Degradable Gemini morpholine quaternary ammonium salt, and preparation method and application thereof

Abstract

The application discloses a degradable gemini morpholine quaternary ammonium salt. The application further discloses a preparation method of the degradable gemini morpholine quaternary ammonium salt, comprising the following steps: S1, performing N-alkylation reaction on morpholine and halogenated alkane to obtain N-alkyl morpholine; S2, performing reaction on substance A and halogenated acetyl halide to obtain substance B; S3, continuously performing N-alkylation reaction on the N-alkyl morpholine and the substance B to obtain the degradable gemini morpholine quaternary ammonium salt. The application further discloses application of the degradable gemini morpholine quaternary ammonium salt in a bactericide and in preparation of a medicine for treating helicobacter pylori infection. The gemini morpholine quaternary ammonium salt has a good effect of killing helicobacter pylori; the gemini morpholine quaternary ammonium salt can be degraded in an alkaline environment, can avoid drug resistance of helicobacter pylori to the gemini morpholine quaternary ammonium salt, and can make the degradation product be rapidly discharged out of the body.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, in particular to a degradable gemini morpholine quaternary ammonium salt, a preparation method and application thereof. BACKGROUND

[0002] Helicobacter pylori (HP) infection is the most common chronic infectious disease in the world, but the prevalence rate varies greatly. HP can cause a variety of diseases, including gastric ulcer, duodenal ulcer, 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] At present, single drug treatment cannot completely eradicate Hp infection, and combined drug therapy is often used to treat Hp infection, especially triple therapy. In recent years, Hp drug resistance has gradually increased, especially clarithromycin, and the eradication rate of triple therapy has gradually decreased, and quadruple therapy has gradually replaced triple therapy, so it has strong practical significance and value to find a treatment regimen with lower drug resistance, higher eradication rate and better efficacy. SUMMARY

[0004] Based on the technical problems existing in the background art, the present application provides a degradable gemini morpholine quaternary ammonium salt, a preparation method and application thereof. The present application provides a gemini morpholine quaternary ammonium salt with a specific structure, which has good effect on killing Helicobacter pylori. And the gemini morpholine quaternary ammonium salt can be degraded in an alkaline environment, which can avoid the drug resistance of Helicobacter pylori, and the degradation product can be quickly excreted out of the body.

[0005] The present application provides a degradable gemini morpholine quaternary ammonium salt, and the structural formula of the degradable gemini morpholine quaternary ammonium salt is shown as formula (I): Formula (I);

[0006] Wherein, X is halogen, R1 and R2 are each independently H or alkyl, and R3 and R4 are each independently alkyl.

[0007] Preferably, R1 and R2 are each independently one of H and alkyl with 1-6 carbon atoms.

[0008] More preferably, R1 and R2 are each independently H or methyl.

[0009] Preferably, R3 is one of alkyl with 8-12 carbon atoms; more preferably, R3 is one of linear alkyl with 8-10 carbon atoms.

[0010] Preferably, R4 is one of alkyl with 2-6 carbon atoms; more preferably, R4 is one of alkyl with 2-4 carbon atoms.

[0011] Preferably, X is Cl or Br.

[0012] Preferably, the degradable gemini morpholine quaternary ammonium salt has the following structure:

[0013] .

[0014] The application also provides a preparation method of the degradable gemini morpholine quaternary ammonium salt, comprising the following steps:

[0015] S1, N-alkylating morpholine and halogenated alkane to obtain N-alkyl morpholine;

[0016] S2, reacting substance A with halogenated acetyl halide to obtain substance B;

[0017] S3, continuing N-alkylating N-alkyl morpholine and substance B to obtain the degradable gemini morpholine quaternary ammonium salt;

[0018] wherein, the structure of substance A is shown in formula (II), and the structure of substance B is shown in formula (III): formula (II), formula (III);

[0019] X is halogen, R1 and R2 are independently H or alkyl, and R4 is alkyl.

[0020] Preferably, in S1, the chemical formula of halogenated alkane is C n H 2n+1 X, and n is an integer of 8-12.

[0021] Preferably, in S1, the temperature of N-alkylation reaction is 70-120℃, and the time is 10-40h.

[0022] In the above S2, the temperature of reaction is 30-40℃, and the time is 3.5-4.5h.

[0023] In the above S3, the temperature of reaction is 50-120℃, and the time is 20-30h.

[0024] The application further provides application of the degradable gemini morpholine quaternary ammonium salt in preparation of a bactericide and in preparation of a medicine for treating H. pylori infection.

[0025] The medicine for treating H. pylori infection comprises the degradable gemini morpholine quaternary ammonium salt and a pharmaceutically acceptable pharmaceutical adjuvant.

[0026] The pharmaceutically acceptable pharmaceutical adjuvant can be classified into solvents, propellants, solubilizers, co-solvents, emulsifiers, coloring agents, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, integrating agents, penetration promoters, pH regulators, buffers, plasticizers, surfactants, antifoaming agents, thickening agents, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retardants and the like.

[0027] Preferably, the dosage form of the medicine is an oral preparation, a respiratory tract administration dosage form, a skin administration dosage form, a mucosa administration dosage form or a cavity administration dosage form.

[0028] The oral preparation can be a powder, a tablet, a granule, a capsule, a solution, an emulsion, a suspension and the like.

[0029] The respiratory tract administration dosage form can be a spray, an aerosol, a powder mist and the like.

[0030] The skin administration dosage form can be a topical solution, a lotion, a liniment, an ointment, a plaster, a paste, a patch and the like.

[0031] The mucosa administration dosage form can be an eye drop, a nose drop, an eye ointment, a gargle, a sublingual tablet, a sticking tablet, a patch film and the like.

[0032] The cavity administration dosage form can be a suppository, an aerosol, an effervescent tablet, a drop and a dripping pill and the like.

[0033] The application provides the gemini morpholine quaternary ammonium salt with the specific structure, which has good H. pylori killing effect, even when the dosage is small, and the effect is much better than that of the existing quaternary ammonium salt. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 The figure is a nuclear magnetic spectrum of compound 2.

[0035] Figure 2 The figure is a nuclear magnetic spectrum of compound 7. DETAILED DESCRIPTION

[0036] The technical solutions of the present application will be described in detail below through specific embodiments.

[0037] Example 1

[0038] A preparation method of a degradable gemini morpholine quaternary ammonium salt, comprising the following steps:

[0039] S1, 0.015 mol of morpholine, 0.01 mol of bromododecane, and 0.01 mol of sodium hydroxide are added to isopropyl alcohol, heated to 90°C, and condensed to reflux for 24 hours, then filtered, and the filtrate is concentrated by vacuum distillation, then extracted with ethyl acetate and water three times, and the organic phase is concentrated under reduced pressure to obtain N-dodecyl morpholine;

[0040] S2, 0.02 mol of bromoacetyl bromide is dissolved in dichloromethane, then 0.01 mol of N,N'-dimethyl-1,3-propanediamine is slowly added dropwise under ice bath and stirring conditions, and after the dropwise addition is completed, it is reacted in a 35°C water bath for 4 hours, then evaporated under reduced pressure at 60°C using a rotary evaporator for 1 hour, dissolved in water, filtered, and then recrystallized once with anhydrous ethanol to obtain substance B;

[0041] S3, 0.006 mol of N-dodecyl morpholine and 0.003 mol of substance B are added to isopropyl alcohol, heated to 90°C, and condensed to reflux for 24 hours, then concentrated by vacuum distillation, washed with acetone three times, and then concentrated under reduced pressure to remove acetone to obtain a degradable gemini morpholine quaternary ammonium salt, denoted as compound 1, whose structural formula is as shown below: .

[0042] 1 H NMR (400 MHz, DMSO) δ 4.14 (s, 4H), 3.83 (t, J = 8.1 Hz, 8H), 3.48 (s, 6H), 3.42 (t, J = 6.7 Hz, 8H), 3.24-3.18 (m, 8H), 1.86 (t, J = 6.8 Hz, 2H), 1.69 (dd, J = 5.5, 4.2 Hz, 4H), 1.31-1.25 (m, 36H), 0.89 (t, J = 7.4 Hz, 6H).

[0043] Example 2

[0044] A preparation method of a degradable gemini morpholine quaternary ammonium salt, comprising the following steps:

[0045] In S1, bromododecane is replaced by bromodecane, and the rest is the same as in Example 1 to obtain a degradable gemini morpholine quaternary ammonium salt, denoted as compound 2, whose structural formula is as shown below: .

[0046] 1 H NMR (400 MHz, DMSO) δ 4.15 (s, 4H), 3.82 (t, J = 8.3 Hz, 8H), 3.47 (s, 6H), 3.39 (t, J = 6.2 Hz, 8H), 3.26-3.20 (m, 8H), 1.88 (t, J = 6.4 Hz, 2H), 1.72 (dd, J = 5.3, 4.0 Hz, 4H), 1.31-1.22 (m, 28H), 0.90 (t, J = 7.2 Hz, 6H).

[0047] The nuclear magnetic spectrum thereof is as shown in Figure 1 .

[0048] Example 3

[0049] A preparation method of a degradable gemini morpholine quaternary ammonium salt, comprising the following steps:

[0050] The bromododecane in S1 is replaced by bromooctane, and the rest is the same as in Example 1 to prepare a degradable gemini morpholine quaternary ammonium salt, denoted as compound 3, and the structural formula is as shown below: .

[0051] 1 H NMR (400 MHz, DMSO) δ 4.15 (s, 4H), 3.82 (t, J = 8.3 Hz, 8H), 3.47 (s, 6H), 3.39 (t, J = 6.2 Hz, 8H), 3.26-3.20 (m, 8H), 1.88 (t, J = 6.4 Hz, 2H), 1.72 (dd, J = 5.3, 4.0 Hz, 4H), 1.31-1.22 (m, 28H), 0.90 (t, J = 7.2 Hz, 6H).

[0052] Example 4

[0053] A preparation method of a degradable gemini morpholine quaternary ammonium salt, comprising the following steps:

[0054] The N,N'-dimethyl-1,3-propanediamine in S2 is replaced by N,N'-dimethyl-1,4-butanediamine, and the rest is the same as in Example 1 to prepare a degradable gemini morpholine quaternary ammonium salt, denoted as compound 4, and the structural formula is as shown below: .

[0055] 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).

[0056] Example 5

[0057] A method for preparing a biodegradable geminate morpholine quaternary ammonium salt includes the following steps:

[0058] 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: .

[0059] 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).

[0060] Example 6

[0061] A method for preparing a biodegradable geminate morpholine quaternary ammonium salt includes the following steps:

[0062] 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: .

[0063] 1H 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).

[0064] Example 7

[0065] A method for preparing a biodegradable geminate morpholine quaternary ammonium salt includes the following steps:

[0066] 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: .

[0067] 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).

[0068] Its NMR spectrum is as follows Figure 2 As shown.

[0069] Example 8

[0070] A method for preparing a biodegradable geminate morpholine quaternary ammonium salt includes the following steps:

[0071] 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: .

[0072] 1H 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).

[0073] Comparative Example 1

[0074] Compounds 9, 10, and 11 were prepared according to Examples 1-3 of application document No. 202311620124.5, and their structures are shown below:

[0075] Compound 9 Compound 10 Compound 11.

[0076] 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.

[0077]

[0078] 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.

[0079] 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.

[0080] 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.

[0081] As can be seen from Table 2, the biodegradable geminomorpholine quaternary ammonium salt of the present invention has good killing performance against Helicobacter pylori.

[0082] 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.

[0083] 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.

[0084]

[0085] 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.

[0086] 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, Includes 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 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 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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