WO2024109952A1 - 非共价二聚体阳离子、其盐、其制备方法及其用途 - Google Patents

非共价二聚体阳离子、其盐、其制备方法及其用途 Download PDF

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WO2024109952A1
WO2024109952A1 PCT/CN2023/134364 CN2023134364W WO2024109952A1 WO 2024109952 A1 WO2024109952 A1 WO 2024109952A1 CN 2023134364 W CN2023134364 W CN 2023134364W WO 2024109952 A1 WO2024109952 A1 WO 2024109952A1
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hydrogen
salt
reactant
group
ion
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French (fr)
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赵梓圳
王志刚
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苏州质子链生物技术有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine

Definitions

  • the present application relates to the field of biomedicine, and more specifically to a non-covalent dimer cation, its salt, its preparation method, and its use in cell repair, cell proliferation or wound repair.
  • the repair ability of cells also shows significant differences among different cells.
  • Cells of various glandular organs that show strong repair ability such as liver, pancreas, endocrine glands, sweat glands, sebaceous glands and renal tubular epithelial cells, show strong repair ability when they are damaged internally or externally.
  • Cells with weak or no repair ability such as central nervous cells and ganglion cells, are extremely difficult to restore their original functions after being damaged.
  • the repair ability of myocardial cells is extremely weak. After being damaged, they are replaced by fibrous connective tissue and it is difficult to restore their original structure and function.
  • the occurrence of many diseases is also closely related to the decline or insufficiency of cell repair ability.
  • the probability of elderly people and those exposed to risks suffering from certain diseases has increased significantly due to the decline or insufficiency of their body's cell repair level.
  • elderly people are prone to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, long-term alcoholics are prone to gastric mucosal damage, gastric ulcers, etc., or some organ diseases caused by excessive pressure on organ function, all of which are caused by insufficient cell repair ability.
  • Cell proliferation is one of the important physiological functions of living cells and an important life characteristic of organisms. Cell proliferation is the basis of growth, development, reproduction and heredity of organisms. Cell proliferation is also an important life characteristic of organisms. Human cells proliferate by dividing to replenish aging or dead cells in the body.
  • Cell proliferation is a complex and vital life activity. From the fertilized egg to an independent individual, it undergoes countless cell proliferations. In order to maintain physiological life activities, each organ also carries out regulated cell proliferation all the time. When invaded by pathogens, related immune cells proliferate to protect individual health. When an individual suffers physical trauma, related cells will also begin to proliferate to repair tissue or organ damage.
  • Wound healing refers to a series of complex pathophysiological processes in which local tissues are repaired through proliferation or regeneration after tissue defects are caused by trauma or other diseases. After trauma, the body undergoes a very coordinated healing process, including the intricate network effects of multiple cells, cytokines, and extracellular matrix.
  • the cells involved in skin wound healing mainly include various inflammatory cells and tissue repair cells.
  • the former include neutrophils, macrophages, etc., and the latter mainly include vascular endothelial cells, epidermal cells, fibroblasts, and nerve cells. This series of cells realize their respective functions through cell proliferation and promote the healing of wounds, and none of them can be missing.
  • non-covalent dimer cation of the present application which is a cation of formula (A), its tautomer, or its stereoisomer, wherein the bond "" in formula (A) is a non-covalent bond;
  • R 1 is selected from the group consisting of hydrogen, hydroxyl, thiol, amino, methyl, ethyl, and phenyl;
  • Q 1 is selected from the group consisting of hydrogen, hydroxyl, thiol, amino, methyl, ethyl, phenyl, chlorine, cyano, and carboxyl;
  • R 2 and Q 2 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, benzyloxymethyl, and triphenylmethyl;
  • R 3 and Q 3 are each independently selected from the group consisting of hydrogen,
  • R 5 is each independently selected from the group consisting of hydrogen, benzyl, amino, methylamino, hydrazine, trimethylammonium, pyrrolyl, and a substituent derived from the C-terminal carbon atom of an amino acid, a dipeptide, or a tripeptide to which the amino group is further connected;
  • R 6 and Q 6 are each independently selected from the group consisting of hydroxyl, deprotonated hydroxyl, methoxy, methylamino, ethylamino, and a substituent derived from the N-terminal nitrogen atom of an amino acid, a dipeptide, or a tripeptide; and m and n are each independently selected from the group consisting of 0 and 1.
  • a salt of the present application comprising the cation of the present application and at least one first anion selected from the group consisting of fluoride ion, chloride ion, bromide ion, iodide ion, sulfide ion, nitrate ion, sulfate ion, sulfite ion, thiosulfate ion, persulfate ion, selenate ion, phosphate ion, carbonate ion, hexafluorophosphate ion, hexafluorosilicate ion, acetate ion, sulfonate ion, benzoate ion, and polyphosphate ion.
  • first anion selected from the group consisting of fluoride ion, chloride ion, bromide ion, iodide ion, sulfide ion, nitrate ion, s
  • a method for preparing the cation or salt of the present application comprising: contacting a first reactant with a first acid to obtain a first reactant first acid salt; in an acidic environment, contacting the first reactant first acid salt with a first salt including a first anion to obtain a first solution including a protonated first reactant first acid salt cation and a first anion; and in a strongly reducing and acidic environment, adding a second reactant to the first solution to obtain a second solution or a first intermediate product; and adding a first base to the second solution or contacting the first intermediate product, wherein the first reactant includes a compound of formula (C), and the second reactant includes a compound of formula (D).
  • a drug for treating diseases or symptoms associated with oxidative stress or oxygen free radicals.
  • a method for preparing a drug comprising preparing the cation or salt of the present application.
  • a method for preparing a drug comprising preparing the cation or salt of the present application.
  • FIG1 shows the results of oxygen free radical scavenging experiments using a 2-phenyl-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxyl-3-oxide (PTIO) model according to some embodiments of the present application.
  • PTIO 2-phenyl-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxyl-3-oxide
  • FIG. 2 shows the cell viability of the ethanol gastric mucosal epithelial cell injury model according to some embodiments of the present application.
  • FIG3 shows the cell viability of the Parkinson's disease model according to some embodiments of the present application.
  • FIG4 shows the cell viability of the Alzheimer's disease model according to some embodiments of the present application.
  • FIG. 5 is the transcriptomic analysis results of some embodiments of the present application.
  • FIG. 6 shows the cell viability of the dermal fibroblast proliferation experiment according to some embodiments of the present application.
  • FIG. 7 shows the cell viability of keratinocyte proliferation assay according to some embodiments of the present application.
  • FIG8 shows the cell viability of vascular endothelial cell proliferation experiments in some embodiments of the present application.
  • FIG. 9 shows the cell viability of a neural cell proliferation experiment according to some embodiments of the present application.
  • FIG. 10 is the transcriptomic analysis results of some embodiments of the present application.
  • Figure 11 is formula (A).
  • the term “about” refers to approximation, in the range of about or near. When the term “about” is used in conjunction with a numerical range, it modifies the range by expanding the limit above or below the provided numerical value. In general, the term “about” is used herein to make the numerical value change 10% above and below the provided value. On the one hand, the term “about” refers to adding or subtracting 20% of the numerical value of the number modified by it. For example, “about 50%” refers to within the range of 45%-55%.
  • the numerical range mentioned herein by endpoints includes all integers and fractions contained in the range (for example, “1 to 5" includes 1, 1.5, 2, 2.75, 3, 3.90, 4 and 5). It should also be understood that all integers and fractions thereof are considered to be modified by the term "about”.
  • the term “comprising”, “including”, or “containing”, as a non-exclusive or open term, is intended to indicate that a combination (e.g., a device, a composition, a method, etc.) includes the listed elements (e.g., each unit of the device, each component of the composition, the substantial steps of the method, etc.), but does not exclude other elements.
  • a combination e.g., a device, a composition, a method, etc.
  • the term “substantially consisting of" when used to define compositions and methods means excluding other elements that have any substantial impact on the combination of the stated purpose, but does not exclude other elements that do not substantially affect the basic and novel features of the present invention.
  • the term “consisting of" refers to a combination (units, components, substantial steps, etc.) excluding other elements, but unless otherwise specified, it is not intended to exclude trace amounts of unavoidable impurities.
  • the embodiments defined by each of these connecting terms are within the scope of the present invention.
  • the technical solution disclosed including the terms “comprising”, “including”, or “containing” should also be deemed to simultaneously disclose the corresponding technical solutions including the terms “substantially consisting of York and “consisting of!.
  • the term “and/or” refers to and encompasses any and all possible combinations of one or more associated listed items. When used in a list of two or more items, the term “and/or” means that any one of the listed items may be included alone, or may include any combination of two or more listed items.
  • the composition may include A alone; B alone; C alone; D alone; a combination of A and B; a combination of A and C; a combination of A and D; a combination of B and C; a combination of B and D; a combination of C and D; a combination of A, B and C; a combination of A, B and D; a combination of A, C and D; a combination of B, C and D; or a combination of A, B, C, and D.
  • the compounds or ions of the present application include a plurality of variable groups.
  • One of ordinary skill in the art will recognize that the combinations of groups contemplated by the present application are chemically permitted combinations of compounds or ions.
  • the stereochemistry of a chiral center may be defined according to the conventions of those skilled in the art, i.e., using solid lines and wedged bonds.
  • Indicate groups facing out of the page (towards the reader) and use a hashed bond Indicates groups facing inward (away from the reader) of the paper. If such a representation is used, it can be understood to indicate that the chemical structures in this article are Any bond not specifically represented by a solid wedge bond or a dashed wedge bond herein should be considered as not specifically indicating whether the bond is facing out of the paper plane, facing into the paper plane, or located in the paper plane, but does not prevent it from facing out of the paper plane or facing into the paper plane when chemically allowed.
  • the term “isomer” means a compound having the same molecular formula but different bonding properties or order of its atoms or the arrangement of its atoms in space.
  • the term “stereoisomer” means an isomer with different arrangement of atoms in space;
  • the term “enantiomer” means a stereoisomer with one or more asymmetric centers, which are non-superimposable mirror images of each other;
  • the term “diastereomer” means a stereoisomer that does not belong to an enantiomer with an opposite configuration at one or more asymmetric centers.
  • a compound When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, there can be a pair of enantiomers.
  • Enantiomers can be characterized by the absolute configuration of one or more asymmetric centers and designated as R-configuration or S-configuration, or designated as right-handed or left-handed in the way in which the molecule rotates the plane of polarized light.
  • Chiral compounds can exist as individual enantiomers or as a mixture thereof, for example, as a racemic mixture.
  • the compounds of the present application may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is considered that all stereoisomers of the compounds of the present application, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof such as racemic mixtures, form part of the present application.
  • the term “dimer” generally refers to a complex formed by two molecules or ions, such as amino acids or peptides or derivatives thereof or protonated ions thereof, via interactions, particularly non-covalent interactions.
  • covalent bond refers to any bond that contains or involves electron sharing. Non-limiting examples of covalent bonds include, but are not limited to, peptide bonds, glycosidic bonds, ester bonds, phosphodiester bonds.
  • non-covalent bond includes any bond or interaction between two or more parts that does not contain or involve electron sharing. Non-limiting examples of non-covalent bonds or interactions include, but are not limited to, electrostatics, ⁇ - ⁇ effects, van der Waals forces, hydrogen bonds, and hydrophobic effects, particularly hydrogen bonds.
  • the present application provides a non-covalent dimer cation.
  • the present application provides a non-covalent dimer cation, comprising a moiety of formula (A1) and a moiety of formula (A2), wherein the hydrogen on the imidazole ring shown in the moiety of formula (A1) (N ⁇ -H, i.e., the H marked with an asterisk in formula (A1), or N ⁇ -H when R 2 is hydrogen) forms a non-covalent bond with the atom with a stronger or strongest electronegativity in the moiety of formula (A2), such as the oxygen on the carbonyl group shown in the moiety of formula (A2) (i.e., the O marked with an asterisk in formula (A2)).
  • the present application provides a non-covalent dimer cation, comprising a cation of formula (A), its tautomer, or its stereoisomer, or consisting thereof, wherein the bond in formula (A) It is a non-covalent bond.
  • the non-covalent bond i.e., the bond in formula (A) It should be considered to include or consist of all chemically permitted non-covalent bonds that allow the non-covalent dimer cation of the present application to exist stably in its salt.
  • the non-covalent bond may be understood as a hydrogen bond.
  • the applicant has experimentally confirmed that the non-covalent bond can be stably present in a general environment, for example, in the form of a salt; in particular, at least when the mass spectrum is measured, it can still remain stable without breaking, that is, the non-covalent dimer cation of the present application can be kept intact when the mass spectrum is measured, thereby generating the corresponding ion peak of the m/z value of the non-covalent dimer cation of the present application.
  • the substituent Q1 can be any member of the ring to which it is directed (i.e., the benzene ring in the indole part in formula (A) and formula (A2)). Specifically, Q1 can be formed at position 4, position 5, position 6, or position 7 of the indole part in formula (A) and formula (A2).
  • Q 1 is located on the carbon at the 4th position of the indole part, as shown in formula (A-4) and formula (A2-4). In some embodiments, in the cation of formula (A) or the moiety of formula (A2), Q 1 is located on the carbon at the 5th position of the indole part, as shown in formula (A-5) and formula (A2-5). In some embodiments, in the cation of formula (A) or the moiety of formula (A2), Q 1 is located on the carbon at the 6th position of the indole part, as shown in formula (A-6) and formula (A2-6). In some embodiments, in the cation of formula (A) or the moiety of formula (A2), Q 1 is located on the carbon at the 7th position of the indole part, as shown in formula (A-7) and formula (A2-7).
  • R 1 is selected from the group consisting of hydrogen, hydroxyl, thiol, amino, methyl, ethyl, and phenyl. In some embodiments, R 1 is selected from the group consisting of hydrogen, hydroxyl, thiol, amino, methyl, and phenyl. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is hydroxyl. In some embodiments, R 1 is thiol. In some embodiments, R 1 is amino. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is phenyl.
  • Q 1 is selected from the group consisting of hydrogen, hydroxyl, thiol, amino, methyl, ethyl, phenyl, chloro, cyano, and carboxyl. In some embodiments, Q 1 is selected from the group consisting of hydrogen, hydroxyl, amino, chloro, cyano, and carboxyl. In some embodiments, Q 1 is hydrogen. In some embodiments, Q 1 is hydroxyl. In some embodiments, Q 1 is thiol. In some embodiments, Q 1 is amino. In some embodiments, Q 1 is methyl. In some embodiments, Q 1 is ethyl. In some embodiments, Q 1 is phenyl. In some embodiments, Q 1 is chloro. In some embodiments, Q 1 is cyano. In some embodiments, Q 1 is carboxyl.
  • R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, benzyloxymethyl, and triphenylmethyl. In some embodiments, R 2 is selected from the group consisting of hydrogen, methyl, phenyl, and triphenylmethyl. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is phenyl. In some embodiments, R 2 is benzyloxymethyl. In some embodiments, R 2 is triphenylmethyl.
  • Q 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, benzyloxymethyl, and triphenylmethyl. In some embodiments, Q 2 is selected from the group consisting of hydrogen and methyl. In some embodiments, Q 2 is hydrogen. In some embodiments, Q 2 is methyl. In some embodiments, Q 2 is ethyl. In some embodiments, Q 2 is propyl. In some embodiments, Q 2 is phenyl. In some embodiments, Q 2 is benzyloxymethyl. In some embodiments, Q 2 is triphenylmethyl.
  • R 3 is selected from the group consisting of hydrogen, hydroxyl, thiol, amino, methyl, ethyl, and phenyl. In some embodiments, R 3 is selected from the group consisting of hydrogen, thiol, and methyl. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is hydroxyl. In some embodiments, R 3 is thiol. In some embodiments, R 3 is amino. In some embodiments, R 3 is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is phenyl.
  • Q 3 is selected from the group consisting of hydrogen, hydroxyl, thiol, amino, methyl, ethyl, and phenyl. In some embodiments, Q 3 is selected from the group consisting of hydrogen, thiol, and methyl. In some embodiments, Q 3 is hydrogen. In some embodiments, Q 3 is hydroxyl. In some embodiments, Q 3 is thiol. In some embodiments, Q 3 is amino. In some embodiments, Q 3 is methyl. In some embodiments, Q 3 is ethyl. In some embodiments, Q 3 is phenyl .
  • R 4 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl. In some embodiments, R 4 is selected from the group consisting of hydrogen and methyl. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl. In some embodiments, Q 4 is selected from the group consisting of hydrogen, methyl, ethyl, and propyl. In some embodiments, Q 4 is selected from the group consisting of hydrogen and methyl. In some embodiments, Q 4 is hydrogen. In some embodiments, Q 4 is methyl. In some embodiments, Q 4 is ethyl. In some embodiments, Q 4 is propyl.
  • R 5 is selected from the group consisting of hydrogen, benzyl, amino, methylamino, hydrazine, trimethylammonium, pyrrolyl, and a substituent further connected to the amino group and derived from the C-terminal carbon atom of an amino acid or peptide.
  • Q 5 is selected from the group consisting of hydrogen, benzyl, amino, methylamino, hydrazine, trimethylammonium, pyrrolyl, and a substituent further connected to the amino group and derived from the C-terminal carbon atom of an amino acid or peptide.
  • the substituent further connected to the amino group and derived from the C-terminal carbon atom of an amino acid or peptide is a substituent further connected to the amino group and derived from the C-terminal carbon atom of an amino acid, a dipeptide, or a tripeptide.
  • R 5 is selected from the group consisting of hydrogen, benzyl, amino, methylamino, hydrazine, trimethylammonium, pyrrole, and a substituent further connected to the amino group by an amino acid, dipeptide, or tripeptide C-terminal carbon atom derived from the group consisting of.
  • Q 5 is selected from the group consisting of hydrogen, benzyl, amino, methylamino, hydrazine, trimethylammonium, pyrrole, and a substituent further connected to the amino group by an amino acid, dipeptide, or tripeptide C-terminal carbon atom derived from the group consisting of.
  • R 5 is selected from the group consisting of hydrogen, benzyl, amino, methylamino, hydrazine, trimethylammonium, pyrrolyl, acetamide, 2-aminoacetamide, 3-aminopropionamide, and pyrrolamide. In some embodiments, R 5 is selected from the group consisting of hydrogen, amino, hydrazine, trimethylammonium, pyrrolyl, acetamide, 2-aminoacetamide, 3-aminopropionamide, and pyrrolamide.
  • R 5 is selected from the group consisting of hydrogen, amino, hydrazine, trimethylammonium, pyrrolyl, acetamide, 2-aminoacetamide, 3-aminopropionamide, and pyrrolamide. In some embodiments, R 5 is selected from the group consisting of hydrogen, benzyl, amino, methylamino, hydrazine , pyrrolyl, and acetamide. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is benzyl . In some embodiments, R 5 is amino. In some embodiments, R 5 is methylamino. In some embodiments, R 5 is hydrazine. In some embodiments, R 5 is trimethylammonium.
  • R 5 is pyrrolyl. In some embodiments, R 5 is a substituent further connected to the amino group and derived from the C-terminal carbon atom of an amino acid or peptide. In some embodiments, R 5 is acetamido. In some embodiments, R 5 is 2-aminoacetamido. In some embodiments, R 5 is 3-aminopropionamido. In some embodiments, R 5 is pyroglutamylamino.
  • Q 5 is selected from the group consisting of hydrogen, benzyl, amino, methylamino, hydrazine, trimethylammonium, pyrrolyl, acetamido, 2-aminoacetamido, 3-aminopropionamido, and pyroglutamylamino. In some embodiments, Q 5 is selected from the group consisting of hydrogen, amino, hydrazine, trimethylammonium, pyrrolyl, acetamido, 2-aminoacetamido, 3-aminopropionamido, and pyroglutamylamino.
  • Q 5 is selected from the group consisting of hydrogen, benzyl, amino, methylamino, hydrazine, pyrrolyl, and acetamido. In some embodiments, Q 5 is hydrogen. In some embodiments, Q 5 is benzyl. In some embodiments, Q 5 is amino. In some embodiments, Q 5 is methylamino. In some embodiments, Q 5 is hydrazine. In some embodiments, Q 5 is trimethylammonium. In some embodiments, Q 5 is pyrrolyl. In some embodiments, Q 5 is a substituent further connected to the amino group and derived from the C-terminal carbon atom of an amino acid or peptide.
  • Q 5 is acetamido. In some embodiments, Q 5 is 2-aminoacetamido. In some embodiments, Q 5 is 3-aminopropionamido. In some embodiments, Q 5 is pyroglutamylamino .
  • R 6 is selected from the group consisting of hydroxyl, deprotonated hydroxyl, methoxy, methylamino, ethylamino, and a substituent derived from the N-terminal nitrogen atom of an amino acid or peptide.
  • Q 6 is selected from the group consisting of hydroxyl, deprotonated hydroxyl, methoxy, ethoxy, methylamino, ethylamino, and a substituent derived from the N-terminal nitrogen atom of an amino acid or peptide.
  • the substituent derived from the N-terminal nitrogen atom of an amino acid or peptide can be represented as "-N AA HZ", wherein N AA is the N-terminal nitrogen atom of an amino acid or peptide, and Z is the remainder of the amino acid or peptide, i.e., ZN AA H2 is a complete amino acid or peptide, in particular an amino acid, a dipeptide, or a tripeptide.
  • the substituent derived from the N-terminal nitrogen atom of an amino acid or peptide is a substituent derived from the N-terminal nitrogen atom of an amino acid, a dipeptide, or a tripeptide.
  • R 6 is selected from the group consisting of hydroxyl, deprotonated hydroxyl, methoxy, ethoxy, methylamino, ethylamino, and a substituent derived from the N-terminal nitrogen atom of an amino acid, dipeptide, or tripeptide.
  • Q 6 is selected from the group consisting of hydroxyl, deprotonated hydroxyl, methoxy, ethoxy, methylamino, ethylamino, and a substituent derived from the N-terminal nitrogen atom of an amino acid, dipeptide, or tripeptide.
  • the substituent derived from the N-terminal nitrogen atom of an amino acid or peptide is selected from the group consisting of N2-lysine (i.e., a substituent derived from the N2 nitrogen atom of L-lysine) and glycine proline (i.e., a substituent derived from the N-terminal nitrogen atom of L-prolyl-L-glycine).
  • R 6 is selected from the group consisting of hydroxyl, deprotonated hydroxyl, methoxy, ethoxy, methylamino, ethylamino, N2-lysine, and glycine proline.
  • R 6 is selected from the group consisting of hydroxyl, methoxyl, methylamino, and ethylamino. In some embodiments, R 6 is hydroxyl. In some embodiments, R 6 is deprotonated hydroxyl. In some embodiments, R 6 is methoxyl. In some embodiments, R 6 is ethoxyl. In some embodiments, R 6 is methylamino. In some embodiments, R 6 is ethylamino. In some embodiments, R 6 is a substituent derived from the N-terminal nitrogen atom of an amino acid or peptide. In some embodiments, R 6 is N2-lysine. In some embodiments, R 6 is glycine proline.
  • Q 6 is selected from the group consisting of hydroxyl, deprotonated hydroxyl, methoxyl, ethoxyl, methylamino, ethylamino, N2-lysine, and glycine proline. In some embodiments, Q 6 is selected from the group consisting of hydroxyl, methoxyl, methylamino, and ethylamino. In some embodiments, Q 6 is hydroxyl. In some embodiments, Q 6 is deprotonated hydroxyl. In some embodiments, Q 6 is methoxyl . In some embodiments, Q 6 is ethoxy. In some embodiments, Q 6 is methylamino. In some embodiments, Q 6 is ethylamino. In some embodiments, Q 6 is a substituent derived from the N-terminal nitrogen atom of an amino acid or peptide. In some embodiments, Q 6 is N2-lysine. In some embodiments, Q 6 is glycine proline.
  • m and n are each independently selected from the group consisting of 0 and 1. In some embodiments, m is 1. In some embodiments, m is 0. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, m is 1 and n is 1. In some embodiments, m is 1 and n is 0. In some embodiments, m is 0 and n is 1. In some embodiments, m is 0 and n is 0.
  • R 1 and Q 1 are the same. In some embodiments, R 2 and Q 2 are the same. In some embodiments, R 3 and Q 3 are the same. In some embodiments, R 4 and Q 4 are the same. In some embodiments, R 5 and Q 5 are the same. In some embodiments, R 6 and Q 6 are the same. In some embodiments, R 1 and Q 1 are different. In some embodiments, R 2 and Q 2 are different. In some embodiments, R 3 and Q 3 are different. In some embodiments, R 4 and Q 4 are different. In some embodiments, R 5 and Q 5 are different. In some embodiments, R 6 and Q 6 are different.
  • R 4 is hydrogen or methyl
  • R 5 is selected from the group consisting of hydrogen, benzyl, amino, methylamino, hydrazine, pyrrolyl, and acetamido
  • R 6 is selected from the group consisting of hydroxyl, methoxy, methylamino, and ethylamino
  • n is 1.
  • Q 4 is hydrogen or methyl
  • Q 5 is selected from the group consisting of hydrogen, benzyl, amino, methylamino, hydrazine, pyrrolyl, and acetamido
  • Q 6 is selected from the group consisting of hydroxyl, methoxy, methylamino, and ethylamino
  • m is 1.
  • Q 1 is hydrogen or hydroxy; Q 2 is hydrogen; and Q 3 is hydrogen.
  • at least two of R 4 , R 5 , and R 7 are hydrogen.
  • R 4 is hydrogen and R 5 is hydrogen.
  • R 5 is hydrogen and R 7 is hydrogen.
  • Q 4 is hydrogen and Q 5 is hydrogen.
  • any chemical structure disclosed or included shall be deemed to further disclose or include stereoisomers of the chemical structure.
  • any one or more chiral centers do not specify their stereochemistry, they shall be deemed to disclose or include various possible stereoisomers and combinations or mixtures thereof.
  • a chiral center does not specify its stereochemistry, it shall be deemed to disclose or include chemical structures in which the chiral center is (R)-configuration, and chemical structures in which the chiral center is (S)-configuration, and combinations thereof in any proportion, including racemic mixtures.
  • two chiral centers do not specify their stereochemistry, they shall be deemed to disclose or include chemical structures in which the two chiral centers are (R, R)-configuration, chemical structures in which the two chiral centers are (S, S)-configuration, chemical structures in which the two chiral centers are (R, S)-configuration, and chemical structures in which the two chiral centers are (S, R)-configuration, and combinations thereof in any proportion.
  • the carbon to which R 4 , R 5 and R 7 are connected is an asymmetric carbon (hereinafter referred to as the "first asymmetric carbon").
  • any chemical structure including the first asymmetric carbon disclosed or included, if the configuration of the first asymmetric carbon is not further indicated, should be deemed to disclose or include two possible configurations of the first asymmetric carbon at the same time.
  • any disclosure or inclusion of the formula (A1) part, if the configuration of the first asymmetric carbon is not further indicated, should be deemed to disclose or include the formula (A1-R) part and the formula (A1-S) part at the same time.
  • the bond between the first asymmetric carbon and the R 4 is a bond with the R 4 facing outside the paper
  • the bond between the first asymmetric carbon and the R 5 is a bond with the R 5 facing inside the paper.
  • the first asymmetric carbon is represented by "*".
  • the first asymmetric carbon is generally in R-configuration. D-histidine has this configuration.
  • the bond between the first asymmetric carbon and R 4 is a bond with R 4 facing inside the paper
  • the bond between the first asymmetric carbon and R 5 is a bond with R 5 facing outside the paper.
  • the first asymmetric carbon is represented by "*".
  • the first asymmetric carbon is generally in S-configuration. L-histidine has this configuration.
  • Q4 and Q5 are different groups.
  • the carbon to which Q4 and Q5 are connected is an asymmetric carbon (hereinafter referred to as the second asymmetric carbon).
  • any chemical structure including the second asymmetric carbon is disclosed or included, if the configuration of the second asymmetric carbon is not further specified, it should be deemed that the possible two configurations of the second asymmetric carbon are also disclosed or included.
  • any disclosure or inclusion of the formula (A2) part if the configuration of the second asymmetric carbon is not further specified, should be deemed to also disclose or include the formula (A2-R) part and the formula (A2-S) part.
  • the bond between the second asymmetric carbon and the Q 4 is the bond that the Q 4 faces outside the paper
  • the bond between the second asymmetric carbon and the Q 5 is the bond that the Q 5 faces inside the paper.
  • the first asymmetric carbon is in (R)-configuration. In some embodiments, the first asymmetric carbon is in (S)-configuration. In some embodiments, the second asymmetric carbon is in (R)-configuration. In some embodiments, the second asymmetric carbon is in (S)-configuration. In some embodiments, the first asymmetric carbon is in (R)-configuration, and the second asymmetric carbon is in (R)-configuration. In some embodiments, the first asymmetric carbon is in (R)-configuration, and the second asymmetric carbon is in (S)-configuration. In some embodiments, the first asymmetric carbon is in (S)-configuration, and the second asymmetric carbon is in (R)-configuration. In some embodiments, the first asymmetric carbon is in (S)-configuration, and the second asymmetric carbon is in (R)-configuration.
  • the first asymmetric carbon is in (S)-configuration
  • the second asymmetric carbon is in (R)-configuration
  • the first asymmetric carbon is in (S)-configuration
  • the second asymmetric carbon is in (S)-configuration.
  • the bond between the first asymmetric carbon and R 4 is a bond with R 4 facing outside the paper
  • the bond between the first asymmetric carbon and R 5 is a bond with R 5 facing inside the paper
  • the bond between the second asymmetric carbon and Q 4 is a bond with Q 4 facing outside the paper
  • the bond between the second asymmetric carbon and Q 5 is a bond with Q 5 facing inside the paper.
  • the bond between the first asymmetric carbon and R 4 is a bond with R 4 facing outside the paper
  • the bond between the first asymmetric carbon and R 5 is a bond with R 5 facing inside the paper
  • the bond between the second asymmetric carbon and Q 4 is a bond with Q 4 facing inside the paper
  • the bond between the second asymmetric carbon and Q 5 is a bond with Q 5 facing outside the paper.
  • the bond between the first asymmetric carbon and R 4 is a bond with R 4 facing inside the paper
  • the bond between the first asymmetric carbon and R 5 is a bond with R 5 facing outside the paper
  • the bond between the second asymmetric carbon and Q 4 is a bond with Q 4 facing outside the paper
  • the bond between the second asymmetric carbon and Q 5 is a bond with Q 5 facing inside the paper.
  • the bond between the first asymmetric carbon and R 4 is a bond with R 4 facing inside the paper
  • the bond between the first asymmetric carbon and R 5 is a bond with R 5 facing outside the paper
  • the bond between the second asymmetric carbon and Q 4 is a bond with Q 4 facing inside the paper
  • the bond between the second asymmetric carbon and Q 5 is a bond with Q 5 facing outside the paper.
  • R 4 and R 5 are different groups
  • Q 4 and Q 5 are different groups.
  • R 4 and R 5 are different groups
  • Q 4 and Q 5 are different groups
  • the first asymmetric carbon is (R)-configuration
  • the second asymmetric carbon is (R)-configuration, as shown in formula (A-RR).
  • R 4 and R 5 are different groups
  • Q 4 and Q 5 are different groups
  • the first asymmetric carbon is (R)-configuration
  • the second asymmetric carbon is (S)-configuration, as shown in formula (A-RS).
  • R4 and R5 are different groups
  • Q4 and Q5 are different groups
  • the first asymmetric carbon is (S)-configuration
  • the second asymmetric carbon is (R)-configuration, as shown in formula (A-SR).
  • R4 and R5 are different groups
  • Q4 and Q5 are different groups
  • the first asymmetric carbon is in (S)-configuration
  • the second asymmetric carbon is in (S)-configuration, as shown in formula (A-SS).
  • any disclosure or inclusion of any specific part R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and/or Q 6 in formula (A) and/or other structural formulas, the position to which Q 1 is attached, and the chemical structure specified by the specific parameters m and n shall be deemed to further disclose or include the chemically allowed tautomers of the specified chemical structure.
  • any disclosure or inclusion of any chemical structure shall be deemed to further disclose or include the chemically allowed tautomers of the chemical structure, such as keto-enol tautomers.
  • any chemical structure disclosed or included including "a carbon having a double bond or located on an aromatic ring, and a hydroxyl or thiol group on it” should be deemed to further disclose or include the corresponding tautomer, that is, a chemical structure including "a carbonyl or thiocarbonyl" part.
  • the chemical structure of the part shall be deemed to further disclose or include the corresponding Partial tautomers; any disclosure or inclusion including The chemical structure of the part shall be deemed to further disclose or include the corresponding Some tautomers.
  • any disclosed or contained aromatic ring includes Part of the chemical structure should be deemed to further disclose or include the corresponding
  • any disclosed or contained imidazole ring The chemical structure of the part shall be deemed to further disclose or include the corresponding Some tautomers.
  • any resonance structure that constitutes a hybrid is disclosed or included, which should be deemed to further disclose or include all other resonance structures that constitute the hybrid, as well as the hybrid itself.
  • any disclosed or contained aromatic ring includes Part of the chemical structure should be deemed to further disclose or include the corresponding
  • any disclosed or contained imidazole ring The chemical structure of the part shall be deemed to further disclose or include the corresponding The resonance chemical structure of the part, and further discloses or includes the corresponding hybrid (for example, represented by ).
  • any disclosure or inclusion of a protonated imidazole ring The hydrogen on N1 forms a non-covalent bond such as a hydrogen bond
  • the chemical structure should be deemed to further disclose or include the corresponding protonated imidazole ring.
  • any chemical structure disclosed or included in which the hydrogen on N ⁇ in a protonated histidine, protonated histamine, protonated myosamine or a similar compound having a 1H-imidazole-4-yl group or a derivative thereof forms a non-covalent bond, such as a hydrogen bond shall be deemed to further disclose or include the corresponding chemical structure disclosed or included in which the hydrogen on N ⁇ in a protonated histidine, protonated histamine, protonated myosamine or a similar compound having a 1H-imidazole- 4 -yl group or a derivative thereof forms a non-covalent bond, such as a hydrogen bond.
  • any chemical structure in which R 2 is hydrogen is disclosed or included, in addition to disclosing or including the chemical structure in which hydrogen (N ⁇ -H) that forms a non-covalent bond as shown in formula (A) forms a non-covalent bond, it also further discloses or includes the corresponding chemical structure in which hydrogen (N ⁇ -H) of R 2 forms a non-covalent bond, and vice versa.
  • the structure of formula (A) in which R 2 is hydrogen and its corresponding structure of formula (A′) may be tautomers.
  • any structure of formula (A) in which R 2 is hydrogen is disclosed or included, and it should be deemed that the structure of formula (A′) is also further disclosed or included, and vice versa.
  • the structure represented by formula (A′) also includes a first asymmetric carbon and a second asymmetric carbon.
  • the structure of formula (A') is as shown in formula (A'-RR). In some embodiments, the structure of formula (A') is as shown in formula (A'-RS). In some embodiments, the structure of formula (A') is as shown in formula (A'-SR). In some embodiments, the structure of formula (A') is as shown in formula (A'-SS).
  • any disclosure or inclusion of one of the (Br ⁇ nsted-Lowry) conjugate acids and bases shall be deemed to be further disclosed or included as the corresponding or predominant conjugate acids and bases under certain pH conditions, provided that it is chemically reasonable and does not affect the main chemical structure and technical effects of the non-covalent dimer cation or salt of the present application.
  • any disclosure or inclusion of a specific part or group as a hydroxyl group shall be deemed to be further disclosed or included as a deprotonated hydroxyl group (-O-) or a protonated hydroxyl group (-OH 2 + ), provided that it is chemically reasonable and does not affect the main chemical structure and technical effects of the non-covalent dimer cation or salt of the present application.
  • the present application provides a salt.
  • the salt of the present application includes the non-covalent dimer cation of the present application, and in particular includes the non-covalent dimer cation of the present application and the first anion.
  • the salt of the present application can be represented by the structure of formula (B) or the structure of formula (B'), wherein X is the first anion.
  • the first anion of the present application enables the cation of the present application to exist stably in the form of salts.
  • the first anion (X in formula (B)) includes at least one selected from the group consisting of fluoride ion, chloride ion, bromide ion, iodide ion, sulfide ion, nitrate ion, sulfate ion, sulfite ion, thiosulfate ion, persulfate ion, selenate ion, phosphate ion, carbonate ion, hexafluorophosphate ion, hexafluorosilicate ion, acetate ion, sulfonate ion, benzoate ion, and polyphosphate ion or consists of it.
  • the first anion includes at least one selected from the group consisting of hexafluorophosphate ion, hexafluorosilicate ion, chloride ion, and sulfate ion or consists of it.
  • the first anion is fluoride ion.
  • the first anion is chloride ion.
  • the first anion is bromide ion.
  • the first anion is iodide ion.
  • the first anion is sulfide ion.
  • the first anion is nitrate ion.
  • the first anion is sulfate ion.
  • the first anion is sulfite ion. In some embodiments, the first anion is a thiosulfate ion. In some embodiments, the first anion is a persulfate ion. In some embodiments, the first anion is a selenate ion. In some embodiments, the first anion is a phosphate ion. In some embodiments, the first anion is a carbonate ion. In some embodiments, the first anion is a hexafluorophosphate ion. In some embodiments, the first anion is a hexafluorosilicate ion. In some embodiments, the first anion is an acetate ion.
  • the first anion is a sulfonate ion, such as an aminosulfonate ion. In some embodiments, the first anion is a benzoate ion. In some embodiments, the first anion is a polyphosphate ion.
  • parameter k is obtained according to the valence of the non-covalent dimer cation and the first anion of the present application.
  • the value of parameter k is equal to the valence of the first anion.
  • k is 1.
  • k is 2.
  • k is 3.
  • the preparation method of the salt including the non-covalent dimer cation of the present application may include the following steps.
  • the first reactant is contacted with the first acid. Then, the first reactant first acid salt is obtained.
  • the first reactant first acid salt comprises the first reactant and the first acid, and/or the protonated first reactant and the conjugate base of the first acid (first acid conjugate base), or consists of the same.
  • the first reactant comprises a compound of formula (C) or consists essentially of it, especially consists of it.
  • the first reactant, the first acid salt comprises a salt represented by formula (C1) or consists essentially of it, especially consists of it, wherein A is the first acid conjugate base, a is the valence of the first acid conjugate base, and p is the equivalent number of Ha A.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n in formula (C) or formula (C1) may be consistent with the corresponding parts or parameters of the cation (formula (A)) and salt (formula (B)) of the embodiment of the present application to be obtained.
  • the first reactant is contacted with the first acid in the presence of a first solvent, particularly in the first solvent.
  • the first acid is selected from at least one of the group consisting of nitric acid, phosphoric acid, sulfuric acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid, particularly hydrochloric acid, i.e., the first acid conjugate base (A in formula (C1)) is at least one of the group consisting of nitrate ions, phosphate ions, hydrogen phosphate ions, dihydrogen phosphate ions, sulfate ions, hydrogen sulfate ions, fluoride ions, chloride ions, bromide ions and iodide ions, particularly chloride ions.
  • the first solvent is water.
  • parameters p and a are obtained corresponding to the type of the first acid.
  • the first acid is hydrochloric acid
  • conjugate acid when not further defined, includes and refers to the Bronsted-Lowry conjugate acid of the compound to which the term refers, and includes not only the first conjugate acid obtained by the compound gaining a proton, but also the acid obtained by the compound further gaining more protons, if chemically permitted, such as the second conjugate acid obtained by the first conjugate acid further gaining a proton, the third conjugate acid obtained by the second conjugate acid further gaining a proton, etc.
  • conjugate base when not further defined, includes and refers to the Bronsted-Lowry conjugate base of the compound to which the term refers, and includes not only the first conjugate base obtained by the compound losing a proton, but also the base obtained by the compound further losing more protons, if chemically permitted, such as the second conjugate base obtained by the first conjugate base further losing a proton, the third conjugate base obtained by the second conjugate base further losing a proton, etc.
  • the conjugate base of sulfuric acid described herein when not further defined, should be deemed to include not only hydrogen sulfate ions, but also sulfate ions.
  • the conjugate base of phosphoric acid described herein unless further limited, should be considered to include not only hydrogen phosphate ions, but also dihydrogen phosphate ions and phosphate ions.
  • the first acid is in excess relative to the first reactant.
  • the molar ratio of the first reactant to the first acid is 1:2 to 1:10, particularly 1:2.5 to 1:8, more particularly 1:4 to 1:6, and more particularly about 1:5.
  • the concentration of the first acid in the first solvent is greater than 1 M. In some embodiments, the concentration of the first acid in the first solvent is between 1 M and 5 M. In some embodiments, the concentration of the first acid in the first solvent is about 2 M.
  • the contacting of the first reactant with the first acid is at a first temperature.
  • the first temperature is 0°C to 70°C.
  • the first temperature is 10°C to 40°C, more particularly 20°C to 30°C, more particularly about 25°C.
  • the first temperature is 20°C to 50°C, more particularly 30°C to 40°C, more particularly about 37°C.
  • the first temperature is 0°C to 20°C, more particularly 0°C to 10°C, more particularly about 4°C.
  • the first temperature is 40°C to 70°C, more particularly 50°C to 60°C, more particularly about 60°C.
  • the process further comprises heating and recrystallizing to obtain the first reactant first acid salt.
  • the heating temperature is 70°C to 100°C, particularly 80°C to 90°C, and more particularly about 85°C.
  • the first reactant, the first acid salt is contacted with a first salt including a first anion, particularly a first cation and a first anion, to obtain a first solution including a protonated first reactant, the first acid salt cation, and the first anion, as shown in formula (C2).
  • X and k in formula (C2) may be consistent with the corresponding parts or parameters of the desired salt (formula (B)) of the embodiment of the present application.
  • the first salt is selected from at least one of the group consisting of ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, ammonium sulfide, ammonium nitrate, ammonium sulfate, ammonium sulfite, ammonium thiosulfate, ammonium persulfate, ammonium selenate, ammonium phosphate, ammonium carbonate, ammonium hexafluorophosphate, ammonium hexafluorosilicate, ammonium acetate, various ammonium sulfonates, ammonium benzoate, and ammonium polyphosphate.
  • the first salt is selected from at least one of the group consisting of ammonium hexafluorophosphate, ammonium hexafluorosilicate, ammonium chloride, and ammonium sulfate, or consists of them.
  • the first salt is ammonium fluoride.
  • the first salt is ammonium chloride.
  • the first salt is ammonium bromide.
  • the first salt is Ammonium iodide.
  • the first salt is ammonium sulfide.
  • the first salt is ammonium nitrate.
  • the first salt is ammonium sulfate.
  • the first salt is ammonium sulfite. In some embodiments, the first salt is ammonium thiosulfate. In some embodiments, the first salt is ammonium persulfate. In some embodiments, the first salt is ammonium selenate. In some embodiments, the first salt is ammonium phosphate. In some embodiments, the first salt is ammonium carbonate. In some embodiments, the first salt is ammonium hexafluorophosphate. In some embodiments, the first salt is ammonium hexafluorosilicate. In some embodiments, the first salt is ammonium acetate.
  • the first salt is various ammonium sulfonates, such as ammonium sulfamate. In some embodiments, the first salt is ammonium benzoate. In some embodiments, the first salt is ammonium polyphosphate.
  • the first reactant, the first acid salt is contacted with the first salt in the presence of a second solvent, particularly in the second solvent.
  • the second solvent is water.
  • the first cation is an ammonium ion.
  • the ammonium ion as the first cation can serve as a hydrogen donor.
  • the first salt is in excess relative to the first reactant first acid salt.
  • the molar ratio of the first reactant first acid salt to the first salt is 1:2 to 1:10, particularly 1:2.5 to 1:8, more particularly 1:4 to 1:6, and more particularly about 1:5.
  • the first solution further comprises a first acid conjugate base. In some embodiments, the first solution further comprises a first cation. In some embodiments, the first solution further comprises a second solvent. In some embodiments, the first solution consists essentially of, in particular of, the protonated first reactant first acid salt cation, the first cation, the first anion, the first acid conjugate base, and the second solvent.
  • the first reactant, the first acid salt is contacted with the first salt at a second temperature.
  • the second temperature is 0°C to 70°C.
  • the second temperature is 10°C to 40°C, more particularly 20°C to 30°C, more particularly about 25°C.
  • the second temperature is 20°C to 50°C, more particularly 30°C to 40°C, more particularly about 37°C.
  • the second temperature is 0°C to 20°C, more particularly 0°C to 10°C, more particularly about 4°C.
  • the second temperature is 40°C to 70°C, more particularly 50°C to 60°C, more particularly about 60°C.
  • the first temperature and the second temperature are equal.
  • the first acidic environment has a pH value less than or equal to 6. In some embodiments, the first acidic environment has a pH value of 4 to 6, particularly 4.5 to 5.5, particularly 4.8 to 5.2, particularly 4.9 to 5.1, and more particularly about 5. Generally speaking, for a weaker acidic or more alkaline first anion, a first acidic environment with a lower pH value is selected. In some embodiments, the first anion is a hexafluorophosphate ion, and the first acidic environment has a pH value of 4 to 6, particularly 4.5 to 5.5, particularly 4.8 to 5.2, particularly 4.9 to 5.1, and more particularly about 5.
  • the first acidic environment is obtained by allowing the first salt to be in a second solvent. In some embodiments, the first acidic environment is obtained by allowing the first salt and an acid consisting of a first anion and a hydrogen ion to be in a second solvent.
  • the second reactant is added to the first solution, in particular, contacting the protonated first reactant cation in the first solution. Then a bond is formed to obtain a second solution including the cation of the embodiment of the present application, the first acid salt cation, and the first anion, as shown in the structure of formula (B1) or the structure of formula (B1′).
  • the second reactant comprises or is substantially composed of a compound of formula (D), in particular, Q1 , Q2 , Q3 , Q4 , Q5 , Q6 , the position to which Q1 is attached, and m can be the same as the cation (formula (A)) and salt of the embodiment of the present application to be obtained. (Formula (B)) is consistent.
  • the second reactant is in excess relative to the protonated first reactant cation.
  • the molar ratio of the protonated first reactant cation to the second reactant is 1:1 to 1:2, such as about 1:1.0, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, or about 1:2.0.
  • the first solution further comprises a first acid conjugate base. In some embodiments, the first solution further comprises a first cation. In some embodiments, the first solution further comprises a second solvent. In some embodiments, the first solution consists essentially of, in particular of, the protonated first reactant first acid salt cation, the first cation, the first anion, the first acid conjugate base, and the second solvent.
  • the adding of the second reactant to the first solution is at a third temperature.
  • the third temperature is 0°C to 70°C.
  • the third temperature is 10°C to 40°C, more particularly 20°C to 30°C, more particularly about 25°C.
  • the third temperature is 20°C to 50°C, more particularly 30°C to 40°C, more particularly about 37°C.
  • the third temperature is 0°C to 20°C, more particularly 0°C to 10°C, more particularly about 4°C.
  • the third temperature is 40°C to 70°C, more particularly 50°C to 60°C, more particularly about 60°C.
  • the first temperature and the third temperature are equal.
  • the second temperature and the third temperature are equal.
  • the first temperature, the second temperature, and the third temperature are equal.
  • the second acidic environment has a pH value less than or equal to 6. In some embodiments, the second acidic environment has a pH value of 4 to 6, particularly 4.5 to 5.5, particularly 4.8 to 5.2, particularly 4.9 to 5.1, and more particularly about 5. Generally speaking, for a first anion that is less acidic or more alkaline, a second acidic environment with a lower pH value is selected. In some embodiments, the first anion is a hexafluorophosphate ion, and the second acidic environment has a pH value of 4 to 6, particularly 4.5 to 5.5, particularly 4.8 to 5.2, particularly 4.9 to 5.1, and more particularly about 5. In some embodiments, the pH value of the first acidic environment and the second acidic environment is the same.
  • the second acidic environment is obtained by allowing the first salt to be in a second solvent. In some embodiments, the second acidic environment is obtained by allowing the first salt and the acid composed of the first anion and the hydrogen ion to be in a second solvent. In some embodiments, it also includes adding a reducing agent to the first solution, especially before, after or at the same time as the second reactant is added to the first solution. That is, in some embodiments, the second acidic environment is reducing, especially strongly reducing.
  • the addition of a reducing agent helps to reduce the proportion of the non-covalent dispecific cations of the present application that are oxidized in the reaction, which is beneficial to improve the yield of the salt of the present application.
  • the reducing agent includes at least one or more selected from the group consisting of vitamin C, vitamin E and derivatives thereof.
  • the second solution is also purified to obtain a first intermediate product including a first acid salt cation of the present application embodiment cation and a first anion.
  • the purification includes dialysis.
  • the dialysis can be dialyzed by a membrane with a molecular weight cutoff (MWCO) of 50Da to 500Da, particularly about 100Da or 200Da.
  • MWCO molecular weight cutoff
  • the first base is added to the second solution or brought into contact with the first intermediate product to remove the first acid (H a A in formula (B1)) in the second solution or the first intermediate product, and then the salt of the present application is obtained.
  • the salt of the present application includes the non-covalent dimer cation of the present application and a first anion.
  • the salt of the present application can be represented by formula (B).
  • the first base includes at least one selected from the group consisting of ammonia water, sodium hydroxide, potassium hydroxide, and triethanolamine, or consists of them, but is not limited thereto. It should be understood by those skilled in the art that any base that can adjust the pH value to alkaline and does not cause further redox reaction can be used as the first base here.
  • the first base is ammonia water, especially dilute ammonia water.
  • the first base is sodium hydroxide.
  • the first base is potassium hydroxide.
  • the first base is triethanolamine.
  • the adding of the first base to the second solution or contacting the first intermediate product is to adjust the pH value of the second solution or the solution including the first intermediate product to alkaline.
  • the alkalinity is a pH value of 8 or more, particularly a pH value of 8 to 10, particularly 8.5 to 9.5, particularly 8.8 to 9.2, and more particularly about 9.
  • the step of contacting the first intermediate product with the first base comprises contacting the first intermediate product with the first base in water.
  • the purification includes dialysis.
  • the dialysis can be dialyzed by a membrane with a molecular weight cutoff (MWCO) of 50Da to 500Da, particularly about 100Da or 200Da.
  • the purification includes filtration.
  • the use of the cation or salt of the present application for promoting cell repair is provided. In some embodiments, the use of the cation or salt of the present application in the preparation of a drug for promoting cell repair is provided. In some embodiments, a method for promoting cell repair is provided, comprising administering the cation or salt of the present application. In some embodiments, the cation or salt of the present application is provided for promoting cell repair.
  • the antioxidant use of the cation or salt of the present application is provided. In some embodiments, the use of the cation or salt of the present application in the preparation of an antioxidant is provided. In some embodiments, an antioxidant method is provided, comprising administering the cation or salt of the present application. In some embodiments, the cation or salt of the present application is provided for antioxidant use.
  • the antioxidant is a drug that inhibits, reduces or reverses oxidative stress in human or animal cells. In some embodiments, the antioxidant is a drug that inhibits, reduces or removes oxygen free radicals in the human or animal body.
  • the use of the cation or salt of the present application in inhibiting, reducing or removing oxygen free radicals in human or animal bodies is provided.
  • the use of the cation or salt of the present application in the preparation of a drug for inhibiting, reducing or removing oxygen free radicals in human or animal bodies is provided.
  • a method for inhibiting, reducing or removing oxygen free radicals in human or animal bodies is provided, comprising administering the cation or salt of the present application, particularly to the human or animal cells.
  • the cation or salt of the present application is provided for inhibiting, reducing or removing oxygen free radicals in human or animal bodies.
  • the use of the cation or salt of the present application in treating a disease or symptom associated with oxygen free radicals is provided.
  • the use of the cation or salt of the present application in preparing a drug for treating a disease or symptom associated with oxygen free radicals is provided.
  • a method for treating a disease or symptom associated with oxygen free radicals comprising administering the cation or salt of the present application, particularly to a patient suffering from the disease or symptom associated with oxygen free radicals.
  • the cation or salt of the present application is provided for treating a disease or symptom associated with oxygen free radicals.
  • the promoting cell repair includes but is not limited to treating aging, inflammation, overweight, obesity, cancer, tumor, liver disease, neurodegenerative disease (such as Parkinson's disease or Alzheimer's disease), arterial hypertension, atherosclerosis, cardiovascular disease, diabetes, hypercholesterolemia, chronic fatigue syndrome, ischemia-reperfusion injury, neurodegenerative disease, ultraviolet-induced damage or alcohol-induced damage.
  • the promoting cell repair is to treat mucosal damage, particularly gastric mucosal damage.
  • the promoting cell repair is to treat alcohol-induced damage, particularly including alcohol-induced gastric mucosal damage.
  • the disease or symptom associated with oxygen free radicals includes, but is not limited to, aging, inflammation, overweight, obesity, cancer, tumor, liver disease, neurodegenerative disease (e.g., Parkinson's disease or Alzheimer's disease), arterial hypertension, atherosclerosis, cardiovascular disease, diabetes, hypercholesterolemia, chronic fatigue syndrome, ischemia-reperfusion injury, neurodegenerative disease, ultraviolet-induced damage, or alcohol-induced damage.
  • the disease or symptom associated with oxygen free radicals is gastric mucosal damage.
  • the disease or symptom associated with oxygen free radicals is alcohol-induced damage, particularly including alcohol-induced gastric mucosal damage.
  • the disease or condition associated with oxygen free radicals is a neurodegenerative disease.
  • the neurodegenerative disease is Parkinson's disease or Alzheimer's disease.
  • the neurodegenerative disease is Parkinson's disease.
  • the neurodegenerative disease is Alzheimer's disease.
  • the neurodegenerative disease includes 2-phenyl
  • the neurodegenerative disease comprises a disease associated with an increase in 2-phenyl-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxyl-3-oxide, an increase in 6-hydroxydopamine, and/or an increase in beta-amyloid protein.
  • the neurodegenerative disease comprises a disease associated with an increase in 2-phenyl-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxyl-3-oxide. In some embodiments, the neurodegenerative disease comprises a disease associated with an increase in 6-hydroxydopamine. In some embodiments, the neurodegenerative disease comprises a disease associated with an increase in beta-amyloid protein.
  • the cations or salts of the present application can effectively act on the pro-repair signaling pathways in cells, can enhance the self-repair function of cells, and enable them to perform self-repair, thereby preventing, treating or alleviating diseases that are susceptible to weakened cell repair ability, such as Parkinson's disease, Alzheimer's disease and other neurodegenerative diseases.
  • the use of the cation or salt of the present application in promoting cell proliferation is provided. In some embodiments, the use of the cation or salt of the present application in preparing a drug for promoting cell proliferation is provided. In some embodiments, a method for promoting cell proliferation is provided, comprising applying the cation or salt of the present application. In some embodiments, the cation or salt of the present application is provided for promoting cell proliferation.
  • the cell is a cell located in the skin. In some embodiments, the cell is a skin cell. In some embodiments, the cell is selected from the group consisting of epidermal fibroblasts, keratinocytes, vascular endothelial cells, and neural cells.
  • the cell is an epidermal fibroblast. In some embodiments, the cell is a keratinocyte. In some embodiments, the cell is a vascular endothelial cell. In some embodiments, the cell is a neural cell, particularly a neural cell of the skin. In some embodiments, the cell belongs to epithelial tissue. In some embodiments, the cell belongs to connective tissue. In some embodiments, the cell belongs to muscle tissue. In some embodiments, the cell belongs to neural tissue.
  • the cation or salt of the present application is provided for use in treating, alleviating or repairing wounds. In some embodiments, the cation or salt of the present application is provided for use in preparing a medicament for treating, alleviating or repairing wounds. In some embodiments, a method for treating, alleviating or repairing wounds is provided, comprising administering the cation or salt of the present application. In some embodiments, the cation or salt of the present application is provided for treating, alleviating or repairing wounds. In some embodiments, the wound comprises a skin wound.
  • the cations or salts of the present application can activate signal pathways that promote cell proliferation in biological cells, so that various cells can accelerate cell proliferation activities under the premise of being regulated, thereby promoting wound healing and repair, and improving wound repair effects.
  • the cations or salts of the present application can improve and treat diseases related to insufficient cell proliferation ability, or accelerate the wound healing process.
  • the compound including the first reactant, the second reactant, the cation of the embodiment, or the salt of the embodiment, has chirality but the chirality is not explicitly specified, the compound may be a chiral mixture, such as a racemic compound.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the hydrochloride salt of the first reactant in this example is white crystals with a yield of about 0.8 g and a yield of about 80%.
  • the salt yield in this example is about 1.6 g, with a yield of about 85%.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorosilicate, that is, the first anion is a hexafluorosilicate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 37° C. for 12 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • the hydrochloride salt of the first reactant in this example is white crystals with a yield of about 0.8 g and a yield of about 80%.
  • the salt yield in this example is about 1.2 g, and the yield is about 63%.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium chloride, ie the first anion is chloride ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 2 g of the first salt of this example was added, and stirring was continued at 60° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • the hydrochloride salt of the first reactant in this example is white crystals with a yield of about 0.8 g and a yield of about 80%.
  • the salt yield in this example is about 0.6 g, and the yield is about 32%.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(5-hydroxy-1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 2 g of the first salt of this example was added, and stirring was continued at 4° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • the hydrochloride salt of the first reactant in this example is white crystals with a yield of about 0.8 g and a yield of about 80%.
  • the salt yield in this example is about 1.6 g, and the yield is about 64%.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(5-amino-1H-indol-3-yl)propionic acid
  • the first salt is ammonium sulfate, that is, the first anion is a sulfate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 3 g of the first salt of this example was added, and stirring was continued at 4° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • the hydrochloride salt of the first reactant in this example is white crystals with a yield of about 0.8 g and a yield of about 80%.
  • the salt yield in this example is about 1.6 g, and the yield is about 64%.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(4-amino-1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(5-cyano-1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(5-chloro-1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(6-carboxy-1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1-methyl-1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-methyl-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-methylamino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-acetamido-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-(1H-pyrrol-1-yl)-3-(1H-indol-3-yl)propanoic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-benzyl-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is methyl 2-amino-3-(1H-indol-3-yl)propanoate
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionylethylamide
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(2-hydroxy-1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(2-mercapto-1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(2-amino-1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(2-methyl-1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(2-phenyl-1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1-methyl-1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1-phenyl-1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1-triphenylmethyl-1H-imidazol-4-yl)propionic acid;
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-methylamino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-acetamido-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-hydrazino-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-(1H-pyrrol-1-yl)-3-(1H-imidazol-4-yl)propanoic acid;
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the first reactant is 2-benzyl-3-(1H-imidazol-4-yl)propionic acid
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is 2-amino-3-(1H-imidazol-4-yl)propionyl methylamide
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • the preparation method of the salt of this embodiment is as follows.
  • the first reactant is methyl 2-amino-3-(1H-imidazol-4-yl)propionate
  • the second reactant is 2-amino-3-(1H-indol-3-yl)propionic acid
  • the first salt is ammonium hexafluorophosphate, that is, the first anion is a hexafluorophosphate ion.
  • first reactant hydrochloride 0.8 g was placed in 10 mL of ultrapure water, and stirred vigorously until completely dissolved. 4 g of the first salt of this example was added, and stirring was continued at 25° C. for 6 hours to obtain a first aqueous solution including protonated first reactant hydrochloride cations and first anions.
  • 0.89 g of the second reactant was added to the first aqueous solution at 25°C, and gently stirred for 24 hours to obtain a second aqueous solution including the cation of this embodiment, which was fully dialyzed with a dialysis bag with a molecular weight cutoff of 200 Da, and dried to obtain a first intermediate product.
  • the first intermediate product was dissolved in 10 mL of ultrapure water, and dilute ammonia was added to adjust the pH value to 9 to precipitate a large amount of beige precipitate, which was filtered and the filter cake was washed twice with water, and dried to obtain the product, which is the salt of this embodiment.
  • Example 1 The salts of Examples 1, 4, and 18 were used as experimental compounds, and a mixture of histidine and tryptophan at a molar ratio of 1:1 was used as a control compound. Each compound was tested at a final concentration of 0.025 mg/mL, 0.05 mg/mL, 0.1 mg/mL, 0.2 mg/mL, 0.4 mg/mL, and 0.8 mg/mL.
  • the results are shown in Figure 1 and Table 1.
  • the horizontal axis is the concentration of the compound in the experimental group or the control group, and the vertical axis is the normalized residual PTIO content concentration ratio, with the initial concentration of PTIO as 100%.
  • the non-covalent dimer cation of the present application can more effectively scavenge oxygen free radicals represented by PTIO at least at 0.2 mg/mL compared to histidine and tryptophan monomers, and its scavenging efficiency is at least 3-4 times that of histidine and tryptophan monomers; and as its concentration increases, the effect of scavenging oxygen free radicals also increases.
  • the salts of Examples 1, 4, and 18 were used as experimental compounds, and glycyrrhetinic acid was used as a control compound.
  • a blank control group (without ethanol) and a model group (with ethanol but without the salts or glycyrrhetinic acid of the examples) were set up.
  • GES-1 human gastric mucosal epithelial cells were evenly inoculated into 96-well plates, with about 5,000 cells per well. The cells were cultured in RPMI 1640 complete medium for 6 hours. After the cells were completely attached to the wall, all the medium was removed, and the cells were incubated in 100 ⁇ L of RPMI 1640 serum-free medium containing 7% ethanol (not included in the blank group) for 12 hours. After the cells were incubated with ethanol for 12 hours, the cell viability was significantly reduced to about 60%.
  • the results of the model group showed that after the cells were cultured in a medium containing carbon tetrachloride for 12 hours, the cell viability was significantly reduced to about 60%.
  • the results of the experimental group and the control group are shown in Figure 2 and Table 2; it can be seen that after adding the salt of the present application to the cell culture medium, the cell viability increased with the increase in concentration, and the cell viability of the group of the salt of the present application was significantly higher than that of the control group of glycyrrhetinic acid.
  • 6-Hydroxydopamine (6-OHDA) can be taken up by nerve cells, causing metabolic disorders in nerve cells and inducing Parkinson's disease models in vitro. Therefore, this experiment uses 6-OHDA to establish a Parkinson's disease cell model at the cellular level, and adds the salt of the present application or other control group compounds to obtain the technical effect of the non-covalent dimer cation of the present application in the Parkinson's disease cell model.
  • Examples 1, 4, and 18 were used as experimental group compounds, and selegiline was used as control group compound.
  • a blank control group (without 6-OHDA) and a model group (with 6-OHDA but without the salts of the examples or selegiline) were set up.
  • SH-SY5Y human neuroblastoma cells were evenly seeded into 96-well plates, with about 5000 cells per well. The cells were cultured in DMEM/F12 complete medium for 6 hours. After the cells were completely attached, all the medium was removed, and the cells were incubated in 100 ⁇ L cell culture medium containing 150 ⁇ mol/L 6-OHDA (not included in the blank group) in each well for 24 hours. After incubation of cells with 6-OHDA for 12 hours, the cell viability was significantly reduced to about 30%.
  • the results of the model group showed that after the cells were cultured in a medium containing 6-OHDA for 24 hours, the cell viability was significantly reduced to about 30%.
  • the results of the experimental group and the control group are shown in Figure 3 and Table 3; it can be seen that after the salt of the present application was added to the cell culture medium, the cell viability increased with the increase in concentration, and the cell viability of the group of the salt of the present application was significantly higher than that of the control group of selegiline.
  • beta amyloid protein (A ⁇ ) is often present, causing damage to hippocampal neuronal cells and leading to Alzheimer's disease. Therefore, this experiment uses one of the A ⁇ subtypes, A ⁇ (1-42), to establish an Alzheimer's disease cell model at the cellular level, and adds the salt of the present application or other control group compounds to obtain the technical effect of the non-covalent dimer cation of the present application in the Alzheimer's disease cell model.
  • the salts of Examples 1, 4, and 18 were used as experimental compounds, and gangliosides were used as control compounds.
  • a blank control group (without A ⁇ (1-42)) and a model group (with A ⁇ (1-42) but without the salts or gangliosides of the examples) were set up.
  • SH-SY5Y human neuroblastoma cells were evenly seeded into 96-well plates, with approximately 5,000 cells per well. The cells were cultured in DMEM/F12 complete medium for 6 hours. After the cells were completely attached, all the medium was removed, and the cells were incubated in 100 ⁇ L of DMEM/F12 serum-free medium containing 20 ⁇ mol/L A ⁇ (1-42) (not included in the blank group) for 24 hours. After incubation of cells with A ⁇ (1-42) for 48 hours, cell viability was significantly reduced to approximately 50%.
  • the results of the model group showed that after the cells were cultured in the medium containing A ⁇ (1-42) for 48 hours, the cell viability was significantly reduced to about 50%.
  • the results of the experimental group and the control group are shown in Figure 4 and Table 4; it can be seen that after adding the salt of the present application to the cell culture medium, the cell viability increased with the increase in concentration, and the cell viability of the salt group of the present application was significantly higher than that of the ganglioside control group.
  • transcriptomic analysis was performed.
  • Neuro-2a mouse brain neuroma cells were evenly spread into two 10 cm culture dishes and cultured using MEM complete medium. When the density reached 90%, all the culture medium was discarded, 10 mL of serum-free MEM medium was added, and the salt solution of Example 1 was added to one of the dishes to a final concentration of 0.1 mg/mL. An equal volume of PBS solution was added to another dish. After culturing in a 37°C cell culture incubator for 3 hours, all the culture medium was removed again, and Trizol was used to extract the cell RNA in the two dishes, and transcriptomic analysis was performed.
  • the GO enrichment analysis results of the differentially expressed genes were classified according to molecular function (MF), biological process (BP) and cell component (CC).
  • MF molecular function
  • BP biological process
  • CC cell component
  • Epidermal fibroblasts play a decisive role in epidermal wound repair, participate in the formation of connective tissue, and are related to the recovery speed and effect of skin damage.
  • HFF-1 human epidermal fibroblasts are cultured and the salt or other control group compounds of the present application are added to obtain the technical effect of the non-covalent dimer cation of the present application in promoting the proliferation of human epidermal fibroblasts.
  • HFF-1 human epidermal fibroblasts were evenly inoculated into a 96-well plate, with about 2000 cells per well. The cells were cultured for 6 hours using DMEM complete medium.
  • each experimental group compound containing 0.025 mg/mL, 0.05 mg/mL, 0.1 mg/mL, 0.2 mg/mL, 0.4 mg/mL, and 0.8 mg/mL was added to each well according to the group (the blank group did not contain it) and added to 100 ⁇ L of DMEM complete medium in the cell culture solution and cultured for 24 hours.
  • Keratinocytes also play a key role in epidermal wound repair. They are involved in the repair of the stratum corneum on the skin surface and are related to scar formation.
  • HaCaT human immortalized keratinocytes were cultured and the salt or other control group compounds of the present application were added to obtain the non-covalent The technical effect of dimer cations in promoting the proliferation of human immortalized keratinocytes.
  • Example 1 The salts of Examples 1, 4, and 18 were used as experimental group compounds, and the histidine + tryptophan molar ratio of 1:1 was used as the control group compound.
  • HaCaT human immortalized keratinocytes were evenly inoculated into 96-well plates, with about 2000 cells per well. The cells were cultured for 6 hours using DMEM complete medium.
  • each experimental group compound containing 0.025 mg/mL, 0.05 mg/mL, 0.1 mg/mL, 0.2 mg/mL, 0.4 mg/mL, and 0.8 mg/mL was added to each well according to the group (the blank group did not contain it) and added to 100 ⁇ L of DMEM complete medium in the cell culture solution and cultured for 24 hours.
  • Endothelial cells participate in the reconstruction of the vascular system and support wound healing during tissue repair.
  • HUVEC human umbilical vein endothelial cells are cultured and the salt or other control group compounds of the present application are added to obtain the technical effect of the non-covalent dimer cation of the present application in promoting the proliferation of human umbilical vein endothelial cells.
  • HUVEC human umbilical vein endothelial cells were evenly inoculated into a 96-well plate, with about 2000 cells per well. The cells were cultured for 6 hours using a complete medium for endothelial cells.
  • each experimental group compound containing 0.025 mg/mL, 0.05 mg/mL, 0.1 mg/mL, 0.2 mg/mL, 0.4 mg/mL, and 0.8 mg/mL was added to each well according to the group (the blank group did not contain it) and added to 100 ⁇ L of a complete medium for endothelial cells in the cell culture medium, and cultured for 24 hours.
  • CATH.a mouse nerve cells are cultured and the salt or other control group compounds of the present application are added to obtain the technical effect of the non-covalent dimer cation of the present application in promoting the proliferation of nerve cells.
  • CATH.a mouse neural cells were evenly inoculated into a 96-well plate, with about 2000 cells per well. The cells were cultured in RPMI 1640 complete medium for 6 hours. After the cells were completely attached to the wall, all the medium was removed, and 0.025 mg/mL, 0.05 mg/mL, 0.1 mg/mL, 0.2 mg/mL, 0.4 mg/mL, and 0.8 mg/mL of the compound in each experimental group (not included in the blank group) were added to 100 ⁇ L of RPMI 1640 complete medium in the cell culture medium and cultured for 24 hours.
  • transcriptomic analysis was performed. HFF-1 human skin fibroblasts were evenly spread into two 10 cm culture dishes and cultured using DMEM complete medium. When the density reached 90%, all the culture medium was discarded, 10 mL of serum-free DMEM medium was added, and the salt solution of Example 1 was added to one of the dishes to a final concentration of 0.1 mg/mL. An equal volume of PBS solution was added to another dish. After culturing in a 37°C cell culture incubator for 3 hours, all the culture medium was removed again, and Trizol was used to extract the cell RNA in the two dishes, and transcriptomic analysis was performed. The results are shown in Figure 10.
  • the KEGG enrichment analysis results of differentially expressed genes were classified according to the cell process CP, the internal environment information process EIP, the gene information process GIP and the metabolic process MP.

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Abstract

提供了一种本申请的非共价二聚体阳离子，为摘要附图所示阳离子、其互变异构体、或其立体异构体。提供了一种本申请的一种盐，包括本申请的阳离子和第一阴离子。提供了本申请的阳离子或本申请的盐的用途，例如是制备促进细胞修复、或细胞增殖或创伤修复的药物的用途。

Description

非共价二聚体阳离子、其盐、其制备方法及其用途 技术领域
本申请涉及生物医药领域，更具体涉及一种非共价二聚体阳离子、其盐、其制备方法，及其在细胞修复、或细胞增殖或创伤修复等方面的用途。
背景技术
细胞修复能力在生物体内具有重要作用。许多因素会造成细胞损伤进而造成组织及器官损伤从而出现病症，此时细胞的自我修复能力就显得尤为重要。多项研究表明，年轻细胞比老年细胞具有更强的自我修复能力以及自我修复意愿，即年轻细胞更倾向于进行自身修复，而非等待免疫细胞处理，且年轻细胞具有更强的修复能力。
细胞的修复能力也随不同细胞而体现出较为显著的差异。体现较强修复力的各种腺体器官的细胞，如肝、胰、内分泌腺、汗腺、皮脂腺及肾小管上皮细胞等，当受到内部或外部损伤时，表现出较强的修复能力。修复力微弱或无修复力的细胞，如中枢神经细胞和神经节细胞，遭损伤后极难恢复原有功能，心肌细胞的修复能力极弱，损伤后均由纤维结缔组织代替，很难恢复原有的结构和功能。
许多疾病的产生也与细胞修复能力的下降或不足息息相关，老年人及风险暴露者罹患某些疾病的概率大幅增高正与其机体有关细胞修复水平下降或者不足导致的。如老年人易患的神经退行性疾病帕金森病、阿尔兹海默症等，长期酗酒人群易患胃黏膜损伤、胃溃疡等，或脏器功能压力过大而导致的一些脏器疾病，均是由于细胞修复力不足的原因导致的。
有研究表明，在绝大多数损伤细胞中，通常存在着较高水平的氧化应激状态，即细胞在被损伤的情况下，体现出一种非正常状态，或由于损伤导致，或由于修复损伤而产生的，会出现较高的ROS水平，从而抑制了细胞自我修复功能，进而使得疾病恶化。因此降低细胞内ROS水平也是一种有效的恢复细胞修复能力的手段，但该方法作用不直接，故导致效果不佳。
影响细胞修复力的因素有很多，包括损伤的类型、程度以及范围，个体年龄，机体营养状况，或药物作用导致。而目前临床阶段对于相关疾病的治疗仍聚焦与对疾病的“定向”治疗，而忽略了细胞本身的修复能力，因此在一些疾病的治疗手段上进展缓慢，而且由于一些药物的副作用，经常会导致顾此失彼的现象出现。
细胞增殖是生活细胞的重要生理功能之一，是生物体的重要生命特征。细胞的增殖是生物体生长、发育、繁殖以及遗传的基础。细胞增殖也是生物体的重要生命特征，人体细胞以分裂的方式进行增殖，用来补充体内衰老或死亡的细胞。
细胞增殖是一个复杂而又至关重要的生命活动，从受精卵发育成一个独立的个体经历了无数次的细胞增殖；各个器官为了维持生理生命活动也会无时无刻的进行着可调控的细胞增殖；遭到病原体侵入时有关免疫细胞增殖以保护个体健康；当个体受到物理创伤时相关细胞也会开始增殖以修复组织或者器官损伤。.
创伤是机械因素引起人体组织或器官的破坏，同时又极为常见，不仅可以大量发生在战争时期，也可发生在和平时期。其中创伤是一个广泛命题，其中包括：割伤、刺伤、挫伤、扭伤。由于工业、农业、交通业及体育事业的高速发展，各种事故所造成的创伤日趋增多。创伤发生率高，影响范围大，且由于内科、外科手术的成熟和普及，手术伤口作为创伤的一种，也常常出现在人们的日常生活当中。
创伤愈合是指外伤或其他疾病过程中，造成组织缺损后局部组织通过增生或再生方式进行修补的一系列复杂的病理生理过程。创伤后机体出现非常协调的愈合过程，包括多种细胞、细胞因子和细胞外基质错综复杂的网络作用。参与皮肤伤口愈合的细胞主要包括各种炎性细胞和组织修复细胞，前者包括中性粒细胞、巨噬细胞等，后者主要包括血管内皮细胞、表皮细胞、成纤维细胞以及神经细胞。这一系列细胞都在通过细胞增殖来实现各自的功能，促进伤口创面的愈合，缺一不可。
而目前在临床处理当中，多仅对伤口进行灭菌消毒的洁净处理，而至于具体的修复工作则仍要靠机体自身的协同修复能力，老年人组织细胞增殖能力较弱，导致创伤愈合缓慢，感染风险高，影响正常生活，严重 者可因感染导致的炎症威胁生命。而当愈合组织细胞增殖速度缓慢时，会形成较为肥大的结缔组织，该结缔组织难以与原先皮肤融为一体，故而呈现为疤痕，影响美观。因此一些研究推测，加速创伤愈合过程可有助于减小创伤疤痕。
发明内容
提供了一种本申请的非共价二聚体阳离子，为式(A)阳离子、其互变异构体、或其立体异构体，其中，式(A)中的键“”为非共价键；所述R7选自由氢、羟甲基、-C-R6和-C(＝O)-R6所组成的组；R1选自由氢、羟基、巯基、氨基、甲基、乙基、和苯基所组成的组；Q1选自由氢、羟基、巯基、氨基、甲基、乙基、苯基、氯、氰基、和羧基所组成的组；R2和Q2各自独立地选自由氢、甲基、乙基、丙基、苯基、苯甲氧基甲基、和三苯基甲基所组成的组；R3和Q3各自独立地选自由氢、羟基、巯基、氨基、甲基、乙基、和苯基所组成的组；R4和Q4各自独立地选自由氢、甲基、乙基、和丙基所组成的组；R5和Q5各自独立地选自由氢、苯甲基、氨基、甲氨基、肼基、三甲基铵基、吡咯基、和氨基上进一步连接由氨基酸、二肽、或三肽的C端碳原子衍生的取代基，所组成的组；R6和Q6各自独立地选自由羟基、去质子化羟基、甲氧基、甲氨基、乙氨基、和由氨基酸、二肽、或三肽的N端氮原子衍生的取代基，所组成的组；且m和n各自独立地选自由0和1所组成的组。
提供了一种本申请的盐，包括本申请的阳离子，和包括选自由氟离子、氯离子、溴离子、碘离子、硫离子、硝酸根离子、硫酸根离子、亚硫酸根离子、硫代硫酸根离子、过硫酸根离子、硒酸根离子、磷酸根离子、碳酸根离子、六氟磷酸根离子、六氟硅酸根离子、醋酸根离子、磺酸根离子、苯甲酸根离子、和多聚磷酸根离子所组成的组的至少一个的第一阴离子。
提供了一种本申请的阳离子或本申请的盐的制备方法，包括：将第一反应物接触第一酸，得到第一反应物第一酸盐；在酸性环境下，将第一反应物第一酸盐接触包括第一阴离子的第一盐，得到包括质子化第一反应物第一酸盐阳离子、和第一阴离子，的第一溶液；以及在强还原性和酸性环境下，将第二反应物加入第一溶液，得到第二溶液或第一中间产物；以及将第一碱加入至第二溶液中或接触第一中间产物，其中，所述第一反应物包括式(C)化合物，且所述第二反应物包括式(D)化合物。
提供了本申请的阳离子或本申请的盐，在制备药物中的用途，特别是在抗氧化、制备抗氧化剂、制备抑制、减少或逆转人类或动物细胞的氧化应激或抑制、减少或清除人类或动物体内的氧自由基的药物、或制备治疗与氧化应激或氧自由基相关联的疾病或症状的药物中的用途。提供了一种制备药物的方法，包括制备本申请的阳离子或本申请的盐。
提供了本申请的阳离子或本申请的盐，在制备药物中的用途，特别是在促进细胞增殖、或制备促进细胞增殖或治疗、缓解、或修复创伤的药物中的用途。提供了一种制备药物的方法，包括制备本申请的阳离子或本申请的盐。
附图说明
图1为本申请的一些实施例的2-苯基-4,5-二氢-4,4,5,5-四甲基-1H-咪唑基-1-氧基-3-氧化物(PTIO)模型氧自由基清除实验结果。
图2为本申请的一些实施例的乙醇的胃黏膜上皮细胞的损伤模型的细胞活力。
图3为本申请的一些实施例的帕金森病模型的细胞活力。
图4为本申请的一些实施例的阿尔兹海默症模型的细胞活力。
图5为本申请的一些实施例的转录组学分析结果。
图6为本申请的一些实施例的表皮成纤维细胞增殖实验的细胞活力。
图7为本申请的一些实施例的角质形成细胞增殖实验的细胞活力。
图8为本申请的一些实施例的血管内皮细胞增殖实验的细胞活力。
图9为本申请的一些实施例的神经细胞增殖实验的细胞活力。
图10为本申请的一些实施例的转录组学分析结果。
图11为式(A)。
具体实施方式
如本文所用，单数术语指一个或多于一个。举例来说，“元件”或“一个元件”皆指一个元件或多于一个的元件。如本文所用，术语“多个”是指至少二个。
如本文所用，术语“约”指近似，在大约或附近的范围。当结合数值范围使用术语“约”时，其通过扩大界限高于或低于所提供数值来修改该范围。一般来说，本文使用术语“约”使数值与所提供值上下变化10％。一方面，术语“约”指加上或减去其所修饰的数的数值的20％。举例来说，“约50％”指在45％–55％的范围内。本文通过端点提及的数值范围包括包含在该范围内的所有整数和分数(例如“1至5”包括1、1.5、2、2.75、3、3.90、4和5)。还应当理解其所有整数和分数视为被术语“约”修饰。
如本文所用，术语“包含”、“包括”、或“含有”，作为非排他性或开放性术语，旨在表示组合(例如装置、组合物、方法等)包括所列举的要素(例如装置的各单元、组合物的各组分、方法的实质性步骤等)，但不排除其他要素。如本文所用，术语“实质上由……组成”当用于定义组合物和方法时，意味着排除对于所述目的的组合具有任何实质上影响的其他要素，但不排除不会实质上影响本发明的基本和新颖性特征的其他要素。如本文所用，术语“由……组成”是指排除其他要素的组合(单元、组分、实质性步骤等)，但除非另有说明，否则并非意指排除痕量的不可避免的杂质。由这些连接术语中的每一个定义的实施方式都在本发明的范围内。作为其特定实施方式，披露包括术语“包含”、“包括”或“含有”的技术方案也应视为同时披露包括术语“实质上由……组成”和“由……组成”的对应技术方案。
如本文所用，术语“和/或”是指并且涵盖一个或多个相关联的所列项目的任何和所有可能的组合。当在二个或多个项目的列表中使用时，术语“和/或”表示所列出的项目中的任何一个可以单独被包含，或者可以包含二个或多个所列出的项目的任何组合。例如，如果组、组合、或组合物等，被描述为包括(或包含)组分A、B、C和/或D，则该组合物可以单独包含A；单独包含B；单独包含C；单独包含D；包含A和B的组合；包含A和C的组合；包含A和D的组合；包含B和C的组合；包含B和D的组合；包含C和D的组合；包含A和B和C的组合；包含A和B和D的组合；包含A和C和D的组合；包含B和C和D的组合；或包含A和B和C和D的组合。
如本文所用，本申请的化合物或离子包括多个可变基团。本领域普通技术人员应当认识到，本申请所设想的基团的组合是化学上允许的化合物或离子的组合。
如本文所用，手性中心的立体化学可以根据本领域技术人员的惯例来定义，即使用实线楔形键(wedged bond)指示朝向纸面之外(朝向读者的一侧)的基团、并使用虚线楔形键(hashed bond)指示朝向纸面之内(远离读者的一侧)的基团。如果使用此类表示方式，那么可以理解为指示本文中各化学结 构所示的基团的特定单一立体异构体。本文中任意未具体使用实线楔形键或虚线楔形键表示的键，应视为未具体指示该键是朝向纸面之外、或朝向纸面之内、或位于纸面，但不妨碍其在化学上允许的情况下朝向纸面之外或朝向纸面之内。
如本文所用，术语“异构体”意指，具有相同分子式但其原子的键合性质或顺序或其原子在空间中的排列不同的化合物。其中，术语“立体异构体”意指原子在空间中的排列不同的异构体；术语“对映异构体”意指带有一个或多个不对称中心的立体异构体，彼此互为不可重叠的镜像；术语“非对映异构体”意指在一个或多个不对称中心处具有相反构型的不属于对映异构体的立体异构体。当化合物具有不对称中心时，例如，如果碳原子键合到四个不同的基团，则可以有一对对映异构体。对映异构体可通过其一个或多个不对称中心的绝对构型来表征并指定为R-构型或S-构型，或以其中分子旋转偏振光平面的方式指定为右旋或左旋。手性化合物可以单独的对映异构体或以其混合物存在，例如是以外消旋混合物存在。本申请的化合物可含有不对称或手性中心，并因此以不同的立体异构形式存在。应视为本申请的化合物的所有立体异构体，包括但不限于非对映异构体、对映异构体、和阻转异构体，及其混合物如外消旋混合物，构成本申请的一部分。
如本文所用，术语“二聚体”通常指由二个分子或离子，例如氨基酸或肽或其衍生物或其质子化离子，经由相互作用，特别是非共价的相互作用，形成的复合物。如本文所用，术语“共价键”指代包含或涉及电子共享的任何键。共价键的非限制性实例包括但不限于：肽键、糖苷键、酯键、磷二酯键。如本文所用，术语“非共价键”包括两个或更多个部分之间的不包含或不涉及电子共享的任何键或相互作用。非共价键或相互作用的非限制性实例包括但不限于静电、π-π效应、范德华力、氢键和疏水效应，特别是氢键。
如本文所用，各种具有手性的氨基酸，在未有明确说明手性的情况下，应视为至少意指L-氨基酸，但并非用于明确排除D-氨基酸的相关实施方式。
如本文所用，特别是如下所述的用语“公开或包含”，包括但不限于本申请说明书(例如是实施例)的、其附图的、或权利要求书的公开，并包括但不限于本申请权利要求请求保护范围的、或任意一个或更多个实施方式(例如是如本文所述的术语“在一个实施方式中”或“在一些实施方式中”后接的实施方式)的包含。
为更进一步阐述本申请为了达成预定目的所采取的技术手段及功效，以下结合附图及较佳实施例，对依据本申请的具体实施方式、结构、特征及其功效，详细说明如下。
本申请的非共价二聚体阳离子
在一方面，本申请提供了一种非共价二聚体阳离子。
本申请提供了一种非共价二聚体阳离子，包括式(A1)部分(moiety)和式(A2)部分，其中式(A1)部分所示咪唑环上的氢(Nπ-H即式(A1)中以星号标记的H，或是R2为氢条件下的Nτ-H)与式(A2)部分中电负性较强或最强的原子，例如是式(A2)部分所示羰基上的氧(即式(A2)中以星号标记的O)形成非共价键。
本申请提供了一种非共价二聚体阳离子，包括式(A)阳离子、其互变异构体、或其立体异构体，或由其组成，其中式(A)中的键为非共价键。
该非共价键，即式(A)中的键应视为包括所有化学上允许的、得以使得本申请的非共价二聚体阳离子在其盐类中稳定存在的非共价键，或由其组成。
根据本领域技术人员的理解，可能将该非共价键理解为氢键。然而，经申请人实验证实，该非共价键在一般环境中得以稳定存在，例如是以盐的形式存在；特别是至少在测定质谱时仍可保持稳定存在而未断裂，即本申请的非共价二聚体阳离子在测定质谱时得以保持完整，从而产生本申请的非共价二聚体阳离子的m/z值的对应离子峰。亦即，应理解为一些氢键的性质可能适用于该非共价键，但该非共价键并非必然依循本领域技术人员对于氢键性质的所有理解，特别是在键能方面上。在一些实施方式中，该非共价键为其键能较一般“NH—∶O＝C”氢键强的键，例如是键能大于8kJ/mol的键。
在式(A)与式(A2)中的表记意指取代基Q1可以是形成在其所指向的环(在式(A)与式(A2)中即其吲哚部分中的苯环部分)上的任意组成原子(member)。具体来说，Q1可以是形成在式(A)与式(A2)中的吲哚部分的4号位、5号位、6号位、或7号位上。
在一些实施方式中，在式(A)阳离子或式(A2)部分中，Q1位于其中吲哚部分的4号位的碳上，如式(A-4)与式(A2-4)所示。在一些实施方式中，在式(A)阳离子或式(A2)部分中，Q1位于其中吲哚部分的5号位的碳上，如式(A-5)与式(A2-5)所示。在一些实施方式中，在式(A)阳离子或式(A2)部分中，Q1位于其中吲哚部分的6号位的碳上，如式(A-6)与式(A2-6)所示。在一些实施方式中，在式(A)阳离子或式(A2)部分中，Q1位于其中吲哚部分的7号位的碳上，如式(A-7)与式(A2-7)所示。
在一些实施方式中，R7选自由氢、羟甲基、-C-R6和-C(＝O)-R6所组成的组。在一些实施方式中，R7为氢。 在一些实施方式中，R7为羟甲基。在一些实施方式中，R7为-C-R6。在一些实施方式中，R7为-C(＝O)-R6。
在一些实施方式中，R1选自由氢、羟基、巯基、氨基、甲基、乙基、和苯基所组成的组。在一些实施方式中，R1选自由氢、羟基、巯基、氨基、甲基、和苯基所组成的组。在一些实施方式中，R1为氢。在一些实施方式中，R1为羟基。在一些实施方式中，R1为巯基。在一些实施方式中，R1为氨基。在一些实施方式中，R1为甲基。在一些实施方式中，R1为乙基。在一些实施方式中，R1为苯基。在一些实施方式中，Q1选自由氢、羟基、巯基、氨基、甲基、乙基、苯基、氯、氰基、和羧基所组成的组。在一些实施方式中，Q1选自由氢、羟基、氨基、氯、氰基、和羧基所组成的组。在一些实施方式中，Q1为氢。在一些实施方式中，Q1为羟基。在一些实施方式中，Q1为巯基。在一些实施方式中，Q1为氨基。在一些实施方式中，Q1为甲基。在一些实施方式中，Q1为乙基。在一些实施方式中，Q1为苯基。在一些实施方式中，Q1为氯。在一些实施方式中，Q1为氰基。在一些实施方式中，Q1为羧基。
在一些实施方式中，R2选自由氢、甲基、乙基、丙基、苯基、苯甲氧基甲基、和三苯基甲基所组成的组。在一些实施方式中，R2选自由氢、甲基、苯基、和三苯基甲基所组成的组。在一些实施方式中，R2为氢。在一些实施方式中，R2为甲基。在一些实施方式中，R2为乙基。在一些实施方式中，R2为丙基。在一些实施方式中，R2为苯基。在一些实施方式中，R2为苯甲氧基甲基。在一些实施方式中，R2为三苯基甲基。在一些实施方式中，Q2选自由氢、甲基、乙基、丙基、苯基、苯甲氧基甲基、和三苯基甲基所组成的组。在一些实施方式中，Q2选自由氢和甲基所组成的组。在一些实施方式中，Q2为氢。在一些实施方式中，Q2为甲基。在一些实施方式中，Q2为乙基。在一些实施方式中，Q2为丙基。在一些实施方式中，Q2为苯基。在一些实施方式中，Q2为苯甲氧基甲基。在一些实施方式中，Q2为三苯基甲基。
在一些实施方式中，R3选自由氢、羟基、巯基、氨基、甲基、乙基、和苯基所组成的组。在一些实施方式中，R3选自由氢、巯基、和甲基所组成的组。在一些实施方式中，R3为氢。在一些实施方式中，R3为羟基。在一些实施方式中，R3为巯基。在一些实施方式中，R3为氨基。在一些实施方式中，R3为甲基。在一些实施方式中，R3为乙基。在一些实施方式中，R3为苯基。在一些实施方式中，Q3选自由氢、羟基、巯基、氨基、甲基、乙基、和苯基所组成的组。在一些实施方式中，Q3选自由氢、巯基、和甲基所组成的组。在一些实施方式中，Q3为氢。在一些实施方式中，Q3为羟基。在一些实施方式中，Q3为巯基。在一些实施方式中，Q3为氨基。在一些实施方式中，Q3为甲基。在一些实施方式中，Q3为乙基。在一些实施方式中，Q3为苯基。
在一些实施方式中，R4选自由氢、甲基、乙基、和丙基所组成的组。在一些实施方式中，R4选自由氢和甲基所组成的组。在一些实施方式中，R4为氢。在一些实施方式中，R4为甲基。在一些实施方式中，R4为乙基。在一些实施方式中，R4为丙基。在一些实施方式中，Q4选自由氢、甲基、乙基、和丙基所组成的组。在一些实施方式中，Q4选自由氢和甲基所组成的组。在一些实施方式中，Q4为氢。在一些实施方式中，Q4为甲基。在一些实施方式中，Q4为乙基。在一些实施方式中，Q4为丙基。
在一些实施方式中，R5选自由氢、苯甲基、氨基、甲氨基、肼基、三甲基铵基、吡咯基、和氨基上进一步连接由氨基酸或肽的C端碳原子衍生的取代基，所组成的组。在一些实施方式中，Q5选自由氢、苯甲基、氨基、甲氨基、肼基、三甲基铵基、吡咯基、和氨基上进一步连接由氨基酸或肽的C端碳原子衍生的取代基，所组成的组。在一些实施方式中，所述的氨基上进一步连接由氨基酸或肽的C端碳原子衍生的取代基可表示为“-N-CAA(＝O)-Z”，其中CAA为氨基酸或肽的C端碳原子，Z为氨基酸或肽的剩余部分，即Z-CAAOOH为氨基酸或肽，特别是为氨基酸、二肽、或三肽。在一些实施方式中，所述的氨基上进一步连接由氨基酸或肽的C端碳原子衍生的取代基，为氨基上进一步连接由氨基酸、二肽、或三肽的C端碳原子衍生的取代基。在一些实施方式中，R5选自由氢、苯甲基、氨基、甲氨基、肼基、三甲基铵基、吡咯基、和氨基上进一步连接由氨基酸、二肽、或三肽的C端碳原子衍生的取代基，所组成的组。在一些实施方式中，Q5选自由氢、苯甲基、氨基、甲氨基、肼基、三甲基铵基、吡咯基、和氨基上进一步连接由氨基酸、二肽、或三肽的C端碳原子衍生的取代基，所组成的组。在一些实施方式中，所述的氨基上进一步连接由氨基酸或肽的C端碳原子衍生的取代基选自由乙酰胺基、2-氨基乙酰胺基(即甘氨酰氨基，即氨基上进一步连接甘氨酸的C端碳原子衍生的取 代基所得的基团)、3-氨基丙酰胺基(即β-丙氨酰氨基，即氨基上进一步连接β-丙氨酸的C端碳原子衍生的取代基所得的基团)、和焦谷氨酰氨基(即氨基上进一步连接焦谷氨酸的C端碳原子衍生的取代基所得的基团)所组成的组。在一些实施方式中，R5选自由氢、苯甲基、氨基、甲氨基、肼基、三甲基铵基、吡咯基、乙酰胺基、2-氨基乙酰胺基、3-氨基丙酰胺基、和焦谷氨酰氨基，所组成的组。在一些实施方式中，R5选自由氢、氨基、肼基、三甲基铵基、吡咯基、乙酰胺基、2-氨基乙酰胺基、3-氨基丙酰胺基、和焦谷氨酰氨基所组成的组。在一些实施方式中，R5选自由氢、苯甲基、氨基、甲氨基、肼基、吡咯基、和乙酰胺基，所组成的组。在一些实施方式中，R5为氢。在一些实施方式中，R5为苯甲基。在一些实施方式中，R5为氨基。在一些实施方式中，R5为甲氨基。在一些实施方式中，R5为肼基。在一些实施方式中，R5为三甲基铵基。在一些实施方式中，R5为吡咯基。在一些实施方式中，R5为氨基上进一步连接由氨基酸或肽的C端碳原子衍生的取代基。在一些实施方式中，R5为乙酰胺基。在一些实施方式中，R5为2-氨基乙酰胺基。在一些实施方式中，R5为3-氨基丙酰胺基。在一些实施方式中，R5为焦谷氨酰氨基。在一些实施方式中，Q5选自由氢、苯甲基、氨基、甲氨基、肼基、三甲基铵基、吡咯基、乙酰胺基、2-氨基乙酰胺基、3-氨基丙酰胺基、和焦谷氨酰氨基，所组成的组。在一些实施方式中，Q5选自由氢、氨基、肼基、三甲基铵基、吡咯基、乙酰胺基、2-氨基乙酰胺基、3-氨基丙酰胺基、和焦谷氨酰氨基所组成的组。在一些实施方式中，Q5选自由氢、苯甲基、氨基、甲氨基、肼基、吡咯基、和乙酰胺基，所组成的组。在一些实施方式中，Q5为氢。在一些实施方式中，Q5为苯甲基。在一些实施方式中，Q5为氨基。在一些实施方式中，Q5为甲氨基。在一些实施方式中，Q5为肼基。在一些实施方式中，Q5为三甲基铵基。在一些实施方式中，Q5为吡咯基。在一些实施方式中，Q5为氨基上进一步连接由氨基酸或肽的C端碳原子衍生的取代基。在一些实施方式中，Q5为乙酰胺基。在一些实施方式中，Q5为2-氨基乙酰胺基。在一些实施方式中，Q5为3-氨基丙酰胺基。在一些实施方式中，Q5为焦谷氨酰氨基。
在一些实施方式中，R6选自由羟基、去质子化羟基、甲氧基、甲氨基、乙氨基、和由氨基酸或肽的N端氮原子衍生的取代基，所组成的组。在一些实施方式中，Q6选自由羟基、去质子化羟基、甲氧基、乙氧基、甲氨基、乙氨基、和由氨基酸或肽的N端氮原子衍生的取代基，所组成的组。所述由氨基酸或肽的N端氮原子衍生的取代基可表示为“-NAAH-Z”，其中NAA为氨基酸或肽的N端氮原子，Z为氨基酸或肽的剩余部分，即Z-NAAH2为完整的氨基酸或肽，特别是为氨基酸、二肽、或三肽。在一些实施方式中，所述的由氨基酸或肽的N端氮原子衍生的取代基，为由氨基酸、二肽、或三肽的N端氮原子衍生的取代基。在一些实施方式中，R6选自由羟基、去质子化羟基、甲氧基、乙氧基、甲氨基、乙氨基、和由氨基酸、二肽、或三肽的N端氮原子衍生的取代基，所组成的组。在一些实施方式中，Q6选自由羟基、去质子化羟基、甲氧基、乙氧基、甲氨基、乙氨基、和由氨基酸、二肽、或三肽的N端氮原子衍生的取代基，所组成的组。在一些实施方式中，所述的由氨基酸或肽的N端氮原子衍生的取代基，选自由N2-赖氨酸基(即L-赖氨酸的N2氮原子衍生的取代基)、和甘氨酸基脯氨酸基(即L-脯氨酰‐L-甘氨酸的N端氮原子衍生的取代基)所组成的组。在一些实施方式中，R6选自由羟基、去质子化羟基、甲氧基、乙氧基、甲氨基、乙氨基、N2-赖氨酸基、和甘氨酸基脯氨酸基所组成的组。在一些实施方式中，R6选自由羟基、甲氧基、甲氨基、和乙氨基所组成的组。在一些实施方式中，R6为羟基。在一些实施方式中，R6为去质子化羟基。在一些实施方式中，R6为甲氧基。在一些实施方式中，R6为乙氧基。在一些实施方式中，R6为甲氨基。在一些实施方式中，R6为乙氨基。在一些实施方式中，R6为由氨基酸或肽的N端氮原子衍生的取代基。在一些实施方式中，R6为N2-赖氨酸基。在一些实施方式中，R6为甘氨酸基脯氨酸基。在一些实施方式中，Q6选自由羟基、去质子化羟基、甲氧基、乙氧基、甲氨基、乙氨基、N2-赖氨酸基、和甘氨酸基脯氨酸基所组成的组。在一些实施方式中，Q6选自由羟基、甲氧基、甲氨基、和乙氨基所组成的组。在一些实施方式中，Q6为羟基。在一些实施方式中，Q6为去质子化羟基。在一些实施方式中，Q6为甲氧基。在一些实施方式中，Q6为乙氧基。在一些实施方式中，Q6为甲氨基。在一些实施方式中，Q6为乙氨基。在一些实施方式中，Q6为由氨基酸或肽的N端氮原子衍生的取代基。在一些实施方式中，Q6为N2-赖氨酸基。在一些实施方式中，Q6为甘氨酸基脯氨酸基。
在一些实施方式中，m和n各自独立地选自由0和1所组成的组。在一些实施方式中，m为1。在一些实施 方式中，m为0。在一些实施方式中，n为1。在一些实施方式中，n为0。在一些实施方式中，m为1，且n为1。在一些实施方式中，m为1，且n为0。在一些实施方式中，m为0，且n为1。在一些实施方式中，m为0，且n为0。
在一些实施方式中，R1和Q1相同。在一些实施方式中，R2和Q2相同。在一些实施方式中，R3和Q3相同。在一些实施方式中，R4和Q4相同。在一些实施方式中，R5和Q5相同。在一些实施方式中，R6和Q6相同。在一些实施方式中，R1和Q1相异。在一些实施方式中，R2和Q2相异。在一些实施方式中，R3和Q3相异。在一些实施方式中，R4和Q4相异。在一些实施方式中，R5和Q5相异。在一些实施方式中，R6和Q6相异。
在一些实施方式中：R4为氢或甲基；R5选自由氢、苯甲基、氨基、甲氨基、肼基、吡咯基、和乙酰胺基所组成的组；R6选自由羟基、甲氧基、甲氨基、和乙氨基所组成的组；且n为1。在一些实施方式中：Q4为氢或甲基；Q5选自由氢、苯甲基、氨基、甲氨基、肼基、吡咯基、和乙酰胺基所组成的组；Q6选自由羟基、甲氧基、甲氨基、和乙氨基所组成的组；且m为1。在一些实施方式中，R4为氢；R5为氨基；且R7为-C(＝O)-R6且R6为羟基。在一些实施方式中，R4为氢；R5为氨基；R7为-C(＝O)-R6；且R6为羟基。在一些实施方式中，R4为氢；R5为3-氨基丙酰胺基；R7为-C(＝O)-R6；且R6为羟基。在一些实施方式中，R4为氢；R5为氨基；且R7为氢。在一些实施方式中，Q4为氢；Q5为氨基；且Q6为羟基。在一些实施方式中，R1为氢或羟基；R2为氢；且R3为氢。在一些实施方式中，Q1为氢或羟基；Q2为氢；且Q3为氢。在一些实施方式中，R7为-C(＝O)-R6，R2和Q2相同，R3和Q3相同，R4和Q4相同，R5和Q5相同，且R6和Q6相同。在一些实施方式中，R4、R5和R7中的至少二个为氢。在一些实施方式中，R4为氢、且R5为氢。在一些实施方式中，R5为氢、且R7为氢。在一些实施方式中，Q4为氢、且Q5为氢。
在本申请中，任意公开或包含式(A)和/或其他结构式中选择任何特定的部分R1、R2、R3、R4、R5、R6、R7、Q1、Q2、Q3、Q4、Q5、和/或Q6，Q1所连接的位置，以及特定的参数m和n所指定的化学结构，应视为还进一步公开或包含该指定的化学结构的立体异构体。在本申请中，特别是在各个实施例中，任意公开或包含任何化学结构，应视为还进一步公开或包含该化学结构的立体异构体。
在本申请中，若任意的一个或更多个手性中心未具体指明其立体化学，则应当视为公开或包含其各种可能的立体异构体及其组合或混合。例如是，若一个手性中心未具体指名其立体化学，则应当视为分别公开或包含该手性中心为(R)-构型的化学结构、和该手性中心为(S)-构型的化学结构，以及其以任意比例的组合，包括外消旋混合物。例如是，若二个手性中心未具体指名其立体化学，则应当视为分别公开或包含二个手性中心分别为(R,R)-构型的化学结构、二个手性中心分别为(S,S)-构型的化学结构、二个手性中心分别为(R,S)-构型的化学结构、和二个手性中心分别为(S,R)-构型的化学结构，以及其以任意比例的组合。
在一些实施方式中，R4、R5和R7为彼此不同的基团，例如是R4和R5为不同基团，且R7为选自由羟甲基和-C(＝O)-R6所组成的组，特别是-C(＝O)-R6。此时，R4、R5和R7所连接的碳为不对称碳(下称“第一不对称碳”)。
作为上述定义的一个具体例子，任意公开或包含包括该第一不对称碳的化学结构，若没有进一步指出该第一不对称碳的构型，则应视为同时还分别公开或包含该第一不对称碳的可能的二种构型。具例来说，任意公开或包含式(A1)部分，若没有进一步指出该第一不对称碳的构型，则应视为同时还分别公开或包含式(A1-R)部分和式(A1-S)部分。在一些实施方式中，在式(A)或式(A1)中，所述第一不对称碳与所述R4的键为所述R4朝向纸面之外的键，且所述第一不对称碳与所述R5的键为所述R5朝向纸面之内的键。此即如式(A1-R)部分所示，其中第一不对称碳以“*”表示。在所述R5连接所述第一不对称碳的原子为氮原子、且R7为选自由羟甲基和-C(＝O)-R6所组成的组的情况下，此时所述第一不对称碳一般为R-构型。D-组氨酸具备此构型。在一些实施方式中，在式(A)或式(A1)中，所述第一不对称碳与所述R4的键为所述R4朝向纸面之内的键，且所述第一不对称碳与所述R5的键为所述R5朝向纸面之外的键。此即如式(A1-S)部分所示，其中第一不对称碳以“*”表示。在所述R5连接所述第一不对称碳的原子为氮原子、且R7为选自由羟甲基和-C(＝O)-R6所组成的组的情况下，此时所述第一不对称碳一般为S-构型。L-组氨酸具备此构型。
在一些实施方式中，Q4和Q5为不同基团。此时，Q4和Q5所连接的碳为不对称碳(下称第二不对称碳)。
作为上述定义的一个具体例子，任意公开或包含包括该第二不对称碳的化学结构，若没有进一步指出该第二不对称碳的构型，则应视为同时还分别公开或包含该第二不对称碳的可能的二种构型。具例来说，任意公开或包含式(A2)部分，若没有进一步指出该第二不对称碳的构型，则应视为同时还分别公开或包含式(A2-R)部分和式(A2-S)部分。在一些实施方式中，在式(A)或式(A2)中，所述第二不对称碳与所述Q4的键为所述Q4朝向纸面之外的键，且所述第二不对称碳与所述Q5的键为所述Q5朝向纸面之内的键。此即如式(A2-R)部分所示，其中第二不对称碳以“*”表示。在所述Q5连接所述第二不对称碳的原子为氮原子的情况下，此时所述第二不对称碳一般为R-构型。D-组氨酸具备此构型。在一些实施方式中，在式(A)或式(A2)中，所述第二不对称碳与所述Q4的键为所述Q4朝向纸面之内的键，且所述第二不对称碳与所述Q5的键为所述Q5朝向纸面之外的键。此即如式(A2-S)部分所示，其中第二不对称碳以“*”表示。在所述Q5连接所述第二不对称碳的原子为氮原子的情况下，此时所述第二不对称碳一般为S-构型。L-组氨酸具备此构型。
在一些实施方式中，所述第一不对称碳为(R)-构型。在一些实施方式中，所述第一不对称碳为(S)-构型。在一些实施方式中，所述第二不对称碳为(R)-构型。在一些实施方式中，所述第二不对称碳为(S)-构型。在一些实施方式中，所述第一不对称碳为(R)-构型，且所述第二不对称碳为(R)-构型。在一些实施方式中，所述第一不对称碳为(R)-构型，且所述第二不对称碳为(S)-构型。在一些实施方式中，所述第一不对称碳为(S)-构型，且所述第二不对称碳为(R)-构型。在一些实施方式中，所述第一不对称碳为(S)-构型，且所述第二不对称碳为(S)-构型。
在一些实施方式中，在式(A)中，所述第一不对称碳与所述R4的键为所述R4朝向纸面之外的键，且所述第一不对称碳与所述R5的键为所述R5朝向纸面之内的键，所述第二不对称碳与所述Q4的键为所述Q4朝向纸面之外的键，且所述第二不对称碳与所述Q5的键为所述Q5朝向纸面之内的键。在一些实施方式中，在式(A)中，所述第一不对称碳与所述R4的键为所述R4朝向纸面之外的键，且所述第一不对称碳与所述R5的键为所述R5朝向纸面之内的键，所述第二不对称碳与所述Q4的键为所述Q4朝向纸面之内的键，且所述第二不对称碳与所述Q5的键为所述Q5朝向纸面之外的键。在一些实施方式中，在式(A)中，所述第一不对称碳与所述R4的键为所述R4朝向纸面之内的键，且所述第一不对称碳与所述R5的键为所述R5朝向纸面之外的键，所述第二不对称碳与所述Q4的键为所述Q4朝向纸面之外的键，且所述第二不对称碳与所述Q5的键为所述Q5朝向纸面之内的键。在一些实施方式中，在式(A)中，所述第一不对称碳与所述R4的键为所述R4朝向纸面之内的键，且所述第一不对称碳与所述R5的键为所述R5朝向纸面之外的键，所述第二不对称碳与所述Q4的键为所述Q4朝向纸面之内的键，且所述第二不对称碳与所述Q5的键为所述Q5朝向纸面之外的键。
在一些实施方式中，R4和R5为不同基团，R7为选自由羟甲基和-C(＝O)-R6所组成的组，且Q4和Q5为不同基团。在一些实施方式中，R4和R5为不同基团，R7为选自由羟甲基和-C(＝O)-R6所组成的组，Q4和Q5为不同基团，所述第一不对称碳为(R)-构型，且所述第二不对称碳为(R)-构型，如式(A-RR)所示。在一些实施方式中，R4和R5为不同基团，R7为选自由羟甲基和-C(＝O)-R6所组成的组，Q4和Q5为不同基团，所述第一不对称碳为(R)-构型，且所述第二不对称碳为(S)-构型，如式(A-RS)所示。在一些实施方式中，R4和R5为不同基团，R7为选自由羟甲基和-C(＝O)-R6所组成的组，Q4和Q5为不同基团，所述第一不对称碳为(S)-构型，且所述第二不对称碳为(R)-构型，如式(A-SR)所示。在一些实施方式中，R4和R5为不同基团，R7为选自由羟甲基和-C(＝O)-R6 所组成的组，Q4和Q5为不同基团，所述第一不对称碳为(S)-构型，且所述第二不对称碳为(S)-构型，如式(A-SS)所示。
在本申请中，任意公开或包含式(A)和/或其他结构式中选择任何特定的部分R1、R2、R3、R4、R5、R6、R7、Q1、Q2、Q3、Q4、Q5、和/或Q6，Q1所连接的位置，以及特定的参数m和n所指定的化学结构，应视为还进一步公开或包含该指定的化学结构的化学上允许的互变异构体。在本申请中，特别是在各个实施例中，任意公开或包含任何化学结构，应视为还进一步公开或包含该化学结构的化学上允许的互变异构体，例如是酮－烯醇互变异构体。
作为上述定义的一个具体例子，任意公开或包含包括“具有双键或位于芳香环上的碳、及其上的羟基或巯基”部分的化学结构，应视为同时还进一步公开或包含对应的互变异构体，即包括“羰基或硫羰基”部分的化学结构。例如是，任意公开或包含包括部分的化学结构，应视为还进一步公开或包含对应的包括部分的互变异构体；任意公开或包含包括部分的化学结构，应视为还进一步公开或包含对应的包括部分的互变异构体。
作为上述定义的一个具体例子，任意公开或包含芳香环中包括部分的化学结构，应视为同时还进一步公开或包含对应的包括部分的互变异构体。例如是，任意公开或包含包括咪唑环部分的化学结构，应视为还进一步公开或包含对应的包括部分的互变异构体。
在本申请中，任意公开或包含组成杂化体的任一共振结构，应视为还进一步公开或包含组成该杂化体的其他所有共振结构、以及该杂化体本身。
作为上述定义的一个具体例子，任意公开或包含芳香环中包括部分的化学结构，应视为同时还进一步公开或包含对应的包括部分的共振化学结构。例如是，任意公开或包含包括咪唑环部分的化学结构，应视为还进一步公开或包含对应的部分的共振化学结构，并进一步进一步公开或包含对应的杂化体(例如表示为)。
在本申请中，任意公开或包含包括质子化咪唑环中N1上的氢形成非共价键例如氢键的化 学结构，应视为同时还进一步公开或包含对应的包括质子化咪唑环中N3上的氢形成非共价键例如氢键的化学结构。在本申请中，任意公开或包含包括质子化组氨酸、质子化组胺、质子化肌胺或类似具有1H-咪唑-4-基或其衍生基团的化合物中Nτ上的氢形成非共价键例如氢键的化学结构，应视为同时还进一步公开或包含对应的包括质子化组氨酸、质子化组胺、质子化肌胺或类似具有1H-咪唑-4-基或其衍生基团的化合物中Nπ上的氢形成非共价键例如氢键的化学结构。
在本申请中，任意公开或包含其中R2为氢的化学结构，除了公开或包含按照式(A)中所示形成非共价键的氢(Nπ-H)形成非共价键的化学结构之外，同时还进一步公开或包含对应的由R2的氢(Nτ-H)形成非共价键的化学结构，反之亦然。应理解的是，R2为氢的式(A)结构与其对应的式(A′)结构可为互变异构体。在本申请中，任意公开或包含R2为氢的式(A)结构，应视为同时还进一步公开或包含式(A′)结构，反之亦然。
与式(A)所示结构类似，对应地，式(A′)结构也包括第一不对称碳和第二不对称碳。
在一些实施方式中，式(A′)结构如式(A′-RR)所示。在一些实施方式中，式(A′)结构如式(A′-RS)所示。在一些实施方式中，式(A′)结构如式(A′-SR)所示。在一些实施方式中，式(A′)结构如式(A′-SS)所示。
在本申请中，任意公开或包含(布朗斯特–劳里)共轭酸碱的其中一个，应视为在化学上合理、且不影响本申请的非共价二聚体阳离子或盐的主要化学结构和技术效果的情况下，还进一步公开或包含其在一定pH值条件下对应存在或为主的共轭酸碱。例如是，在化学上合理、且不影响本申请的非共价二聚体阳离子或盐的主要化学结构和技术效果的情况下，任意公开或包含特定部分或基团为羟基，应视为还进一步公开或包含特定部分或基团为去质子化羟基(-O-)或质子化羟基(-OH2 +)。
本申请的盐
在一方面，本申请提供了一种盐。
在一些实施方式中，本申请的盐包括本申请的非共价二聚体阳离子，特别是包括本申请的非共价二聚体阳离子和第一阴离子。例如，本申请的盐可以以式(B)结构或式(B′)结构表示，其中X为第一阴离子。
通过本申请的第一阴离子，得以使得本申请的阳离子以盐类的形式稳定存在。
在一些实施方式中，第一阴离子(式(B)中X)包括选自由氟离子、氯离子、溴离子、碘离子、硫离子、硝酸根离子、硫酸根离子、亚硫酸根离子、硫代硫酸根离子、过硫酸根离子、硒酸根离子、磷酸根离子、碳酸根离子、六氟磷酸根离子、六氟硅酸根离子、醋酸根离子、磺酸根离子、苯甲酸根离子、和多聚磷酸根离子所组成的组的至少一个或由其组成。在一些实施方式中，第一阴离子包括选自由六氟磷酸根离子、六氟硅酸根离子、氯离子、和硫酸根离子所组成的组的至少一个或由其组成。在一些实施方式中，第一阴离子为氟离子。在一些实施方式中，第一阴离子为氯离子。在一些实施方式中，第一阴离子为溴离子。在一些实施方式中，第一阴离子为碘离子。在一些实施方式中，第一阴离子为硫离子。在一些实施方式中，第一阴离子为硝酸根离子。在一些实施方式中，第一阴离子为硫酸根离子。在一些实施方式中，第一阴离子为亚硫酸根离子。在一些实施方式中，第一阴离子为硫代硫酸根离子。在一些实施方式中，第一阴离子为过硫酸根离子。在一些实施方式中，第一阴离子为硒酸根离子。在一些实施方式中，第一阴离子为磷酸根离子。在一些实施方式中，第一阴离子为碳酸根离子。在一些实施方式中，第一阴离子为六氟磷酸根离子。在一些实施方式中，第一阴离子为六氟硅酸根离子。在一些实施方式中，第一阴离子为醋酸根离子。在一些实施方式中，第一阴离子为磺酸根离子，例如是氨基磺酸根离子。在一些实施方式中，第一阴离子为苯甲酸根离子。在一些实施方式中，第一阴离子为多聚磷酸根离子。
参数k的值根据本申请的非共价二聚体阳离子和第一阴离子的价数而得到。在本申请的非共价二聚体阳离子为带一价正电的情况下，参数k的值等于第一阴离子的价数。在一些实施方式中，k为1。在一些实施方式中，k为2。在一些实施方式中，k为3。
本申请的非共价二聚体阳离子或本申请的盐的制备方法
在一些实施方式中，包括本申请的非共价二聚体阳离子的盐，即本申请的盐，的制备方法，可包括以下所述步骤。
第一反应物的成盐
将第一反应物接触第一酸。然后得到第一反应物第一酸盐。在一些实施方式中，所述的第一反应物第一酸盐包括第一反应物与第一酸，和/或质子化的第一反应物与第一酸的共轭碱(第一酸共轭碱)，或由其组成。
在一些实施方式中，所述第一反应物包括式(C)化合物或基本上由其组成、特别是由其组成。在一些实施方式中，所述第一反应物第一酸盐包括式(C1)所示的盐或基本上由其组成、特别是由其组成，其中A为第一酸共轭碱，a为第一酸共轭碱的价数，p为HaA的当量数。式(C)或式(C1)中的R1、R2、R3、R4、R5、R6、R7和n，可与所要得到的本申请的实施例的阳离子(式(A))和盐(式(B))的对应部分或参数一致。
在一些实施方式中，所述的将第一反应物接触第一酸是在第一溶剂的存在下，特别是在第一溶剂中。在一些实施方式中，第一酸为选自由硝酸、磷酸、硫酸、氢氟酸、盐酸、氢溴酸和氢碘酸组成的组中的至少一个，特别是盐酸，即第一酸共轭碱(式(C1)中A)为由硝酸根离子、磷酸根离子、磷酸氢根离子、磷酸二氢根离子、硫酸根离子、硫酸氢根离子、氟离子、氯离子、溴离子和碘离子所组成的组中的至少一个，特别是氯离子。在一些实施方式中，第一溶剂为水。在式(C1)中，参数p和a是对应第一酸的种类得到。例如，在一些实施方式中，第一酸为盐酸，且p为1。
在本文中，术语“共轭酸”，在没有进一步限定时，包括意指该术语所针对的化合物的布朗斯特–劳里共轭酸，且不仅包括该化合物获得一个质子所得到的第一共轭酸，在化学上允许的情况下还包括该化合物进一步获得更多质子所获得的酸，例如是这些第一共轭酸进一步获得一个质子所得到的第二共轭酸、这些第二共轭酸更进一步获得一个质子所得到的第三共轭酸等等。在本文中，术语“共轭碱”，在没有进一步限定时，包括意指该术语所针对的化合物的布朗斯特–劳里共轭碱，且不仅包括该化合物失去一个质子所得到的第一共轭碱，在化学上允许的情况下还包括该化合物进一步失去更多质子所获得的碱，例如是这些第一共轭碱进一步失去一个质子所得到的第二共轭碱、这些第二共轭碱更进一步失去一个质子所得到的第三共轭碱等等。举例来说，本文中所述的硫酸的共轭碱，在没有进一步限定时，应视为不仅包括硫酸氢根离子，还包括硫酸根离子。举例来说，本文中所述的磷酸的共轭碱，在没有进一步限定时，应视为不仅包括磷酸氢根离子，还包括磷酸二氢根离子和磷酸根离子。
在一些实施方式中，第一酸相对第一反应物为过量。在一些实施方式中，第一反应物和第一酸的摩尔比为1∶2至1∶10，特别是1∶2.5至1∶8，更特别是1∶4至1∶6，更特别是约1∶5。
在一些实施方式中，第一酸在第一溶剂中的浓度为1M以上。在一些实施方式中，第一酸在第一溶剂中的浓度为1M至5M。在一些实施方式中，第一酸在第一溶剂中的浓度为约2M。
在一些实施方式中，所述的将第一反应物接触第一酸是在第一温度下。在一些实施方式中，所述第一温度为0℃至70℃。在一些实施方式中，所述第一温度为10℃至40℃，更特别是20℃至30℃，更特别是约25℃。在一些实施方式中，所述第一温度为20℃至50℃，更特别是30℃至40℃，更特别是约37℃。在一些实施方式中，所述第一温度为0℃至20℃，更特别是0℃至10℃，更特别是约4℃。在一些实施方式中，所述第一温度为40℃至70℃，更特别是50℃至60℃，更特别是约60℃。
在一些实施方式中，在第一反应物接触第一酸后，还包括加热重结晶得到第一反应物第一酸盐。在一些实施方式中，所述加热的温度为70℃至100℃，特别是80℃至90℃，更特别是约85℃。
第一反应物第一酸盐的质子化
在第一酸性环境下，将第一反应物第一酸盐接触包括第一阴离子，特别是由第一阳离子和第一阴离子组成，的第一盐。然后得到包括质子化第一反应物第一酸盐阳离子、和第一阴离子，如式(C2)所示，的第一溶液。
式(C2)中的X和k，可与所要得到的本申请的实施例的盐(式(B))的对应部分或参数一致。
在一些实施方式中，第一盐选自由氟化铵、氯化铵、溴化铵、碘化铵、硫化铵、硝酸铵、硫酸铵、亚硫酸铵、硫代硫酸铵、过硫酸铵、硒酸铵、磷酸铵、碳酸铵、六氟磷酸铵、六氟硅酸铵、醋酸铵、各种磺酸铵、苯甲酸铵、和多聚磷酸铵所组成的组的至少一个或由其组成。在一些实施方式中，第一盐选自由六氟磷酸铵、六氟硅酸铵、氯化铵、和硫酸铵所组成的组的至少一个或由其组成。在一些实施方式中，第一盐为氟化铵。在一些实施方式中，第一盐为氯化铵。在一些实施方式中，第一盐为溴化铵。在一些实施方式中，第一盐为 碘化铵。在一些实施方式中，第一盐为硫化铵。在一些实施方式中，第一盐为硝酸铵。在一些实施方式中，第一盐为硫酸铵。在一些实施方式中，第一盐为亚硫酸铵。在一些实施方式中，第一盐为硫代硫酸铵。在一些实施方式中，第一盐为过硫酸铵。在一些实施方式中，第一盐为硒酸铵。在一些实施方式中，第一盐为磷酸铵。在一些实施方式中，第一盐为碳酸铵。在一些实施方式中，第一盐为六氟磷酸铵。在一些实施方式中，第一盐为六氟硅酸铵。在一些实施方式中，第一盐为醋酸铵。在一些实施方式中，第一盐为各种磺酸铵，例如是氨基磺酸铵。在一些实施方式中，第一盐为苯甲酸铵。在一些实施方式中，第一盐为多聚磷酸铵。
在一些实施方式中，所述的将第一反应物第一酸盐接触第一盐，是在第二溶剂的存在下，特别是在第二溶剂中。在一些实施方式中，第二溶剂为水。在一些实施方式中，第一阳离子为铵离子。此处铵离子作为第一阳离子，可以作为供氢体。
在一些实施方式中，第一盐相对第一反应物第一酸盐为过量。在一些实施方式中，第一反应物第一酸盐和第一盐的摩尔比为1∶2至1∶10，特别是1∶2.5至1∶8，更特别是1∶4至1∶6，更特别是约1∶5。
在一些实施方式中，第一溶液还包括第一酸共轭碱。在一些实施方式中，第一溶液还包括第一阳离子。在一些实施方式中，第一溶液还包括第二溶剂。在一些实施方式中，第一溶液实质上由、特别是由质子化第一反应物第一酸盐阳离子、第一阳离子、第一阴离子、第一酸共轭碱、和第二溶剂组成。
在一些实施方式中，所述的将第一反应物第一酸盐接触第一盐，是在第二温度下。在一些实施方式中，所述第二温度为0℃至70℃。在一些实施方式中，所述第二温度为10℃至40℃，更特别是20℃至30℃，更特别是约25℃。在一些实施方式中，所述第二温度为20℃至50℃，更特别是30℃至40℃，更特别是约37℃。在一些实施方式中，所述第二温度为0℃至20℃，更特别是0℃至10℃，更特别是约4℃。在一些实施方式中，所述第二温度为40℃至70℃，更特别是50℃至60℃，更特别是约60℃。在一些实施方式中，所述第一温度和所述第二温度相等。
在一些实施方式中，所述第一酸性环境为pH值小于或等于6。在一些实施方式中，所述第一酸性环境为pH值为4至6，特别是4.5至5.5，特别是4.8至5.2，特别是4.9至5.1，更特别是约5。一般来说，对于酸性更弱、或说碱性更强的第一阴离子，选用pH值较低的第一酸性环境。在一些实施方式中，第一阴离子为六氟磷酸根离子，且所述第一酸性环境为pH值为4至6，特别是4.5至5.5，特别是4.8至5.2，特别是4.9至5.1，更特别是约5。
在一些实施方式中，所述第一酸性环境为通过让第一盐在第二溶剂中所得到。在一些实施方式中，所述第一酸性环境为让第一盐、和由第一阴离子和氢离子组成的酸，在第二溶剂中所得到。
非共价键的形成
在第二酸性环境下，将第二反应物加入第一溶液，特别是接触第一溶液中的质子化第一反应物阳离子。然后形成键，得到包括本申请实施例阳离子第一酸盐阳离子、和第一阴离子，如式(B1)结构或式(B1′)结构所示，的第二溶液。
在一些实施方式中，所述第二反应物包括式(D)化合物或基本上由其组成、特别是由其组成，其中Q1、Q2、Q3、Q4、Q5、Q6，Q1所连接的位置，以及m可以和所要得到的本申请的实施例的阳离子(式(A))和盐 (式(B))一致。
在一些实施方式中，第二反应物相对质子化第一反应物阳离子为过量。在一些实施方式中，质子化第一反应物阳离子和第二反应物的摩尔比为1∶1至1∶2，例如是约1∶1.0、约1∶1.1、约1∶1.2、约1∶1.3、约1∶1.4、约1∶1.5、约1∶1.6、约1∶1.7、约1∶1.8、约1∶1.9、或约1∶2.0。
在一些实施方式中，第一溶液还包括第一酸共轭碱。在一些实施方式中，第一溶液还包括第一阳离子。在一些实施方式中，第一溶液还包括第二溶剂。在一些实施方式中，第一溶液实质上由、特别是由质子化第一反应物第一酸盐阳离子、第一阳离子、第一阴离子、第一酸共轭碱、和第二溶剂组成。
在一些实施方式中，所述的将第二反应物加入第一溶液，是在第三温度下。在一些实施方式中，所述第三温度为0℃至70℃。在一些实施方式中，所述第三温度为10℃至40℃，更特别是20℃至30℃，更特别是约25℃。在一些实施方式中，所述第三温度为20℃至50℃，更特别是30℃至40℃，更特别是约37℃。在一些实施方式中，所述第三温度为0℃至20℃，更特别是0℃至10℃，更特别是约4℃。在一些实施方式中，所述第三温度为40℃至70℃，更特别是50℃至60℃，更特别是约60℃。在一些实施方式中，所述第一温度和所述第三温度相等。在一些实施方式中，所述第二温度和所述第三温度相等。在一些实施方式中，所述第一温度、所述第二温度、和所述第三温度相等。
在一些实施方式中，所述第二酸性环境为pH值小于或等于6。在一些实施方式中，所述第二酸性环境为pH值为4至6，特别是4.5至5.5，特别是4.8至5.2，特别是4.9至5.1，更特别是约5。一般来说，对于酸性更弱、或说碱性更强的第一阴离子，选用pH值较低的第二酸性环境。在一些实施方式中，第一阴离子为六氟磷酸根离子，且所述第二酸性环境为pH值为4至6，特别是4.5至5.5，特别是4.8至5.2，特别是4.9至5.1，更特别是约5。在一些实施方式中，所述第一酸性环境和所述第二酸性环境的pH值相同。
在一些实施方式中，所述第二酸性环境为通过让第一盐在第二溶剂中所得到。在一些实施方式中，所述第二酸性环境为让第一盐、和由第一阴离子和氢离子组成的酸，在第二溶剂中所得到。在一些实施方式中，还包括将还原剂加入第一溶液中，特别是在所述的第二反应物加入第一溶液之前、之后或同时，将还原剂加入第一溶液中。即，在一些实施方式中，所述第二酸性环境为还原性，特别是强还原性。由于本申请的非共价二具体阳离子具有强还原力，因此，加入还原剂有助于降低本申请的非共价二具体阳离子在反应中被氧化的比例，有利于提高本申请的盐的产率。在一些实施方式中，所述的还原剂包括选自由维生素C、维生素E和其衍生物组成的组的至少一种或多种。
在一些实施方式中，还包括对第二溶液纯化以得到包括本申请实施例阳离子第一酸盐阳离子、和第一阴离子的第一中间产物。在一些实施方式中，所述纯化包括透析。在一些实施方式中，所述透析可为通过截留分子量(MWCO)50Da至500Da，特别是约100Da或200Da的膜进行透析。
本申请的盐的形成
将第一碱加入所述第二溶液中或接触所述第一中间产物，以除去第二溶液或第一中间产物中的第一酸(式(B1)中HaA)。然后得到本申请的盐。
在一些实施方式中，本申请的盐，包括本申请的非共价二聚体阳离子，以及第一阴离子。例如是，本申请的盐可以以式(B)表示。
在一些实施方式中，第一碱包括选自由氨水、氢氧化钠、氢氧化钾、和三乙醇胺所组成的组的至少一个，或由其组成，但不限于此。本领域技术人员应当理解，任何可以在此调整pH值至碱性、且不会发生进一步的氧化还原反应的碱，都可以作为此处的第一碱。在一些实施方式中，第一碱为氨水，特别是稀氨水。在一些 实施方式中，第一碱为氢氧化钠。在一些实施方式中，第一碱为氢氧化钾。在一些实施方式中，第一碱为三乙醇胺。
在一些实施方式中，所述的将第一碱加入所述第二溶液中或接触所述第一中间产物，是将第二溶液或包括第一中间产物的溶液的pH值调整为碱性。在一些实施方式中，所述碱性为pH值为8以上，特别是pH值为8至10，特别是8.5至9.5，特别是8.8至9.2，更特别是约9。
在一些实施方式中，所述的使第一中间产物接触第一碱，是在水中使第一中间产物接触第一碱。
在一些实施方式中，在所述的在第二溶液中加入第一碱之后，还包括纯化以得到本申请的盐。在一些实施方式中，所述纯化包括透析。在一些实施方式中，所述透析可为通过截留分子量(MWCO)50Da至500Da，特别是约100Da或200Da的膜进行透析。在一些实施方式中，所述纯化包括过滤。
本申请的非共价二聚体阳离子或本申请的盐的用途
在一些实施方式中，提供了本申请的阳离子或盐的促进细胞修复的用途。在一些实施方式中，提供了本申请的阳离子或盐在制备促进细胞修复的药物的用途。在一些实施方式中，提供了一种促进细胞修复的方法，包括施用本申请的阳离子或盐。在一些实施方式中，提供了本申请的阳离子或盐用于促进细胞修复。
在一些实施方式中，提供了本申请的阳离子或盐的抗氧化用途。在一些实施方式中，提供了本申请的阳离子或盐在制备抗氧化剂的用途。在一些实施方式中，提供了一种抗氧化方法，包括施用本申请的阳离子或盐。在一些实施方式中，提供了本申请的阳离子或盐用于抗氧化。在一些实施方式中，所述抗氧化剂为抑制、减少或逆转人类或动物细胞的氧化应激的药物。在一些实施方式中，所述抗氧化剂为抑制、减少或清除人类或动物体内的氧自由基的药物。
在一些实施方式中，提供了本申请的阳离子或盐，在抑制、减少或清除人类或动物体内的氧自由基的用途。在一些实施方式中，提供了本申请的阳离子或盐在制备抑制、减少或清除人类或动物体内的氧自由基的药物的用途。在一些实施方式中，提供了抑制、减少或清除人类或动物体内的氧自由基的方法，包括施用本申请的阳离子或盐，特别是施用到所述的人类或动物细胞。在一些实施方式中，提供了本申请的阳离子或盐用于抑制、减少或清除人类或动物体内的氧自由基。
在一些实施方式中，提供了本申请的阳离子或盐在治疗与氧自由基相关联的疾病或症状的用途。在一些实施方式中，提供了本申请的阳离子或盐在制备治疗与氧自由基相关联的疾病或症状的药物的用途。在一些实施方式中，提供了治疗与氧自由基相关联的疾病或症状的方法，包括施用本申请的阳离子或盐，特别是施用到患有所述与氧自由基相关联的疾病或症状的患者。在一些实施方式中，提供了本申请的阳离子或盐用于治疗与氧自由基相关联的疾病或症状。
在一些实施方式中，所述促进细胞修复包括但不限于治疗衰老、炎症、超重、肥胖、癌症、肿瘤、肝病、神经退行性疾病(例如帕金森病或阿尔兹海默症)、动脉高血压、动脉粥样硬化、心血管疾病、糖尿病、高胆固醇血症、慢性疲劳综合征、缺血再灌注损伤、神经退行性疾病、紫外线引发的损伤、或酒精引发的损伤。在一些实施方式中，所述促进细胞修复为治疗黏膜损伤，特别是胃黏膜损伤。在一些实施方式中，所述促进细胞修复为治疗酒精引发的损伤，特别是包括酒精引发的胃黏膜损伤。
在一些实施方式中，所述与氧自由基相关联的疾病或症状，包括但不限于：衰老、炎症、超重、肥胖、癌症、肿瘤、肝病、神经退行性疾病(例如帕金森病或阿尔兹海默症)、动脉高血压、动脉粥样硬化、心血管疾病、糖尿病、高胆固醇血症、慢性疲劳综合征、缺血再灌注损伤、神经退行性疾病、紫外线引发的损伤、或酒精引发的损伤。在一些实施方式中，所述与氧自由基相关联的疾病或症状为胃黏膜损伤。在一些实施方式中，所述与氧自由基相关联的疾病或症状为酒精引发的损伤，特别是包括酒精引发的胃黏膜损伤。
在一些实施方式中，所述与氧自由基相关联的疾病或症状为神经退行性疾病。在一些实施方式中，所述神经退行性疾病为帕金森病或阿尔兹海默症。在一些实施方式中，所述神经退行性疾病为帕金森病。在一些实施方式中，所述神经退行性疾病为阿尔兹海默症。在一些实施方式中，所述神经退行性疾病包括与2-苯基 -4,5-二氢-4,4,5,5-四甲基-1H-咪唑基-1-氧基-3-氧化物的增加、6-羟基多巴胺的增加、和/或β淀粉样蛋白的增加相关连的疾病。在一些实施方式中，所述神经退行性疾病包括与2-苯基-4,5-二氢-4,4,5,5-四甲基-1H-咪唑基-1-氧基-3-氧化物的增加相关连的疾病。在一些实施方式中，所述神经退行性疾病包括与6-羟基多巴胺的增加相关连的疾病。在一些实施方式中，所述神经退行性疾病包括与β淀粉样蛋白的增加相关连的疾病。
在一些实施方式中，本申请的阳离子或盐可以有效作用于细胞中的促修复信号通路，可以增强细胞自我修复功能，使之有能力进行自我修复，从而从细胞功能上预防、治疗或缓解由于细胞修复能力变弱而易患的疾病，如帕金森病、阿尔兹海默症等神经退行性疾病。
在一些实施方式中，提供了本申请的阳离子或盐，在促进细胞增殖中的用途。在一些实施方式中，提供了本申请的阳离子或盐在制备促进细胞增殖的药物的用途。在一些实施方式中，提供了一种促进细胞增殖的方法，包括施用本申请的阳离子或盐。在一些实施方式中，提供了本申请的阳离子或盐用于促进细胞增殖。在一些实施方式中，所述细胞为位于皮肤的细胞。在一些实施方式中，所述细胞为皮肤细胞。在一些实施方式中，所述细胞选自由表皮成纤维细胞、角质形成细胞、血管内皮细胞、和神经细胞所组成的组。在一些实施方式中，所述细胞为表皮成纤维细胞。在一些实施方式中，所述细胞为角质形成细胞。在一些实施方式中，所述细胞为血管内皮细胞。在一些实施方式中，所述细胞为神经细胞，特别是皮肤的神经细胞。在一些实施方式中，所述细胞属于上皮组织。在一些实施方式中，所述细胞属于结缔组织。在一些实施方式中，所述细胞属于肌肉组织。在一些实施方式中，所述细胞属于神经组织。
在一些实施方式中，提供了本申请的阳离子或盐，在治疗、缓解或修复创伤中的用途。在一些实施方式中，提供了本申请的阳离子或盐在制备用于治疗、缓解或修复创伤的药物的用途。在一些实施方式中，提供了一种治疗、缓解或修复创伤的方法，包括施用本申请的阳离子或盐。在一些实施方式中，提供了本申请的阳离子或盐用于治疗、缓解或修复创伤。在一些实施方式中，所述创伤包括皮肤创伤。
在一些实施方式中，本申请的阳离子或盐可以激活生物体细胞中促进细胞增殖的信号通路，使得多种细胞可以在受调控的前提下，加速细胞增殖活动，进而促进创伤的愈合修复，改善创伤修复效果。在一些实施方式中，本申请的阳离子或盐可以改善、治疗与细胞增殖能力不足的疾病，或加速创伤愈合过程。
实施例
在以下实施例中，若其中的化合物，包括第一反应物、第二反应物、该实施例的阳离子、或该实施例的盐，具有手性但未明确指定手性，则该化合物可以是手性混合物，例如是外消旋化合物。
实施例1
实施例1的盐，具体如式(1)或式(1′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
制备方法
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
本实施例的第一反应物盐酸盐为白色晶体，产量为约0.8g，产率约80％。
本实施例的盐产量为约1.6g，产率约85％。
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C17H22N5O4)+的m/z＝360.4。
实施例2
实施例2的盐，具体如式(2)或式(2′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝2、且X为六氟硅酸根离子。
制备方法
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟硅酸铵，即第一阴离子为六氟硅酸根离子。
在37℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在37℃继续搅拌12小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在37℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌36小时，得到包括本实施例的阳离子的第二水溶液。在第二水溶液中加入1M氢氧化钠溶液，将其pH值调节至9。以截留分子量为200Da的透析袋充分透析。干燥后得到产物，即本实施例的盐。
产物或中间产物的检测
本实施例的第一反应物盐酸盐为白色晶体，产量为约0.8g，产率约80％。
本实施例的盐产量为约1.2g，产率约63％。
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C17H22N5O4)+的m/z＝360.4。
实施例3
实施例3的盐，具体如式(3)或式(3′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为氯离子。
制备方法
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为氯化铵，即第一阴离子为氯离子。
在60℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入2g的本实施例的第一盐，在60℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在60℃下将0.65g的第二反应物投入第一水溶液中，温和搅拌48小时，得到包括本实施例的阳离子的第二水溶液。在第二水溶液中加入1M氢氧化钠溶液，将其pH值调节至9。以截留分子量为200Da的透析袋充分透析。干燥后得到产物，即本实施例的盐。
产物或中间产物的检测
本实施例的第一反应物盐酸盐为白色晶体，产量为约0.8g，产率约80％。
本实施例的盐产量为约0.6g，产率约32％。
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C17H22N5O4)+的m/z＝360.4。
实施例4
实施例4的盐，具体如式(4)或式(4′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为位于吲哚部分5号位的羟基、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
制备方法
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(5-羟基-1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在4℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入2g的本实施例的第一盐，在4℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在4℃下将1.5g的第二反应物投入第一水溶液中，温和搅拌48小时，得到包括本实施例的阳离子的第二水溶液。在第二水溶液中加入1M氢氧化钠溶液，将其pH值调节至9。以截留分子量为200Da的透析袋充分透析。干燥后得到产物，即本实施例的盐。
产物或中间产物的检测
本实施例的第一反应物盐酸盐为白色晶体，产量为约0.8g，产率约80％。
本实施例的盐产量为约1.6g，产率约64％。
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C17H22N5O5)+的m/z＝376.3。
实施例5
实施例5的盐，具体如式(5)或式(5′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为位于吲哚部分5号位的氨基、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝2、且X为硫酸根离子。
制备方法
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(5-氨基-1H-吲哚-3-基)丙酸；且
-第一盐为硫酸铵，即第一阴离子为硫酸根离子。
在4℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入3g的本实施例的第一盐，在4℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在4℃下将1.5g的第二反应物投入第一水溶液中，温和搅拌48小时，得到包括本实施例的阳离子的第二水溶液。在第二水溶液中加入1M氢氧化钠溶液，将其pH值调节至9。以截留分子量为200Da的透析袋充分透析。干燥后得到产物，即本实施例的盐。
产物或中间产物的检测
本实施例的第一反应物盐酸盐为白色晶体，产量为约0.8g，产率约80％。
本实施例的盐产量为约1.6g，产率约64％。
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C17H23N6O4)+的m/z＝375.2。
实施例6
实施例6的盐，具体如式(6)或式(6′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为位于吲哚部分4号位的甲基、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(4-氨基-1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C18H24N5O4)+的m/z＝374.2。
实施例7
实施例7的盐，具体如式(7)或式(7′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为位于吲哚部分5号位的氰基、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、 n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(5-氰基-1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C18H21N6O4)+的m/z＝385.1。
实施例8
实施例8的盐，具体如式(8)或式(8′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为位于吲哚部分5号位的氯、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(5-氯-1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C17H21N5O4Cl)+的m/z＝394.9。
实施例9
实施例9的盐，具体如式(9)或式(9′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为位于吲哚部分6号位的羧基、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(6-羧基-1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C18H22N5O6)+的m/z＝404.1。
实施例10
实施例10的盐，具体如式(10)或式(10′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为甲基、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1-甲基-1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C18H24N5O4)+的m/z＝374.2。
实施例11
实施例11的盐，具体如式(11)或式(11′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为甲基、Q5为氢、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-甲基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐， 在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C18H23N4O4)+的m/z＝359.3。
实施例12
实施例12的盐，具体如式(12)或式(12′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为甲氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-甲氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C18H24N5O4)+的m/z＝374.3。
实施例13
实施例13的盐，具体如式(13)或式(13′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为乙酰胺基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-乙酰胺基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C19H24N5O5)+的m/z＝402.2。
实施例14
实施例14的盐，具体如式(14)或式(14′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为吡咯基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-(1H-吡咯-1-基)-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分 钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C21H24N5O4)+的m/z＝410.1。
实施例15
实施例15的盐，具体如式(15)或式(15′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为苯甲基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-苯甲基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C24H27N4O4)+的m/z＝429.1。
实施例16
实施例16的盐，具体如式(16)或式(16′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为甲氧基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸甲酯；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C18H24N5O4)+的m/z＝374.3。
实施例17
实施例17的盐，具体如式(17)或式(17′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为乙氨基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酰乙胺；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐， 在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C19H27O3N6)+的m/z＝387.2。
实施例18
实施例18的盐，具体如式(18)或式(18′)所示。即，R1为羟基、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(2-羟基-1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C17H22O5N5)+的m/z＝376.2。
实施例19
实施例19的盐，具体如式(19)或式(19′)所示。即，R1为巯基、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(2-巯基-1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C17H22O4N5S)+的m/z＝392.1。
实施例20
实施例20的盐，具体如式(20)或式(20′)所示。即，R1为氨基、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(2-氨基-1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐， 在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C17H23O4N6)+的m/z＝375.2。
实施例21
实施例21的盐，具体如式(21)或式(21′)所示。即，R1为甲基、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(2-甲基-1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C18H22O4N6)+的m/z＝374.2。
实施例22
实施例22的盐，具体如式(22)或式(22′)所示。即，R1为苯基、R2为氢、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(2-苯基-1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C23H26O4N5)+的m/z＝436.2。
实施例23
实施例23的盐，具体如式(23)所示。即，R1为氢、R2为甲基、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1-甲基-1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C18H24O4N5)+的m/z＝374.2。
实施例24
实施例24的盐，具体如式(24)所示。即，R1为氢、R2为苯基、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1-苯基-1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C23H26O4N5)+的m/z＝436.2。
实施例25
实施例25的盐，具体如式(25)所示。即，R1为氢、R2为三苯基甲基、R3为氢、R4为氢、R5为氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1-三苯基甲基-1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C36H36O4N5)+的m/z＝602.3。
实施例26
实施例26的盐，具体如式(26)或式(26′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氢、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C17H21O4N4)+的m/z＝345.2。
实施例27
实施例27的盐，具体如式(27)或式(27′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为甲氨基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-甲氨基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C18H24O4N5)+的m/z＝374.2。
实施例28
实施例28的盐，具体如式(28)或式(28′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为乙酰胺基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-乙酰胺基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C19H24O5N5)+的m/z＝402.2。
实施例29
实施例29的盐，具体如式(29)或式(29′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为肼基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-肼基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐， 在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C17H23O4N6)+的m/z＝375.2。
实施例30
实施例30的盐，具体如式(30)或式(30′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为吡咯基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-(1H-吡咯-1-基)-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C21H24O4N5)+的m/z＝410.2。
实施例31
实施例31的盐，具体如式(31)或式(31′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为苯甲基、R6为羟基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-苯甲基-3-(1H-咪唑-4-基)丙酸；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C24H27O4N4)+的m/z＝435.2。
实施例32
实施例32的盐，具体如式(32)或式(32′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为甲氨基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酰甲胺；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐， 在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C18H25O3N6)+的m/z＝373.2。
实施例33
实施例33的盐，具体如式(33)或式(33′)所示。即，R1为氢、R2为氢、R3为氢、R4为氢、R5为氨基、R6为甲氧基、R7为-C(＝O)-R6、Q1为氢、Q2为氢、Q3为氢、Q4为氢、Q5为氨基、Q6为羟基、n＝1、m＝1、k＝1、且X为六氟磷酸根离子。
本实施例的盐的制备方法如下。其中：
-第一反应物为2-氨基-3-(1H-咪唑-4-基)丙酸甲酯；
-第二反应物为2-氨基-3-(1H-吲哚-3-基)丙酸；且
-第一盐为六氟磷酸铵，即第一阴离子为六氟磷酸根离子。
在25℃下，将1g的第一反应物置于10mL的2M盐酸中，剧烈搅拌直至完全溶解。加热至85℃保温30分钟，减压浓缩至2mL。冷却后有结晶析出，将结晶以乙醇溶液洗涤3次，干燥可得第一反应物盐酸盐。
将0.8g的第一反应物盐酸盐置于10mL超纯水中，剧烈搅拌至完全溶解，加入4g的本实施例的第一盐，在25℃继续搅拌6小时，得到包括质子化第一反应物盐酸盐阳离子和第一阴离子的第一水溶液。
在25℃下将0.89g的第二反应物投入第一水溶液中，温和搅拌24小时，得到包括本实施例的阳离子的第二水溶液，截留分子量为200Da的透析袋充分透析，干燥后得到第一中间产物。将第一中间产物溶于10mL超纯水中，加入稀氨水将pH值调节至9析出大量米色沈淀，过滤并将滤饼水洗二遍，干燥得到产物即本实施例的盐。
产物或中间产物的检测
将本实施例的盐进行高分辨率质谱检测，得到本实施例的阳离子，(C18H24O4N5)+的m/z＝374.2。
细胞修复相关实验
PTIO模型氧自由基清除实验
以实施例1、4、和18的盐作为实验组化合物，组氨酸+色氨酸摩尔比1∶1混合物作为对照组化合物。每种化合物都进行终浓度0.025mg/mL、0.05mg/mL、0.1mg/mL、0.2mg/mL、0.4mg/mL、0.8mg/mL的组别。
将20μL的各模型组或对照组化合物加入80μL的0.1mg/mL的PTIO水溶液中，得到PTIO终浓度0.08mg/mL、各实验组或对照组化合物上述终浓度的水溶液。37℃震荡1小时后，测定560nm波长处吸光度 以测定剩余PTIO含量。
结果如图1和表1。横轴为实验组或对照组化合物浓度，而纵轴为归一化剩余PTIO含量浓度比值，以PTIO的初始浓度含量为100％。如图1所示，本申请的非共价二聚体阳离子，相较于组氨酸与色氨酸单体，至少在0.2mg/mL即可更有效地清除以PTIO为代表的氧自由基，且其清除的效率至少是组氨酸与色氨酸单体的3–4倍；且随着其浓度增加，清除氧自由基的效果也就随之增加。
表1 PTIO模型氧自由基清除实验结果
乙醇的胃黏膜上皮细胞的损伤模型
长期酗酒者由于长期酒精损伤，易导致胃黏膜损伤。本实验通过乙醇在细胞水平建立胃黏膜上皮细胞损伤模型，并加入本申请的盐或其他对照组化合物，将得到本申请的非共价二聚体阳离子在胃黏膜上皮细胞损伤模型中体现的技术效果。
以实施例1、4、和18的盐作为实验组化合物，甘草次酸作为对照组化合物。并设置空白对照组(不加入乙醇)以及模型组(加入乙醇，但不加入实施例的盐或甘草次酸)。
将GES-1人胃黏膜上皮细胞均匀接种至96孔板中，每孔约5000个细胞。使用RPMI 1640完全培养基培养细胞6小時。待细胞完全贴壁后，撤去全部培养基，并向各孔中将细胞在加入含7％乙醇(空白组不含)的RPMI 1640无血清培养基100μL细胞培养液中孵育培养12小时。细胞与乙醇孵育12小时后，细胞活力显著降低到约60％。
然后再次撤去全部培养基，并按照组别向各孔中加入含0.025mg/mL、0.05mg/mL、0.1mg/mL、0.2mg/mL、0.4mg/mL、0.8mg/mL的各实验组或对照组化合物(空白组和模型组不含)加入到细胞培养液中的RPMI 1640无血清培养基100μL，培养24小时。
然后检测细胞活性。模型组的结果显示，细胞经过含四氯化碳的培养基培养12小时，细胞活力显著降低到约60％。实验组与对照组的结果如图2和表2所示；可以看到，在细胞培养液中加入本申请的盐后，细胞活力随浓度的增加而升高，且本申请的盐的组别的细胞活力明显较甘草次酸的对照组更高。
表2乙醇的胃黏膜上皮细胞的损伤模型的细胞活力
神经退行性疾病——帕金森病模型
6-羟基多巴胺(6-OHDA)可以被神经细胞摄取，引起神经细胞代谢紊乱进而在体外诱发帕金森病模型。故本实验通过6-OHDA在细胞水平建立帕金森细胞模型，并加入本申请的盐或其他对照组化合物，将得到本申请的非共价二聚体阳离子在帕金森病细胞模型中体现的技术效果。
以实施例1、4、和18的盐作为实验组化合物，司来吉兰作为对照组化合物。并设置空白对照组(不加入6-OHDA)以及模型组(加入6-OHDA，但不加入实施例的盐或司来吉兰)。
将SH-SY5Y人神经母细胞瘤细胞均匀接种至96孔板中，每孔约5000个细胞。使用DMEM/F12完全培养基培养细胞6小時。待细胞完全贴壁后，撤去全部培养基，并向各孔中将细胞在加入含150μmol/L的6-OHDA(空白组不含)的DMEM/F12无血清培养基100μL细胞培养液中孵育培养24小时。细胞与6-OHDA孵育12小时后，细胞活力显著降低到约30％。
然后再次撤去全部培养基，并按照组别向各孔中加入含0.025mg/mL、0.05mg/mL、0.1mg/mL、0.2mg/mL、0.4mg/mL、0.8mg/mL的各实验组或对照组化合物(空白组和模型组不含)加入到细胞培养液中的DMEM/F12无血清培养基100μL，培养24小时。
然后检测细胞活性。模型组的结果显示，细胞经过含6-OHDA的培养基培养24小时，细胞活力显著降低到约30％。实验组与对照组的结果如图3和表3所示；可以看到，在细胞培养液中加入本申请的盐后，细胞活力随浓度的增加而升高，且本申请的盐的组别的细胞活力明显较司来吉兰的对照组更高。
表3帕金森病模型的细胞活力
神经退行性疾病——阿尔兹海默症模型
在阿尔兹海默症的海马神经元细胞中，常存在β淀粉样蛋白(Aβ)，引起海马神经元细胞损伤造成阿尔兹海默症。故本实验通过Aβ亚型之一Aβ(1-42)在细胞水平建立阿尔兹海默症细胞模型，并加入本申请的盐或其他对照组化合物，将得到本申请的非共价二聚体阳离子在阿尔兹海默症细胞模型中体现的技术效果。
以实施例1、4、和18的盐作为实验组化合物，神经节苷脂作为对照组化合物。并设置空白对照组(不加入Aβ(1-42))以及模型组(加入Aβ(1-42)，但不加入实施例的盐或神经节苷脂)。
将SH-SY5Y人神经母细胞瘤细胞均匀接种至96孔板中，每孔约5000个细胞。使用DMEM/F12完全培养基培养细胞6小時。待细胞完全贴壁后，撤去全部培养基，并向各孔中将细胞在加入含20μmol/L的Aβ(1-42)(空白组不含)的DMEM/F12无血清培养基100μL细胞培养液中孵育培养24小时。细胞与Aβ(1-42)孵育48小时后，细胞活力显著降低到约50％。
然后再次撤去全部培养基，并按照组别向各孔中加入含0.025mg/mL、0.05mg/mL、0.1mg/mL、0.2mg/mL、0.4mg/mL、0.8mg/mL的各实验组或对照组化合物(空白组和模型组不含)加入到细胞培养液中的DMEM/F12无血清培养基100μL，培养24小时。
然后检测细胞活性。模型组的结果显示，细胞经过含Aβ(1-42)的培养基培养48小时，细胞活力显著降低到约50％。实验组与对照组的结果如图4和表4所示；可以看到，在细胞培养液中加入本申请的盐后，细胞活力随浓度的增加而升高，且本申请的盐的组别的细胞活力明显较神经节苷脂的对照组更高。
表4阿尔兹海默症模型的细胞活力
转录组学分析
为探索化合物如何在细胞中发挥功效，进行转录组学分析。
将Neuro-2a小鼠脑神经瘤细胞均匀铺至两个10cm培养皿中，使用MEM完全培养基进行培养。待密度至90％时，弃去全部培养基，加入无血清MEM培养基10mL，向其中一个皿中加入实施例1的盐的溶液，并使其终浓度为0.1mg/mL。另外一皿加入等体积PBS溶液。37℃细胞培养箱中培养3小时后，再次撤去全部培养基，使用Trizol分别提取两个皿中细胞RNA，并进行转录组学分析。
转录组学结果中，对差异表达的基因的GO富集分析结果，按照分子功能(MF)、生物过程(BP)和细胞组分(CC)进行GO分类，挑选每个分类中p-value最小，即富集最显著的前10个条目进行分析，结果如图5。可以发现经实施例1的盐处理的细胞在细胞保护功能、蛋白结合能力、生长因子活性、细胞信号受体结合活性显著增强，同时还伴随细胞迁移能力的提升。共同促进细胞修复功能的恢复，提升细胞修复水平。
细胞增殖和创伤修复相关实验
表皮成纤维细胞增殖实验
表皮成纤维细胞在表皮创伤修复中起决定性作用，参与结缔组织的形成，关系到皮肤损伤的恢复速度和效果。本实验培养HFF-1人表皮成纤维细胞，并加入本申请的盐或其他对照组化合物，将得到本申请的非共价二聚体阳离子在促进人表皮成纤维细胞增殖中体现的技术效果。
以实施例1、4、和18的盐作为实验组化合物，以组氨酸+色氨酸摩尔比1:1为对照组化合物。将HFF-1人表皮成纤维细胞均匀接种至96孔板中，每孔约2000个细胞。使用DMEM完全培养基培养细胞6小時。待细胞完全贴壁后，撤去全部培养基，按照组别向各孔中加入含0.025mg/mL、0.05mg/mL、0.1mg/mL、0.2mg/mL、0.4mg/mL、0.8mg/mL的各实验组化合物(空白组不含)加入到细胞培养液中的DMEM完全培养基100μL，培养24小时。
然后检测细胞活力，结果如图6和表5所示。结果显示，在细胞培养液中加入本申请的盐后，细胞活力随浓度的增加而升高，体现出对人表皮成纤维细胞生长增殖作用的促进作用。
表5表皮成纤维细胞增殖实验的细胞活力
角质形成细胞增殖实验
角质形成细胞在表皮创伤修复中同样起关键作用，其参与皮肤表面角质层的修复，关系到疤痕形成。本实验培养HaCaT人永生化角质形成细胞，并加入本申请的盐或其他对照组化合物，将得到本申请的非共价 二聚体阳离子在促进人永生化角质形成细胞增殖中体现的技术效果。
以实施例1、4、和18的盐作为实验组化合物，以组氨酸+色氨酸摩尔比1:1为对照组化合物。将HaCaT人永生化角质形成细胞均匀接种至96孔板中，每孔约2000个细胞。使用DMEM完全培养基培养细胞6小時。待细胞完全贴壁后，撤去全部培养基，按照组别向各孔中加入含0.025mg/mL、0.05mg/mL、0.1mg/mL、0.2mg/mL、0.4mg/mL、0.8mg/mL的各实验组化合物(空白组不含)加入到细胞培养液中的DMEM完全培养基100μL，培养24小时。
然后检测细胞活力，结果如图7和表6所示。结果显示，在细胞培养液中加入本申请的盐后，细胞活力随浓度的增加而升高，体现出对人永生化角质形成细胞生长增殖作用的促进作用。
表6角质形成细胞增殖实验的细胞活力
血管内皮细胞增殖实验
血管内皮细胞在组织修复过程中，参与血管体系的重建，支持创伤的愈合。本实验培养HUVEC人脐静脉血管内皮细胞，并加入本申请的盐或其他对照组化合物，将得到本申请的非共价二聚体阳离子在促进人脐静脉血管内皮细胞增殖中体现的技术效果。
以实施例1、4、和18的盐作为实验组化合物，以组氨酸+色氨酸摩尔比1:1为对照组化合物。将HUVEC人脐静脉血管内皮细胞均匀接种至96孔板中，每孔约2000个细胞。使用血管内皮专用完全培养基培养细胞6小時。待细胞完全贴壁后，撤去全部培养基，按照组别向各孔中加入含0.025mg/mL、0.05mg/mL、0.1mg/mL、0.2mg/mL、0.4mg/mL、0.8mg/mL的各实验组化合物(空白组不含)加入到细胞培养液中的血管内皮专用完全培养基100μL，培养24小时。
然后检测细胞活性，结果如图8和表7所示。结果显示，在细胞培养液中加入本申请的盐后，细胞活力随浓度的增加而升高，体现出对人脐静脉血管内皮细胞生长增殖作用的促进作用。
表7血管内皮细胞增殖实验的细胞活力
神经细胞增殖实验
神经细胞在组织修复过程中，参与神经系统的重建，为创后神经系统健全起决定性作用。本实验培养CATH.a小鼠神经细胞，并加入本申请的盐或其他对照组化合物，将得到本申请的非共价二聚体阳离子在促进神经细胞增殖中体现的技术效果。
以实施例1、4、和18的盐作为实验组化合物，以组氨酸+色氨酸摩尔比1:1为对照组化合物。将CATH.a小鼠神经细胞均匀接种至96孔板中，每孔约2000个细胞。使用RPMI 1640完全培养基培养细胞6小時。待细胞完全贴壁后，撤去全部培养基，按照组别向各孔中加入含0.025mg/mL、0.05mg/mL、0.1mg/mL、 0.2mg/mL、0.4mg/mL、0.8mg/mL的各实验组化合物(空白组不含)加入到细胞培养液中的RPMI 1640完全培养基100μL，培养24小时。
然后检测细胞活性，结果如图9和表8所示。结果显示，在细胞培养液中加入本申请的盐后，细胞活力随浓度的增加而升高，体现出对神经细胞生长增殖作用的促进作用。
表8神经细胞增殖实验的细胞活力
转录组学分析
为探索化合物如何在细胞水平中发挥创伤愈合的功效，进行转录组学分析。将HFF-1人皮肤成纤维细胞均匀铺至两个10cm培养皿中，使用DMEM完全培养基进行培养。待密度至90％时，弃去全部培养基，加入无血清DMEM培养基10mL，向其中一个皿中加入实施例1的盐的溶液，并使其终浓度为0.1mg/mL。另外一皿加入等体积PBS溶液。37℃细胞培养箱中培养3小时后，再次撤去全部培养基，使用Trizol分别提取两个皿中细胞RNA，并进行转录组学分析。结果如图10。
转录组学结果中，对差异表达的基因的KEGG富集分析结果，按照细胞进程CP、内环境信息进程EIP、基因信息进程GIP和代谢进程MP进行KEGG分类，挑选每个分类中p-value最小，即富集最显著的前10个条目进行分析，可以发现经实施例1的盐处理的细胞在细胞自噬、生长因子受体、DNA合成、细胞代谢调节等功能的活性显著增强，同时还伴随细胞迁移能力的提升。共同促进细胞可调控增殖，进而促进组织创伤修复。
上述实施方式仅为本申请的优选实施方式，不能以此来限定本申请保护的范围，本领域的技术人员在本申请的基础上所做的任何非实质性的变化及替换均属于本申请所要求保护的范围。

Claims (10)

  1. 一种非共价二聚体阳离子，其特征在于，为式(A)阳离子、其互变异构体、或其立体异构体，
    其中，
    式(A)中的键为非共价键；
    所述R7选自由氢、羟甲基、-C-R6和-C(＝O)-R6所组成的组；
    所述R1选自由氢、羟基、巯基、氨基、甲基、乙基、和苯基所组成的组；
    所述Q1选自由氢、羟基、巯基、氨基、甲基、乙基、氯、氰基、羧基、和苯基所组成的组；
    所述R2和所述Q2各自独立地选自由氢、甲基、乙基、丙基、苯基、苯甲氧基甲基、和三苯基甲基所组成的组；
    所述R3和所述Q3各自独立地选自由氢、羟基、巯基、氨基、甲基、乙基、和苯基所组成的组；
    所述R4和所述Q4各自独立地选自由氢、甲基、乙基、和丙基所组成的组；
    所述R5和所述Q5各自独立地选自由氢、苯甲基、氨基、甲氨基、肼基、三甲基铵基、吡咯基、和氨基上进一步连接由氨基酸、二肽、或三肽的C端碳原子衍生的取代基，所组成的组；
    所述R6和所述Q6各自独立地选自由羟基、去质子化羟基、甲氧基、甲氨基、乙氨基、和由氨基酸、二肽、或三肽的N端氮原子衍生的取代基，所组成的组；且
    所述m和所述n各自独立地选自由0和1所组成的组。
  2. 如权利要求1所述的阳离子，其特征在于，
    所述R4为氢或甲基；
    所述R5选自由氢、苯甲基、氨基、甲氨基、肼基、吡咯基、和乙酰胺基所组成的组；
    所述R6选自由羟基、甲氧基、甲氨基、和乙氨基所组成的组；且
    所述n为1；
    且/或
    所述Q4为氢或甲基；
    所述Q5选自由氢、苯甲基、氨基、甲氨基、肼基、吡咯基、和乙酰胺基所组成的组；
    所述Q6选自由羟基、甲氧基、甲氨基、和乙氨基所组成的组；且
    所述m为1。
  3. 如权利要求1或2所述的阳离子，其特征在于，
    所述R4为氢；
    所述R5为氨基；且
    所述R7为-C(＝O)-R6且所述R6为羟基；
    且/或
    所述Q4为氢；
    所述Q5为氨基；且
    所述Q6为羟基。
  4. 如权利要求1至3任一所述的阳离子，其特征在于，
    所述R1为氢或羟基；
    所述R2为氢；且
    所述R3为氢；
    且/或
    所述Q1为氢或羟基；
    所述Q2为氢；且
    所述Q3为氢；
    且/或
    所述R7为-C(＝O)-R6；
    所述R2和所述Q2相同；
    所述R3和所述Q3相同；
    所述R4和所述Q4相同；
    所述R5和所述Q5相同；且
    所述R6和所述Q6相同。
  5. 一种盐，其特征在于，包括：
    权利要求1至4任一所述的阳离子；和
    第一阴离子，
    其中所述第一阴离子包括选自由氟离子、氯离子、溴离子、碘离子、硫离子、硝酸根离子、硫酸根离子、亚硫酸根离子、硫代硫酸根离子、过硫酸根离子、硒酸根离子、磷酸根离子、碳酸根离子、六氟磷酸根离子、六氟硅酸根离子、醋酸根离子、磺酸根离子、苯甲酸根离子、和多聚磷酸根离子所组成的组的至少一个。
  6. 如权利要求5所述的盐，其特征在于，所述第一阴离子包括选自由六氟磷酸根离子、六氟硅酸根离子、氯离子、和硫酸根离子所组成的组的至少一个。
  7. 权利要求1至4任一所述的阳离子或权利要求5或6所述的盐的制备方法，其特征在于，包括：
    将第一反应物接触第一酸，得到第一反应物第一酸盐；
    在第一酸性环境下，将所述第一反应物第一酸盐接触包括第一阴离子的第一盐，得到包括质子化第一反应物第一酸盐阳离子、和所述第一阴离子，的第一溶液；
    在第二酸性环境下，将第二反应物加入所述第一溶液，得到第二溶液或第一中间产物；以及
    将第一碱加入所述第二溶液中或接触所述第一中间产物，
    其中，所述第一反应物包括式(C)化合物，且所述第二反应物包括式(D)化合物，
  8. 如权利要求7所述的制备方法，其特征在于，
    所述第一酸选自由盐酸、氢溴酸、和氢碘酸所组成的组；且
    所述第一盐由第一阳离子和所述第一阴离子组成，所述第一阳离子为铵离子；
    且/或
    所述的将第一反应物接触第一酸是在第一温度下，所述第一温度为0℃至70℃；
    所述的将第一反应物第一酸盐接触第一盐是在第二温度下，所述第二温度为0℃至70℃；且
    所述的将第二反应物加入第一溶液是在第三温度下，所述第三温度为0℃至70℃；
    且/或
    第一反应物和第一酸的摩尔比为1∶2至1∶10；
    第一反应物第一酸盐和第一盐的摩尔比为1∶2至1∶10；且
    质子化第一反应物阳离子和第二反应物的摩尔比为1∶1至1∶2；
    且/或
    所述第一酸性环境为pH值小于或等于6；且
    所述第二酸性环境为pH值小于或等于6；
    且/或
    所述第一碱包括选自由氨水、氢氧化钠、氢氧化钾、和三乙醇胺所组成的组的至少一个；且
    所述的将第一碱加入所述第二溶液中或接触所述第一中间产物，是将所述第二溶液或包括所述第一中间产物的溶液的pH值调整为8以上。
  9. 权利要求1至4任一所述的阳离子、或权利要求5或6所述的盐、或权利要求7或8所述的方法所制备的阳离子或盐，在抗氧化、制备抗氧化剂、制备抑制、减少或逆转人类或动物细胞的氧化应激或抑制、减少或清除人类或动物体内的氧自由基的药物、或制备治疗与氧化应激或氧自由基相关联的疾病或症状的药物中的用途；
    可选地，所述疾病或症状选自由：衰老、炎症、超重、肥胖、癌症、肿瘤、肝病、神经退行性疾病、动脉高血压、动脉粥样硬化、心血管疾病、糖尿病、高胆固醇血症、慢性疲劳综合征、缺血再灌注损伤、神经退行性疾病、紫外线引发的损伤、和酒精引发的损伤，所组成的组；
    可选地，所述疾病或症状为帕金森病或阿尔兹海默症；
    可选地，所述疾病或症状为黏膜损伤。
  10. 权利要求1至4任一所述的阳离子、或权利要求5或6所述的盐、或权利要求7或8所述的方法所制备的阳离子或盐，在促进细胞增殖、或制备促进细胞增殖或治疗、缓解、或修复创伤的药物中的用途；
    可选地，所述细胞为位于皮肤的细胞；
    可选地，所述细胞选自由表皮成纤维细胞、角质形成细胞、血管内皮细胞、和神经细胞所组成的组；
    可选地，所述创伤包括皮肤创伤。
PCT/CN2023/134364 2022-11-25 2023-11-27 非共价二聚体阳离子、其盐、其制备方法及其用途 WO2024109952A1 (zh)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113620883A (zh) * 2021-07-22 2021-11-09 西南大学 一种半质子型化合物的制备方法及其产品和应用

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
GERVASIO FRANCESCO LUIGI, CHELLI RICCARDO; MARCHI MASSIMO; PROCACCI PIERO; SCHETTINO VINCENZO: "Determination of the Potential of Mean Force of Aromatic Amino Acid Complexes in Various Solvents Using Molecular Dynamics Simulations: The Case of the Tryptophan−Histidine Pair", JOURNAL OF PHYSICAL CHEMISTRY PART B, AMERICAN CHEMICAL SOCIETY, US, vol. 105, no. 32, 1 August 2001 (2001-08-01), US , pages 7835 - 7846, XP093173610, ISSN: 1520-6106, DOI: 10.1021/jp010434w *
JI, LIFEI: "Theroretical Studies on Structures And Stability of C36 Dimers", ENGINEERING SCIENCE & TECHNOLOGY I, CHINA MASTER’S THESES FULL-TEXT DATABASE, no. 12, 15 December 2015 (2015-12-15) *
XIE, BINGYUN ET AL.: "Study on Hydrogen Bonding Dimers with 3,5-diamino-1,2,4-triazole Ion and Picrie Acid Ion", JOURNAL OF SICHUAN NORMAL UNIVERSITY (NATURAL SCIENCE), vol. 36, no. 6, 30 November 2013 (2013-11-30) *
ZHAO, ZIZHEN ET AL.: "Specific Antitumor Activity And Mechanism of Protonic Bis-Phenanthroline", ACTA PHARMACEUTICA SINICA, vol. 57, no. 5, 25 February 2022 (2022-02-25) *

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