CN114437068A - Naphthyridine derivative and application thereof as monoamine oxidase inhibitor - Google Patents

Abstract

The present invention relates to naphthyridine derivatives which are useful for inhibiting monoamine oxidase (MAO), in particular for selectively inhibiting MAO-B. It has development and application prospects, and can be used for treating diseases such as brain injury, cerebral apoplexy, traumatic brain injury, anxiety disorder, mood disorder, autism, vascular dementia, Alzheimer disease and the like.

Description

A kind of naphthyridine derivative and its use as monoamine oxidase inhibitor

technical field

The present invention relates to a naphthyridine derivative and its use as a monoamine oxidase inhibitor.

Background technique

Monoamine oxidase (Monoamine oxidase, MAO) is a very important enzyme in the body, and its role is to oxidatively metabolize some monoamines in the brain and peripheral nerve tissue. MAOs can be divided into two types, MAO-A and MAO-B, according to their substrate selectivity. The main difference between the two is in the selectivity to the substrate and the sensitivity to the inhibitor. The former is mainly distributed in placental tissue, adipose tissue, thyroid and lung, and less distributed in the brain. , epinephrine, AD) has a high affinity; the latter is mainly distributed in various parts of the central nervous system: hypothalamus, prefrontal cortex, amygdala, spinal cord, etc., also in the uterus, kidney, liver and heart, to benzylamine and Non-polar aromatic amines such as phenethylamine have strong affinity. When the MAO activity is abnormal, it can accelerate the oxidation of some monoamines in the brain, which can cause neurological diseases, such as anxiety, depression, Parkinson's disease, Alzheimer's disease and so on.

Various MAO inhibitors have been reported, including phenylcoumarin derivatives (ES2343347), substituted azole derivatives (WO2010098600), azabenzoxazole derivatives (WO2010051196), pyrazole derivatives (US20070203154), benzene derivatives Pyran derivatives (WO2006102958), pyrrolidinylphenylbenzyl ether derivatives (WO 2006097270), arylpyrrolidone derivatives (WO200402687), substituted oxadiazole derivatives (EP504574) and substituted naphthyridines and Quinoline compounds (WO2014158916).

However, MAO inhibitors have generally been associated with a number of side effects that have often limited their applicability and tolerability. The first generation of MAO inhibitors - originally introduced in the 1950s to treat depression - were irreversible and non-selective. The phasing out of these inhibitors has largely been attributed to their possible drug-drug and drug-food interactions, most commonly known as tyramine-containing food interactions (the "cheese" effect). Furthermore, cardiovascular effects appear to be significantly increased when MAO inhibitors are used at high doses, and since MAO selectivity is lost at such high doses, tyramide can induce a potentially dangerous hypertensive response. Newer drugs, including selegiline and rasagiline, show greater selectivity for MAO-B and may have better side effect profiles, but they still suffer from limitations due to irreversible binding ( Chen and Swope, J. Clin. Pharmacol. 2005, 45, 878-894).

Therefore, there is a need to develop new monoamine oxidase inhibitors, especially monoamine oxidase inhibitors with better selectivity and better side effects.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to provide a naphthyridine derivative, which can be used as a monoamine oxidase inhibitor.

A first aspect of the present invention is to provide a compound shown in formula I and a pharmaceutically acceptable salt thereof, which has the following structure:

wherein: R ₁ , R ₂ , R ₃ and R ₄ are each independently selected from H, halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy.

Preferably, the structural formula of the compound of formula I is as follows:

Another aspect of the present invention provides a kind of method for preparing the compound of formula I, and its synthetic route is as follows:

The specific reaction steps are as follows:

Step 1): add 3,4,5-trimethoxybenzoic acid and benzene to the reaction kettle, stir and dissolve, then add SOCl ₂ , and react at 70-80° C. for 6 hours. After the reaction is completed, benzene is recovered by vacuum distillation, At the same time, excess SOCl ₂ was removed to obtain 3,4,5-trimethoxybenzoyl chloride, which was directly used in the next reaction without purification;

Step 2): add 2-hydroxy-1,5-naphthyridine compounds (0.22mol) and 50ml of tetrahydrofuran to the reaction kettle, stir to dissolve, and slowly add dropwise the 3,4,5-trimethoxyl group obtained in the step A solution of benzoyl chloride in tetrahydrofuran (20 ml) was added dropwise for half an hour, and the reaction was carried out at room temperature overnight. After the reaction is completed, the compound of formula I is obtained by post-treatment.

Preferably, step 1): the molar ratio of 3,4,5-trimethoxybenzoic acid and SOCl is: ₁ :1-5, preferably 1:3;

Preferably, step 2): the molar ratio of 3,4,5-trimethoxybenzoyl chloride and 2-hydroxy-1,5-naphthyridine is: 1:1-1.5, preferably 1:1.1;

Preferably, the step 1) and step 2) are both reacted under an inert gas environment, more preferably, the inert gas is nitrogen;

Preferably, the post-processing process of step 2) is as follows: after the reaction is completed, tetrahydrofuran is recovered by distillation, and the residue is washed with dichloromethane solution and 10% aqueous sodium carbonate solution, then washed with water until neutral, dried over anhydrous sodium sulfate, and rotary evaporated. Removal of dichloromethane gave crude product which was purified by column chromatography to give compound of formula I.

Another aspect of the present invention provides a pharmaceutical composition comprising a compound represented by formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and excipient.

Another aspect of the present invention relates to the use of a compound of formula I and a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same in the preparation of a medicament for the treatment of a disease mediated by a monoamine oxidase inhibitor (MAO); in particular, the preparation of a monoamine oxidase- Use in B inhibitors. At the same time, the compound can treat diseases mediated by MAO, especially diseases mediated by MAO-B; the diseases are selected from neurodegenerative disorders: for example, brain injury, stroke, traumatic brain injury, anxiety, mood Disorders, autism, vascular dementia, Alzheimer's disease, Parkinson's disease, trauma-dependent cognitive loss (associated with cerebrovascular disease, head injury, or traumatic brain injury).

definition:

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 such as hydrochloric, hydrobromic, phosphoric, sulfuric, perchloric, acetic, oxalic, maleic, tartaric, citric, succinic or malonic, acetic, propylene Acids, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like form salt forms with the compounds.

"Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like. A pharmaceutically acceptable carrier or excipient does not destroy the pharmacological activity of the disclosed compounds and is non-toxic when administered in doses 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 beneficial effects of the present invention are:

(1) The present invention provides a new class of MAO inhibitors, especially MAO-B inhibitors, which broadens the existing compounds with MAO inhibitory activity, and can be used as lead compounds for further optimization;

(2) The compounds of the present invention have selective inhibitory activity, and the inhibitory activity on MAO-B is much greater than that of MAO-A, and can selectively treat neurodegenerative diseases and reduce side effects.

Detailed ways

The content of the present invention will be specifically described by the following 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. The materials, reagents, etc. used in the following examples can be obtained from commercial sources unless otherwise specified.

Example 1 Preparation of Compound I-1

Step 1): under nitrogen atmosphere, add 3,4,5-trimethoxybenzoic acid (4.24g, 0.02mol), 40ml benzene, stir to dissolve, then add SOCl ₂ (7.15g, 0.06mol) to the reactor , and reacted at 70-80 °C for 6 hours. After the reaction, benzene was recovered by distillation under reduced pressure, and excess SOCl ₂ was removed at the same time, which was directly used in the next reaction without purification;

Step 2): under nitrogen environment, add 2-hydroxy-1,5-naphthyridine (3.21g, 0.22mol), 50ml tetrahydrofuran to the reaction kettle, stir and dissolve, and slowly add the 3,4, 5-Trimethoxybenzoyl chloride tetrahydrofuran solution (20ml) was added dropwise for half an hour, and the reaction was carried out at room temperature overnight. After the reaction was detected by TLC, tetrahydrofuran was recovered by distillation, and the residue was washed with dichloromethane solution and 10% sodium carbonate aqueous solution, and then washed with water until neutral, dried over anhydrous sodium sulfate, and the dichloromethane was removed by rotary evaporation to obtain the crude product. After purification by column chromatography, 4.58 g of the target product was obtained, and the yield was 67.4%.

1HNMR(400MHz, CDCl3)δ(ppm)8.71-8.78(d,1H),8.25-8.40(m,2H),7.45(m,1H),7.31(s,2H),6.74(d,1H),3.92 (s,6H),3.79(s,3H).

Example 2-3 Preparation of Compounds I-2 and I-3

With reference to the method of Example 1, compounds I-2 and I-3 were prepared, and their structure confirmation data were as follows:

Example 4 Inhibitory activity of compound I on monoamine oxidase A and B

Recombinant human MAO-A was prepared into a 12.5 μg/mL sample solution with 100 mM potassium phosphate buffer pH 7.4, and MAO-B was prepared into a 75 μg/mL sample solution. Add 20 μL of the test compound solution and 80 μL of monoamine oxidase to the black 96-well plate, mix well, incubate at 37°C for 15 minutes in a dark place, add 200 μM Amplex Red reagent, 2U/mL horseradish peroxidase, 2mM p-hydroxyphenethylamine (inhibit MAO-A) or 2mM benzylamine (inhibit MAO-B) to initiate the reaction, incubate at 37°C for 20min, on a multi-function microplate reader, with a fixed excitation wavelength of 545nm, measure the fluorescence emission intensity at 590nm, buffer with potassium phosphate Instead of MAO-A or MAO-B, the solution is blank; the formula for the inhibition rate of the compound to inhibit monoamine oxidase is: 100-(IFi)/(IFc)*100, where IFi and IFc are the presence of inhibitor and the absence of inhibitor, respectively The difference between the fluorescence intensity and the blank fluorescence intensity.

Three replicate wells were used for each measurement, and each group of experiments was independently repeated three times. The final concentration of 0.25, 1, 4, 16, 64, 256, 512, and 1024 μmol/L was added to the 192-well plate, and the enzyme inhibition rate was determined, and the negative logarithm of the molar concentration of the compound was linear with the enzyme inhibition rate. Regression, the molar concentration at which the 50% inhibition rate is obtained is the IC50 of the compound. The test results of each compound are as follows:

compound IC50(μM) for MAO-A IC50(μM) for MAO-B I-1 147.9 1.58 I-2 258.8 92.42 I-3 182.4 63.73

The assay results show that the compound (I) disclosed in the examples of the present invention has a significant inhibitory effect on MAO-B, and its IC50 is 1.58 μM; the IC50 of the inhibition on MAO-A is 147.9 μM, indicating that the compounds disclosed in the present invention are effective against MAO-B. MAO-B and MAO-A have good inhibitory effect, especially selective inhibitory effect on MAO-B.

Claims (10)

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

wherein: r₁、R₂、R₃And R₄Each independently selected from H, halogen, nitro, C1-C6 alkyl, C1-C6 alkoxy.

2. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound of formula I is a compound of formula I:

3. a process for the preparation of a compound of formula I according to claim 1, characterized in that:

step 1): adding 3,4, 5-trimethoxybenzoic acid and benzene into a reaction kettle, stirring for dissolving, and then adding SOCl₂Reacting at 70-80 deg.C for 6 hr, vacuum distilling to recover benzene and remove excessive SOCl₂To obtain 3,4, 5-trimethoxy benzoyl chloride which is directly used for the next reaction without purification;

step 2): adding 2-hydroxy-1, 5-naphthyridine compounds and tetrahydrofuran into a reaction kettle, stirring for dissolving, slowly dripping the prepared 3,4, 5-trimethoxybenzoyl chloride tetrahydrofuran solution, finishing dripping for half an hour, and reacting at room temperature overnight. After the reaction is finished, carrying out post-treatment to obtain a compound shown in the formula I;

wherein: r is₁、R₂、R₃And R₄Have the meaning as defined in claim 1.

4. The production method according to claim 3, wherein:

3,4, 5-trimethoxybenzoic acid and SOCl in step 1)₂The molar ratio of (A) to (B) is: 1:1 to 5, preferably 1: 3;

in the step 2), the molar ratio of the 3,4, 5-trimethoxybenzoyl chloride to the 2-hydroxy-1, 5-naphthyridine compounds is as follows: 1:1-1.5, preferably 1: 1.1.

5. The preparation method according to claim 3, wherein the post-treatment process of the step 2) is as follows: after the reaction is finished, distilling and recovering tetrahydrofuran, washing residues with a dichloromethane solution and a 10% sodium carbonate aqueous solution, washing the residues with water to be neutral, drying the residues with anhydrous sodium sulfate, removing dichloromethane by rotary evaporation to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound shown in the formula I.

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 medicament for treating a disease mediated by monoamine oxidase inhibitors (MAOs).

8. The use of claim 7, wherein the disease is mediated by MAO-B.

9. Use according to claim 7 or 8, said disease being selected from brain injury, stroke, anxiety disorders, mood disorders, autism, vascular dementia, Alzheimer's disease, Parkinson's disease.

10. Use according to claim 7 or 8, said disease being selected from traumatic brain injury, trauma-dependent loss of cognitive function.