Degradable gemini morpholine quaternary ammonium salt as well as preparation method and application thereof

Abstract

The invention discloses a degradable gemini morpholine quaternary ammonium salt. The invention also discloses a preparation method of the degradable gemini morpholine quaternary ammonium salt, and the preparation method comprises the following steps: S1, morpholine and halogenated alkane are subjected to an N-alkylation reaction to obtain N-alkyl morpholine; s2, reacting the substance A with halogenated acetyl halide to obtain a substance B; s3, N-alkyl morpholine and the substance B are continuously subjected to an N-alkylation reaction, and the degradable gemini morpholine quaternary ammonium salt is obtained. The invention also discloses application of the degradable dimeric morpholine quaternary ammonium salt as a bactericide in preparation of drugs for treating helicobacter pylori infection. The gemini morpholine quaternary ammonium salt disclosed by the invention has a good effect of killing helicobacter pylori; and the gemini morpholine quaternary ammonium salt can be degraded in an alkaline environment, so that the drug resistance of helicobacter pylori to the gemini morpholine quaternary ammonium salt can be avoided, and the degradation product can be quickly discharged out of the body.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a biodegradable geminal morpholine quaternary ammonium salt, its preparation method, and its application. Background Technology

[0002] Helicobacter pylori (HP) infection is the most common chronic infectious disease worldwide, but its prevalence varies greatly. HP can cause a variety of diseases, including gastric ulcers, duodenal ulcers, gastric mucosa-associated lymphoid tissue lymphoma (MALT), and gastric cancer. Eradication of Helicobacter pylori has been proven to reduce the incidence of gastric cancer.

[0003] Currently, single-drug treatment cannot completely eradicate *H. pylori* infection; combination therapy is often used, with triple therapy being the most common. In recent years, *H. pylori* resistance has gradually increased, particularly with clarithromycin, and the eradication rate of triple therapy has gradually decreased. Quadruple therapy is gradually replacing triple therapy. Therefore, finding treatment options with lower resistance, higher eradication rates, and better efficacy is of great practical significance and value. Summary of the Invention

[0004] Based on the technical problems existing in the background art, the present invention proposes a degradable geminate morpholine quaternary ammonium salt, its preparation method and application. The present invention provides a geminate morpholine quaternary ammonium salt with a specific structure, which has a good effect on killing Helicobacter pylori; and the geminate morpholine quaternary ammonium salt can be degraded in an alkaline environment, which can avoid Helicobacter pylori from developing drug resistance to it, and can make the degradation products be quickly excreted from the body.

[0005] This invention proposes a biodegradable geminimorpholine quaternary ammonium salt, the structural formula of which is shown in formula (I): Formula (I); Wherein, X is a halogen, R1 and R2 are each independently H or alkyl, and R3 and R4 are each independently alkyl.

[0006] Preferably, R1 and R2 are each independently H and an alkyl group having 1-6 carbon atoms.

[0007] More preferably, R1 and R2 are each independently H or methyl.

[0008] Preferably, R3 is one of an alkyl group having 8-12 carbon atoms; more preferably, it is one of a straight-chain alkyl group having 8-10 carbon atoms.

[0009] Preferably, R4 is one of an alkyl group having 2-6 carbon atoms; more preferably, it is one of an alkyl group having 2-4 carbon atoms.

[0010] Preferably, X is Cl or Br.

[0011] Preferably, the structural formula of the biodegradable geminate morpholine quaternary ammonium salt is shown below: .

[0012] This invention also proposes a method for preparing the above-mentioned biodegradable geminal morpholine quaternary ammonium salt, comprising the following steps: S1. Morpholine and haloalkane are subjected to N-alkylation reaction to obtain N-alkylmorpholine; S2. React substance A with a haloacetyl halide to obtain substance B; S3. Further N-alkylation reaction of N-alkylmorpholine and substance B yields biodegradable geminate morpholine quaternary ammonium salt; Among them, the structural formula of substance A is shown in formula (II), and the structural formula of substance B is shown in formula (III): Formula (II) Formula (Ⅲ); X is a halogen, R1 and R2 are each independently H or alkyl, and R4 is an alkyl group.

[0013] Preferably, in S1, the general chemical formula of the haloalkane is C1. n H 2n+1 X, where n is an integer between 8 and 12.

[0014] Preferably, in S1, the N-alkylation reaction is carried out at a temperature of 70-120°C for a time of 10-40 h.

[0015] In the above S2 reaction, the reaction temperature is 30-40℃ and the reaction time is 3.5-4.5h.

[0016] In the above S3, the reaction temperature is 50-120℃ and the time is 20-30h.

[0017] This invention also proposes the application of the above-mentioned degradable geminate morpholine quaternary ammonium salt in the preparation of bactericides and in the preparation of drugs for treating Helicobacter pylori infection.

[0018] The aforementioned drugs for treating Helicobacter pylori infection include: degradable geminomorpholine quaternary ammonium salts and pharmaceutically acceptable excipients.

[0019] The pharmaceutically acceptable pharmaceutical excipients mentioned above can be categorized into solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, binding agents, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and anti-flocculation agents, filter aids, release inhibitors, etc.

[0020] Preferably, the dosage form of the drug is an oral preparation, a respiratory tract preparation, a skin preparation, a mucosal preparation, or a cavity preparation.

[0021] The above-mentioned oral preparations can be: powders, tablets, granules, capsules, solutions, emulsions, suspensions, etc.

[0022] The above-mentioned respiratory drug delivery formulations can be sprays, aerosols, powder inhalers, etc.

[0023] Dermal drug delivery formulations can include topical solutions, lotions, liniments, ointments, plasters, pastes, patches, etc.

[0024] Mucosal drug delivery formulations can include eye drops, nasal drops, ophthalmic ointments, mouthwashes, sublingual tablets, adhesive patches, and films.

[0025] Intracavitary drug delivery dosage forms can include suppositories, aerosols, effervescent tablets, drops, and pellets.

[0026] This invention provides a geminimorpholine quaternary ammonium salt with a specific structure, which has a good effect on killing Helicobacter pylori. Even at very small doses, it still has a good effect on killing Helicobacter pylori, and its effect on killing Helicobacter pylori is far better than that of existing quaternary ammonium salts. Furthermore, geminimorpholine quaternary ammonium salt can be degraded in an alkaline environment, which can prevent Helicobacter pylori from developing drug resistance to it, and can also make the degradation products be quickly excreted from the body. Attached Figure Description

[0027] Figure 1 This is the NMR spectrum of compound 2.

[0028] Figure 2 This is the NMR spectrum of compound 7. Detailed Implementation

[0029] The technical solution of the present invention will now be described in detail through specific embodiments.

[0030] Example 1

[0031] A method for preparing a biodegradable geminate morpholine quaternary ammonium salt includes the following steps: S1. Add 0.015 mol morpholine, 0.01 mol bromododecane, and 0.01 mol sodium hydroxide to isopropanol, heat to 90℃, reflux for 24 h, then filter, take the filtrate and concentrate under reduced pressure, then extract three times with ethyl acetate and water, take the organic phase and concentrate under reduced pressure to obtain N-dodecylmorpholine. S2. Dissolve 0.02 mol of bromoacetyl bromide in dichloromethane, then add 0.01 mol of N,N'-dimethyl-1,3-propanediamine slowly dropwise under ice bath and stirring conditions. After the addition is complete, react in a water bath at 35°C for 4 hours, then evaporate under reduced pressure in a rotary evaporator at 60°C for 1 hour. Dissolve the residue in water, filter, and then recrystallize once with anhydrous ethanol to obtain substance B. S3. Add 0.006 mol of N-dodecylmorpholine and 0.003 mol of substance B to isopropanol, heat to 90 °C, reflux for 24 h, then concentrate under reduced pressure, wash three times with acetone, and concentrate under reduced pressure to remove acetone to obtain a biodegradable geminate morpholine quaternary ammonium salt, denoted as compound 1, with the following structural formula: .

[0032] 1 H NMR (400MHz, DMSO) δ 4.14 (s, 4H), 3.83 (t, J=8.1Hz, 8H), 3.48 (s, 6H), 3.42 (t, J=6.7Hz, 8H), 3.24-3.18 (m, 8H), 1.86 (t, J=6.8Hz, 2H ), 1.69(dd, J=5.5, 4.2Hz, 4H), 1.31-1.25(m, 36H), 0.89(t, J=7.4Hz, 6H). Example 2

[0033] A method for preparing a biodegradable geminate morpholine quaternary ammonium salt includes the following steps: By replacing dodecane bromo in S1 with decane bromo, and otherwise following the same procedure as in Example 1, a biodegradable geminomorpholine quaternary ammonium salt, denoted as compound 2, was prepared. Its structural formula is shown below: .

[0034] 1H NMR (400MHz, DMSO) δ 4.15 (s, 4H), 3.82 (t, J=8.3Hz, 8H), 3.47 (s, 6H), 3.39 (t, J=6.2Hz, 8H), 3.26-3.20 (m, 8H), 1.88 (t, J=6.4Hz, 2H), 1.72 (dd, J=5.3, 4.0Hz, 4H), 1.31-1.22 (m, 28H), 0.90 (t, J=7.2Hz, 6H). Its NMR spectrum is as follows Figure 1 As shown.

[0035] Example 3

[0036] A method for preparing a biodegradable geminate morpholine quaternary ammonium salt includes the following steps: By replacing dodecane bromopropylidene in S1 with octane bromopropylidene, and otherwise following the same procedure as in Example 1, a biodegradable geminomorpholine quaternary ammonium salt, denoted as compound 3, was prepared. Its structural formula is shown below: .

[0037] 1 H NMR (400MHz, DMSO) δ 4.13 (s, 4H), 3.82 (t, J=8.5Hz, 8H), 3.47 (s, 6H), 3.40 (t, J=6.0Hz, 8H), 3.26-3.20 (m, 8H), 1.86 (t, J=6.6Hz, 2H ), 1.68(dd, J=5.6, 4.2Hz, 4H), 1.32-1.24(m, 20H), 0.92(t, J=7.4Hz, 6H). Example 4

[0038] A method for preparing a biodegradable geminate morpholine quaternary ammonium salt includes the following steps: By replacing N,N'-dimethyl-1,3-propanediamine in S2 with N,N'-dimethyl-1,4-butanediamine, and otherwise following the same procedure as in Example 1, a biodegradable geminomorpholine quaternary ammonium salt was prepared, denoted as compound 4, with the following structural formula: .

[0039] 1H NMR (400MHz, DMSO) δ 4.14 (s, 4H), 3.81 (t, J=8.2Hz, 8H), 3.45 (s, 6H), 3.41 (t, J=6.4Hz, 8H), 3.26-3.20 (m, 8H), 1.76 (t, J=5.8Hz, 4H ), 1.53(t, J=6.8Hz, 4H), 1.31-1.20(m, 36H), 0.88(t, J=7.0Hz, 6H). Example 5

[0040] A method for preparing a biodegradable geminate morpholine quaternary ammonium salt includes the following steps: By replacing bromododecane in S1 with chlorododecane, and replacing bromoacetyl bromide in S2 with chloroacetyl chloride, and otherwise following the same procedure as in Example 1, a biodegradable geminate morpholine quaternary ammonium salt, denoted as compound 5, was prepared. Its structural formula is shown below: .

[0041] 1 H NMR (400MHz, DMSO) δ 4.13 (s, 4H), 3.81 (t, J=8.3Hz, 8H), 3.47 (s, 6H), 3.39 (t, J=6.5Hz, 8H), 3.26-3.20 (m, 8H), 1.86 (t, J=6.4Hz, 2H ), 1.65(dd, J=5.5, 4.2Hz, 4H), 1.32-1.22(m, 36H), 0.88(t, J=7.0Hz, 6H). Example 6

[0042] A method for preparing a biodegradable geminate morpholine quaternary ammonium salt includes the following steps: By replacing N,N'-dimethyl-1,3-propanediamine in S2 with 1,3-propanediamine, and otherwise following the same procedure as in Example 1, a biodegradable geminomorpholine quaternary ammonium salt, denoted as compound 6, was prepared. Its structural formula is shown below: .

[0043] 1 H NMR (400MHz, DMSO) δ 7.98 (s, 2H), 4.14 (s, 4H), 3.81 (t, J=8.8Hz, 8H), 3.42-3.38 (m, 12H), 3.22 (t, J=4.8Hz, 4H), 1.86 (t, J=6.6Hz, 2H ), 1.70(dd, J=5.8, 4.0Hz, 4H), 1.32-1.24(m, 36H), 0.88(t, J=7.0Hz, 6H). Example 7

[0044] A method for preparing a biodegradable geminate morpholine quaternary ammonium salt includes the following steps: By replacing dodecane bromo in S1 with decane bromo, and replacing N,N'-dimethyl-1,3-propanediamine in S2 with 1,3-propanediamine, and otherwise following the same procedure as in Example 1, a biodegradable geminate morpholine quaternary ammonium salt, denoted as compound 7, was prepared. Its structural formula is shown below: .

[0045] 1 H NMR (400MHz, DMSO) δ 7.95 (s, 2H), 4.16 (s, 4H), 3.80 (t, J=9.1Hz, 8H), 3.42-3.38 (m, 12H), 3.24 (t, J=5.2Hz, 4H), 1.86 (t, J=6.4Hz, 2H ), 1.68(dd, J=5.5, 4.0Hz, 4H), 1.31-1.20(m, 28H), 0.88(t, J=7.8Hz, 6H). Its NMR spectrum is as follows Figure 2 As shown.

[0046] Example 8

[0047] A method for preparing a biodegradable geminate morpholine quaternary ammonium salt includes the following steps: By replacing N,N'-dimethyl-1,3-propanediamine in S2 with 1,2-propanediamine, and otherwise following the same procedure as in Example 1, a biodegradable geminomorpholine quaternary ammonium salt was prepared, denoted as compound 8, with the following structural formula: .

[0048] 1 H NMR (400MHz, DMSO) δ 8.03 (s, 2H), 4.39 (t, J=5.3Hz, 1H), 4.13 (s, 4H), 3.81 (t, J=8.5Hz, 8H), 3.54 (d, J=12.8Hz, 2H), 3.41-3.24 (m, 12H ), 1.75(t, J=6.8Hz, 4H), 1.31-1.20(m, 39H), 0.88(t, J=8.2Hz, 6H). Comparative Example 1 Compounds 9, 10, and 11 were prepared according to Examples 1-3 of application document No. 202311620124.5, and their structures are shown below: Compound 9 Compound 10 Compound 11.

[0049] Each substance was placed in simulated gastric acid (pH=1.5) at 37℃ for 1 hour to investigate its bactericidal effect on Helicobacter pylori. The concentration of each substance was the same, 0.05% w / w. The results are shown in Table 1.

[0050]

[0051] As shown in Table 1, compounds 1-8 all have good bactericidal effects against Helicobacter pylori, with a bactericidal rate as high as 99.9999% at a concentration of only 0.05% w / w.

[0052] Compounds 1-11 were tested in a simulated gastric acid solution to detect their bactericidal effects on Helicobacter pylori. Metronidazole, a commonly used drug for treating Helicobacter pylori, was used as a comparison. The results are shown in Table 2.

[0053] The specific method is as follows: each group of substances is placed in simulated gastric acid (pH=1.5) at 37℃ for 1 hour, and each is diluted 0.1% w / w to achieve a minimum bactericidal rate of 99.999% as the minimum bactericidal concentration of the compound.

[0054] As can be seen from Table 2, the biodegradable geminomorpholine quaternary ammonium salt of the present invention has good killing performance against Helicobacter pylori.

[0055] The biodegradable geminomorpholine quaternary ammonium salt of this invention carries a positive charge and can adsorb negatively charged Helicobacter pylori. It also has a straight-chain alkyl group with a suitable chain length, which allows it to achieve hydrophobic binding with Helicobacter pylori. Furthermore, it contains an amide group, which can form hydrogen bonds with the groups on the surface of the Helicobacter pylori cell wall. Through multiple interactions such as electrostatic adsorption, hydrophobic binding, and hydrogen bonding, it accumulates on the cell wall of Helicobacter pylori, producing a compartment resistance effect and destroying the cell wall, leading to the inhibition of Helicobacter pylori growth and death.

[0056] Compounds 1-8 were tested for degradation in simulated intestinal fluid (pH=7.6) at 37℃, with each compound having a concentration of 1 wt%. The results are shown in Table 3.

[0057]

[0058] As can be seen from Table 3, the gemimomorpholine quaternary ammonium salt described in this invention is degradable in simulated intestinal fluid, which can prevent Helicobacter pylori from developing drug resistance to it, and can make the degradation products be quickly excreted from the body.

[0059] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A biodegradable geminimorpholine quaternary ammonium salt, characterized in that, The structural formula of the biodegradable geminate morpholine quaternary ammonium salt is shown in formula (I): Formula (I); Where X is a halogen, R1 and R2 are each independently one of H and an alkyl group having 1-6 carbon atoms; R3 is one of the alkyl groups having 8-12 carbon atoms; R4 is one of the alkyl groups having 2-6 carbon atoms.

2. The biodegradable geminomorpholine quaternary ammonium salt according to claim 1, characterized in that, X is either Cl or Br.

3. The biodegradable geminomorpholine quaternary ammonium salt according to claim 1, characterized in that, The structural formula of the biodegradable geminate morpholine quaternary ammonium salt is shown below: 。 4. A method for preparing the biodegradable geminal morpholine quaternary ammonium salt as described in any one of claims 1-3, characterized in that, The steps include: S1. Morpholine and haloalkane are subjected to N-alkylation reaction to obtain N-alkylmorpholine; S2. React substance A with a haloacetyl halide to obtain substance B; S3. Further N-alkylation reaction of N-alkylmorpholine and substance B yields biodegradable geminate morpholine quaternary ammonium salt; Among them, the structural formula of substance A is shown in formula (II), and the structural formula of substance B is shown in formula (III): Formula (II) Formula (Ⅲ); X is a halogen. R1 and R2 are each independently one of H and an alkyl group having 1-6 carbon atoms; R4 is one of the alkyl groups having 2-6 carbon atoms; In S1, the general chemical formula of haloalkanes is C n H 2n+1 X, where n is an integer between 8 and 12.

5. The method for preparing the biodegradable geminal morpholine quaternary ammonium salt according to claim 4, characterized in that, In S1, the N-alkylation reaction is carried out at a temperature of 70-120℃ for a time of 10-40h.

6. The use of the biodegradable geminate morpholine quaternary ammonium salt as described in any one of claims 1-3 in the preparation of a bactericide.

7. The use of the degradable geminomorpholine quaternary ammonium salt as described in any one of claims 1-3 in the preparation of a drug for treating Helicobacter pylori infection.

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