Patent Application
20250230126
The present invention relates to the technical field of chemical medicines, and in particular to an intermediate of a polyamine derivative, a preparation method therefor, and use thereof.
Systemic inflammatory response syndrome and autoimmune disorder-related diseases, such as sepsis and autoimmune diseases, are two categories of diseases caused by the body's own excessive immune response. Currently, there is still a lack of effective therapeutic drugs, and the targeted prevention and treatment of these diseases are the focus and hot issues of clinical concern. Sepsis refers to the systemic inflammatory response syndrome (SIRS) caused by infection. Septic shock is a severe stage of sepsis and is one of the main factors causing patient mortality in ICU.
Studies show that the pathogenesis of sepsis lies in the fact that pathogen-associated molecular patterns (PAMPs) released by bacteria, viruses, fungi, and other pathogens are recognized by pattern recognition receptors (PRRs) of the host's innate immune system, mediating the activation of inflammatory response cells and thus causing a systemic excessive inflammatory response. Epidemiological surveys show that PAMP molecules that cause sepsis mainly include bacterial lipopolysaccharide (LPS), bacterial genomic DNA (CpG DNA), peptidoglycan (PGN), lipoteichoic acid (LTA), viral RNA, and zymosan.
Chinese patent No. CN105348137B discloses a pharmaceutically acceptable salt of a polyamine derivative, a preparation method therefor, and use thereof, wherein the pharmaceutically acceptable salt of the polyamine derivative can be used in the preparation of a medicament for treating sepsis; however, in the preparation process, the purity of the intermediates and final product was not considered, so that the preparation method needs to be further improved.
Therefore, it is very necessary to develop a preparation method suitable for industrialization that can obtain a polyamine derivative and an intermediate thereof with high purity.
In order to overcome the defects of the prior art, the present invention provides a preparation method for a polyamine derivative and an intermediate thereof and use of the polyamine derivative and the intermediate thereof.
In a first aspect of the present invention, provided is a compound of formula I, having the following structure:
Specifically, m1 is selected from an integer of 1-3, such as 1, 2, or 3, particularly 2.
Specifically, m2 is selected from an integer of 1-3, such as 1, 2, or 3, particularly 2.
Specifically, R1 and R2 are independently selected from: OH and C1-C6 alkoxy; more specifically, R1 and R2 are independently selected from: OH and C1-C3 alkoxy; and further specifically, R1 and R2 are independently selected from: OH, methoxy, and ethoxy.
Specifically, the compound of formula I may have the following structure:
Specifically, R4 and R5 are independently selected from C1-C6 alkyl, particularly C1-C3 alkyl, such as methyl, ethyl, and n-propyl.
In some embodiments of the present invention, R3 is selected from:
In some embodiments of the present invention, the compound of formula I has the following structure:
In a second aspect of the present invention, provided is a preparation method for the compound of formula I, comprising a step of reacting a compound of formula II with R3-G-H:
Specifically, the reaction is carried out under a protective gas, wherein the protective gas may be an inert gas, such as nitrogen or argon, preferably nitrogen.
Specifically, the reaction is carried out at a temperature of 15 to 35° C. (e.g., 15, 16, 18, 20, 22, 24, 25, 26, 28, 30, 32, 34 or 35° C.), particularly a temperature of 20-30° C.
Specifically, the reaction may be carried out for a period of 1-6 h (e.g., 1, 2, 3, 4, 5 or 6 h), particularly a period of 2-4 h.
Specifically, the reaction is carried out in a solvent, wherein the solvent is selected from: dichloromethane, chloroform, ethyl acetate, n-hexane, cyclohexane, and methyl tert-butyl ether, particularly dichloromethane.
Specifically, the reaction system further comprises an acid scavenger, such as an organic weak base and an inorganic weak base, which can be selected from pyridine, triethylamine, N,N-diisopropylethylamine, an alkali metal acetate (e.g., sodium acetate), and/or an alkali metal carbonate (e.g., sodium carbonate or potassium carbonate), preferably triethylamine.
Specifically, the preparation method further comprises a step of purifying the reaction product.
Specifically, the purification step comprises one or more selected from: washing, concentrating, crystallizing, filtering, and drying.
Specifically, the preparation method comprises: under a protective gas, mixing R3-G-H with
Specifically, the acid scavenger is dropwise added at a temperature of −10 to 10° C. (e.g., −10, −8, −6, −5, −4, −2, 0, 2, 4, 5, 6, 8 or 10° C.), particularly at a temperature of at −5 to 5° C.
In a third aspect of the present invention, provided is a preparation method for a compound of formula III:
Specifically, n8 is an integer of 1-3, such as 1, 2, or 3, particularly 2.
Specifically, R16 and R17 are independently selected from C1-C6 alkyl, particularly C1-C3 alkyl, such as methyl, ethyl, and n-propyl.
In some embodiments of the present invention, R14 and R15 are independently selected from:
In some embodiments of the present invention, R11a is
In some embodiments of the present invention, R12a is an amino protecting group.
Specifically, the reaction described above is carried out under a protective gas, wherein the protective gas may be an inert gas, such as nitrogen or argon, preferably nitrogen.
Specifically, the reaction described above is carried out at a temperature of 50-70° C. (e.g., 50, 52, 54, 55, 56, 58, 60, 62, 64, 65, 66, 68 or 70° C.), particularly a temperature of 55-65° C.
Specifically, the reaction described above is carried out for a period of 6-60 h (e.g., 6, 12, 24, 30, 36, 40, 42, 48, 54 or 60 h), particularly a period of 40-48 h.
Specifically, the reaction described above is carried out in a solvent, wherein the solvent can be selected from: ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, toluene, xylene, chlorobenzene, dioxane, and the like; particularly, the solvent is ethyl acetate, toluene, or dioxane, preferably ethyl acetate.
Specifically, the preparation method further comprises a step of purifying the reaction product.
Specifically, the purification step may comprise washing the reaction product, wherein a solvent for the washing may be water.
Specifically, the purification step may further comprise concentrating the washed reaction product. More specifically, the preparation method comprises: under a protective gas, mixing the compound of formula IV with a reaction solvent, heating, adding the compound of formula V and/or the compound of formula VI, and reacting; and
Specifically, n1 is an integer of 1-5, such as an integer of 1-3, for example, 2.
Specifically, n2 is an integer of 0-5, such as an integer of 1-3, for example, 2.
Specifically, n3 is an integer of 0-5, such as an integer of 1-3, for example, 2.
Specifically, n4 is an integer of 1-5, such as an integer of 1-3, for example, 2.
Specifically, n5 is an integer of 0-5, such as an integer of 1-3, for example, 2.
Specifically, n6 is an integer of 0-5, such as an integer of 1-3, for example, 2.
Specifically, n7 is an integer of 0-5, such as an integer of 1-3, for example, 2.
In some embodiments of the present invention, n′ is 1.
Specifically, the compound of formula IV has the following structure:
Specifically, the compound of formula V has the following structure:
Specifically, the compound of formula VI has the following structure:
Specifically, R1 is H.
Specifically, R4 is H.
Specifically, R5 is H.
Specifically, R6 is H.
Specifically, R9 is H.
Specifically, R10 is H.
Specifically, R2, R3, R7, and R8 are independently selected from: H, OH, alkoxy, aryloxy, and aralkoxy; more specifically, R2, R3, R7, and R8 are independently selected from: H, OH, C1-C6 alkoxy, C6-C12 aryloxy, and C7-C12 aralkoxy; further specifically, R2, R3, R7, and R8 are independently selected from: H, OH, and C1-C6 alkoxy; and still further specifically, R2, R3, R7, and R8 are independently selected from: OH, methoxy, and ethoxy.
Specifically, R2 and R3 are the same, and/or R7 and R8 are the same; and preferably, R2, R3, R7, and R8 are all the same.
In some embodiments of the present invention, the compound of formula V has the same structure as the compound of formula VI.
In some embodiments of the present invention, the preparation method described above comprises the step of reacting the compound of formula IV with the compound of formula V, wherein the compound of formula IV has a structure of formula IV-1, and the compound of formula V has a structure of V-1, V-2 or V-3.
In some embodiments of the present invention, in formula III, R11 is
R12 is an amino protecting group, and R13 is —CH2—NH2; the preparation method further comprises step (b): reducing a reaction product of step (a).
Specifically, the reduction reaction system may further comprise a solvent such as an alcohol, for example, ethanol, isopropanol, or tert-butanol, particularly ethanol.
Specifically, the reduction reaction system further comprises a catalyst such as Raney Ni, palladium on carbon, or the like.
In other embodiments of the present invention, in formula III, R11 is
R12 is H, and R13 is —CH2—NH2; the preparation method further comprises step (c): subjecting the reduced product of step (b) to an amino deprotection treatment.
In some embodiments of the present invention, the preparation method described above comprises the step of reacting the compound of formula IV with the compound of formula V, wherein the compound of formula IV has a structure of formula IV-1, and the compound of formula V is selected from the following structures:
the compound of formula I obtained has the following structure:
which can be further reduced to prepare
and then further deprotected to prepare
In a fourth aspect of the present invention, provided is use of the compound according to the first aspect in the preparation of a polyamine derivative or a pharmaceutically acceptable salt thereof. Specifically, the polyamine derivative has the following structure:
Specifically, n1 is an integer of 1-5, such as an integer of 1-3, for example, 2.
Specifically, n2 is an integer of 0-5, such as an integer of 1-3, for example, 2.
Specifically, n3 is an integer of 0-5, such as an integer of 1-3, for example, 2.
Specifically, n4 is an integer of 1-5, such as an integer of 1-3, for example, 2.
Specifically, n5 is an integer of 0-5, such as an integer of 1-3, for example, 2.
Specifically, n6 is an integer of 0-5, such as an integer of 1-3, for example, 2.
Specifically, n7 is an integer of 0-5, such as an integer of 1-3, for example, 2.
In some embodiments of the present invention, n′ is 1.
Specifically, R1 is H.
Specifically, R4 is H.
Specifically, R5 is H.
Specifically, R6 is H.
Specifically, R9 is H.
Specifically, R10 is H.
Specifically, R2, R3, R7, and R8 are independently selected from: H, OH, alkoxy, aryloxy, and aralkoxy; more specifically, R2, R3, R7, and R8 are independently selected from: H, OH, C1-C6 alkoxy, C6-C12 aryloxy, and C7-C12 aralkoxy; further specifically, R2, R3, R7, and R8 are independently selected from: H, OH, and C1-C6 alkoxy; and still further specifically, R2, R3, R7, and R8 are independently selected from: OH, methoxy, and ethoxy.
Specifically, R2 and R3 are the same, and/or R7 and R8 are the same; preferably, R2, R3, R7, and R8 are all the same, for example, all are methoxy.
In some embodiments of the present invention, R11 is
In one embodiment of the present invention, the polyamine derivative has the following structure:
In a fifth aspect of the present invention, provided is use of the compound according to the first aspect in the preparation of a medicament for antagonizing bacterial lipopolysaccharide (LPS), bacterial genomic DNA (CpG DNA), peptidoglycan (PGN), lipoteichoic acid (LTA), viral RNA, and zymosan.
In a sixth aspect of the present invention, provided is use of the compound according to the first aspect in the preparation of a medicament for treating sepsis.
The present invention provides an intermediate of a polyamine derivative, a preparation method therefor, and use thereof, wherein the intermediate is easy to prepare and has a high purity; when the intermediate is used for preparing the polyamine derivative, it is beneficial to improving the purity and yield of the product, and the operation is simple and convenient, which is beneficial to the purity and yield of the polyamine derivative and simplification of the purification process for the product, thereby facilitating the improvement of the industrial production of the polyamine derivative and a pharmaceutically acceptable salt thereof. The present invention further provides a preparation method for the polyamine derivative, which is simple and convenient to operate, yields a product with high purity, and thus has very good application prospects in the field of chemical medicines.
Unless otherwise defined, all scientific and technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention relates.
The amino protecting group involved in the present invention may be any suitable known amino protecting group, such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methanesulfonyl (Ms), or p-toluenesulfonyl (Ts), particularly Boc.
The inert gas involved in the present invention refers to a gas that does not participate in the reaction, and may include nitrogen and the like in addition to rare gases such as helium, neon, argon, krypton, and xenon, depending on the specific reaction conditions.
The term “alkyl” refers to a hydrocarbyl group that is linear or branched and that does not contain unsaturated bonds, and that is linked to the rest of the molecule via a single bond. The alkyl used herein generally contains 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, and preferably contains 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, and the like.
The term “alkoxy” refers to a substituent formed from a hydroxy group by substituting the hydrogen atom with alkyl. The alkoxy used herein generally contains 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms, and preferably contains 1 to 6 carbon atoms (i.e., C1-C6 alkoxy). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. The substituent formed from a hydroxy group by substituting the hydrogen atom with aryl is aryloxy, and the aryloxy used herein generally contains 6 to 18 (e.g., 6, 8, 10, 12, 14, 16, or 18) carbon atoms, and preferably contains 6 to 12 carbon atoms (i.e., C6-C12 aryloxy). Examples of the aryloxy include, but are not limited to, phenoxy. The substituent formed from an alkoxy group by substituting the hydrogen atom of a hydroxy group with aralkyl is aralkoxy, and the aralkoxy used herein generally contains 7 to 18 (e.g., 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) carbon atoms, and preferably contains 7 to 12 carbon atoms (i.e., C7-C12 aralkoxy). Examples of aralkoxy include, but are not limited to, benzyloxy.
The term “halogen” refers to bromine, chlorine, iodine, or fluorine, preferably chlorine.
The disclosures of the various publications, patents, and published patent specifications cited herein are hereby incorporated by reference in their entireties.
The technical solutions of the present invention will be clearly and completely described below with reference to the examples of the present invention, and it is obvious that the described examples are only a part of the examples of the present invention but not all of them. Based on the examples of the present invention, all other examples obtained by those of ordinary skills in the art without creative work shall fall within the protection scope of the present invention.
Under nitrogen atmosphere, 798 g of dichloromethane was added into a glass reaction kettle, followed by the addition of 90 g (0.78 mol) of NHS (N-hydroxysuccinimide). The mixture was stirred for 5-15 min, cooled to −5 to 5° C., controlled at −5 to 5° C., and dropwise added with 79.5 g of triethylamine. During the dropwise addition, the solid was gradually dissolved to give a clear solution. Compound 2 (3,4-dimethoxyphenylpropionyl chloride) (0.85 mol, 195.6 g) was added with the temperature controlled at −5 to 5° C. A white mist was generated, and a solid was precipitated. The mixture was slowly heated to 20-30° C., stirred for reaction for 2-4 h with the temperature controlled at 20-30° C., washed, concentrated, crystallized, filtered, and dried to give 199.5 g of a solid, namely compound 1a with a purity of 99.3%.
Compound 1a: Mass spectrum: m/z=307.3, and nuclear magnetic resonance hydrogen spectrum as shown in
Under nitrogen atmosphere, 798 g of dichloromethane was added into a glass reaction kettle, followed by the addition of 92 g of 2-diethylaminoethanol (0.78 mol). The mixture was stirred for 5-15 min, cooled to −5 to 5° C., controlled at −5 to 5° C., and dropwise added with 79.5 g of triethylamine. During the dropwise addition, the solid was gradually dissolved to give a clear solution. 3,4-dimethoxyphenylpropionyl chloride (0.85 mol, 195.6 g) was added with the temperature controlled at −5 to 5° C. A white mist was generated, and a solid was precipitated. The mixture was slowly heated to 20-30° C., stirred for reaction for 2-4 h with the temperature controlled at 20-30° C., washed, concentrated, crystallized, filtered, and dried to give 170.2 g of a solid, namely compound 1b with a purity of 96.2%.
Under nitrogen atmosphere, 798 g of dichloromethane was added into a glass reaction kettle, followed by the addition of 103.7 g of 2-diethylaminoethanethiol (0.78 mol). The mixture was stirred for 5-15 min, cooled to −5 to 5° C., controlled at −5 to 5° C., and dropwise added with 79.5 g of triethylamine. During the dropwise addition, the solid was gradually dissolved to give a clear solution. 3,4-dimethoxyphenylpropionyl chloride (0.85 mol, 195.6 g) was added with the temperature controlled at −5 to 5° C. A white mist was generated, and a solid was precipitated. The mixture was slowly heated to 20-30° C., stirred for reaction for 2-4 h with the temperature controlled at 20-30° C., washed, concentrated, crystallized, filtered, and dried to give 165.2 g of a solid, namely compound 1c with a purity of 94.3%.
Under nitrogen atmosphere, 60.9 g (0.18 mol) of compound 4 was added into a 1000 mL three-neck flask, followed by the addition of 265.6 g of ethyl acetate. The mixture was stirred for 5-15 min, heated to 55-65° C., controlled at 55-65° C., and added with 98.6 g (0.32 mol) of compound 1a. After the addition, the mixture was stirred for reaction for another 40-48 h with the temperature controlled at 55-65° C., washed with water, and concentrated to give 115 g of compound 5 with a purity of 79.29%.
Under nitrogen atmosphere, 60.9 g (0.18 mol) of compound 4 was added into a 1000 mL three-neck flask, followed by the addition of 265.6 g of ethyl acetate. The mixture was stirred for 5-15 min, heated to 55-65° C., controlled at 55-65° C., and added with 98.9 g (0.32 mol) of compound 1b. After the addition, the mixture was stirred for reaction for another 40-48 h with the temperature controlled at 55-65° C., washed with water, and concentrated to give 103 g of compound 5 with a purity of 72.56%.
Under nitrogen atmosphere, 60.9 g (0.18 mol) of compound 4 was added into a 1000 mL three-neck flask, followed by the addition of 265.6 g of ethyl acetate. The mixture was stirred for 5-15 min, heated to 55-65° C., controlled at 55-65° C., and added with 104 g (0.32 mol) of compound 1c. After the addition, the mixture was stirred for reaction for another 40-48 h with the temperature controlled at 55-65° C., washed with water, and concentrated to give 96 g of compound 5 with a purity of 70.89%.
Under nitrogen atmosphere, 60.9 g (0.18 mol) of compound 4 was added into a 1000 mL three-neck flask, followed by the addition of 266 g of toluene. The mixture was stirred for 5-15 min, heated to 55-65° C., controlled at 55-65° C., and added with 98.6 g (0.32 mol) of compound 1a. After the addition, the mixture was stirred for reaction for another 40-48 h with the temperature controlled at 55-65° C., washed with water, and concentrated to give 100 g of compound 5 with a purity of 62.46%.
Under nitrogen atmosphere, 60.9 g (0.18 mol) of compound 4 was added into a 1000 mL three-neck flask, followed by the addition of 266 g of dioxane. The mixture was stirred for 5-15 min, heated to 55-65° C., controlled at 55-65° C., and added with 98.6 g (0.32 mol) of compound 1a. After the addition, the mixture was stirred for reaction for another 40-48 h with the temperature controlled at 55-65° C., washed with water, and concentrated to give 98 g of compound 5 with a purity of 59.38%.
Under nitrogen atmosphere, 60.9 g (0.18 mol) of compound 4 was added into a 1000 mL three-neck flask, followed by the addition of 265.6 g of ethyl acetate. The mixture was stirred for 5-15 min, heated to 55-65° C., controlled at 55-65° C., and added with 72.8 g (0.32 mol) of compound 2. After the addition, the mixture was stirred for reaction for another 40-48 h with the temperature controlled at 55-65° C., washed with water, and concentrated to give 91 g of compound 5 with a purity of 45.71%.
5.3 g of compound 4 was dissolved in 25 mL of dichloromethane, followed by the addition of 6 mL of triethylamine. 40 mL of a solution of compound 2 dissolved in dichloromethane (at a concentration of 10%) was dropwise added at 0° C. The mixture was allowed to react for 24 h, and concentrated to remove the organic solvent. The residue was extracted with diethyl ether, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to remove the solvent to give 7.8 g of compound 5 with a purity of 33.62%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention, and is not intended to limit the scope of the present invention. Any modifications, equivalents, and the like made without departing from the spirit and principle of the present invention shall fall in the protection scope of the present invention.
The foregoing examples and methods described herein may vary based on the abilities, experience, and preferences of those skilled in the art.
The certain order in which the steps of the method are listed in the present invention does not constitute any limitation on the order of the steps of the method.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202111310146.2 | Nov 2021 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2022/129147 | 11/2/2022 | WO |
