CN114149386A - Aryl pentadiene amide aldehyde dehydrogenase inhibitor, and synthesis method and application thereof - Google Patents

Abstract

The invention belongs to the technical field of medicinal chemistry, and in particular relates to a class of amide aldehyde dehydrogenase agonists, a synthesis method and uses thereof. The amide compounds provided by the present invention show higher agonistic activity to ALDH2, so these compounds have the potential to prepare therapeutic drugs for diseases related to ALDH2 activity; the amide compounds of the present invention are more active and water-soluble than the positive control. Improve, have better druggability. Therefore, the compounds of the present invention have good development prospects.

Description

Aryl pentadiene amide aldehyde dehydrogenase inhibitor, and synthesis method and application thereof

The application is a divisional application of an invention patent application with the application number of 2018105625623, which is filed in 2018, 6, month and 4 and is named as 'amide aldehyde dehydrogenase agonist, a synthetic method and application thereof'.

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an aryl pentadiene amide aldehyde dehydrogenase inhibitor, a synthesis method and application thereof.

Background

Aldehyde dehydrogenase 2(ALDH2) is responsible for detoxification of acetaldehyde generated by metabolism of exogenous alcohol in vivo and acrolein and the like in environmental pollution; also responsible for the detoxification of the final products of lipid peroxidation, such as 4-hydroxynonenal (4-HNE) and Malondialdehyde (MDA) and the like, under endogenous oxidative stress, is an important link of the defense system of oxidative stress in vivo (Physiol Rev.2014, 94(1): 1-34; Cardiovasc Res.2010, 88(1): 51-7). There are distinct species-distinct single nucleotide mutations in ALDH2, with about 35-45% of east asian populations carrying the less active variant ALDH2 x 2, up to 65% in southern china, and very low in others (Ann Hum genet.2009, 73: 335-45).

Initially, researchers' knowledge of ALDH2 was largely limited in their metabolism of alcohol consumption by humans, and the less active variant ALDH2 x 2 was known to limit the ability of humans to tolerate alcohol, thereby being susceptible to acute alcoholism. However, recent studies have shown that ALDH2 has a more widespread and important impact on human health disorders (Annu Rev Pharmacol Toxicol.2015, 55107-27; Physiol Rev.2014, 94(1): 1-34). The first is the higher risk of multiple malignancies in the variant carriers if drinking for a long period, the most abundant evidence being upper gastrointestinal tract (UADT, including head and neck and esophagus) cancer (Oncotarget.2017, 8(60):102401 and 102412; Sci Rep.2017, 7(1): 9701). More importantly, even with the exclusion of alcohol consumption, the less active variant ALDH2 x 2 carriers have a higher health risk of oxidative stress related diseases, since ALDH2 is an important link in the oxidative stress defense system in vivo. Including cardiovascular and cerebrovascular diseases, diabetes, neurodegenerative diseases, fanconi anemia, pain, osteoporosis, radiodermatitis, malignant tumor metastasis, etc. Especially the close relationship with cardiovascular and cerebrovascular diseases, has been proved in recent years by a large number of studies, including acute (myocardial ischemia) and chronic (heart failure) cardiovascular diseases, ischemic brain injury and ischemic stroke (cerebral infarction) etc. (science.2008,321(5895): 1493-5; Cell Res.2013, 23(7): 915-30).

To date, only one class of small molecule agonists of ALDH2 has been reported, representing the drug Alda-1. The discovery of the compounds proves the significance and feasibility of ALDH2 small molecule agonist research (science.2008,321(5895): 1493-5). However, due to the problems of pharmacokinetic properties such as low activity and short half-life existing in the compounds, the real clinical application of the compounds is hindered. Because the increase of the expression or activity of the ALDH2 is proved to have a relevant disease protection effect clearly, the development of the ALDH2 small molecule agonist has important potential clinical application value, and is particularly important for the variant ALDH2 x 2 carriers with high proportion in east Asian population centered on Han nationality of China. In addition, the ALDH2 small molecule agonist can also be used as an important molecular probe for further deeply exploring the target function and the relation between the target function and human health diseases.

Acute alcoholism is a common disease in clinic, and if a patient suffering from severe alcoholism is not treated in time, the life of the patient can be threatened. The acute measures generally taken by the severely poisoned patients include the excretion of alcohol in the digestive tract, blood purification therapy, symptomatic support therapy and the like. The current alcoholism treatment medicines which are most commonly used clinically comprise opioid receptor antagonists such as naloxone and naltrexone, and only can support the treatment to the symptoms, improve the intoxication symptoms and have limited curative effect. After a human body drinks a large amount of alcohol, except for a small amount of ethanol which is not metabolized in the body, the ethanol volatilizes through a respiratory tract or is discharged out of the body through urine, and most of the ethanol is metabolized in the liver. Ethanol is oxidized to acetaldehyde by Alcohol Dehydrogenase (ADH) in the liver cell fluid, acetaldehyde is oxidized to acetic acid by acetaldehyde dehydrogenase 2(ALDH2) in mitochondria, and acetic acid is unstable and decomposed into water and carbon dioxide. Ethanol itself is not very toxic, and acetaldehyde can be combined with protein, DNA and the like in vivo to form compounds, which cause lipid peroxidation, mitochondrial damage and glutathione deficiency, and cause alcoholism. ADH subtype ADH1C1 is most critical for alcohol metabolism in vivo, it metabolizes 41.5% of the ethanol in the liver. The ADH inhibitor, methylpyrazole (4-MP), has been approved by the FDA for the treatment of ethylene glycol and methanol poisoning, and is currently undergoing a phase II clinical trial for acute alcoholism, which acts therapeutically by slowing down the production of acetaldehyde. The dual-function regulator of the ALDH2 and the ADH inhibitor can inhibit the ethanol from being metabolized into acetaldehyde, promote the acetaldehyde to be metabolized into acetic acid, reduce the accumulation of acetaldehyde in the body, prevent and treat the damage of acetaldehyde to the human body, and is expected to fundamentally treat acute alcoholism.

Disclosure of Invention

The invention aims to provide a novel structural amide aldehyde dehydrogenase agonist aiming at the problems in the prior art.

In order to achieve the purpose, the technical scheme of the invention is as follows: the structure is shown as formula I:

wherein R is₁、R₂Each independently selected from H, halogen, C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6A carbonyl group; or R₁、R₂Are connected with each other to form a five-membered cycloalkyl or a five-membered heterocycloalkyl;

x is C, N or O; when X is N or O, R₁Is absent;

y is methylene or sulfonyl;

z is H or C_1-6An alkyl group;

l is carbonyl or sulfonyl;

n is 0, 1, 2, 3, 4 or 5;

R₃selected from aryl, substituted benzyl, substituted aryl, heteroaryl or substituted heteroaryl; the substituted benzyl is a benzyl, and the benzene ring of the benzyl has 1-3 substituents; the substituted aryl is substituted by 1-3 substituents on an aromatic ring; the substituted heteroaryl is substituted on a heteroaryl ring by 1-3 substituents; the substituent group comprises halogen, carboxyl and C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Cycloalkoxy, C_1-6Alkenyloxy radical, C_1-6Alkynyloxy, C_1-6A carbonyl or carboxylic acid derivative; the carboxylic acid derivative has the following structure:

wherein R is₄Is selected from C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkyl carboxylic acid, C_1-6An alkyl carboxylate; r₅Selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkyl carboxylic acids or C_1-6An alkyl carboxylate; said C is_1-6The alkyl carboxylic acid ester is composed of C_1-6Alkyl carboxylic acids with C_1-6Ester generated by alkyl alcohol reaction;

or Y, Z, N, L are not allWhen present, n is 0, 1, 2, 3, 4 or 5, R₃In this case, the following structure is selected:

the term "aryl" as used herein, unless otherwise indicated, refers to monocyclic aromatic hydrocarbons containing 6 carbon atoms, bicyclic aromatic hydrocarbons containing 10 carbon atoms, tricyclic aromatic hydrocarbons containing 14 carbon atoms, and which may have 1 to 3 substituents on each ring; aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl.

The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon of 5 to 8 atoms, a bicyclic aromatic hydrocarbon of 8 to 12 atoms, or a tricyclic aromatic hydrocarbon of 11 to 14 atoms, and contains 1 or more heteroatoms (e.g., N, O, S); heteroaryl groups include, but are not limited to, pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, pyrazolyl.

The term "cycloalkyl" refers to saturated or partially unsaturated cyclic hydrocarbons containing from 3 to 8 carbon atoms, unless otherwise specified. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl; the "cycloalkoxy" refers to a group containing an oxygen atom and a cycloalkyl group, wherein the cycloalkyl group may be directly bonded to the oxygen atom or may be bonded through C_1-6The alkyl group is bonded to an oxygen atom.

Preferably, wherein R₁、R₂Each independently selected from H, halogen, C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6A carbonyl group; or R₁、R₂Are connected with each other to form a five-membered cycloalkyl or a five-membered heterocycloalkyl;

x is C, N or O; when X is N or O, R₁Is absent;

y is methylene or sulfonyl;

z is H or C_1-6An alkyl group;

l is carbonyl or sulfonyl;

n is 0, 1, 2 or 3;

R₃selected from aryl, substituted benzyl, substituted phenyl, pyridyl or substituted pyridineA group; the substituted benzyl is a benzyl, and the benzene ring of the benzyl has 1-2 substituents; the substituted phenyl is substituted by 1-3 substituent groups on a benzene ring; the substituted pyridyl is substituted by 1-3 substituents on a pyridyl ring; the substituent group comprises halogen, carboxyl and C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Cycloalkoxy, C_1-6Alkenyloxy radical, C_1-6Alkynyloxy, C_1-6A carbonyl or carboxylic acid derivative; the carboxylic acid derivative has the following structure:

wherein R is₄Is selected from C_1-6Alkyl radical, C_1-6Alkyl carboxylic acid, C_1-6An alkyl carboxylate; r₅Selected from H, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkyl carboxylic acids or C_1-6An alkyl carboxylate;

or Y, Z, N, L, n is 0, 1, 2, 3, 4 or 5, R₃In this case, the following structure is selected:

preferably, the amide aldehyde dehydrogenase agonist is selected from the group consisting of:

1) n- (benzo [ d ] [1, 3] dioxol-5-ylmethyl) anthracene-9-carboxamide;

2) n- (benzo [ d ] [1, 3] dioxol-5-ylmethyl) -1-naphthamide;

3)2- ((benzo [ d ] [1, 3] dioxol-5-ylmethyl) carbamoyl) -3-chlorobenzoic acid;

4)2- ((benzo [ d ] [1, 3] dioxol-5-ylmethyl) carbamoyl) -6-chlorobenzoic acid;

5)N¹- (benzo [ d ]][1，3]Dioxol-5-ylmethyl) -3-chloro-N²-phenylphthalamide;

6)N²- (benzo [ d ]][1，3]Dioxol-5-ylmethyl) -3-chloro-N¹-phenyl o-benzeneA dimethylamide;

7)N¹- (benzo [ d ]][1，3]Dioxol-5-ylmethyl) -N²-phenylphthalamide;

8) (2- ((benzo [ d ] [1, 3] dioxol-5-ylmethyl) carbamoyl) -3-chlorobenzoyl amide;

9) (2- ((benzo [ d ] [1, 3] dioxol-5-ylmethyl) carbamoyl) -3-chlorobenzoylamino) benzoic acid methyl ester;

10) ethyl 2- (4- (2- ((benzo [ d ] [1, 3] dioxol-5-ylmethyl) carbamoyl) -3-chlorobenzoylamino) phenyl) acetate;

11) (2- ((benzo [ d ] [1, 3] dioxol-5-ylmethyl) carbamoyl) -3-chlorobenzoylamino) acetic acid ethyl ester;

12) (2- ((benzo [ d ] [1, 3] dioxol-5-ylmethyl) carbamoyl) -3-chlorobenzoylamino) acetic acid;

13)N²- (benzo [ d ]][1，3]Dioxol-5-ylmethyl) -3-chloro-N¹-isopropyl phthalamide;

14)2, 6-dichloro-N- ((6-methoxypyridin-3-yl) methyl) benzamide;

15) 2-chloro-6- (cyclopropylmethoxy) -N- ((6-methoxypyridin-3-yl) methyl) benzamide;

16) 2-chloro-6-isopropoxy-N- ((6-methoxypyridin-3-yl) methyl) benzamide;

17) 2-chloro-6-ethoxy-N- ((6-methoxypyridin-3-yl) methyl) benzamide;

18) 2-chloro-6-isobutoxy-N- ((6-methoxypyridin-3-yl) methyl) benzamide;

19) 2-chloro-6-cyclobutoxy-N- ((6-methoxypyridin-3-yl) methyl) benzamide;

20)2- (allyloxy) -6-chloro-N- ((6-methoxypyridin-3-yl) methyl) benzamide;

21) 2-chloro-N- ((6-methoxypyridin-3-yl) methyl) -6- ((2-methylallyl) oxy) benzamide;

22) 2-chloro-6- (cyclobutylmethoxy) -N- ((6-methoxypyridin-3-yl) methyl) benzamide;

23) 2-chloro-N- ((6-methoxypyridin-3-yl) methyl) -6-propoxybenzamide;

24) 2-butoxy-6-chloro-N- ((6-methoxypyridin-3-yl) methyl) benzamide;

25) 2-chloro-N- ((6-methoxypyridin-3-yl) methyl) -6- (pentyloxy) benzamide;

26) 2-chloro-6- (hexyloxy) -N- ((6-methoxypyridin-3-yl) methyl) benzamide;

27)2, 4-dichloro-N- ((6-methoxypyridin-3-yl) methyl) nicotinamide;

28) 4-chloro-2- (cyclopropylmethoxy) -N- ((6-methoxypyridin-3-yl) methyl) nicotinamide;

29) 4-chloro-2-ethoxy-N- ((6-methoxypyridin-3-yl) methyl) nicotinamide;

30) 4-chloro-N- ((6-methoxypyridin-3-yl) methyl) -2-propoxytinamide;

31) 2-chloro-4-ethoxy-N- ((6-methoxypyridin-3-yl) methyl) nicotinamide;

32) 2-chloro-N- ((6-methoxypyridin-3-yl) methyl) -4-propoxytinamide;

33) 2-chloro-6- (1-cyclopropylethoxy) -N- ((6-methoxypyridin-3-yl) methyl) benzamide;

34) 4-chloro-2-methoxy-N- ((6-methoxypyridin-3-yl) methyl) nicotinamide;

35) 4-chloro-2-isobutoxy-N- ((6-methoxypyridin-3-yl) methyl) nicotinamide;

36) 4-chloro-2-cyclobutoxy-N- ((6-methoxypyridin-3-yl) methyl) nicotinamide;

37)2, 6-dichloro-N- ((6-methoxypyridin-3-yl) methyl) benzenesulfonamide;

38) n- (benzo [1, 3-d ] dioxol-5-alkylsulfonyl) -2, 6-dichlorobenzamide;

39) n- (benzo [1, 3-d ] dioxol-5-methyl) amino) -2-ethyl) benzoic acid;

40) (2E,4E) -5- (3-fluoro-4-methoxyphenyl) -1- (piperidin-1-yl) -2, 4-pentadien-1-one;

41) (2E,4E) -5- (6-methoxypyridin-3-yl) -1- (piperidin-1-yl) -2, 4-pentadien-1-one;

a third aspect of the invention provides a use in the manufacture of a medicament for the treatment of a disease or condition associated with aldehyde dehydrogenase 2(ALDH2) activity.

The diseases or symptoms related to the activity of aldehyde dehydrogenase 2(ALDH2) comprise acute alcoholism, malignant tumor, cardiovascular and cerebrovascular diseases, diabetes, neurodegenerative diseases, fanconi anemia, pain, osteoporosis, radiodermatitis and malignant tumor metastasis; the cardiovascular and cerebrovascular diseases comprise myocardial ischemia, heart failure, ischemic brain injury and ischemic stroke.

The fifth aspect of the present invention provides a pharmaceutical composition, which comprises the above amide-based aldehyde dehydrogenase agonist, a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

In this application, "prodrug" refers to an agent that is converted in vivo to the proto-drug. Prodrugs are often useful because, in some cases, they may be easier to administer than the proto-drug. Prodrugs are generally precursors to drugs which, following administration and absorption, are converted to the active species or, by some process, are converted to more active species, such as by metabolic pathways. Some prodrugs have chemical groups that make them less active and/or less soluble than the proto-drug or some other property. Once the chemical groups of the prodrug are removed and/or modified, the active drug is obtained.

The pharmaceutically acceptable salt comprises pharmaceutically acceptable inorganic acid salt and organic acid salt; the pharmaceutically acceptable inorganic acid salt can be selected from hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate, and the pharmaceutically acceptable organic acid salt can be selected from acetate, maleate, fumarate, tartrate, succinate, lactate, p-toluenesulfonate, salicylate and oxalate.

The pharmaceutical composition can be in solid form or liquid form, and can be in the dosage forms of tablets, dispersible tablets, buccal tablets, orally disintegrating tablets, sustained release tablets, capsules, soft capsules, dripping pills, granules, injections, powder injections or aerosols and the like. When the compounds of the present invention are used for the above-mentioned purpose, they may be mixed with one or more pharmaceutically acceptable carriers or excipients, such as solvents, diluents, etc., and may be orally administered in the form of: tablets, pills, capsules, dispersible powders, granules or suspensions (containing, for example, from about 0.05 to 5% suspending agent), syrups (containing, for example, from about 10 to 50% sugar), and elixirs (containing, for example, from about 20 to 50% ethanol), or by external administration: ointments, gels, medicated plasters, etc., or parenterally in the form of sterile injectable solutions or suspensions (containing about 0.05-5% suspending agent in an isotonic medium). For example, these pharmaceutical preparations may contain from about 0.01% to about 99%, more preferably from about 0.1% to about 90%, by weight of the active ingredient in admixture with a carrier. Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, auditory, nasal, and topical administration.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant that the components of the composition are capable of being blended with the compounds of the present invention and with each other without significantly diminishing the efficacy of the compounds. Examples of the pharmaceutically acceptable carrier moiety are sugars (e.g., glucose, sucrose, lactose, etc.), starches (e.g., corn starch, potato starch, etc.), celluloses and derivatives thereof (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., sodium stearate, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tweens), wetting agents (e.g., sodium dodecylsulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc

The beneficial effects of the invention include: (1) the amide compounds of the invention show higher agonistic activity to ALDH2, so that the compounds have the potential of preparing therapeutic drugs for diseases related to ALDH2 activity; (2) compared with a positive control substance, the amide compound provided by the invention has the advantages that the activity and the water solubility are obviously improved, and the amide compound has better drug properties. Therefore, the compound of the invention is expected to have good development prospect.

The invention has the advantages that:

1. the amide compounds of the invention show higher agonistic activity to ALDH2, so that the compounds have the function of preparing therapeutic drugs for diseases related to ALDH2 activity.

2. Compared with a positive control substance, the amide compound provided by the invention has the advantages that the activity and the water solubility are obviously improved, and the amide compound has better drug properties. Therefore, the compound of the invention is expected to have good development prospect.

It is to be understood that within the scope of the present invention, each of the above-described features of the present invention and each of the features described in detail below (e.g., in the examples) may be combined with each other to form new or preferred embodiments, i.e., each of the substituent groups of the present invention may be combined with each other to form new specific compounds which are part of the present invention.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.

Example 1

Preparation of N- (benzo [ d ] [1, 3] dioxol-5-ylmethyl) anthracene-9-carboxamide

Dissolving anthracene-9-carboxylic acid (114mg, 0.51mmol) in anhydrous DMF, adding HATU (235mg, 0.6mmol) and 1mL DIEA, stirring for 5 min, adding piperine (79mg, 0.52mmol), reacting at room temperature for 24h, monitoring by TLC, pouring the reaction solution into 50mL1N diluted hydrochloric acid solution after the reaction of the raw materials is finished, precipitating a large amount of white solid, standing the mixed solution overnight, filtering, and drying to obtain the compound 1 with the yield of 84.1%.

Examples 2 to 4

Example 1 was repeated, with the difference that: different starting materials were used to prepare compounds 2, 14, 27 of table 1. The method comprises the following specific steps: compound 2 was prepared using 1-naphthoic acid instead of anthracene-9-carboxylic acid as the starting material in example 1; compounds 14 and 27 were prepared, respectively, using 2, 5-dichlorobenzoic acid and 2, 4-dichloronicotinic acid instead of anthracene-9-carboxylic acid (6-methoxypyridin-3-yl) methylamine, the raw material piperine in example 1.

Example 5

Preparation of 2- ((benzo [ d ] [1, 3] dioxol-5-ylmethyl) carbamoyl) -3-chlorobenzoic acid

1) Preparation of 2-chloro-6- ((2-ethoxy-2-oxoethyl) carbamoyl) benzoic acid

Dissolving 4-chloro-isobenzofuran-1, 3-dione (274mg, 1.5mmol) in 10mL ethyl acetate, stirring at room temperature for dissolution, dropwise adding ethyl 2-aminoacetate (155mg, 1.5mmol) to generate a large amount of white solid immediately, monitoring by TLC, standing for filtration after the reaction is finished, and drying to obtain an intermediate 2-chloro-6- ((2-ethoxy-2-oxoethyl) carbamoyl) benzoic acid with the yield of 90%.

2) Preparation of methyl 2- (2- ((benzo [ d ] [1, 3] dioxol-5-ylmethyl) carbamoyl) -3-chlorobenzoylamino) acetate

Dissolving an intermediate 2-chloro-6- ((2-ethoxy-2-oxoethyl) carbamoyl) benzoic acid (213mg, 0.51mmol) in anhydrous DMF, adding HATU (235mg, 0.6mmol) and 1mL of DIEA, stirring for 5 minutes, adding piperine (79mg, 0.52mmol), reacting at room temperature for 24 hours, monitoring by TLC, pouring the reaction solution into 50mL of 1N diluted hydrochloric acid solution after the raw materials are reacted, separating out a large amount of white solid, standing the mixed solution overnight, filtering, and drying to obtain a white solid with the yield of 84.1%.

3) Preparation of 2- ((benzo [ d ] [1, 3] dioxol-5-ylmethyl) carbamoyl) -3-chlorobenzoic acid

Taking 2- (2- ((benzo [ d)][1，3]Dioxolen-5-ylmethyl) carbamoyl) -3-chlorobenzoylamino) acetic acid methyl ester (218mg, 0.52mmol) was added to EtOH/H₂Adding NaOH (41.6mg, 1.04mmol) into 5mL of mixed solution of O & ltSUB & gt 5:1, stirring at room temperature for 30 minutes, monitoring by TLC, after the reaction is finished, carrying out vacuum spin-drying on the reaction solution, adding 5mL of water, dropwise adding concentrated hydrochloric acid to adjust the pH & ltSUB & gt 5, precipitating a large amount of white solid, cooling, standing, filtering, and drying to obtain a compound 3, wherein the yield is as follows: 76.3 percent.

Example 6

Preparation of 2- ((benzo [ d ] [1, 3] dioxol-5-ylmethyl) carbamoyl) -6-chlorobenzoic acid

Dissolving 4-chloro-isobenzofuran-1, 3-dione (230mg, 1.25mmol) in 5mL ethyl acetate, stirring at room temperature to dissolve, dropwise adding piperine (188mg, 1.25mmol) to generate a large amount of white solid immediately, monitoring by TLC, standing for filtering after the reaction is finished, and drying to obtain a compound 4, wherein the yield is as follows: 80.3 percent.

Example 7

N¹- (benzo [ d ]][1，3]Dioxol-5-ylmethyl) -3-chloro-N²Preparation of (E) -phenylphthalamides

1) Dissolving piperine (30mg, 0.2mmol) in 10mL ethyl acetate, stirring at room temperature for dissolving, dropwise adding 4-chloro-isobenzofuran-1, 3-dione (36mg, 0.2mmol) to generate a large amount of white solid immediately, monitoring by TLC, standing for filtering after the reaction is finished, and drying to obtain an intermediate 2-chloro-6- (phenylcarbamoyl) benzoic acid.

2) Dissolving the intermediate (57mg, 0.17mmol) in anhydrous DMF, adding HATU (70mg, 0.19mmol) and 1mLDIEA, stirring for 5 min, adding aniline (16mg, 0.17mmol), reacting at room temperature for 24h, monitoring by TLC, pouring the reaction solution into 50mL of 1N diluted hydrochloric acid solution after the reaction of the raw materials is finished, precipitating a large amount of white solid, standing the mixed solution overnight, filtering, and drying to obtain the compound 5, wherein the yield is as follows: and (3.9).

Examples 8 to 14

Example 7 was repeated, with the difference that: different starting materials were used to prepare compounds 6, 7, 8, 9, 10, 11, 13 in table 1.

The method comprises the following specific steps: aniline is used for replacing piperine in example 9 to react with benzofuran-1, 3-dione to generate an intermediate, and piperine is used for replacing aniline in example 9 to react to prepare a compound 7; compounds 6, 8-11 and 13 were prepared by reacting piperine with 4-chloroisobenzofuran-1, 3-dione to give intermediates, and then reacting piperine with aniline in example 9, using aniline, methyl 3-aminobenzoate, methyl 4-aminobenzoate, ethyl 4-aminophenylacetate, ethyl 2-aminoacetate and propan-2-amine, respectively, instead of piperine in example 9.

Example 15

Preparation of (2- ((benzo [ d ] [1, 3] dioxol-5-ylmethyl) carbamoyl) -3-chlorobenzoylamino) acetic acid

Compound 11, i.e. ethyl, 2- (2- ((benzo [ d)][1，3]Dioxolen-5-ylmethyl) carbamoyl) -3-chlorobenzamide) ethyl acetate (23mg, 0.05mmol) was dissolved in EtOH/H₂To a 5mL solution of O5: 1 in ice bath, KOH (4mg, 0.1mmol) was added, TLC monitoring was performed, 10 minutes of reaction was complete, ethanol was dried under vacuum at 30 ℃, 5mL water was added, dilute hydrochloric acid solution was added to adjust PH 6, a solid precipitated, the mixture was left to stand overnight in a refrigerator (4 ℃), filtered, and dried to give compound 12 in yield: 23.1 percent.

Example 16

Preparation of 2-chloro-6-isopropoxy-N- ((6-methoxypyridin-3-yl) methyl) benzamide

1) 2-chloro-6-hydroxybenzoic acid (100mg, 0.58mmol) was dissolved in 5mL DMF, and K was added sequentially₂CO₃(317mg, 2.30mmol) and 2-bromopropane (150mg, 1.22mmol) were reacted at 100 ℃ and monitored by TLC, and after completion of the reaction, the reaction was poured into 50mL of water, 5mL of saturated brine, the solution was extracted three times with ethyl acetate (30mL x 3), the organic phase was collected and directly dried to give an oil, which was dried using EtOH/H2O ═ 5:1 mixed solution 5mL dissolve crude oily intermediate 1.

2) Adding NaOH (36mg.0.9mmol) into the crude oily intermediate 1, stirring at room temperature, removing the organic solvent at 50 ℃, adding 5mL of water, adjusting the pH value to 3 by using 1N hydrochloric acid solution, separating out a large amount of white solid, filtering, and drying to obtain an intermediate 2-isopropyl-2-chloro-6-isopropylbenzoic acid.

3) Intermediate 2(96mg, 0.45mmol) was dissolved in anhydrous DMF, HATU (200mg, 0.54mmol) and 1mL DIEA were added in order, stirred for 5 min, then (6-methylpyridin-3-yl) methylamine (70mg, 0.46mmol) was added, reacted at room temperature for 24h, poured into 50mL aqueous solution, a white solid precipitated, the white solid was found impure on the plaque, filtered off the white solid, dried, the crude product obtained was purified by silica gel column chromatography, eluent: petroleum ether ethyl acetate 3:1 to give compound 16 in yield: 80.3 percent.

Examples 17 to 27

Example 16 was repeated, with the difference that: different starting materials were used to prepare compounds 15 and 17-26 in Table 1. The method comprises the following specific steps: compounds 15 and 17 to 26 were prepared, respectively, using (bromomethyl) cyclopropane, bromoethane, 1-bromo-2-methylpropane, bromocyclobutane, 3-bromoprop-1-ene, 3-bromo-2-methylpropan-1-ene, (bromomethyl) cyclobutane, 1-bromopropane, 1-bromobutane, 1-bromopentane, 1-bromohexane instead of the starting material 2-bromopropane in example 17.

Example 28

Preparation of 4-chloro-2-methoxy-N- ((6-methoxypyridin-3-yl) methyl) nicotinamide

1) Dissolving raw material 2, 4-chloronicotinic acid (100mg, 0.67mmol) in 5mL of anhydrous DMF, sequentially adding HATU (350mg, 8.1mmol) and 1mL of DIEA organic base, reacting at room temperature for 5 minutes, adding (6-methylpyridin-3-yl) methylamine (132mg, 0.71mmol), stirring at room temperature for 24 hours, monitoring by TLC until the reaction is complete, pouring the reaction solution into 50mL of water, adding 10mL of saturated saline to prevent emulsification, extracting with ethyl acetate (30mL x 3), concentrating the organic phase, and purifying the obtained crude product by silica gel column chromatography. Eluent: ethyl acetate 2:1 to give 2, 4-dichloro-N- ((6-methylpyridin-3-yl) methyl) nicotinamide intermediate 1.

2) After stirring at room temperature for 5 minutes, intermediate 1(100mg, 0.31mmol) dissolved in 2mL of DMF was again injected into the flask with a disposable syringe and detected by TLC, and the reaction was completed after 4 hours. The reaction mixture was poured into 50mL of water, 10mL of saturated saline was added to prevent emulsification, extraction was performed with ethyl acetate (30 mL. multidot.3), the organic phase was concentrated, and the resulting crude product was purified by silica gel column chromatography. Eluent: ethyl acetate 1:1 to give compound 34 in yield: 50%).

Examples 29 to 36

Example 28 was repeated, with the difference that: different starting materials were used to prepare compounds 28-33 and compounds 35-36 of Table 1. The method comprises the following specific steps: using cyclopropylmethanol, ethanol, n-propanol, 1-cyclopropylmethyl alcohol, 2-methylpropan-1-ol, cyclobutanol instead of the raw material methanol in example 30, compounds 28 to 30 and 33 and compounds 35 to 36 were obtained, respectively; the compounds 31 to 32 were obtained by extraction and separation using excess ethanol and n-propanol instead of the raw material methanol in example 30.

Example 37

Preparation of 2, 6-dichloro-N- ((6-methoxypyridin-3-yl) methyl) benzenesulfonamide

To a round bottom flask were added 6-methoxypyridin-3-yl-methylamine (0.2g, 14.5mmol) and 2, 6-dichlorobenzenesulfonyl chloride (0.36g, 14.5mmol), 10mL of tetrahydrofuran, 3mL of triethylamine was added, the mixture was stirred at room temperature overnight, the reaction was monitored by spotting, and after the reaction was completed, an appropriate amount of distilled water was added, and the mixture was washed twice with a 1M dilute hydrochloric acid solution, distilled water and saturated saline solution, to obtain compound 37(0.46g, 92.0%).

Example 38

Preparation of N- (benzodioxin [ d ] [1, 3] dioxin-5-ylsulfonyl) -2, 6-dichlorobenzamide

To a round bottom flask were added 5-sulfanylbenzo [1, 3-d ] dioxole (0.2g, 0.99mmol) and 2, 6-dichlorobenzoyl chloride (0.21g, 0.99mmol), tetrahydrofuran 10mL, triethylamine 3mL, and stirred at room temperature overnight, followed by spotting, and after completion of the reaction, appropriate amount of water was added, and washed twice with 1M dilute hydrochloric acid solution, distilled water, and saturated brine to obtain compound 38(0.30g, 81.1%).

Example 39

To a round-bottomed flask were added methyl 3- (benzo [1, 3-d ] dioxol-5-oxy) methylbenzoate (0.098g, 0.34mmol), sodium hydroxide (0.027g, 0.068mmol), tetrahydrofuran (10 mL) and distilled water (5 mL), and reacted for 2.5 h. After the reaction, tetrahydrofuran was evaporated to dryness, the pH was adjusted with 1M hydrochloric acid solution until no more precipitate was precipitated, and the reaction mixture was filtered and dried to obtain compound 39(0.088g, yield: 94.6%).

Example 40

To a round-bottomed flask were added (2E,4E) -5- (3-fluoro-4-methoxyphenyl) -2, 4-pentadienoic acid (0.1g, 0.45mmol), DMAP (0.07g, 0.45mmol), EDCI (0.4g, 1.80mmol) and 10mL of dichloromethane, and after stirring at room temperature for 0.5h, piperidine (0.05g, 0.45mmol) was added, followed by stirring at room temperature overnight, spot-plate monitoring, washing with 1M hydrochloric acid solution, saturated NaHCO3 solution, saturated brine washing, drying over anhydrous magnesium sulfate, concentration, silica gel sampling, and column chromatography (elution system, petroleum ether/ethyl acetate 2:1 isocratic elution) to obtain compound 40(0.11g, yield: 84.6%).

EXAMPLE 41

Example 40 was repeated, except that: using different starting materials, compound 41 was prepared. The method comprises the following specific steps: compound 41 was obtained using 6-methoxynicotinaldehyde instead of the starting material 3-fluoro-4-methoxybenzaldehyde in example 40.

The chemical structure of the target product in the general formula (I) synthesized by the invention is shown in Table 1. The nuclear magnetic hydrogen spectrum and the mass spectrum system characterize the chemical structure of the target product, and specific data thereof are shown in Table 2.

TABLE 1 chemical Structure of the target product in the general formula (I) synthesized according to the invention

"-" indicates that the group is absent.

TABLE 2 nuclear magnetic hydrogen and mass spectra of the target products

Example 42

ALDH2 Activity assay

ALDH2 enzyme activity test the agonistic action of the target compound on ALDH2 enzyme activity was examined by fluorescence quantification method using ALDH2 agonist Alda-1 as control drug. The basic principle of the fluorescence quantitative method is that ALDH2 oxidizes acetaldehyde into acetic acid with the aid of NAD +, and reduces NAD + into NADH, so that the generation rate of NADH is in direct proportion to the activity of ALDH2, a dye is used for coupling with NADH to form a yellow product, and the absorbance value of the yellow product is monitored under the excitation wavelength of 340nm and the emission wavelength of 440nm to obtain the change of the concentration of NADH. The agonistic or inhibitory activity of mutant and wild type ALDH2 under the effect of the compound of interest is calculated.

TABLE 3 ALDH2 Activity of the target Compounds

^*++++：EC₅₀≤1μM；+++：1μM＜EC₅₀≤5μM；++：5μM＜EC₅₀≤25μM；+：25μM＜EC₅₀(ii) a "+" Activity is comparable to that of Alda-1, a positive drug (science.2008,321(5895):1493-5)

The results show that the amide compounds of the invention show better agonistic activity with ALDH2, so that the compounds have potential application in preparing medicaments for treating diseases related to ALDH2 activity.

Example 43

Neuronal sugar oxygen deprivation model (OGD) test

Well-grown human neuroblastoma cells SH-SY5Y were plated at a plating density of 5X 104 cells/ml on a 96-well cell culture plate and were subjected to OGD treatment and drug stimulation, respectively. mu.L of MTT solution (5mg/ml, i.e.0.5% MTT) was added to each well and incubation in the incubator at 37 ℃ was continued for 4 h. The cell supernatant was then aspirated off, 150. mu.L DMSO was added to each well, and the mixture was shaken on a shaker at low speed for 10min to dissolve the crystals deposited in the cells. The absorbance value (OD value) of each well was measured at 490nm of a microplate reader. The survival rate of the cells was calculated from the OD values obtained for each group, wherein the survival rates of the cells of the normal group without OGD treatment were unified to 100%, and the survival rates of the cells of the other groups were ratios to the normal group.

The invention uses human neuroblastoma cell SH-SY5Y sugar oxygen deprivation (OGD) test to simulate the ischemic injury in brain. Experiments show that the compounds 15 and 38 of the invention show obvious protective activity on SH-SY5Y nerve cells on an OGD model at the concentration of 100 mu M, and are superior to Alda-1. The compounds can be used for preparing potential application of medicaments for treating in-vivo ischemic injury.

The above description is only for the specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.

Claims (7)

1. An aryl pentadiene amide aldehyde dehydrogenase inhibitor, and a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the structure of the aryl pentadiene amide aldehyde dehydrogenase inhibitor is shown as a formula I:

wherein R is₁、R₂Each independently selected from H, halogen, C_1-6Alkyl or C_1-6An alkoxy group;

x is C or N; when X is N, R₁Is absent;

y, Z, N, L are absent;

n is 0, 1, 2, 3, 4 or 5;

R₃selected from the following structures:

2. the aryl pentadiene amide aldehyde dehydrogenase inhibitor, pharmaceutically acceptable salt, hydrate or solvate thereof according to claim 1, wherein the structure is shown as formula I:

wherein R is₁、R₂Each independently selected from H, halogen or C_1-6An alkoxy group;

x is C or N; when X is N, R₁Is absent;

y, Z, N, L are absent;

n is 1, 2, 3, 4 or 5;

R₃selected from the following structures:

3. an arylpentadiene amide aldehyde dehydrogenase inhibitor, a pharmaceutically acceptable salt, hydrate or solvate thereof, characterized by being selected from the following compounds:

40) (2E,4E) -5- (3-fluoro-4-methoxyphenyl) -1- (piperidin-1-yl) -2, 4-pentadien-1-one;

41) (2E,4E) -5- (6-methoxypyridin-3-yl) -1- (piperidin-1-yl) -2, 4-pentadien-1-one.

4. Use of an arylpentadiene amide aldehyde dehydrogenase inhibitor according to any of claims 1 to 3 for the preparation of a medicament for the treatment of a disease or condition associated with aldehyde dehydrogenase 2 activity.

5. The use of claim 4, wherein the disease or condition associated with aldehyde dehydrogenase 2 activity comprises acute alcoholism, malignancy, cardiovascular disease, diabetes, neurodegenerative disease, fanconi anemia, pain, osteoporosis, radiodermatitis, and metastasis.

6. The use of claim 5, wherein the cardiovascular and cerebrovascular diseases comprise myocardial ischemia, heart failure, ischemic brain injury, and ischemic stroke.

7. A pharmaceutical composition comprising the arylpentadiene amide aldehyde dehydrogenase inhibitor of any of claims 1-3, a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier.