CN114524806A

CN114524806A - Triazole derivative and application thereof as PDE10 inhibitor

Info

Publication number: CN114524806A
Application number: CN202210160858.9A
Authority: CN
Inventors: 谭回
Original assignee: Shenzhen Childrens Hospital
Current assignee: Shenzhen Childrens Hospital
Priority date: 2022-02-22
Filing date: 2022-02-22
Publication date: 2022-05-24

Abstract

The invention relates to a triazole derivative and application thereof as a PDE10 inhibitor. And the compounds may be used to treat diseases mediated by PDE 10; the disease is selected from schizophrenia, e.g. disorganized, catatonic, unclassified or residual schizophrenia; a schizophrenia-like disorder; affective schizophrenia, such as delusional disorder or depressive type; delusional disorder; substance-induced psychotic disorder; personality disorder of the paranoid type; and schizophrenic personality disorder.

Description

Triazole derivative and application thereof as PDE10 inhibitor

Technical Field

The invention relates to a triazole derivative and application thereof as a PDE10 inhibitor.

Background

Phosphodiesterases (PDEs) are a class of intracellular enzymes that are involved in the hydrolysis of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) to their respective nucleotide monophosphates. The cyclic nucleotides cAMP and cGMP are synthesized by adenylyl and guanylyl cyclases, respectively, and act as secondary messengers in multiple cellular channels. cAMP and cGMP serve as intracellular secondary messengers that regulate numerous intracellular processes, particularly in nerve cells of the central nervous system. In nerve cells, it involves the activation of cAMP and cGMP-dependent kinases, and the subsequent phosphorylation of proteins involved in the acute regulation of synaptic transmission and in neuronal differentiation and survival. The complexity of cyclic nucleotide signaling is manifested by the molecular diversity of enzymes involved in cAMP and cGMP synthesis and degradation. There are at least ten families of adenylyl cyclases, two families of guanylyl cyclases and eleven families of phosphodiesterases. Furthermore, it is known that different types of nerve cells are capable of expressing multiple isozymes of each of these types, and there is ample evidence for the differentiation and functional specificity of the different isozymes within a given nerve cell.

The primary mechanism by which cyclic nucleotide signals are regulated is by phosphodiesterase-catalyzed cyclic nucleotide catabolism. There are 11 known families of PDEs encoded by 21 different genes. Each gene typically produces multiple splice variants, further increasing the diversity of isoenzymes. The PDE family is generally functionally distinguished by cyclic nucleotide substrate specificity, regulatory mechanisms, and sensitivity to inhibitors. In addition, PDE expression is differential throughout the organism (including in the central nervous system). Due to these different enzymatic activities and regional distributions, isoenzymes of different PDEs may have different physiological functions. Furthermore, compounds capable of selectively inhibiting different PDE families or isozymes may provide specific therapeutic effects and/or fewer side effects.

PDE10 was identified as a unique family based on its major amino acid sequence and distinct enzymatic activities. PDE10 has higher affinity for cAMP (Km ═ 0.05 μ M) than for cGMP (Km ═ 3 μ M). However, it has about 5-fold higher Vmax for cGMP than cAMP. The PDE10 family of polypeptides showed a lower degree of sequence homology compared to the previously identified PDE families, and was shown to be insensitive to certain inhibitors known to be specific for other PDE families. PDE10 is mainly expressed in the brain, testis, thyroid gland, etc. of humans. In particular, it is highly expressed in Mesomeric Spinodal Neurons (MSN) of the striatum in the brain, and moderately expressed in the thalamus, hippocampus, frontal cortex and olfactory tubercle. Moreover, PDE10 is also highly expressed in the brain and testis of mice and rats. These brain sites expressing PDE10 showed important roles in the pathological mechanisms of psychiatric diseases, and therefore, PDE10 was suggested to be involved in the pathological mechanisms of psychiatric disorders, neurodegenerative diseases, and the like.

The potential antipsychotic effects of PDE10 inhibitors have been well documented. US2003/0032579 reports that papaverine, which is a PDE10 inhibitor having moderate selectivity, reduces apomorphine-induced stereotypy in rats as an animal model of psychosis, increases haloperidol-induced stiffness in rats, and simultaneously reduces dopamine concentration in rat brains, thereby showing a conventional antipsychotic effect. Furthermore, papaverine was confirmed to be useful as a PDE10 inhibitor for treating psychosis, as well as being applicable to patients. In WO2005/082883 and EP1250923, papaverine and various aromatic heterocyclic compounds (such as quinazoline and isoquinazoline compounds) as PDE10 inhibitors are disclosed. Also, a PDE10 inhibitor is disclosed to be useful for the treatment or prevention of a disease or symptom such as a mental disorder, anxiety disorder, movement disorder, drug dependence, a disease accompanied by a symptom of cognitive disorder, mood disorder, or mood symptom. Also, PDE10 inhibitors are disclosed as being useful for the treatment or prevention of neurodegenerative diseases (e.g., Parkinson's disease, Huntington's disease, etc.).

In the prior art, a large number of PDE10 inhibitors with pyrazole and triazole as parent nucleus structures are reported: the Standby pharmaceutical company has disclosed a novel class of pyrazole derivatives (CN107011343A, CN106957317A) which are useful in various diseases associated with PDE 10; Hofmann-Rackey, Inc. discloses a series of triazole compounds (CN104364249A) as PDE10 inhibitors; the company Peucedani (CN101611029A) discloses a class of pyrazole derivatives as PDE10 inhibitors.

Therefore, the development of a novel PDE10 inhibitor still has huge market prospect and social benefit.

Disclosure of Invention

The technical problem to be solved by the invention is as follows: triazole derivatives are provided which are useful as PDE10 inhibitors.

In a first aspect of the present invention, there is provided a compound of formula I and pharmaceutically acceptable salts thereof, having the structure:

preferably, the pharmaceutically acceptable salt is selected from: hydrochloride, hydrobromide, phosphate, sulphate, acetate, oxalate, tartrate, citrate, trifluoroacetate, methanesulphonate, ethanesulphonate, p-toluenesulphonate or salicylate;

in another aspect of the invention, there is provided a process for the preparation of a compound of formula I, the synthetic route for which is as follows:

the specific reaction steps are as follows:

step 1): dissolving 1, 1-dimethylethyl-3-formyl-1- (1-methylethyl) -1H-1,2, 4-triazole-5-carboxylic ester, namely the raw material A, in anhydrous DCM, introducing nitrogen for protection, then adding morpholine, reacting for 3 hours at room temperature, then adding sodium triacetoxyborohydride, stirring the reaction mixture for 24 hours at room temperature, and after the reaction is finished, carrying out post-treatment to obtain 1, 1-dimethylethyl-1- (1-methylethyl) -3- (4-morpholinylmethyl) -1H-1,2, 4-triazole-5-carboxylic ester, namely an intermediate B;

step 2): dissolving the intermediate B in 1, 4-dioxane, adding a 1, 4-dioxane solution containing 4M hydrogen chloride, stirring the mixture at room temperature, after 24 hours, adding a 4M 1, 4-dioxane solution containing 4M hydrogen chloride, stirring the mixture at room temperature for 48 hours, adding a drop of water, stirring the mixture at room temperature for 24 hours, and performing aftertreatment to obtain 1- (1-methylethyl) -3- (4-morpholinomethyl) -1H-1,2, 4-triazole-5-carboxylic acid, namely an intermediate C;

step 3): and (3) dissolving the intermediate C and 4-amino-3-alkyl-6-phenyl-1, 2, 4-triazine-5- (4H) -ketone in DCM under stirring, adding DCC and DMAP, stirring at room temperature for reaction, detecting the reaction by TLC completely, and performing post-treatment to obtain the compound shown in the formula I.

Preferably, the reaction step is specifically operated as follows:

step 1): dissolving 2.39g of 1, 1-dimethylethyl-3-formyl-1- (1-methylethyl) -1H-1,2, 4-triazole-5-carboxylic ester, namely the raw material A, in 80ml of anhydrous DCM, introducing nitrogen for protection, then adding 1ml of morpholine, reacting for 3 hours at room temperature, then adding 4.5g of sodium triacetoxyborohydride, stirring the reaction mixture for 24 hours at room temperature, adding 150ml of sodium bicarbonate solution and 150ml of DCM after the reaction is finished, and collecting an organic phase; the aqueous phase was extracted three times with DCM, the organic phases were combined, the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel to give 1, 1-dimethylethyl-1- (1-methylethyl) -3- (4-morpholinylmethyl) -1H-1,2, 4-triazole-5-carboxylate, intermediate B;

step 2): 1.55g of 1, 1-dimethylethyl-1- (1-methylethyl) -3- (4-morpholinomethyl) -1H-1,2, 4-triazole-5-carboxylate, intermediate B, was dissolved in 10ml of 1, 4-dioxahexane, then 20ml of 1, 4-dioxahexane containing 4M hydrogen chloride was added, and the mixture was stirred at room temperature for 24 hours, then 15ml of 1, 4-dioxahexane containing 4M hydrogen chloride was added and the mixture was stirred at room temperature for 48 hours, a drop of water was added and the mixture was stirred at room temperature for 24 hours, the solvent was removed in vacuo, 50ml of toluene was added without constant grinding, a white solid precipitated, filtered, and the filter cake was dried in a vacuum oven overnight to give 1- (1-methylethyl) -3- (4-morpholinomethyl) -1H-one-substituted carboxylic acid 1,2, 4-triazole-5-carboxylic acid, namely an intermediate C;

step 3): under stirring, 0.51g of intermediate C and 0.49g of 4-amino-3-alkyl-6-phenyl-1, 2, 4-triazin-5- (4H) -one are dissolved in 20mL of DCM, then 0.70g of DCC and 0.10g of DMAP are added, the reaction is stirred at room temperature, the reaction is detected by TLC to be complete, the filtration is carried out, and the filter cake is recrystallized by absolute ethyl alcohol to obtain the compound of the formula I.

In another aspect of the present invention, a pharmaceutical composition is provided, which comprises a compound represented by formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

In another aspect, the invention relates to the use of a compound of formula I and pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same in the preparation of PDE10 inhibitors. And the compounds may be used to treat diseases mediated by PDE 10; the disorder is selected from schizophrenia, e.g. disorganized, catatonic, unclassified or residual schizophrenia; schizophrenia-like disorders; schizoaffective disorder, such as delusional disorder or depressive type; delusional disorder; substance-induced psychotic disorder; personality disorder of the paranoid type; and schizophrenic personality disorder.

Defining:

in certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt, which is well known in the art. Examples of pharmaceutically acceptable salts are forms which form salts with compounds such as hydrochloric, hydrobromic, phosphoric, sulfuric, perchloric, acetic, oxalic, maleic, tartaric, citric, succinic or malonic, acetic, propionic, glycolic, pyruvic, oxalic, lactic, trifluoroacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic acid and the like.

"pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coating agents, isotonic and absorption delaying agents and the like. Pharmaceutically acceptable carriers or excipients do not destroy the pharmacological activity of the disclosed compounds and are non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound. The use of such media and agents for pharmaceutically active substances is well known in the art.

Compared with the prior art, the invention has the beneficial effects that:

(1) the invention provides a new PDE10 inhibitor, widens the existing compound with MAO inhibitory activity, and can be continuously optimized as a lead compound;

(2) compared with the existing PDE10 inhibitor, the compound of the invention has better inhibition effect.

(3) The compound of the invention has simple preparation method and short process flow, and is easy to realize industrialization.

Detailed Description

The present invention will be described in detail with reference to examples. In the present invention, the following examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

Example 1

Step 1): 1, 1-dimethylethyl-3-formyl-1- (1-methylethyl) -1H-1,2, 4-triazole-5-carboxylic ester (raw material A, 2.39g) is dissolved in anhydrous DCM (80ml), nitrogen is introduced for protection, then morpholine (1ml) is added, and reaction is carried out for 2.5 hours at room temperature. Sodium triacetoxyborohydride (4.5g) was then added thereto, and the reaction mixture was stirred at room temperature for 24 hours. After the reaction, sodium bicarbonate solution (150ml) and DCM (150ml) were added and the organic phase was collected; the aqueous phase was extracted three times with DCM and the organic phases were combined. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel to give 1, 1-dimethylethyl-1- (1-methylethyl) -3- (4-morpholinylmethyl) -1H-1,2, 4-triazole-5-carboxylate (intermediate B, 2.75 g).

¹HNMR(400MHz，CDCl3)δ(ppm)：3.91-3.99(m,1H),3.84(s,2H),3.60-3.73(m,4H), 2.58-2.71(m,4H),1.49(s,9H),1.37(s,6H).

Step 2): 1, 1-Dimethylethyl-1- (1-methylethyl) -3- (4-morpholinylmethyl) -1H-1,2, 4-triazole-5-carboxylate (1.55g) was dissolved in 1, 4-dioxane (10 ml). Then, a solution of 1, 4-dioxane (20ml) containing 4M hydrogen chloride was added, and the mixture was stirred at room temperature. After 24 hours, a further solution of 4M hydrogen chloride in 1, 4-dioxan (15ml) was added and the mixture was stirred at room temperature for 48 hours. A drop of water was added and the mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and toluene (50ml) was added and trituration was continued and a white solid precipitated. Filtering, and drying the filter cake in a vacuum oven overnight to obtain 1- (1-methylethyl) -3- (4-morpholinylmethyl) -1H-1,2, 3-triazole-5-carboxylic acid (intermediate C, 1.08g) as a white solid;

step 3): intermediate C (0.51g) and 4-amino-3-alkyl-6-phenyl-1, 2, 4-triazin-5- (4H) -one (0.49g) were dissolved with stirring in 20mL DCM, then 0.70g DCC, 0.10g DMAP were added. Stirring and reacting at room temperature, detecting by TLC to completely react, performing suction filtration, and recrystallizing the filter cake with absolute ethyl alcohol to obtain 0.51g of white solid, namely the compound of the formula I.

¹HNMR(400MHz，CDCl3)δ(ppm)：8.01-8.10(d,2H),7.48-7.62(m,4H),3.89-3.98(m,1H), 3.74(s,2H),3.63-3.74(m,4H),2.41-2.53(m,4H),1.58(s,6H).

EXAMPLE 2 evaluation of Compound (I) in vitro Compound (evaluation of enzyme inhibitory Activity: inhibition of human PDE 10)

The assay was performed using an IMAP TR-FRET phosphodiesterase detection kit (Molecular Device). To a 384-well plate (Corning), 10. mu.L of each diluted test compound and a reaction buffer containing 0.1% BSA in 1 XMIMAP (prepared 5X with a kit, 10mM Tris-HCl, pH 7.2, 10mM MgCl) were added₂、0.05％NaN₃And 0.1% BSA) 5 μ L of PDE10 enzyme diluted to 2ng/mL, and pre-incubated for 5 minutes at room temperature. 5. mu.L of cAMP substrate with a kit diluted to 400nM with 1 XIMAP reaction buffer containing 0.1% BSA was added and reacted at room temperature for 60 minutes. Then, 60. mu.L of an IMAP TR-FRET binding solution attached to the kit was added and left for 3 hours or more, and the fluorescence intensity of terbium (Emission 490nm) and TR-FRET (Emission 520nm) were measured at an excitation wavelength of 340nm using ARVO SX (Perkinelmer), and the amount of 5' -AMP produced was calculated. The inhibitory activity of each test compound was calculated by taking the number of wells to which the solvent was added instead of the test compound as 0% and the number of wells to which the PDE10 enzyme was not added as 100%.

The results of the assay show the IC of PDE10 inhibitory activity of Compound (I) disclosed in the examples of the present invention₅₀The value was 115. + -. 27.4nmol/L, indicating that the compound of the present invention has good PDE10 inhibitory activity.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, having the structure:

2. a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, selected from: hydrochloride, hydrobromide, phosphate, sulphate, acetate, oxalate, tartrate, citrate, trifluoroacetate, methanesulphonate, ethanesulphonate, p-toluenesulphonate or salicylate.

3. A process for the preparation of a compound of formula I according to claim 1, which reaction scheme is as follows:

4. the method according to claim 3, characterized by comprising the steps of:

step 1): dissolving 1, 1-dimethylethyl-3-formyl-1- (1-methylethyl) -1H-1,2, 4-triazole-5-carboxylic ester, namely a raw material A, in anhydrous DCM, introducing nitrogen for protection, then adding morpholine, reacting at room temperature for 3 hours, then adding sodium triacetoxyborohydride, stirring the reaction mixture at room temperature for 24 hours, and after the reaction is finished, carrying out post-treatment to obtain 1, 1-dimethylethyl-1- (1-methylethyl) -3- (4-morpholinylmethyl) -1H-1,2, 4-triazole-5-carboxylic ester, namely an intermediate B;

5. The preparation method according to claim 4, wherein the reaction step is specifically operated as follows:

step 1): dissolving 2.39g of 1, 1-dimethylethyl-3-formyl-1- (1-methylethyl) -1H-1,2, 4-triazole-5-carboxylic ester, namely the raw material A, in 80ml of anhydrous DCM, introducing nitrogen for protection, then adding 1ml of morpholine, reacting for 3 hours at room temperature, then adding 4.5g of sodium triacetoxyborohydride, stirring the reaction mixture for 24 hours at room temperature, adding 150ml of sodium bicarbonate solution and 150ml of DCM after the reaction is finished, and collecting an organic phase; the aqueous phase is extracted three times with DCM, the organic phases are combined, the solvent is removed in vacuo and the residue is purified by flash chromatography on silica gel to give 1, 1-dimethylethyl-1- (1-methylethyl) -3- (4-morpholinomethyl) -1H-1,2, 4-triazole-5-carboxylate, intermediate B;

6. A pharmaceutical composition comprising a compound of formula I as described in any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. Use of a compound of any one of claims 1-2 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 6 in the manufacture of a disease mediated by PDE 10.

8. Use according to claim 7, wherein the disease is selected from schizophrenia, delusional disorders, substance-induced psychotic disorders, delusional personality disorders, and schizotypal personality disorders.