CN111995563A - Inhibitors of phosphodiesterase PDE2 activity - Google Patents

Inhibitors of phosphodiesterase PDE2 activity Download PDF

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CN111995563A
CN111995563A CN202010771205.5A CN202010771205A CN111995563A CN 111995563 A CN111995563 A CN 111995563A CN 202010771205 A CN202010771205 A CN 202010771205A CN 111995563 A CN111995563 A CN 111995563A
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pde2
indole
oxo
disorder
ethyl
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宋国强
高英
孔韧
唐龙
黄险峰
冯筱晴
谈颖
夏颜
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Changzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a phosphodiesterase PDE2 activity inhibitor. Sulfonamide compounds or hydrates, pharmaceutically acceptable thereofAt least one of the salts, tautomers, stereoisomers, precursor compounds as an active ingredient for the preparation of a medicament for the prevention or treatment of a PDE2 disorder. The sulfonamide compounds selected by the present invention are effective in inhibiting PDE2 enzyme activity
Figure DDA0002616653250000011
kit and PDE-GloTMPhosphodiesterase Assay for determining the enzymatic level IC50Has good PDE2 enzyme inhibition effect. The compound of the invention is used as an effective inhibitor of PDE2, is expected to be used as an active ingredient for preparing a medicament for treating PDE2 disorder, and has medicinal prospect.

Description

Inhibitors of phosphodiesterase PDE2 activity
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a phosphodiesterase PDE2 activity inhibitor.
Background
Adenosine cyclophosphate (Cyclic adenosine 3 ', 5' monophosphosphate, cAMP) was first discovered by all and Sutherland et al in 1958; guanosine monophosphate (cGMP) was discovered by Ashman et al in 1963. Since then, studies on cyclic adenosine monophosphate and cyclic guanosine monophosphate have received increasing attention.
Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) regulate gene expression in cells by means of controlling ion channels, are important second messengers in cells and are involved in the realization of numerous physiological functions, such as learning memory, cell cycle regulation, cell differentiation, proliferation, inflammatory processes, smooth muscle contraction relaxation, visual signal transduction, and metabolic functions, such as steroid synthesis, insulin secretion, glycogen synthesis, lipogenesis, etc.
Intracellular levels of cAMP and cGMP are controlled by the corresponding cyclases and Phosphodiesterases (PDEs) to maintain their concentrations within an optimal range for responding to a signal. Adenylate cyclase and guanylate cyclase respectively catalyze ATP and GTP in vivo to be converted into cAMP and cGMP, and the concentration of a second messenger is increased; while PDEs are the only family of enzymes in the body that can hydrolyze cAMP and cGMP to the inactive substances 5 '-AMP and 5' -GMP, reducing the intracellular concentration of the second messenger. Therefore, PDE can be used as target of action of various disease drugs, and the effect of disease treatment is achieved by blocking hydrolysis process of PDE on cAMP/cGMP, maintaining intracellular concentration of second messenger, and reversing reduction of concentration in the disease process.
Cyclic nucleoside phosphodiesterases contain at least 11 structurally related but functionally distinct gene families (PDE1-PDE 11). High levels of PDE will lead to visual deterioration, congestive heart failure, depression, asthma, erectile dysfunction and inflammation. Selective PDE inhibitors play an important role in inhibiting platelet aggregation, treating depression, parkinson's disease and learning disorders. Each family has 21 gene products with different isoforms and splice variants, and encodes these 11 PDE protein families. Examples of the PDE1 include PDE1A, PDE1B, PDE1C and the like.
PDE2(Phosphodiesterase2) is a member of the PDEs isozyme family, has only one subtype (PDE2A), is a homodimer structure, and has a dual action of hydrolyzing cAMP and cGMP simultaneously. PDE2 is mainly distributed in the central nervous system of human body and is expressed more in cortex of brain and hippocampus, and studies have shown that PDE2 can be involved in the regulation of central nervous system diseases, and corresponding PDE2 inhibitors have been shown to treat central nervous system diseases related to depression, anxiety and learning and memory disorders. The PDE2 inhibitor can improve mild cognitive impairment and age-related memory disorder diseases by inhibiting PDE2 protein activity to increase cAMP and cGMP levels, and inhibit thrombosis, and can be used for treating cancer, dementia and blood disorders. The existing PDE2 inhibitors are mainly EHNA, BAY60-7750, dipyridamole and the like, but are not yet on the market. It would therefore be desirable to find novel PDE2 inhibitors that would aid in later drug development.
Disclosure of Invention
The invention provides a phosphodiesterase PDE2 activity inhibitor, which is a compound shown as a formula I or a pharmaceutically acceptable salt thereof
Figure BDA0002616653230000021
Wherein X is NH-R1；
R1Selected from hydrogen, alkyl, aryl, heteroaryl, -C (═ O) -alkyl, -C (═ O) -aryl, or-C (═ O) -heteroaryl, any of which may optionally be substituted with one or more independent Q1Substituted by groups;
Q1selected from hydrogen, halogen, -CN, -CF3，-OCF3，-NO2Oxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycloaryl, -OR2，-S(O)nR3，-NR4R5，-SO2NR4R5，-C(O)R6，-C(O)NR4R5，-C(O)OR7，-OC(O)R8，-NR4C(O)R6，-NR4S(O)2R9，-NR10C(O)NR4R5，-NR10S(O)2NR4R5or-NR10S(O)NR4R5Any of the foregoing groups may optionally be substituted with one or more independent hydrogen, halogen, -CN, -OH, -NH2，-NO2Oxy, -CF3，-OCF3，-CO2H, -S (O) nH, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, heterocycloaryl or-O-alkyl, any of the above substituents being partially or fully halogenated;
n is 0, 1, or 2.
Further, the compound as an inhibitor is 1-ethyl-2-oxo-1,2-dihydro-benzo [ cd]Indole-6-sulfonic acid (4-fluoro-phenyl) -amide (1-Ethyl-2-oxo-1, 2-dihydro-benzol [ cd)]indole-6-sulfonic acid (4-fluoro-phenyl) -amide) with the structural formula:
Figure BDA0002616653230000031
1-Ethyl-N- (furan-2-ylmethyl) -2-oxo-1,2-dihydrobenzo [ cd]Indole-6-sulfonamide (1-ethyl-N- (furan-2-ylmethyl) -2-oxo-1, 2-dihydrobenzol [ cd)]indole-6-sulfonimide), structureThe formula is as follows:
Figure BDA0002616653230000032
n- (3,4-Dimethoxybenzyl) -1-ethyl-2-oxo-1,2-dihydrobenzo [ cd]Indole-6-sulfonamide (N- (3,4-dimethoxybenzyl) -1-ethyl-2-oxo-1, 2-dihydrobenzol [ cd)]indole-6-sulfonamide) with a structural formula:
Figure BDA0002616653230000041
1-ethyl-2-oxo-N-phenethyl-1,2-dihydrobenzo [ cd]Indole-6-sulfonamide (1-ethyl-2-oxo-N-phenylethynyl-1, 2-dihydrobenzol [ cd)]indole-6-sulfonamide) with a structural formula:
Figure BDA0002616653230000042
1-Ethyl-N- (4-methoxyphenyl) -2-oxo-1,2-dihydrobenzo [ cd]Indole-6-sulfonamide (1-ethyl-N- (4-methoxyphenyl) -2-oxo-1, 2-dihydrobenzol [ cd)]indole-6-sulfonamide) with a structural formula:
Figure BDA0002616653230000043
or 1-ethyl-2-oxo-N- (((tetrahydrofuran-2-yl) methyl) -1,2-dihydrobenzo [ cd]Indole-6-sulfonamide (1-ethyl-2-oxo-N- ((tetrahydrofuran-2-yl) methyl) -1, 2-dihydrobenzol [ cd)]indole-6-sulfonamide) with a structural formula:
Figure BDA0002616653230000051
the compound shown in the formula I, the hydrate, the pharmaceutically acceptable salt, the tautomer, the stereoisomer and the precursor compound thereof can be used as an activity inhibitor of phosphodiesterase PDE 2.
The compound shown in the formula I, the hydrate, the pharmaceutically acceptable salt, the tautomer, the stereoisomer or the precursor compound thereof and one or more pharmaceutically acceptable carriers are prepared into a pharmaceutical composition.
The carrier includes diluent, excipient, filler, binder, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier, lubricant, etc. which are conventional in the pharmaceutical field.
The dosage form of the medicine is tablets, capsules, granules, pills or other conventional dosage forms which can be prepared.
The pharmaceutical composition treats a PDE2 disorder by inhibiting phosphodiesterase PDE2 activity; by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method into body such as muscle, intradermal, subcutaneous, vein, mucosa tissue; or mixed or coated with other materials and introduced into body.
The PDE2 disorder is a central nervous system disorder that is: psychiatric disorders and conditions; anxiety disorders; movement disorders; a substance-related disorder; mood disorders; neurodegenerative disorders; pain; autistic disorder.
The neurodegenerative disorder includes a disorder or condition that is symptomatic of attention and/or cognitive deficits.
The invention searches and discovers that the compound in the formula I can inhibit the activity of PDE2 enzyme from a ChemDiv compound library by adopting a method of integrating virtual screening and experimental determination, and combines experiments to verify the inhibitory activity of the compound on PDE2, although the research on the compound inhibitor in the formula I is not mature to enter the clinical stage, the research is crucial to the final development of anti-PDE 2 medicaments, and has important application prospect.
The invention adopts a computer simulation method to carry out advanced evaluation on the effectiveness of drug molecules, adopts a biological experiment method to detect and verify the activity, obtains an effective PDE2 enzyme inhibitor, and carries out the steps of
Figure BDA0002616653230000061
cAMP kit and PDE-GloTMPhosphodiesterase Assay for determining the enzymatic level IC50Has good PDE2 enzyme inhibition effect.
Drawings
FIG. 1:
Figure BDA0002616653230000062
cAMP kit measurement of 1-ethyl-2-oxo-1,2-dihydro-benzo [ cd]A graph of IC50 values of indole-6-sulfonic acid (4-fluoro-phenyl) -amide at the PDE2 protein level;
FIG. 2: PDE-GloTM1-Ethyl-2-oxo-1,2-dihydro-benzo [ cd ] measured by Phosphodienesterase Assay]A graph of IC50 values of indole-6-sulfonic acid (4-fluoro-phenyl) -amide at the PDE2 protein level;
FIG. 3:
Figure BDA0002616653230000063
AMP kit determination of 1-ethyl-N- (furan-2-ylmethyl) -2-oxo-1,2-dihydrobenzo [ cd]A graph of the IC50 values of indole-6-sulfonamide at the PDE2 protein level;
FIG. 4: PDE-GloTMPhosphodiesterase Assay of 1-Ethyl-N- (furan-2-ylmethyl) -2-oxo-1,2-dihydrobenzo [ cd]A graph of the IC50 values of indole-6-sulfonamide at the PDE2 protein level;
FIG. 5:
Figure BDA0002616653230000064
AMP kit determination of N- (3,4-dimethoxybenzyl) -1-ethyl-2-oxo-1,2-dihydrobenzo [ cd]A graph of the IC50 values of indole-6-sulfonamide at the PDE2 protein level;
FIG. 6: PDE-GloTMPhosphodiesterase Assay of N- (3,4-Dimethoxybenzyl) -1-ethyl-2-oxo-1,2-dihydrobenzo [ cd]A graph of the IC50 values of indole-6-sulfonamide at the PDE2 protein level;
FIG. 7: PDE-GloTM1-Ethyl-2-oxo-N-phenylethyl-1, 2-dihydrobenzo [ cd ] measured by Phosphodiesterase Assay]A graph of the IC50 values of indole-6-sulfonamide at the PDE2 protein level;
FIG. 8: PDE-GloTMPhosphodiesterase Assay of 1-Ethyl-N- (4-methoxyphenyl) -2-oxo-1,2-dihydrobenzo [ cd]A graph of the IC50 values of indole-6-sulfonamide at the PDE2 protein level;
FIG. 9:
Figure BDA0002616653230000065
AMP kit determination of 1-ethyl-2-oxo-N- (((tetrahydrofuran-2-yl) methyl) -1,2-dihydrobenzo [ cd]Indole-6-sulfonamides on PIC50 value plot at DE2 protein level;
FIG. 10: PDE-GloTMPhosphodiesterase Assay of 1-Ethyl-2-oxo-N- (((tetrahydrofuran-2-yl) methyl) -1,2-dihydrobenzo [ cd)]Graph of IC50 values of indole-6-sulfonamide at the PDE2 protein level.
Detailed Description
The present invention is further described below with reference to examples, but is not limited thereto.
1. Experimental methods
1.1 virtual receptor-based screening
First adopt
Figure BDA0002616653230000071
The Protein Preparation module in the software package was used to manipulate the crystal structure of PDE2 (PDB: 4 HTX). The library of SPECS compounds (http:// www.specs.net /) was pretreated with ligaprep for compounds including removal of heavies, salt ions and minerals, possible ionization states and tautomers of the compounds at pH 7.4, and ring conformations, etc.
Before virtual screening by adopting a molecular docking method, the effectiveness of the adopted Glide docking method needs to be verified, a PDE2 active site is defined, and the center of mass of ligand molecules BAY60-7550 in a crystal structure is set as the center
Figure BDA0002616653230000072
In the cube region, the ligand molecule BAY60-7550 was treated with LigPrep in the same manner as in SP (Standard precision) parameter setting of Glide software, and then docked into the active pocket of PDE2 again, and Glide was found to better reproduce the binding conformation in the crystal structure.
The SPECS library compounds were docked and scored using the Glide SP (Standard Precision) mode, retaining the 3 ten thousand small molecule binding mode that precedes the score. In the crystal structure of the binding of BAY60-7550 to PDE2, hydrogen bond interactions with the active region residue GLN859 and pi-pi interactions with PHE862 are formed. For 3 ten thousand small molecule binding modes generated by docking, hydrogen bond standards are adopted as screening conditions, binding modes which form more than 1 hydrogen bond with GLN859 are selected, and 3660 qualified binding modes are obtained. In order to fully consider the structural diversity of the compounds, a Canvas module in Schrodinger is adopted for carrying out cluster analysis, reasonable binding modes are manually selected, 48 compounds are finally obtained, Shanghai ceramic company is entrusted as a proxy to purchase compound entities from SPECS company, and experimental determination is carried out. The compound of the formula I is found to have better PDE2 enzyme inhibition activity.
1.2 PDE2 in vitro enzyme Activity detection assay procedure
1) Expression and purification of PDE2 protein: pET15b-PDE2A (580-941) wild-type and truncated plasmids were awarded by the professor Cazechun university, North Ka, USA. After sequencing, the cells were transformed into E.coli BL21+ (Codon Plus) and induced to express (after induction with 0.1mM IPTG, incubation was continued at 15 ℃ for 20 hours), and then purified by Ni column to obtain His-tagged PDE2 protein.
2) PDE2 in vitro enzyme activity detection procedure:
use
Figure BDA0002616653230000081
cAMP kit assay inhibitory effect of compounds on PED 2:
add 4. mu.L PDE2 protein and 2. mu.L candidate compound (7 concentrations per compound, 3 parallel experiments) and incubate for 30 min;
then adding 4. mu.L Bio-cAMP to react with the residual PDE2 protein in the previous step for 1 hour;
adding 15 mu L of mixed solution of Donor Bead and Acceptor in a dark environment for reaction for 1 hour;
and reading the signal value of the micropore plate by using a multifunctional microplate reader.
Each group of experiments is provided with a positive maximum value control and a negative minimum value control, only a Bio-cAMP substrate is added without adding protein to be used as the positive control, and the substrate is the most at the moment, the signal value is the largest, and the control can be also called as a full inhibition control; protein and Bio-cAMP substrates were added as negative controls, protein was all involved in hydrolysis, and excess substrate gave the signal when the signal value was minimal, also referred to as the perhydrolysis control. Each of the above experiments was performed in 3 parallel experiments, each step requiring centrifugation (rotation speed 1000r/min, centrifugation for 1 minute).
② use of PDE-GloTMPhosphodiesterase Assay compounds were tested for their inhibitory effect on PDE 2:
mu.L of the compound to be screened (7 concentrations of each compound determined, 3 parallel experiments) and 1.5. mu.L of PDE2 were added to each well and incubated for 30 minutes at room temperature;
2.5. mu.L of 2. mu.M cAMP was added and incubated at room temperature for 20 minutes;
add 2.5. mu.L PDE-Glo per wellTMTermination Buffer，2.5μL PDE-GloTMDetection Solution, incubation for 20 minutes at room temperature;
finally adding 10 μ L of a solution containing
Figure BDA0002616653230000091
Of substrates
Figure BDA0002616653230000092
Buffer, incubation for 10 minutes at room temperature;
and reading the signal value of the micropore plate by using a multifunctional microplate reader.
Negative and positive controls were set for each set of experiments, negative controls: cAMP and no PDE protein were added. The highest cAMP content, highest PKA activity, and most ATP consumed by phosphorylated substrates, and therefore the weakest luminescent signal, is obtained with the lowest plate reading value without addition of PDE protein. Positive control: cAMP and PDE proteins were added. PDE hydrolyzes most of cAMP, PKA activity is reduced, ATP consumed by phosphorylated substrates is reduced, remaining ATP is increased, and luminescence signal is strongest, which is the set of the maximum plate reading value.
Example 1
1-ethyl-2-oxo-1,2-dihydro-benzo [ cd]Indole-6-sulfonic acid (4-fluoro-phenyl) -amide (SPECS library number: AQ-390/40910475) via
Figure BDA0002616653230000093
AMP kit for detecting its enzymatic level IC50The value was 6.098. + -. 2.619. mu. mol/L (as shown in FIG. 1), in turn via PDE-GloTMPhosphodiesterase Assay for determining the enzymatic level IC50Has a value of3.554 +/-0.396 mu mol/L (shown in figure 2), has good PDE2 enzyme inhibition effect
Example 2
1-Ethyl-N- (furan-2-ylmethyl) -2-oxo-1,2-dihydrobenzo [ cd]Indole-6-sulfonamides via Alph
Figure BDA0002616653230000094
AMP kit for detecting its enzymatic level IC50The value was 24.49. + -. 3.03. mu. mol/L (as shown in FIG. 3), which was in turn determined by PDE-GloTMPhosphodiesterase Assay for determining the enzymatic level IC50The value is 17.56 +/-3.68 mu mol/L (shown in figure 4), and the PDE2 enzyme inhibition effect is good.
Example 3
N- (3,4-Dimethoxybenzyl) -1-ethyl-2-oxo-1,2-dihydrobenzo [ cd]Indole-6-sulfonamides via A
Figure BDA0002616653230000101
AMP kit for detecting its enzymatic level IC50The value was 22.16. + -. 1.36. mu. mol/L (as shown in FIG. 5), which was in turn determined by PDE-GloTMPhosphodiesterase Assay for determining the enzymatic level IC50The value was 17.76. + -. 1.1. mu. mol/L (as shown in FIG. 6), and had a good PDE2 enzyme inhibitory effect.
Example 4
1-ethyl-2-oxo-N-phenethyl-1,2-dihydrobenzo [ cd]Indole-6-sulfonamides via PDE-GloTMDetection of Phos Phodienesterase Assay for its enzymatic level IC50The value was 39.54. + -. 3.19. mu. mol/L (as shown in FIG. 7), which was excellent in PDE2 enzyme inhibition effect.
Example 5
1-Ethyl-N- (4-methoxyphenyl) -2-oxo-1,2-dihydrobenzo [ cd]Indole-6-sulfonamides via PDE-Gl oTMPhosphodiesterase Assay for determining the enzymatic level IC50The value is 29.24 +/-2.66 mu mol/L (shown in figure 8), and the PDE2 enzyme inhibition effect is good.
Example 6
1-Ethyl-2-oxo-N- (((tetrahydrofuran-2-yl) methyl) -1,2-dihydrobenzo [ cd)]Indole-6-sulfonamides via
Figure BDA0002616653230000102
AMP kit for detecting its enzymatic level IC50The value was 29.83. + -. 1.93. mu. mol/L (as shown in FIG. 9), which was in turn determined by PDE-GloTMPhosphodiesterase Assay for determining the enzymatic level IC50The value was 21.66. + -. 2.93. mu. mol/L (as shown in FIG. 10), which was excellent in PDE2 enzyme inhibition effect.
In conclusion, a series of compounds with the structure shown in the formula I are effective phosphodiesterase PDE2 inhibitors and can effectively inhibit the enzymatic activity of the compounds in vitro. Due to the important role of PDE2 in adjusting cAMP and cGMP, a series of compounds with the structure of formula I as PDE2 inhibitors have potential effects of treating PDE2 disorder, are expected to be active as medicaments for treating PDE2 disorder, are especially expected to be used for preparing medicaments for treating psychosis or neuropathy, and have medicinal prospects.
It is to be understood and appreciated that while the present invention has been described in conjunction with the detailed description set forth above, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined in the following claims. Other aspects, benefits, and modifications are within the scope of the claims. The entire contents of all publications cited in this application are incorporated by reference into this application and are a part of this application.

Claims (9)

1. An inhibitor for phosphodiesterase PDE2 activity, which is characterized in that the compound used as the inhibitor is a sulfonamide compound with a structural formula shown in a formula I,
Figure FDA0002616653220000011
wherein X is NH-R1；
R1Selected from hydrogen, alkyl, aryl, heteroaryl, -C (═ O) -alkyl, -C (═ O) -aryl, or-C (═ O) -heteroaryl, any of which may optionally be substituted with one or more independent Q1Substituted by groups;
Q1selected from hydrogen, halogen, -CN, -CF3，-OCF3，-NO2Oxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycloaryl, -OR2，-S(O)nR3，-NR4R5，-SO2NR4R5，-C(O)R6，-C(O)NR4R5，-C(O)OR7，-OC(O)R8，-NR4C(O)R6，-NR4S(O)2R9，-NR10C(O)NR4R5，-NR10S(O)2NR4R5or-NR10S(O)NR4R5Any of the foregoing groups may optionally be substituted with one or more independent hydrogen, halogen, -CN, -OH, -NH2，-NO2Oxy, -CF3，-OCF3，-CO2H, -S (O) nH, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, heterocycloaryl or-O-alkyl, any of the above substituents being partially or fully halogenated;
n is 0, 1, or 2.
2. The inhibitor of phosphodiesterase PDE2 activity according to claim 1, wherein said compound as inhibitor is 1-ethyl-2-oxo-1,2-dihydro-benzo [ cd ] indole-6-sulfonic acid (4-fluoro-phenyl) -amide, 1-ethyl-N- (furan-2-ylmethyl) -2-oxo-1,2-dihydrobenzo [ cd ] indole-6-sulfonamide, N- (3,4-dimethoxybenzyl) -1-ethyl-2-oxo-1,2-dihydrobenzo [ cd ] indole-6-sulfonamide, 1-ethyl-2-oxo-N-phenylethyl-1, 2-dihydrobenzo [ cd ] indole-6-sulfonamide, 1-ethyl-N- (4-methoxyphenyl) -2-oxo-1,2-dihydrobenzo [ cd ] indole-6-sulfonamide or 1-ethyl-2-oxo-N- (((tetrahydrofuran-2-yl) methyl) -1,2-dihydrobenzo [ cd ] indole-6-sulfonamide.
3. The inhibitor of phosphodiesterase PDE2 activity according to claim 1, wherein said inhibitor of activity is a compound of formula I, a hydrate, a pharmaceutically acceptable salt, a tautomer, a stereoisomer, a precursor compound thereof.
4. A pharmaceutical composition made from a therapeutically effective amount of a compound, hydrate, pharmaceutically acceptable salt, tautomer, stereoisomer, or precursor compound thereof, according to claim 1, and one or more pharmaceutically acceptable carriers.
5. The pharmaceutical composition according to claim 4, wherein the dosage form of the drug is tablets, capsules, granules, pills or other conventional dosage forms which can be prepared; the carrier comprises diluent, excipient, filler, adhesive, wetting agent, disintegrating agent, absorption enhancer, surfactant, adsorption carrier and lubricant which are conventional in the pharmaceutical field.
6. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition treats a PDE2 disorder by inhibiting phosphodiesterase PDE2 activity; by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemical mediated method into body such as muscle, intradermal, subcutaneous, vein, mucosa tissue; or mixed or coated with other materials and introduced into body.
7. The pharmaceutical composition of claim 6, wherein the PDE2 disorder is a central nervous system disorder.
8. The pharmaceutical composition of claim 7, wherein the central nervous system disorder is: psychiatric disorders and conditions; anxiety disorders; movement disorders; a substance-related disorder; mood disorders; neurodegenerative disorders; pain; autistic disorder.
9. The pharmaceutical composition of claim 8, wherein the neurodegenerative disorder comprises a disorder or condition that is symptomatic of attention and/or cognitive deficits.
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