Quaternary ammonium salt compound, preparation method therefor and use thereof

Abstract

A compound is shown in formula I and can be in the form of a pharmaceutically acceptable salt, or a stereoisomer, or a solvate, or a prodrug, or a metabolite. The compound takes effect rapidly and has a long-time local anesthetic effect following a single dose, with the sensory nerve blocking time being greater than the motor nerve blocking time, has both a long-acting local anesthetic effect and a selective local anesthetic effect, significantly reduces side effects of the compositions QX314 and QX314 and a quaternary ammonium salt compound with surfactant structural characteristics, and is safer. The compound of formula I of the present invention and a pharmaceutically acceptable salt thereof can be used for preparing drugs that have a long-time local anesthetic effect and a selective local anesthetic effect.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a metabolite thereof: ##STR00083## wherein, X and Y are independently selected from O, S, and NR.sub.10, in which R.sub.10 is H, deuterium, or C.sub.1-4 alkyl; Z.sup.− is a pharmaceutically acceptable anion; R.sub.1 is an aryl substituted by a n.sub.1 R.sub.11 group; R.sub.2 is an aryl substituted by a n.sub.1′ R.sub.11′ group; wherein, n.sub.1 and n.sub.1′ are independently selected from an integer of 0 to 4, and R.sub.11 and R.sub.11′ are independently deuterium, C.sub.1-4 alkyls, C.sub.1-4 alkoxys, halogen, nitro, cyano, hydroxyl, carboxyl, amino, thiol, and ester group; with the proviso that when one of R.sub.3 and R.sub.4 is C.sub.1 alkyl, the other is a C.sub.1-4 alkyl; with the proviso that when one of R.sub.3 and R.sub.4 is C.sub.2 alkyl, the other is selected from C.sub.1, C.sub.3, C.sub.4 alkyls; with the proviso that when one of R.sub.3 and R.sub.4 is C.sub.3 alkyl, the other is selected from C.sub.3-4 alkyls; with the proviso that when one of R.sub.3 and R.sub.4 is C.sub.4 alkyl, the other is C.sub.4 alkyl; L.sub.1 is a substituted or unsubstituted C.sub.1-14 alkylenyl; wherein the main chain of said alkylenyl contains 0-4 heteroatoms, and said heteroatoms are selected from O, S, and NR.sub.12, in which said R.sub.12 is selected from hydrogen, deuterium, C.sub.1-4 alkyls, and C.sub.1-4 alkoxys; said substituent is deuterium, a C.sub.1-4 alkyl, a C.sub.1-4 alkoxy, and a halogen; wherein, when the dashed line in formula I is none, L.sub.2 is selected from hydrogen, deuterium, substituted or unsubstituted C.sub.1-8 alkyls, and substituted or unsubstituted C.sub.1-8 alkoxys, in which said substituent is deuterium, a C.sub.1-4 alkyl, a C.sub.1-4 alkoxy, or a halogen; and wherein, when the dashed line in formula I is a bond, L.sub.2 is a substituted or unsubstituted C.sub.1-8 alkylenyl, in which the substituent is deuterium, a C.sub.1-4 alkyl, a C.sub.1-4 alkoxy, or a halogen.

2. The compound according to claim 1, wherein said pharmaceutically acceptable anion Z.sup.− is a halogen anion, a sulfate, an acetate, a tartrate, a p-toluenesulfonate, a methanesulfonate, or a citrate.

3. The compound according to claim 1, wherein said pharmaceutically acceptable anion Z.sup.− is a halogen anion.

4. The compound according to claim 1, wherein said pharmaceutically acceptable anion Z.sup.− is Br.sup.−.

5. The pharmaceutically acceptable salt of claim 1, comprising compound of formula I and a pharmaceutically acceptable inorganic acid or organic acid.

6. The pharmaceutically acceptable salt of claim 5, wherein said inorganic acid or organic acid is selected from hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, tartaric acid, lauric acid, maleic acid, citric acid, and benzoic acid.

7. The compound according to claim 1, wherein X and Y are independently selected from O, S, and NR.sub.10, in which R.sub.10 is H, deuterium, or a C.sub.1-2 alkyl.

8. The compound according to claim 1, wherein, in n.sub.1 R.sub.11 and n.sub.1′ R.sub.11′, n.sub.1 and n.sub.1′ are independently selected from an integer of 0 to 4, and r.sub.11 and R.sub.11′ are independently selected from deuterium, C.sub.1-4 alkyls, C.sub.1-4 alkoxys, halogens, nitro, cyano, hydroxyl, carboxyl, amino, thiol, and ester group, with the proviso that when R.sub.3 is a C.sub.1 alkyl, R.sub.4 is a C.sub.1-2 alkyl.

9. The compound according to claim 8, wherein, n.sub.1 and n.sub.1′ are independently selected from an integer of 0 to 4, and R.sub.11 and R.sub.11′ are independently selected from deuterium, C.sub.1-3 alkyls, methoxy, halogens, nitro, cyano, hydroxyl, carboxyl, amino, thiol, and ester group.

10. The compound according to claim 1, wherein: L.sub.1 is selected from substituted C.sub.2-14 alkylenyls and unsubstituted C.sub.2-14 alkylenyls; wherein the main chain of said alkylenyl contains 0-3 heteroatoms, and said heteroatoms are selected from O, S, and NR.sub.12, in which said R.sub.12 is selected from hydrogen, deuterium, and C.sub.1-2 alkyl; said substituent is selected from deuterium, C.sub.1-2 alkyls, and C.sub.1-2 alkoxys; wherein, when the dashed line in formula I is none, L.sub.2 is selected from hydrogen, deuterium, unsubstituted C.sub.1-8 alkyls, and substituted C.sub.1-8 alkyls in which the substituent is deuterium or a C.sub.1-2 alkyl; and when the dashed line in formula I is a bond, L.sub.2 is selected from unsubstituted C.sub.2-6 alkylenyl and substituted C.sub.2-6 alkylenyl in which the substituent is deuterium, a C.sub.1-2 alkyl, or a C.sub.1-2 alkoxy.

11. The compound according to claim 10, wherein: L.sub.1 is selected from substituted C.sub.2-14 alkylenyls in which the substituent is selected from deuterium, C.sub.1-2 alkyls and unsubstituted C.sub.2-14 alkylenyls, wherein the main chain of said alkylenyl contains 0-2 heteroatoms, and said heteroatoms are selected from O, S, and NR.sub.12, in which said R.sub.12 is hydrogen or deuterium, when the dashed line in formula I is none, L.sub.2 is hydrogen, deuterium, or a C.sub.1-8 alkyl; and when the dashed line in formula I is a bond, L.sub.2 is a substituted or unsubstituted C.sub.2-6 alkylenyl, in which the substituent is deuterium, methyl, or methoxyl.

12. The compound according to claim 1, wherein the compound is of formula II: ##STR00084## wherein: X and Y are each independently selected from O and NR.sub.10, in which R.sub.10 is H, deuterium, or a C.sub.4 alkyl, R.sub.11 and R.sub.11′ are independently selected from deuterium, C.sub.1-3 alkyls, methoxyl, halogens, nitro, cyano, hydroxyl, carboxyl, amino, thiol, and ester group, n.sub.1 and n.sub.1′ are independently 2 or 3, L.sub.1 is a C.sub.3-14 alkylenyl, wherein the main chain of said alkylenyl contains 0-2 heteroatoms, and said heteroatoms are selected from O, S, and NR.sub.12, in which said R.sub.12 is hydrogen or deuterium, and L.sub.2 is a substituted or unsubstituted C.sub.2-6 alkylenyl, in which said substituent is methyl or methoxyl.

13. The compound according to claim 12 selected from ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091##

14. The compound according to claim 1, wherein the compound is of formula III: ##STR00092## wherein: X and Y are each independently selected from O, S, and NR.sub.10, in which R.sub.10 is H, deuterium, or a C.sub.4 alkyl; R.sub.11 and R.sub.11′ are independently selected from deuterium, C.sub.1 alkyl, methoxyl, and halogens; n.sub.1 and n.sub.1′ are independently of selected from an integer of 2-4; L.sub.1 is a C.sub.2-10 alkylenyl; wherein the main chain of said alkylenyl contains 0-2 heteroatoms, and said heteroatoms are selected from O, S, and NR.sub.12, in which said R.sub.12 is hydrogen or deuterium; and L.sub.2 is selected from H, deuterium, and C.sub.1-8 alkylenyls.

15. The compound according to claim 1 selected from ##STR00093## ##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100##

16. A method for preparing compound according to claim 1, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or solvates thereof, or metabolites thereof, comprising the step of reacting the quaternary ammonium compound of formula IV with the amine compound of formula V in the presence of a base to obtain the target compound of formula I: ##STR00101## wherein L.sub.3 in formula V is hydrogen.

17. The preparative method according to claim 16, wherein said base is an inorganic base or an organic base, and wherein said inorganic base is potassium carbonate or cesium carbonate; and said organic base is triethylamine or 1,8-diazabicycloundec-7-ene.

18. The preparative method according to claim 16, wherein said reaction is carried out in a polar protic solvent.

19. The preparative method according to claim 18, wherein said solvent is methanol or ethanol.

20. A drug comprising the compound of formula I, or the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, or the solvate thereof, or the metabolite thereof according to claim 1, and one or more pharmaceutically acceptable adjuvants.

Description

EXAMPLES

(1) The starting materials and equipment used in the specific examples of the present invention are all known products and can be obtained by purchasing commercially available items.

Example 1 Preparation of Compound of the Present Invention

(2) ##STR00006##

(3) Compound 1a (10.0 g, 45.39 mmol) was dissolved in 1,3-dibromopropane (15 mL), and the mixture was heated to 75° C. and reacted for 40 h. The reaction was monitored by TLC (DCM:MeOH=10:1, Rf=0.3). A suitable amount of ethyl acetate was added to form a viscous syrupy substance. The supernatant was poured out, to obtain the residue of 15 g crude product, which was dissolved in 30 mL methanol and mixed with silica gel. After dry loading, silica gel column chromatography was used for purification, with eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluent was collected and concentrated to obtain 7.0 g crude product. The resultant product was recrystallized in ethyl acetate and dichloromethane, to prepare 6.6 g off-white solid powder (intermediate 1b) with a yield of 34.4%, which was used in the next reaction.

(4) Intermediate 1b (1.00 g, 2.37 mmol) prepared above and N-(2,6-dimethylphenyl)-2-piperidinecarboxamide (0.604 g, 2.61 mmol, CAS: 15883-20-2) were dissolved in 10 mL ethanol, to which was added DIPEA (0.99 g, 0.78 mL, 4.74 mmol). The mixture was warmed to 80° C. and kept for 40 hours. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluate was collected and concentrated to obtain 600 mg white solid (1). Yield: 44.15%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ (ppm): 10.35 (s, 1H), 7.84 (s, 1H), 7.11-7.01 (m, 6H), 4.89 (s, 2H), 3.80-3.45 (m, 6H), 3.20 (s, 3H), 2.71-2.57 (m, 2H), 2.28-2.17 (m, 14H), 2.02 (m, 1H), 1.90-1.63 (m, 6H), 1.60-1.27 (m, 3H).

Example 2 Preparation of Compound of the Present Invention

(5) ##STR00007##

(6) Compound 2a (10.0 g, 40.32 mmol) was dissolved in 1,3-dibromobutane (20 mL), and the mixture was heated to 75° C. and reacted for 24 h. The reaction was monitored by TLC (DCM:MeOH=10:1, Rf=0.3). A suitable amount of ethyl acetate was added, then the reaction solution solidified to produce white solids, and 16.0 g crude product was filtered out as white solid, that was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=20:1. The eluent was collected and concentrated to obtain 5.9 g white solid (intermediate 2b), with a yield of 31.5%, which was used in the next reaction.

(7) Intermediate 2b (1.0 g, 2.16 mmol) prepared above and N-(2,6-dimethylphenyl)-2-piperidinecarboxamide (0.55 g, 2.37 mmol, CAS: 15883-20-2) were dissolved in 15 mL ethanol, to which was added DIPEA (0.53 g, 0.68 mL, 4.12 mmol). The mixture was allowed to react for 10 days at the temperature of 30° C. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluate was collected and concentrated to obtain 995 mg white powder solid (2). Yield: 75.1%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ (ppm): 9.79 (s, 1H), 7.60 (s, 1H), 7.02-6.90 (m, 5H), 4.33 (s, 2H), 3.63-3.41 (m, 6H), 3.25-3.01 (m, 2H), 2.94 (s, 2H), 2.08 (s, 6H), 2.07 (s, 6H), 1.89-1.74 (m, 12H), 1.60-1.40 (m, 1H), 1.40-1.20 (m, 6H).

Example 3 Preparation of Compound of the Present Invention

(8) ##STR00008##

(9) Compound 3a (2.0 g, 8.06 mmol) was dissolved in 1,5-dibromopentane (4 mL), and the mixture was heated to 70° C. and reacted for 24 h. The reaction was monitored by TLC (DCM:MeOH=20:1, Rf=0.3). A suitable amount of ethyl acetate was added, then the reaction solution solidified to produce white solids, and 16.0 g crude product was filtered out as white solid, that was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=20:1. The eluent was collected and concentrated to obtain 1.8 g white powder solid (intermediate 3b), with a yield of 46.7%, which was used in the next reaction.

(10) Intermediate 3b (1.8 g, 3.77 mmol) prepared above and N-(2,6-dimethylphenyl)-2-piperidinecarboxamide (0.96 g, 4.14 mmol, CAS: 15883-20-2) were dissolved in the solvent mixture of 30 mL ethanol and 5 mL methanol, to which was added DIPEA (0.97 g, 1.24 mL, 7.54 mmol). The mixture was allowed to react for 18 days at the temperature of 30° C. After completion of the reaction, the crude product was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluate was collected and concentrated to obtain 500 mg white powder solid (3). Yield: 20.1%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ (ppm): 10.24 (s, 1H), 8.39 (s, 1H), 7.05-6.87 (m, 5H), 4.68 (s, 2H), 3.60-3.50 (m, 6H), 3.30-3.05 (m, 2H), 2.90-2.70 (m, 1H), 2.35 (s, 1H), 2.17-2.14 (m, 12H), 2.05-1.55 (m, 10H), 1.49-1.31 (m, 11H).

Example 4 Preparation of Compound of the Present Invention

(11) ##STR00009##

(12) Compound 4a (10.0 g, 40.3 mmol) was dissolved in 1,8-dibromooctane (15 mL), and the mixture was heated to 75° C. and reacted for 40 h. The reaction was monitored by TLC (DCM:MeOH=10:1). A suitable amount of ethyl acetate was added to form a viscous syrupy substance. The supernatant was poured out, and the residual solid was dissolved, mixed with silica gel, and purified by silica gel column chromatography, with eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluent was collected and concentrated to obtain 7.4 g crude product. The resultant product was recrystallized in ethyl acetate and dichloromethane, to prepare 6.9 g off-white solid powder (intermediate 4b), which was directly used in the next reaction.

(13) Intermediate 4b (1.00 g, 1.92 mmol) prepared above and N-(2,6-dimethylphenyl)-2-piperidinecarboxamide (498 mg, 2.11 mmol, CAS: 15883-20-2) were dissolved in 10 mL ethanol, to which was added DIPEA (0.63 mL, 3.84 mmol). The mixture was warmed to 80° C. and kept for 40 hours. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluate was collected and concentrated to obtain 600 mg white solid (4). Yield: 46.6%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ (ppm): 10.50 (s, 1H), 8.13 (s, 1H), 7.11-7.01 (m, 5H), 4.88 (s, 2H), 3.64-3.61 (d, J=7.02 Hz, 4H), 3.48 (s, 2H), 2.96 (s, 1H), 2.86-2.79 (m, 2H), 2.27 (s, 6H), 2.23 (s, 6H), 2.17-1.96 (m, 4H), 1.76 (s, 10H), 1.60-1.42 (m, 14H).

Example 5 Preparation of Compound of the Present Invention

(14) ##STR00010##

(15) Compound 5a (1.0 g, 3.8 mmol) was dissolved in 1 mL bis(2-bromoethyl) ether and slowly added dropwise to 1.5 mL bis(2-bromoethyl) ether, and the mixture was heated to 70° C. and reacted. The reaction was monitored by TLC (DCM:MeOH=10:1). After completion of the reaction, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=20:1. The eluent was collected and concentrated to obtain 1.3 g brown compound (intermediate 5b), with a yield of 69.0%, which was used in the next reaction. Intermediate 5b (1.3 g, 2.6 mmol) prepared above and N-(2,6-dimethylphenyl)-2-piperidinecarboxamide (0.67 g, 2.89 mmol, CAS: 15883-20-2) were dissolved in 15 mL ethanol, to which was added DIPEA (0.86 g, 5.2 mmol). The mixture was allowed to react for 13 days at the temperature of 30° C., and the reaction was detected by TLC (DCM:MeOH=10:1). After completion of the reaction, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluate was collected and concentrated to obtain 500 mg white solid (5). Yield: 29.4%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ (ppm): 10.09 (s, 1H), 9.81 (s, m), 8.69 (s, 1H), 7.06-6.90 (m, 6H), 4.73 (s, 2H), 4.67-3.97 (d, J=4.05 Hz, 2H), 3.85-3.63 (m, 8H), 3.28-3.16 (m, 2H), 3.07-2.95 (m, 1H), 2.65-2.56 (m, 1H), 2.30-1.95 (m, 13H), 1.80-1.60 (m, 4H), 1.60-1.12 (m, 11H).

Example 6 Preparation of Compound of the Present Invention

(16) ##STR00011##

(17) Compound 6a (10.0 g, 39.4 mmol) was dissolved in 1,3-dibromopropane (15 mL), and the mixture was heated to 75° C. and reacted for 40 h. The reaction was monitored by TLC (DCM:MeOH=10:1, Rf=0.3). A suitable amount of ethyl acetate was added to form a viscous syrupy substance. The supernatant was poured out, to obtain the residue of 14 g crude product, which was dissolved in 30 mL methanol and mixed with silica gel. After dry loading, silica gel column chromatography was used for purification, with eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluent was collected and concentrated to obtain 8.0 g crude product. The resultant product was recrystallized in ethyl acetate and dichloromethane, to prepare 7.6 g off-white solid powder (intermediate 6b) with a yield of 42.3%, which was used in the next reaction.

(18) Intermediate 1b (1.00 g, 2.19 mmol) prepared above and N-(2,6-dimethylphenyl)-2-piperidinecarboxamide (0.559 g, 2.4 mmol, CAS: 15883-20-2) were dissolved in 10 mL ethanol, to which was added DIPEA (0.57 g, 0.72 mL, 4.38 mmol). The mixture was heated to 80° C. and kept for 40 hours. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluate was collected and concentrated to obtain 500 mg white solid (6). Yield: 37.6%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ (ppm): 10.35 (s, 1H), 7.84 (s, 1H), 7.11-7.01 (m, 5H), 4.89 (s, 2H), 3.80-3.45 (m, 6H), 3.20 (s, 3H), 2.71-2.57 (m, 2H), 2.28-2.17 (m, 14H), 2.02 (m, 1H), 1.90-1.63 (m, 6H), 1.60-1.27 (m, 3H).

Example 7 Preparation of Compound of the Present Invention

(19) ##STR00012##

(20) Compound 7a (10.0 g, 37.88 mmol) was dissolved in 1,8-dibromooctane (15 mL), and the mixture was heated to 75° C. and reacted for 40 h. The reaction was monitored by TLC (DCM:MeOH=10:1). A suitable amount of ethyl acetate was added to form a viscous syrupy substance. The supernatant was poured out, and the residual solid was dissolved, mixed with silica gel, and purified by silica gel column chromatography, with eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluent was collected and concentrated to obtain 8.4 g crude product. The resultant product was recrystallized in ethyl acetate and dichloromethane, to prepare 7.4 g off-white solid powder (intermediate 7b), which was directly used in the next reaction.

(21) Intermediate 7b (1.00 g, 1.87 mmol) prepared above and N-(2,6-dimethylphenyl)-2-piperidinecarboxamide (475 mg, 2.05 mmol, CAS: 15883-20-2) were dissolved in 10 mL ethanol, to which was added DIPEA (0.62 mL, 3.74 mmol). The mixture was heated to 80° C. and kept for 40 hours. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluate was collected and concentrated to obtain 500 mg white solid (7). Yield: 38.8%. 41 NMR (300 MHz, CDCl.sub.3) δ (ppm): 10.50 (s, 1H), 8.13 (s, 1H), 7.11-7.01 (m, 6H), 4.88 (s, 2H), 3.64-3.61 (d, J=7.02 Hz, 4H), 3.86 (s, 3H), 3.48 (s, 2H), 2.96 (s, 1H), 2.86-2.79 (m, 2H), 2.27 (s, 6H), 2.23 (s, 3H), 2.17-1.96 (m, 4H), 1.76 (s, 10H), 1.60-1.42 (m, 14H).

Example 8 Preparation of Compound of the Present Invention

(22) ##STR00013##

(23) Compound 8a (2.0 g, 8.54 mmol) was dissolved in 1,5-dibromopentane (4 mL), and the mixture was heated to 70° C. and reacted for 24 h. The reaction was monitored by TLC (DCM:MeOH=20:1, Rf=0.3). A suitable amount of ethyl acetate was added, then the reaction solution solidified to produce white solids, and 1.8 g crude product was filtered out as white solid, that was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=20:1. The eluent was collected and concentrated to obtain 1.6 g white powder solid (intermediate 8b), with a yield of 39.2%, which was used in the next reaction.

(24) Intermediates 8b (1.5 g, 3.23 mmol) and 8c (0.91 g, 3.55 mmol) were dissolved in the solvent mixture of 30 mL ethanol and 5 mL methanol, to which was added DIPEA (0.83 g, 1.06 mL, 6.46 mmol). The mixture was allowed to react for 18 days at the temperature of 30° C. After completion of the reaction, the crude product was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluate was collected and concentrated to obtain 600 mg white powder solid (8). Yield: 29.0%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ (ppm): 10.24 (s, 1H), 8.39 (s, 1H), 7.05-6.87 (m, 5H), 4.68 (s, 2H), 3.60-3.50 (m, 6H), 3.33 (s, 3H), 2.90-2.70 (m, 1H), 2.35 (s, 1H), 2.17-2.14 (m, 12H), 2.05-1.55 (m, 10H), 1.49-1.31 (m, 11H).

Example 9 Preparation of Compound of the Present Invention

(25) ##STR00014##

(26) Compound 9a (10.0 g, 45.45 mmol) was dissolved in 1,3-dibromopropane (15 mL), and the mixture was heated to 75° C. and reacted for 40 h. The reaction was monitored by TLC (DCM:MeOH=10:1, Rf=0.3). A suitable amount of ethyl acetate was added to form a viscous syrupy substance. The supernatant was poured out, to obtain the residue of 14 g crude product, which was dissolved in 30 mL methanol and mixed with silica gel. After dry loading, silica gel column chromatography was used for purification, with eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluent was collected and concentrated to obtain 8.0 g crude product. The resultant product was recrystallized in ethyl acetate and dichloromethane, to prepare 7.2 g off-white solid powder (intermediate 9b) with a yield of 37.5%, which was used in the next reaction.

(27) Intermediates 9b (1.00 g, 2.37 mmol) and 9c (0.504 g, 2.61 mmol) prepared above were dissolved in 10 mL ethanol, to which was added DIPEA (0.99 g, 0.78 mL, 4.74 mmol). The mixture was heated to 80° C. and kept for 40 hours. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluate was collected and concentrated to obtain 500 mg white solid (9). Yield: 39.6%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ (ppm): 10.35 (s, 1H), 7.84 (s, 1H), 7.11-7.01 (m, 6H), 4.89 (s, 2H), 3.80-3.45 (m, 6H), 3.20 (s, 3H), 2.71-2.57 (m, 2H), 2.32 (s, 3H) 2.28-2.17 (m, 11H), 2.02 (m, 1H), 1.90-1.63 (m, 2H), 1.60-1.27 (m, 3H).

Example 10 Preparation of Compound of the Present Invention

(28) ##STR00015##

(29) Compound 10a (10.0 g, 37.59 mmol) was dissolved in 1,3-dibromobutane (20 mL), and the mixture was heated to 75° C. and reacted for 24 h. The reaction was monitored by TLC (DCM:MeOH=10:1, Rf=0.3). A suitable amount of ethyl acetate was added, then the reaction solution solidified to produce white solids, and 15.0 g crude product was filtered out as white solid, that was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=20:1. The eluent was collected and concentrated to obtain 6.5 g white solid (intermediate 10b), with a yield of 35.9%, which was used in the next reaction.

(30) Intermediates 10b (1.0 g, 2.07 mmol) and 10c (0.47 g, 2.28 mmol) prepared above were dissolved in 15 mL ethanol, to which was added DIPEA (0.54 g, 0.69 mL, 4.14 mmol). The mixture was allowed to react for 10 days at the temperature of 30° C. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography, using eluent: CH.sub.2Cl.sub.2:MeOH=10:1. The eluate was collected and concentrated to obtain 900 mg white powder solid (10). Yield: 71.6%. .sup.1H NMR (300 MHz, CDCl.sub.3) δ (ppm): 9.79 (s, 1H), 7.60 (s, 1H), 7.02-6.90 (m, 5H), 4.33 (s, 2H), 3.26-3.06 (m, 6H), 2.64-2.42 (m, 4H), 2.10 (s, 6H), 2.09 (s, 6H), 1.89-1.74 (m, 8H), 1.40-1.20 (m, 9H).

Example 11 Preparation of Compound of the Present Invention

(31) ##STR00016##

(32) 200 mg product obtained in Example 4 was dissolved in 10 mL dichloromethane, and an equal molar amount of hydrochloric acid-methanol solution at the concentration of 0.1 mol/L was added dropwise on an ice bath. The mixture was concentrated to dryness under reduced pressure. Then, the resultant product was dried in vacuo to obtain a pale yellow solid (11).

Example 12 Preparation of Compound of the Present Invention

(33) ##STR00017##

(34) 200 mg product obtained in Example 10 was dissolved in 10 mL dichloromethane, to which was added 1 eq p-toluenesulfonic acid. The mixture was concentrated to dryness under reduced pressure. Then, the resultant product was dried in vacuo to obtain a pale yellow solid (12).

Example 13 Preparation of Compound of the Present Invention

(35) ##STR00018##

(36) 200 mg product obtained in Example 8 was dissolved in 10 mL dichloromethane, to which was added 0.5 eq D-tartaric acid. The mixture was concentrated to dryness under reduced pressure. Then, the resultant product was dried in vacuo to obtain a pale yellow solid (13).

(37) According to the preparative methods in above examples, compounds 14-77 in the following examples are obtained:

(38) TABLE-US-00001 Molecular formula and the molecular Structure weight in MS ESI[M.sup.+]: 493.4 0 ESI[M.sup.+]: 591.5 ESI[M.sup.+]: 493.4 ESI[M.sup.+]: 675.6 ESI[M.sup.+]: 569.4 ESI[M.sup.+]: 591.5 ESI[M.sup.+]: 605.5  ESI[M.sup.+]: 619.50 ESI[M.sup.+]: 607.5 ESI[M.sup.+]: 634.5 ESI[M.sup.+]: 636.4 0 ESI[M.sup.+]: 591.5 ESI[M.sup.+]: 660.4 ESI[M.sup.+]: 666.4 ESI[M.sup.+]: 651.4 ESI[M.sup.+]: 680.5 ESI[M.sup.+]: 594.4 ESI[M.sup.+]: 698.4 ESI[M.sup.+]: 567.4 ESI[M.sup.+]: 623.5 ESI[M.sup.+]: 565.4 0 ESI[M.sup.+]: 565.4 ESI[M.sup.+]: 535.4 ESI[M.sup.+]: 649.5 ESI[M.sup.+]: 609.5 ESI[M.sup.+]: 623.5 ESI[M.sup.+]: 523.4 ESI[M.sup.+]: 613.4 ESI[M.sup.+]: 597.4 ESI[M.sup.+]: 608.5 ESI[M.sup.+]: 564.4 0 ESI[M.sup.+]: 649.5 ESI[M.sup.+]: 599.4 ESI[M.sup.+]: 651.5 ESI[M.sup.+]: 641.5 ESI[M.sup.+]: 580.5 ESI[M.sup.+]: 555.4 ESI[M.sup.+]: 597.4 ESI[M.sup.+]: 596.4 ESI[M.sup.+]: 537.4 ESI[M.sup.+]: 495.4 0 ESI[M.sup.+]: 623.5 ESI[M.sup.+]: 555.4 ESI[M.sup.+]: 599.4 ESI[M.sup.+]: 553.4 ESI[M.sup.+]: 555.4 ESI[M.sup.+]: 525.4 ESI[M.sup.+]: 579.5 ESI[M.sup.+]: 495.4 ESI[M.sup.+]: 509.4 ESI[M.sup.+]: 551.4 0 ESI[M.sup.+]: 620.5 ESI[M.sup.+]: 527.3 ESI[M.sup.+]: 525.4 ESI[M.sup.+]: 481.4 ESI[M.sup.+]: 495.4 ESI[M.sup.+]: 523.4 ESI[M.sup.+]: 555.4 ESI[M.sup.+]: 499.3 ESI[M.sup.+]: 613.4 ESI[M.sup.+]: 511.4 0 ESI[M.sup.+]: 555.4 ESI[M.sup.+]: 523.4 ESI[M.sup.+]: 525.4

(39) In the following, experimental examples are used to illustrate the beneficial effects of the compound of the present invention.

Experimental Example 1. Study on the Local Anesthetic Effect of the Compound of the Present Invention

(40) For selected compounds of Example 1-77, the lidocaine positive control group, and the levobupivacaine positive control group, 8 groups of test rats that were fully adapted to the experimental environment were respectively divided, 8 rats for each group.

(41) For the dosage, the lidocaine group is 2% aqueous solution, the levobupivacaine group is 0.75% aqueous solution, and test drug groups are all distilled water solution at the concentration of 20 mmol/mL.

(42) The injection volume for each rat or the control was 0.5 mL, which was guided by a nerve locator and injected near the rat's sciatic nerve. Using von Frey stimulator, the rats were stimulated the soles of the feet in the injected side, to observe the effect of local anesthesia. Meanwhile, Postural Extensor Thrust (PET) was used to evaluate the motor function of the rat: the rat was lifted vertically and the hindlimb in the injected side pedaled on the platform of the electronic balance. At this time, the muscle strength of the rat's hindlimb was displayed by the value on the balance caused by pedal. When the limb was completely paralyzed, the reading was the limb's own weight, about 20 g. If the measured value was more than half of the difference between the baseline and the limb weight, the motor function was regarded as recovery, and if the value was less than or equal to this difference, the motor function was regarded as loss.

(43) TABLE-US-00002 TABLE 1 Local anesthetic effect of compound of the present invention on the sciatic nerve Local Time of Time of anesthesia sensory motor onset time block block Test drug (Median) (Median) (Median) Product in example 1 3 min 24 h 18 h Product in example 2 2 min 35 h 15 h Product in example 3 1 min 27 h 10 h Product in example 4 1 min 33 h 10 h Product in example 5 6 min 28 h 11 h Product in example 6 3 min 30 h 19 h Product in example 7 2 min 28 h 10 h Product in example 8 1 min 24 h 18 h Product in example 9 5 min 24 h 10 h Product in example 10 2 min 26 h 18 h Product in example 11 1 min 34 h 11 h Product in example 12 2 min 26 h 19 h Product in example 13 1 min 25 h 17 h Product in example 14 3 min 32 h 18 h Product in example 15 2 min 38 h 25 h Product in example 16 1 min 25 h 19 h Product in example 17 5 min 24 h 17 h Product in example 18 1 min 31 h 21 h Product in example 19 1 min 29 h 22 h Product in example 20 2 min 25 h 20 h Product in example 21 1 min 24 h 18 h Product in example 22 3 min 29 h 18 h Product in example 23 2 min 35 h 28 h Product in example 24 1 min 24 h 16 h Product in example 25 5 min 32 h 24 h Product in example 26 3 min 25 h 18 h Product in example 27 2 min 28 h 22 h Product in example 28 4 min 26 h 18 h Product in example 29 1 min 33 h 28 h Product in example 30 4 min 28 h 19 h Products in example 31-42 <5 min 25-30 h 14-20 h Products in example 43-55 <5 min 24-28 h 14-18 h Products in example 56-65 <5 min 30-35 h 17-20 h Products in example 66-77 <2 min 35-41 h 21-25 h 0.75% Levobupivacaine 1 min 2.5 h 2.5 h Hydrochloride 2% Lidocaine hydrochloride 1 min 1 h 1 h

(44) Experimental results show that this class of drugs can produce local anesthesia lasting more than 24 h in the sciatic nerve block model, and the block time of the sensory nerve is significantly longer than that of the motor nerve, and the difference time is greater than or equal to 5 h.

Experimental Example 2. Study on the Local Anesthetic Effect of the Compound of the Present Invention

(45) After the back of rat weighing 250-300 g was shaved and disinfected, a circle with a diameter of about 1.5 cm was drawn on the side of the exposed back, and the circle is divided into 6 equal parts. 0.5 mL solution containing compounds of Examples 1-13 according to the present invention was subcutaneously injected into the skin of the center (using saline as the solvent, the concentration of bupivacaine being 23 mmol/L, and the concentration of compound of the present invention being 6 mmol/L). Among the Von Frey fiber yarns, the one with a strength of 100 g was bound to the needle for local skin stimulation. One minute After the drug was injected, the above method was used to stimulate in 6 divisions. If no back skin contraction behavior was observed in the same aliquot after three consecutive stimulations, the drug was considered to have positive effect. If back skin contraction was observed, the local anesthetic effect was considered as loss. If four or more areas in 6 aliquots showed positive local anesthesia, the local anesthesia of the drug was considered as effective, while if less than 4 areas in 6 aliquots showed positive, the local anesthesia was considered as failure. Each compound was tested with 10 rats.

(46) TABLE-US-00003 TABLE 2 Local anesthetic effect of compound of the present invention by subcutaneous infiltration Local anesthesia Lasting time of onset time local anesthesia Test drug (Median) (Median) Product in example 1 1 min 34 h Product in example 2 1 min 45 h Product in example 3 1 min 37 h Product in example 4 2 min 44 h Product in example 5 1 min 68 h Product in example 6 1 min 47 h Product in example 7 1 min 57 h Product in example 8 1 min 33 h Product in example 9 2 min 28 h Product in example 10 1 min 36 h Product in example 11 1 min 54 h Product in example 12 1 min 24 h Product in example 13 1 min 45 h 0.75% Levobupivacaine 1 min  7 h Hydrochloride 2% Lidocaine hydrochloride 1 min  4 h

(47) Experimental results show that this class of drugs can produce local anesthesia lasting more than 24 hours in the subcutaneous infiltration model of rat.

Experimental Example 3. Study on Neuropathological Damage of Compound of the Present Invention

(48) For selected compounds of Example 1-13, the lidocaine positive control group, and the levobupivacaine positive control group, 8 groups of test rats that were fully adapted to the experimental environment were respectively divided, 8 rats for each group.

(49) For the dosage, the lidocaine group is 2% aqueous solution, the levobupivacaine group is 0.75% aqueous solution, and test drug groups are all distilled water solution at the concentration of 20 mmol/mL. The injection volume for each rat or the control was 0.5 mL, which was injected near the rat's sciatic nerve. On day 7 and day 14 after injection near the sciatic nerve, the experimental rats were euthanized by injecting bupivacaine into the heart under isoflurane anesthesia. About 1.5 cm sciatic nerve was collected at the injection site, stored in 10% formaldehyde solution for 48 hours, stained with HE, and cut into slices with 5 μm thickness.

(50) For the dosage, the lidocaine group is 2% aqueous solution, the levobupivacaine group is 0.75% aqueous solution, and test drug groups are all distilled water solution at the concentration of 20 mmol/mL. The injection volume for each rat or the control was 0.5 mL, which was injected near the rat's sciatic nerve. On day 7 and day 14 after injection near the sciatic nerve, the experimental rats were euthanized by injecting bupivacaine into the heart under isoflurane anesthesia. About 1.5 cm sciatic nerve was collected at the injection site, stored in 10% formaldehyde solution for 48 hours, stained with HE, and cut into slices with 5 μm thickness.

(51) The evaluation of neuropathological damage showed that compared with the lidocaine positive control group and the levobupivacaine positive control group, compounds of Examples 1-13 did not show significant differences in the aspects of nerve injury, vascular proliferation, demyelination, muscle inflammation, and connective tissue inflammation, and thus had good safety.

(52) In summary, the present invention provides a new class of quaternary ammonium compounds with novel structures, as well as the preparative method and the use thereof. The compound has a fast onset of action and a long-time local anesthetic effect (more than 24 hours) after a single administration. The compound was selective for nerve block (The block time of sensory nerve is longer than that of motor nerve, and the difference time is greater than or equal to 5 hours), and has both long-acting and selective local anesthetic effect, that significantly reduced the side effects of QX314, QX314 composition, and the quaternary ammonium compound with surfactant structure characteristics, with better safety. That is, the compound of formula I according to the present invention and its pharmaceutically acceptable salts can be used to prepare safe drugs with long-acting and selective local anesthesia, which has the advantages of long-time local anesthetic action, good local anesthetic selectivity, less nerve damage, and high safety.