silica gel column to give the desired product m46-08 (0.13 g, 66.8%). 1 HNMR(400MHz,Chloroform-d)δ10.55(s,1H),7.84(d,J＝2.4Hz,1H),7.59(dd,J＝8.5,2.4Hz,1H),6.87(d,J＝8.6Hz,1H),5.03–4.96(m,1H),4.76(s,2H),4.67(s,2H),4.02(t,J＝6.7Hz,4H),2.30(tt,J＝8.9,5.3Hz,2H),1.60–1.53(m,12H),1.42(td,J＝8.0,3.9Hz,4H),1.26(d,J＝9.0Hz,48H),0.87(t,J＝6.7Hz,12H)。
Step 8: synthesis of m 46-09: 0.15mmol of m46-08 is dissolved in 10mL of dichloromethane, 0.3mmol of N, N-dimethylaminobutyrate hydrochloride, 0.75mmol of 4-dimethylaminopyridine and 0.36mmol of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride are added in sequence, the mixture is reacted for 12h at room temperature, saturated sodium chloride solution is washed, anhydrous sodium sulfate is dried and then spin-dried, and the mixture is purified by a silica gel column to obtain a target product IBMC-004 (0.12 g, 81.6%). 1 H NMR(400MHz,Chloroform-d)δ10.54(s,1H),7.86(d,J＝2.4Hz,1H),7.53(dd,J＝8.6,2.4Hz,1H),6.85(d,J＝8.5Hz,1H),5.06(s,2H),4.99(p,J＝6.1Hz,1H),4.75(s,2H),4.04(t,J＝6.6Hz,4H),2.38(t,J＝7.4Hz,2H),2.33–2.26(m,4H),2.21(s,6H),1.80(p,J＝7.4Hz,2H),1.63–1.52(m,12H),1.46–1.39(m,4H),1.32–1.20(m,48H),0.89–0.84(m,12H)。
Step 9: synthesis of IBMC-034: 0.05mmol of m46-09 was dissolved in 8mL of methanol, 0.056mmol of sodium borohydride was added, the reaction was performed at room temperature for 2h, the solvent was spin-dried, and purified by silica gel column to give the target product IBMC-034 (17.5 g, 35%). 1 H NMR (400 mhz, chloroform-d) delta 7.34 (d, j=2.2 hz, 1H), 7.23 (dd, j=8.3, 2.3hz, 1H), 6.76 (d, j=8.3 hz, 1H), 5.05 (s, 2H), 4.98 (p, j=6.3 hz, 1H), 4.71 (d, j=14.1 hz, 4H), 4.04 (t, j=6.6 hz, 4H), 3.64 (s, 1H), 2.52 (t, j=7.7 hz, 2H), 2.41 (d, j=7.7 hz, 8H), 2.30 (tt, j=8.9, 5.3hz, 2H), 1.91 (p, j=7.2 hz, 2H), 1.58 (dt, j=13.4, 6.5hz, 12H), 1.42 (t, 6.6hz, 9hz, 7.9 hz), and (t, 9hz, 7.7H), and 48H, as shown in the magnetic spectrum (s, 1H, 7.7hz, 7H).
Example 22: specific synthetic procedure for IBMC-035: 0.022mmol Bi-150013, 0.067mmol EDCI and 0.067mmol HOBT are dissolved in 5mL of dichloromethane, after 1h N, N-dimethylpropanolamine 0.088mmol, DIEA 0.088mmol are added, stirred at room temperature for 8h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried purified with a silica gel column to give IBMC-035 (8 mg, 32%). 1 H NMR (400 mhz, chloro-d) delta 8.74 (t, j=4.8 hz, 2H), 7.96 (s, 1H), 7.52 (s, 2H), 4.99 (t, j=6.2 hz, 1H), 4.70 (s, 2H), 4.04 (t, j=6.6 hz, 4H), 3.56 (q, j=5.6 hz, 4H), 2.59 (t, j=6.1 hz, 4H), 2.40 (s, 12H), 2.30 (ddd, j=8.8, 5.3,3.5hz, 2H), 1.83 (p, j=6.1 hz, 4H), 1.64-1.19 (m, 64H), 0.87 (t, j=6.7 hz, 12H), nuclear magnetic hydrogen spectra as shown in fig. 2.40 (b, 12H)Shown at 22.
The specific synthetic procedure of Bi-150013 is the same as in example 1.
Example 23: specific synthetic procedure for IBMC-036: 0.022mmol Bi-150013, 0.067mmol EDCI and 0.067mmol HOBT were dissolved in 5mL of dichloromethane, after 1h morpholinopropanol 0.088mmol, DIEA 0.088mmol were added thereto, stirred at room temperature for 8h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried purified with silica gel column to give IBMC-036 (14 mg, 54.73%). 1 H NMR (400 mhz, chloroform-d) delta 8.06 (t, j=4.8 hz, 2H), 7.87 (d, j=1.6 hz, 1H), 7.52 (d, j=1.4 hz, 2H), 5.04-4.96 (m, 1H), 4.72 (s, 2H), 4.06 (dt, j=10.4, 6.6hz, 4H), 3.74 (t, j=4.6 hz, 8H), 3.57 (q, j=5.8 hz, 4H), 2.53 (dt, j=18.6, 5.3hz, 12H), 2.30 (tt, j=8.8, 5.4hz, 2H), 1.81 (q, j=6.1 hz, 4H), 1.65-1.20 (m, 64H), 0.87 (td, j=6.8, 1.5hz, 12H), nuclear magnetic spectrum as shown in fig. 23.
The specific synthetic procedure of Bi-150013 is the same as in example 1.
Example 24: specific synthetic procedure for IBMC-037: 0.022mmol Bi-150013, 0.067mmol EDCI and 0.067mmol HOBT were dissolved in 5mL of dichloromethane, after 1h 0.088mmol DIEA and 0.088mmol morpholinoethanol were added thereto, stirred at room temperature for 8h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and spin-dried purified with silica gel column to give IBMC-037 (14 mg, 56%). 1 H NMR (400 mhz, chloro-d) delta 8.10-8.02 (m, 2H), 7.88 (s, 1H), 7.53 (d, j=1.4 hz, 2H), 5.00 (p, j=6.5 hz, 1H), 4.71 (s, 2H), 4.04 (t, j=6.6 hz, 4H), 3.74 (t, j=4.7 hz, 8H), 3.57 (q, j=5.8 hz, 4H), 2.62-2.43 (m, 10H), 2.30 (tt, j=8.8, 5.4hz, 2H), 1.80 (p, j=6.0 hz, 4H), 1.66-1.20 (m, 62H), 0.87 (td, j=6.8, 1.5hz, 12H), nuclear magnetic hydrogen spectra are shown in fig. 24.
The specific synthetic procedure of Bi-150013 is the same as in example 1.
Example 25: the synthetic route for IBMC-040 is shown below:
specific synthetic procedure for IBMC-040: step 1: si-H02 combinationThe method comprises the following steps: 36.2mmol of Si-H01 (p-hydroxybenzoic acid), 38.0mmol of benzyl bromide and 43.4mmol of sodium carbonate were dissolved in 150mL of DMF and stirred at 60℃for 5H. Dilute methylene chloride, wash with water, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate and concentrate, and separate by column chromatography to give Si-H02 (7.1 g, 85.9%). 1 H NMR(400MHz,Chloroform-d)δ8.00(d,J＝8.8Hz,2H),7.48–7.30(m,5H),6.85(d,J＝8.8Hz,2H),5.34(s,1H),5.18(s,1H)。
Step 2: synthesis of Si-H0303: 3.0mmol of Si-H02, 6.0mmol of cesium carbonate and 3.3mmol of T-13-Br are dissolved in 100mL of DMF and stirred at 80℃for 5H, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated by evaporation and separated by column chromatography to give Si-H0303 (1.2 g, 44.6%). 1 H NMR(400MHz,Chloroform-d)δ8.01(d,J＝8.9Hz,2H),7.46–7.27(m,5H),6.87(d,J＝8.9Hz,2H),5.33(s,2H),4.31(p,J＝5.8Hz,1H),4.05(t,J＝6.6Hz,4H),2.30(tt,J＝9.0,5.3Hz,2H),1.76–1.50(m,11H),1.50–1.33(m,9H),1.24(br,42H),0.94–0.77(m,12)。
Step 3: synthesis of Si-H030003: 2.5mmol of Si-H0303 and 80mg of palladium on carbon were dissolved in 20mL of tetrahydrofuran, hydrogen gas was introduced, the mixture was stirred at 25℃for 12 hours, the reaction mixture was filtered through celite, and Si-H030003 (450.0 mg, 67.0%) was obtained by evaporation and concentration. 1 H NMR(400MHz,Chloroform-d)δ8.02(d,J＝8.6Hz,2H),6.88(d,J＝8.6Hz,2H),4.33(p,J＝5.9Hz,1H),4.05(t,J＝6.6Hz,4H),2.29(tt,J＝8.9,5.3Hz,2H),1.79–1.51(m,8H),1.51–1.32(m,12H),1.25(m,44H),0.94–0.81(m,12H)。
Step 4: synthesis of IBMC-040: 124.8. Mu. Mol of Si-H030003, 282.6. Mu. Mol of N, N-dimethylpropanolamine and 374.4. Mu. Mol of DMAP were dissolved in 15mL of anhydrous DCM, stirred at 25℃for 24H, saturated brine, dried over anhydrous sodium sulfate, concentrated by evaporation, and separated by column chromatography to give IBMC-040 (18 mg, 10.3%). 1 H NMR (400 mhz, chloroform-d) delta 8.03-7.89 (m, 2H), 6.92-6.81 (m, 2H), 4.33 (dt, j=14.9, 6.0hz, 3H), 4.05 (t, j=6.6 hz, 4H), 2.60 (t, j=7.6 hz, 2H), 2.39 (s, 6H), 2.32-2.24 (m, 2H), 2.09-1.98 (m, 2H), 1.62 (ddq, j=22.2, 14.7,8.4,6.9hz, 12H), 1.48-1.33 (m, 12H), 1.25 (d, j=3.8 hz, 40H), 0.87 (td, j=6.9, 2.3hz, 12H), nuclear magnetic hydrogen spectra are shown in fig. 25.
The specific synthesis steps of T-13-Br are as follows: 3.7mmol of carbon tetrabromide and 3.7mmol of triphenylphosphine were dissolved in 20mL of anhydrous tetrahydrofuran, stirred at room temperature, 1.2mmol of T-13 was added, the mixture was heated to 45℃and reacted for 1 hour, and the mixture was concentrated by evaporation and separated by column chromatography to give T-13-Br (1.0 g, 92.9%). 1 H NMR(400MHz,Chloroform-d)δ4.07(t,J＝6.6Hz,4H),4.00(tt,J＝8.0,5.0Hz,1H),2.31(tt,J＝8.9,5.3Hz,2H),1.93–1.73(m,4H),1.71–1.52(m,9H),1.51–1.33(m,8H),1.32–1.08(m,42H),0.87(t,J＝6.7Hz,12H)。
Example 26: specific synthetic procedures for IBMC-041 differ from those of example 24: morpholinopropanol is used instead of N, N-dimethylpropanolamine. Hydrogen spectrum of IBMC-041: 1 h NMR (400 mhz, chloroform-d) delta 8.00-7.89 (m, 2H), 6.94-6.80 (m, 2H), 4.33 (dt, j=14.0, 6.1hz, 3H), 4.05 (t, j=6.6 hz, 4H), 3.74-3.70 (m, 4H), 2.50 (dd, j=13.3, 5.9hz, 4H), 2.29 (tt, j=8.9, 5.4hz, 2H), 2.00-1.89 (m, 2H), 1.70-1.52 (m, 12H), 1.48-1.33 (m, 12H), 1.30-1.19 (m, 42H), 0.87 (td, j=6.9, 2.3hz, H), nuclear magnetic hydrogen spectra are shown in fig. 26.
Example 27: specific synthetic procedure for IBMC-042 differs from example 24: 3- (4-methyl-1-piperazinyl) -1-propanol was used instead of N, N-dimethylpropanolamine. Hydrogen spectrum of IBMC-042: 1 h NMR (400 MHz, chloroform-d) delta 8.01-7.88 (m, 2H), 6.95-6.78 (m, 2H), 4.32 (dt, J=8.8, 6.0Hz, 3H), 4.05 (t, J=6.6 Hz, 4H), 2.66-2.44 (m, 8H), 2.33 (s, 3H), 2.32-2.25 (m, 2H), 1.99-1.91 (m, 2H), 1.71-1.52 (m, 12H), 1.48-1.33 (m, 12H), 1.25 (d, J=3.8 Hz, 42H), 0.87 (td, J=6.9, 2.3Hz, 12H), nuclear magnetic hydrogen spectra are shown in FIG. 27.
Example 28: the synthetic route for IBMC-043 is shown below:
specific synthetic procedure for IBMC-043: step 1: synthesis of Si-H03: 8.8mmol of Si-H02, 17.5mmol of cesium carbonate and 9.6mmol of N, N-dimethyl-3-chloropropylamine are dissolved in 100mL of DMF and stirred at 80 ℃ for 5H, diluted with dichloromethane, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated by evaporation, and the column layerThe Si-H03 (1.8 g, 65.6%) was obtained by separation. 1 H NMR(400MHz,Chloroform-d)δ8.01(d,J＝9.0Hz,2H),7.47–7.30(m,5H),6.91(d,J＝8.9Hz,2H),5.33(s,2H),4.07(t,J＝6.4Hz,2H),2.46(t,J＝7.2Hz,2H),2.26(s,4H),1.98(p,2H)。
Step 2: synthesis of Si-H04: 2.55mmol of Si-H03 and 80mg of palladium on carbon were dissolved in 20mL of methanol, hydrogen was introduced, and the mixture was stirred at 25℃for 12 hours, and concentrated by evaporation to give Si-H04 (550 mg, 96.5%). 1 H NMR(400MHz,Methanol-d4)δ7.87(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),4.13(t,J＝5.9Hz,2H),3.14(t,J＝7.7Hz,2H),2.77(s,6H),2.16(p,2H)。
Step 3: synthesis of IBMC-043: 223.9. Mu. Mol of Si-H04, 268.7. Mu. Mol of T-13, 335.9. Mu. Mol of EDCI and 671.8. Mu. Mol of DMAP were dissolved in 15mL of DCM and stirred at 30℃for 24H, the reaction was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated by evaporation and column chromatography to give IBMC-043 (40 mg, 23.1%). 1 H NMR (400 mhz, chloro-d) delta 7.97 (d, j=8.9 hz, 2H), 6.91 (d, j=8.9 hz, 2H), 5.10 (dq, j=9.8, 3.7,2.4hz, 1H), 4.08 (t, j=6.3 hz, 2H), 4.04 (t, j=6.6 hz, 4H), 3.75 (t, j=4.7 hz, 2H), 2.53 (br, 6H), 2.29 (tt, j=9.0, 5.4hz, 2H), 2.02 (br, 2H), 1.73-1.47 (m, 8H), 1.48-1.31 (m, 12H), 1.24 (s, 44H), 0.90-0.83 (m, 12H), nuclear magnetic hydrogen spectra are shown in fig. 28.
Example 29:
the specific synthetic procedure for IBMC-044 differs from that of example 28: t-11 was used instead of T-13. Hydrogen spectrum of IBMC-044: 1 h NMR (400 MHz, chloroform-d) delta 2.13 (s, 6H), 2.29 (t, 2H), 1.85 (m, 2H), 3.97-4.05 (t, 6H), 7.05-7.93 (dd, 4H), 4.42 (m, 1H), 2.15 (m, 1H), 2.29 (t, 2H), 1.29-1.63 (m, 52H), 0.93 (t, 9H), nuclear magnetic resonance hydrogen spectra are shown in FIG. 29.
Example 30: the synthetic route for IBMC-048 is shown below:
the synthetic procedure of IBMC-048 differs from that of example 29:
1) The synthesis method of Si-H05 is different from Si-H03: morpholinopropanol is adopted to replace N, N-dimethyl-3-chloropropylamine;
2) The synthesis method of Si-H06 is different from Si-H04: si-H05 was used instead of Si-H03.
Hydrogen spectrum of IBMC-048: 1 h NMR (400 MHz, chloroform-d) delta 7.97 (d, J=8.9 Hz, 2H), 6.91 (d, J=8.9 Hz, 2H), 5.19-4.98 (m, 1H), 4.08 (t, J=6.3 Hz, 2H), 4.04 (t, J=6.6 Hz, 4H), 3.84-3.59 (m, 4H), 2.53 (br, 6H), 2.02 (br, 2H), 1.72-1.50 (m, 12H), 1.47-1.32 (m, 12H), 1.24 (m, 40H), 0.92-0.81 (m, 12H), nuclear magnetic hydrogen spectra are shown in FIG. 30.
Example 31: the synthetic route for IBMC-051 is shown below:
specific synthetic steps of IBMC-051:
step 1: synthesis of Bi-070813: 0.277mmol of Bi-070013 is dissolved in 10mL of dichloromethane, 0.138mmol C3Y09,4-dimethylaminopyridine 0.415mmol, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.166mmol are added sequentially, the reaction is carried out at room temperature for 12h, saturated sodium chloride solution is washed, anhydrous sodium sulfate is dried and then spin-dried, and the target product Bi-070813 (71 mg, 45.5%) is obtained after purification by silica gel column. 1 H NMR(400MHz,Chloroform-d)δ6.93(s,1H),6.80(dt,J＝13.8,2.1Hz,2H),5.02(s,2H),5.01–4.91(m,1H),4.59(d,J＝14.8Hz,4H),3.98(t,J＝6.7Hz,4H),3.64(t,J＝6.5Hz,2H),2.45(t,J＝6.5Hz,2H),2.39–2.21(m,6H),2.20(s,3H),1.75(p,J＝7.4Hz,2H),1.61–1.11(m,64H),0.83(m,18H)。
Step 2: synthesis of IBMC-051: 0.075mmol Bi-070813 is dissolved in 4mL dichloromethane, 1.52mL saturated concentrated hydrochloric acid is added dropwise, reacted for 12h, and spin-dried and purified by silica gel column to obtain the target product IBMC-051 (23 mg, 30.1%). 1 H NMR (400 mhz, chloroform-d) delta 6.94 (s, 1H), 6.77 (dt, j=10.1, 2.2hz, 2H), 5.01 (s, 2H), 4.92 (td, j=7.2, 3.6hz, 1H), 4.57 (d, j=10.8 hz, 4H), 3.97 (t, j=6.7 hz, 4H), 3.60-3.44 (m, 2H), 2.56-2.47 (m, 2H), 2.45 (t, j=7.1 hz, 2H), 2.35 (t, j=7.0 hz, 2H), 2.29-2.19 (m, 5H), 1.81 (p, j=7.0 hz, 2H), 1.58-1.10 (m, 64H), 0.80 (t, j=6.7 hz, 12H), nuclear magnetic hydrogen as shown in fig. 31.
The specific synthetic procedure for Bi-070013 is as in example 4.
The synthetic route for C3Y09 is as follows:
specific synthesis steps of C3Y 09: step 1: synthesis of C3-2: 6.52mmol of C3-1 (4- (methylamino) butanoic acid methyl ester hydrochloride) and 19.5mmol of potassium carbonate were dissolved in 40mL of acetonitrile, the temperature was raised to 50℃and after addition of 8.5mmol of (2-bromoethoxy) -tert-butyldimethylsilane, the mixture was refluxed for 5 hours at 80℃and after completion of the reaction, the solvent was dried by spinning and purified by column chromatography to give C3-2 (1.25 g, 66.4%). 1 H NMR(400MHz,Chloroform-d)δ3.68(td,J＝6.6,1.3Hz,2H),3.65(d,J＝1.4Hz,3H),2.50(td,J＝6.6,1.4Hz,2H),2.40(dd,J＝7.9,6.5Hz,2H),2.33(td,J＝7.5,1.4Hz,2H),2.25(d,J＝1.4Hz,3H),1.77(pd,J＝7.4,1.3Hz,2H),0.88(d,J＝1.4Hz,9H),0.06(d,J＝1.2Hz,6H)。
Step 2: synthesis of C3Y 09: 1.72mmol of C3-2 and 5.2mmol of sodium hydroxide were dissolved in 10mL of methanol and 5mL of water, stirred at room temperature for 3 hours, after the reaction was completed, methanol was distilled off by spin, the ethyl acetate was washed, the aqueous phase was acidified with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and dried by spin to give C3Y09 (0.35 g, 74%). 1 H NMR(400MHz,Chloroform-d)δ3.93–3.82(m,2H),2.83(qd,J＝5.4,3.1Hz,4H),2.64–2.56(m,2H),2.53(s,3H),1.87–1.77(m,2H),0.89(s,9H),0.07(d,J＝2.7Hz,6H)。
Example 32: specific synthetic procedure for IBMC-052: 0.125mmol Bi-070013 is dissolved in 10mL methylene dichloride, N-dimethyl amino butyrate hydrochloride 0.498mmol, 4-dimethyl amino pyridine 0.747mmol, 1-ethyl- (3-dimethyl amino propyl) carbodiimide hydrochloride 0.597mmol are added sequentially, the reaction is carried out for 12h at room temperature, saturated sodium chloride solution is washed, anhydrous sodium sulfate is dried, spin-dried and purified by silica gel column to obtain the target product IBMC-052 (40 mg, 33.8%). 1 H NMR(400MHz,Chloroform-d)δ6.89(d,J＝1.7Hz,1H),6.79(d,J＝1.4Hz,2H),5.00(s,4H),4.93(td,J＝7.0,3.5Hz,1H),4.54(s,2H),3.98(t,J＝6.6Hz,4H),2.34(t,J＝7.4Hz,4H),2.30–2.25(m,4H),2.24-2.21 (m, 2H), 2.18 (s, 12H), 1.78 (H, j=7.4, 6.9hz, 4H), 1.59-1.08 (m, 64H), 0.83-0.77 (m, 12H), nuclear magnetic resonance hydrogen spectrum is shown in fig. 32.
The specific synthetic procedure for Bi-070013 is as in example 4.
Example 33: the synthetic route for IBMC-053 is shown below:
specific synthetic procedure for IBMC-053: step 1: synthesis of JY-02: 2.43mmol JY-01 (2- (4-methoxyphenyl) malonic acid-1, 3-dimethyl ester) was dissolved in 10mL anhydrous DCM, 2.92mmol of boron tribromide was added at-20℃and stirred overnight, the reaction was quenched with ice-water mixture and extracted three times with DCM, the organic phase was combined and dried over anhydrous Na 2 SO 4 Drying and column chromatography gave JY-02 (0.84 g, 90.0%). 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.27(d,J＝8.6Hz,2H),6.81(d,J＝8.6Hz,2H),4.58(s,1H),3.75(s,6H)。
Step 2: synthesis of JY-03: 2.85mmol JY-02 was dissolved in 15mL acetonitrile and 4.28mmol Cs was added 2 CO 3 3.43mmol (3-bromopropyl) dimethylamine, and then stirred at 60℃for 12 hours, after the completion of the reaction, the mixture was filtered and dried by spin-drying, followed by column chromatography to give JY-03 (0.31 g, 35.0%). 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.16(d,J＝8.6Hz,2H),6.87(d,J＝8.6Hz,2H),4.12(t,J＝6.1Hz,2H),4.02-3.99(m,4H),3.48(s,1H),3.33(br,12H)。
Step 3: synthesis of IBMC-053: 1.21mmol JY-03 was dissolved in 5mL EtOH and 7.26mmol NaBH was added under ice-bath 4 Stirring at room temperature for reaction for 6h, and adding saturated NH after the reaction is finished 4 The reaction was quenched with aqueous Cl, extracted 3 times with DCM, dried by spin-drying and dissolved in dichloromethane, 3.02mmol ROH, 0.84mmol EDC, 0.84mmol DMAP were added sequentially and stirred at room temperature for 24h, after the reaction was completed, filtered, dried by spin-drying and column chromatography gave IBMC-053 (367.0 mg, 39.0%). 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.16-7.12(m,2H),6.87-6.82(m,2H),5.42-5.28(m,8H),3.81-3.78(m,7H),2.77(t,J＝6.4Hz,4H),2.12-2.02(m,8H) 1.58 (br, 4H), 1.37-1.23 (m, 42H), 0.89 (t, j=6.8 hz, 6H), nuclear magnetic hydrogen spectra are shown in fig. 33.
Example 34: specific synthetic procedure for IBMC-054: 223.9. Mu. Mol of Si-H04, 268.7. Mu. Mol of T-08, 335.9. Mu. Mol of EDCI and 671.8. Mu. Mol of DMAP were dissolved in 15mL of DCM, stirred at 30℃for 24H, washed with saturated NaCl, dried over anhydrous sodium sulfate, concentrated by evaporation and separated by column chromatography to give IBMC-054 (30 mg, 18.3%). 1 HNMR (400 mhz, chloro-d) delta 7.98 (d, j=8.5 hz, 2H), 6.90 (d, j=8.5 hz, 2H), 5.47-5.24 (m, 8H), 5.08 (q, j=6.2 hz, 1H), 4.08 (t, j=6.2 hz, 2H), 2.76 (t, j=6.5 hz, 2H), 2.62 (t, j=7.4 hz, 2H), 2.37 (s, 6H), 2.12-1.95 (m, 8H), 1.76-1.50 (m, 4H), 1.45-1.15 (m, 40H), 0.95-0.76 (m, 6H), nuclear magnetic hydrogen spectra are shown in fig. 34.
The specific synthetic procedure for Si-H04 was as in example 28.
The specific synthetic procedure for T-08 is as in example 3.
Example 35: the specific synthetic procedure for IBMC-055 differs from that of example 34: morpholinopropanol was used instead of N, N-dimethyl-3-chloropropylamine. Hydrogen spectrum of IBMC-055: 1 h NMR (400 mhz, chloroform-d) delta 7.98 (d, j=8.5 hz, 2H), 6.90 (d, j=8.7 hz, 2H), 5.34 (tq, j=10.9, 6.7,5.8hz, 8H), 5.08 (p, j=6.0 hz, 1H), 4.08 (t, j=6.2 hz, 2H), 3.82-3.62 (m, 4H), 2.76 (t, j=6.4 hz, 2H), 2.62-2.47 (m, 4H), 2.16-1.90 (m, 8H), 1.74-1.52 (m, 4H), 1.41-1.16 (m, 40H), 0.88 (t, j=6.7 hz, 6H), nuclear magnetic hydrogen spectra are shown in fig. 35.
Example 36: the specific synthetic procedure for IBMC-056 differs from that of example 3: morpholinopropanol was used instead of N-methyldiethanolamine. Hydrogen spectrum of IBMC-056: 1 h NMR (400 mhz, chloro-d) delta 8.29 (t, j=1.4 hz, 1H), 7.76 (d, j=1.4 hz, 2H), 5.00 (p, j=6.2 hz, 1H), 4.70 (s, 2H), 4.40 (t, j=6.6 hz, 4H), 3.75-3.68 (m, 8H), 2.55-2.36 (m, 12H), 1.96 (p, j=6.8 hz, 4H), 1.24 (q, j=3.5, 2.8hz, 68H), 0.90-0.85 (m, 6H), nuclear magnetic hydrogen spectra are shown in fig. 36.
Example 37: the specific synthetic procedure for IBMC-057 differs from that of example 3: n, N-dimethyl propanolamine is used to replace N-methyl diethanolamine. Hydrogen spectrum of IBMC-057: 1 H NMR(400MHz,Chloroform-d)δ8.31(d,J＝1.5Hz,1H),7.77(d,J＝1.4Hz, 2H), 5.01 (q, j=6.1 hz, 1H), 4.70 (s, 2H), 4.39 (t, j=6.6 hz, 4H), 2.44 (t, j=7.3 hz, 4H), 2.27 (s, 12H), 1.97 (H, j=6.8, 6.0hz, 4H), 1.54 (t, j=6.1 hz, 4H), 1.24 (d, j=5.4 hz, 64H), 0.88 (t, j=6.8 hz, 6H), nuclear magnetic hydrogen spectra are shown in fig. 37.
Example 38: the specific synthetic procedure for IBMC-058 differs from that of example 3: 1, 4-bis (2-hydroxyethyl) piperazine was used instead of N-methyldiethanolamine. Hydrogen spectrum of IBMC-058: 1 h NMR (400 mhz, chloro-d) delta 8.29 (t, j=1.5 hz, 1H), 7.77 (d, j=1.5 hz, 2H), 5.00 (p, j=6.2 hz, 1H), 4.70 (s, 2H), 4.47 (t, j=5.9 hz, 4H), 3.66-3.58 (m, 4H), 2.78 (q, j=7.0, 6.5hz, 4H), 2.54 (d, j=5.3 hz, 20H), 1.25 (d, j=4.9 hz, 68H), 0.90-0.85 (m, 6H), nuclear magnetic hydrogen spectra are shown in fig. 38.
Example 39: specific synthetic procedure for IBMC-059: 0.23mmol Bi-070013 is dissolved in 10mL methylene dichloride, 0.11mmol N, N-dimethylamino propionic acid hydrochloride, 0.34mmol 4-dimethylamino pyridine, 0.14mmol 1-ethyl- (3-dimethylamino propyl) carbodiimide hydrochloride are added in sequence, the reaction is carried out for 12h at room temperature, saturated sodium chloride solution is washed, anhydrous sodium sulfate is dried and then spin-dried, and the target product IBMC-059 (60 mg, 54.1%) is obtained by purifying with a silica gel column. 1 H NMR (400 mhz, chloro form-d) delta 6.97 (s, 1H), 6.86 (dt, j=13.6, 2.2hz, 2H), 5.09 (s, 2H), 5.02-4.97 (m, 1H), 4.64 (d, j=16.0 hz, 4H), 4.03 (t, j=6.7 hz, 4H), 2.69 (t, j=7.1 hz, 2H), 2.57 (t, j=6.9 hz, 2H), 2.34-2.24 (m, 8H), 1.62-1.52 (m, 12H), 1.42 (ddd, j=13.6, 7.2,3.4hz, 4H), 1.25 (s, 48H), 0.89-0.85 (m, 12H), nuclear magnetic hydrogen spectra are shown in fig. 39.
The specific synthetic procedure for Bi-070013 is as in example 4.
Example 40: specific synthetic procedure for IBMC-060: 0.23mmol Bi-070013 is dissolved in 10mL methylene dichloride, 0.11mmol N, N-dimethyl amino valeric acid hydrochloride, 0.34mmol 4-dimethyl amino pyridine and 0.14mmol 1-ethyl- (3-dimethyl amino propyl) carbodiimide hydrochloride are added in sequence to react for 12h at room temperature, saturated sodium chloride solution is washed, anhydrous sodium sulfate is dried and then spin-dried, and a silica gel column is used for purification to obtain a target product IBMC-060 (100 mg, 53.6%). 1 H NMR(400MHz,Chloroform-d)δ7.02(s,1H),6.80(dt,J＝13.9,2.1Hz,2H),5.06(s,2H),4.98(td,J＝7.2,3.6Hz1H), 4.62 (d, j=12.7hz, 4H), 4.02 (t, j=6.7hz, 4H), 2.79-2.73 (m, 2H), 2.57 (s, 6H), 2.41 (t, j=6.3hz, 2H), 2.29 (ddd, j=8.9, 7.1,4.5hz, 2H), 1.72-1.68 (m, 2H), 1.61-1.51 (m, 12H), 1.44-1.38 (m, 4H), 1.24 (d, j=7.9hz, 48H), 0.85 (t, j=6.7hz, 12H), nuclear magnetic hydrogen spectra are shown in fig. 40.
The specific synthetic procedure for Bi-070013 is as in example 4.
Example 41: specific synthetic steps of IBMC-061: 0.23mmol Bi-070013 is dissolved in 10mL methylene dichloride, 0.11mmol 1-piperidinepropionic acid, 0.34mmol 4-dimethylaminopyridine and 0.14mmo 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride are added in sequence, reacted for 12h at room temperature, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and spun dry, and purified by silica gel column to obtain the target product IBMC-061 (100 mg, 53.6%). 1 H NMR (400 mhz, chloro-d) delta 6.97 (s, 1H), 6.85 (d, j=18.1 hz, 2H), 5.07 (s, 2H), 5.00 (p, j=6.1 hz, 1H), 4.64 (d, j=14.3 hz, 4H), 4.04 (t, j=6.7 hz, 4H), 2.72 (t, j=7.4 hz, 2H), 2.59 (t, j=7.4 hz, 2H), 2.49-2.37 (m, 4H), 2.30 (tt, j=9.2, 5.3hz, 2H), 1.64-1.52 (m, j=5.5, 5.0hz, 16H), 1.43 (p, j=6.8 hz, 6H), 1.33-1.20 (m, 48H), 0.87 (t, j=6.5 hz, 12H), as shown in fig. 41.
The specific synthetic procedure for Bi-070013 is as in example 4.
Example 42: specific synthetic steps of IBMC-062: 0.23mmol Bi-070013 is dissolved in 10mL methylene dichloride, 0.11mmol 3-pyrrolidin-1-yl propionic acid, 0.34mmol 4-dimethylaminopyridine and 0.14mmol 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride are added in sequence, the reaction is carried out for 12h at room temperature, saturated sodium chloride solution is washed, anhydrous sodium sulfate is dried and then spun dry, and the target product IBMC-062 (100 mg, 53.6%) is obtained by purifying with a silica gel column. 1 H NMR (400 mhz, chloroform-d) delta 6.98 (s, 1H), 6.85 (dt, j=16.9, 2.1hz, 2H), 5.09 (s, 2H), 5.00 (tt, j=7.2, 3.6hz, 1H), 4.65 (d, j=15.6 hz, 4H), 4.03 (t, j=6.7 hz, 4H), 2.96 (t, j=7.5 hz, 2H), 2.78-2.63 (m, 6H), 2.30 (td, j=8.9, 4.5hz, 2H), 1.91-1.82 (m, 4H), 1.63-1.52 (m, 12H), 1.47-1.39 (m, 4H), 1.33-1.21 (m, 48H), 0.87 (t, j=6.7 hz, 12H), nuclear hydrogen, as shown in fig. 42.
The specific synthetic procedure for Bi-070013 is as in example 4.
Example 43: specific synthetic procedure for IBMC-066: 0.23mmol Bi-070013 is dissolved in 10mL methylene chloride, 0.11mmol 4- (azepan-1-yl) butyric acid, 0.34mmol 4-dimethylaminopyridine, 0.14mmol 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride are added in sequence, reacted for 12h at room temperature, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and spun dried, purified by silica gel column to give the target product IBMC-066 (100 mg, 53.6%). 1 H NMR (400 mhz, chloroform-d) delta 7.04 (s, 1H), 6.82 (dt, j=16.6, 2.2hz, 2H), 5.08 (s, 2H), 5.01-4.95 (m, 1H), 4.64 (d, j=19.0 hz, 4H), 4.03 (t, j=6.6 hz, 4H), 3.11 (s, 4H), 2.97-2.89 (m, 2H), 2.48 (t, j=6.6 hz, 2H), 2.30 (tt, j=8.9, 5.3hz, 2H), 2.16 (dq, j=14.1, 6.7hz, 2H), 1.92 (s, 4H), 1.70 (s, 4H), 1.57 (dq, j=14.3, 6.6hz, 12H), 1.42 (td, j=8.4, 7.6 hz, 2H), 2.30 (tt, j=8.9, 5.3hz, 2H), 1.70 (dq, 1.57 (dq, j=14.6.6 hz, 6 hz), and 48H), as shown in fig. 4.43 (H).
The specific synthetic procedure for Bi-070013 is as in example 4.
Example 44: preparation and testing of lipid nanoparticle compositions (LNP formulations)
To prepare nanoparticle compositions for delivery of therapeutic and/or prophylactic agents to cells, a series of nanoparticle formulations were tested and the lipid components of the nanoparticle compositions were optimized. Nanoparticles can be prepared by manual and microfluidic methods, none of which are exhaustive, and all that is possible to prepare nanoparticle compositions of the formulations of the present invention are within the scope of the present invention.
Lipid compositions are formulated with lipid molecules represented by the general formulae (I), (Ia), (Ib), (Ic), (ii), (iia), (iib), (iic), (iid), (iie), (iif), (iig), (ih), (iii), (iia), (iib), (iic) (such as DSPC, ai Weita (Shanghai) medical technology, inc.), steroid compounds (such as cholesterol, ai Weita (Shanghai) medical technology, inc.) and polymer conjugated lipids (such as DMG-PEG2000, ai Weita (Shanghai) medical technology, inc.) in mole percentages (lipid molecules: DSPC: cholesterol: DMG-pe2000 = 20% -100%:0% -40%:0% -80%:0% -20%). Formulations in this mole percent range can be used to prepare nanoparticle compositions, and are within the scope of the present invention as long as LNP is obtained by such formulations.
In this example, the lipid components described above were prepared in a molar percentage of 50:10:38.5:1.5 to prepare an ethanol phase solution having a total concentration of 50mM for use. Lipid DLin-MC3-DMA (MC 3) is the current standard in the art, and thus standard MC3 nanoparticle compositions were prepared using the molar percentage of MC3:dspc: cholesterol: DMG-pe2000=50:10:38.5:1.5 as a control for this study.
The active ingredient (e.g., mRNA, EGFP, luciferase or SARS-CoV2 Spike) was added to 10-50mM buffer (citrate, acetate, pH=3-6) to prepare an aqueous mRNA solution for use. Nanoparticle compositions were prepared by mixing an ethanol phase lipid solution and an aqueous phase mRNA solution using a manual or microfluidic device. Wherein the volume ratio of the water phase to the ethanol phase is between 1:1 and 5:1, and the volume ratio is set to be 3:1 in the embodiment; wherein the mass ratio of total lipid to mRNA is 5-65:1 (or the N/P of lipid molecules to mRNA is 4-12:1), three N/P are respectively set to be 8:1, 6:1 and 4:1 in the embodiment, and three groups of experimental data are obtained; wherein the manual operation is rapid injection of post-vortex 30-60s, the embodiment sets vortex 30s; wherein the total liquid flow rate of the microfluidic system is between 10 and 25mL/min, and the total liquid flow rate is set to be 20mL/min in the embodiment.
The nanoparticle composition was purified by dialysis, and the nanoparticle composition solution was dialyzed through multiple DPBS to remove ethanol and free molecules, and then filtered through a 0.2 μm sterile filter to obtain a lipid nanoparticle composition (LNP formulation) encapsulating mRNA.
Nanoparticle composition testing the particle size, polydispersity index (PDI) and potential of the lipid nanoparticle composition were determined by dynamic light scattering using Malvern Zetasizer Nano ZS ZEN3600 (Malvern UK) and the encapsulation efficiency of mRNA by the nanoparticle composition was assessed using RNA quantification kit Quant-iTTM RiboGreenTM RNA Assay Kit (Thermo Fisher Scientific).
As shown in tables 1A-1C, particle size, PDI, potential and encapsulation efficiency of nanoparticle compositions encapsulating mRNA (EGFP and/or Luciferase, SARS-CoV2 Spike) according to lipid molecules represented by the general formulae (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), (IIIc) were compared.
TABLE 1A nanoparticle combination physical Property parameters for cell transfection in which mRNA is mixed at equal mass ratios of EGFP and Luciferase
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N/P of # = lipid molecule and mRNA 6
Table 1B parameters of physical properties of nanoparticle combinations entrapped for animal administration wherein mRNA is Luciferase
Lipid molecules Particle size (nm) PDI Potential (mV) Encapsulation efficiency%
MC3 # N/P＝6 161.13 0.18 -4.35 94.3
MC3*N/P＝6 121.97 0.20 -7.53 96.4
SM-102 # N/P＝6 168.90 0.20 -5.29 95.8
SM-102*N/P＝6 91.80 0.15 -2.61 97.2
IBMC-023 # N/P＝6 147.23 0.23 -3.61 93.2
IBMC-023*N/P＝6 97.33 0.20 -1.41 96.7
IBMC-023 # N/P＝8 157.23 0.22 -2.01 95.4
IBMC-023 # N/P＝4 157.43 0.24 -2.52 95.3
# = manual procedure to prepare nanoparticle compositions; * Microfluidic preparation of nanoparticle mixtures
TABLE 1 combination of nanoparticle combinations physical Properties parameters for animal administration wherein mRNA is SARS-CoV2 Spike
# = manual procedure to prepare nanoparticle compositions; * Microfluidic preparation of nanoparticle mixtures
The test results are shown in tables 1A, 1B and 1C, and the encapsulation rate of the nanoparticle composition on mRNA is not much different from that of the marketed product in tables 1A, 1B and 1C, so that the nanoparticle composition prepared by the product meets the marketed requirement.
Example 45: evaluation of lipid nanoparticle composition (LNP formulation) cell transfection effect
In 96-well plates, 2X 10 wells per well are plated 4 After culturing 293T or Hela cells for 24h, cells were incubated with lipid nanoparticle composition at a mixed mRNA dose of 0.1 μg EGFP and 0.1 μg Luciferase per well, and after 24h, 20X fluorescence images of EGFP were taken by Olympus CKX53 fluorescence microscopy.
As shown in fig. 44, 45, 46, it is clear from fig. 44, 45, 46 that at the cellular level, the novel lipid molecules can efficiently deliver mRNA to cells and express, and that the screened partial lipid material is superior to the lipid molecule MC3 that has been marketed.
Example 46: in vivo delivery level assessment of lipid nanoparticle compositions (LNP formulations)
Nanoparticle formulations entrapping Luciferase mRNA were administered by intramuscular or intravenous injection to 6-8 week old female Babl/c mice at a dose of 0.1mg/kg, and small animal fluorescence imaging (3 h, 6h and 24 h) was performed by IVIS Lumina III (PE company) at a specific time node after administration.
The test results are shown in fig. 47 and 48, and it is clear from fig. 47 and 48 that the nanoparticle composition of lipid molecule IBMC-023 can efficiently deliver mRNA in animals and express related proteins at high levels; meanwhile, IBMC-023 did not observe a significant liver enrichment compared to MC 3.
Example 47: lipid nanoparticle composition (LNP formulation) in vivo delivery of SARS-CoV2 Spike-induced S protein expression level assessment
Nanoparticle formulations entrapping SARS-CoV2 Spike mRNA were administered to 6-8 week old female Babl/c mice by intramuscular injection at a dose of 0.5mg/kg, and the amount of S protein expressed in the blood, muscle, liver of the mice was analyzed 6h after administration according to the procedure of the commercial SARS-CoV-2 (2019-nCoV) SpikeELISA KIT (KIT 40591, yiqishen).
The test results are shown in FIGS. 49, 50 and 51, and it is understood from FIGS. 49, 50 and 51 that the nanoparticle composition of lipid molecule IBMC-023 can efficiently deliver mRNA in animals and express the related protein at high level.
Experiments prove that the cationic lipid compound can deliver nucleic acid molecules, small molecular compounds, polypeptides or proteins and the like, the encapsulation efficiency of the carrier prepared by using the cationic lipid compound is high, and the nucleic acid molecules can be successfully transported into cells and/or organs and can be expressed with high efficiency.
The conventional technology in the above embodiments is known to those skilled in the art, and thus is not described in detail herein. The foregoing is merely illustrative of the present invention, and the present invention is not limited thereto, and any person skilled in the art will readily recognize that variations or substitutions are within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (10)

1. A lipid molecule for delivering an active ingredient comprising: lipid compounds represented by general formulas (I), (II), (III), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non-covalent complexes thereof;
wherein,
m is selected from benzene ring, cyclobutane, cyclopentyl, cyclohexyl, pyrrole ring, pyridine, piperazine, imidazole, biphenyl, naphthalene ring, anthracene ring, pyrimidine ring or 4-8 membered heterocycle;
G 1 、G’ 1 Each independently selected from- (CH) 2 ) x -O(C＝O)-、-(CH 2 ) x -(C＝O)O-、-(CH 2 ) x -(C＝O)S-、-(CH 2 ) x -(C＝O)NH-、-(CH 2 ) x -O-、-(CH 2 ) x -O(C＝O)NH-、-(CH 2 ) x -O(C＝O)O-、-(CH 2 ) x NH (c=o) -wherein x is an integer between 0 and 4;
L 1 、L’ 1 each independently selected from unsubstituted C 1-6 One of the alkyl groups;
G 2 selected from- (CH) 2 ) 0-3 -、-O-(CH 2 ) y -(C＝O)O-、-(CH 2 ) y -(C＝O)O-、-(CH 2 ) y -(C＝O)NH-、-S-
(CH 2 ) y -(C＝O)O-、-(CH 2 ) y One of- (c=o) S-, -O-, wherein y is an integer between 0 and 4;
G 1 、G’ 1 、G 2 each independently linked to any site in MThe site is a carbon or nitrogen atom;
x is selected from carbon or nitrogen atoms; n is selected from integers between 0 and 6;
L 2 selected from H, OH, C 1-3 Alkyl, C 2-3 One of alkenyl groups;
L 3 、L 4 each independently selected from C 0-25 Alkyl, C 2-25 Alkenyl, C 3-25 One of the alkynyl groups;
G 3 、G 4 each independently selected from-CH 2 -one of-O (c=o) -, - (c=o) O-, -O (c=o) O-, -NH (c=o) -, -S (c=o) -, - (c=o) S-, -S-;
L 5 、L 6 each independently selected from C 1-25 Alkyl, C 2-25 Alkenyl, C 3-25 One of the alkynyl groups;
R 1 、R 2 and R'. 1 、R’ 2 Each independently selected from optionally substituted or unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, - (c=o) C 1-3 Alkyl group,Wherein the substituent is 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxy, C 1-3 Alkoxy, - (c=o) OC 1-3 Alkyl, C 1-3 An alkyl group; x is X 1 、X 2 Each independently selected from C 1-3 An alkyl group;
Or alternatively
R 1 And R is 2 、R’ 1 And R'. 2 Taken together to form an optionally substituted 4-8 membered heterocyclic ring, pyrimidine ring, purine ring; wherein the substituents are 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxy, C 1-3 Alkoxy, - (c=o) OC 1-3 Alkyl, C 1-3 An alkyl group;
z in formula (II) is selected from H, FOH、-SH-、-NH 2 、-CF 3 、-NH-(CH 2 ) r CH 3 、-N(CH 3 )-(CH 2 ) r CH 3 Wherein r is an integer between 0 and 4;
z' in formula (III) is selected from optionally substituted or unsubstituted H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 One of cycloalkynyl, phenyl, 4-8 membered heterocycle, wherein the substituents are 1 or 2 independent OH, SH, C 1-3 Hydroxy, C 1-3 Alkoxy, amino, nitro, cyano, - (c=o) OC 1-3 An alkyl group.
2. The lipid molecule for delivery of an active ingredient according to claim 1, characterized in that: the lipid compound of the general formula (I) comprises a structure shown in a formula (Ia), (Ib), (Ic) or (Id), or pharmaceutically usable salt, stereoisomer, tautomer, solvate, chelate or non-covalent complex thereof;
wherein,
G 1 、G’ 1 each independently selected from- (CH) 2 ) x -O(C＝O)-、-(CH 2 ) x -(C＝O)O-、-(CH 2 ) x -(C＝O)S-、-(CH 2 ) x -(C＝O)NH-、-(CH 2 ) x -O-、-(CH 2 ) x -O(C＝O)NH-、-(CH 2 ) x -O(C＝O)O-、-(CH 2 ) x NH (c=o) -wherein x is an integer between 0 and 4;
L 1 、L’ 1 each independently selected from unsubstituted C 1-6 One of the alkyl groups;
G 1 、G’ 1 each independently linked to an arbitrary site in the benzene ring;
R 1 、R 2 and R'. 1 、R’ 2 Each independently selected from optionally substituted or unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, - (c=o) C 1-3 Alkyl group,Wherein the substituent is 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxy, C 1-3 Alkoxy, - (c=o) OC 1-3 Alkyl, C 1-3 An alkyl group; x is X 1 、X 2 Each independently selected from C 1-3 An alkyl group;
or alternatively
R 1 And R is 2 、R’ 1 And R'. 2 Taken together to form an optionally substituted 4-8 membered heterocyclic ring, pyrimidine ring, purine ring; wherein the substituents are 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxy, C 1-3 Alkoxy, - (c=o) OC 1-3 Alkyl, C 1-3 An alkyl group;
m is an integer between 0 and 4;
t comprises one of the structures of formula (1) -formula (18):
3. the lipid molecule for delivery of an active ingredient according to claim 1, characterized in that: the lipid compound of the general formula (II) comprises a structure shown in a formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg) or (IIh), or pharmaceutically usable salts, stereoisomers, tautomers, solvates, chelates and non-covalent complexes;
Wherein,
G 1 selected from- (CH) 2 ) x -O(C＝O)-、-(CH 2 ) x -(C＝O)O-、-(CH 2 ) x -(C＝O)S-、-(CH 2 ) x -(C＝O)NH-、-
(CH 2 ) x -O-、-(CH 2 ) x -O(C＝O)NH-、-(CH 2 ) x -O(C＝O)O-、-(CH 2 ) x NH (c=o) -wherein x is an integer between 0 and 4;
L 1 selected from unsubstituted C 1-6 One of the alkyl groups; g 1 Is connected with any site in benzene ring;
R 1 、R 2 each independently selected from optionally substituted or unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, - (c=o) C 1-3 Alkyl group,Wherein the substituent is 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxy, C 1-3 Alkoxy, - (c=o) OC 1-3 Alkyl, C 1-3 An alkyl group; x is X 1 、X 2 Each independently selected from C 1-3 An alkyl group;
or alternatively
R 1 And R is 2 Taken together to form an optionally substituted 4-8 membered heterocyclic ring, pyrimidine ring, purine ring; wherein the substituents are 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxy, C 1-3 Alkoxy, - (c=o) OC 1-3 Alkyl, C 1-3 An alkyl group;
e is selected from oxygen or sulfur atoms;
m is an integer between 0 and 4;
t comprises one of the structures of formulae (1) - (18):
4. the lipid molecule for delivery of an active ingredient according to claim 1, characterized in that: the lipid compound of the general formula (III) comprises a structure shown in a formula (IIIa), (IIIb) or (IIIc), or pharmaceutically usable salts, stereoisomers, tautomers, solvates, chelates and non-covalent complexes thereof;
Wherein,
G 1 selected from- (CH) 2 ) x -O(C＝O)-、-(CH 2 ) x -(C＝O)O-、-(CH 2 ) x -(C＝O)S-、-(CH 2 ) x -(C＝O)NH-、-
(CH 2 ) x -O-、-(CH 2 ) x -O(C＝O)NH-、-(CH 2 ) x -O(C＝O)O-、-(CH 2 ) x NH (c=o) -wherein x is an integer between 0 and 4;
L 1 selected from unsubstituted C 1-6 One of the alkyl groups; g 1 Is connected with any site in benzene ring;
z' is selected from optionally substituted or unsubstituted H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 One of cycloalkynyl, phenyl, 4-8 membered heterocycle; wherein the substituent groups are 1 or 2 independent OH, SH, C 1-3 Hydroxy, C 1-3 Alkoxy, amino, nitro, cyano, - (c=o) OC 1-3 An alkyl group;
R 1 、R 2 each independently selected from optionally substituted or unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl radicals、C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, - (c=o) C 1-3 Alkyl group,Wherein the substituent is 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxy, C 1-3 Alkoxy, - (c=o) OC 1-3 Alkyl, C 1-3 An alkyl group; x is X 1 、X 2 Each independently selected from C 1-3 An alkyl group;
or alternatively
R 1 And R is 2 Taken together to form an optionally substituted 4-8 membered heterocyclic ring, pyrimidine ring, purine ring; wherein the substituents are 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxy, C 1-3 Alkoxy, - (c=o) OC 1-3 Alkyl, C 1-3 An alkyl group;
e is selected from oxygen or sulfur atoms;
m is an integer between 0 and 4;
t comprises one of the structures of formulae (1) - (18):
5. the lipid compound according to any one of claims 1 to 4, characterized in that: the saidEach independently selected from one of the structures represented by formulas Y01-Y30:
6. a nanoparticle composition comprising one or more of the lipid compounds of any one of claims 1-5.
7. A nanoparticle composition as in claim 6, wherein: the nanoparticle composition also comprises a therapeutic and/or prophylactic agent.
8. A nanoparticle composition as in claim 7, wherein: the therapeutic and/or prophylactic agent comprises a nucleic acid, a small molecule compound, a polypeptide or a protein; the nucleic acid comprises single-stranded DNA, double-stranded DNA, short isomer, agomir, antagomir, antisense molecule, small interfering RNA, asymmetric interfering RNA, microRNA,
At least one of Dicer-substrate RNA, small hairpin RNA, transfer RNA, messenger RNA, circular RNA, and aptamer.
9. A nanoparticle composition as in claim 6, wherein: the nanoparticle composition further comprises one or more neutral lipids, one or more steroids, one or more polymer conjugated lipids; wherein the mole percent of lipid molecules for delivering an active ingredient of claim 1 is 20-100%; the mole percentage of the steroid is 0-80%; the mole percentage of neutral lipid is 0-40%; the mole percent of the polymer conjugated lipid is 0-20%.
10. Use of the nanoparticle composition of claim 6 in the preparation of a medicament.
CN202311345249.1A 2022-07-15 2022-07-15 Lipid molecule and composition thereof Pending CN117486738A (en)

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