Class of dicationic compounds as well as the preparative method and the use thereof

Abstract

A dication compound represented by formula (I), stereoisomers having the structure of formula (I) or a mixture of the stereoisomers, a pharmaceutically acceptable salt, a solvate, or a eutectic crystal, and a composition thereof, and use of a composition, are capable of producing neuromuscular junction retardation, formed of same with a pharmaceutically acceptable carrier in the field of preparation of a medicament for muscular flaccidity.

Claims

1. The dicationic compound of formula (I) or a stereoisomer thereof: ##STR00072## Wherein, n=1, 2, 3; a=0, 1, 2; Y is O, substituted or unsubstituted methylene, and the substituted group is halogen and C.sub.1-C.sub.6 alkyl; L.sub.1 and L.sub.2 are independently of each other selected from substituted or unsubstituted C.sub.1-C.sub.8 alkylene, wherein the substitution means that C in the alkylene is replaced by O or S and/or H is substituted by alkyl or halogen; R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are independently of each other selected from the group consisting of halogen, substituted or unsubstituted and/or saturated or unsaturated C.sub.1-C.sub.20 hydrocarbon groups, in which the substituted groups are selected from one or more halogens, alkoxys, nitros, cyanos, hydroxyls, C.sub.1-C.sub.6 alkyls, trifluoromethyls, C.sub.3-C.sub.6 heterocyclic groups, ester groups, alkoxycarbonyl groups, and the skeletons of R.sub.1, R.sub.2, R.sub.3, and R.sub.4 contain or don't contain heteroatoms; R.sub.5 is selected from H, C.sub.1-C.sub.6 alkyl, and C.sub.3-C.sub.6 cycloalkyl; M is a pharmaceutically acceptable anion.

2. The dicationic compound of formula (I) or the stereoisomer thereof according to claim 1, characterized in that Y is 0, CH.sub.2, CHCH.sub.3, CF.sub.2; said heteroatom is S or O.

3. The dicationic compound of formula (I) or the stereoisomer thereof according to claim 1, characterized in that L.sub.1 and L.sub.2 are independently of each other selected from substituted or unsubstituted C.sub.1-C.sub.6 alkylene, wherein the substitution means that C in the alkylene is replaced by O or S and/or H is substituted by C.sub.1-C.sub.3 alkyl.

4. The dicationic compound of formula (I) or the stereoisomer thereof according to claim 1, characterized in that R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are independently of each other selected from the group consisting of halogen, substituted or unsubstituted C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, ##STR00073## in which R.sub.6 is selected from one or more H, nitros, halogens, methoxys, hydroxyls, cyanos, C.sub.1-C.sub.3 alkyls, phenyls, and trifluoromethyls.

5. The dicationic compound of formula (I) or the stereoisomer thereof according to claim 1, characterized in that n=1, 2; a=0, 1.

6. The dicationic compound of formula (I) or the stereoisomer thereof according to claim 1, characterized in that M is Br.sup.−, Cl.sup.−, and R—SO.sub.3.sup.−, and said R is a hydrocarbon group; preferably, R—SO.sub.3.sup.−is selected from p-toluenesulfonate, methanesulfonate and benzenesulfonate.

7. The dicationic compound of formula (I) or the stereoisomer thereof according to claim 1, characterized in that said halogen is F, Cl, Br, and I.

8. The dicationic compound of formula (I) or the stereoisomer thereof according to claim 1, characterized in that when a=1, said compound is one of the following compounds: ##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079##

9. The dicationic compound of formula (I) or the stereoisomer thereof according to claim 1, characterized in that when a=0, said compound is one of the following compounds: ##STR00080##

10. The preparative method of the dicationic compound of formula (I) or the stereoisomer thereof according to claim 1, characterized in that the method includes the following steps: ##STR00081## (1) Preparation of quaternary ammonium intermediate 1 (1-i) Compound a-1 reacts with compound a-2 to prepare compound a-3; (1-ii) Compound a-3 reacts with compound R.sub.1—Br to prepare compound a-4; (1-iii) Compound a-4 reacts with sodium hydroxide to prepare quaternary ammonium intermediate 1; (2) Preparation of quaternary ammonium intermediate 2 (2-i) Compound b-1 reacts with compound R.sub.4—Br to prepare compound b-2; (2-ii) Compound b-2 reacts with the coupling molecule to prepare quaternary ammonium intermediate 2; (3) Quaternary ammonium intermediate 1 reacts with quaternary ammonium intermediate 2, to prepare the dicationic compound; wherein, compound a-1 is ##STR00082## compound a-2 is ##STR00083## compound a-3 is ##STR00084## compound a-4 is ##STR00085## and quaternary ammonium intermediate 1 is ##STR00086## compound b-1 is ##STR00087## compound b-2 is ##STR00088## the coupling molecule is ##STR00089## quaternary ammonium intermediate 2 is ##STR00090## and the dicationic compound is ##STR00091##

11. A method for causing muscle relaxation, comprising administering the bicationic compound of formula (I) or the stereoisomer thereof to a subject in need thereof.

12. A muscle relaxant comprising an active ingredient that is the bicationic compound of formula (I) or the stereoisomer thereof according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a crystalline form thereof, and one or more pharmaceutically acceptable adjuvents.

13. A method for causing muscle relaxation, comprising administering the muscle relaxant of claim 12 to a subject in need thereof.

Description

EXAMPLES

Example 1 Preparation of Compound 1

(1) ##STR00022## ##STR00023##

(2) Methyl 2-bromoacetate (1.53 g) was dissolved in 30 mL acetonitrile, to which were added 0.85 g piperidine and 1.38 g anhydrous potassium carbonate. The mixture was stirred at 50° C. for 10 hours, and then p-nitrobenzyl bromide (2.16 g) was added. The reaction was further stirred at 55° C. for 6 hours, and filtered, then the solvent was evaporated under reduced pressure. To the residue, was added 2N sodium hydroxide aqueous solution (40 mL), and the resultant solution was stirred at room temperature for 2 hours, then pH value was adjusted to 9 with hydrobromic acid aqueous solution. The solvent was evaporated to dryness under reduced pressure, and then 50 mL dichloromethane was added to the residue. The mixture was heated to a slight boiling, and filtered while hot. The filtrate was evaporated to dryness to obtain bright yellow crude product of intermediate (1-1) (1.71 g).

(3) 4-Hydroxybutyl-methyl-benzylamine (1.93 g) was dissolved in 30 mL acetonitrile, to which was added p-nitrobenzyl bromide (2.16 g), and then stirred for 8 hours at 55° C. The solvent was evaporated to dryness under reduced pressure, and yellow solid was precipitated. The solid was dissolved in 50 mL dichloromethane, and then 1.6 g pyridine was added. The mixture was cooled to 5° C., and 1.3 g chloromethyl chloroformate was added. After addition, the mixture was stirred for 3 hours at room temperature. The solvent was evaporated to dryness under reduced pressure, and then the residue was subjected to column chromatography to provide 1.32 g intermediate (1-2).

(4) Intermediate 1-2 (1.32 g) and intermediate 1-1 (1.0 g) were dissolved in 50 mL acetonitrile, and stirred at 40° C. for 12 hours, then the solvent was evaporated to dryness under reduced pressure.

(5) The residue was separated by reversed-phase preparative chromatography, to provide white powder (0.53 g), i.e. compound 1, with a yield of 23.5%.

(6) .sup.1HNMR (DMSO-d.sub.6, 400 MHz) δ:1.52-1.56 (2H, m), 1.61-1.84 (8H, m), 3.01 (3H, s), 3.13-3.24 (4H, m), 3.41-3.43 (2H, m), 3.65-3.74 (2H, m), 4.51 (1H, d, J=12.8 Hz), 4.67-4.77 (5H, m), 4.85 (1H, d, J=12.8 Hz), 4.96 (1H, d, J=12.8 Hz), 5.74 (2H, s), 7.52-7.55 (3H, m), 7.62-7.64 (2H, m), 7.75-7.77 (2H, m), 7.96-7.98 (2H, m), 8.28-8.36 (4H, m).

Example 2 Preparation of Compound 2

(7) ##STR00024##

(8) Quaternary ammonium intermediates 1-1 and 2-2 were prepared by referring to Example 1. Intermediate 1-1 (1.91 g) and intermediate 2-2 (2.36 g) were dissolved in 50 mL acetonitrile, and stirred at 40° C. for 12 hours, then the solvent was evaporated to dryness under reduced pressure. The residue was separated by preparative chromatography, to provide white powder (1.03 g), i.e. compound 2, with a yield of 25.9%.

(9) .sup.1HNMR (DMSO-d.sub.6, 400 MHz) δ: 1.58-1.59 (2H, m), 1.92 (4H, s, broad), 3.06 (3H, s), 3.51-3.53 (3H, m), 3.71-3.76 (3H, m), 4.52-4.55 (3H, m), 4.75-4.77 (3H, m), 4.90-5.08 (4H, m), 5.86 (2H, s), 7.51-7.55 (3H, m), 7.61-7.62 (2H, m), 7.75-7.77 (2H, m), 7.95-7.96 (2H, m), 8.29-8.36 (4H, m).

Example 3 Preparation of Compound 3

(10) ##STR00025##

(11) Quaternary ammonium intermediates 3-1 and 3-2 were prepared by referring to Example 1. Intermediate 3-1 (2.05 g) and intermediate 3-2 (2.95 g) were dissolved in 50 mL acetonitrile, and stirred at 40° C. for 12 hours, then the solvent was evaporated to dryness under reduced pressure. The residue was separated by preparative chromatography, to provide white powder (1.1 g), i.e. compound 3, with a yield of 25.7%.

(12) .sup.1HNMR (DMSO-d.sub.6, 400 MHz) δ: 1.43 (1H, s, broad), 1.60-1.64 (1H, m), 1.83 (4H, s, broad), 2.08 (2H, s, broad), 2.57-2.61 (2H, m), 3.04 (3, s), 3.23-3.28 (3H, m), 3.41-3.44 (3K, m), 3.67 (2H, s), 4.54-4.57 (1H, m), 4.68-4.78 (5H, m), 4.91-5.03 (2H, m), 5.78 (2H, s), 7.36-7.40 (2H, m), 7.67-7.71 (2H, m), 7.85-7.95 (4H, m), 8.32-8.38 (4H, m).

Example 4 Preparation of Compound 4

(13) ##STR00026##

(14) Quaternary ammonium intermediates 3-1 and 4-2 were prepared by referring to Example 1. Intermediate 3-1 (2.05 g) and intermediate 4-2 (2.51 g) were dissolved in 50 mL acetonitrile, and stirred at 40° C. for 12 hours, then the solvent was evaporated to dryness under reduced pressure.

(15) The residue was separated by preparative chromatography, to provide white powder (1.19 g), i.e. compound 4, with a yield of 27.2%.

(16) .sup.1HNMR (DMSO-d.sub.6, 400 MHz) δ: 1.42 (1H, s, broad), 1.60 (1H, s, broad), 1.83-1.88 (4H, m), 2.08-2.09 (2H, m), 2.57-2.60 (2H, m), 3.05 (3H, s), 3.24-3.33 (4H, m), 3.41-3.44 (2H, m), 2.68 (2H, s, broad), 4.57 (11H, d, J=12.0 Hz), 4.69-4.78 (5H, m), 4.93 (H, d, J=12.0 Hz), 5.03 (1H, d, J=12.0 Hz), 5.77 (2H, s), 7.58-7.67 (4H, m), 7.84-7.95 (4H, m), 8.31-8.36 (4H, m).

Example 5 Preparation of Compound 5

(17) ##STR00027##

(18) Quaternary ammonium intermediates 3-1 and 5-2 were prepared by referring to Example 1. Intermediate 3-1 (2.05 g) and intermediate 5-2 (2.71 g) were dissolved in 50 mL acetonitrile, and stirred at 40° C. for 12 hours, then the solvent was evaporated to dryness under reduced pressure.

(19) The residue was separated by preparative chromatography, to provide white powder (1.02 g), i.e. compound 5, with a yield of 20.6%.

(20) .sup.1HNMR (DMSO-d.sub.6, 400 MHz) δ: 1.41 (1H, s, broad), 1.60 (1H, s, broad), 1.83 (4H, s, broad), 2.07 (2H, s, broad), 2.55-2.65 (2H, m), 3.05 (3H, s), 3.22-3.26 (4H, m), 3.39-3.42 (2H, m), 3.72-3.81 (2H, m), 4.59-4.62 (1H, m), 4.67-4.78 (5H, m), 4.91-4.99 (2H, m), 5.77 (2H, s), 7.64-7.65 (1H, m), 7.82-7.96 (6H, m), 8.33-8.38 (4H, m).

Example 6 Preparation of Compound 6

(21) ##STR00028##

(22) Quaternary ammonium intermediates 3-1 and 6-2 were prepared by referring to Example 1. Intermediate 3-1 (2.05 g) and intermediate 6-2 (2.71 g) were dissolved in 50 mL acetonitrile, and stirred at 40° C. for 12 hours, then the solvent was evaporated to dryness under reduced pressure.

(23) The residue was separated by preparative chromatography, to provide white powder (0.75 g), i.e. compound 6, with a yield of 17.4%.

(24) .sup.1HNMR (DMSO-d.sub.6, 400 MHz) δ: 1.44 (1H, s, broad), 1.60 (1H, s, broad), 1.84 (4H, s, broad), 2.05 (2H, s, broad), 2.56-2.59 (2H, m), 3.05 (3H, s), 3.22-3.28 (3H, m), 3.41-3.45 (3H, m), 3.70-3.73 (1H, m), 3.85-3.88 (1H, m), 4.54-4.58 (1H, m), 4.77 (4H, s, broad), 4.90-5.00 (3H, m), 5.78 (2H, s), 7.31-7.36 (2K, m), 7.72-7.76 (1H, m), 7.84-7.86 (2H, m), 7.99-8.01 (2, m), 8.32-8.38 (4H, m).

Example 7 Preparation of Compound 7

(25) ##STR00029##

(26) Quaternary ammonium intermediates 3-1 and 7-2 were prepared by referring to Example 1. Intermediate 3-1 (2.05 g) and intermediate 7-2 (2.59 g) were dissolved in 50 mL acetonitrile, and stirred at 40° C. for 12 hours, then the solvent was evaporated to dryness under reduced pressure. The residue was separated by preparative chromatography, to provide white powder (1.13 g), i.e. compound 7, with a yield of 26.0%. .sup.1HNMR (DMSO-d.sub.6, 400 MHz) δ: 1.43 (1H, s, broad), 1.60 (1H, s, broad), 1.84 (4H, s, broad), 2.08 (2H, s, broad), 2.57-2.60 (2H, m), 3.10 (3H, s), 3.25-3.29 (2H, m), 3.42-3.44 (4H, m), 3.73 (2H, s, broad), 4.72-4.77 (6n, m), 5.08 (2H, s, broad), 5.78 (2H, s), 7.85-7.87 (2H, m), 7.94-7.95 (4H, m), 8.32-8.38 (6H, m).

Example 8 Preparation of Compound 8

(27) ##STR00030##

(28) Quaternary ammonium intermediates 2-1 and 13-2 were prepared by referring to Example 1. Intermediate 3-1 (2.05 g) and intermediate 8-2 (2.5 g) were dissolved in 50 mL acetonitrile, and stirred at 40° C. for 12 hours, then the solvent was evaporated to dryness under reduced pressure. The residue was separated by preparative chromatography, to provide white powder (0.69 g), i.e. compound 8, with a yield of 16.2%.

(29) .sup.1HNMR (DMSO-d.sub.6, 400 MHz) δ: 1.43 (1H, s, broad), 1.60-1.63 (1H, m), 1.83 (4H, s, broad), 2.08-2.09 (2H, m), 2.53-2.59 (2H, m), 3.08 (3H, s), 3.25-3.28 (4H, m), 3.41-3.44 (2H, m), 3.70 (2H, s, broad), 4.65-4.78 (6H, m), 5.03-5.10 (2H, m), 5.78 (2H, s), 7.85-7.86 (4H, m), 7.93-7.95 (2H, m), 8.02-8.04 (2H, m), 8.32-8.37 (4H, m).

Example 9 Preparation of Compound 9

(30) ##STR00031##

(31) Quaternary ammonium intermediates 3-1 and 9-2 were prepared by referring to Example 1. Intermediate 3-1 (2.05 g) and intermediate 9-2 (2.7 g) were dissolved in 50 mL acetonitrile, and stirred at 40° C. for 12 hours, then the solvent was evaporated to dryness under reduced pressure. The residue was separated by preparative chromatography, to provide white powder (0.73 g), i.e. compound 9, with a yield of 16.4%.

(32) .sup.1HNMR (DMSO-d.sub.6, 400 MHz) δ: 1.43 (1H, s, broad), 1.60-1.63 (1H, m), 1.83 (4H, s, broad), 2.08-2.09 (2H, m), 2.57-2.61 (2H, m), 3.09 (3H, s), 3.24-3.44 (6H, m), 3.71-3.75 (2H, m), 4.65-4.78 (6H, m), 4.94-5.09 (2H, m), 5.78 (2H, s), 7.85-7.96 (8H, m), 8.33-8.39 (4H, m).

Example 10 Preparation of Compound 10

(33) ##STR00032##

(34) Quaternary ammonium intermediates 10-1 and 2-2 were prepared by referring to Example 1. Intermediate 10-1 (2.16 g) and intermediate 2-2 (2.37 g) were dissolved in 50 mL acetonitrile, and stirred at 40° C. for 12 hours, then the solvent was evaporated to dryness under reduced pressure. The residue was separated by preparative chromatography, to provide white powder (0.88 g), i.e. compound 10, with a yield of 20.8%.

(35) .sup.1HNMR (DMSO-d.sub.6, 400 MHz) δ: 1.44 (1H, s, broad), 1.61 (1H, s, broad), 1.84 (4H, s, broad), 2.1 (2H, m), 2.58-2.59 (2H, m), 3.06 (3H, s), 3.26-3.29 (3H, m), 3.41-3.44 (3H, m), 3.69 (2H, s, broad), 4.55-4.58 (1H, m), 4.74 (5H, s, broad), 4.94-5.08 (2H, m), 5.78 (2H, s), 7.53-7.63 (5H, m), 7.80-7.99 (6H, m), 8.36-8.38 (2H, m).

Example 11 Preparation of Compound 11

(36) ##STR00033##

(37) Quaternary ammonium intermediates 3-1 and 11-2 were prepared by referring to Example 1. Intermediate 3-1 (2.05 g) and intermediate 11-2 (2.75 g) were dissolved in 50 mL acetonitrile, and stirred at 40° C. for 12 hours, then the solvent was evaporated to dryness under reduced pressure. The residue was separated by preparative chromatography, to provide white powder (1.16 g), i.e. compound 11, with a yield of 25.1%.

(38) .sup.1HNMR (DMSO-d.sub.6, 400 MHz) δ: 1.43 (1H, s, broad), 1.60 (1H, s, broad), 1.84 (4H, s, broad), 2.33-2.34 (2H, m), 2.51-2.53 (2H, m), 3.07 (3H, s), 3.19-3.28 (4H, m), 3.39-3.42 (2H, m), 3.69 (2H, s, broad), 4.55-4.58 (1H, m), 4.71-4.76 (5H, m), 4.86-4.89 (1H, m), 4.96-4.99 (1H, m), 5.79 (2H, s), 7.41-7.45 (11H, m), 7.49-7.53 (2H, m), 7.69-7.75 (4H, m), 7.83-7.86 (4H, m), 7.94-7.96 (2H, m), 8.33-8.40 (4H, m).

Example 12 Preparation of Compound 12

(39) ##STR00034##

(40) Quaternary ammonium intermediates 12-1 and 12-2 were prepared by referring to Example 1. Intermediate 12-1 (2.12 g) and intermediate 12-2 (2.74 g) were dissolved in 50 mL acetonitrile, and stirred at 40° C. for 10 hours, then the solvent was evaporated to dryness under reduced pressure. The residue was separated by preparative chromatography, to provide white powder (1.04 g), i.e. compound 12, with a yield of 22.7%.

(41) .sup.1HNMR (DMSO-d.sub.6, 400 MHz) δ: 1.45-1.30 (m, 1H), 1.70-1.55 (m, 1H), 1.90-1.75 (m, 4H), 2.07-1.95 (m, 2H), 2.65-2.55 (m, 2H), 3.01 (s, 3H), 3.41-3.31 (m, 2H), 3.63 (d, J=13.2 Hz, 2H), 3.79 (s, 18H), 3.92 (s, 3H), 4.63-4.43 (m, 4H), 4.88-4.67 (m, 4H), 5.76 (s, 2H), 7.06 (d, J=6.4 Hz, 4H), 7.27 (s, 2H), 7.18 (s, 3H).

Example 13 Preparation of Compound 13

(42) ##STR00035##

(43) Quaternary ammonium intermediates 13-1 and 13-2 were prepared by referring to Example 1. Intermediate 13-1 (1.82 g) and intermediate 13-2 (2.56 g) were dissolved in 50 mL acetonitrile, and stirred at 40° C. for 12 hours, then the solvent was evaporated to dryness under reduced pressure. The residue was separated by preparative chromatography, to provide white powder (1.07 g), i.e. compound 13, with a yield of 26.1%.

(44) .sup.1HNMR (DMSO-d.sub.6, 400 MHz) δ: 1.69-1.50 (m, 4H), 2.03-1.86 (m, 6H), 2.26 (d, J=4.4 Hz, 18H), 2.88-2.78 (m, 3H), 3.15-3.01 (m, 2H), 3.58-3.46 (m, 2H), 3.71 (d, J=12.4 Hz, 2H), 4.24 (t, J=6.4 Hz, 2H), 4.47-4.34 (m, 4H), 4.60-4.51 (m, 2H), 5.87 (s, 2H), 4.72 (s, 2H), 7.20-7.13 (m, 2H), 7.27 (td, J=8.0, 15.2 Hz, 5H), 7.34 (s, 2H).

Example 14 Preparation of Compound 14

(45) By referring to Example 1, methyl 2-bromoacetate and p-nitrobenzyl bromide used in the synthesis of quaternary ammonium intermediates 1-1 and 1-2 were replaced with methyl 2-chloroacetate and p-nitrobenzyl chloride, which can ensure that the anion of the final target compound (I) is Cl.sup.−, i.e. compound 14.

Example 15 Preparation of Compound 15

(46) Compound 14 (100 mg) was dissolved in 300 mL water, to which was drop added the aqueous solution of silver p-toluenesulfonate (40 mg) under stirring. The precipitate was removed by filtration. After the filtrate was lyophilized, 109 mg of target compound (I) containing the anion p-toluenesulfonate was obtained, i.e. compound 15.

Example 16. Synthesis of Other Compounds

(47) For other compounds disclosed in this patent, the synthetic method could refer to the preparative method described in Example 1, and the quaternary ammonium intermediates 1 and 2 were synthesized, respectively. Both of intermediates were dissolved in nonprotonic polar solvents such as DMF or acetonitrile and the like, and then heated and stirred at the temperature of r.t.-80° C. for 6-24 hours, followed by separation and purification, to obtain the target compounds. The structures and mass spectra of preferred compounds are shown in Table 1.

(48) TABLE-US-00001 TABLE 1 The structures and mass spectra of part of preferred compounds Compound No. Structure [M].sup.2+ (without anion) Compound 17 332.1 Compound 18 346.1 Compound 19 340.1 Compound 20 348.1 Compound 21 0 354.1 Compound 22 347.1 Compound 23 355.1 Compound 24 325.1 Compound 25 410.1 Compound 26 387.5 Compound 27 343.6 Compound 28 369.6 Compound 29 362.1 Compound 30 343.6 Compound 31 0 377.6 Compound 32 347.6 Compound 33 323.6 Compound 34 323.6 Compound 35 339.1 Compound 36 312.6 Compound 37 304.6 Compound 38 335.1 Compound 39 327.1 Compound 40 315.6 Compound 41 0 334.6 Compound 42 357.1 Compound 43 333.1 Compound 44 345.1 Compound 45 350.1 Compound 46 357.1 Compound 47 334.1 Compound 48 373.1 Compound 49 346.1 Compound 50 339.1 Compound 51 0 323.1 Compound 52 332.1

(49) The beneficial effect of the present invention was illustrated by the following experimental example.

Experimental Example 1 Experiment on Muscle Relaxation

(50) Male New Zealand white rabbits weighing 2-3.5 kg were used as experimental animals for muscle relaxation test. The specific procedures were: propofol emulsion was intravenously administrated to induce and maintain general anesthesia (induction dose: 10 mg/kg; maintenance dose: 105 mg/hr/kg). Tracheal intubation was carried out and respiratory support was used. After 2× ED.sub.95 equivalent dose of the positive control drug and the compounds described in the present patent were intravenously injected, the onset time (TOF=0) of the drug and the recovery time (TOF=90%) of muscle relaxation were observed with a neuromuscular transmission monitors (TOF). The results are shown in Table 1.

(51) TABLE-US-00002 TABLE 1 The onset time and the duration of muscle relaxant action of drugs in rabbits (N = 8) 2 × ED.sub.95 Onset time Recovery time Drug (mg/kg) (s) (min) Cisatracurium 0.08 >90 17.6 ± 5.2  Succinylcholine 1.8 <40 13.3 ± 3.5  Compound 1 0.8 <40 5.2 ± 1.1 Compound 2 0.9 <40 6.4 ± 1.4 Compound 3 1.8 <40 4.8 ± 0.5 Compound 4 1.4 <40 5.4 ± 0.9 Compound 5 1.6 <40 5.2 ± 1.2 Compound 6 0.8 <40 4.1 ± 1.1 Compound 7 1.6 <40 5.2 ± 1.1 Compound 8 1.7 <40 7.2 ± 1.4 Compound 9 1.6 <40 5.2 ± 1.2 Compound 10 2.4 <40 6.2 ± 0.9 Compound 11 1.5 <40 7.7 ± 1.6 Compound 12 4.4 <40 6.3 ± 2.1 Compound 13 6.2 <40 6.9 ± 1.7 Compound 14 1.0 <40 4.9 ± .09 Compound 15 1.2 <40 5.4 ± 1.1 Compound 19 0.8 <40 4.1 ± 0.8 Compound 35 1.0 <40 7.2 ± 2.3 Compound 38 1.2 <40 4.4 ± 1.1 Compound 45 0.8 <40 5.1 ± 1.4 Compound 47 1.4 <40 3.1 ± 0.7

(52) Above results showed that the compound of the present invention could rapidly produce muscle relaxation in animals (<40 seconds), and the continuous time of muscle relaxation was significantly shorter than that of the positive control drug cisatracurium, even shorter than that of the positive control drug succinylcholine. These characteristics showed that the compounds of the present invention had the characteristics of rapid onset and rapid recovery. In addition, after administration of succinylcholine, the levels of TOF 1-4 decreased in the same proportion until disappearance, showing the typical characteristics of depolarized muscle relaxants, while, after the compound of the present invention and cisatracurium were administrated, the TOF 1-4 of the tested animals successively and gradually decreased, rather than in equal proportion. The change characteristics of TOF indicate that the compound in the present invention belongs to a typical non-depolarizing muscle relaxant.

(53) In summary, the present invention provides the bicationic compound of formula (I), or the stereoisomer or the stereoisomer mixture, or the pharmaceutically acceptable salt, or the solvate, or the crystal, as well as the preparative method thereof. The experiments indicate that compared with the positive control drugs cisatracurium and succinylcholine, the compound of the present invention has more significant characteristics of rapid onset and rapid recovery, and belongs to a typical non-depolarizing muscle relaxant, with a good application prospect.