CN117088825A - Ionizable lipid, pharmaceutical composition containing same and application thereof - Google Patents
Ionizable lipid, pharmaceutical composition containing same and application thereof Download PDFInfo
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- CN117088825A CN117088825A CN202311319550.5A CN202311319550A CN117088825A CN 117088825 A CN117088825 A CN 117088825A CN 202311319550 A CN202311319550 A CN 202311319550A CN 117088825 A CN117088825 A CN 117088825A
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K9/127—Liposomes
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Abstract
The invention discloses an ionizable lipid, a pharmaceutical composition containing the ionizable lipid and application thereof, belonging to the field of biotechnology; the invention provides a compound shown as a formula (I), or a stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt or a deuterated compound thereof, which is used as ionizable lipid, and solves the technical defect that other ionizable lipid compounds in the prior art are mainly delivered to liver expression antigen proteins and cannot be delivered to spleen; the compound shown in the formula (I) provided by the invention has the characteristics of good spleen organ targeting, high delivery efficiency and the like; the compound shown in the formula (I) provided by the invention can be used for preparingIs prepared into liposome, lipid nanoparticle, drug carrier or complex for delivering nucleic acid drug.
Description
Technical Field
The invention belongs to the technical field of biology, and in particular relates to a compound and application thereof as ionizable lipid for liposome or lipid nanoparticle, drug carrier, compound and drug composition.
Background
mRNA vaccine is an emerging nucleic acid vaccine, and has the outstanding advantages of rapidness and high efficiency in coping with new coronavirus infection. The working principle of the mRNA vaccine is that mRNA encoding specific antigen protein is directly led into somatic cells, and the antigen protein is synthesized by an expression system of host cells, so that the host immune system is induced to generate various effects such as B, T cell specific immune response to the antigen, and the treatment and prevention effects of diseases are effectively exerted. Compared with DNA nucleic acid vaccine and traditional protein/polypeptide vaccine, mRNA vaccine has the advantages of quick research and development, simple production process, high safety and the like, and is a novel anti-tumor nucleic acid vaccine with more clinical application prospect.
mRNA delivery vectors are closely related to storage stability and immunogenicity of vaccines, and are a key technology for mRNA vaccine development. Currently, nucleic acid delivery systems mainly include two major classes, viral vectors and non-viral vectors. Liposomes as a representative non-viral vector are considered to be ideal nucleic acid delivery systems because of their low immunogenicity, good biocompatibility, and high transfection efficiency. Whereas, among non-viral vectors for nucleic acid delivery, LNP as a representative, has been used in three batches of nucleic acid drugs (Patisiran, BNT b2 and mRNA-1273).
The new crown vaccine of mRNA developed by Moderna and Biontech company adopts LNP as a delivery carrier, ionized lipids of the new crown vaccine are SM-102 and ALC-0135 respectively, and the new crown vaccine can deliver mRNA to liver to express antigen protein, and the new crown vaccine can activate immune response of organisms, but has the problem of insufficient immunogenicity. The mRNA vaccine has stronger immune efficacy, and the best delivery target organs are immune organs such as spleen; other ionizable lipid compounds disclosed in the prior art are also mainly delivered to the liver for expression of antigen proteins; therefore, there is a need to develop lipid compounds with high delivery efficiency and good targeting of spleen organs.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art to at least some extent. Therefore, the invention provides a novel compound which is taken as ionizable lipid and has the characteristics of good organ targeting, high delivery efficiency and the like.
The present invention provides a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof:
，
wherein A is N or absent;
m, n, p, q are each independently any integer of 1, 2, 4;
X 1 、X 2 、X 3 And X 4 Each independently is a substituted or unsubstituted C 2 -C 10 Alkylene or hydrogen and X 1 、X 2 、X 3 、X 4 Are not hydrogen at the same time;
Y 1 、Y 2 、Y 3 and Y 4 Each independently is-C (=o) O-, -OC (=o) -, -O-, -S-, -NH-, -S-, -OC (=o) O-, -C (=o) N (R) a )-、-(R a )NC(=O)-、-CH 2 O-、-OCH 2 -、-C(=O)NHN=、=NNHC(=O)-、-S(CR c R d ) rS-or absent; wherein R is a Is hydrogen or C 1-16 An alkyl group; r is R c 、R d Each independently is hydrogen or C 1-6 An alkyl group; r is 1 or 2; y is Y 1 、Y 2 、Y 3 、Y 4 Not both simultaneously absent;
R 1 、R 2 、R 3 、R 4 each independently is a substituted or unsubstituted C 1 -C 18 Straight-chain or branched alkyl, substituted or unsubstituted C 1 -C 18 Straight-chain or branched heteroalkyl, substituted or unsubstituted C 2 -C 18 Straight-chain or branched alkenyl, substituted or unsubstituted C 2 -C 18 Straight-chain or branched heteroalkenyl, substituted or unsubstituted C 2 -C 18 Straight-chain or branched alkynyl, substituted or unsubstituted C 2 -C 18 Straight or branched heteroalkynyl or is absent; r is R 1 、R 2 、R 3 、R 4 Not both simultaneously absent;
when X is 1 、X 2 、X 3 、X 4 、R 1 、R 2 、R 3 、R 4 When substituted, wherein the substituted groups are each independently selected from one or more of halogen, -OH, -SH, -NH 2 、-NO 2 Cyano, oxo, C 1 -C 3 Alkyl, -C (=o) OR 7 、-OC(=O)R 7 、-C(=O)NHR 7 、-NHC(=O)R 7 、-S-SR 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 7 Selected from C 1 -C 20 Straight-chain or branched alkyl, C 1 -C 20 Straight-chain or branched heteroalkyl, C 2 -C 20 Straight-chain or branched alkenyl, C 2 -C 20 Straight-chain or branched heteroalkenyl, C 2 -C 20 Straight-chain or branched alkynyl or C 2 -C 20 Straight or branched heteroalkynyl or hydrogen; the hetero in the heteroalkyl, the heteroalkenyl and the heteroalkynyl refers to a heteroatom, and the heteroatom is N, O, S.
Further, the invention provides a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, which is characterized in that,
R 1 、R 2 、R 3 、R 4 each independently is a substituted or unsubstituted C 6 -C 18 Straight-chain or branched alkyl, substituted or unsubstituted C 6 -C 18 Straight-chain or branched heteroalkyl, substituted or unsubstituted C 6 -C 18 Straight-chain or branched alkenyl, substituted or unsubstituted C 6 -C 18 Straight or branched heteroalkenyl or absent;
wherein when R is 1 、R 2 、R 3 、R 4 When substituted, the substituted groups are each independently selected from one or more of halogen, -OH, -SH, -NH 2 、-NO 2 Cyano, oxo, C 1 -C 3 Alkyl, -C (=o) OR 7 or-OC (=o) R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 7 Selected from C 6 -C 18 Straight-chain or branched alkyl, C 6 -C 18 Straight or branched alkenyl groups.
Further, the invention provides a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, characterized in that m, n, p, q is each independently selected from 1 or 2.
The invention provides a compound of formula (I) or a stereoisomer thereof,Tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds characterized by Y 1 、Y 2 、Y 3 And Y 4 Each independently is-C (=o) O-, -OC (=o) -, -O-, -S-, -NH-, -S-, -OC (=o) O-, -C (=o) N (R) a )-、-(R a )NC(=O)-、-CH 2 O-、-OCH 2 -、-C(=O)NHN=、=NNHC(=O)-、-S(CR c R d ) rS-or absent; wherein R is a Is hydrogen or C 12 An alkyl group; r is R c 、R d Each independently is hydrogen, methyl, ethyl, propyl, isopropyl; r is 1 or 2.
The invention provides a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, characterized in that when A is N,
m, n, p, q are each independently 2;
X 1 、X 2 、X 3 and X 4 Each independently is unsubstituted C 2 -C 10 An alkylene group;
Y 1 、Y 2 、Y 3 and Y 4 Each independently is-C (=O) O-, -OC (=O) -, -S-S-, -NH-, -C (=O) N (R) a )-、-(R a ) NC (=o) -wherein R a Is hydrogen;
R 1 、R 2 、R 3 、R 4 each independently is unsubstituted C 6 -C 18 Straight-chain or branched alkyl, unsubstituted C 6 -C 18 Straight-chain or branched heteroalkyl, unsubstituted C 6 -C 18 Straight-chain branched alkenyl, unsubstituted C 6 -C 18 Straight or branched heteroalkenyl.
The invention provides a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, when a is N, having one of the following characteristics:
X 1 is unsubstituted C 2 -C 10 Alkylene, X 2 、X 3 And X 4 Each independently selected from hydrogen, Y 2 、Y 3 And Y 4 Is absent, R 2 、R 3 、R 4 Is absent;
or (2) X 1 、X 2 Each independently selected from unsubstituted C 2 -C 10 Alkylene, X 3 And X 4 Each independently selected from hydrogen; y is Y 3 And Y 4 R is not present, R 3 、R 4 Is absent;
or (3) X 1 、X 2 、X 3 Each independently selected from unsubstituted C 2 -C 10 Alkylene, X 4 Is hydrogen, Y 4 R is not present, R 4 Is absent;
or (4) X 1 、X 2 、X 3 、X 4 Each independently is unsubstituted C 2 -C 10 An alkylene group.
The invention provides a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, characterized in that when A is absent,
n and p are each independently 1, m and q are each independently 2;
X 1 、X 2 、X 3 each independently is unsubstituted C 2 -C 10 An alkylene group;
Y 1 、Y 2 、Y 3 each independently is-C (=O) O-, -OC (=O) -, -NH-, -S-S-, -C (=O) N (R) a )-、-(R a ) NC (=o) -, wherein R a Is hydrogen;
R 1 、R 2 、R 3 each independently is unsubstituted C 6 -C 18 Straight-chain or branched alkyl, unsubstituted C 6 -C 18 Straight-chain or branched heteroalkyl, unsubstituted C 6 -C 18 Straight-chain branched alkenyl, unsubstituted C 6 -C 18 Straight or branched heteroalkenyl.
The invention provides a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, wherein when a is absent, it has one of the following characteristics:
(1) X 1 is unsubstituted C 2 -C 10 Alkylene, X 2 、X 3 Each independently selected from hydrogen, Y 2 、Y 3 Is absent, R 2 、R 3 Is absent;
or (2) X 1 、X 2 Each independently selected from unsubstituted C 2 -C 10 Alkylene, X 3 Is hydrogen; y is Y 3 R is not present, R 3 Is absent;
or (3) X 1 、X 2 、X 3 Each independently is unsubstituted C 2 -C 10 An alkylene group.
The present invention provides a compound or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, characterized in that when X 1 、X 2 、X 3 、X 4 X, when present 1 、X 2 、X 3 、X 4 Selected from the same groups.
The present invention provides a compound or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, characterized in that when Y 1 、Y 2 、Y 3 And Y 4 Y, when present 1 、Y 2 、Y 3 、Y 4 Selected from the same groups.
The present invention provides a compound or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, characterized in that when R 1 Or R is 2 、R 3 、R 4 When any one is present, each independently has a structure represented by formula (II):
，
wherein t is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
s is an integer of 1 to 10, and s is preferably 1, 2 or 3;
R 5 and R is 6 Each independently is H, substituted or unsubstituted C 1 -C 18 Linear or branched alkyl, substituted or notSubstituted C 1 -C 18 Straight-chain or branched heteroalkyl, substituted or unsubstituted C 2 -C 18 Straight-chain or branched alkenyl, substituted or unsubstituted C 2 -C 18 Straight-chain or branched heteroalkenyl, wherein the substituted groups are each independently selected from one or more halogen, -OH, -SH, -NH 2 、-NO 2 Cyano or C 1 -C 3 Alkyl, -C (=o) OR 7 、-OC(=O)R 7 、-C(=O)NHR 7 、-NHC(=O)R 7 、-S-SR 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 7 Selected from C 6 -C 18 Straight-chain or branched alkyl, C 6 -C 18 Straight or branched alkenyl groups.
The invention provides a compound or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, which is characterized in that R 1 Or R is 2 、R 3 、R 4 When present, the R 1 、R 2 、R 3 、R 4 Each independently having a structure of at least one of:
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the invention provides a compound or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, which is characterized in that R 1 、R 2 、R 3 、R 4 When present, the R 1 、R 2 、R 3 、R 4 Selected from the same groups.
The compound provided by the invention or a stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt or a deuterated compound thereof, when A is absent, the absence is direct connection between C atoms on rings on both sides of A.
The compounds provided by the invention or stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds thereof have the following structure:
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in another aspect, the present invention provides the use of the above compound or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof in the preparation of a liposome, lipid nanoparticle, pharmaceutical carrier or complex.
In another aspect, the invention provides a pharmaceutical composition, which is characterized by comprising the compound or a stereoisomer, a tautomer, a solvate, a pharmaceutically acceptable salt or deuterated compound, a pharmaceutically active molecule and a pharmaceutically acceptable auxiliary material thereof.
Further, the invention provides a pharmaceutical composition, wherein the composition comprises at least one excipient selected from the group consisting of neutral phospholipids, steroids and polyethylene glycol lipids.
Further, the invention provides a pharmaceutical composition wherein the pharmaceutically active molecule is selected from DNA, ASO, siRNA, miRNA, mRNA, ribozymes, nucleic acid aptamers, or combinations thereof; preferably mRNA.
Further, a pharmaceutical composition, wherein the pharmaceutical composition is prepared as lipid nanoparticles.
In another aspect of the invention, the invention provides the use of the aforementioned compounds for the preparation of liposomes, lipid nanoparticles, pharmaceutical carriers or complexes. According to the embodiment of the invention, the compound has ionization property, can be used for preparing liposome and lipid nanoparticles, and the prepared liposome or lipid nanoparticles can be used as a drug carrier to form a nucleic acid drug-liposome complex.
In some embodiments, the above compounds may be prepared in polymeric form as liposomes; the compound can form covalent connection with other substances to prepare liposome; the compound can be chemically reacted with other substances to prepare liposome. According to the embodiments of the present invention, the specific manner of preparing the liposome from the above-mentioned compound is not limited, and the liposome prepared from the above-mentioned compound may have all or part of the structure of the above-mentioned compound, which is regarded as the use of the present invention.
For administration purposes, the compounds of the invention (typically in the form of liposomes in combination with biologically active ingredients) may be administered as crude chemicals or may be formulated as pharmaceutical compositions. The pharmaceutical compositions of the present invention comprise a compound of structure (I) and one or more pharmaceutically acceptable carriers, diluents or excipients. The compound of structure (I) is present in the composition in an amount effective to form liposomes and deliver the bioactive ingredient, e.g., for the treatment of the particular disease or condition of interest. The appropriate concentrations and dosages can be readily determined by those skilled in the art.
In yet another aspect, the invention provides a liposome or lipid nanoparticle comprising the foregoing compounds. According to the embodiment of the invention, the liposome or the lipid nanoparticle can be effectively delivered to organs such as heart, liver, spleen, lung, kidney and the like, especially to the spleen, so that the liposome or the lipid nanoparticle can effectively activate the organism immunity and improve the specific antibody level in the organism of an animal.
In yet another aspect of the invention, a pharmaceutical carrier is provided. According to an embodiment of the invention, the pharmaceutical carrier comprises the aforementioned compound or the aforementioned liposome or lipid nanoparticle. According to an embodiment of the present invention, the aforementioned compound is an ionizable lipid, the drug carrier is an ionizable carrier, the aforementioned compound or liposome or lipid nanoparticle is used to carry the drug, and the drug is delivered into the cell.
In yet another aspect of the invention, a composite is provided. According to an embodiment of the invention, the complex comprises the aforementioned compound or comprises the aforementioned liposome or lipid nanoparticle or the aforementioned pharmaceutical carrier; a bioactive ingredient. From the foregoing, the aforementioned compound is an ionizable lipid, and the drug carrier is an ionizable carrier, whereby, by using the aforementioned compound or liposome or lipid nanoparticle, a drug-loaded composition can be prepared, which contains a bioactive ingredient, and the bioactive ingredient can be delivered into cells of the body for the treatment of diseases.
In yet another aspect, the invention provides a pharmaceutical composition. According to an embodiment of the invention, the pharmaceutical composition comprises the aforementioned compound or comprises the aforementioned liposome or lipid nanoparticle or the aforementioned pharmaceutical carrier or the aforementioned complex. From the above, the aforementioned compounds, liposomes or lipid nanoparticles, drug carriers and complexes have the advantages of strong delivery capacity, good immune activation effect and the like, and the aforementioned compounds, liposomes or lipid nanoparticles or drug carriers are loaded with bioactive components, so that the bioactive components can be delivered into the body, the loaded bioactive components can exert drug effects, and the compounds, the liposomes or lipid nanoparticles or the drug carriers are used for treating diseases.
In some embodiments, pharmaceutically acceptable excipients are also included.
In yet another aspect, the invention provides a pharmaceutical use. According to an embodiment of the present invention, the present invention proposes the use of the aforementioned compounds or of a liposome or lipid nanoparticle comprising the aforementioned or of the aforementioned pharmaceutical carrier or of the aforementioned complex or of the aforementioned pharmaceutical composition for the preparation of a medicament. From the foregoing, the aforementioned compounds, liposomes or lipid nanoparticles, drug carriers and complexes have the advantages of small cytotoxicity, good biocompatibility, strong delivery capacity, good immune activation effect and the like, and the aforementioned compounds, liposomes or drug carriers load bioactive components, so that the bioactive components can be delivered into the body, which is beneficial for the loaded bioactive components to exert drug effects and be used for treating diseases.
In a final aspect of the invention, the invention provides a method for preparing the compound. According to an embodiment of the present invention, the present invention proposes a method for preparing the aforementioned compound.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
The foregoing and/or additional aspects and advantages of the application will become apparent and may be better understood from the following description of embodiments taken in conjunction with the accompanying drawings in which:
FIG. 1 is a plot of particle size and polydispersity variation for 4, 7 and 28 days for 4 N4@mRNA stored at different temperatures, respectively;
FIG. 2 shows graphs of the results of expression of 4N4@mRNA in vivo after 4, 7 and 28 days of storage at different temperatures, respectively; wherein A is a statistical histogram of the expression quantity of 4N4@mRNA in a mouse; b is an actual image graph of 4 N4@mRNA expressed in a mouse body;
FIG. 3 shows a graph of the positive rate of GFP fluorescence signal;
FIG. 4 Compound LNP S In vivo expression distribution result diagram;
FIG. 5 is a graph of data for stimulation of BMDC antigen presentation by the compound 4N4@OVA-mRNA; wherein A is a histogram and B is a punctiform graph;
FIG. 6 is a plot of tumor volume change for compound 4N4@OVA-mRNA vaccine against tumors;
FIG. 7 is a graph showing the results of flow-through detection of immune cells (CD8+ T cells) in mice that are tumor-resistant with the compound 4N4@OVA-mRNA vaccine.
Detailed Description
Embodiments of the present application are described in detail below. The following examples are illustrative only and are not to be construed as limiting the application.
It is intended that the present application cover the alternatives, modifications and equivalents as may be included within the scope of the application as defined by the structural formulas and chemical formulas in the examples or embodiments of the present application. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The present application is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments or implementations, may also be provided in combination in a single embodiment or implementation. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment or implementation, may also be provided separately or in any suitable subcombination.
And (3) the following steps:
unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise indicated, all patent publications cited throughout the disclosure of this invention are incorporated by reference in their entirety.
The invention will apply to the following definitions unless otherwise indicated. For the purposes of the present invention, chemical elements are defined according to the periodic Table of the elements, CAS version and chemical handbook, 75, thred, 1994. In addition, the general principles of organic chemistry are found in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999, and "March's Advanced Organic Chemistry", by Michael b. Smith and Jerry March, john Wiley & Sons, new York 2007, and the entire disclosure of this invention is hereby incorporated by reference.
In this document, the terms "comprise" or "include" are used in an open-ended fashion, i.e., to include what is indicated by the present invention, but not to exclude other aspects.
In this context, the compounds of the invention also include isotopically-labelled compounds of the invention which are identical to those recited in the invention except for the fact that: one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number common in nature. Exemplary isotopes that can also be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H、 3 H、 13 C、 14 C、 15 N、 16 O、 17 O、 31 P、 32 P、 36 S、 18 F and F 37 Cl。
The compounds of the invention containing the aforementioned isotopes and/or other isotopes of other atoms, and pharmaceutically acceptable salts of such compounds, are included within the scope of the invention. Isotopically-labelled compounds of the invention, e.g. radioactive isotopes, e.g 3 H and 14 c incorporation into the compounds of the present invention may be useful in drug and/or substrate tissue distribution assays. Tritiated, i.e. due to ease of preparation and detection 3 H, and carbon-14, i.e 14 C, isotopes are particularly preferred. Furthermore, with heavy isotopes, e.g. deuterium, i.e 2 H substitution may provide some therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Thus, it may be preferable in some situations.
The stereochemical definitions and conventions used in the present invention are generally in accordance with S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, e.and Wilen, s., "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (attopiomers) and mixtures thereof, such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefix D and L or R and S are used to denote the absolute configuration of the molecule in terms of chiral center (or chiral centers) in the molecule. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is left-handed. The compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are generally referred to as mixtures of enantiomers. Enantiomer 50: the 50 mixture is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Depending on the choice of starting materials and methods, the compounds according to the invention may be present in the form of one of the possible isomers or mixtures thereof, for example as pure optical isomers or as isomer mixtures, for example as racemic and non-corresponding isomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may be in cis or trans (cis-or trans-) configuration.
The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (attospimers) and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
Unless otherwise indicated, structures described herein are also meant to include all isomeric (e.g., enantiomer, diastereomeric atropisomer (attiosomer) and geometric (or conformational)) forms of such structures; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, individual stereochemical isomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (or conformational) isomer mixtures of the compounds of the invention are all within the scope of the invention.
Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration. The substituents on the atoms having unsaturated double bonds may be present in cis- (Z) -or trans- (E) -form, if possible.
Thus, unless otherwise indicated, a compound of the invention may exist as one of the possible isomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, atropisomers) or as a mixture thereof, e.g., as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or as a mixture thereof.
Here, a solid line [ ] can be used ) Wedge (++)>) Or virtual wedge (+)>) Carbon-carbon bonds of the compounds of the application are described. The use of a solid line to depict a bond to an asymmetric carbon atom indicates that all possible stereoisomers at that carbon atom (e.g., a particular enantiomer, a racemic mixture, etc.) are included. The use of a real or virtual wedge to depict the stereoisomers shown by the presence of linkages to asymmetric carbons. When present in a racemic mixture, real and imaginary wedges are used to define the relative stereochemistry, not the absolute stereochemistry.
Any of the resulting isomer mixtures may be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, based on the physicochemical differences of the components, for example by chromatography and/or fractional crystallization.
Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Pressure Liquid Chromatography (HPLC) using chiral adsorbents. IN particular, enantiomers may be prepared by asymmetric synthesis (e.g., jacques, et al, enntiomers, racemates and Resolutions (Wiley Interscience, new York, 1981)), principles of Asymmetric Synthesis (2 nd Ed. Robert E, gawley, jeffrey Aub e, elsevier, oxford, UK, 2012), eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, ed., univ, of Notre Dame Press, notre Dame, IN 1972).
Herein, the term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be converted to each other by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers (prototropic tautomer)) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valance tautomers) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
As used herein, the term "solvate" refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.
As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
Herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: s.m. Berge et al describe pharmaceutically acceptable salts in detail in j Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid-forming salts, including, but not limited to, inorganic acid salts formed by reaction with amino groups (e.g., hydrochloride, hydrobromide, phosphate, sulfate, perchlorate), and organic acid salts (e.g., acetate, oxalate, maleate, tartrate, citrate, succinate, malonate), or by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts including adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropyl Salts of acids, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodite, 2-hydroxy-ethanesulfonate, lactoaldehyde, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by suitable bases, including alkali metals, alkaline earth metals, ammonium and N + (C 1 -C 4 Alkyl group 4 Is a salt of (a). The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali or alkaline earth metal salts including sodium, lithium, potassium, calcium, magnesium, and the like. The pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations, such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C 1 -C 8 Sulfonate and aromatic sulfonate.
In this document, the terms "optionally," "optional," or "optionally" generally refer to the subsequently described event or condition may, but need not, occur, and the description includes instances in which the event or condition occurs, as well as instances in which the event or condition does not.
The term "optionally substituted" is used interchangeably herein with "substituted or unsubstituted". In general, the term "optionally" whether or not prior to the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. An optional substituent group may be substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from the group consisting of specific groups, thenThe substituents may be substituted identically or differently at various positions. Wherein the substituents may be, but are not limited to F, cl, br, CN, OH, NH 2 、NO 2 Etc.
The term "one or more" (e.g., in the definition of substituents of compounds of the general formula of the present invention) means "one, two, three, four or five, especially one, two, three or four, more especially one, two or three, more especially one or two".
In addition, unless explicitly indicated otherwise, the descriptions used in this disclosure of the manner in which each … is independently "and" … is independently "and" … is independently "are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.
In this context, the term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.
Herein, the minimum and maximum values of the carbon atom content in the hydrocarbon groups are represented by prefixes, for example, prefix C a -C b Refers to a compound containing from "a" to "b" carbon atoms. Exemplary, "C 1 -C n "refers to a linear or branched, saturated/unsaturated carbon chain containing 1, 2, 3, 4, 5, … … or n carbon atoms; further understanding, "C 1 -C n "should be construed as including any subrange therein, e.g., C 1 -C 40 、C 2 -C 40 、C 1 -C 18 、C 3 -C 24 、C 1 -C 16 、C 4 -C 10 、C 4 -C 8 、C 1 -C 3 。
Herein, the term "C 1 -C 40 Alkyl "means a straight or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, … … or 40 carbon atoms, e.g. C 2 -C 40 Alkyl, C 2 -C 24 Alkyl group,C 3 -C 24 Alkyl, C 3 -C 11 Alkyl, C 4 -C 10 Alkyl, C 4 -C 8 An alkyl group. Including but not limited to methyl, ethyl, n-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu, -CH) 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like, wherein the alkyl groups may independently be absentSubstituted or substituted with one or more substituents described herein.
Herein, the term "C 2 -C 40 Alkenyl "refers to a straight or branched monovalent hydrocarbon radical having 2,3, 4, 5, … …, or 40 carbon atoms, wherein at least one position C-C is an sp2 double bond unsaturated state, wherein the alkenyl groups may independently be unsubstituted or substituted with one or more substituents described herein, including the positioning of the groups" cis "," trans "or" Z "," E ", wherein specific examples include, but are not limited to, an ethylene radical (-ch=ch =ch) 2 ) Allyl (-CH) 2 CH=CH 2 ) Etc. For example C 2 -C 40 Alkenyl, C 2 -C 18 Alkenyl, C 3 -C 24 Alkenyl, C 3 -C 11 Alkenyl, C 4 -C 10 Alkenyl, C 4 -C 8 Alkenyl groups.
Herein, the term "C 2 -C 40 Alkynyl "refers to a straight or branched monovalent hydrocarbon radical having 2, 3, 4, 5, … …, or 40 carbon atoms, wherein at least one position C-C is an sp triple bond unsaturated state, wherein the alkynyl group may be independently unsubstituted or substituted with one or more substituents described herein, specific examples include, but are not limited to, alkynylethyl (-C≡CH) 2 ) Propargyl (-CH) 2 C.ident.CH), 1-propynyl (-C.ident.C-CH) 3 ) Etc. For example C 2 -C 40 Alkynyl, C 2 -C 18 Alkynyl, C 3 -C 24 Alkynyl, C 3 -C 11 Alkynyl, C 4 -C 10 Alkynyl, C 4 -C 8 Alkynyl groups.
"in the description of the radicals according to the invention""is used to describe the position of a group substitution.
"in the description of the radicals according to the invention""is used to describe that the carbon-carbon bond of the compound herein may be a single bond (++>) May also be a double bond (+)>）。
Y in the present invention 1 、Y 2 、Y 3 And Y 4 Each independently is C (=O) O-, -OC (=O) -, -O-, -S-S-, -OC (=O) O-, -C (=O) N (R) a )-、-(R a )NC(=O)-、-CH 2 O-、-OCH 2 -、-C(=O)NHN=、=NNHC(=O)-、-S(CR c R d ) rS-, which is associated with R 1 、R 2 、R 3 、R 4 X is X 1 、X 2 、X 3 、X 4 The connection sequence of the (C) is that the compounds are sequentially connected from left to right according to the structure shown in the formula (I).
Herein, "Ionizable lipids" include Cationic lipids (Cationic lipids), ionizable lipids (Ionizable lipids), and derivatives thereof.
Herein, "liposome" or "Lipid Nanoparticle (LNP)" refers to a drug-carrying system in which a drug or other bioactive substance is dissolved or encapsulated in a lipid core or adsorbed, attached to the surface of a nanoparticle, using a biocompatible lipid material as a carrier.
As used herein, the term "pharmaceutically acceptable adjuvant" includes any solvent, dispersion medium, coating, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, pharmaceutical stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or combination thereof, as known to those of skill in the art (as described in Remington's Pharmaceutical Sciences, 18th Ed Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
In this context, the term "treatment" refers to the use to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing the disease or symptoms thereof, and/or may be therapeutic in terms of partially or completely curing the disease and/or adverse effects caused by the disease. As used herein, "treating" encompasses diseases in mammals, particularly humans, including: (a) Preventing the occurrence of a disease or disorder in an individual susceptible to the disease but not yet diagnosed with the disease; (b) inhibiting disease, e.g., arresting disease progression; or (c) alleviating a disease, e.g., alleviating symptoms associated with a disease. As used herein, "treating" or "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, alleviate, ameliorate, reduce or inhibit a disease in the individual, including, but not limited to, administration of a drug comprising a compound described herein to an individual in need thereof.
The effective amount of the complex or pharmaceutical composition of the present invention may vary depending on the mode of administration and the severity of the disease to be treated, etc. The selection of the preferred effective amount can be determined by one of ordinary skill in the art based on a variety of factors (e.g., by clinical trials). Such factors include, but are not limited to: pharmacokinetic parameters of the bioactive ingredient such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated in the patient, the weight of the patient, the immune status of the patient, the route of administration, etc. For example, separate doses may be administered several times per day, or the dose may be proportionally reduced, as dictated by the urgent need for the treatment of the condition.
The complexes or pharmaceutical compositions of the invention may be incorporated into medicaments suitable for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). These drugs can be prepared in various forms. Such as liquid, semi-solid, and solid dosage forms, and the like, including but not limited to liquid solutions (e.g., injection solutions and infusion solutions) or lyophilized powders. A typical drug is an injectable solution. The foregoing complex or pharmaceutical composition may be administered by intravenous infusion or injection or intramuscular or subcutaneous injection.
According to embodiments of the invention, the route of administration of the method is intramuscular or intravenous.
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
SM102 structure:
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example 1 preparation of Compounds
1.4N series of chemical synthesis and characterization
1.1 Synthesis of 4NR
(1) Synthesis of Compound 1: 2-hexyl undecanoic acid 1a (5.12 g,1.2 equiv.) was added to a round bottom flask, dissolved in dichloromethane, and N, N' -dicyclohexylcarbodiimide (DCC, 4.95 g,2.5 equiv.) and 4-dimethylaminopyridine (DMAP, 293.28 mg,0.1 equiv.) were added and reacted in an ice bath of 1 h. 6-bromo-1-hexanol 1b (4.35 g,1.0 equiv.) was dissolved in dichloromethane and added to the above round bottom flask and reacted at room temperature 6 h. After the reaction is finished, insoluble solids are removed by suction filtration, clear and transparent filtrate is obtained, and the reaction solvent is removed by rotary evaporation under reduced pressure, so that colorless oily liquid is obtained. The crude product was isolated by column chromatography on silica gel eluting with PE/ea=50:1 (V/V) to give a colorless transparent liquid, compound 1, 90% yield. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) =4.05 (t, 2H), 3.38 (t, 2H), 2.29 (m, 1H), 1.85 (m, 2H), 1.64-1.23 (m, 30H), 0.86 (m, 6H). The chemical structure and synthetic route of compound 1 are as follows:
。
(2) Synthesis of Compound 2: 1,4,7, 10-tetraazacyclododecane 1c (1.72 g,1.0 equiv.) and triethylamine (TAE, 3.0 equiv.) were added to a round bottom flask and dissolved in dichloromethane. Taking di-tert-butyl dicarbonate [ (BOC) 2 O，7.63 g，3.0 equiv.]Dissolving in dichloromethane, adding constantThe dropping funnel was pressed and added dropwise to the round bottom flask described above in an ice-water bath. After reaction 6h in an ice-water bath, the reaction was stopped and the reaction solvent was removed by rotary evaporation. The crude product was isolated by column chromatography on silica gel eluting with PE: ea=30:1 (V/V) to give the product as a white solid, compound 2, in 90% yield. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 3.61 (m, 4H), 3.42-3.18 (m, 4H), 2.38 (s, 4H), 1.45 (m, 27H)。
(3) Synthesis of Compound 3: compound 2 (0.47 g,1.0 equiv.), potassium carbonate (0.28 g,2.0 equiv.), potassium iodide (0.032 g,0.1 equiv.) and compound 1 (0.84 g,2.0 equiv.) were added to the pressure-resistant tube, and delamination occurred after adding an appropriate amount of acetonitrile. Placing the mixture in an oil bath at 80 ℃ for reaction 24 h, adding a proper amount of dichloromethane, removing light yellow insoluble matters by suction filtration to obtain clear and transparent yellow transparent liquid, and performing rotary evaporation to obtain orange oily liquid which is a crude product. Separating the crude product by silica gel column chromatography, eluting with CH 2 Cl 2 : CH 3 Oh=80:1 (V/V), the product was purified as a yellow oil. Namely compound 3, with 65% yield. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 4.06 (t, 2H), 3.54-3.23 (m, 12H), 2.65-2.59 (m, 4H), 2.52-2.48 (t, 2H)，2.33-2.26 (m, 1H), 1.64-1.23 (m, 57H), 0.87-0.84 (m, 6H)。
(4) Synthesis of Compound 4NR of the present invention: compound 3 (0.55 g,1.0 equiv.) and trifluoroacetic acid (TFA, 5 mL.) were added to a round bottom flask, dissolved in dichloromethane (CH 2 Cl 2 Tfa=1:1, V/V), room temperature reaction 24 h. The solvent and residual TFA were removed by rotary evaporation, and an appropriate amount of methylene chloride was added to dissolve the product, followed by rotary evaporation to remove the solvent and residual TFA. After repeating 2-3 times, a tan oil was obtained, i.e. 4NR, in 100% yield. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 4.06 (t, 2H), 3.62-3.16 (m, 18H), 2.36-2.29 (m, 1H), 1.74-1.24 (m, 32H), 0.87-0.84 (m, 6H)。
The chemical structure and synthetic route of the compound 4NR of the invention are as follows:
。
1.2 Synthesis of 4N2R
(1) Synthesis of Compound 4: 1,4,7, 10-tetraazacyclododecane 1c (1.72 g,1.0 equiv.) and triethylamine (TAE, 2.17 g,2.2 equiv.) were added to a round bottom flask and dissolved in dichloromethane. In addition, tert-butyl N-succinimidyl carbonate 1d (Boc-Osu, 4.59 g,2.2 equiv.) was dissolved in methylene chloride, added to a constant pressure dropping funnel, and added dropwise to the above round bottom flask in an ice-water bath. After reaction 6 h in an ice-water bath, the reaction was stopped and the reaction solvent was removed by rotary evaporation. The crude product was isolated by column chromatography on silica gel eluting with PE/ea=1:1 (V/V) to give the product as a white solid, compound 4, 80% yield. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 3.75-3.38 (m, 8H), 3.31-2.82 (m, 8H), 1.47-1.32 (m, 18H)。
(2) Synthesis of Compound 5: to a pressure-resistant tube, compound 4 (0.38 g,1.0 equiv.), potassium carbonate (0.56 g,2.0 equiv.), potassium iodide (0.064 g,0.1 equiv) and compound 1 (1.68 g,4.0 equiv.) were added, and delamination occurred after addition of an appropriate amount of acetonitrile. Placing the mixture in an oil bath at 80 ℃ for reaction 24 h, adding a proper amount of dichloromethane, removing yellow insoluble matters by suction filtration to obtain clear and transparent yellow transparent liquid, and performing rotary evaporation to obtain orange oily liquid which is a crude product. Separating the crude product by silica gel column chromatography, eluting with CH 2 Cl 2 : CH 3 Oh=70:1 (V/V), the product was purified as a yellow oil. Namely compound 5, in 60% yield. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 4.02 (t, 4H), 3.32 (m, 8H), 2.62 (m, 8H), 2.40 (t, 4H), 2.30-2.24 (m, 2H), 1.60-1.22 (m, 76H), 0.86-0.83 (m, 12H)。
(3) Synthesis of Compound 4N2R of the present invention: compound 5 (0.63 g,1.0 equiv.) and trifluoroacetic acid (TFA, 5 mL) were added to a round bottom flask and dissolved in dichloromethane (CH 2 Cl 2 Tfa=1:1, V/V), room temperature reaction 24 h. The solvent and residual TFA were removed by rotary evaporation, and an appropriate amount of methylene chloride was added to dissolve the product, followed by rotary evaporation to remove the solvent and residual TFA. Repeating for 2-3 times to obtain yellow brown oily substance, namely 4N2R,the yield was 100%. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 4.03 (t, 4H), 3.71-3.01 (m, 20H), 2.35-2.28 (m, 2H), 1.64-1.25 (m, 68H), 0.88-0.85 (m, 12H)。
The chemical structure and the synthetic route of the compound 4N2R are as follows:
。
1.3 Synthesis of 4N3R
1,4,7, 10-tetraazacyclododecane 1c (0.17 g,1.0 equiv.), potassium carbonate (0.70 g,5.0 equiv.), potassium iodide (0.08 g,0.5 equiv.) and Compound 1 (2.10 g,5.0 equiv.) were added to the pressure-resistant tube, and delamination occurred after addition of an appropriate amount of acetonitrile. Placing the mixture in an oil bath at 80 ℃ for reaction 24 h, adding a proper amount of dichloromethane, removing yellow insoluble matters by suction filtration to obtain clear and transparent yellow transparent liquid, and performing rotary evaporation to obtain orange oily liquid which is a crude product. Separating the crude product by silica gel column chromatography, eluting with CH 2 Cl 2 : CH 3 Oh=70:1 (V/V), the product was purified as a yellow oil, 4N3R, 60% yield. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 4.04 (t, 6H), 3.15-2.95 (m, 6H), 2.77-2.74 (m, 4H), 2.63-2.58 (m, 8H), 2.31-2.25 (m, 3H), 1.65-1.23 (m, 96H), 0.87-0.83 (m, 18H)。
The chemical structure and the synthetic route of the compound 4N3R are as follows:
。
1.4 Synthesis of 4N4R
1,4,7, 10-tetraazacyclododecane 1c (1.0 equiv.), sodium hydride (4.0 equiv.), potassium carbonate (6.0 equiv.), and potassium iodide (0.1 equiv.) were added to the pressure-resistant tube, and then a proper amount of acetonitrile was added thereto and stirred at room temperature for reaction for 30 minutes. Then, compound 1 (6.0 equiv.) and an appropriate amount of acetonitrile (which may cause delamination) were added, and the mixture was placed in an oil bath at 80 ℃ to react 24 h. After the reaction is finished, adding a proper amount of dichloromethane, removing light yellow insoluble matters by suction filtration to obtain And (3) obtaining clear and transparent orange transparent liquid, and performing rotary evaporation to obtain orange oily liquid which is a crude product. Separating the crude product by silica gel column chromatography, eluting with CH 2 Cl 2 : CH 3 Oh=70:1 (V/V), the product was purified as a yellow oil, i.e. 4N4R, in 30% yield. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 4.03 (t, 8H), 2.84 (s, 16H), 2.67 (t, 8H), 2.32-2.25 (m, 4H), 1.63-1.23 (m, 128H), 0.86-0.83 (m, 24H)。
The chemical structure and the synthetic route of the compound 4N4R are as follows:
。
2.3N series of what synthesis and characterization
2.1 Synthesis of 3NR
(1) Synthesis of Compound 6: 1,4, 7-triazacyclononane 1e (1.29 g,1.0 equiv.) and triethylamine (TAE, 2.17 g,2.1 equiv.) were added to a round bottom flask and dissolved in dichloromethane. The di-tert-butyl dicarbonate [ (BOC) 2O,4.55 g,2.1 equiv ] is additionally taken.]Dissolved in dichloromethane, added to a constant pressure dropping funnel and added dropwise to the round bottom flask described above in an ice-water bath. After reaction 6 h in an ice-water bath, the reaction was stopped and the reaction solvent was removed by rotary evaporation. The crude product was isolated by column chromatography on silica gel eluting with PE: ea=30:1 (V/V) to give the product as a white solid, compound 6, in 90% yield. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 3.4 (m, 4H), 3.2-3.16 (m, 4H), 2.86 (m, 4H), 1.41 (s, 18H)。
(2) Synthesis of Compound 7: compound 6 (0.33 g,1.0 equiv.), potassium carbonate (0.28 g,2.0 equiv.), potassium iodide (0.032 g,0.1 equiv.) and compound 1 (0.84 g,2.0 equiv.) were added to the pressure-resistant tube, and delamination occurred after adding an appropriate amount of acetonitrile. Placing the mixture in an oil bath at 80 ℃ for reaction 24 h, adding a proper amount of dichloromethane, removing yellow insoluble matters by suction filtration to obtain clear and transparent yellow transparent liquid, and performing rotary evaporation to obtain orange oily liquid which is a crude product. Separating the crude product by silica gel column chromatography, eluting with CH 2 Cl 2 : CH 3 OH = 80 : 1 （V/V), the product was purified as a yellow oil. Namely compound 7, with a yield of 80%. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 4.05 (m, 2H), 3.47-3.42 (m, 4H), 3.25-3.21 (m, 4H), 2.61-2.58 (m, 4H), 2.48-2.44 (t, 2H), 2.33-2.26 (m, 1H), 1.61-1.54 (m, 4H), 1.45 (s, 18H), 1.35-1.18 (m, 24H), 0.88-0.84 (m, 6H)。
(3) Synthesis of Compound 3NR of the present invention: compound 7 (0.53 g,1.0 equiv.) and trifluoroacetic acid (TFA, 5 mL) were added to a round bottom flask and dissolved in dichloromethane (CH 2 Cl 2 Tfa=1:1, V/V), room temperature reaction 24 h. The solvent and residual TFA were removed by rotary evaporation, and an appropriate amount of methylene chloride was added to dissolve the product, followed by rotary evaporation to remove the solvent and residual TFA. After repeating 2-3 times, a tan oil, i.e. 3NR, was obtained in 100% yield. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 4.05 (t, 2H), 3.47-3.42 (m, 4H), 3.25-3.21 (m, 4H), 2.61-2.58 (m, 4H), 2.48-2.44 (t, 2H), 2.32-2.28 (m, 1H), 1.61-1.54 (m, 4H), 1.43-1.25 (m, 24H), 0.88-0.85 (m, 6H)。
The chemical structure and synthetic route of the compound 3NR of the invention are as follows:
。
2.2 Synthesis of 3N2R
1,4, 7-Triazacyclononane 1e (0.13 g,1.0 equiv.), potassium carbonate (0.42 g,3 equiv.), potassium iodide (0.048 g,0.3 equiv.) and Compound 1 (1.26 g,3 equiv.) were added to the pressure-resistant tube, and delamination occurred after addition of an appropriate amount of acetonitrile. Placing the mixture in an oil bath at 80 ℃ for reaction 24 h, adding a proper amount of dichloromethane, removing yellow insoluble matters by suction filtration to obtain clear and transparent orange transparent liquid, and performing rotary evaporation to obtain orange oily liquid which is a crude product. Separating the crude product by silica gel column chromatography, eluting with CH 2 Cl 2 : CH 3 Oh=60:1 (V/V), the product was purified as a yellow oil. Namely 3N2R, and the yield is 70%. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 4.05 (t, 4H),2.97-2.58 (m, 16H), 2.34-2.27 (m, 2H), 1.64-1.55 (m, 12H), 1.45-1.25 (m, 52H), 0.88-0.85 (m, 12H)。
The chemical structure and the synthetic route of the compound 3N2R are as follows:
。
2.3 Synthesis of 3N3R
1,4, 7-Triazacyclononane 1e (0.13 g,1.0 equiv.), potassium carbonate (0.7 g,5 equiv.), potassium iodide (0.08 g,0.1 equiv.) and a proper amount of acetonitrile were added to the pressure-resistant tube and stirred at room temperature for 30 minutes. Then compound 1 (2.10 g,5 equiv.) was added with an appropriate amount of acetonitrile, and delamination was likely to occur. Placing the mixture in an oil bath at 80 ℃ for reaction 24 h, adding a proper amount of dichloromethane, removing yellow insoluble matters by suction filtration to obtain clear and transparent orange transparent liquid, and performing rotary evaporation to obtain orange oily liquid which is a crude product. Separating the crude product by silica gel column chromatography, eluting with CH 2 Cl 2 : CH 3 Oh=70:1 (V/V), the product was purified as a yellow oil. Namely 3N3R, and the yield is 65%. 1 H NMR (400 MHz, CDCl 3 ) δ (ppm) = 4.05 (t, 6H), 3.09-2.76 (m, 18H), 2.33-2.27 (m, 3H), 1.64-1.57 (m, 18H), 1.44-1.24 (m, 78H), 0.88-0.85 (m, 18H)。
The chemical structure and the synthetic route of the compound 3N3R are as follows:
。
EXAMPLE 2 Synthesis of other exemplary Compounds of the invention
Other exemplary compounds of the present disclosure were prepared from different starting materials by a similar route as described in example 1.
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、
。
The nuclear magnetism of the above chemical structure is shown in table 1:
TABLE 1
| Names of Compounds | Nuclear magnetic hydrogen spectrum (400 MHz, CDCl) 3 ) |
| 4N4R1 | 4.05 (t, 8H), 2.84 (s, 16H), 2.67 (t, 8H), 2.32-2.25 (t, 8H), 1.66-1.54 (m, 16) 1.40-1.23 (m, 56H), 0.85-0.83 (m, 12H) |
| 4N4R2 | 4.06 (t, 8H), 2.85 (s, 16H), 2.68-2.56 (t, 8H), 1.66-1.54 (m, 8H), 1.40-1.23 (m, 64H), 0.85-0.83 (m, 12H) |
| 4N4R3 | 4.04 (t, 8H), 2.82 (s, 16H), 2.68-2.32 (m, 16H), 1.62-1.54 (m, 16) 1.32-1.23 (m, 72H), 0.85-0.83 (m, 12H) |
| 4N4R4 | 4.06 (t, 8H), 2.87 (s, 16H), 2.67-2.53 (m, 16H), 1.66-1.54 (m, 8H), 1.40-1.23 (m, 88H), 0.85-0.83 (m, 12H) |
| 4N4R5 | 4.07 (t, 8H), 2.93 (t, 8H), 2.87 (s, 16H), 2.73-2.65 (m, 8H), 1.40-1.23 (m, 128H), 0.85-0.83 (m, 12H) |
| 4N4R6 | 5.32 (t, 8H), 4.08 (t, 8H), 2.90 (t, 8H). 2.84 (s, 16H), 2.78-2.68 (m, 8H), 1.66-1.54 (m, 16H), 1.32-1.25 (m, 96H) |
| 4N4R7 | 3.23-2.98 (m, 24H), 2.82 (s, 16H), 1.66-1.54 (m, 8H) 1.45-1.23 (m, 72H), 0.85-0.83 (m, 12H) |
| 3N3R1 | 4.07 (t, 6H), 3.09-2.82 (m, 18H), 2.33-2.27 (t, 6H), 1.64-1.57 (m, 6H), 1.48-1.24 (m, 64H), 0.88-0.85 (m, 9H) |
。
Other compounds of the invention can be prepared by a similar route to example 1, using different starting materials.
Example 3 preparation of LNPs@mRNA and investigation of formulation Properties
The inventors constructed an mRNA delivery system lnps@mrna (mRNA-loaded LNP) based on the compounds prepared in the above examples, and examined their formulation properties such as particle size, potential, encapsulation efficiency, mRNA integrity, etc., to evaluate their formulation properties.
The preparation method of LNPs@mRNA is as follows:
(1) Preparing a solution: the ionizable lipid (compound prepared by the invention), DOPE, cholesterol (Chol) and DMG-PEG2000 are respectively dissolved in absolute ethyl alcohol to obtain lipid solution, and meanwhile, fluc mRNA is dissolved in 50 mM PBS buffer salt solution (prepared by RNase-free water) and finally prepared into 10 mM PBS buffer salt solution as water phase, and diluted to a proper concentration for standby.
(2) LNP preparation: mixing the lipid solution obtained in the step (1) with the mRNA solution to obtain an LNP initial preparation. Wherein, the mass ratio of the ionizable lipid to the mRNA is controlled to be 20:1; the mixing treatment is carried out in a microfluidic device, and the technological parameters of the microfluidic device are as follows: the volume ratio of the ethanol phase to the water phase was 1:4 and the total flow rate was 12 mL/min.
(3) Ultrafiltration: diluting the LNP initial preparation by 25 times with PBS buffer solution, ultrafiltering to the initial volume by an ultrafiltration cup to obtain the LNP final preparation, and removing ethanol in the initial preparation in the ultrafiltration process to obtain the LNPs@mRNA drug of the compound. Ultrafiltration process parameters: the pore diameter of the filter membrane is 100 kDa, the ultrafiltration pressure is 0.2 MPa, and the rotating speed is 100-200 rpm.
Lnps@mrna formulation property review:
particle size potential measurement: the LNPs@Fluc particle size potential of the compounds of the invention was measured using a Markov laser particle sizer. A certain volume of the newly prepared LNPs@Fluc solution is diluted by 10 times by pure water, the particle size and the potential of the solution are measured by a Markov laser particle size analyzer, each sample is measured in parallel for 3 times, and the measurement temperature is 25 ℃.
And (3) detecting encapsulation rate: the Quant-iT ™ RiboGreen ™ kit detects encapsulation efficiency.
mRNA stability investigation: after storing 4 n4@mrna at-80 ℃, -20 ℃, 4 ℃ and 25 ℃ for 4, 7 and 28 days, respectively, the particle size, PDI and in vivo mRNA expression were examined to evaluate the possibility of application development of the compound @ mRNA vaccine. The stability investigation results of the 4 N4@mRNA are shown in figures 1 and 2, and the particle size of the 4 N4@mRNA is not obviously changed under the condition of-80 ℃ as shown in figure 1; as shown in FIG. 2, the 4 N4@mRNA of the invention has unchanged expression level in a mouse body at-80 ℃;
the 4 N4@mRNA of the invention can be stably stored for 28 days at the temperature of-80 ℃.
Particle size, potential, encapsulation efficiency data for the compounds of the invention are shown in table 2:
TABLE 2
| Compounds of formula (I) | Particle size nm | Potential mV | Encapsulation efficiency% |
| 3NR | 134 | +9.8 | 59.0 |
| 3N2R | 133 | +9.8 | 99.2 |
| 3N3R | 82 | +6.2 | 99.3 |
| 4NR | 83 | +9.7 | 99.3 |
| 4N2R | 98 | +8.9 | 98.1 |
| 4N3R | 112 | +7.6 | 99.3 |
| 4N4R | 141 | +9.8 | 99.1 |
| 4N4R1 | 138 | +9.7 | 99.2 |
| 4N4R2 | 143 | +9.8 | 99.1 |
| 4N4R3 | 142 | +9.8 | 99.1 |
| 4N4R4 | 139 | +9.8 | 99.1 |
| 4N4R5 | 138 | +9.8 | 99.1 |
| 4N4R6 | 135 | +9.8 | 99.1 |
| 4N4R7 | 141 | +9.8 | 99.1 |
Based on the results, the LNPs preparation prepared from the compound has excellent performance, and can be further used for the development of nano preparations.
EXAMPLE 4 mRNA delivery Performance investigation of the inventive Compounds
The expression of the LNPs@GFP-mRNA vaccine prepared by the compound in HEK 293T cells is examined.
(1) Cell plating: HEK 293T cell suspension was adjusted to appropriate concentration with 1640 complete medium, plated in 24 well plates, 5X 10 5 500. Mu.L/well, continued at 37℃with 5% CO 2 Culture 24 h in an incubator;
(2) Preparation and cell transfection: the compound @ GFP mRNA and positive control preparation lipo2000 @ GFP-mRNA were prepared as in example 3, and the concentration of the mRNA in the preparation to be administered was controlled to 0.025. Mu.g/. Mu.L. 20. Mu.L of each well, i.e. 0.5. Mu.g/well, was administered at 37℃with 5% CO 2 Is incubated 24 h in the incubator.
The expression of the LNPs@GFP-mRNA vaccines of the compounds I-1 and II-1 in CN 116589435A in HEK 293T cells was examined by the same experimental method as described above.
The mRNA delivery efficiency of each compound of the invention was expressed as the GFP fluorescence signal positive rate of the cells, as shown in figure 3. The compounds of the invention have better delivery efficiency relative to the positive control formulation lipo 2000, and relative to compounds I-1, II-1.
EXAMPLE 5 investigation of in vivo expression of LNPs prepared by Compounds of the invention
Further, the in vivo expression of LNPs prepared by the compounds of the invention was examined by intravenous route.
LNP@Fluc mRNA preparation was prepared according to the method described in example 3, using 4N4R as representative lipid structure, and the mRNA concentration of the preparation was adjusted to 0.05 mg/mL with PBS solution, while the osmotic pressure of the preparation was adjusted to isotonicity, 200. Mu.L, i.e., 10. Mu.g of Fluc mRNA per mouse tail was intravenously injected per C57BL/6 mouse tail, 3 in each group, using PBS as negative Control. Mice were kept on normal diet after dosing. After 6 h, 200. Mu.L of substrate solution (15 mg/mL, potassium salt of fluorescein) was intraperitoneally injected. Timing was started after substrate injection, euthanasia was performed after 10 min, heart, liver, spleen, lung, kidney were rapidly released, and bioluminescence intensity of each isolated organ was detected in an IVIS instrument with an exposure time of 60 s. Total flux of each organ was counted after the completion of imaging.
Experimental results as shown in fig. 4, LNP constructed from the ionizable lipid compounds of the invention can target mRNA delivery into mice to express the encoded protein. In particular, the highest expression intensity of 4N4@Fluc mRNA is observed at the spleen part of a mouse, and the method can be used for constructing spleen-targeted mRNA anti-tumor vaccines.
It was shown that LNPs of the compounds of the invention are highly expressed in vivo in the spleen compared to the in vivo expression of the compound venous pathway of CN 116589435A, example 6, investigating the experimental targeting lung (CN 116589435A fig. 5 and fig. 6); is favorable for constructing spleen-targeted mRNA anti-tumor vaccine.
EXAMPLE 6 investigation of the anti-tumor Immunity Effect of the mRNA vaccine of the Compound of the invention
1. In vitro stimulated immunocompetence investigation of 4 N4@mRNA vaccine
The activation of the LNPs@OVA mRNA vaccine prepared by the compound of the invention to BMDC cells and the antigen presentation of BMDC to the LNPs@OVA mRNA vaccine of the invention are further examined to verify the effectiveness of the vaccine.
BMDC maturation activation and antigen presentation detection method:
(1) Cell plating: BMDC cell suspension was adjusted to appropriate concentration with 1640 complete medium, plated with 24 well plates, 5X 10 5 500. Mu.L/well, continued at 37℃with 5% CO 2 Culture 4 h in an incubator.
(2) LNPs preparation and administration: the 4N4 R@OVA mRNA and the positive control preparation SM-102-LNPs@OVA mRNA were prepared in the same manner as in example 3, and the concentration of the administration preparation mRNA was controlled to be 0.05. Mu.g/. Mu.L. 20. Mu.L of each well, i.e. 1. Mu.g/well, was administered at 37℃with 5% CO 2 Is incubated 24 h in the incubator.
(3) Dyeing and detecting: after incubation, cells in the 24 well plates were collected into flow tubes and centrifuged at 1 mL PBS 1500 rpm pre-chilled for 5 min to wash the cells twice. mu.L of the above cell suspension and 1. Mu.L of Anti-mouse CD16/32 were added to each flow tube, and after mixing, incubation was performed at 4℃for 15 min to block non-specific binding. mu.L of PE-anti-mouse CD11c, FITC-anti-mouse CD80, APC/Cy7-anti-mouse CD86 and APC-anti-mouse H-2Kb bound to SIINFEKL streaming antibody were added to the corresponding streaming tube, respectively, and incubated at 4℃for 40 min. After the incubation, cells were washed twice by centrifugation for 5 min at 1 mL PBS 1500 rpm pre-chilled, then mixed with 300 μl PBS, and flow cytometry was used to detect BMDC maturation activation status and antigen presentation.
As shown in fig. 5, the LNP (4n4@ova mRNA) constructed by using the 4N4R ionizable lipid of the present invention can promote rapid maturation and activation of BMDC, and the antigen presenting rate (61.42%) is far higher than that of ionizable lipid SM-102 (33.62%) used by the modern new crown vaccine. Thus, it was demonstrated that mRNA vaccines constructed using the compounds of the present invention can efficiently stimulate body immunity.
2. Antitumor Activity of 4 N4@OVAmRNA vaccine
(1) Construction of lymphoma mouse model:
subcutaneous injection of 10 in C57BL/6 mice 6 E.G7-OVA cells with OVA antigen are used for observing the growth state of mice and the size of subcutaneous tumor, and tumors with macroscopic grain size are formed after 7 days of injection inoculation, so that the construction of lymphoma mouse models is completed and can be used for subsequent experiments.
(2) Antitumor immunity: tumor-bearing C57BL/6 mice grown to about the size of a grain on day 7 in the above (1) were randomly divided into five groups of 6 mice each; the Control group was not dosed, the positive Control group was dosed with the mRA vaccine of Moderna vector containing SM-102 (SM-102@OVA mRNA), the remaining three groups were dosed with 4 N4@OVA mRNA by tail vein at 5 μg, 15 μg, all groups then all groups were immunized again on days 10, 15. Tumor volumes were monitored every two days during treatment (days 7, 9, 11, 13, 15, 17, 19, 21, 23, respectively), mice were sacrificed on day 23 and OVA antigen specific immune cells (cd8+ T cells) were detected in the mice.
The experimental results are shown in fig. 6 and 7, fig. 6 is a line graph of tumor volume observation results of the mice, and fig. 7 is a graph of flow detection results of immune cells (CD8+T cells) in the mice;
From the tumor volume observations of FIG. 6, it was shown that the mRNA vaccine constructed by the compound 4N4R of the present invention showed better antitumor effect at different groups of 5. Mu.g and 15. Mu.g of the dose, relative to the SM-102@OVA mRNA vaccine obtained from Control and vector Moderna comprising SM-102.
The results of flow-test experiments from figure 7 on OVA antigen-specific immune cells (cd8+ T cells) in mice showed that the proportion of specific cd8+ T cells activated in mice (functioning as apoptotic tumor cells) was higher, especially at the spleen site, in groups immunized with the 4 nzr@mrna vaccine constructed by the series of compounds of the invention, relative to the SM-102@ova mRNA vaccine obtained by Control and the vector Moderna comprising SM-102, the vector Moderna comprising SM-102. The mice of the mice group with 4N4R@mRNA vaccine constructed by the series of compounds have better antitumor activity; the experimental result is consistent with the in vitro BMDC maturation activation experimental result.
The experimental results show that the mRNA vaccine constructed based on the series of compounds can efficiently activate the body immunity and play a better anti-tumor role.
In conclusion, the nucleic acid delivery carrier constructed based on the series of compounds can efficiently activate the body immunity, and the nucleic acid medicine prepared by using the nucleic acid delivery carrier can exert better immune efficacy. The nucleic acid delivery vector constructed by using the series of compounds can specifically target the spleen of the mouse, which shows that the compounds are favorable for developing spleen-targeted nucleic acid delivery vectors and/or medicaments, in particular spleen-targeted tumor nucleic acid medicaments.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (17)
1. A compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof:
wherein A is N;
m, n, p, q are each independently any integer of 1, 2, 4;
X 1 、X 2 、X 3 and X 4 Each independently is a substituted or unsubstituted C 2 -C 10 Alkylene or hydrogen and X 1 、X 2 、X 3 、X 4 Are not hydrogen at the same time;
Y 1 、Y 2 、Y 3 and Y 4 Each independently is-C (=o) O-, -OC (=o) -, -O-, -S-, -NH-, -OC (=o) O-, -C (=o) N (R a )-、-(R a )NC(=O)-、-CH 2 O-、-OCH 2 -、-C(=O)NHN=、=NNHC(=O)-、-S(CR c R d ) rS-or absent; wherein R is a Is hydrogen or C 1-16 An alkyl group; r is R c 、R d Each independently is hydrogen or C 1-6 An alkyl group; r is 1 or 2; y is Y 1 、Y 2 、Y 3 、Y 4 Not both simultaneously absent;
R 1 、R 2 、R 3 、R 4 each independently is a substituted or unsubstituted C 1 -C 18 Straight-chain or branched alkyl, substituted or unsubstituted C 1 -C 18 Straight-chain or branched heteroalkyl, substituted or unsubstituted C 2 -C 18 Straight-chain or branched alkenyl, substituted or unsubstituted C 2 -C 18 Straight-chain or branched heteroalkenyl, substituted or unsubstituted C 2 -C 18 Straight-chain or branched alkynyl, substituted or unsubstituted C 2 -C 18 Straight or branched heteroalkynyl or is absent; r is R 1 、R 2 、R 3 、R 4 Not both simultaneously absent;
when X is 1 、X 2 、X 3 、X 4 、R 1 、R 2 、R 3 、R 4 When substituted, wherein the substituted groups are each independently selected from one or more of halogen, -OH, -SH, -NH 2 、-NO 2 Cyano, oxo, C 1 -C 3 Alkyl, -C (=o) OR 7 、-OC(=O)R 7 、-C(=O)NHR 7 、-NHC(=O)R 7 、-S-SR 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 7 Selected from C 1 -C 20 Straight-chain or branched alkyl, C 1 -C 20 Straight-chain or branched heteroalkyl, C 2 -C 20 Straight-chain or branched alkenyl, C 2 -C 20 Straight-chain or branched heteroalkenyl, C 2 -C 20 Straight-chain or branched alkynyl or C 2 -C 20 Straight or branched heteroalkynyl or hydrogen; the hetero in the heteroalkyl, the heteroalkenyl and the heteroalkynyl refers to a heteroatom, and the heteroatom is N, O, S.
2. A compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof according to claim 1 wherein,
R 1 、R 2 、R 3 、R 4 each independently is a substituted or unsubstituted C 6 -C 18 Straight-chain or branched alkyl, substituted or unsubstituted C 6 -C 18 Straight-chain or branched heteroalkyl, substituted or unsubstituted C 6 -C 18 Straight-chain or branched alkenyl, substituted or unsubstituted C 6 -C 18 Straight or branched heteroalkenyl or absent;
wherein when R is 1 、R 2 、R 3 、R 4 When substituted, the substituted groups are each independently selected from one or more of halogen, -OH, -SH, -NH 2 、-NO 2 Cyano, oxo, C 1 -C 3 Alkyl, -C (=o) OR 7 or-OC (=o) R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 7 Selected from C 6 -C 18 Straight-chain or branched alkyl, C 6 -C 18 Straight or branched alkenyl groups.
3. A compound of formula (I) according to claim 1, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, characterized in that m, n, p, q is each independently selected from 1 or 2.
4. A compound of formula (I) according to claim 1, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, characterized in that Y 1 、Y 2 、Y 3 And Y 4 Each independently is-C (=O) O-, -OC (=O) -, -O-, -S-, and,-NH-、-OC(=O)O-、-C(=O)N(R a )-、-(R a )NC(=O)-、-CH 2 O-、-OCH 2 -、-C(=O)NHN=、=NNHC(=O)-、-S(CR c R d ) rS-or absent; wherein R is a Is hydrogen or C 12 An alkyl group; r is R c 、R d Each independently is hydrogen, methyl, ethyl, propyl, isopropyl; r is 1 or 2.
5. A compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof according to claim 1 wherein when A is N,
m, n, p, q are each independently 2;
X 1 、X 2 、X 3 and X 4 Each independently is unsubstituted C 2 -C 10 An alkylene group;
Y 1 、Y 2 、Y 3 and Y 4 Each independently is-C (=o) O-, -OC (=o) -, -NH-, -C (=o) N (R a )-、-(R a ) NC (=o) -wherein R a Is hydrogen;
R 1 、R 2 、R 3 、R 4 each independently is unsubstituted C 6 -C 18 Straight-chain or branched alkyl, unsubstituted C 6 -C 18 Straight-chain or branched heteroalkyl, unsubstituted C 6 -C 18 Straight-chain branched alkenyl, unsubstituted C 6 -C 18 Straight or branched heteroalkenyl.
6. A compound of formula (I) according to claim 1, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, when a is N, having one of the following characteristics:
（1）X 1 is unsubstituted C 2 -C 10 Alkylene, X 2 、X 3 And X 4 Each independently selected from hydrogen, Y 2 、Y 3 And Y 4 Is absent, R 2 、R 3 、R 4 Is absent;
or (2) X 1 、X 2 Each independently selected from unsubstituted C 2 -C 10 Alkylene, X 3 And X 4 Each independently selected from hydrogen; y is Y 3 And Y 4 R is not present, R 3 、R 4 Is absent;
or (3) X 1 、X 2 、X 3 Each independently selected from unsubstituted C 2 -C 10 Alkylene, X 4 Is hydrogen, Y 4 R is not present, R 4 Is absent;
or (4) X 1 、X 2 、X 3 、X 4 Each independently is unsubstituted C 2 -C 10 An alkylene group.
7. The compound according to claim 1, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, wherein when X is 1 、X 2 、X 3 、X 4 X, when present 1 、X 2 、X 3 、X 4 Selected from the same groups.
8. The compound according to claim 1, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, wherein when Y 1 、Y 2 、Y 3 And Y 4 Y, when present 1 、Y 2 、Y 3 、Y 4 Selected from the same groups.
9. The compound of claim 1, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, wherein R 1 、R 2 、R 3 、R 4 When present, the R 1 、R 2 、R 3 、R 4 Selected from the same groups.
10. A compound according to claim 1 or a stereoisomer, tautomer, solvent thereofA compound, pharmaceutically acceptable salt or deuterated compound characterized in that when R 1 Or R is 2 、R 3 、R 4 When any one is present, each independently has a structure represented by formula (II):
wherein t is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
s is any integer of 1 to 10;
R 5 and R is 6 Each independently is H, substituted or unsubstituted C 1 -C 18 Straight-chain or branched alkyl, substituted or unsubstituted C 1 -C 18 Straight-chain or branched heteroalkyl, substituted or unsubstituted C 2 -C 18 Straight-chain or branched alkenyl, substituted or unsubstituted C 2 -C 18 Straight-chain or branched heteroalkenyl, wherein the substituted groups are each independently selected from one or more halogen, -OH, -SH, -NH 2 、-NO 2 Cyano or C 1 -C 3 Alkyl, -C (=o) OR 7 、-OC(=O)R 7 、-C(=O)NHR 7 、-NHC(=O)R 7 、-S-SR 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 7 Selected from C 6 -C 18 Straight-chain or branched alkyl, C 6 -C 18 Straight or branched alkenyl groups.
11. The compound of claim 10, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, wherein R 1 Or R is 2 、R 3 、R 4 When present, the R 1 、R 2 、R 3 、R 4 Each independently selected from the following structures:
、/>、、/>、、/>、、/>、、/>、
、/>、、/>、
、/>、、/>、
、/>、、/>、/>、、、、/>、、、、、、、。
12. the compound of claim 1, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, having the structure:
、、、、
、、、、、、、、、、、、、、、、、、、、、、、、、、、。
13. use of a compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, for the preparation of a liposome, lipid nanoparticle, pharmaceutical carrier or complex.
14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or deuterated compound thereof, a pharmaceutically active molecule, and pharmaceutically acceptable adjuvant.
15. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition comprises at least one excipient selected from the group consisting of neutral phospholipids, steroids and polyethylene glycol lipids.
16. The pharmaceutical composition of claim 14, wherein the pharmaceutically active molecule is selected from DNA, ASO, siRNA, miRNA, mRNA, ribozyme, aptamer, or a combination thereof.
17. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is prepared as a lipid nanoparticle.
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