MAGL INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

The present invention belongs to the field of medicine, and relates to a compound

##STR00001##

of Formula I and a pharmaceutically acceptable salt thereof for using as a MAGL inhibitor, as well as a preparation method and use thereof, and an intermediate for preparing the same.

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof: ##STR00048## wherein R is H or C.sub.1-5 alkyl, and the C.sub.1-5 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, neo-butyl, n-pentyl, isopentyl, neo-pentyl, cyclopentyl, or C.sub.1-5 alkyl substituted by halogen, hydroxy, carboxyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocyclyl, C.sub.3-8 cycloalkoxy, aryl, and heteroaryl; the number of R is 0, 1, 2, 3 or 4; Ar.sub.1 and Ar.sub.2 are respectively and independently selected from C.sub.5-18 aryl, heteroaryl, (C.sub.6-10 aryl)-C.sub.1-4 alkyl-, (C.sub.6-10 aryl)-C.sub.1-4 alkyl-(C.sub.6-10 aryl), (5 to 10-membered heteroaryl)--(C.sub.1-4 alkyl--(C.sub.6-10 aryl), (C.sub.6-10 aryl)-(C.sub.6-10 aryl), (C.sub.6-10 aryl)-O-(C.sub.6-10 aryl), (C.sub.6-10 aryl )-O-(5 to 10-membered heteroaryl), (5 to 10-membered heteroaryl)-O-(5 to 10-membered heteroaryl), and (5 to 10-membered heteroaryl)-(5 to 10-membered heteroaryl), at any substitution position; X.sub.1 and X.sub.2 are respectively and independently selected from one or more of H, hydroxy, carboxyl, halogen, acyloxy, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocyclyl, C.sub.3-8 cycloalkoxy, aryl, heteroaryl, and C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocyclyl, C.sub.3-8 cycloalkoxy, aryl, and heteroaryl that are substituted by hydroxy, carboxyl, halogen and alkyl, at any substitution position.

2. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein the R is H or C.sub.1-5 alkyl, and the C.sub.1-5 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, neo-butyl, n-pentyl, isopentyl, neo-pentyl, cyclopentyl, or C.sub.1-5 alkyl substituted by halogen, hydroxy, carboxyl, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocyclyl, C.sub.3-8 cycloalkoxy, aryl, and heteroaryl; the number of the R is 0, 1, 2, 3 or 4; the Ar.sub.1 and the Ar.sub.2 are respectively and independently selected from C.sub.5-18 aryl, heteroaryl, (C.sub.6-10 aryl)-C.sub.1-4 alkyl-, (C.sub.6-10 aryl)-Cl-4 alkyl-(C.sub.6-10 aryl), (5 to 10-membered heteroaryl)-C.sub.1-4 alkyl-(C.sub.6-10 aryl), (C.sub.6-10 aryl)-(C.sub.6-10 aryl), (C.sub.6-10 aryl)-O-(C.sub.6-10 aryl), (C.sub.6-10 aryl)-O-(5 to 10-membered heteroaryl), (5 to 10-membered heteroaryl)-O-(5 to 10-membered heteroaryl), and (5 to 10-membered heteroaryl)-(5 to 10-membered heteroaryl) at any substitution position; the X.sub.1 and the X.sub.2 are respectively and independently selected from one or more of H, hydroxy, carboxyl, halogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocyclyl, C.sub.3-8 cycloalkoxy, aryl, heteroaryl, and C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocyclyl, C.sub.3-8 cycloalkoxy, aryl, and heteroaryl that are substituted by hydroxy, carboxyl, halogen and alkyl, at any substitution position.

3. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein the Ar.sub.1 and the Ar.sub.2 are respectively and independently selected from phenyl, C.sub.5-18 aryl, heteroaryl, (C.sub.6-10 aryl)-(C.sub.6-10 aryl), (C.sub.6-10 aryl)-O-(C.sub.6-10 aryl); the X.sub.1 and the X.sub.2 are respectively and independently selected from one or more of H, hydroxy, halogen, acyloxy, C.sub.1-3 alkyl, and C.sub.1- .sub.3 alkoxy, at any substitution position.

4. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein the Ar.sub.1 is one or more substituents selected from phenyl, naphthyl, diphenyl ether, indolyl and biphenyl, at any substitution position.

5. The compound of Formula I or a pharmaceutically acceptable salt thereof of claim 1, wherein if the R is H, the corresponding structural formula is, ##STR00049## where, the Ar.sub.1 and the Ar.sub.2 are respectively and independently selected from C.sub.5-18 aryl, heteroaryl, (C.sub.6-10 aryl)-C.sub.1-4 alkyl-, (C.sub.6-10 aryl)-C.sub.1-4 alkyl-(C.sub.6-10 aryl), (5 to 10-membered heteroaryl)-C.sub.1-4 alkyl-(C.sub.6-10 aryl), (C.sub.6-10 aryl)-(C.sub.6-10 aryl), (C.sub.6-10 aryl)-O-(C.sub.6-10 aryl), (C.sub.6-10 aryl)-O-(5 to 10-membered heteroaryl), (5 to 10-membered heteroaryl)-O-(5 to 10-membered heteroaryl), and (5 to 10-membered heteroaryl)-(5 to 10-membered heteroaryl) at any substitution position; the X.sub.1 and the X.sub.2 are respectively and independently selected from one or more of H, hydroxy, carboxyl, halogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocyclyl, C.sub.3-8 cycloalkoxy, aryl, heteroaryl, and C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.3-8 cycloalkyl, C.sub.3-8 heterocyclyl, C.sub.3-8 cycloalkoxy, aryl, and heteroaryl that are substituted by hydroxy, carboxyl, halogen and alkyl, at any substitution position.

6. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein the Ar.sub.1 and the Ar.sub.2 are respectively and independently selected from C.sub.5-18 aryl, heteroaryl, (C.sub.6-10 aryl)-C.sub.1-4 alkyl-, (C.sub.6-10 aryl)-C.sub.1-4 alkyl-(C.sub.6-10 aryl), (5 to 10-membered heteroaryl)-C.sub.1-4 alkyl-(C.sub.6-10 aryl), (C.sub.6-10 aryl)-(C.sub.6-10 aryl), (C.sub.6-10 aryl)-O-(C.sub.6-10 aryl), (C.sub.6-10 aryl )-O-(5 to 10-membered heteroaryl), (5 to 10-membered heteroaryl)-O-(5 to 10-membered heteroaryl), and (5 to 10-membered heteroaryl)-(5 to 10-membered heteroaryl) at any substitution position; the X.sub.1 and the X.sub.2 are respectively and independently selected from one or more of H, hydroxy, halogen, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.3-8 heterocyclyl, C.sub.3-8 cycloalkoxy, and C.sub.1-3 alkyl and C.sub.1-3 alkoxy that are substituted by hydroxy, halogen and alkyl, at any substitution position.

7. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein, the Ar.sub.1 is one or more of phenyl, naphthyl, diphenyl ether and biphenyl, at any substitution position; the X.sub.1 is one or more of H, methoxy, hydroxy, F and Cl, at any substitution position; the Ar.sub.2 is phenyl, at any substitution position; and the X.sub.2 is one or more of H, methyl, dimethyl, methoxy, hydroxy, F and Cl, at any substitution position.

8. The compound or a pharmaceutically acceptable salt thereof of claim 5, wherein the Ar.sub.1 has a substitution position of meta-position.

9. The compound or a pharmaceutically acceptable salt thereof of claim 1, wherein, the Ar.sub.1 is one or more of benzofuryl, benzimidazolyl, benzoxazolyl, benzothiophenyl, indolyl, quinolyl, isoquinolyl and purinyl, at any substitution position; the X.sub.1 is one or more of H, methyl, methoxy, hydroxy, F, Cl and Br, at any substitution position; the Ar.sub.2 is phenyl, at any substitution position; the X.sub.2 is one or more of H, methyl, dimethyl, methoxy, hydroxy, F and Cl, at any substitution position.

10. The compound of the Formula I or a pharmaceutically acceptable salt thereof of claim 1, wherein the specific structural formula is selected from ##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082## .

11. The compound of claim 1, which is a compound of Formula III ##STR00083## or a pharmaceutically acceptable salt thereof, wherein the R.sub.1 is selected from hydroxy, F, Cl, Br, I, methyl, ethyl, propyl, and methoxy; the R.sub.2 is selected from hydroxy, F, Cl, Br, I, methyl, ethyl, propyl, methoxy, phenyl, and aryl substituted by hydroxy, F, Cl, Br, I, methyl, ethyl, propyl, and methoxy; the number of the R.sub.1 and the R.sub.2 is 0, 1, 2, 3, or 4; the link mode between the R.sub.1, the R.sub.2 and nucleus is not limited to a single connection via a single bond.

12. A compound of formula b ##STR00084## for synthesizing the compound of Formula I, wherein the X.sub.2 and the Ar.sub.2 are as described in claim 1.

13. A method of synthesizing the compound of Formula I, comprising the following specific steps: ##STR00085## ’, wherein b or a salt of b is reacted with ##STR00086## to obtain I; the X.sub.1, the X.sub.2, the Ar.sub.1 and the Ar.sub.2 are one or more of phenyl, naphthyl, diphenyl ether and biphenyl, at any substitution position; the X.sub.1 is one or more of H, methoxy, hydroxy, F and Cl, at any substitution position.

14. The synthesizing method of claim 13, wherein the b or the salt of b is reacted with ##STR00087## to obtain I; a condensating agent and an alkali are added in this step to facilitate the reaction; wherein, the condensating agent is selected from HBTU, DMC, HOBT, HOBT/EDCI, HATU, HATU/DIEPA, DCC, CDI, and isopropyl chloroformate.

15. The synthesizing method of claim 13, wherein the b or the salt of b is obtained by deprotection of a; ##STR00088## .

16. The synthesizing method of claim 13, wherein the a or the salt of a is obtained by reacting sm with ##STR00089## or a salt thereof; ##STR00090## .

17. A pharmaceutical composition, comprising the compound or a pharmaceutically acceptable salt thereof of claim 1, and a pharmaceutically acceptable carrier.

18-19. (canceled)

20. A method for inhibiting MAGL, comprising contacting the MAGL with the compound or a pharmaceutically acceptable salt thereof of claim 1.

21. A method for treating a MAGL-mediated disease or condition in a mammal, the method comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof of claim 1 to the mammal.

22. The method of claim 21, wherein the condition is selected from: metabolic disorders, nephrosis, emesis or vomiting or nausea, eating disorders, neuropathy, schizophrenia, depressive disorders, bipolar disorders, fremitus, dyskinesia, abstinence syndromes, traumatic brain injury, non-traumatic brain injury, spinal cord injury, epileptic seizure, conditions associated with abnormal cell growth or proliferation, inflammatory conditions, immune system conditions, irritable bowel syndromes, ulcer colonitis, acute stress disorders, substance-inducing anxiety, obsessive-compulsive disorders, anxiety disorders; attention deficiency disorders, attention deficit hyperactivity disorders, pains, migraine, demyelinating diseases, and cognitive impairments.

23. The method of claim 22, wherein the conditions associated with abnormal cell growth or proliferation is benign tumors or cancers.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0083] The specific compound representative of the present invention may be synthesized by the synthesizing method of the general formula disclosed herein. The present invention will be further described by reference to detailed embodiments, but the present invention is not limited thereto. Furthermore, under the guidance of the general formula, synthesizing method of the general formula and detailed embodiments of the present invention, a person skilled in the art may obtain other specific compounds without any inventive effort, and these compounds fall within the scope of the present invention.

##STR00015##

Preparation of an Intermediate A

[0084] N—Boc—4 piperidine formic acid (458.6 mg, 2 mmol, 1 eq) was dissolved into 15 ml DCM; DIPEA (0.7 ml, 4 mmol, 2 eq) and HATU (912 mg, 2.4 mmol, 1.2 eq) were added, and stirred for 10 min at room temperature. Phenylamine (0.365 ml, 4 mmol, 2 eq) was added and stirred for 12 min at room temperature, then washed with water twice, and washed twice by 0.1 M diluted hydrochloric acid, then distilled under reduced pressure to remove the solvent to obtain an intermediate a without purification.

Preparation of an Intermediate B

[0085] The intermediate a was dissolved into 10 ml ethyl acetate, and 2 ml HCl/EA solution was added and stirred for 24 h at room temperature to separate out a white solid, then the white solid was subjected to suction filtration and washed by ethyl acetate to obtain an intermediate b, namely, white solid 347.5 mg (72.4%).

Preparation of MAGLZ-II-01

[0086] The intermediate b (120 mg, 0.5 mmol, 1.5 eq) was dissolved into 10 ml DMF, and TEA (0.23 ml, 1.65 mmol, 5 eq) was added and stirred for 30 min at room temperature, then HATU (152 mg, 0.4 mmol, 1.2 eq) and 4-phenoxybenzoic acid (71.4 mg, 0.33 mmol, 1 eq) were added and stirred for 2 h at room temperature for full reaction; a saturated sodium chloride solution was added to the reaction solution, and ethyl acetate was used for extraction for 3 times, and organic phases were combined, and washed with a saturated sodium chloride solution for 3 times, and dried by anhydrous sodium sulfate, separated and purified by column chromatography (petroleum ether/ethyl acetate=1:1) to obtain a target compound, a light yellow solid 102.4 mg (76.8%).

[0087] .sup.1HNMR (CDCl.sub.3) 6(ppm):7.80-7.88(m,1H),7.47-7.54(m,2H),7.29-7.39(m,5H),6.96-7.19(m,6H),2.79-3.0 5(m,2H),2.45-2.58(m,1H),1.65-2.06(m,6H). The MS result is equivalent to the theoretical value.

[0088] Preparation processes of Examples 2-23 were based on the synthesizing method of the general formula and similar to those of Example 1, where, b in Examples 22 and 23 was changed into

##STR00016##

and

##STR00017##

. The MS result of each target product is equivalent to the theoretical value; and the NMR result is as follows:

TABLE-US-00001 No. Target product No. Characterization data Example 2 [00018] .sup.1H NMR (CDCl.sub.3) δ (ppm):7.32-7.42(m,4H),7.11-7.20(m,3H),6.95 -7.07(m,4H),6.74(s,1H),2.79-3.05(m,2H),2.43 -2,56(m,1H),2.27(s,6H), 1.71-2.07(m,6H). Example 3 [00019] .sup.1H NMR(300 MHz, DMSO-d.sub.6) δ (ppm): 9.92 (s,lH), 7.40-7.47(m,4H), 7.32-7.34 (m,1H), 7.07-7.23 (m,5H), 7.00-7.05 (m,2H), 3.78-4.68 (m,2H), 3.72 (s,3H), 2.78-3.17 (m,2H), 2.57-2.68 (m,1H), 1.74-1.93 (m,2H), 1.53-1.68 (m,2H); Example 4 [00020] .sup.1H NMR(DMSOd.sub.6) δ (ppm): 9.83(s,1H),9.37(s,1H),7.40-7.46(m,4H),7.17-7.25(m,2H),7.08-7.13(m,2H),7.00-7.06(m,3H ),6.93-6.99(m,1H),6.38-6.45(m,1H),2.88-2.92 (m,1H),2.68-2.75(m,3H),2.56-2.66(m,1H), 1.75-1.93(m,2H),1.50-1.65(m,2H) Example 5 [00021] .sup.1H NMR(CDCl.sub.3) δ (ppm):7.32-7.44(m,5H),7.17-7.25(m,1H),6.92 -6.99(m,1H),6.65-6.71(m,1H),3.80(s,3H),2.73 -3.31(m,4H),2.46-2.56(m,1H),1.78-1.97(m,4 H). Example 6 [00022] .sup.1H NMR(DMSOd.sub.6) δ (ppm):9.82(s,1H),9.38(s, 1H),7.42-7.55(m,4H) ,7.16-7.20(m,1H),7.01-7.09(m,1H),6.93-6.99( m,1H),6.39-6.45(m,1H),2.68-2.91(m,4H),2.55 -2.64(m,1H),1.80-2.02(m,2H),1.53-1.65(m,2 H). Example 7 [00023] .sup.1H NMR(CDCl.sub.3) δ (ppm):7.70(s,1H),7.42-7.52(m,2H),7.21-7.37( m,3H),6.92-6.98(m,2H),3.81(s,3H),2.80-2.99( m,4H),2.45-2.55(m, 1H), 1.99-2.12(m,2H), 1.78-1.89(m,2H). Example 8 [00024] .sup.1H NMR(DMSOd.sub.6) δ (ppm):10.08(s,1H),9.68(s,1H),7.60-7.66(m,2 H),7.32-7.38(m,2H),7.20-7.28(m,1H),6.73-6. 86(m,3H),2.67-2.93(m,3H),2.57-2.66(m,1H), 1.68-2.00(m,3H), 1.52-1.65(m,2H). Example 9 [00025] .sup.1H NMR(DMSOd.sub.6) δ (ppm):10.02(s,1H),9.72(s,1H),7.60-7.66(m,2 H),7.31-7.37(m,2H),7.18-7.25(m,1H),7.08-7. 13(m,1H),6.81-6.89(m,2H),3.98-4.13(m,2H), 2.85-2.97(m,2H),2.54-2.66(m,1H), 1.75-1.86( m,2H), 1.52-1.66(m,2H). Example 10 [00026] .sup.1H NMR(DMSOd.sub.6) δ (ppm): 10.10(s,1H),9.87(s,1H),7.61-7.66(m,2H),7.33 -7.38(m,2H),7.23-7.29(m,2H),6.77-6.83(m,2 H),2.86-3.02(m,2H),2.54-2.85(m,3H),1.77-1. 87(m,2H),1.52-1.62(m,2H). Example 11 [00027] .sup.1H NMR(DMSOd.sub.6) δ (ppm): 10.08(s,1H), 9.62(s,1H),7.82(t,1H,J=3 Hz),7.44-7.50 (m,1H),7.32(t,1H, J=6 Hz), 7.24 (t,1H,J=6 Hz), 7.07-7.12(m,1H), 6.74-6.86(m,3H), 2.89-2.98 (m,2H), 2.60-2.74 (m,1H), 2.49-2.58 (m,2H), 1.82-1.91 (m,2H), 1.52-1.64 (m,2H); Example 12 [00028] .sup.1H NMR(DMSOd.sub.6) δ (ppm): 10.15(s,1H),9.79(s,1H),7.835(t,1H,J=1.5 Hz),7 .42-7.48(m,1H),7.32(t,1H,J=6 Hz),7.18-7.26( m,1H),7.06-7.13(m,2H),6.80-6.89(m,2H),2.69 -2.89(m,4H),2.55-2.65(m,1H),1.69-1.93(m,2H ),1.49-1.67(m,2H). Example 13 [00029] .sup.1H NMR(DMSOd.sub.6) δ (ppm): 9.64(s,1H),9.07(s,1H),7.87-8.00(m,1H), 7.24(t,1H,J=7.8 Hz),6.99-7.13(m,2H),6.72-6.94 (m,4H),3.83(s,3H),2.62-3.16(m,4H),1.43-1.95 (m,5H). Example 14 [00030] .sup.1H NMR(DMSOd.sub.6) δ (ppm): 10.12(s,1H), 7.83(t,1H,J=1.92 Hz),7.43-7.50(m,1H),7.30-7. 39(m,2H),7.07-7.11(m,1H),7.00-7.04(m,1H), 6.91-6.96(m,2H),3.79(s,3H),2.67-3.30(m,4H), 2.58-2.67(m,1H),1.76-1.95(m,2H),1.53-1.66( m,2H). Example 15 [00031] .sup.1H NMR(DMSOd.sub.6) δ (ppm): 9.68(s,1H), 9.23(s,1H),7.32-7.42(m,1H),7.15-7.20(m,1H), 6.90-7.06(m,5H),6.40-6.48(m,1H),3.80(s,3H), 2.68-3.20(m,4H),2.56-2.68(m,1H),1.76-1.79( m,2H),1.54-1.66(m,2H). Example 16 [00032] .sup.1H NMR(DMSOd.sub.6) δ (ppm): 10.13(s,1H), 7.79-7.88(m,1H),7.41-7.48(m,5H),7.29-7.36( m,1H),7.17-7.24(m,1H),7.07-7.12(m,3H),7.01 -7.05(m,3H),2.56-3.29(m,4H),1.46-1.99(m,5H ) Example 17 [00033] .sup.1H NMR(DMSOd.sub.6) δ (ppm): 10.14(s,1H),7.97-8.04(m,4H),7.81-7.87(m,1H ), 7.57-7.62(m,2H),7.44-7.54(m,2H),7.29-7.38 (m,1H),7.06-7.14(m,1H),3.65-4.66(m,2H),2.8 8-3.22(m,2H),2.64-2.7 1(m, 1H), 1.62-1.97(m,4 H). Example 18 [00034] .sup.1H NMR(DMSOd.sub.6) δ (ppm): 11.58(s,1H), 10.17(s,1H),7.82-7.88(m,1H),7.58-7.65(m,1H ),7.40-7.50(m,2H),7.29-7.37(m,1H),7.15-7.23 (m,1H),7.01-7.13(m,2H),6.78-6.82(m,1H),4.4 4-4.58(m,2H),3.00-3.26(m,2H),2.66-2.74(m,1 H),1.86-2.00(m,2H),1.58-1.74(m,2H). Example 19 [00035] .sup.1H NMR(DMSOd.sub.6) δ (ppm): 10.16(s,1H),7.83-7.86(m,1H),7.69-7.78(m,4H ),7.47-7.52(m,4H),7.37-7.46(m,2H),7.33(t,1H, J=8.04),7.07-7.13(m,1H),3.67-4.61(m,2H),2.8 9-3.16(m,2H),2.61-2.69(m, 1H), 1.82-1.99(m,2 H),1.56-1.69(m,2H). Example 20 [00036] [M+H].sup.+401.2. Example 21 [00037] .sup.1H NMR(300 MHz, DMSO-d.sub.6) δ (ppm): 10.17(s,1H),7.83-7.87(t,1H),7.59-7.65(d,1H), 7.50-7.56(d,1H),7.45-7.49(m,1H),7.30-7.37(t, 1H),7.23-7.30(t,1H),7.11-7.14(m,1H),7.07-7.11 (m,1H),6.67(s,1H),3.77(s,3H),2.63-2.76(m,2 H),1.98-2.06(s,1H),1.85-1.97(d,2H),1.57-1.73 (m,2H),1.15-1.28(m,2H). MS: [M+Na].sup.+: 418.2. Example 22 [00038] .sup.1H NMR(300 MHz, DMSO-d.sub.6) δ (ppm): 9.68 (s,1H), 7.83-7.84(d,1H), 7.73-7.75 (d,1H), 7.40-7.43 (m,1H), 7.21-7.25 (t,1H), 6.81-6.84 (m,1H), 6.78-6.80 (d,1H), 6.75-6.76 (m,1H), 4.40 (d,1H), 3.67 (s,1H), 3.21 (s,2H),3.09-3.15 (m,1H), 2.11-2.15 (m,2H), 1.75-1.78 (m2H); [M+Na].sup.+379.1 Example 23 [00039] .sup.1H NMR(300 MHz, DMSO-d.sub.6) δ (ppm): 12.48 (s,1H), 9.73 (s,1H), 7.56-7.62(t,1H), 7.50-7.56 (d,1H), 7.24-7.29 (t,1H), 7.18-7.20 (m,1H), 6.80-6.87 (m,3H), 4.50 (d,1H), 3.71 (d,1H), 2.03-2.10 (m,2H), 1.71-1.81 (m,2H);3.21 (s,2H), 3.02-3.17 (m,1H),2.03-2.10 (m,2H), 1.71-1.81 (m,2H); [M+H].sup.+356.1

[0089] The target products synthesized in Examples 24-30 are described on the basis of the following structural formula:

##STR00040##

where, the R.sub.1 is selected from hydroxy, F, Cl, Br, I, methyl, ethyl, propyl, and methoxy; R.sub.2 is selected from hydroxy, F, Cl, Br, I, methyl, ethyl, propyl, methoxy, phenyl, and aryl substituted by hydroxyl, F, Cl, Br, I, methyl, ethyl, propyl, and methoxy. The number of R.sub.1 and R.sub.2 is 0, 1, 2, 3 or 4; the link mode between the R.sub.1, the R.sub.2 and nucleus is not limited to a single bond.

TABLE-US-00002 Example Compound R.sub.1 R2 Characterization data Example 24 MAGLZ-II-20 3-C1 4-OH .sup.1H NMR(300 MHz, DMSO-d.sub.6) δ (ppm): 10.12 (s,1H), 9.83 (s,1H), 7.81-7.84 (m,1H), 7.42-7.49 (m,1H), 7.29-7.36 (m,1H), 7.22-7.28 (m,2H), 7.06-7.12 (m,1H), 6.77-6.83 (m,2H), 2.89-2.90 (m,2H), 2.73-2.74 (m,2H), 2.55-2.67 (m,1H), 1.77-1.89 (m,2H), 1.50-1.65 (m,2H); [M+H].sup.+359.1 Example 25 MAGLZ-II-21 3-C1 4-Cl .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 10.12 (s,1H), 7.81-7.84 (m,1H), 7.49-7.55 (m,2H), 7.41-7.48 (m,3H), 7.29-7.36 (m,1H), 7.07-7.12 (m,1H), 3.16-3.19 (m,2H), 2.79-3.11 (m,2H), 2.58-2.69 (m,1H), 1.71-1.95 (m,2H), 1.52-1.68 (m,2H); [M+H].sup.+377.08 Example 26 MAGLZ-II-22 3-Cl, and 4-Cl 3-OH .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 10.24 (s,1H), 9.67 (s,1H),8.00-8.03 (m,1H), 7.47-7.58 (m,2H), 7.24 (t,1H, J = 7.5 Hz), 6.80-6.86 (m,1H), 6.74-6.80 (m,2H), 2.88-2.91 (m,2H), 2.69-2.74 (m,2H), 2.56-2.67 (m,lH), 1.72-1.93 (m,2H), 1.50-1.63 (m,2H); [M+H].sup.+393.08 Example 27 MAGLZ-II-23 3-Cl and 5-Cl 3-OH .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 10.27 (s,1H), 9.67 (s,1H), 7.94-7.97 (m,1H), 7.67-7.70 (m,2H), 7.25-7.28 (m,1H), 6.72-6.85 (m,3H), 2.88-2.91 (m,2H), 2.73-2.74 (m,2H), 2.56-2.67 (m,1H), 1.73-1.92 (m,2H), 1.48-1.63 (m,2H); [M+H].sup.+393.08 Example 28 MAGLZ-II-24 3-Cl, and 4-Cl [00041] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 10.24 (s,1H), 7.95-8.02 (m,5H), 7.57-7.60 (m,2H), 7.48-7.54 (m,3H), 2.89 (s,2H), 2.73 (s,2H), 2.61-2.65 (m,1H), 1.74-1.90 (m,2H), 1.57-1.67 (m,2H); [M+H].sup.+ 427.09 Example 29 MAGLZ-II-25 3-Cl and 5-C1 [00042] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 10.28 (s,1H), 7.95-8.00 (m,4H), 7.68-7.69 (d,2H), 7.57-7.60 (m,2H), 7.49-7.52 (m,1H), 7.25-7.26 (t,1H), 2.89 (s,2H), 2.73 (s,2H), 2.59-2.63 (m,1H), 1.73-1.91 (m,2H), 1.58-1.65 (m,2H); [M+H].sup.+ 427.09 Example 30 MAGLZ-II-26 3-F 3-OH .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 10.16 (s,1H), 9.69 (s,1H), 7.58-7.65 (m,1H), 7.27-7.38 (m,2H), 7.24 (t,1H, J = 7.5 Hz), 6.73-6.90 (m,4H), 2.71-3.12 (m,4H), 2.56-2.68 (m,1H), 1.73-1.93 (m,2H), 1.49-1.65 (m,2H); [M+H].sup.+343.15 Example 31 MAGLZ-II-27 3-F and 4-Cl 3-OH .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 10.30 (s,1H), 9.76 (s,1H), 7.76-7.81 (m,1H), 7.47-7.53 (t,1H), 7.32-7.36 (m,1H), 7.21-7.27 (t,1H), 6.74-6.85 (m,3H), 2.66-2.89 (m,4H), 2.63-2.73 (m,1H), 1.76-1.85 (m,2H), 1.54-1.57 (m,2H); [M+H].sup.+377.10 Example 32 MAGLZ-II-29 3-Cl [00043] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 10.13 (s,1H), 9.93 (s,1H), 7.82-7.87 (m,3H), 7.72-7.75 (d,1H), 7.44-7.47 (m,1H), 7.37-7.40(m,1H),7.29-7.34 (t,1H), 7.07-7.15 (m,3H), 2.64-3.02 (m,4H), 2.60-2.64 (m,1H), 1.82-1.85 (m,2H), 1.56-1.68 (m,2H); [M+Na].sup.+431.12 Example 33 MAGLZ-II-11 (a) 3-Cl 2-F and 5-OH .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 10.17 (s,1H), 9.68 (s,1H), 7.82 (s,1H), 7.43-7.45 (d,1H), 7.29-7.35 (t,1H), 7.06-7.09 (m,2H), 6.79-6.82 (m,1H), 6.67 (s,1H), 2.84-2.89 (d,2H), 2.68-2.73 (d,2H), 2.61-2.62 (m,1H), 1.76-1.93 (m,4H); [M+Na].sup.+399.1

##STR00044##

[0090] A raw material N-Boc-4-piperidine formic acid (20) (229.3 mg, 1 mmol) was dissolved into 10 mL CH.sub.2Cl.sub.2, DIPEA (0.35 mL, 2 mmol) and HATU (456 mg, 1.2 mmol) were added, and stirred for 10 min at room temperature, then 3-chloroaniline (0.21 mL, 2 mmol) was added and stirred for 6 h at room temperature, washed with water for three times, and washed by 10% diluted hydrochloric acid for three times, and dried by anhydrous Na.sub.2SO.sub.4, subjected to rotary evaporation to remove CH.sub.2Cl.sub.2, thus obtaining an intermediate 21 h without further purification.

[0091] The intermediate 21 h was dissolved into 10 mL EtOAc, and 4M HCl/EtOAc solution (2 mL) was added and stirred for 12 h at room temperature to separate out a white solid, then the white solid was subjected to suction filtration, and a filter cake was washed with EtOAc to obtain an intermediate 22 h, namely, a white solid (188.1 mg and yield: 68.4%).

##STR00045##

[0092] The intermediate 24 (62.5 mg, 0.3 mmol) was dissolved into anhydrous DMF, HATU (136.8 mg, 0.36 mmol) and TEA (151.8 mg, 1.5 mmol) were added and stirred for 30 min at room temperature, then the hydrochloride intermediate 22 h (107.33 mg, 0.39 mmol) was added and stirred for 12 h at room temperature to stop the reaction; then a saturated salt solution was added and EtOAc was used for extraction for three times, organic phases were combined and washed for three times with a saturated salt solution and dried by anhydrous Na.sub.2SO.sub.4, then separated and purified by column chromatography (petroleum ether: ethyl acetate =1:1) to obtain a yellow solid (94.9 mg and yield: 74.1%).

Characterization Data

[0093] .sup.1H NMR (300 MHz, CDCl.sub.3) δ (ppm): 7.65 (s, 1H), 7.40-7.45 (t, 1H), 7.34-7.36 (d, 2H),7.23-7.28 (d, 1H), 7.14-7.16 (m, 2H), 7.07-7.10 (m, 1H), 2.96 (s, 1H), 2.88 (s, 1H), 2.52-2.58 (t, 2H), 2.04 (s, 1H), 1.74-1.86 (m, 2H), 1.59 (s, 4H), 1.24-1.28 (m, 3H), 1.02-1.07 (t, 3H); [M+Na].sup.+: 451.2.

[0094] Example 35 Synthesis of MAGLZ-II-11J

##STR00046##

[0095] A raw material N-Boc-L-tyrosine (0.5 mmol, 140.5 mg) was dissolved into 10 mL anhydrous CH.sub.2Cl.sub.2, and the intermediate II-11 (179.5 mg, 0.5 mmol) and DMAP (0.1 mmol, 12.2 mg) were added, reacted and cooled to 0° C., then dissolved into DCC (0.55 mmol, 113.4 mg) of 3 mL anhydrous CH.sub.2Cl.sub.2, and stirred for 10 min, and reacted to room temperature, then the above materials were stirred for 12 h at room temperature; the reaction was incomplete, after the reaction was stopped, suction filtration was performed, and a filter liquor was rotary dried, and added with 20 mL CH.sub.2Cl.sub.2 and washed with a saturated salt solution for three times, and dried by anhydrous sodium sulfate. The above product was separated and purified by column chromatography (dichloromethane: methanol=100:1) to obtain an intermediate 25, namely, a white solid (52.6 mg, yield: 16.9%).

##STR00047##

[0096] The intermediate 25 (37 mg) was dissolved into 10 mL EtOAc, and 4 M HCl/EtOAc solution (2 mL) was added and stirred for 12 h at room temperature to separate out a white solid, then the white solid was subjected to suction filtration and a filter cake was washed with EtOAc, and the filter cake was added with 10 mL sodium bicarbonate and extracted with EtOAc for three times, then, organic phases were combined and washed with a saturated salt solution for three times and dried by anhydrous sodium sulfate, then subjected to rotary evaporation to remove EtOAc, thus obtaining a light white solid (12 mg and yield: 40%).

[0097] Characterization data of MAGLZ-II-11J: .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ (ppm): 11.95 (s, 1H), 10.14 (s, 1H), 7.83 (s, 1H), 7.54-7.56 (d, 1H), 7.48-7.51 (t, 1H), 7.44-7.46 (d, 1H), 7.28-7.34 (m, 2H), 7.10-7.12 (m, 2H), 7.04-7.07 (d, 2H), 6.69-6.71 (d, 2H), 4.40-4.49 (m, 1H), 4.26-4.30 (t, 1H), 4.00-4.06 (m, 2H), 3.61 (s, 1H), 3.07-3.14 (d, 2H), 2.89-2.98 (d, 2H), 2.60-2.65 (m, 1H), 1.58-1.78 (m, 4H); [M+Na].sup.+544.17.

Example 36: MAGL Enzyme Analysis

[0098] A kit for screening the MAGL inhibitor from Cayman was used; according to the specification, an ethanol solution of 4-nitrophenylacetic acid served as a MAGL substrate, and the substrate had a final concentration of 236 UM. 150 .Math.L 1Xassay buffer, 10 .Math.L recombinant human protein MAGL and 10 .Math.L different concentrations of MAGL inhibitors (six points within 1 nM to 1000 nM) were added to per well of a 96-well plate. JZL195 (a positive control inhibitor) served as a positive control well, after incubation for 5 min at room temperature, per well was added with 10 .Math.L MAGL substrate, and 86 wells were vibrated for 10 s and placed for 10 min at room temperature, then an absorbance was detected at 410 nm. 100% inhibition control wells (150 .Math.L 1Xassay buffer, 10 .Math.L MAGL and 10 .Math.L DMSO were added per well of the 96-well plate, and three repeated wells were set) and background wells (160 .Math.L 1Xassay buffer and 10 .Math.L DMSO were added per well, and three repeated wells were set) were further set. Graphad Prism 5.0 was taken to calculate IC50 curves fitting each inhibitor. Specific values are shown in Table 2.

TABLE-US-00003 Activity data Compound No. MAGLXIC50 (.Math.M) MAGLZ-II-01 0.045 MAGLZ-II-02 0.027 MAGLZ-II-03 0.749 MAGLZ-II-04 ND MAGLZ-II-05 4.07 MAGLZ-II-06 1.96 MAGLZ-II-07 0.576 MAGLZ-II-08 1.34 MAGLZ-II-09 10.8 MAGLZ-II-10 0.662 MAGLZ-II-11 0.096 MAGLZ-II-12 ND MAGLZ-II-13 0.926 MAGLZ-II-14 0.333 MAGLZ-II-15 ND MAGLZ-II-16 0.018 MAGLZ-II-17 0.015 MAGLZ-II-18 0.670 MAGLZ-II-19 2.82 MAGLZ-II-18 (c) 0.0026 MAGLZ-II-18 (a) 2.15 MAGLZ-II-20 9.92 MAGLZ-II-21 ND MAGLZ-II-22 1.77 MAGLZ-II-23 4.03 MAGLZ-II-24 0.275 MAGLZ-II-25 0.139 MAGLZ-II-26 12.2 MAGLZ-II-27 2.90 MAGLZ-II-29 0.252 MAGLZ-II-30 0.011 MAGLZ-II-31 ND MAGLZ-II-11 (a) 2.15 MAGLZ-II-11F 0.126 MAGLZ-II-11J 1.60

Example 37 Tissue Distribution Test on the MAGL Inhibitor Of the Present Invention

[0099] Detection reagent: MAGLZ-II-11, MAGLZ-II-16, and MAGLZ-II-17; [0100] test object: mice; [0101] administration dose: 16 mg/kg (formulation concentration: 8 mg/ml); administration mode: subcutaneous injection; [0102] sampling time: sampling was performed 1, 2, and 5 hours later after administration; [0103] test tissues: brain, heart, liver, spleen, lung, kidney, pancreas, and blood; [0104] experimental results indicate that:

[0105] 3 test substances are distributed in the brain detected, where, the content of MAGLZ-II-16 in the brain is up to the highest, MAGLZ-II-17 is ranking the second, and MAGLZ-II-11 is the lowest (see Table 3).

TABLE-US-00004 Tissue distribution diagram Time/h MAGLZ-II-01 MAGLZ-II-02 MAGLZ-II-11 MAGLZ-II-16 MAGLZ-II-17 1.0 0 0 0 0 2.9 2.0 0.6 1.2 1.6 32.8 9.4 5.0 0.9 3.7 1.3 16.9 4.8

Example 38 Effect of the MAGL Inhibitor of the Present Invention on Reserpine-Induced Mice Depression

1) Basic Information

[0106] Species: ICR mouse [0107] Microbiological level: SPF [0108] Quantity and sex of the animals purchased: male: 75; female: 75 [0109] Quantity and sex of the animals used: male: 75; female: 75 [0110] Body weight: 13-18 g when accepted

2) Animal Grouping

[0111] Group design: there were 50 pieces for each batch of animals and 3 batches in total; each batch of animals were randomly divided into 5 groups; low, middle and high-dose groups of the samples for test, blank control group and model group; a sample for test was tested per batch.

3) Test Method

[0112] 3.1 Animals were administrated via subcutaneous injection per day with doses of 4, 8 and 16 mg/kg for 6 d in total. 2 h later after the final administration, each animal was subcutaneously injected with 4 mg/kg reserpine except the blank control group; afterwards, indicators, such as, awakening, finger contact, fear, head touch, autonomic activity, upright and eyelid closure were determined 2 h later.

4) Statistical Analysis

[0113] Data statistics and analysis were completed via a computer by SPSS 17.0 software and office 2016, and data statistics was inspected by Kruskal-Wallis. If the Kruskal-Wallis inspection result is significant ((P<0.05), multiple comparison inspection is further performed by a Mann-Whitney U nonparametric test method.

[0114] 5) Results are shown in Tables 4A, 4B and 4C

TABLE-US-00005 Group Awakenin g Finger contact Head touch Fear Autonom ic activity Upright Eyelid closure Blank control group 4±0 4±0 4±0 4±0 4±0 4±0 4±0 Model group 2.2±1.40* * 1.2±0.98* * 1.4±0.92* * 0.2±0.60* * 0±0** 0±0** 1.2±1.33 ** MAGL-II-11-L 3±1.61 1.6±1.50 1±1.34 0±0 0.8±1.60 0.8±1.6 0 1.2±0.98 MAGL-II-11-M 2.6±1.56 1.8±1.66 1.8±1.40 0±0 0.8±1.60 0.8±1.6 0 1.4±1.28 MAGL-II-11-H 3.2±1.33 2±1.79 2.6±1.56 0.2±0.60 1.8±1.66* * 1±1.61* * 2±1.26 Note: a comparison between the model group and the blank group: *P<0.05, **P<0.01; a comparison between the administration group and the model group: *P<0.05, **P<0.01.

TABLE-US-00006 Group Awakening Finger Contact Head Touch Fear Autonomic Activity Upright Eyelid Closure Blank control group 4±0 4±0 4±0 4±0 4±0 4±0 4±0 Model group 3.5±1.32 ** 3.5±1.32 ** 3.58±1.10 ** 0.25±0.66 ** 0.58±0.85 ** 0±0** 1.83±0.44 ** MAGL-II-17 -L 4±0 4±0 3.75±0.66 3.5±1.32 0.5±0.87 0.25±0. 66 2.25±0.66 MAGL-II-17 -M 4±0 4±0 4±0 0±0 1.5±1.66 1±1.41 1±1.00 MAGL-II-17 -H 4±0 4±0 3.75±0.66 0±0 0.25±0.66 0±0 0.25±0.66 Note: a comparison between the model group and the blank group: *P<0.05, **P<0.01; a comparison between the administration group and the model group: *P<0.05, **P<0.01.

TABLE-US-00007 Group Awakening Finger contact Head touch Fear Autonomic Activity Upright Eyelid Closure Blank control group 4±0 4±0 4±0 4±0 4±0 4±0 4±0 Model group 1.6±1.2** 1.2±0.98* 0±0** 0±0** 0.2±0.6** 0±0** 0±0** MAGL-II-16-L 2±0 1.4±0.92 0.4±0.8 0±0 0±0 0±0 0±0 MAGL-II-16-M 1.8±0.6 1.2±0.98 0.8±0.98* 0±0 0.2±0.6 0±0 0±0 MAGL-II-16-H 2±0 1.6±0.8 0.8±0.98* 0±0 0.6±0.6* 0.4±1.2 0±0 Note: a comparison between the model group and the blank group: *P<0.05, **P<0.01; a comparison between the administration group and the model group: *P<0.05, **P<0.01.

5.1) MAGLZ-II-11

[0115] Nonparametric test

[0116] Each indicator of the Kruskal-Wallis test has a statistic difference (P<0.05);

[0117] Comparison of difference between groups

[0118] Mann-Whitney U test

[0119] The comparison between the model group and the blank control group shows a statistic difference (P<0.05), indicating a good modeling result; the comparison between the low/middle/high-dose group and the model group shows no statistic difference (P>0.05); the comparison between the high-dose group and the model control group (autonomic activity and upright) shows a statistic difference (P<0.01, P<0.05); the variation trend of the indicator is consistent with the blank control.

5.2) MAGLZ-II-17: Each Indicator of the Kruskal-Wallis Test has a Statistic Difference (P<0.05); Mann-Whitney U Test

[0120] The comparison between the model group and the blank control group shows a statistic difference (P<0.05), indicating a good modeling result; [0121] the comparison between the low-dose group and the model group shows no statistic difference (P>0.05); [0122] the comparison between the middle-dose group (eyelid closure) and the model group shows a statistic difference (P<0.05); but the mean value is less than that of the model group; and other indicators show no statistic difference (P>0.05); [0123] the comparison between the high-dose group (eyelid closure) and the model group shows a statistic difference (P<0.01); but the mean value is less than that of the model group; and other indicators show no statistic difference (P>0.05);

5.3) MAGLZ-II-16: Each Indicator of the Kruskal-Wallis Test has a Statistic Difference (P<0.05); Mann-Whitney U Test

[0124] The comparison between the model group and the blank control group shows a statistic difference (P<0.05), indicating a good modeling result; [0125] the comparison between the low-dose group and the model group shows no statistic difference (P>0.05); [0126] the comparison between the middle-dose group (head touch) and the model group shows a statistic difference (P<0.05); but the mean value is greater than that of the model group and has a trend change the same as that of the blank control group; and other indicators show no statistic difference (P>0.05); [0127] the comparison between the high-dose group (head touch and autonomic activity) and the model group shows a statistic difference (P<0.05); but the mean value is greater than that of the model group and has a trend change the same as that of the blank control group; and other indicators show no statistic difference (P>0.05).

6) Conclusion

[0128] 6.1) MAGLZ-II-11 has a certain effect on reserpine-induced depression under this test condition.

[0129] 6.2) MAGLZ-II-16 has a certain effect on reserpine-induced depression under this test condition.

[0130] 6.3) MAGLZ-II-17 may enhance the effect on reserpine-induced depression under this test condition.

[0131] Example 39 Effect of the MAGL inhibitor of the present invention on mice forced swimming test and tail suspension model

1 Materials and Methods

1.1 Experimental Animal

[0132] Male ICR mice having a body weight of 18-22 g. The animals were active on a schedule of normal illumination for 12 h and in the dark for 12 h. Environmental temperature and relative humidity were relatively kept for 22±1° C. and 55±5%.

1.2 Experimental Method

1.2.1 Animal Grouping and Administration Method

[0133] There were 7 groups of laboratory mice, 10 pieces each group, set as a control group (normal saline), a positive control group (fluoxetine hydrochloride capsule, 5 mg/kg), 5 MAGLZ-II series of administration treatment groups: MAGLZ-II-06, MAGLZ-II-07, MAGLZ-II-11, MAGLZ-II-17 and MAGLZ-II-18, respectively, with an administration concentration of 5 mg/kg.

[0134] All medicaments were used once per day via intragastric administration with a dose of 20 mL/kg (body weight), lasting for 10 d. 1 h later after the final administration, the detection of animal behaviors was started.

1.2.2 Mice Forced Swimming Test

[0135] Mice forced swimming test was performed according to the method established by Porsolt (Porsolt R D. Behavioural despair in mice: A primary screening test for antidepressants[J]. Arch. Int. Pharmacolodyn. 1977, 229). The mice were separately subjected to forced swimming in an open cylindrical container (diameter: 10 cm and height: 25 cm); the container had a water temperature of 25±1° C. and a water depth of 19 cm; the total time that each animal kept still in the course of 6 min was recorded as immobility time (unit: s). Each mouse was judged as still when stopped struggling, kept suspension in water and only made necessary movement to keep the head above the water. Decrease of the immobility time indicates that there is an anti-depression effect.

1.2.3 Mice Tail Suspension Test

[0136] The tail suspension test (TST) was performed by the method established by Porsolt, et al. (Porsolt R D, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments[J]. Nature, 1977, 266(5604):730-732). Mice were respectively suspended on the tail portions with tail suspension clamps at a distance of 10 mm away from the tail portion of the box (250 mm×250 mm×300 mm) and a distance of 5 cm where the head of each mouse was away from the bottom portion. Noise was tested in a dark room having minimum background, and each mouse was suspended for 6 min, and an immobility time was recorded at intervals in the final 4 min. Judgment standard: the mice stopped struggling and kept still completely.

1.2.4 Data Processing

[0137] All data are shown by x̅±SD, and the comparison among groups is analyzed by one-way variance.

2 Results

2.1 Influences of MAGLZ-II Series of Compounds on Forced Swimming Test

[0138] The test for the influences of MAGLZ-II series of compounds on mice forced swimming test indicates that the positive control medicament, fluoxertine hydrochloride and MAGLZ-II series of compounds may obviously shorten the accumulated immobility time (P<0.05) of mice forced swimming test (Table 5).

TABLE-US-00008 Influences of the MAGLZ-II series of compounds on mice forced swimming test Group Dose (mg/kg) Number animals (pcs.) of Accumulated immobility time (S) Control group - 10 136.84±46.69 Fluoxetine hydrochloride capsule 5 10 92.64±29.17** MAGLZ-II-06 5 10 89.23±46.37* MAGLZ-II-07 5 10 91.31±41.85* MAGLZ-II-11 5 10 73.57±27.28** MAGLZ-II-17 5 10 79.38±41.67** MAGLZ-II-18 5 10 81.71±38.12** Note: compared with the control group, *P<0.05 and **P<0.01.

2.2 Influences of the MAGLZ-II Series of Compounds on Mice Tail Suspension Test

[0139] Compared with the control group, the MAGLZ-II series of compounds may obviously shorten the accumulated immobility time (P<0.05) of tail suspension mice (Table 6).

TABLE-US-00009 Influences of the MAGLZ-II series of compounds on mice tail suspension behaviors Group Dose (mg/kg) Number animals (pcs.) of Accumulated immobility time (S) Control group - 10 132.38±44.51 Fluoxetine hydrochloride capsule 5 10 92.19±23.63** MAGLZ-II-06 5 10 90.73±30.51** MAGLZ-II-07 5 10 89.66±31.52* MAGLZ-II-11 5 10 72.81±23.49** MAGLZ-II-17 5 10 89.87±29.68** MAGLZ-II-18 5 10 79.68±25.72** Note: compared with the control group, *P<0.05 and **P<0.01.

3 Discussion

[0140] Mice forced swimming test and tail suspension test are comparatively common and classical depression models for animals. Despair, behavior distortion and other conditions of the mice reflected by the model are significant features of in vitro depression simulation; meanwhile, the mice are more sensitive to antidepressants and easy to operate. Therefore, the two models are common screening models for antidepressants. Such two classical depression models for animals are used in this study to further evaluate and verify the anti-depression activity of the MAGLZ-II series of compounds. The results indicate that the MAGLZ-II series of compounds may significantly shorten the accumulated immobility time of the mice forced swimming test and tail suspension test, showing that the MAGLZ-II series of compounds have a specific antidepression effect.

Example 40 Influences of the MAGL Inhibitor of the Present Invention on the Mice Writhing Times Caused by Acetic Acid

1. Animal Grouping and Administration

[0141] 200 male ICR mice (20±2) g were divided into 20 groups randomly according to body weight, 10 pieces for each group. The specific grouping conditions are as follows: model group: an equal volume of 0.5% sodium carboxymethylcellulose, ig [0142] positive control group: 10 mg/kg diclofenac sodium, ig [0143] MAGLZ-II-11 low-dose group: 7.5 mg/kg, ig [0144] MAGLZ-II-11 middle-dose group: 15 mg/kg, ig [0145] MAGLZ-II-11 high-dose group: 30 mg/kg, ig [0146] MAGLZ-II-11a low-dose group: 7.5 mg/kg, ig [0147] MAGLZ-II-11a middle-dose group: 15 mg/kg, ig [0148] MAGLZ-II-11a high-dose group: 30 mg/kg, ig [0149] MAGLZ-II-18a low-dose group: 7.5 mg/kg, ig [0150] MAGLZ-II-18a middle-dose group: 15 mg/kg, ig [0151] MAGLZ-II-18a high-dose group: 30 mg/kg, ig [0152] MAGLZ-II-18 low-dose group: 7.5 mg/kg, ig [0153] MAGLZ-II-18 middle-dose group: 15 mg/kg, ig [0154] MAGLZ-II-18 high-dose group: 30 mg/kg, ig [0155] MAGLZ-II-18c low-dose group: 7.5 mg/kg, ig [0156] MAGLZ-II-18c middle-dose group: 15 mg/kg, ig [0157] MAGLZ-II-18c high-dose group: 30 mg/kg, ig [0158] MAGLZ-II-10 low-dose group: 7.5 mg/kg, ig [0159] MAGLZ-II-10 middle-dose group: 15 mg/kg, ig [0160] MAGLZ-II-10 high-dose group: 30 mg/kg, ig

[0161] Each compound was prepared into a suspension by 0.5% sodium carboxymethylcellulose respectively, and then set according to the dose, and each administration group was administered intragastrically; the model group was administered intragastrically an equal volume of 0.5% sodium carboxymethylcellulose.

2. Experimental Method and Data Processing

[0162] Mice were intraperitoneally injected with acetic acid to cause a large area and more lasting painful stimuli in deep enterocoelia, causing mice to produce writhing responses. After being administered for 1 h, each dose group was intraperitoneally injected with 0.7% acetic acid-normal saline solution (0.1 ml/10 g).

[0163] The time (pain latent time) that the mice started to appear writhing after being intraperitoneally injected with acetic acid was recorded.

[0164] The writhing response times of each mouse within 20 min were recorded after injecting acetic acid to cause pain, and then, the writhing inhibition ratio of each administration group was calculated.

[0165] Writhing inhibition ratio = [(writhing times of the control group -writhing times of the administration group)/writhing times of the control group] × 100%

[0166] Experimental data is shown by x±s and subjected to variance analysis by SPSS 15.0 software.

3. Experimental Results

[0167] Experimental results are shown in Table 7.

TABLE-US-00010 Influences of the MAGL inhibitor of the present invention on the mice writhing times caused by acetic acid Group Writhing times Inhibition ratio (%) Latent time (s) Model group 39.3±12.9 - 226.5±38.2 Positive medicament group 24.5±12.9* 37.7 358.5±172.7* MAGLZ-II-18a low-dose group 24.2±8.5** 38.4 355.5±136.5* MAGLZ-II-18a middle-dose group 20.8±12.5** 47.1 380.7±130.7** MAGLZ-II-18a high-dose group 17.8±11.1*** 54.7 422.4±137.9*** MAGLZ-II-11 low-dose group 23.4±11.7** 40.5 379.7±129.3** MAGLZ-II-11 middle-dose group 17.5±9.6*** 55.5 408.4±128.2*** MAGLZ-II-11 high-dose group 13.6±13.1*** 65.4 467.8±175.6*** MAGLZ-II-11a low-dose group 22.6±12.0** 42.5 401.2±168.3** MAGLZ-II-11a middle-dose group 18.6±14.6** 52.7 438.9±230.0** MAGLZ-II-11a high-dose group 12.5±9.4*** 68.2 488.8±172.0*** MAGLZ-II-18 low-dose group 25.0±13.5* 36.4 318.7±120.2* MAGLZ-II-18 middle-dose group 21.8±12.4** 44.5 381.4±127.1** MAGLZ-II-18 high-dose group 15.8±15.3** 59.8 410.9±186.5** MAGLZ-II-18c low-dose group 28.3±11.9 28.0 263.5±77.7 MAGLZ-II-18c middle-dose group 24.9±12.2* 36.6 312.7±90.9* MAGLZ-II-18c high-dose group 19.9±12.2** 49.4 373.6±114.0** MAGLZ-II-10 low-dose group 34.0±9.1 13.5 235.4±59.6 MAGLZ-II-10 middle-dose group 32.8±11.6 16.5 246.2±69.5 MAGLZ-II-10 high-dose group 24.8±11.1.sup.∗ 36.9 306.4±90.2.sup.∗

[0168] Compared with the model group, *P<0.05, **P<0.01 and ***P<0.001.

[0169] It can be seen from the experimental results shown in Table 1 that compared with the model group, the MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a and MAGLZ-II-18c of the present invention may significantly decrease the mice writhing times caused by acetic acid and extend latent time.

Example 41 Influences of the MAGL Inhibitor of the Present Invention on the Mice Pain Response Induced by Hot Plate

[0170] Female ICR mice (20±2) g were placed on an intelligent hot plate at 55±0.5° C., and latency (s) that the plantar of mice touched the hot plate until the occurrence of a hind paws licking response served as a pain threshold indicator; the mice (response latency <5 s or >30 s) or jumping mice were eliminated.

[0171] Grouping and administration were the same as those in Example 40.

[0172] The mice were continuously administered intragastrically for 7 consecutive days; the pain threshold of each group of mice was respectively determined once at 30, 60, 90 and 120 min after the final administration; the pain threshold greater than 60 s was calculated by 60 s.

[0173] Experimental results are shown in Table 8.

TABLE-US-00011 Influences of the MAGL inhibitor of the present invention on the pain threshold of mice pain response induced by hot plate Pain thresholds of the mice at different periods of time after administration (s) Group 30 min 60 min 90 min 120 min Model group 15.63±7.32 16.85±7.46 15.50±6.11 15.38±6.93 Positive medicament group 22.32±6.76* 24.34±8.19* 22.64±6.48* 22.52±6.91* MAGLZ-II-11 low-dose group 37.92±8.83*** 44.14±7.56*** 45.93±8.38*** 43.80±6.12*** MAGLZ-II-11 middle-dose group 40.33±8.25*** 44.87±5.67*** 46.41±5.36*** 43.44±5.91 *** MAGLZ-II-11 high-dose group 41.43±5.15*** 46.16±6.63*** 47.22±5.98*** 45.49±6.31*** MAGLZ-II-11a low-dose group 36.18±8.50*** 43.17±7.43*** 42.83±7.34*** 42.16±7.05*** MAGLZ-II-11a middle-dose group 38.16±7.00*** 45.47±7.03*** 43.71±5.87*** 42.34±7.04*** MAGLZ-II-11a high-dose group 39.45±6.75*** 46.56±6.35*** 45.42±6.84*** 43.73±5.68*** MAGLZ-II-18a low-dose group 34.62±6.65*** 40.29±6.73*** 43.98±6.55*** 43.56±6.01*** MAGLZ-II-18a middle-dose group 37.51±6.07*** 42.42±5.90*** 45.86±7.09*** 44.38±5.44*** MAGLZ-II-18a high-dose group 40.86±7.17*** 46.29±5.27*** 48.70±5.73*** 47.04±5.54*** MAGLZ-II-18 low-dose group 26.33±7.52** 26.74±7.05** 27.16±7.32** 26.64±10.03** MAGLZ-II-18 middle-dose group 26.41±7.53 ** 27.09±7.53** 27.58±7.71** 27.38±9.97** MAGLZ-II-18 high-dose group 26.73±7.37** 27.22±7.29** 27.86±7.93** 27.62±10.01 ** MAGLZ-II-18c low-dose group 23.98±6.89* 24.75±6.91* 25.16±8.87* 24.28±7.17* MAGLZ-II-18c middle-dose group 26.82±7.99** 28.52±6.18** 28.66±8.73** 27.88±7.74** MAGLZ-II-18c high-dose group 29.23±7.95** 30.24±7.80** 30.66±8.35** 29.87±7.43** MAGLZ-II-10 low-dose group 16.37±6.00 17.93±5.75 19.24±4.72 19.14±4.63 MAGLZ-II-10 middle-dose group 16.67±5.97 18.79±5.95 22.43±5.31 20.60±4.64 MAGLZ-II-10 high-dose group 17.73±6.20 19.77±6.73 25.25±7.01* 24.90±5.73*

[0174] Compared with the model group, *P<0.05, **P<0.01 and ***P<0.001.

[0175] Compared with the model group, the MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, MAGLZ-II-18, and MAGLZ-II-18c of the present invention may significantly extend pain thresholds of the thermal-stimulus mice.

Example 42 Influences of the MAGL Inhibitor of the Present Invention on a Pain Threshold of the Mice with Inflammatory Pain

[0176] Male SD mice (180±20) g were injected with a complete Freund’s adjuvant (50 .Math.L/piece) at the right rear plantar of mice, and mice in the control group were injected with the corresponding volume of 0.5% sodium carboxymethylcellulose to establish a paw edema inflammatory pain model. After modeling, the mice were administered for 7 d continuously, and administered intragastrically once per day. Pain thresholds (s) of the mice were respectively determined on the 1st, 3rd and 7th day before administration and after modeling at different periods of time.

[0177] Grouping and administration were the same as those of Example 40.

TABLE-US-00012 Influences of the MAGL inhibitor of the present invention on the pain thresholds of the mice with inflammatory pain Group Pain thresholds of the mice at different periods of time after administration (s) 0 d 1 d 3 d 7 d Control group 12.67±2.52 13.02±3.03 12.91±2.81 12.88±2.88 Model group 12.56±2.50 5.49±0.94.sup.### 7.06±0.63.sup.### 8.27±0.57.sup.### Positive medicament group 12.71±2.55 6.38±0.91.sup.∗ 8.05±1.23.sup.∗ 9.00±0.911.sup.∗ MAGLZ-II-11 low-dose group 12.94±2.41 7.55±1.29.sup.∗∗∗ 9.00±0.73.sup.∗∗∗ 10.26±1.08.sup.∗∗∗ MAGLZ-II-11 middle-dose group 12.80±2.27 7.73±1.10.sup.∗∗∗ 9.47±0.79.sup.∗∗∗ 10.93±1.62.sup.∗∗∗ MAGLZ-II-11 high-dose group 12.88±2.27 7.99±0.90.sup.∗∗∗ 9.88±1.34.sup.∗∗∗ 11.26±1.82.sup.∗∗∗ MAGLZ-II-11a low-dose group 12.96±2.44 7.38±1.19.sup.∗∗∗ 8.87±0.74.sup.∗∗∗ 9.91±1.05.sup.∗∗∗ MAGLZ-II-11a middle-dose group 13.03±2.35 7.58±0.84.sup.∗∗∗ 9.30±0.75.sup.∗∗∗ 10.66±1.30.sup.∗∗∗ MAGLZ-II-11a high-dose group 12.97±2.32 7.83±1.01.sup.∗∗∗ 9.55±1.58.sup.∗∗∗ 11.00±161.00.sup.∗∗∗ MAGLZ-II-18a low-dose group 12.73±2.43 6.97±0.87.sup.∗∗ 8.44±1.03.sup.∗∗∗ 9.56±0.92.sup.∗∗ MAGLZ-II-18a middle-dose group 12.86±2.25 7.26±0.70.sup.∗∗∗ 9.01±0.68.sup.∗∗∗ 10.37±1.49.sup.∗∗∗ MAGLZ-II-18a high-dose group 12.85±2.26 7.49±0.79.sup.∗∗∗ 9.35±1.2.sup.∗∗∗ 10.37±1.59.sup.∗∗∗ MAGLZ-II-18 low-dose group 12.73±2.43.sup.∗ 6.39±0.91.sup.∗ 8.12±1.29.sup.∗ 9.16±1.17.sup.∗ MAGLZ-II-18 middle-dose group 12.86±2.25.sup.∗∗ 6.62±0.69.sup.∗∗ 8.24±0.73.sup.∗∗ 9.51±1.15.sup.∗∗ MAGLZ-II-18 high-dose group 12.85±2.26.sup.∗∗ 6.95±0.85.sup.∗∗ 8.49±1.15.sup.∗∗ 9.62±0.93.sup.∗∗ MAGLZ-II-18c low-dose group 12.75±2.46.sup.∗ 6.36±0.89.sup.∗ 7.98±1.21.sup.∗ 8.95±0.67.sup.∗ MAGLZ-II-18c middle-dose group 12.86±2.07.sup.∗ 6.41±0.91.sup.∗ 8.10±1.30.sup.∗ 8.99±0.92.sup.∗ MAGLZ-II-18c high-dose group 12.85±2.09.sup.∗ 6.44±0.92.sup.∗ 8.17±1.14.sup.∗ 9.05±0.84.sup.∗ MAGLZ-II-10 low-dose group 12.71±2.47 5.59±0.89 7.15±0.59 8.33±0.57 MAGLZ-II-10 middle-dose group 12.77±2.48 5.62±0.84 7.18±0.55 8.36±0.59 MAGLZ-II-10 high-dose group 12.93±2.26 5.67±0.93 7.95±0.66* 8.93±0.61*

[0178] Compared with the model group, *P<0.05, **P<0.01 and ***P<0.001.

[0179] Compared with the model group, the MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, MAGLZ-II-18 and MAGLZ-II-18c of the present invention may significantly extend the pain threshold of the mice with inflammatory pain.

Example 43 Therapeutical Effect of the MAGL Inhibitor of the Present Invention on Irritable Bowel Syndrome Rats Induced by Early Maternal Separation

[0180] Irritable Bowel Syndrome (IBS) is a kind of common functional disease of stomach and intestine, manifested as chronic abdominal pain, abdominal discomfort and change of bowl evacuation habit, and no obvious intestinal lesion. This experiment is mainly used to discuss the therapeutical effect of the MAGL inhibitor of the present invention on irritable bowel syndrome rats induced by early maternal separation.

1. Animal Grouping and Administration

[0181] 200 SD rats (20±2) g were divided into 20 groups randomly according to body weight, 10 pieces for each group. The specific grouping conditions are as follows: [0182] blank group: an equal volume of 0.5% sodium carboxymethylcellulose, ig [0183] model group: an equal volume of 0.5% sodium carboxymethylcellulose, ig [0184] MAGLZ-II- 11 low-dose group: 7.5 mg/kg, ig [0185] MAGLZ-II-11 middle-dose group: 15 mg/kg, ig [0186] MAGLZ-II-11 high-dose group: 30 mg/kg, ig [0187] MAGLZ-II-11a low-dose group: 7.5 mg/kg, ig [0188] MAGLZ-II-11a middle-dose group: 15 mg/kg, ig [0189] MAGLZ-II-11a high-dose group: 30 mg/kg, ig [0190] MAGLZ-II-18a low-dose group: 7.5 mg/kg, ig [0191] MAGLZ-II-18a middle-dose group: 15 mg/kg, ig [0192] MAGLZ-II- 18a high-dose group: 30 mg/kg, ig [0193] MAGLZ-II-18 low-dose group: 7.5 mg/kg, ig [0194] MAGLZ-II-18 middle-dose group: 15 mg/kg, ig [0195] MAGLZ-II-18 high-dose group: 30 mg/kg, ig [0196] MAGLZ-II-18c low-dose group: 7.5 mg/kg, ig [0197] MAGLZ-II-18c middle-dose group: 15 mg/kg, ig [0198] MAGLZ-II-18c high-dose group: 30 mg/kg, ig [0199] MAGLZ-II-10 low-dose group: 7.5 mg/kg, ig [0200] MAGLZ-II-10 middle-dose group: 15 mg/kg, ig [0201] MAGLZ-II-10 high-dose group: 30 mg/kg, ig

[0202] Each compound was prepared into a suspension by 0.5% sodium carboxymethylcellulose respectively, and then set according to the dose, and each administration group was administered intragastrically; the model group was administered intragastrically an equal volume of 0.5% sodium carboxymethylcellulose.

2. Experimental Method and Data Processing

[0203] The newborn SD male rats were separated from the mother rat in lactation period for 3 h every day on the 2nd to the 21st day after the birth of the newborn SD rats, namely, the mother rat in lactation period was taken out of the cage at 8:30 a.m., and then the newborn rats were removed from the initial cage and put to another separate cage, then the cage was transferred to an adjacent room, then the newborn rats were returned to the initial cage 3 h later, namely, at 11:30 such that the newborn rats and the mother rat got together; the newborn rats were weaned on the 22nd day after birth and separated from the initial cage on the 30th day, grouped on the 60th day, and administered, 20 d in total.

[0204] Intragastric administration was performed within the administration period once a day with continuous administration for 20 d.

[0205] End point of the experiment: dissection was performed after finishing the corresponding test indicators of the experiment.

[0206] Test indicators: abdominal withdrawal reflex (AWR); test method: rats were fasted 18 h before the experiment and drank water freely, and narcotized with diethyl ether; then an air sac coated with paraffin oil was inserted into the rats’ colorectum for 4.0 cm, and a catheter outside the anus was fixed at the root of the rat tail with an adhesive tape, and connected with an injection syringe and a sphygmomanometer via three links. The rats were put to an organic glass inspection box (20 cmx12 cm×9 cm), after the rats were awake and fully adapted to the environment for 30 min, the experiment was started. 20, 40 and 60 mm Hg of pressure were respectively applied on the rats, and continuous expansion was performed for 20 s each time with a stimulus interval of 4 min; each pressure was performed for 3 times repeatedly for AWR scoring. AWR scoring was performed by a single blind method; scoring standard: 0 points: no obvious behavior change; 1 point: simple head movement only; 2 points: abdominal muscles started to shrink but are not separated from the table top; 3 points: abdominal muscles obviously shrank to flatten or inferior abdominal wall was separated from the table top; 4 points: abdominal wall hunched up or body/pelvis hunched up.

[0207] At the end of the experiment, the animals were dissected and weighed, and narcotized to take blood, then the content of 5-HT in serum was determined by high performance liquid chromatography. Cerebrum was taken on an ice and precooled and cleaned slightly with 0.5% sodium carboxymethylcellulose, and then sucked dry with a filter paper, and placed into a cryogenic tube, and preserved at -20° C. for further use, then the content of 5-HT in brain tissues was detected by high performance liquid chromatography.

[0208] Colon histological observation: after the experiment on colectasia, distal colon (5-6 cm away from the anus) of the rat was taken and subjected to conventional HE dyeing to observe the inflammation and damage conditions of the colon wall.

[0209] Data is presented by a mean±SD, and the difference among groups is subjected to statistics with t tests or a one-way ANOVA method, and P<0.05 shows a significant difference.

3. Experimental Results

[0210] Experimental results are shown in Table 10.

TABLE-US-00013 Influences of the MAGL inhibitor of the present invention on the AWR scoring and 5-HT of the IBS rats Group Qu ant ity AWR scoring Colon (.Math.g/mg) Serum (.Math.g/ml) 20 mm Hg 40 mm Hg 60 mm Hg 5-HT 5-HT Blank group 10 1.93±0.43 2.78±0.35 3.29±0.25 11.78±1.78 28.55±4.03 Model group 10 2.85+0.28.sup.## # 3.53+0.22.sup.### 3.86+0.13.sup.### 19.76±2.52.sup.### 38.73±3.42.sup.### MAGLZ-II-1 8c Low-dose group 10 2.28±0.58* 3.20±0.43* 3.61±0.24** 16.84±2.87* 34.2±5.37* MAGLZ-II-1 8c Middle-dose group 10 1.79±0.23.sup.∗∗ ∗ 2.87±0.65.sup.∗∗ 3.27±0.51.sup.∗∗ 14.99±2.90.sup.∗∗ 31.88±4.40.sup.∗∗ MAGLZ-II-1 8c High-dose group 10 1.38±0.51.sup.∗∗ ∗ 2.20±0.57.sup.∗∗∗ 2.96±0.70.sup.∗∗∗ 14.34±2.40.sup.∗∗∗ 29.03±5.29.sup.∗∗∗ MAGLZ-II-1 1a Low-dose group 10 2.12±0.36.sup.∗∗ ∗ 3.02±0.53.sup.∗ 3.58±0.26.sup.∗∗ 16.33±2.78.sup.∗∗ 31.76±5.42.sup.∗∗ MAGLZ-II-1 1a Middle-dose group 10 1.51±0.43.sup.∗∗ ∗ 2.52±0.38.sup.∗∗∗ 3.27±0.48.sup.∗∗∗ 14.79±2.73.sup.∗∗∗ 29.89±5.34.sup.∗∗∗ MAGLZ-II-1 1a High-dose group 10 1.23±0.50.sup.∗∗ ∗ 2.13±0.48.sup.∗∗∗ 2.87±0.46.sup.∗∗∗ 12.65±3.36.sup.∗∗∗ 24.05±6.17.sup.∗∗∗ MAGLZ-II-1 0 Low-dose group 10 2.87±0.39 3.43±0.30 3.79±0.20 21.44±2.72 36.32±3.14 MAGLZ-II-1 0 Middle-dose group 10 2.83±0.47 3.56±0.22 3.80±0.17 20.97±2.24 38.65±2.68 MAGLZ-II-1 0 High-dose group 10 2.89±0.46 3.21±0.35.sup.∗ 3.65±0.17.sup.∗ 18.66±2.38.sup.∗ 33.09±2.31.sup.∗ MAGLZ-II-1 1 Low-dose group 10 2.50±0.38.sup.∗ 3.00±0.49.sup.∗∗ 3.60±0.22.sup.∗∗ 16.24±2.34.sup.∗∗ 31.75±5.33.sup.∗∗ MAGLZ-II-1 1 Middle-dose group 10 2.02±0.57.sup.∗∗ 2.42±0.41.sup.∗∗∗ 3.03±0.37.sup.∗∗∗ 14.33±2.10.sup.∗∗∗ 29.47±4.91.sup.∗∗∗ MAGLZ-II-1 1 High-dose group 10 1.39±0.30.sup.∗∗ ∗ 1.92±0.33.sup.∗∗∗ 2.86±0.26.sup.∗∗∗ 12.00±2.93.sup.∗∗∗ 23.82±6.34.sup.∗∗∗ MAGLZ-II-1 8 Low-dose group 10 2.59±0.33 3.26±0.39 3.65±0.23.sup.∗ 21.91±2.46 35.73±3.32 MAGLZ-II-1 8 Middle-dose group 10 2.29±0.36.sup.∗∗ 3.01±0.40.sup.∗∗ 3.3±0.45.sup.∗∗ 14.89±3.19.sup.∗∗ 29.12±7.05.sup.∗∗ MAGLZ-II-1 8 High-dose group 10 1.87±0.36.sup.∗∗ ∗ 2.6±0.54.sup.∗∗∗ 3.09±0.34.sup.∗∗∗ 14.33±2.10.sup.∗∗∗ 30.86±5.28.sup.∗∗∗ MAGLZ-II-1 8aLow-dose group 10 2.58±0.26* 3.06±0.38** 3.50±0.29** 16.43±2.15** 32.51±5.01** MAGLZ-II-1 8a Middle-dose group 10 2.35±0.40** 3.02±0.51** 3.39±0.34*** 14.64±2.17*** 30.20±5.59*** MAGLZ-II-1 8a High-dose group 10 1.96±0.46** * 2.60±0.58*** 3.00±0.54*** 13.90±1.13*** 29.44±4.37***

[0211] Compared with the blank group, .sup.#P<0.05, .sup.##p< 0.01, .sup.###P< 0.001;

[0212] and compared with the model group, *P<0.05, **P<0.01 and ***P<0.001.

[0213] It can be seen from the experimental results shown in Table 10 that compared with the model group, the MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, MAGLZ-II-18 and MAGLZ-II-18c of the present invention may significantly decrease the AWR scoring, and the 5-HT level in colon and serum.

Example 44 Influences of the MAGL Inhibitor of the Present Invention on Reserpine-Induced Mice Migraine

1. Animal Grouping and Administration

[0214] 210 male ICR mice (20±2) g were divided into 21 groups randomly according to body weight, 10 pieces for each group. The specific grouping conditions are as follows: blank group: an equal volume of 0.5% sodium carboxymethylcellulose, ig [0215] model group: an equal volume of 0.5% sodium carboxymethylcellulose, ig [0216] positive control group: 0.5 mg/kg Zolmitriptan, ig [0217] MACJLZ-II-11 low-dose group: 7.5 mg/kg, ig [0218] MAGLZ-II-11 middle-dose group: 15 mg/kg, ig [0219] MAGLZ-II-11 high-dose group: 30 mg/kg, ig [0220] MAGLZ-II-11a low-dose group: 7.5 mg/kg, ig [0221] MAGLZ-II-11a middle-dose group: 15 mg/kg, ig [0222] MAGLZ-II-11a high-dose group: 30 mg/kg, ig [0223] MAGLZ-II-18a low-dose group: 7.5 mg/kg, ig [0224] MAGLZ-II-18a middle-dose group: 15 mg/kg, ig [0225] MAGLZ-II-18a high-dose group: 30 mg/kg, ig [0226] MAGLZ-II-18 low-dose group: 7.5 mg/kg, ig [0227] MAGLZ-II-18 middle-dose group: 15 mg/kg, ig [0228] MAGLZ-II-18 high-dose group: 30 mg/kg, ig [0229] MAGLZ-II-18c low-dose group: 7.5 mg/kg, ig [0230] MAGLZ-II-18c middle-dose group: 15 mg/kg, ig [0231] MAGLZ-II-18c high-dose group: 30 mg/kg, ig [0232] MAGLZ-II-10low-dose group: 7.5 mg/kg, ig [0233] MAGLZ-II-10 middle--dose group: 15 mg/kg, ig [0234] MAGLZ-II-10high-dose group: 30 mg/kg, ig

[0235] Each compound was prepared into a suspension by 0.5% sodium carboxymethylcellulose respectively, and then set according to the dose, and each administration group was administered intragastrically; the model group was administered intragastrically an equal volume of 0.5% sodium carboxymethylcellulose.

2. Experimental Method and Data Processing

[0236] The blank control group was subcutaneously injected with normal saline, and the rest groups of mice were subcutaneously injected with a reserpine solution (0.2 mg/kg), 10 d in total; if the mice showed eye closure, squat and reduced activity, diarrhea, less food-intake, back arching and other typical reserpine symptoms after being injected with reserpine, the modeling was believed successful.

[0237] The mice in the blank control group and model group were administered intragastrically via a solvent from the 5th day after modeling, and the rest groups of mice were respectively administered corresponding medicaments and doses for intragastric administration for 10 consecutive days; 1 h later after the final administration, the mice were weighed; blood was taken at inner canthus to detect blood coagulation time; whole blood was taken, and cerebrum was taken on an ice and preserved at -20° C. for the subsequent experiment.

[0238] End point of the experiment: model administration was continued for 10 d, detection and blood taking were performed 1 h later after the final administration on the 10th day, thus finishing the experiment.

[0239] Test indicator: the mice were weighed once every two days after the beginning of the experiment.

[0240] Behavioral test: tail suspension activity was performed; the position 1 cm away from the tail of the mice was glued by an adhesive tape on the 9th day of the test, and the adhesive tape was penetrated by a steel needle, and hung in a dark box such that the mice were hung upside down; then the mice struggling times (total number of overturning from hanging) within 2 min were observed.

[0241] The mice were weighed 1 h later after the final administration; blood of inner canthus was taken via a capillary to detect the blood coagulation time.

[0242] Blood was taken to detect the content of 5-HT in serum via high-performance liquid chromatography. Cerebrum was taken on an ice and precooled and cleaned slightly with 0.5% sodium carboxymethylcellulose, and then sucked dry with a filter paper, and placed into a cryogenic tube, and preserved at -20° C. for further use, then the content of 5-HT in brain tissues was detected by high performance liquid chromatography.

[0243] 5-HT test method: a sample was precipitated with 10% perchloric acid solution according to 1:1, and then centrifuged to take supernatant for test. Chromatographic conditions: the chromatographic column is a SHIMADZU VP-ODS C.sub.18 column (250*4.6 mm, 5 um), the mobile phase is a methanol-0.01 mol/L potassium acetate buffer solution (10:90, V/V, PH is adjusted to 4.00 with 0.2 mol/L citric acid) for gradient elution; the column temperature is 25° C., flow rate is 1.00 ml/min and test wavelength is 275 nm.

[0244] Data is presented by a mean±SD, and the difference among groups is subjected to statistics with t tests or a one-way ANOVA method, and P<0.05 shows a significant difference.

3. Experimental Results

[0245] Experimental results are shown in Tables 11-13.

TABLE-US-00014 Influences of the MAGL inhibitor of the present invention on blood coagulation time Grouping Dose Blood coagulation time (S) Normal group - 352.50±37.48 Model group - 115.38±24.05*** Zolmitriptan 0.5 mg/kg 185.12±38.86.sup.### MAGLZ-II-18a low-dose group 7.5 mg/kg 137.25±67.22 MAGLZ-II-18a middle-dose group 15 mg/kg 191.50±63.66.sup.## MAGLZ-II-18a high-dose group 30 mg/kg 252.25±30.99.sup.### MAGLZ-II-11 low-dose group 7.5 mg/kg 222.5±35.52.sup.### MAGLZ-II-11 middle-dose group 15 mg/kg 326.88±45.9.sup.### MAGLZ-II -11 high-dose group 30 mg/kg 336.88±33.09.sup.### MAGLZ-II-10 low-dose group 7.5 mg/kg 113.25±23.31 MAGLZ-II-10 middle-dose group 15 mg/kg 125.25±19.31 MAGLZ-II -10 high-dose group 30 mg/kg 148.00±30.23.sup.# MAGLZ-II-11a low-dose group 7.5 mg/kg 136.75±33.22 MAGLZ-II-11a middle-dose group 15 mg/kg 256.88±42.93.sup.### MAGLZ-II-11a high-dose group 30 mg/kg 300.63±45.26.sup.### MAGLZ-II-18c low-dose group 7.5 mg/kg 148.00±30.23.sup.# MAGLZ-II-18c middle-dose group 15 mg/kg 198.63±21.36.sup.### MAGLZ-II -18c high-dose group 30 mg/kg 237.13±28.75.sup.### MAGLZ-II-18 low-dose group 7.5 mg/kg 186.5±51.71.sup.## MAGLZ-II-18 middle-dose group 15 mg/kg 212.63±46.02.sup.### MAGLZ-II -18 high-dose group 30 mg/kg 241.5+41.63***

[0246] Compared with the model group, .sup.#P<0.05, .sup.##P<0.01, .sup.###P<0.001.

[0247] It can be seen from the experimental results shown in Table 11 that compared with the model group, the MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, MAGLZ-II-18 and MAGLZ-II-18c of the present invention may significantly extend the blood coagulation time.

TABLE-US-00015 Influences of the MAGL inhibitor of the present invention on the times of tail suspension Grouping Dose Times Normal group - 22.38±3.38 Model Group - 8.38±2.62*** Zolmitriptan 0.5 mg/kg 18.13+3.94.sup.### MAGLZ-II-18a low-dose group 7.5 mg/kg 11.38±2.67.sup.# MAGLZ-II-18a middle-dose group 15 mg/kg 13.38±2.67.sup.## MAGLZ-II-18a high-dose group 30 mg/kg 18.50±2.00*** MAGLZ-II-10 low-dose group 7.5 mg/kg 9.25±2.66 MAGLZ-II -10 middle-dose group 15 mg/kg 10.63±1.19.sup.# MAGLZ-II -10 high-dose group 30 mg/kg 11.63±1.85.sup.# MAGLZ-II-11 low-dose group 7.5 mg/kg 14.13±1.89.sup.### MAGLZ-II -11 middle-dose group 15 mg/kg 16.13±1.73.sup.### MAGLZ-II -11 high-dose group 30 mg/kg 23.00±3.59.sup.### MAGLZ-II-11a low-dose group 7.5 mg/kg 16.13±3.68.sup.### MAGLZ-II-11a middle-dose group 15 mg/kg 19.88+4.09.sup.### MAGLZ-II-11a high-dose group 30 mg/kg 20.75±4.98.sup.### MAGLZ-II-18c low-dose group 7.5 mg/kg 10.13±2.3.sup.## MAGLZ-II -18c middle-dose group 15 mg/kg 12.75±2.6.sup.## MAGLZ-II -18c high-dose group 30 mg/kg 15.88±3.8.sup.### MAGLZ-II-18 low-dose group 7.5 mg/kg 11.88±4.02.sup.### MAGLZ-II -18 middle-dose group 15 mg/kg 13.75±4.56.sup.### MAGLZ-II -18 high-dose group 30 mg/kg 16.51±4.38.sup.###

[0248] Compared with the model group, .sup.#P<0.05, .sup.##P<0.01, .sup.###P<0.001.

[0249] It can be seen from the experimental results shown in Table 12 that compared with the model group, the MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, MAGLZ-II-18 and MAGLZ-II-18c of the present invention may significantly increase the times of the tail suspension activity.

TABLE-US-00016 Influences of the MAGL inhibitor of the present invention on a brain tissue 5-hydroxytryptamine Grouping Dose 5-HT (nmol/g) Normal group - 3.36±0.4 Model group - 0.88±0.23*** Zolmitriptan 0.5 mg/kg 1.93±0.37.sup.### MAGLZ-II-18a low-dose group 7.5 mg/kg 1.21±0.17.sup.## MAGLZ-II-18a middle-dose group 15 mg/kg 1.65±0.18.sup.### MAGLZ-II-18a high-dose group 30 mg/kg 2.76±0.34.sup.### MAGLZ-II-10 low-dose group 7.5 mg/kg 0.85±0.20 MAGLZ-II -10 middle-dose group 15 mg/kg 1.05±0.14 MAGLZ-II -10 high-dose group 30 mg/kg 0.90±0.21.sup.# MAGLZ-II-11 low-dose group 7.5 mg/kg 1.54±0.27.sup.### MAGLZ-II -11 middle-dose group 15 mg/kg 2.10±0.22.sup.### MAGLZ-II -11 high-dose group 30 mg/kg 3.63±5.34.sup.### MAGLZ-II-11a low-dose group 7.5 mg/kg 1.35±0.38.sup.## MAGLZ-II-11a middle-dose group 15 mg/kg 1.86±0.29.sup.### MAGLZ-II-11a high-dose group 30 mg/kg 2.97±0.28.sup.### MAGLZ-II-18c low-dose group 7.5 mg/kg 1.14±0.22.sup.# MAGLZ-II -18c middle-dose group 15 mg/kg 1.37±0.34.sup.## MAGLZ-II -18c high-dose group 30 mg/kg 1.79±0.32.sup.### MAGLZ-II-18 low-dose group 7.5 mg/kg 1.13±0.45.sup.# MAGLZ-II -18 middle-dose group 15 mg/kg 1.54±0.54.sup.### MAGLZ-II -18 high-dose group 30 mg/kg 2.08±0.59.sup.###

[0250] Compared with the model group, .sup.#P<0.05, .sup.##P<0.01, .sup.###P<0.001.

[0251] It can be seen from the experimental results shown in Table 13 that compared with the model group, the MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, MAGLZ-II-18 and MAGLZ-II-18c of the present invention may significantly increase the level of 5-HT in the brain tissue of reserpine-induced low 5-HT model mice.

Example 45 Study on the Effect of the MAGL Inhibitor on Mice Ulcerative Colitis

1. Animal Grouping and Administration

[0252] Healthy male SPF-level BALB/c mice (8-week old and body mass: (20±2) g).

[0253] The mice were quarantined for 7 d after entering to a room, and healthy male mice were selected as subject animals. Major examination contents within the quarantine period include but not limited to: whether to be consistent with the quantity and body indicators of the animals required during application, general state, and body weight; animals not passing through the above quarantine items were not brought into the test.

[0254] Modeling: the mice were randomly divided into 21 groups at the end of the quarantine, 10 pieces for each group. The mice in the normal group drank normal water freely, and the rest groups of mice drank 1.0%-1.5% DSS solution freely for modeling, 7 d later after modeling, the mice in the modeling group drank normal water freely for 7 d, and 14 d served as a modeling period for four continuous periods, and the mice in the modeling group were administered at the same time.

Blank Group: an Equal Volume of 0.5% Sodium Carboxymethylcellulose, ig

Model Group: an Equal Volume of 0.5% Sodium Carboxymethylcellulose, ig

Positive Control Group: Mesalazine (100 mg/kg), ig

[0255] MAGLZ-II-11 low-dose group: 7.5 mg/kg, ig [0256] MAGLZ-II-11 middle-dose group: 15 mg/kg, ig [0257] MAGLZ-II-11 high-dose group: 30 mg/kg, ig [0258] MAGLZ-II-11a low-dose group: 7.5 mg/kg, ig [0259] MAGLZ-II-11a middle-dose group: 15 mg/kg, ig [0260] MAGLZ-II-11a high-dose group: 30 mg/kg, ig [0261] MAGLZ-II-18a low-dose group: 7.5 mg/kg, ig [0262] MAGLZ-II-18a middle-dose group: 15 mg/kg, ig [0263] MAGLZ-II-18a high-dose group: 30 mg/kg, ig [0264] MAGLZ-II-18 low-dose group: 7.5 mg/kg, ig [0265] MAGLZ-II-18 middle-dose group: 15 mg/kg, ig [0266] MAGLZ-II-18 high-dose group: 30 mg/kg, ig [0267] MAGLZ-II-18c low-dose group: 7.5 mg/kg, ig [0268] MAGLZ-II-18c middle-dose group: 15 mg/kg, ig [0269] MAGLZ-II-18c high-dose group: 30 mg/kg, ig [0270] MAGLZ-II-10 low-dose group: 7.5 mg/kg, ig [0271] MAGLZ-II-10 middle-dose group: 15 mg/kg, ig [0272] MAGLZ-II-10 high-dose group: 30 mg/kg, ig

[0273] Each compound was prepared into a suspension by 0.5% sodium carboxymethylcellulose respectively, and then set according to the dose, and each administration group was administered intragastrically; the model group was administered intragastrically an equal volume of 0.5% sodium carboxymethylcellulose.

2. Test Process and Method

[0274] End point of the experiment: experimental administration was performed for four periods, and dissection was performed on the 3rd and 4th day of the recovery period of the 4th period.

[0275] Test indicators: the mice were weighed twice a week after the beginning of the administration; diarrhea and hematochezia of the mice were observed, and times of hematochezia were recorded.

[0276] At the end of the experiment, the mice were dissected and weighed, and narcotized to take blood, then serum was preserved at -80° C. Spleen was taken and weighed to calculate the spleen index. The content of IL-1β in serum was detected via ELISA. Colorectum was cut and taken to measure the length of colorectum, then immobilized by formaldehyde and dyed by HE to detect the pathological change. Data is presented by a mean±SD, and the difference among groups is subjected to statistics with t tests or a one-way ANOVA method, and P<0.05 shows a significant difference.

3. Result and Discussion

[0277] Experimental results are shown in Table 14.

TABLE-US-00017 Influences of the MAGL inhibitor of the present invention on the colon length, hematochezia times and IL-1 content of ulcerative colitis mice Group Qua ntity Colon length (cm) Total times of IL-1 content hematochezia within (pg/mL) the four periods Blank group 10 8.22±1.45 0±0 35.36±5.92 Model group 10 5.70±0.78.sup.### 38.60±2.80.sup.### 55.53±3.62.sup.### Mesalazine (100 mg/kg) 10 6.66±0.68** 32.80±4.96** 48.33±6.49** MAGLZ-II-11 low-dose group 10 6.88±0.89** 32.00±4.94** 44.57±10.32** MAGLZ-II-11 middle-dose group 10 7.26±0.67*** 27.20±5.39*** 41.40±9.50*** MAGLZ-II-11 high-dose group 10 7.68±0.75*** 24.80±5.43*** 33.83±7.14*** MAGLZ-II-18a low-dose group 10 6.51±0.90* 33.60±5.83** 47.32±9.06* MAGLZ-II-18a middle-dose group 10 7.06±1.20** 29.90±8.95** 43.77±10.69** MAGLZ-II-18a high-dose group 10 7.72±0.92*** 27.90±7.28*** 36.22±4.31*** MAGLZ-II-18c low-dose group 10 6.25±1.17 43.10±7.59 48.08±13.18 MAGLZ-II-18c middle-dose group 10 6.47±0.71* 43.20±5.31* 44.09±9.13** MAGLZ-II-18c high-dose group 10 6.65±0.67** 31.80±6.6** 45.10±8.88** MAGLZ-II-11a low-dose group 10 7.21±1.10** 28.80±7.04** 42.01±13.92** MAGLZ-II-11a middle-dose group 10 7.20±0.97** 29.10±7.14** 40.70±8.50*** MAGLZ-II-11a high-dose group 10 7.56±0.74*** 27.90±3.73*** 38.61±10.98*** MAGLZ-11-10 low-dose group 10 5.92±0.66 38.40±5.02 51.81±7.86 MAGLZ-11-10 middle-dose group 10 5.72±0.60 38.20±7.83 50.83±7.79 MAGLZ-11-10 high-dose group 10 6.35±0.61* 35.15±4.52* 47.25±6.37* MAGLZ-II-18 low-dose group 10 6.44±0.64* 32.80±4.64** 46.15±9.65* MAGLZ-II-18 middle-dose group 10 6.37±0.39* 33.90±4.77* 49.01±5.65* MAGLZ-II-18 high-dose group 10 6.73±0.63** 32.80±4.37** 46.98±7.56**

[0278] Compared with the blank group, .sup.#P<0.05, .sup.##P<0.01, .sup.###P<0.001;

[0279] and compared with the model group, .sup.∗P<0.05, .sup.∗∗∗P<0.01 and .sup.∗∗∗P< 0.001.

[0280] Compared with the model group, the MAGLZ-II-11, MAGLZ-II-11a, MAGLZ-II-18a, MAGLZ-II-18 and MAGLZ-II-18c of the present invention may significantly increase the colon length, reduce the total times of hematochezia and decrease the IL-1 content.

[0281] The present invention has been described by the above examples; any equivalent replacement is apparent and contained in the present invention.