CN115232128B - Imidazo-pyridinyl lipid compound, and preparation method and application thereof - Google Patents
Imidazo-pyridinyl lipid compound, and preparation method and application thereof Download PDFInfo
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- CN115232128B CN115232128B CN202210978270.4A CN202210978270A CN115232128B CN 115232128 B CN115232128 B CN 115232128B CN 202210978270 A CN202210978270 A CN 202210978270A CN 115232128 B CN115232128 B CN 115232128B
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- imidazopyridinyl
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- lipid
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- -1 Imidazo-pyridinyl lipid compound Chemical class 0.000 title claims abstract description 202
- 238000002360 preparation method Methods 0.000 title claims abstract description 81
- 150000001875 compounds Chemical class 0.000 claims abstract description 179
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- 108020004707 nucleic acids Proteins 0.000 claims abstract description 24
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 24
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 24
- 150000002632 lipids Chemical class 0.000 claims description 41
- 239000002105 nanoparticle Substances 0.000 claims description 36
- 108090000623 proteins and genes Proteins 0.000 claims description 5
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- 230000002452 interceptive effect Effects 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 238000012546 transfer Methods 0.000 claims description 3
- 238000002255 vaccination Methods 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 abstract description 12
- 210000004027 cell Anatomy 0.000 abstract description 11
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 5
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- 230000009286 beneficial effect Effects 0.000 abstract description 4
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- 238000001228 spectrum Methods 0.000 description 26
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 24
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- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 description 21
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- A61K48/0008—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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Dispersion Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an imidazo pyridinyl lipid compound, a preparation method and application thereof, and belongs to the technical field of drug delivery carriers. Wherein the imidazopyridinyl lipid compound is a compound represented by formula (I), or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt, prodrug, or solvate thereof:the imidazopyridinyl lipid compound has imidazopyridinyl cations and long-chain hydrophobic alkyl chains, and the film fusion can be improved by the interaction synergistic effect of the imidazopyridinyl cations and the long-chain hydrophobic alkyl chains; meanwhile, the imidazopyridinyl lipid compound can be kept stable in vivo circulation, can be rapidly degraded under the action of lysosomes after being phagocytized by cells, realizes remarkable enhancement of delivery efficiency, has lower cytotoxicity and better biocompatibility, and is used as a delivery carrier of nucleic acid medicaments, thereby being beneficial to clinical transformation of the nucleic acid medicaments.
Description
Technical Field
The invention belongs to the technical field of drug delivery carriers, and particularly relates to an imidazo-pyridinyl lipid compound, a preparation method and application thereof.
Background
Nucleic acid drugs, which are DNA or RNA having a disease-treating function, are used for treating diseases by directly acting on pathogenic target genes or target XRNA to regulate the expression of pathogenic-related genes, and have been used for the treatment of tumors, genetic diseases, major infectious diseases, and the like. However, nucleic acid drugs are usually strong electronegative hydrophilic macromolecules, which are easily inactivated by enzymolysis of nucleic acid in plasma in vivo, and have the characteristics of poor target site distribution specificity and difficult membrane barrier permeation, so that the curative effect is obviously reduced, and thus, a delivery carrier is needed to be relied on.
At present, materials which can be used as nucleic acid drug delivery vehicles are mainly pharmaceutical excipients and cationic materials. The pharmaceutic adjuvant basically has no positive charge, can not load nucleic acid medicines through electrostatic action, has higher clinical transformation difficulty, and the cationic material can be combined with the nucleic acid medicines with negative charges to prepare nano preparations, so that the pharmaceutic adjuvant is an important research direction facing to clinical nucleic acid medicine delivery carrier materials.
However, the existing cationic materials generally need multi-step synthesis, and the preparation process is complex, so that the production cost of the delivery carrier material is high, the batch repeatability is poor, most of the cationic materials have the problems of high toxicity, poor biocompatibility and hidden danger in the aspect of biosafety, and the clinical transformation of nucleic acid medicaments is restricted to a great extent.
Disclosure of Invention
The first object of the present invention is to provide an imidazopyridinyl lipid compound having an imidazopyridinyl cation and a long-chain alkyl chain, which can not only improve the encapsulation efficiency and delivery efficiency of nucleic acid drugs, but also have lower cytotoxicity, and can solve the technical problems of high toxicity and poor biocompatibility existing in the use of the existing cationic materials as nucleic acid drug delivery vehicles.
The second purpose of the invention is to provide a preparation method of the imidazopyridinyl lipid compound, which is prepared by a one-pot method, has the characteristics of simple operation, short reaction time, low equipment requirement, mild reaction condition, good selectivity, high yield, easily available raw materials and low cost, and solves the technical problems of complex process, poor batch repeatability and high production cost of multi-step synthetic cationic materials.
A third object of the present invention is to provide a use of an imidazopyridinyl lipid compound, in particular to use the imidazopyridinyl lipid compound for the preparation of lipid nanoparticles, and to use the lipid nanoparticles for the preparation of a medicament, wherein the medicament is a medicament for gene therapy, gene vaccination, interfering RNA therapy and nucleic acid transfer.
In order to achieve the above object, the technical solution of the embodiment of the present invention is:
in a first aspect, embodiments of the present invention provide an imidazopyridinyl lipid compound. The imidazopyridinyl lipid compound is a compound shown in a chemical formula (I), or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the chemical formula (I) is as follows:
in the chemical formula (I):
m is a bond, O, S, S-S, S (=o), O (c=o), (c=o) O, S (c=o), (c=o) S, NR a 、R a N(C＝O)NR a 、O(C＝O)NR a Or R is a N (c=o) O, wherein R a Each independently is H or B 2 -L 2 -R 2 ；
R 2 And R is R 1 Identical or different from each other and each independently of the other is a straight-chain or branched C 1-50 Alkyl, straight or branched C 2-50 Alkenyl, straight-chain or branched C 2-50 Alkynyl;
B 2 and B is connected with 1 Are identical or different from each other and are each independently a bond, C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 Alkynylene;
L 2 and L is equal to 1 Are identical to or different from each other and are each independently a bond, O, S, S-S, S (=o), (c=o), S (c=o), (c=o) S, O (c=o), (c=o) O, O (c=o) O, NR b 、R b N(C＝O)、(C＝O)NR b 、R b N(C＝O)NR b 、R b N(C＝O)O、O(C＝O)NR b 、O(CR b R b ) z O or NH (CR) b R b ) z Any one of NH, wherein R b Each independently H, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl; z is 2, 3 or 4;
L 3 Is (CR) c R d O) m 、(OCR c R d ) m 、(SCR c R d ) m 、(CR c R d S) m 、(CR c R d O) m (CR c R d S) m 、(CR c R d S) m (CR c R d ) m O、(CR c R d ) m NR c (CR c R d S) m 、(CR c R d S) m (CR c R d ) m NR c 、(CR c R d ) m NR c (CR c R d O) m Or (CR) c R d O) m (CR c R d ) m NR c Any of which, wherein m is 2, 3 or 4;
R c and R is d Are identical or different from each other and are each, independently of one another, H, C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl;
L 4 is A r (R e ) x 、C 1-12 Alkylene, C 2-12 Alkenylene or C 2-12 Any of alkynylene groups, wherein a r Is benzene ring; x is 0, 1, 2, 3 or 4;
n=1, 2, 3, 4, 5, and n+x=5;
R e and R is R 4 Are identical or different from each other and are each, independently of one another, H, F, cl, br, I, OCH 3 、OCH 2 CH 3 、OCH 2 CH 2 CH 3 、OCH 2 CH＝CH 2 、OCH 2 C≡CH、CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH 2 CH＝CH 2 、CH 2 C≡CH；
R 3 H, R of a shape of H, R f 、OR f 、NR f R f 、SR f 、(C＝O)R f 、(C＝O)OR f 、O(C＝O)R f OR O (c=o) OR f Any one of, wherein R f Each of which is a single pieceIndependently C 1-12 Alkyl, C 2-12 Alkenyl or C 2-12 Alkynyl groups.
It will be appreciated by those skilled in the art that when M is specifically substituted, the structural formula of the compound of formula (I) is further:
it will be appreciated by those skilled in the art that when L 2 And L is equal to 1 The structural formula of the compound of formula (I), when each independently specifically substituted, is further:
it will be appreciated by those skilled in the art that when L 4 Quilt A r (R e ) x When substituted, the structural formula of the compound of the chemical formula (I) is further:
it will be appreciated by those skilled in the art that when R c And R is d When each is independently substituted, L 3 Specifically selected from CH 2 CH 2 O、OCH 2 CH 2 、CH(CH 3 )CH 2 O、OCH(CH 3 )CH 2 、CH 2 CH 2 S、SCH 2 CH 2 、CH 2 CH 2 NHCH 2 CH 2 O、CH 2 CH 2 OCH 2 CH 2 NH、CH 2 CH 2 SCH 2 CH 2 O or CH 2 CH 2 OCH 2 CH 2 S.
With reference to the first aspect, in a preferred implementation manner of the embodiment of the present invention, M is O (c=o), (c=o) O, NR a 、R a N(C＝O)NR a 、O(C＝O)NR a Or R is a N (c=o) O.
With reference to the first aspect, in a preferred implementation manner of the embodiment of the invention, the straight chain C 1-50 The alkyl group is selected from any one of the following structural formulas:
branched C 1-50 The alkyl group is selected from any one of the following structural formulas:
wherein a is any positive integer from 0 to 12.
With reference to the first aspect, in a preferred implementation manner of the embodiment of the invention, the straight chain C 2-50 Alkenyl groups are selected from any of the following structural formulas:
branched C 2-50 Alkenyl is selected from any one of the following structural formulas:
with reference to the first aspect, in a preferred implementation manner of the embodiment of the invention, the straight chain C 2-50 Alkynyl is selected from any one of the following structural formulas:
branched C 2-50 Alkynyl is selected from any one of the following structural formulas:
with reference to the first aspect, in a preferred implementation manner of the embodiment of the present invention, B 2 And B is connected with 1 Are identical or different from each other and are each independently C 1-20 Alkylene, C 2-20 Alkenylene or C 2-20 Any of the alkynylene groups.
With reference to the first aspect, in a preferred implementation manner of the embodiment of the present invention, L 2 And L is equal to 1 Are the same as or different from each other, and are each independently any one of O (c=o), (c=o) O, O (c=o) O, NHC (=o), C (=o) NH, NHC (=o) NH, OC (=o) NH, or NHC (=o) O.
With reference to the first aspect, in a preferred implementation manner of the embodiment of the present invention, L 2 And L is equal to 1 And are the same and are each selected from O (c=o), (c=o) O or O (c=o) O.
With reference to the first aspect, in a preferred implementation manner of the embodiment of the present invention, when R f When substituted, R 3 Can be H, alkyl, alkoxy, alcoholic hydroxyl, protected alcoholic hydroxyl, thiol hydroxyl, protected thiol hydroxyl, carboxyl, protected carboxyl, amino, protected aminoProtected amino, aldehyde, protected aldehyde, ester, carbonate, carbamate, succinimidyl, maleimido, protected maleimido, dimethylamino, alkenyl, alkenoate, azido, alkynyl, specifically selected from (CH 2 ) y OH、(CH 2 ) y SH、OCH 3 、OCH 2 CH 3 、(C＝O)(CH 2 ) y (C＝O)OH；(C＝O)CH 2 CH 3 、(C＝O)OCH 2 CH 3 、(CH 2 ) y CHO、(CH 2 ) y NH 2 、(C＝O)CH 3 、(CH 2 ) y (C＝O)OH、(C＝O)OCH 3 、(CH 2 ) y N 3 、O(C＝O)OCH 3 、O(C＝O)OCH 2 CH 3 、(CH 2 ) y N(CH 3 ) 2 Any of the above, wherein y is 1, 2, 3, 4 or 5;
alternatively, any of the following structural formulas:
with reference to the first aspect, in a preferred implementation manner of the embodiment of the present invention, when R c And R is d When each is independently substituted, L 3 Selected from CH 2 CH 2 O、OCH 2 CH 2 、CH(CH 3 )CH 2 O、OCH(CH 3 )CH 2 、CH 2 CH 2 S、SCH 2 CH 2 、CH 2 CH 2 NHCH 2 CH 2 O、CH 2 CH 2 OCH 2 CH 2 NH、CH 2 CH 2 SCH 2 CH 2 O、CH 2 CH 2 OCH 2 CH 2 S.
With reference to the first aspect, in a preferred implementation of an embodiment of the invention, the compound of formula (I) is selected from the following formulae:
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in a second aspect, the embodiment of the invention also provides a preparation method of the imidazopyridinyl lipid compound, which comprises the following steps:
Providing an organic solution in which an isonitrile compound 1 and an aldehyde group compound 2 are dissolved, and reacting for 30min at room temperature to form a solution system of an imine structure compound;
adding a compound 3 and a catalyst into a solution system of the imine structure compound, and reacting for 24 hours at room temperature to obtain an imidazopyridinyl lipid compound;
wherein the isonitrile compound 1 is represented by the chemical formula (II): r is R 3 -L 3 -NC；
The aldehyde group compound 2 is represented by the chemical formula (III):
compound 3 is represented by chemical formula (iv):
the organic solution is preferably any one of dichloromethane, methanol, and ethanol; the catalyst is preferably any one of perchloric acid, hydrochloric acid and ammonium chloride.
With reference to the second aspect, the embodiment of the present invention also provides a preparation method of the aldehyde group compound 2, including the following steps:
to compound R 2 -F 4 With compound F 3 -B 1 Sequentially carrying out esterification reaction, amidation reaction and substitution reaction on-OH to obtain a compound R 2 -L 1 -B 1 -OH, wherein L 1 、F 3 And F 4 Each independently is a reactive group, and F 3 And F 4 Can react to generate L 1 ；
To compound R 2 -L 1 -B 1 CHO with compound H 2 N-L 4 reacting-OH to obtain a compound HO-L 4 -(X-B 1 -L 1 -R 2 ) n ；
Compound HO-L by sodium hypochlorite 4 -(X-B 1 -L 1 -R 2 ) n And (3) carrying out an oxidation reaction to obtain the aldehyde compound 2.
In a third aspect, the embodiment of the invention also provides the use of the imidazopyridinyl lipid compound described above in the preparation of lipid nanoparticles, and the use of the lipid nanoparticles in the preparation of a medicament, wherein the medicament is a medicament for gene therapy, gene vaccination, interfering RNA therapy, and nucleic acid transfer.
The medicine includes: 1) Is used for treating cancer, malignant tumor, liver disease, hepatitis, diabetes, gout, rheumatism, rheumatoid disease, senile dementia, cardiovascular diseases, etc., antiallergic, anti-infective, antibiotic, antiviral, antifungal, vaccine, CNS inhibitor, CNS stimulant, psychotropic, respiratory drug, peripheral nervous system drug, drug acting at a synaptic junction or a neuroeffector junction, smooth muscle active drug, histamine energy agent, antihistamine energy agent, blood and hematopoietic drug, gastrointestinal drug, steroid agent, cytostatic agent, anthelmintic agent, antimalarial agent, antiprotozoal agent, antimicrobial agent, antiinflammatory agent, immunosuppressant, alzheimer's disease drug or compound, imaging agent, antidote, antispasmodic agent, drug muscle relaxants, anti-inflammatory agents, appetite suppressants, migraine-treating agents, muscle constrictors, antimalarials, antiemetics/antiemetics, bronchodilators, antithrombotics, antihypertensives, antiarrhythmics, antioxidants, antiasthmatics, diuretics, lipid modulators, antiandrogens, antiparasitics, anticoagulants, neoplastic agents, hypoglycemic agents, nutritional agents, additives, growth supplements, anti-enteritis agents, vaccines, antibodies, diagnostic agents, contrast agents, hypnotics, sedatives, psychostimulants, tranquilizers, antiparkinsonism agents, analgesics, anxiolytics, muscle infectious agents, and auditory disease agents. The method specifically comprises the following steps: doxorubicin, mitoxantrone, camptothecin, cisplatin, bleomycin, cyclophosphamide, streptozotocin, dactinomycin, vincristine, vinblastine, cytosine arabinoside, anthracycline, mechlorethamine, thiotepa, chlorambucil, largonimycin, melphalan, carmustine, robustadine, busulfan, dibromomannitol, mitomycin C, cisplatin (II), methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil dacarbazine, dibucaine, chlorpromazine, propranolol, molubil, labetalol, hydralazine, imipramine, amitriptyline, doxepin, phenytoin, diphenhydramine, chlorpheniramine, chlorphenamine, dacarbazine, pyrimide, and other pharmaceutical compositions promethazine, gentamicin, ciprofloxacin, cefoxitin, miconazole, terconazole, econazole, isoconazole, butoconazole, clotrimazole, itraconazole, nystatin, netitifen, amphotericin B, antiparasitic agents, hormones, hormone antagonists, immunomodulators, neurotransmitter antagonists, anti-glaucoma agents, vitamins, sedatives, imaging agents, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, colchicine, daunorubicin, dihydroxyanthracenedione, mithramycin, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, puromycin, maytansinoids.
Compared with the prior art, the embodiment of the invention has the advantages or beneficial effects that at least the advantages or beneficial effects comprise:
(1) The imidazopyridinyl lipid compound provided by the embodiment of the invention has an imidazopyridinyl cation head and a long-chain hydrophobic alkyl chain tail, wherein the imidazopyridinyl cation can be combined with a nucleic acid drug with negative charges to improve the fusion effect of a nucleic acid drug membrane, so that the improvement of the entrapment effect with the nucleic acid drug is realized, and the long-chain hydrophobic alkyl chain can form a nucleic acid carrier with other components of LNP, so that the entrapment and protection of mRNA are realized. In view of the above, the imidazopyridinyl lipid compound not only can remarkably improve the encapsulation rate of nucleic acid drugs, but also has lower cytotoxicity and better biocompatibility, and can be used as a delivery carrier of the nucleic acid drugs to be beneficial to clinical transformation of the nucleic acid drugs. In addition, the imidazopyridinyl lipid compound can remain stable in the in vivo circulation, can be rapidly degraded under the action of lysosomes after being phagocytized by cells, and remarkably enhances the delivery efficiency.
(2) The preparation method of the imidazopyridinyl lipid compound provided by the embodiment of the invention is prepared by a one-pot method, and compared with the multi-step synthesis of cationic materials, the imidazopyridinyl lipid compound has the characteristics of simple operation, short reaction time, low equipment requirement and low cost, and the preparation method has the advantages of mild reaction conditions, good selectivity, high yield and easily available raw materials.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are required to be used in the description of the embodiments will be briefly described below. It is obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained from these drawings without inventive effort for a person of ordinary skill in the art.
FIG. 1 is a reaction scheme for preparing an imidazopyridinyl lipid compound A1 provided in example 1 of the present invention;
FIG. 2 is a flow chart of the preparation of imidazopyridinyl lipid compound A2 according to example 2 of the present invention;
FIG. 3 is a reaction scheme for preparing imidazopyridinyl lipid compound A3 provided in example 3 of the present invention;
FIG. 4 is a reaction scheme for preparing imidazopyridinyl lipid compound A4 according to example 4 of the present invention;
FIG. 5 is a reaction scheme for preparing imidazopyridinyl lipid compound A5 provided in example 5 of the present invention;
FIG. 6 is a flow chart of the preparation of imidazopyridinyl lipid compound A6 according to example 6 of the present invention;
FIG. 7 is a reaction scheme for preparing imidazopyridinyl lipid compound A7 according to example 7 of the present invention;
FIG. 8 is a reaction scheme for preparing imidazopyridinyl lipid compound A8 according to example 8 of the present invention;
FIG. 9 is a reaction scheme for preparing imidazopyridinyl lipid compound A9 according to example 9 of the present invention;
FIG. 10 is a flow chart of the preparation of imidazopyridinyl lipid compound A10 according to example 10 of the present invention;
FIG. 11 is a flow chart of the preparation of imidazopyridinyl lipid compound A11 according to example 11 of the present invention;
FIG. 12 is a flow chart of the preparation of imidazopyridinyl lipid compound A12 according to example 12 of the present invention;
FIG. 13 is a flow chart of the process for preparing imidazopyridinyl lipid compound A13 according to example 13 of the present invention;
FIG. 14 is a reaction scheme for preparing imidazopyridinyl lipid compound A14 according to example 14 of the present invention;
FIG. 15 is a reaction scheme for preparing imidazopyridinyl lipid compound A15 according to example 15 of the present invention;
FIG. 16 is a reaction scheme for preparing imidazopyridinyl lipid compound A16 according to example 16 of the present invention;
FIG. 17 is a reaction scheme for preparing imidazopyridinyl lipid compound A17 according to example 17 of the present invention;
FIG. 18 is a flow chart of the process for preparing imidazopyridinyl lipid compound A18 according to example 18 of the present invention;
FIG. 19 is a reaction scheme for preparing imidazopyridinyl lipid compound A19 provided in example 19 of the present invention;
FIG. 20 is a flow chart of the preparation of imidazopyridinyl lipid compound A20 according to example 20 of the present invention;
FIG. 21 is a flow chart of the process for preparing imidazopyridinyl lipid compound A21 according to example 21 of the present invention;
FIG. 22 is a flow chart of the process for preparing imidazopyridinyl lipid compound A22 according to example 22 of the present invention;
FIG. 23 is a reaction scheme for preparing imidazopyridinyl lipid compound A23 provided in example 23 of the present invention;
FIG. 24 is a flow chart of the preparation of imidazopyridinyl lipid compound A24 according to example 24 of the present invention;
FIG. 25 is a flow chart of the process for preparing imidazopyridinyl lipid compound A25 according to example 25 of the present invention;
FIG. 26 is a flow chart of the process for preparing imidazopyridinyl lipid compound A26 according to example 26 of the present invention;
FIG. 27 is a graph showing the expression profile of luciferase at lymph nodes 6h after immunization of mLuc-LNP constructed from different imidazopyridinyl lipid nanoparticles provided in the examples of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
This example 1 provides a process for the preparation of an imidazopyridinyl lipid compound A1, A1 being represented by formula (V):
the specific procedure for the preparation of imidazopyridinyl lipid compound A1, shown in connection with fig. 1, is as follows:
tridecyl aldehyde (10.9 g,55 mmol) and pyridin-2-amine (4.7 g,50 mmol) were dissolved in 100mL of dichloromethane and stirred for 20min, then 1- ((isocyanomethyl) sulfonyl) -4-methylbenzene (10.7 g,55 mmol) and perchloric acid (1M dichloromethane solution, 2.5 mmol) were added sequentially and stirring continued for 12h at room temperature. The compound was purified by flash column chromatography system to give imidazopyridinyl lipid compound A1 (21.3 g, yield 91%).
The main data of the nuclear magnetic hydrogen spectrum of the imidazopyridinyl lipid compound A1 are:
1 H NMR(500MHz，Chloroform-d)δ8.08(dd，J＝9.3,1.3Hz,1H)，7.92-7.85(m,2H)，7.67-7.60(m,1H)，7.60-7.53(m,2H)，7.52-7.44(m,2H)，7.30(ddd，J＝9.5,7.3,1.4Hz,1H)，6.96(ddd，J＝9.3,7.3,1.3Hz,1H)，4.82(d，J＝9.9Hz,1H)，2.78-2.70(m,2H)，1.73(tt，J＝11.1,9.5Hz,2H)，1.45-1.36(m,2H)，1.38-1.18(m,17H)，0.93-0.85(m,3H)。
example 2
This example 2 provides a process for the preparation of an imidazopyridinyl lipid compound A2, A2 being represented by formula (VI):
the specific procedure for the preparation of imidazopyridinyl lipid compound A2, shown in conjunction with fig. 2, is as follows:
12-methyltridecaldehyde (11.7 g,55 mmol) and pyridin-2-amine (4.7 g,50 mmol) were dissolved in 100mL of dichloromethane and stirred for 20min, then isocyanatocyclohexane (6.0 g,55 mmol) and perchloric acid (1M in dichloromethane, 2.5 mmol) were added sequentially and stirring continued at room temperature for 12h. The compound was purified by flash column chromatography system to give imidazopyridinyl lipid compound A2 (15.1 g, 76% yield).
The main data of the nuclear magnetic hydrogen spectrum of the imidazopyridinyl lipid compound A2 are:
1 H NMR(500MHz，Chloroform-d)δ7.45-7.33(m,1H)，6.99-6.92(m,1H)，3.55(dp，J＝10.1,7.9Hz,0H)，2.80(t，J＝10.9Hz,1H)，1.88-1.22(m,16H)，0.81(d，J＝4.9Hz,3H)。
example 3
This example 3 provides a process for the preparation of an imidazopyridinyl lipid compound A3, A3 being represented by formula (VII):
the specific procedure for the preparation of imidazopyridinyl lipid compound A3, shown in conjunction with fig. 3, is as follows:
n, N-didecyl-4-formylbenzamide (23.6 g,55 mmol) and pyridin-2-amine (4.7 g,50 mmol) were dissolved in 100mL of dichloromethane and stirred for 20min, then ethyl 2-isocyanoacetate (6.2 g,55 mmol) and perchloric acid (1M dichloromethane solution, 2.5 mmol) were added sequentially and stirring continued at room temperature for 12h. The compound was purified by flash column chromatography system to give imidazopyridinyl lipid compound A3 (26.3 g, yield 85%).
The main data of nuclear magnetic hydrogen spectrum of the imidazopyridinyl lipid compound A3 are:
1 H NMR(500MHz，Chloroform-d)δ8.00(dd，J＝9.4,1.3Hz,1H)，7.91-7.84(m,2H)，7.65-7.56(m,3H)，7.51(dd，J＝9.5,1.4Hz,1H)，7.31(ddd，J＝9.3,7.1,1.3Hz,1H)，6.96(ddd，J＝9.3,7.3,1.4Hz,1H)，4.19(d，J＝8.0Hz,2H)，4.07(q，J＝5.1Hz,2H)，3.32(t,J＝8.6Hz,4H)，1.64(p,J＝8.6Hz,4H)，1.37-1.18(m,30H)，1.18(t，J＝5.1Hz,3H)，0.93-0.85(m,6H)。
example 4
This example 4 provides a process for the preparation of an imidazopyridinyl lipid compound A4, A4 being represented by formula (VIII):
the specific procedure for the preparation of imidazopyridinyl lipid compound A4, shown in conjunction with fig. 4, is as follows:
4-formyl-N, N-tricosylbenzamide (28.2 g,55 mmol) and pyridin-2-amine (4.7 g,50 mmol) were dissolved in 100mL of dichloromethane and stirred for 20min, then ethyl 2-isocyanoacetate (6.2 g,55 mmol) and perchloric acid (1M in dichloromethane, 2.5 mmol) were added in sequence and stirring continued for 12h at room temperature. The compound was purified by flash column chromatography system to give imidazopyridinyl lipid compound A4 (27.4 g, 78% yield).
The main data of nuclear magnetic hydrogen spectrum of the imidazopyridinyl lipid compound A4 are:
1 H NMR(500MHz，Chloroform-d)δ8.01(dd，J＝9.2,1.4Hz,1H)，7.89-7.83(m,2H)，7.63(d，J＝1.8Hz,1H)，7.63-7.56(m,2H)，7.51(dd，J＝9.6,1.3Hz,1H)，7.31(ddd，J＝9.3,7.2,1.3Hz,1H)，6.96(ddd，J＝9.3,7.3,1.3Hz,1H)，4.19(d，J＝8.0Hz,2H)，4.07(q，J＝5.0Hz,2H)，3.33(t，J＝8.7Hz,4H)，1.64(p，J＝8.6Hz,4H)，1.37-1.17(m,47H)，0.93-0.85(m,6H)。
example 5
This example 5 provides a process for the preparation of an imidazopyridinyl lipid compound A5, A5 being represented by formula (IX):
referring to fig. 5, the specific procedure for preparing imidazopyridinyl lipid compound A5 is as follows:
4-formyl-1, 2-phenylenedi (eicosanoate) (39.9 g,55 mmol) and pyridin-2-amine (4.8 g,50 mmol) were dissolved in 100mL of dichloromethane and stirred for 20min, then 1-isocyanohexane (6.1 g,55 mmol) and perchloric acid (1M in dichloromethane, 2.5 mmol) were added in sequence and stirring continued for 12h at room temperature. The compound was purified by flash column chromatography system to give imidazopyridinyl lipid compound A5 (37.9 g, yield 83%).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound A5 are as follows:
1 H NMR(500MHz，Chloroform-d)δ8.34(dd，J＝9.3,1.4Hz,0H)，7.53-7.46(m,1H)，7.43-7.31(m,1H)，7.30-7.25(m,1H)，6.96(ddd，J＝9.3,7.1,1.3Hz,1H)，3.42(q，J＝6.1Hz,1H),2.52-2.44(m,2H),1.67(tt，J＝8.5,6.1Hz,1H)，1.55(tt，J＝10.5,9.0Hz,2H)，1.41-1.32(m,1H)，1.33(dt，J＝4.1,1.5Hz,2H)，1.32-1.22(m,6H)，1.26-1.17(m,26H)，0.89(td，J＝5.6,2.7Hz,4H)。
example 6
This example 6 provides a process for the preparation of an imidazopyridinyl lipid compound A6, A6 being represented by formula (X):
referring to fig. 6, the specific procedure for preparing imidazopyridinyl lipid compound A6 is as follows:
step 1: after hexyl decanoic acid (A6-1, 20.0g,78.0 mmol) was dissolved in 100mL of anhydrous DCM, the solution was placed in a nitrogen-protected flask, heptane-1, 7-diol (A6-2, 20.6g,156.0 mmol) and DMAP (11.4 g,93.8 mmol) were carefully added to the mixed solution after the temperature of the mixed solution was reduced to 0-10℃and EDC (78.1 g,407.0 mmol) was added in portions, and the reaction was continued after the reaction solution was cooled to room temperature. After 18h of reaction, the reaction mixture was washed twice with 500mL of a 0.4N HCl/10% NaCl mixture, once with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give Compound A6-3 (23.10 g).
Step 2: compound A6-3 (23.10 g,62.4 mmol) was dissolved in 500mL of DCM, after the temperature of the solution had fallen to 0deg.C, tempo (3.6 mg) and ABr solution (9.3 g) were added to the solution, dissolved in 50mL of pure water, and NaClO solution (52.5 mmol) was slowly added dropwise, after the dropwise addition was completed, TLC was followed until the consumption of starting material was completed. Then, the reaction was quenched by addition of sodium sulfite solution, the reaction solution was cooled to room temperature, extracted twice with 50mL of DCM, and the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give Compound A6-4 (20.6 g).
Step 3: compound A6-4 (20.6 g,56.2 mmol) was dissolved in a mixed solution of 50mL of THF and 5mL of methanol, and after the temperature of the mixed solution was lowered to 0 ℃, compound A6-5 (11.3 g,49.0 mmol) and glacial acetic acid (2.8 g,49.0 mmol) were added to the mixed solution, and NaHB (OAc) was slowly added in portions 3 (31.1 g,147.0 mmol) and after the addition was complete, the reaction was continued for 2h with TLC tracking until the starting material was consumed. After the reaction was completed, the reaction was quenched by addition of saturated sodium bicarbonate solution, the reaction solution was cooled to room temperature, THF and methanol were concentrated to remove, then the concentrate was extracted twice with 200mL of DCM, and the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give Compound A6-6 (22.9 g).
Step 4: compound A6-6 (22.9 g,39.2 mmol), compound A6-7 (9.8 g,45.0 mmol), TEA (8.7 g,58.8 mmol) were dissolved in 100mL DCM and the reaction stirred at room temperature overnight. After the reaction was concentrated, it was dissolved in 100mL of water, extracted twice with EtOAc (100 mL. Times.2), the aqueous phase was retained, sodium chloride was added, extracted twice with DCM (100 mL. Times.2), the organic phases were combined and backwashed once with saturated aqueous NaCl solution (100 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give a crude product. Purification by column chromatography, concentration and oil pump drainage gave hydroxy TBS protected compound A6-8 (21.0 g).
Step 5: compound A6-8 (21.0 g,27.4 mmol) was dissolved in 50mL of THF and placed in a nitrogen-protected flask, and tetrabutylammonium fluoride solution (TBAF, 12mL,1N in THF) was added. The reaction was carried out for 1h, TLC showed complete consumption of starting material, the reaction was quenched with 10mL of water, THF was concentrated to remove it, then the concentrate was extracted twice with 10mL of DCM, the combined organic phases dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give Compound A6-9 (15.2 g).
Step 6: the hydroxy group of the compound A6-9 (15.2 g,23.3 mmol) was oxidized to an aldehyde group, and the operation was similar to that of step 2, to give the compound A6-10 (13.6 g,21.0 mmol).
Step 7: compound A6-10 (13.6 g,21.0 mmol) and compound A6-11 (1.8 g,19.1 mmol) were dissolved in 50mL of DCM and stirred for 20min. Sequentially (2.4 g,21.0 mmol) and perchloric acid (1M in dichloromethane, 1.2 mmol) were added and the resulting reaction mixture was stirred at room temperature for 12h. The compound was purified by flash column chromatography system to give imidazopyridinyl lipid compound A6 (12.1 g, yield 75.6%).
The main data of nuclear magnetic hydrogen spectrum of the imidazopyridinyl lipid compound A6 are:
1H NMR(500MHz，Chloroform-d)δ8.10-8.03(m,2H)，7.46(dd，J＝9.5,1.4Hz,1H)，7.39(ddd，J＝9.5,7.2,1.4Hz,1H)，6.96(ddd，J＝9.3,7.1,1.5Hz,1H)，4.17(d，J＝8.1Hz,2H)，4.14-4.08(m,2H)，4.10-4.05(m,1H)，4.08-4.00(m,1H)，3.26(td，J＝8.8,2.0Hz,4H)，2.83-2.75(m,2H)，2.44(p，J＝10.7Hz,1H),2.32(t，J＝10.2Hz,2H)，1.79-1.69(m,2H)，1.72-1.61(m,3H)，1.64-1.58(m,5H)，1.60-1.55(m,3H)，1.56(t，J＝1.2Hz,1H)，1.57-1.50(m,1H)，1.48-1.40(m,2H)，1.41(dd，J＝2.2,1.0Hz,1H)，1.42-1.38(m,1H)，1.40-1.36(m,3H),1.36(dq，J＝3.1,1.7Hz,2H)，1.36-1.29(m,6H)，1.29(dt,J＝5.7,1.9Hz,5H)，1.28(d，J＝1.0Hz,0H)，1.28(s,2H)，1.29-1.17(m,20H)，0.93-0.84(m,9H)。
example 7
This example 7 provides a process for the preparation of imidazopyridinyl lipid compound A7, A7 being represented by formula (XI):
the specific procedure for the preparation of imidazopyridinyl lipid compound A7, shown in conjunction with fig. 7, is as follows:
compound A6-10 (6.50 g,10 mmol) and compound A7-1 (0.94 g,10 mmol) of example 6 were dissolved in 100mL of DCM, stirred for 20min, compound A7-2 (0.99 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and stirring was continued at room temperature for 24h. Purification was performed by silica gel column, and the target eluate was collected and concentrated to give imidazopyridinyl lipid compound A7 (4.56 g).
The main data of nuclear magnetic hydrogen spectrum of the imidazopyridinyl lipid compound A7 are:
1 H NMR(500MHz，Chloroform-d)δ8.13(dd，J＝9.4,1.4Hz,1H)，7.80-7.74(m,1H)，7.45(dd，J＝9.3,1.6Hz,1H)，7.41(ddd，J＝9.5,6.9,1.3Hz,1H)，6.96(ddd，J＝9.3,7.0,1.6Hz,1H)，4.15-4.06(m,2H)，3.69-3.59(m,4H)，3.53(q，J＝4.6Hz,2H)，3.26(td，J＝8.8,2.0Hz,4H)，2.76-2.68(m,2H)，2.45(p，J＝10.6Hz,1H)，2.32(t,J＝10.2Hz,2H)，1.79-1.50(m,15H)，1.48-1.28(m,17H)，1.31-1.17(m,22H)，1.15(t，J＝4.6Hz,3H)，0.93-0.84(m,9H)。
Example 8
This example 8 provides a process for the preparation of an imidazopyridinyl lipid compound A8, A8 being represented by formula (XII):
referring to fig. 8, the specific procedure for preparing imidazopyridinyl lipid compound A8 is as follows:
compound A6-10 (6.50 g,10 mmol) and compound A8-1 (1.38 g,10 mmol) of example 6 were dissolved in 100mL of DCM, stirred for 20min, compound A8-2 (0.99 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and stirring was continued at room temperature for 24h. Purification was performed by silica gel column, and the target eluate was collected and concentrated to give imidazopyridinyl lipid compound A8 (5.89 g).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound A8 are as follows:
1 H NMR(500MHz，Chloroform-d)δ8.49(d，J＝8.4Hz,1H),7.92-7.85(m,1H),6.92-6.86(m,2H),4.15-4.06(m,4H)，3.69-3.59(m,4H)，3.53(q，J＝4.6Hz,2H)，3.26(td，J＝8.8,2.0Hz,4H)，2.75(t，J＝10.9Hz,2H)，2.44(p，J＝10.7Hz,1H)，2.32(t，J＝10.2Hz,2H)，1.79-1.62(m,5H),1.64-1.59(m,2H),1.62-1.54(m,7H),1.58-1.50(m,1H)，1.48-1.42(m,1H)，1.44-1.39(m,1H)，1.42-1.35(m,8H)，1.36(d，J＝1.9Hz,1H)，1.37-1.32(m,1H)，1.35-1.28(m,8H)，1.31-1.19(m,21H)，1.15(t，J＝4.5Hz,3H)，0.94-0.84(m,9H)。
example 9
This example 9 provides a process for the preparation of imidazopyridinyl lipid compound A9, A9 being represented by formula (XIII):
the specific procedure for the preparation of imidazopyridinyl lipid compound A9, shown in conjunction with fig. 9, is as follows:
step 1: compound A6-6 (5.8 g,10.0 mmol) was dissolved in dry 120mL THF, naH (60%, 4.0g,100.0 mmol) was slowly added under ice-bath, and reacted under ice-bath for 1h. After completion of the reaction, compound A9-1 (3.3 g,12.0 mmol) was added thereto, and the reaction mixture was stirred in an ice bath for 1 hour, and then returned to room temperature to react overnight. After the reaction was completed, the reaction was placed in an ice bath, 2mL of methanol was slowly added to quench the reaction, and after stirring for 30min, 300mL of water was added to stir and mix. Extraction with EtOAc (150 mL. Times.2) twice, retention of the aqueous phase, extraction with dichloromethane (100 mL. Times.2) twice, collection of the combined organic phases, backwash with 100mL of saturated aqueous sodium chloride, drying of the organic phase over anhydrous sodium sulfate, filtration and concentration of the filtrate gives crude compound A9-2. Purification by column chromatography, concentration and oil pump drainage gave compound A9-2 (5.7 g, yield 73.0%).
Step 2: compound A9-2 (5.7 g,7.3 mmol) was dissolved in 50mL of THF, placed in a nitrogen-protected flask, and tetrabutylammonium fluoride solution (TBAF, 4mL,1N in THF) was added. The reaction was carried out for 1h, TLC showed complete consumption of starting material, the reaction was quenched with 10mL of water, THF was concentrated to remove it, then the concentrate was extracted twice with 10mL of DCM, the combined organic phases dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give compound A9-3 (4.2 g, yield 86.3%).
Step 3: compound A9-3 (4.2 g,6.3 mmol) was dissolved in 500mL of DCM, after the temperature of the above solution was reduced to 0deg.C, tempo (0.36 mg) and ABr solution (0.93 g) were added to the above solution, dissolved in 20mL of pure water, naClO solution (6.8 mmol) was slowly added dropwise, and after the dropwise addition was completed, TLC was followed until the consumption of the starting material was completed. Then the reaction was quenched by addition of sodium sulfite solution, the reaction was brought to room temperature and extracted twice with 50mL of DCM, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give compound A9-4 (3.8 g, yield 92.1%).
Step 4: compound A9-4 (3.8 g,5.8 mmol) and compound A9-5 (0.50 g,5.3 mmol) were dissolved in 50mL of DCM and stirred for 20min. Compounds A9-6 (0.48 g,5.8 mmol) and perchloric acid (1M in dichloromethane, 0.25 mmol) were added sequentially and the resulting reaction mixture was stirred at room temperature for 12h. The compound was purified by flash column chromatography system to give imidazopyridinyl lipid compound A9 (3.7 g, yield 83.7%).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound A9 are as follows:
1H NMR(500MHz，Chloroform-d)δ7.48-7.37(m,1H),6.96(ddd，J＝9.3,7.0,1.6Hz,0H)，4.10(td，J＝8.5,1.0Hz,1H)，3.38(q，J＝6.5Hz,1H)，2.76(t，J＝10.9Hz,1H)，2.47-2.40(m,1H)，2.43-2.35(m,2H)，1.80-1.69(m,1H)，1.71-1.63(m,1H)，1.67-1.58(m,2H)，1.58(dd，J＝3.1,1.6Hz,1H)，1.60-1.54(m,1H)，1.57-1.48(m,2H)，1.50-1.17(m,21H)，0.94-0.84(m,5H)。
example 10
This example 10 provides a process for the preparation of imidazopyridinyl lipid compound a10, a10 being represented by formula (XIII):
the specific procedure for the preparation of imidazopyridinyl lipid compound a10 is as follows, in conjunction with fig. 10: :
compound A9-4 (6.64 g,10 mmol) and compound A10-1 (1.24 g,10 mmol) of example 9 were dissolved in 100mL of DCM, stirred for 20min, compound A10-2 (0.83 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and stirring was continued at room temperature for 24h. Purification was performed by silica gel column, and the target eluate was collected and concentrated to give imidazopyridinyl lipid compound a10 (3.69 g).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a10 are as follows:
1H NMR(500MHz，Chloroform-d)δ7.00-6.93(m,1H),4.10(td，J＝8.5,1.0Hz,1H)，3.77(s,1H)，3.38(q，J＝6.5Hz,1H),2.75(t，J＝10.9Hz,1H)，2.47-2.40(m,1H)，2.43-2.35(m,2H)，1.79-1.69(m,1H),1.71-1.63(m,1H)，1.67-1.59(m,2H)，1.58(dd，J＝3.1,1.6Hz,1H)，1.59-1.54(m,1H)，1.57-1.51(m,1H)，1.54-1.45(m,1H)，1.47-1.16(m,22H)，0.94-0.84(m,5H)。
Example 11
This example 11 provides a process for the preparation of imidazopyridinyl lipid compound a11, a11 being represented by formula (XIV):
referring to fig. 11, the specific procedure for preparing imidazopyridinyl lipid compound a11 is as follows:
compound A6-10 (6.50 g,10 mmol) and compound A11-1 (1.24 g,10 mmol) of example 9 were dissolved in 100mL of DCM and stirred for 20min, then compound A7-2 (0.99 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and stirring was continued at room temperature for 24h. The target eluate was collected and concentrated to give imidazopyridinyl lipid compound a11 (4.86 g).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a11 are as follows:
1H NMR(500MHz，Chloroform-d)δ4.10(td，J＝8.5,1.0Hz,1H)，3.77(s,1H),3.69-3.59(m,2H)，3.53(q，J＝4.6Hz,1H)，2.76-2.68(m,1H),2.50-2.35(m,3H),1.79-1.67(m,1H)，1.71-1.59(m,1H),1.62-1.51(m,3H)，1.55-1.48(m,1H)，1.50-1.17(m,20H)，1.15(t，J＝4.5Hz,1H)，0.94-0.84(m,4H)。
example 12
This example 12 provides a process for the preparation of an imidazopyridinyl lipid compound a12, a12 being represented by the formula (XV):
the specific procedure for the preparation of imidazopyridinyl lipid compound a12, shown in conjunction with fig. 12, is as follows:
step 1: compound A12-1 (24.20 g,100.0 mmol) was dissolved in 250mL of THF solution, placed in a nitrogen-protected flask, naH (6.00 g,150.0mmol, 60%) was carefully added to the mixed solution after the temperature of the mixed solution had fallen to 0-10℃and after 0.5h of reaction, compound A12-2 (26.5 g,90.0 mmol) was slowly added dropwise and the reaction solution was returned to room temperature for further reaction for 12h. TLC showed that compound a12-1 was essentially completely consumed, the reaction was quenched with 100mL of water, THF was concentrated to remove it, then the concentrate was extracted twice with 100mL of DCM, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give compound A12-3 (30.8 g).
Step 2: compound A12-3 (30.8 g,67.5 mmol) was dissolved in 250mL of THF, placed in a nitrogen-protected flask, and tetrabutylammonium fluoride solution (TBAF, 125mL,1N in THF) was added. The reaction was carried out for 1h, TLC showed complete consumption of starting material, the reaction was quenched with 100mL of water, THF was concentrated to remove it, then the concentrate was extracted twice with 100mL of DCM, the combined organic phases dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give compound A12-4 (21.2 g).
Step 3: compound A12-4 (21.2 g,62.1 mmol) was dissolved in 200mL of DCM, after the temperature of the solution had fallen to 0deg.C, tempo (5.0 mg) and ABr solution (0.29 g,2.4 mmol) were added to the solution, dissolved in 20mL of purified water, naClO solution (70 mmol) was slowly added dropwise, and after the dropwise addition was completed, TLC was followed until the consumption of starting material was completed. Then the reaction was quenched by addition of sodium sulfite solution, the reaction was brought to room temperature and extracted twice with 200mL of DCM, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and spun-dried to give the crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give compound A12-5 (17.2 g, 81.7%).
Step 4: compound A12-5 (17.2 g,50.7 mmol) was dissolved in a mixed solution of 150mL of THF and 15mL of methanol, and after the temperature of the mixed solution was lowered to 0 ℃, compound A12-6 (3.3 g,25.0 mmol) and glacial acetic acid (1.5 g,25.0 mmol) were added to the mixed solution, and NaBH (OAc) was slowly added in portions 3 (18.5 g,87.5 mmol) and after the addition was complete, the reaction was continued for 2h with TLC tracking until the starting material was consumed. After the reaction was completed, the reaction was quenched by addition of saturated sodium bicarbonate solution, the reaction solution was returned to room temperature, THF and methanol were concentrated to remove, then the concentrate was extracted twice with 200mL of DCM, and the combined organic phases were dried over anhydrous magnesium sulfate, filtered and dried to give a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give compound A12-7 (14.2 g).
Step 5: the hydroxy group of compound A12-7 (14.2 g,18.2 mmol) was oxidized to an aldehyde group, and the operation was similar to that of step 3, to give compound A12-8 (12.1 g,15.6 mmol).
Step 6: compound A12-8 (12.1 g,15.6 mmol) and 4-methoxypyridin-2-amine (1.8 g,14.1 mmol) were dissolved in 50mL of DCM, stirred for 20min, ethyl 2-isocyanoacetate (1.8 g,15.6 mmol) and perchloric acid (1M in dichloromethane, 0.8 mmol) were added sequentially and stirring was continued at room temperature for 12h. The compound was purified by flash column chromatography system to give imidazopyridinyl lipid compound a12 (11.1 g, 78.5%).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a12 are as follows:
1H NMR(500MHz，Chloroform-d)δ6.92(dd，J＝8.6,1.3Hz,0H)，4.17(d，J＝8.1Hz,1H),4.08(qd，J＝4.9,2.7Hz,1H)，3.77(s,1H),3.39(t，J＝8.1Hz,2H)，3.30(d，J＝8.5Hz,2H),2.76(td，J＝10.9,6.4Hz,1H)，2.40(t，J＝8.2Hz,2H)，1.79-1.63(m,2H)，1.65-1.17(m,30H)，0.93-0.84(m,5H)。
example 13
This example 13 provides a process for the preparation of imidazopyridinyl lipid compound a13, a13 being represented by formula (XVI):
referring to fig. 13, the specific procedure for preparing imidazopyridinyl lipid compound a13 is as follows:
compound A12-8 (7.78 g,10 mmol) and compound A13-1 (0.94 g,10 mmol) of example 12 were dissolved in 100mL of DCM, stirred for 20min, compound A13-2 (1.13 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and stirring was continued at room temperature for 24h. The target eluate was collected and concentrated to give imidazopyridinyl lipid compound a13 (5.96 g).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a13 are as follows:
1H NMR(500MHz，Chloroform-d)δ4.08(qd，J＝4.9,2.7Hz,0H)，3.39(t，J＝8.1Hz,1H)，3.30(d，J＝8.5Hz,1H)，2.40(t，J＝8.2Hz,1H)，1.79-1.65(m,1H)，1.67-1.17(m,14H)，0.93-0.85(m,2H)。
example 14
This example 14 provides a process for the preparation of imidazopyridinyl lipid compound a14, a14 being represented by formula (XVII):
referring to fig. 14, the specific procedure for preparing imidazopyridinyl lipid compound a14 is as follows:
compound A12-8 (7.78 g,10 mmol) and compound A13-1 (0.94 g,10 mmol) of example 12 were dissolved in 100mL of DCM, stirred for 20min, compound A13-2 (0.99 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and stirring was continued at room temperature for 24h. Purification was performed by silica gel column, and the target eluate was collected and concentrated to give imidazopyridinyl lipid compound A14 (6.01 g).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a14 are as follows:
1H NMR(500MHz，Chloroform-d)δ8.13(dd，J＝9.3,1.4Hz,1H)，7.80-7.74(m,1H)，7.45(dd，J＝9.4,1.6Hz,1H)，7.41(ddd，J＝9.5,7.0,1.3Hz,1H)，6.96(ddd，J＝9.3,7.0,1.6Hz,1H)，3.68-3.60(m,2H)，3.64(s,2H)，3.53(q，J＝4.6Hz,2H)，3.39(t,J＝8.1Hz,4H)，3.30(d,J＝8.5Hz,4H)，2.76-2.68(m,2H)，2.40(t,J＝8.2Hz,6H)，1.80-1.72(m,2H)，1.74-1.69(m,1H)，1.72-1.62(m,2H)，1.64-1.55(m,4H)，1.58-1.48(m,5H),1.51-1.40(m,9H)，1.44-1.28(m,31H)，1.31-1.25(m,14H)，1.28-1.17(m,10H)，1.15(t,J＝4.5Hz,3H)，0.93-0.85(m,12H)。
example 15
This example 15 provides a process for the preparation of imidazopyridinyl lipid compound a15, a15 is represented by formula (XVIII):
referring to fig. 15, the specific procedure for preparing imidazopyridinyl lipid compound a15 is as follows:
step 1: compound A15-1 (11.0 g,32.0 mmol) was dissolved in 30mL of DCM under nitrogen, compound A15-2 (36.3 g,128.0 mmol) was added dropwise with stirring at room temperature, followed by slow dropwise addition of pyridine (3.2 mL,40.0 mmol) over 25min, and then DMAP (0.78 g,6.4 mmol) was added in one portion. The reaction was stirred at room temperature for 16h, after completion of the reaction, extracted twice with DCM, the organic phases were combined and washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column separation, and the target eluent was collected and concentrated to give Compound A15-3 (10.3 g).
Step 2: compound A15-3 (10.3 g,21.0 mmol), compound A15-4 (2.3 g,17.5 mmol) and N, N-dimethylethylenediamine (0.92 g,10.5 mmol) were dissolved in 20mL of DMF and reacted at 77℃for 18h. After the reaction was completed, the reaction mixture was cooled and extracted with hexane (3×20 mL). The hexane extracts were combined, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography to give compound A15-5 (7.8 g).
Step 3: compound A15-6 (7.7 g,37.0 mmol) was dissolved in 100mL of anhydrous DCM, placed in a nitrogen-protected flask, after the temperature of the mixed solution was reduced to 0-10deg.C, compound A15-2 (8.7 g,74.0 mmol) and DMAP (5.42 g,44.4 mmol) were carefully added to the mixed solution, and EDCI (78.14 g,407.0 mmol) was added in portions, and the reaction was continued while the temperature was reduced to room temperature. After 16h of reaction, TLC showed complete consumption of Compound A15-6, and the reaction solution was washed twice with 500mL of a 0.4N HCl/10% NaCl mixed solution, once with saturated brine, and the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give Compound A15-7 (5.7 g).
Step 4: compound A15-7 (5.7 g,12.0 mmol) was dissolved in dry THF (60 mL), naH (60%, 4.80g,120.0 mmol) was slowly added under ice-bath, and reacted under ice-bath for 1h. Compound A15-5 (7.8 g,14.4 mmol) was added and the reaction was stirred in an ice bath for 1h and then allowed to slowly return to room temperature overnight. After the reaction was completed, the reaction was placed in an ice bath, 2mL of methanol was slowly added to quench the reaction, and the mixture was stirred for 30min, followed by adding water (200 mL) and stirring. Extraction with EtOAc (200 mL. Times.2) twice, retention of the aqueous phase, extraction with dichloromethane (200 mL. Times.2) twice, collection of the combined organic phases, backwash with saturated sodium chloride (200 mL), drying of the organic phase over anhydrous sodium sulfate, filtration and concentration of the filtrate gives crude compound A15-8. Purification by column chromatography, concentration and oil pump drainage gave compound A15-8 (10.3 g).
Step 5: compound A15-8 (10.3 g,11.0 mmol) was dissolved in 200mL of DCM, after the temperature of the solution had fallen to 0deg.C, tempo (5.0 mg) and ABr solution (0.29 g,2.4 mmol) were added to the solution, dissolved in 20mL of purified water, naClO solution (70 mmol) was slowly added dropwise, and after the dropwise addition was completed, TLC was followed until the consumption of starting material was completed. Then the reaction was quenched by addition of sodium sulfite solution, the reaction was brought to room temperature and extracted twice with 200mL of DCM, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and spun-dried to give the crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give Compound A15-9 (9.6 g).
Step 6: compound A15-9 (9.6 g,10.3 mmol) and pyridin-2-amine (0.97 g,10.3 mmol) were dissolved in 50mL of DCM and stirred for 20min. 1-Isopropane (0.83 g,12.0 mmol) and perchloric acid (1M in dichloromethane, 0.8 mmol) were added sequentially and stirring was continued at room temperature for 12h. The compound was purified by flash column chromatography system to give imidazopyridinyl lipid compound a15 (9.2 g, yield 82.8%).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a15 are as follows:
1H NMR(500MHz，Chloroform-d)δ4.68(dt，J＝28.1,9.0Hz,1H)，4.17-4.10(m,1H)，3.31(td，J＝8.0,6.2Hz,1H)，2.76(t，J＝10.9Hz,1H)，2.43-2.36(m,2H)，2.24(t，J＝10.8Hz,1H)，1.80-1.72(m,1H)，1.75-1.66(m,3H)，1.69-1.62(m,1H)，1.66-1.57(m,1H)，1.60-1.41(m,4H)，1.44-1.27(m,9H)，1.30-1.21(m,12H)，1.25-1.17(m,5H)，0.96(t，J＝4.9Hz,1H)，0.93-0.84(m,4H)。
example 16
This example 16 provides a process for the preparation of imidazopyridinyl lipid compound a16, a16 being represented by formula (XIX):
Referring to fig. 16, the specific procedure for preparing imidazopyridinyl lipid compound a16 is as follows:
compound A15-9 (9.34 g,10 mmol) and compound A13-1 (1.24 g,10 mmol) of example 15 were dissolved in 100mL of DCM, stirred for 20min, A13-2 (0.69 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and stirring was continued at room temperature for 24h. The target eluate was collected by separation and purification on a silica gel column, and concentrated to give imidazopyridinyl lipid compound a16 (7.51 g).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a16 are as follows:
1H NMR(500MHz，Chloroform-d)δ8.50(d，J＝8.6Hz,0H)，7.00-6.93(m,1H)，4.68(dt，J＝28.1,9.0Hz,1H)，4.17-4.10(m,1H)，3.77(s,1H)，3.30(td，J＝8.0,6.2Hz,1H)，2.79-2.71(m,1H)，2.43-2.36(m,3H)，2.24(t,J＝10.9Hz,1H)，1.80-1.62(m,6H)，1.65-1.57(m,1H)，1.61-1.44(m,4H)，1.47-1.35(m,5H)，1.38-1.32(m,2H)，1.35-1.28(m,3H)，1.32-1.23(m,10H)，1.27-1.17(m,11H)，0.96(t，J＝4.9Hz,1H)，0.93-0.84(m,5H)。
example 17
This example 17 provides a process for the preparation of imidazopyridinyl lipid compound a17, a17 being represented by formula (XX):
referring to fig. 17, the specific procedure for preparing imidazopyridinyl lipid compound a17 is as follows:
step 1: compound A15-9 (9.34 g,10 mmol) and compound A13-1 (1.24 g,10 mmol) of example 15 were dissolved in 100mL of DCM, stirred for 20min, compound A13-2 (0.99 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and stirring was continued at room temperature for 24h. Purification was performed by silica gel column, and the target eluate was collected and concentrated to give imidazopyridinyl lipid compound A17 (6.15 g).
The main nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a17 is mainly as follows:
1H NMR(500MHz，Chloroform-d)δ8.49(d，J＝8.5Hz,1H)，7.92-7.85(m,1H)，6.99(d，J＝1.2Hz,1H)，6.91(dd，J＝8.6,1.3Hz,1H)，4.68(dt，J＝28.1,9.0Hz,2H)，4.17-4.10(m,2H),3.77(s,2H),3.69-3.61(m,4H),3.53(q，J＝4.6Hz,2H)，2.72(t，J＝10.9Hz,2H)，2.43-2.36(m,6H)，2.24(t，J＝10.9Hz,2H)，1.80-1.69(m,6H)，1.70(s,2H)，1.72-1.66(m,2H)，1.68-1.60(m,3H)，1.60-1.47(m,6H)，1.46(dt，J＝8.1,1.3Hz,2H)，1.47-1.41(m,1H)，1.44-1.28(m,23H)，1.31-1.18(m,45H)，1.15(t，J＝4.5Hz,3H)，0.93-0.84(m,11H)。
example 18
This example 18 provides a process for the preparation of imidazopyridinyl lipid compound a18, a18 being represented by formula (XXI):
referring to fig. 18, the specific procedure for preparing imidazopyridinyl lipid compound a18 is as follows:
step 1: in a dry clean 1000mL round bottom flask, compound A18-2 (163.9 g,233.2 mmol) was dissolved in dichloromethane, DMAP (62.59 g,513.0 mmol) was added and stirred well, compound A18-1 (119.6 g,467.3 mmol) was added to the reaction solution and stirred at room temperature for 16h. After completion of the reaction, the reaction mixture was dried by spin-drying, and recrystallized from isopropyl alcohol to obtain Compound A18-3 (201.3 g).
Step 2: compound A18-3 (20.1 g,20.5 mmol) was dissolved in 250mL of THF, placed in a nitrogen-protected flask, and tetrabutylammonium fluoride solution (TBAF, 110mL,1N in THF) was added. Reaction for 1h, TLC showed complete consumption of starting material, reaction quenched with 100mL of water, THF was concentrated to remove, then the concentrate was extracted twice with 100mL of DCM, and the organic phases were combined using anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give compound A18-4 (16.5 g).
Step 3: the procedure of example 15, step 4, was analogous to that of example 15, step 4, oxidation of the hydroxy group of Compound A18-4 (16.5 g,19.0 mmol) to an aldehyde group, gave Compound A18-5 (15.8 g,18.2 mmol).
Step 4: compound A18-5 (15.8 g,18.2 mmol) and compound A18-6 (1.6 g,17.1 mmol) were dissolved in 50mL of DCM and stirred for 20min. Compound A18-7 (1.2 g,18.2 mmol) and perchloric acid (1M in dichloromethane, 0.8 mmol) were added sequentially and stirring continued for 12h at room temperature. The compound was purified by flash column chromatography system to give imidazopyridinyl lipid compound a18 (13.6 g, yield 78.7%).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a18 are as follows:
1H NMR(500MHz，Chloroform-d)δ4.14(t，J＝8.1Hz,1H)，2.47-2.36(m,1H)，1.80-1.66(m,2H)，1.65-1.46(m,2H)，1.45-1.31(m,2H)，1.34-1.27(m,1H)，1.30-1.24(m,3H)，1.27-1.17(m,2H)，0.96(t，J＝4.9Hz,0H)，0.93-0.84(m,2H)。
example 19
This example 19 provides a process for the preparation of imidazopyridinyl lipid compound a19, a19 being represented by formula (XXII):
referring to fig. 19, the specific procedure for preparing imidazopyridinyl lipid compound a19 is as follows:
step 1: compound A18-5 (8.66 g,10 mmol) and compound A19-1 (1.24 g,10 mmol) of example 18 were dissolved in 100mL of DCM, stirred for 20min, compound A19-2 (0.69 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and stirring was continued at room temperature for 24h. The target eluate was collected and concentrated to give imidazopyridinyl lipid compound a19 (6.03 g).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a19 are as follows:
1H NMR(500MHz，Chloroform-d)δ4.70(p，J＝9.0Hz,1H)，4.14(t，J＝8.1Hz,1H)，3.31(td，J＝8.0,6.2Hz,1H)，2.76(t，J＝10.9Hz,1H)，2.47-2.36(m,2H)，2.30(t，J＝1.3Hz,1H)，1.80-1.66(m,5H)，1.65-1.46(m,4H)，1.45-1.17(m,18H)，0.96(t，J＝4.9Hz,1H)，0.93-0.84(m,4H)。
example 20
This example 20 provides a process for the preparation of an imidazopyridinyl lipid compound a20, a20 being represented by formula (XXIII):
the specific procedure for the preparation of imidazopyridinyl lipid compound a20, shown in conjunction with fig. 20, is as follows:
step 1: compound A18-5 (8.66 g,10 mmol) and compound A20-1 (1.24 g,10 mmol) of example 18 were dissolved in 100mL of DCM, stirred for 20min, compound A20-2 (0.99 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and stirring was continued at room temperature for 24h. Purification was performed by silica gel column, and the target eluate was collected and concentrated to give imidazopyridinyl lipid compound a20 (5.45 g).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a20 are as follows:
1H NMR(500MHz，Chloroform-d)δ4.70(p，J＝9.0Hz,1H)，4.14(t，J＝8.1Hz，2H)，3.69-3.61(m,2H)，3.53(q，J＝4.6Hz,1H)，2.76-2.68(m,1H)，2.47-2.36(m,2H)，2.32-2.28(m,1H),1.80-1.66(m,6H)，1.60-1.52(m,1H)，1.55-1.46(m,3H)，1.45-1.18(m,22H)，1.15(t，J＝4.5Hz,1H)，0.94-0.84(m,5H)。
example 21
This example 21 provides a process for the preparation of imidazopyridinyl lipid compound a21, a21 being represented by formula (XXIV):
referring to fig. 21, the specific procedure for preparing imidazopyridinyl lipid compound a21 is as follows:
step 1: 3-Hexaundecanoic acid (A21-1, 135.23g,500 mmol) was dissolved in anhydrous DCM (1L), placed in a nitrogen-protected flask, after the temperature of the mixed solution was reduced to 0-10 ℃, pentane-1, 5-diol (A21-2, 104.15g,1000 mmol) and DMAP (73.30 g,600 mmol) were carefully added to the mixed solution, EDCI (115.02 g,600 mmol) was added in portions and the reaction was returned to room temperature to continue the reaction. After 16h of reaction TL C showed complete consumption of Compound A21-1, the reaction was washed twice with 500mL of a 0.4N HCl/10% NaCl mixture, once with saturated saline, and the combined organic phases were dried over anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give Compound A21-3 (120.08 g).
Step 2: compound A21-3 (57.05 g,160 mmol) was dissolved in 500mL of DCM, after the temperature of the solution had fallen to 0deg.C, tempo (12.50 mg,80 mmol) and ABr solution (23.80 g,200 mmol) were added to the solution, dissolved in 50mL of purified water, naClO solution (14.89 g,200 mmol) was slowly added dropwise, after the dropwise addition was completed, TLC was followed until the consumption of starting material was completed. Then the reaction was quenched by addition of sodium sulfite solution, the reaction was warmed to room temperature and extracted twice with 500mL of DCM, and the organic phases were combined over anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give Compound A21-4 (30.02 g).
Step 3: compound A21-4 (21.27 g,60 mmol) was dissolved in a mixed solution of 200mL of THF and 20mL of methanol, and after the above solution temperature was lowered to 0 ℃, compound A21-5 (3.94 g,30 mmol) and glacial acetic acid (1.80 g,30 mmol) were added to the solution. NaBH (OAc) was added slowly in portions 3 (21.19 g,100 mmol) and after the addition was complete, the reaction was continued for 2h with TLC tracking until the starting material was consumed. After completion of the reaction, the reaction was quenched by addition of saturated sodium bicarbonate solution, the reaction mixture was returned to room temperature, THF and methanol were concentrated to remove, then the concentrate was extracted twice with 200mL of DCM, and the organic phases were combined over anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give compound A21-6 (35.62 g).
Step 4: compound A21-6 (16.45 g,20 mmol) was dissolved in 500mL of DCM and after the temperature of the solution had fallen to 0deg.C, tempo (1.56 mg,10 mmol) and ABr solution (2.98 g,25 mmol) were added to the solution, dissolved in 50mL of purified water, naClO solution (1.86 g,25 mmol) was slowly added dropwise, after the dropwise addition was completed, TLC was followed until the starting material was consumed. Then adding sodium sulfite solution to quench the reaction,the reaction was warmed to room temperature and extracted twice with 500mL of DCM, and the organic phases were combined using anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give Compound A21-7 (10.41 g).
Step 5: compound A21-7 (8.20 g,10 mmol) and 2-aminopyridine (A21-9, 0.94g,10 mmol) were dissolved in 100mL of DCM and stirred for 20min, compound A21-8 (0.69 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and stirring was continued at room temperature for 24h. Purification was performed by silica gel column, and the target eluate was collected and concentrated to give imidazopyridinyl lipid compound a21 (6.21 g).
The main nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a21 is mainly as follows:
1H NMR(500MHz，Chloroform-d)δ8.33(dd，J＝9.4,1.4Hz,1H)，7.52(t，J＝6.2Hz,1H)，7.45(dd，J＝9.4,1.7Hz,1H)，7.41(ddd，J＝9.5,6.9,1.3Hz,1H)，6.96(ddd，J＝9.3,7.0,1.6Hz,1H)，4.10(t，J＝8.1Hz,4H)，3.31(td，J＝8.0,6.2Hz,2H)，2.76(t，J＝10.9Hz,2H)，2.50(dd，J＝11.3,1.2Hz,4H),2.40(td，J＝8.3,2.6Hz,6H)，2.06(tt，J＝11.2,10.0Hz,2H)，1.80-1.16(m,71H)，0.96(t，J＝4.9Hz,3H)，0.93-0.84(m,12H)。
example 22
This example 22 provides a process for the preparation of imidazopyridinyl lipid compound a22, a22 being represented by formula (XXV):
the specific procedure for the preparation of imidazopyridinyl lipid compound a22 is as follows, in conjunction with fig. 22:
step 1: 3-Hexaundecanoic acid (A22-1, 135.23g,500 mmol) was dissolved in anhydrous DCM (1L), placed in a nitrogen-protected flask, after the temperature of the mixed solution was reduced to 0-10 ℃, pentane-1, 5-diol (A22-2, 104.15g,1000 mmol) and DMAP (73.30 g,600 mmol) were carefully added to the mixed solution, EDCI (115.02 g,600 mmol) was added in portions and the reaction solution was returned toThe reaction was continued at room temperature. After 16h of reaction, TLC showed complete consumption of Compound A22-1, the reaction was washed twice with 500mL of a 0.4N HCl/10% NaCl mixed solution, once with saturated brine, and the combined organic phases were dried over anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give Compound A22-3 (120.08 g).
Step 2: compound A22-3 (57.05 g,160 mmol) was dissolved in 500mL of DCM, after the temperature of the solution had fallen to 0deg.C, tempo (12.50 mg,80 mmol) and ABr solution (23.80 g,200 mmol) were added to the solution, dissolved in 50mL of purified water, naClO solution (14.89 g,200 mmol) was slowly added dropwise, after the dropwise addition was completed, TLC was followed until the consumption of starting material was completed. Then the reaction was quenched by addition of sodium sulfite solution, the reaction was warmed to room temperature and extracted twice with 500mL of DCM, and the organic phases were combined over anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give Compound A22-4 (30.02 g).
Step 3: compound A22-4 (21.27 g,60 mmol) was dissolved in a mixed solution of 200mL of THF and 20mL of methanol, and after the temperature of the mixed solution was lowered to 0 ℃, compound A22-5 (3.94 g,30 mmol) and glacial acetic acid (1.80 g,30 mmol) were added to the mixed solution. NaBH (OAc) was added slowly in portions 3 (21.19 g,100 mmol) and after the addition was complete, the reaction was continued for 2h with TLC tracking until the starting material was consumed. After completion of the reaction, the reaction was quenched by addition of saturated sodium bicarbonate solution, the reaction mixture was returned to room temperature, THF and methanol were concentrated to remove, then the concentrate was extracted twice with 200mL of DCM, and the organic phases were combined over anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give compound A22-6 (35.62 g).
Step 4: compound A22-6 (16.45 g,20 mmol) was dissolved in 500mL of DCM, after the temperature of the solution had fallen to 0deg.C, tempo (1.56 mg,10 mmol) and ABr solution (2.98 g,25 mmol) were added to the solution, dissolved in 50mL of purified water, naClO solution (1.86 g,25 mmol) was slowly added dropwise, and after the dropwise addition was completed, TLC was followed until the starting material was consumed. Then The reaction was quenched by addition of sodium sulfite solution, the reaction was warmed to room temperature and extracted twice with 500mL of DCM, and the organic phases were combined over anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give compound A22-7 (10.41 g).
Step 5: compound A22-7 (8.20 g,10 mmol) and 2-aminopyridine (A22-8, 0.94g,10 mmol) were dissolved in 100mL of DCM and stirred for 20min, compound A22-9 (1.15 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and the resulting reaction mixture was stirred at room temperature for 24h. The target eluate was collected and concentrated to give imidazopyridinyl lipid compound a22 (4.23 g).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a22 are as follows:
1H NMR(500MHz，Chloroform-d)δ4.16-4.06(m,1H)，3.72-3.60(m,1H)，3.55-3.43(m,1H)，2.50(dd，J＝11.3,1.2Hz,1H),2.40(td，J＝8.3,2.6Hz,1H)，1.78-1.63(m,1H)，1.61-1.51(m,1H)，1.55-1.46(m,1H)，1.50-1.43(m,1H)，1.46-1.35(m,1H)，1.38-1.25(m,4H)，1.26(s,1H)，1.23(dddd，J＝10.7,9.8,4.9,2.7Hz,3H)，0.94-0.84(m,2H)。
example 23
This example 23 provides a process for the preparation of imidazopyridinyl lipid compound a23, a23 being represented by formula (XXVI):
referring to fig. 23, the specific procedure for preparing imidazopyridinyl lipid compound a23 is as follows:
step 1: 3-Hexaundecanoic acid (A23-1, 135.23g,500 mmol) was dissolved in anhydrous DCM (1L), placed in a nitrogen-protected flask, after the temperature of the mixed solution was reduced to 0-10 ℃, pentane-1, 5-diol (A23-2, 104.15g,1000 mmol) and DMAP (73.30 g,600 mmol) were carefully added to the mixed solution, EDCI (115.02 g,600 mmol) was added in portions and the reaction was returned to room temperature to continue the reaction. After 16h of reaction, TLC showed chemical combination The product A23-1 was completely consumed, the reaction mixture was washed twice with 500mL of a 0.4N HCl/10% NaCl mixture, once with saturated brine, and the organic phase was combined with anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give compound A23-3 (120.08 g).
Step 2: compound A23-3 (57.05 g,160 mmol) was dissolved in 500mL of DCM, after the temperature of the solution had fallen to 0deg.C, tempo (12.50 mg,80 mmol) and ABr solution (23.80 g,200 mmol) were added to the solution, dissolved in 50mL of purified water, naClO solution (14.89 g,200 mmol) was slowly added dropwise, after the dropwise addition was completed, TLC was followed until the consumption of starting material was completed. Then the reaction was quenched by addition of sodium sulfite solution, the reaction was warmed to room temperature and extracted twice with 500mL of DCM, and the organic phases were combined over anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give compound A23-4 (30.02 g).
Step 3: compound A23-4 (21.27 g,60 mmol) was dissolved in a mixed solution of 200mL of THF and 20mL of methanol, and after the temperature of the mixed solution was lowered to 0 ℃, compound A23-5 (3.94 g,30 mmol) and glacial acetic acid (1.80 g,30 mmol) were added to the mixed solution. NaBH (OAc) was added slowly in portions 3 (21.19 g,100 mmol) and after the addition was complete, the reaction was continued for 2h with TLC tracking until the starting material was consumed. After completion of the reaction, the reaction was quenched by addition of saturated sodium bicarbonate solution, the reaction mixture was returned to room temperature, THF and methanol were concentrated to remove, then the concentrate was extracted twice with 200mL of DCM, and the organic phases were combined over anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give compound A23-6 (35.62 g).
Step 4: compound A23-6 (16.45 g,20 mmol) was dissolved in 500mL of DCM, after the temperature of the solution had fallen to 0deg.C, tempo (1.56 mg,10 mmol) and ABr solution (2.98 g,25 mmol) were added to the solution, dissolved in 50mL of purified water, naClO solution (1.86 g,25 mmol) was slowly added dropwise, after the dropwise addition was completed, TLC was followed until the material consumption was completed. Then adding sodium sulfite solution to quench reaction, and returning the reaction solutionThe mixture was extracted twice with 500mL of DCM at room temperature, and the organic phases were combined over anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give compound A23-7 (10.41 g).
Step 5: compound A23-7 (8.20 g,10 mmol) and compound A23-8 (1.24 g,10 mmol) were dissolved in 100mL of DCM, stirred for 20min, compound A23-9 (1.15 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and the resulting reaction mixture was stirred at room temperature for 24h. Purification was performed by silica gel column, and the target eluate was collected and concentrated to give imidazopyridinyl lipid compound a23 (5.85 g).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a23 are as follows: 1 HNMR(500MHz,Chloroform-d)δ4.16–4.06(m,1H),3.77(s,0H),3.72–3.60(m,1H),3.55–3.43(m,1H),2.50(dd,J＝11.3,1.2Hz,1H),2.40(td,J＝8.2,2.6Hz,1H),1.78–1.63(m,1H),1.61–1.16(m,11H),0.93–0.84(m,2H)。
example 24
This example 24 provides a process for the preparation of imidazopyridinyl lipid compound a24, a24 being represented by formula (XXVII):
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the specific procedure for the preparation of imidazopyridinyl lipid compound a24 is as follows, in conjunction with fig. 24:
step 1: 3-Hexaundecanoic acid (A24-1, 135.23g,500 mmol) was dissolved in anhydrous DCM (1L), placed in a nitrogen-protected flask, after the temperature of the mixed solution was reduced to 0-10 ℃, compound A24-2 (118.1 g,1000 mmol) and DMAP (73.30 g,600 mmol) were carefully added to the mixed solution, and EDCI (115.02 g,600 mmol) was added in portions, and the reaction was continued back to room temperature. After 16h of reaction, TLC showed complete consumption of Compound A24-1, the reaction was washed twice with 500mL of a 0.4N HCl/10% NaCl mixed solution, once with saturated brine, and the combined organic phases were dried over anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. For crude productsAnd (3) separating and purifying by a silica gel column, collecting target eluent, and concentrating to obtain a compound A24-3 (123.86 g).
Step 2: compound A24-3 (59.25 g,160 mmol) was dissolved in 500mL of DCM, after the temperature of the solution had fallen to 0deg.C, tempo (12.50 mg,80 mmol) and ABr solution (23.80 g,200 mmol) were added to the solution, dissolved in 50mL of purified water, naClO solution (14.89 g,200 mmol) was slowly added dropwise, after the dropwise addition was completed, TLC was followed until the consumption of starting material was completed. Then the reaction was quenched by addition of sodium sulfite solution, the reaction was warmed to room temperature and extracted twice with 500mL of DCM, and the organic phases were combined over anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give Compound A24-4 (32.83 g).
Step 3: compound A24-4 (22.10 g,60 mmol) was dissolved in a mixed solution of 200mL of THF and 20mL of methanol, and after the solution temperature was lowered to 0 ℃, compound A24-5 (3.94 g,30 mmol) and glacial acetic acid (1.80 g,30 mmol) were added to the solution. NaBH (OAc) was added slowly in portions 3 (21.19 g,100 mmol) and after the addition was complete, the reaction was continued for 2h with TLC tracking until the starting material was consumed. After the reaction was completed, the reaction was quenched by addition of saturated sodium bicarbonate solution, the reaction solution was returned to room temperature, THF and methanol were concentrated to remove, then the concentrate was extracted twice with 200mL of DCM, and the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give Compound A24-6 (21.88 g).
Step 4: compound A24-6 (19.32 g,40 mmol), compound A24-7 (15.44 g,40 mmol), TEA (4.04 g,40 mmol) were dissolved in dichloromethane (100 mL) and the reaction was stirred at room temperature overnight. After the reaction was concentrated, it was dissolved in 100mL of water, extracted twice with EtOAc (100 mL. Times.2), the aqueous phase was retained, sodium chloride was added, extracted twice with dichloromethane (100 mL. Times.2), the organic phases were combined and backwashed once with saturated NaCl (100 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give a crude product. Purification by column chromatography, concentration and oil pump drainage gave compound A24-8 (20.86 g).
Step 5: compound A24-8 (16.67 g,20 mmol) was dissolvedIn 500mL of DCM solution, after the solution temperature was reduced to 0deg.C, tempo (1.56 mg,10 mmol) and ABr solution (2.98 g,25 mmol) were added to the solution, dissolved in 50mL of purified water, naClO solution (1.86 g,25 mmol) was slowly added dropwise, and after the dropwise addition was completed, TLC was followed until the material consumption was completed. Then the reaction was quenched by addition of sodium sulfite solution, the reaction was warmed to room temperature and extracted twice with 500mL of DCM, and the organic phases were combined over anhydrous MgSO 4 Drying, filtering and concentrating to obtain a crude product. The crude product was purified by column chromatography on silica gel, and the target eluate was collected and concentrated to give Compound A24-9 (10.55 g).
Step 6: compound A24-9 (8.32 g,10 mmol) and 2-aminopyridine (A24-10, 0.94g,10 mmol) were dissolved in 100mL of DCM and stirred for 20min, compound A24-11 (0.99 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and stirring was continued at room temperature for 24h. Purification was performed by silica gel column, and the target eluate was collected and concentrated to give imidazopyridinyl lipid compound A24 (6.53 g).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a24 are as follows:
1H NMR(500MHz，Chloroform-d)δ7.80-7.74(m,0H)，7.48-7.37(m,1H)，4.10(t，J＝8.2Hz,1H)，3.68-3.59(m,2H)，3.53(q，J＝4.6Hz,1H),3.26(tdd，J＝9.1,5.9,1.6Hz,2H)，2.76-2.68(m,1H)，2.50(dd，J＝11.3,1.2Hz,1H)，2.32(t，J＝10.2Hz,1H)，1.74(ddd，J＝20.4,10.9,9.7Hz,1H)，1.68-1.52(m,4H)，1.54-1.46(m,1H),1.49-1.35(m,7H)，1.38-1.27(m,10H)，1.28(dd，J＝3.1,1.6Hz,2H)，1.29-1.24(m,3H),1.26-1.21(m,3H),1.24-1.16(m,2H),1.15(t，J＝4.5Hz,1H),0.93-0.85(m,5H)。
example 25
This example 25 provides a process for the preparation of imidazopyridinyl lipid compound a25, a25 being represented by formula (XXVIII):
The specific procedure for the preparation of imidazopyridinyl lipid compound a25 is as follows, in conjunction with fig. 25:
compound A24-9 (8.32 g,10 mmol) and compound A25-1 (1.24 g,10 mmol) of example 24 were dissolved in 100mL of DCM, stirred for 20min, A25-2 (0.99 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and stirring was continued at room temperature for 24h. Purification was performed by silica gel column, and the target eluate was collected and concentrated to give imidazopyridinyl lipid compound a25 (7.83 g).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a25 are as follows:
1H NMR(500MHz，Chloroform-d)δ7.92-7.85(m,0H)，4.10(t，J＝8.1Hz,1H)，3.77(s,1H)，3.69-3.61(m,2H)，3.53(q，J＝4.6Hz,1H),3.26(tdd，J＝8.9,5.9,1.6Hz,2H)，2.75(t，J＝10.9Hz,1H),2.50(dd，J＝11.3,1.2Hz,1H)，2.32(t，J＝10.2Hz,1H)，1.79-1.52(m,4H),1.54-1.16(m,28H)，1.15(t，J＝4.5Hz,1H)，0.93-0.84(m,5H)。
example 26
This example 26 provides a process for the preparation of imidazopyridinyl lipid compound a26, a26 being represented by formula (XXIX):
the specific procedure for the preparation of imidazopyridinyl lipid compound a26 is as follows, in conjunction with fig. 26:
compound A24-9 (8.32 g,10 mmol) and compound A27-1 (0.94 g,10 mmol) of example 24 were dissolved in 100mL of DCM, and after stirring for 20min, compound A27-2 (0.69 g,10 mmol) and perchloric acid (0.10 g,1 mmol) were added sequentially and stirring was continued at room temperature for 24h. Purification was performed by silica gel column, and the target eluate was collected and concentrated to give imidazopyridinyl lipid compound a27 (4.23 g).
The main data of nuclear magnetic hydrogen spectrum of imidazopyridinyl lipid compound a27 are as follows:
1H NMR(500MHz，Chloroform-d)δ7.52(t，J＝6.2Hz,0H)，7.48-7.37(m,1H)，4.10(t，J＝8.2Hz,1H)，3.35-3.20(m,3H)，2.76(t，J＝10.9Hz,1H)，2.50(dd，J＝11.3,1.2Hz,1H)，2.32(t，J＝10.2Hz,1H)，1.74(tt，J＝10.9,9.6Hz,1H)，1.68-1.52(m,4H)，1.54-1.16(m,28H)，0.96(t，J＝4.9Hz,1H)，0.93-0.85(m,5H)。
example 27
This example 27 provides a method for preparing an imidazopyridinyl lipid nanoparticle, specifically six groups of imidazopyridinyl lipid nanoparticles, including a positive control group and five experimental groups. The neutral lipids contained in the composition of the six groups of imidazopyridinyl lipid nanoparticles were DSPC, the sterol lipids contained were cholesterol, and the pegylated lipid DMG-PEG2000, except for the lipid compounds. Specifically, positive control group 1: SM102; experiment group 1: the imidazopyridinyl lipid compound is A3; experiment group 2: the imidazopyridinyl lipid compound is a12; experiment group 3: the imidazopyridinyl lipid compound is a15; experiment group 4: imidazopyridinyl lipid compound a20; experimental group 5: the imidazopyridinyl lipid compound is a23.
The structural formula of SM102 is:
example 27-1: preparation of imidazopyridinyl lipid nanoparticle 3 (experimental group 1), comprising the steps of:
step 1: imidazopyridinyl lipid compound A3 (145.45 μmol), distearoyl phosphatidylcholine (DSPC, 29.09 μmol), cholesterol (112 μmol) and PEG conjugated 1, 2-dimyristoyl-sn-glycerol (PEG 2A-DMG,4.37 μmol) were weighed into 200mL of ethanol to prepare an organic phase, 200mg mRNA was weighed into 200mL of citrate buffer to prepare an aqueous phase;
Step 2: the microfluidic device was washed three times with 25mL of absolute ethanol and 75mL of citric acid buffer solution respectively before use, the washing flow rate ratio was 1:3, the organic phase pump flow rate was 4mL/min, and the aqueous phase pump flow rate was 12mL/min.
Step 3: the lipid and mRNA are used for preparing particles through a microfluidic preparation system, the flow rate of the lipid through a microfluidic chip is 3mL/min, the flow rate of the mRNA through the microfluidic chip is 16mL/min, injection water is used for on-line dilution by 3.5 times at a three-time flow rate in the preparation process, the injection water is stirred while dilution, and after the preparation is finished, the injection water is diluted by 10 times again by a PBS solution with the pH of 7.4, so that 10L of mixed solution is obtained.
Step 4: and (5) concentrating the solution to 100mL by overpressure to obtain the imidazopyridinyl lipid nanoparticle 3.
Example 27-2: preparation of imidazopyridinyl lipid nanoparticle 12 (experimental group 2), comprising the steps of:
step 1: imidazopyridinyl lipid compound a12 (145.45 μmol), distearoyl phosphatidylcholine (DSPC, 29.09 μmol), cholesterol (112 μmol) and PEG conjugated 1, 2-dimyristoyl-sn-glycerol (PEG 2A-DMG,4.37 μmol) were weighed to prepare an organic phase in 200mL of ethanol, 200mg mRNA was weighed to dissolve in 200mL of citrate buffer to prepare an aqueous phase;
Step 2: the microfluidic device was washed three times with 25mL of absolute ethanol and 75mL of citric acid buffer solution respectively before use, the washing flow rate ratio was 1:3, the organic phase pump flow rate was 4mL/min, and the aqueous phase pump flow rate was 12mL/min.
Step 3: the lipid and mRNA are used for preparing particles through a microfluidic preparation system, the flow rate of the lipid through a microfluidic chip is 3mL/min, the flow rate of the mRNA through the microfluidic chip is 16mL/min, the preparation process uses water for injection to dilute on line at 3 times of the flow rate for 3.5 times, the water for injection is stirred while diluting, and after the preparation is finished, the water for injection is diluted by 10 times again by using PBS solution with pH of 7.4, so that 10L of mixed solution is obtained.
Step 4: and (5) concentrating the solution to 100mL by overpressure to obtain the imidazopyridinyl lipid nanoparticle 12.
Example 27-3: preparation of imidazopyridinyl lipid nanoparticle 15 (experimental group 3), comprising the steps of:
step 1: imidazopyridinyl lipid compound a15 (145.45 μmol), distearoyl phosphatidylcholine (DSPC, 29.09 μmol), cholesterol (112 μmol) and PEG conjugated 1, 2-dimyristoyl-sn-glycerol (PEG 2A-DMG,4.37 μmol) were weighed into 200mL ethanol to prepare an organic phase, 200mg mRNA was weighed into 200mL citrate buffer to prepare an aqueous phase;
Step 2: the microfluidic device was rinsed 3 times with 25mL absolute ethanol and 75mL citric acid buffer, respectively, before use, at a rinse flow rate ratio of 1:3, at an organic phase pump flow rate of 4mL/min, and at a water phase pump flow rate of 12mL/min.
Step 3: the lipid and mRNA are used for preparing particles through a microfluidic preparation system, the flow rate of the lipid through a microfluidic chip is 3mL/min, the flow rate of the mRNA through the microfluidic chip is 16mL/min, the preparation process uses water for injection to dilute on line at 3 times of the flow rate for 3.5 times, the water for injection is stirred while diluting, and after the preparation is finished, the water for injection is diluted by 10 times again by using PBS solution with pH of 7.4, so that 10L of mixed solution is obtained.
Step 4: and (5) concentrating the solution to 100mL by overpressure to obtain the imidazopyridinyl lipid nanoparticle 15.
Examples 27-4: preparation of imidazopyridinyl lipid nanoparticle 20 (experimental group 4), comprising the steps of:
step 1: imidazopyridinyl lipid compound a20 (145.45 μmol), distearoyl phosphatidylcholine (DSPC, 29.09 μmol), cholesterol (112 μmol) and PEG conjugated 1, 2-dimyristoyl-sn-glycerol (PEG 2A-DMG,4.37 μmol) were weighed to prepare an organic phase in 200mL of ethanol, 200mg mRNA was weighed to dissolve in 200mL of citrate buffer to prepare an aqueous phase;
Step 2: before the microfluidic device is used, the organic phase pump and the aqueous phase pump are respectively washed 3 times by 25mL of absolute ethyl alcohol and 75mL of citric acid buffer solution, the washing flow rate ratio is 1:3, the flow rate of the organic phase pump is 4mL/min, and the flow rate of the aqueous phase pump is 12mL/min;
step 3: preparing particles by using lipid and mRNA through a microfluidic preparation system, wherein the flow rate of the lipid through a microfluidic chip is 3mL/min, the flow rate of the mRNA through the microfluidic chip is 16mL/min, diluting 3.5 times of the flow rate of the mRNA on line by using water for injection at 3 times of the flow rate, stirring while diluting, and diluting 10 times of the PBS solution with pH of 7.4 after the preparation is finished, so as to obtain 10L of mixed solution;
step 4: and (5) concentrating the solution to 100mL by overpressure to obtain the imidazopyridinyl lipid nanoparticle 20.
Examples 27 to 5: preparation of imidazopyridinyl lipid nanoparticle 23 (experimental group 5), comprising the steps of:
step 1: imidazopyridinyl lipid compound a23 (145.45 μmol), distearoyl phosphatidylcholine (DSPC, 29.09 μmol), cholesterol (112 μmol) and PEG conjugated 1, 2-dimyristoyl-sn-glycerol (PEG 2A-DMG,4.37 μmol) were weighed to prepare an organic phase in 200mL of ethanol, 200mg mRNA was weighed to dissolve in 200mL of citrate buffer to prepare an aqueous phase;
Step 2: before the microfluidic device is used, the organic phase pump and the aqueous phase pump are respectively washed 3 times by 25mL of absolute ethyl alcohol and 75mL of citric acid buffer solution, the washing flow rate ratio is 1:3, the flow rate of the organic phase pump is 4mL/min, and the flow rate of the aqueous phase pump is 12mL/min;
step 3: preparing particles by using lipid and mRNA through a microfluidic preparation system, wherein the flow rate of the lipid through a microfluidic chip is 3mL/min, the flow rate of the mRNA through the microfluidic chip is 16mL/min, diluting 3.5 times of the flow rate of the mRNA on line by using water for injection at 3 times of the flow rate, stirring while diluting, and diluting 10 times of the PBS solution with pH of 7.4 after the preparation is finished, so as to obtain 10L of mixed solution;
step 4: and (5) concentrating the solution to 100mL by overpressure to obtain the imidazopyridinyl lipid nanoparticle 23.
Example 28
This example 28 provides a study of the cytotoxicity (biocompatibility) of imidazopyridinyl lipid nanoparticles.
Testing cytotoxicity test based on imidazopyridinyl lipid nanoparticles of the present invention using MTT staining method, vero cells of African green monkey kidney cells were used as a cell model to inoculate a density of 1×10 4 Cells/well, 100 μl/well of cell suspension was seeded into 96-well plates. After inoculation, at 37℃4% CO 2 Is incubated in a cell incubator for 24 hours. The imidazopyridinyl lipid nanoparticle is dissolved in the culture medium to prepare the required concentration, if necessary, a proper amount of cosolvent is added, the old culture medium is sucked and discarded, 100 mu L of culture medium containing three luci-mRNA concentration imidazopyridinyl lipid nanoparticles (N/P is 6/1) with the concentration of 0.1, 0.5 and 2 mu g/mL is added to each well, 100 mu L of fresh culture medium is added to a blank control group, and each concentration of each group is 6 compound wells. After a 24-hour incubation period of the incubation period,incubation was continued with the addition of 25. Mu.L MTT per well of 5mg/mL MTT in PBS buffer. After 4h, the mixed solution of medium and MTT buffer was pipetted off, 150. Mu.L/well of DMSO was added for dissolving the purple formazan crystal of living cells, and after shaking was complete, the absorbance at 490nm was measured with an ELISA reader. The calculation is carried out according to the measured absorbance, and the result is shown in the following table 1.
TABLE 1 cytotoxicity (biocompatibility) of different imidazopyridinyl lipid nanoparticles
As can be seen from table 1: the cell survival rate of the imidazopyridinyl lipid nanoparticle prepared by the invention is more than 80% under the condition of different mRNA concentrations by taking a control group as a benchmark (namely the experimental group/the control group value multiplied by 100%), which indicates that the imidazopyridinyl lipid nanoparticle has good biocompatibility.
Example 29
This example 29 provides an experiment for studying mRNA transport efficiency at cellular level of imidazopyridinyl lipid nanoparticles.
The experiment examined the nucleic acid transport rates of the respective groups of imidazopyridinyl liposome nanoparticles (example 27) with N/P of 6/1 using Vero cells as cell model and firefly luciferase (luc) mRNA as model nucleic acid drug. Culturing cells in 96-well plate until cell density reaches 80%, adding various groups of imidazopyridinyl lipid nanoparticles into culture medium, removing original culture medium, adding specified amount of Opti-MEM (low serum culture medium) into each well, culturing at 37deg.C, 5% CO 2 The cells were incubated in the incubator for 24 hours, then the old medium was removed and replaced with fresh medium for further incubation for 24 hours.
The substrate potassium fluorescein (15 mg/mL, split) was added and the mixture was prepared using sterile PBS to give a final medium concentration of 15. Mu.g/mL. The transfection effect was determined by measuring the intensity of luciferase Luc using a multifunctional microplate reader within 10-30min, and the results are shown in Table 2 below.
TABLE 2 cellular mRNA transport efficiency of imidazopyridinyl lipid nanoparticles
| Component (A) | Luc-mRNA transfection luciferase intensity (a.u.) |
| PBS | 8.5±3.9 |
| mRNA | 10.3±1.5 |
| SM102 | 875.2±33.5 |
| A3 | 1025.3±44.2 |
| A12 | 1589.6±56.9 |
| A15 | 896.5±43.5 |
| A20 | 956.2±78.6 |
| A23 | 2569±86.6 |
As can be seen from table 2: compared with a positive control group, the experimental groups A3, A12, A15, A20 and A23 have better luciferase expression effect, namely, have better gene expression effect, which proves that the lipid nanoparticle prepared from the imidazopyridine lipid can further improve the transfection efficiency of mRNA nucleic acid.
Example 30
This example 30 provides a study of mRNA transport efficiency in imidazopyridinyl lipid nanoparticles.
In order to examine the mRNA transport efficiency of each group of imidazopyridinyl lipid nanoparticles prepared from the imidazopyridinyl lipid compound of the present invention, the present experiment examined the mRNA delivery and expression efficiency of five groups of imidazopyridinyl lipid nanoparticles above with N/P of 6/1 using Luci-mRNA stably expressing luciferase as a model.
After animals are immunized by using mLuc-LNP muscles constructed by different imidazopyridinyl lipid nanoparticles, mice are subjected to in-vivo imaging of small animals and visceral imaging at different time points, expression distribution of luciferase of mLuc-LNP at 24h after immunization in lymph nodes is evaluated by bioluminescence, and mRNA transport efficiency of carrier particle LNP is evaluated.
S1, the experiment is totally provided with 8 groups, 5 groups of test groups, namely a 24h post injection of mLuc-LNP and a PBS group of a control group, and 3 mice in each group. For the experimental group, each mouse was intramuscular injected with 5 μg of mLuc-LNP, and luciferase protein expression was read by in vivo bioluminescence using an In Vivo Imaging System (IVIS) at 6h post immunization after injection of luciferase substrate luciferin;
s2, injecting 100 μl of D-fluorescein (15 mg/mL) into the abdominal cavity after the mice are anesthetized;
S3, imaging organs and tissues, including bioluminescence;
s4, taking drainage lymph nodes after killing the mice;
s5, analyzing data by using a moving Image software, wherein the result is shown in FIG. 27;
as can be seen from fig. 27: the imidazopyridinyl lipid compounds a20, a23 and SM102 were highly expressed in luciferase in draining lymph nodes of mLuc-LNP intramuscular injection mice as lipid component, and both effects of imidazopyridinyl lipid a20 and a23 were found to be superior to SM102.
Various embodiments in this specification are described in an incremental manner, and identical or similar parts of the various embodiments are referred to each other, with each embodiment focusing on differences from the other embodiments.
The above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the present invention; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced with equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (2)
1. An imidazopyridinyl lipid compound, characterized by a compound selected from the group consisting of:
；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；；/>；；；；；/>；；；；/>；；；；；/>；；；；；/>；；；；；/>；；；；；/>。
2. use of an imidazopyridinyl lipid compound according to claim 1 for the preparation of lipid nanoparticles and the use of the lipid nanoparticles for the preparation of a medicament, wherein the medicament is a medicament for gene therapy, gene vaccination, interfering RNA therapy and nucleic acid transfer.
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