CN111481543A

CN111481543A - Use of NR2B negative allosteric modulators in combination with GABA receptor modulators for the preparation of a medicament for the treatment of Alzheimer's disease

Info

Publication number: CN111481543A
Application number: CN202010434536.XA
Authority: CN
Inventors: 刘尚莲; 王杨; 朱少晖; 陈雪峰; 金晨; 杨成德
Original assignee: Suzhou Chien Shiung Institute of Technology
Current assignee: Suzhou Chien Shiung Institute of Technology
Priority date: 2020-05-21
Filing date: 2020-05-21
Publication date: 2020-08-04

Abstract

The invention discloses an application of a NR2B negative allosteric modulator combined with a GABA receptor modulator in preparation of a medicine for treating Alzheimer disease, and the inventor finds that the GABA receptor modulator n-alkylaryl-5-oxyaryl-octahydro-cyclopenta [ c ] pyrrole compound has a remarkably enhanced synergistic effect of drug effects compared with a GABA receptor modulator, particularly Basmisanil or Etazolate when the compound is connected with the GABA receptor modulator, and shows that the NR2B negative allosteric modulator combined with the GABA receptor modulator has positive potential application in preparation of the medicine for treating Alzheimer disease.

Description

Use of NR2B negative allosteric modulators in combination with GABA receptor modulators for the preparation of a medicament for the treatment of Alzheimer's disease

Technical Field

The invention belongs to the field of pharmacy, and particularly relates to a negative allosteric modulator of NR 2B.

Technical Field

Alzheimer's Disease (AD) is a cerebral neurodegenerative disease with memory loss and cognitive decline as major clinical symptoms, and current studies suggest that N-methyl-D-aspartate receptors (NMDARs) play a crucial role in synaptic transmission and synaptic plasticity, and are considered to be the basis of learning and memory.

Activation of NMDARs has been shown in recent studies to be associated with synaptic dysfunction-missense mutations in the GRIN2B coding region are only currently found in the brain of AD patients, suggesting that there is a close relationship between this mutation of the post-synaptic NR2B subunit and changes in synaptic structure-A β (amyloid) -induced early neuronal dysfunction is mediated by NMDAR activation with the NR2B subunit-it has now been found that the NR2B receptor antagonist Ifenprodil prevents A β -induced endoplasmic reticulum stress, hippocampal dysfunction, microtubule dysregulation and calcium elevation-in acute hippocampal slices, the selective NR2B antagonist Ifenprodil also effectively mitigates the inhibitory effect of soluble A β on L-these results suggest that targeting the GluN2B (NR2B) subunit of NMDARs may be another method of preventing AD progression [ J ]. 1037, Scienology 2016 (T7).

GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter of the central nervous system, while gabaergic neurons provide extensive innervation for cholinergic and glutamatergic neurons. It has been shown that dysfunction of the gabaergic system may lead to cognitive impairment in humans. Gabaergic drugs are another class of compounds that have been tried for their cognitive enhancement, SGS742 is a GABA B antagonist that has shown encouraging results in preclinical and phase I clinical studies; etazolate, a modulator of action on GABA a receptors, also has neuroprotective effects, shown in a recent trial to have good safety and tolerability, but its efficacy and long-term benefits remain to be determined ([ J ]. Neuropharmacology,2014,76: 27-50.).

CN106795111A discloses a class of n-alkylaryl-5-oxyaryl-octahydro-cyclopenta [ c ] pyrrole compounds and their use for treating psychoneurological diseases, which act on NR2B subunit of NMDARs, as negative allosteric modulators thereof, having the specific structure as follows:

however, no pharmacological studies have reported that the NR2B negative allosteric modulator and GABA a modulator have a synergistic effect in the treatment of AD.

Disclosure of Invention

In order to solve the problems, the invention discloses an application of a NR2B negative allosteric modulator and a GABA receptor modulator in preparation of medicines for treating/improving various Alzheimer diseases, and the inventor finds that the GABA receptor modulator n-alkylaryl-5-oxyaryl-octahydro-cyclopenta [ c ] pyrrole compound has obviously enhanced synergistic effect on the drug effect compared with the respective single medicines when being connected with the GABA receptor modulator, particularly Basmisanil or Etazolate, and shows that the NR2B negative allosteric modulator and the GABA receptor modulator have positive potential application in preparation of medicines for treating the Alzheimer diseases.

In order to achieve the purpose, the invention provides the following technical scheme:

use of a NR2B negative allosteric modulator, said NR2B negative allosteric modulator being a compound having the general formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or stereoisomer thereof, in combination with a GABA receptor modulator, for the manufacture of a medicament for the treatment of alzheimer's disease:

said A, B, C, D and E are independently N or CRX;

y and Y' are independently H, halogen or C1-6 alkyl;

x is O or S;

rx is each independently alkyl of H, C1-6, halo, -OH, or alkyl of OC 1-6;

l2 is (CH2) n, where n is 1 or 2.

Further, the use of an NR2B negative allosteric modulator as described above in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease, said compound having the general formula (I) being selected from one of the following formulae 1 to 8:

further, the NR2B negative allosteric modulator is combined with a GABA receptor modulator to prepare the medicine for treating the Alzheimer disease, and the pharmaceutically acceptable salt of the compound with the structure of the formula (1-8) is selected from acetate, fumarate, methanesulfonate, maleate, tartrate, sulfate, toluenesulfonate and hydrochloride, preferably hydrochloride.

Further, the use of an NR2B negative allosteric modulator as described above in combination with a GABA receptor modulator selected from GABA a modulators or GABA B modulators for the manufacture of a medicament for the treatment of alzheimer's disease.

Further, the application of the NR2B negative allosteric modulator and a GABA receptor modulator in preparing the medicine for treating the Alzheimer's disease, the GABA A modulator is selected from one of Basmisanil (CAS:1159600-41-5), Etazolate (CAS:51022-77-6), Bamaluzole (CAS:87034-87-5), Gaboxadol (CAS:64603-91-4), Ibotenic acid (CAS:2552-55-8), Isoguvacine (CAS:64603-90-3), Isonipecotic acid (CAS:498-94-2), Muscimol (CAS:2763-96-4), Phenibu (CAS:1078-21-3), Picamilon (CAS: 62936-56-5), Progailide (CAS:62666-20-0), Quisqualamine (CAS:68373-11-5), Thiomucil (CAS:62020-54-6), Topiramate (CAS: 97240-4-79, and Zolmin (CAS: 82626-79).

Further, the use of the NR2B negative allosteric modulator in combination with a GABA receptor modulator for the preparation of a medicament for the treatment of alzheimer's disease, wherein the weight ratio of the compound of formula (1-8) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or stereoisomer thereof to the GABA a modulator is selected from the range of 4:1 to 1:5, preferably 4:1, 2:1, 1:2, 1:3, 1:4 and 1:5, more preferably 2:1, 1:1 and 1: 4.

Further, the use of the NR2B negative allosteric modulator in combination with a GABA receptor modulator for the preparation of a medicament for the treatment of alzheimer's disease, wherein the dosage of the compound represented by the formula (1-8) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or stereoisomer thereof is selected from 1-60 mg, preferably 5mg, 10mg, 20mg, 25mg, 30mg and 60mg, more preferably 5mg, 10mg and 30 mg; the dosage of GABA A modulator is selected from 1-100 mg, preferably 5mg, 10mg, 15mg, 40mg, 80mg and 100mg, more preferably 5mg, 10mg, 15mg, 20mg and 40 mg.

Further, the use of an NR2B negative allosteric modulator as described above in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease, said GABA a modulator being selected from the group consisting of basisaminil or Etazolate; the compound having the structure of formula (1-8) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof is selected from compound 1 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate thereof.

Further, the use of the NR2B negative allosteric modulator described above in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease, said compound 1 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate thereof and bmisanil thereof in a weight ratio of 1: 2; the weight ratio of the compound 1 or the pharmaceutically acceptable salt, the prodrug, the solvate, the hydrate and the Etazolate thereof is 1: 1.

Further, the NR2B negative allosteric modulator is combined with a GABA receptor modulator to prepare a medicine for treating alzheimer's disease, the compound 1 or the pharmaceutically acceptable salt, the prodrug, the solvate, the hydrate and the bmisanil form a compound, wherein the dosage of the compound 1 or the pharmaceutically acceptable salt, the prodrug, the solvate, the hydrate is 5mg or 10mg, and the dosage of the bmisanil is 10mg or 20 mg.

Further, the NR2B negative allosteric modulator combined with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease, said compound 1 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate thereof and Etazolate, wherein the dose of compound 1 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate thereof is 5mg, 10mg or 20mg, and the dose of Etazolate is 5mg, 10mg or 20 mg.

Further, the use of an NR2B negative allosteric modulator as described above in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease, said compound of formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or stereoisomer thereof being administered at a frequency selected from the group consisting of: once a day, twice a day, three times a day, once a week, once in three weeks, once a month, preferably once a day, twice a day; the GABA modulator is administered once a day, twice a day, three times a day, once a week, once three weeks, once a month, preferably once a day and twice a day.

Further, the use of the NR2B negative allosteric modulator in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease, wherein the compound of formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or stereoisomer thereof and the GABA receptor modulator are prepared into a pharmaceutical composition; the pharmaceutical composition comprises optionally one or more pharmaceutically acceptable carriers, excipients and/or diluents; the dosage form of the pharmaceutical composition is any pharmaceutically acceptable dosage form. Can be made into tablet, capsule, pill, granule, solution, suspension, syrup, injection (including injection, injectable sterile powder and injectable concentrated solution), suppository, inhalant or spray.

Further, the use of the NR2B negative allosteric modulator in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease, mild alzheimer's disease or moderate alzheimer's disease.

Further, the use of the NR2B negative allosteric modulator described above in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease with psychotic disorders; the mental disease is schizophrenia, depression or mania.

In the present invention, the term "combination or association" refers to a mode of administration which includes the administration of two or more drugs sequentially or sequentially, or simultaneously, and the term "simultaneously" refers to the administration of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or stereoisomer thereof and a GABA modulator, or a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or stereoisomer thereof and a GABA modulator and any other third component drug, and the administration of two or more drugs within one day, three days, one week, two weeks, one month, or the like, in the same administration cycle. By "sequential or sequential" administration, it is meant to include the case where the compound of formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or stereoisomer thereof and the GABA modulator, or the compound of formula (I) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or stereoisomer thereof and the GABA modulator and any other third component drug, are administered separately over different administration cycles. These administration modes are all the combination administration described in the present invention.

An "effective amount" as described herein comprises an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the method and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

The scheme shows that the invention at least has the following beneficial effects: the invention discloses that NR2B negative allosteric modulator n-alkylaryl-5-oxyaryl-octahydro-cyclopenta [ c ] pyrrole compounds and GABA modulators are combined to have obvious synergistic effect for the first time, and especially the compound 1 and GABA A modulators are combined to be applied. In the invention, the combination of the compound 1 and the Basmisanil and the Etazolate is clearly shown to have obvious synergistic effect of drug effects compared with the single drug, which suggests that the compound has positive potential application in preparing the drug for treating the Alzheimer disease.

Drawings

Is free of

Detailed Description

The present invention is described in further detail below with reference to examples, but the embodiments of the present invention are not limited to the examples. The starting materials, equipment and methods employed in the present invention are not illustrated as being conventional sources and materials, equipment and methods employed in the art, unless otherwise specified.

Examples

The following example examines the improvement effect of compound 1 of the present invention in combination with Basmisanil or Etazolate on learning and memory disorder in dementia model mice induced by aluminum trichloride, D-galactose.

(I) test article

Basmisanil and Etazolate (purchased from chemscene), aluminum trichloride (commercially available), D-galactose (commercially available); compound 1 hydrochloride (hereinafter referred to as compound 1, prepared as described in method 8 on page 49 of the specification of patent CN201580051671.3, 2-bromo-1- (5-hydroxypyridin-2-yl) ethanone was replaced with 2-bromo-1- (4-hydroxyphenyl) ethanone).

(II) test animals

The experimental study was carried out on C57B L/6 mice, SPF-grade, male, purchased from Shanghai Si Laike laboratory animals Co., Ltd., purchased at 20-25 g/mouse, housed at 5 mice/cage, kept at constant temperature of 23 + -1 ℃ for 12/12 hours with light/dark cycle adjustment, kept at humidity of 50-60%, fed with water freely, and after purchase of the animals, the experiment was started after 3 days of adaptive breeding.

(III) test instruments and materials

The SMG-2 Morris water maze (developed by the institute of medicine of Chinese academy of medical sciences).

(IV) preparation of test solution

D-galactose, Basmisanil, Etazolate and the compound 1 are all prepared by normal saline; the aluminum trichloride is prepared by distilled water.

(V) Experimental methods

Grouping method

Mice were randomly divided by body weight into a blank control group (n ═ 10), a model group (n ═ 10), and an administration group (n ═ 70), wherein the administration group was a basal group (n ═ 10), an Etazolate group (n ═ 10), a compound 1 group (n ═ 10), a basal + compound 1 low dose group (n ═ 10), an Etazolate + compound 1 low dose group (n ═ 10), a basal + compound 1 high dose group (n ═ 10), and an Etazolate + compound 1 high dose group (n ═ 10).

Method of administration

The grouped mice are administrated by the following method: the mice of the model group and the administration group are intragastrically administered with 10mg/kg of aluminum trichloride every day, and are simultaneously administered with 120mg/kg of D-galactose by intraperitoneal injection; the blank control group is administered with distilled water with the same volume by intragastric administration and normal saline with the same volume by abdominal cavity every day; each group of mice was dosed for 24 weeks.

Administration of the test drugs was started in the group on day 1 after intraperitoneal injection of the molding drugs in each group of mice on day 13, 11.3 mg/kg/day of the compound 1 (corresponding to 10 mg/day of the dose for human use, the conversion method is referred to as [ J ]. China Pharmacology and therapeutics, 2004,9(9):1069-1072.) was gavaged in the group of compounds 1, 1.3 mg/kg/day of Basmianil (corresponding to 10 mg/day of the dose for human use) was gavaged in the group of compounds 1, 1.3 mg/kg/day of Etazolate (corresponding to 10 mg/day of the dose for human use) was gavaged in the group of compounds 1, 3 mg/kg/day of Basmianil and 10.65 mg/kg/day of the compound for human use (corresponding to 10 mg/day and 5 mg/day) were gavaged in the group of Basmianil + compound 1 at the same time, 0.65 mg/kg/day of Etazolate was gavaged in the group of human use (corresponding to 10 mg/day and 5 mg/day of the compound for 5.65) mg/day and 5 mg/day), Basmisanil + compound high dose group was gavaged simultaneously with Basmisanil 2.6 mg/kg/day and compound 11.3 mg/kg/day (corresponding to human dose of 20 mg/day and 10 mg/day), Etazolate + compound 1 high dose group was gavaged simultaneously with Etazolate 1.3 mg/kg/day and compound 11.3 mg/kg/day (corresponding to human dose of 10 mg/day at 10 mg/day), placebo group and model group were gavaged with the same volume of physiological saline, and administration group mice were continuously administered with test agent for 12 weeks.

Water maze test

The mice are subjected to Morris water maze experimental training 3 days before model making and drug administration, each group of mice is trained for 3 times per day, and the mice are trained to escape from the water surface for swimming from the starting point of the SMG-2 type square water maze to reach the terminal stairs. The square water maze automatically recorded the number of errors the mouse entered each blind and the time to reach the endpoint (latency). The test was started on the day of official administration, 30 minutes after each administration, and 2 times for each group of mice were measured, and the average number of errors and the average incubation period were averaged.

Data expression and statistical processing

The experimental data are expressed as Mean (Mean) ± standard deviation (s.d.), statistical comparison is performed by using excel software t test, the model group and the blank control group are analyzed and compared, whether significant mathematical statistical significance exists or not is determined, # P <0.05 indicates that the model group and the blank control group have significant difference, # P <0.01 indicates that the model group and the blank control group have high significant difference, △ P <0.05 indicates that the tested drug group and the model group have significant difference, △△ P <0.01 indicates that the tested drug group and the model group have high significant difference, and # P <0.05 indicates that the drug combination group and the corresponding single-use group have significant difference.

(VI) Experimental results Table 1 Effect of the model-making drugs on the memory ability of the model mice and the mice administered with the drugs at the end of the 12 th week

n＝10)

TABLE 2 Effect of Compound 1 on memory ability of dementia model mice administered at the end of week 12 in combination with Basmisanil and Etazolate, respectively: (

n＝10)

The experimental results in table 1 show that the data of Morris water maze test performed on each group at the end of the 12 th week of model building show that the latency value of the mice in the normal blank control group is 39.1 ± 12.9 seconds, the error frequency is 4.0 ± 1.7 times, and the latency value and the error frequency of the model group and each administration group are obviously increased compared with those in the blank control group ((the latency value and the error frequency of the model group and each administration group are obviously increased^#p<0.05), and the successful induction of AD model mice on the model group and the mice of each administration group by using aluminum trichloride and D-galactose is proved.

The experimental results in table 2 show that the latency and the number of errors in the model group are significantly increased compared with the blank control group, which indicates that the AD model induced by aluminum trichloride and D-galactose is successful (^##p<0.01); the latency values and the number of errors were significantly reduced in the Basmisanil group, the Etazolate group, and the Compound 1 group among the single administration groups, as compared with the model group (A)^△p<0.05；^△△p<0.01), suggesting that the Basmisanil group, the Etazolate group and the compound 1 group have certain effects on alleviating AD; the combination group had a more significant reduction in latency and number of errors in the Basmianil + Compound 1 Low dose group, Etazolate + Compound 1 Low dose group, Basmianil + Compound 1 high dose group, and Etazolate + Compound 1 high dose group than in the corresponding Individual group: (reduction in latency and number of errors^*p<0.05), suggesting that the compound 1 has synergistic effect when being combined with Basmisanil and Etazolate respectively; has great potential for resisting AD.

In summary, given the suggestion that compound 1 has a synergistic effect with Basmianil and Etazolate, respectively, and has a great potential against AD, it is well-justified that compounds (1-8) with very similar structures, and more generally, GABA receptor modulators n-alkylaryl-5-oxyaryl-octahydro-cyclopenta [ c ] pyrroles, have a synergistic effect with GABA receptor modulators, further with GABAA receptor modulators, especially with Basmianil or Etazolate, with respect to their single drugs, and that the later combined use of NR2B negative allosteric modulators and GABA receptor modulators has a positive potential use in the preparation of drugs for treating/improving various types of Alzheimer's disease.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that modifications can be made by those skilled in the art without departing from the principle of the present invention, and these modifications should also be construed as the protection scope of the present invention.

Claims

1. Use of a NR2B negative allosteric modulator in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease, wherein said NR2B negative allosteric modulator is a compound having the general formula (I):

said A, B, C, D and E are independently N or CRx;

y and Y' are independently H, halogen or C_1-6Alkyl groups of (a);

x is O or S;

rx each independently is H, C_1-6Alkyl, halogen, -OH or OC of_1-6Alkyl groups of (a);

l2 is (CH2) n, where n is 1 or 2.

2. Use of a NR2B negative allosteric modulator in combination with a GABA receptor modulator according to claim 1, characterized in that the compound of general formula (I) is selected from one of the following formulae 1 to 8:

3. use of a NR2B negative allosteric modulator in combination with a GABA receptor modulator according to claim 2 for the preparation of a medicament for the treatment of alzheimer's disease characterized in that the pharmaceutically acceptable salt of the compound having the structure of formula (1-8) is selected from the group consisting of acetate, fumarate, mesylate, maleate, tartrate, sulfate, tosylate, hydrochloride, preferably hydrochloride; the GABA modulator is selected from a GABA A modulator or a GABA B modulator.

4. Use of a NR2B negative allosteric modulator in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of Alzheimer's disease according to claim 3 wherein the GABA A modulator is selected from the group consisting of Basmisanil (CAS:1159600-41-5), Etazolate (CAS:51022-77-6), Bamaluzole (CAS:87034-87-5), Gaboxadol (CAS:64603-91-4), Ibotenic acid (CAS:2552-55-8), Isoguvacine (CAS:64603-90-3), Isonipecotic acid (CAS:498-94-2), Muscimol (CAS:2763-96-4), Phenibu (CAS:1078-21-3), Picamilon (CAS: 62936-56-5), Progatide (CAS:62666-20-0), Quisquarea (CAS: 2711-73), and Thielagic (CAS: 6835: 31-20-3), Topiramate (CAS:97240-79-4) and Zolpidem (CAS: 82626-48-0).

5. The use of a NR2B negative allosteric modulator in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease according to claim 4, wherein the weight ratio of the compound of formula (1-8) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or stereoisomer thereof to the GABA a modulator is selected from the range of 4:1 to 1: 5.

6. The use of a NR2B negative allosteric modulator in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease according to claim 5, wherein the dose of the compound of formula (1-8) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or stereoisomer thereof is selected from 1-60 mg; the dosage of the GABA A regulator is 1-100 mg.

7. The use of a NR2B negative allosteric modulator in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease according to claim 6, characterized in that the GABA a modulator is selected from the group consisting of basisaminil or Etazolate; the compound having the structure of formula (1-8) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or stereoisomer thereof is selected from compound 1 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate thereof.

8. The use of a NR2B negative allosteric modulator in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease according to claim 7, wherein the weight ratio of compound 1, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate thereof, to bmisanil is 1: 2; the weight ratio of the compound 1 or the pharmaceutically acceptable salt, the prodrug, the solvate, the hydrate and the Etazolate thereof is 1: 1.

9. The use of a NR2B negative allosteric modulator in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease according to claim 8, wherein compound 1 or its pharmaceutically acceptable salt, prodrug, solvate, hydrate is in a co-formulation with bmisanil, wherein the dose of compound 1 or its pharmaceutically acceptable salt, prodrug, solvate, hydrate is 5mg or 10mg and the dose of bmisanil is 10mg or 20 mg; or compound 1 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate thereof and Etazolate thereof, wherein the dose of compound 1 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate thereof is 5mg, 10mg, or 20mg, and the dose of Etazolate is 5mg, 10mg, or 20 mg.

10. Use of a NR2B negative allosteric modulator according to any one of claims 1-9 in combination with a GABA receptor modulator for the manufacture of a medicament for the treatment of alzheimer's disease, characterized in that the alzheimer's disease is mild alzheimer's disease, moderate alzheimer's disease or alzheimer's disease with psychotic disorders; the mental disease is schizophrenia, depression or mania.