KR102255957B1 - Novel dibenzooxaphosphinine oxide derivative compounds and pharmaceutical composition for preventing or treating degenerative disease comprising the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel dibenzooxaphosphinin oxide derivative compound in which various nitrogen-containing substituents are introduced at the 6th position of a dibenzooxaphosphinin oxide parent nucleus, and a use thereof, and the dibenzooxaphosphinin oxide derivative compound of the present invention It relates to a pharmaceutical composition for the prevention or treatment of degenerative diseases and a health supplement composition for preventing or improving degenerative diseases, including.

Description

A novel dibenzooxaphosphinin oxide derivative compound and a pharmaceutical composition for preventing or treating degenerative diseases comprising the same TECHNICAL FIELD [NOVEL DIBENZOOXAPHOSPHININE OXIDE DERIVATIVE COMPOUNDS AND PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING DEGENERATIVE DISEASE COMPRISING THE SAME AS AN ACTIVE RED]

The present invention relates to a novel dibenzooxaphosphinin oxide derivative compound in which various nitrogen-containing substituents are introduced at the 6th position of a dibenzooxaphosphinin oxide (DOPO) parent nucleus, and a use thereof, and the dibenzooxaphosphinin of the present invention It relates to a pharmaceutical composition for the prevention or treatment of a degenerative disease comprising an oxide derivative compound and a health supplement composition for the prevention or improvement of a degenerative disease.

With the development of the medical industry and rapid economic growth, the quality of life is improving, and at the same time, various diseases and the elderly population are increasing. The life expectancy of humans has been extended, but the economic burden is increasing. One of them is senile dementia. More than 50% of them are Alzheimer's disease (Alzheimer type, AD) dementia. Alzheimer's disease (AD) is one of the irreversible and progressive cerebrovascular diseases. Age-related neurodegenerative disease accompanied by depression and gradual loss of cognitive abilities such as memory, speech, direction, and attention. to be. The exact cause of the invention of Alzheimer's disease (AD) has not been identified, and there is no cure for it. However, it is known that cholineacetyltransferase (ChAT), which indirectly synthesizes acetylcholine (ACh) in the brain of dementia patients, is reduced to 20-30%, and also acetylcholine (ACh), a neuron transporter. It was confirmed that the concentration decreased by 16~30%.

In order to fundamentally treat Alzheimer's disease (AD), it is necessary to develop a substance that can prevent or inhibit the removal of major lesions found in the brain of AD patients and impairment of cognitive learning function. Methods for replenishing the cholinergic nervous system at synaptic intervals to improve cognitive function include: a) enhancing the synthesis of acetylcholine, b) enhancing the release of acetylcholine, c) inhibiting the degradation of acetylcholine. And d) a method of directly stimulating an acetylcholine receptor.

However, the method of injecting choline directly to increase the concentration of choline, a precursor to Alzheimer's disease (AD) patients, did not have much effect.

As a result, studies using inhibitors that inhibit cholinesterase (ChE), an enzyme that hydrolyzes acetylcholine, which is a neurotransmitter, has been conducted as an indirect treatment method. Cholinesterase has two forms: acetylcholinesterase (AChE) and butylcholinesterase (BuChE).

AChE is a membrane-bound enzyme and is present in brain, muscle and cholinergic neurons. In the mammalian brain, the majority of AChE exists in the form of membrane-bound G4 and decreases as neurons degenerate. In cholinergic synapses, the neurotransmitter acetylcholine is hydrolyzed by AChE. BChE is expressed in neuroglia and is present in the intestine, liver, kidney, heart, lung and serum. BChE is known to play an important role in the metabolism of compounds with ester groups. Like AChE, this enzyme can hydrolyze acetylcholine, and in AD patients, the concentration of this enzyme does not decrease even when a reaction occurs, which can worsen AD.

Previously, the synthesis or development of acetylcholinesterase inhibitors has been the main focus, but in recent studies, it is known that butylcholinesterase is increased in the AD brain, which is drawing high interest in the development of therapeutic agents. Alzheimer's disease (AD) treatments currently used in each country are mostly acetylcholine-degrading enzyme (AChE) inhibitors, tacrine (trade name: cognex), and donepezil (trade name: Aricept). )) or Rivastigmine (trade name: exelon), more recently as Galanthamine (trade name: reminyl), and the cognitive function of Alzheimer's patients improved to some extent. These compounds still exhibit some undesirable side effects, such as tremors, dizziness, vomiting, hepatotoxicity and the like.

<Comparison of reported AD treatment IC _{50 values>}

Most studies so far have also focused on selective acetylcholinesterase (AChE) inhibitors. Although it has been overlooked for many years, butyrylcholinesterase (BuChE) can also hydrolyze acetylcholine (ACh), and its activity in patients with Alzheimer's disease remains higher than that of acetylcholine degrading enzyme. It will play an important role. However, until today, very few compounds with selective BuChE inhibitory activity have been reported, for example, etopropazine (10-(2-diethylaminopropyl) phenothiazine hydrochloride), dansylarginine N-(3-ethyl-1, 5-pentanediyl)amide (DAPA), phenethylnorsimserine and the compounds disclosed in WO1999-002154 or EP 1251131.

Therefore, it is necessary to synthesize a compound targeting butyrylcholinesterase (BuChE), which has few side effects caused by acetylcholinesterase (AChE) inhibitors and is highly active in the brain of Alzheimer's disease patients.

Meanwhile, DOPO of the following structure (9,10-Dihydro-9-oxa-10-phosphaphenanthrene 10-oxide or 6H-Dibenzo[c,E][1,2]oxaphosphinine 6-oxide) reacts with hydroquinone to form DOPO- Known as organophosphorus compounds added to flame retardants in the form of HQ.

In addition, U.S. Patent No. 4,228,064 demonstrates the usefulness of DOPO-based phosphonate and phosphinate as flame retardant additives for polyphenylene ether formulations, and European Patent No. 2,557,085 discloses the synthesis of DOPO-based phosphonamidate and Their use in polyurethane foams is described. US Patent No. 4,618,693 discloses a method of preparing a new cyclic organophosphorus compound by reacting DOPO and p-benzoquinone.

However, conventionally, only studies as flame retardants have been reported for dibenzooxaphosphinin oxide derivatives, and dibenzooxaphosphinin oxide derivative compounds in which various substituents have been introduced and their cholinesterase (ChE; cholinesterase) as inhibitors. No use has been reported yet.

U.S. Patent No. 4,228,064 European Patent No. 2,557,085 U.S. Patent No. 4,618,693

As a result of conducting research to develop a treatment for Alzheimer's disease, the present inventors showed that a novel dibenzooxaphosphinin oxide derivative compound in which various nitrogen-containing substituents were introduced at the 6th position of the DOPO parental nucleus inhibited cholinesterase activity. In addition, it was confirmed that there is an effect of selectively inhibiting butyl cholinesterase (BuChE) activity among cholinesterases, and the present invention was completed.

Accordingly, an object of the present invention is to provide a novel dibenzooxaphosphinin oxide derivative compound having cholinesterase (ChEs) inhibitory activity.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating degenerative diseases containing the dibenzooxaphosphinin oxide derivative compound as an active ingredient.

Another object of the present invention is to provide a dietary supplement for improving cognitive ability or improving degenerative diseases containing the dibenzooxaphosphinin oxide derivative compound as an active ingredient.

Another object of the present invention is to provide a composition for selective inhibitory activity of butyrylcholinesterase containing the dibenzooxaphosphinin oxide derivative compound as an active ingredient.

One aspect of the present invention provides a dibenzooxaphosphinin oxide derivative compound represented by the following Formula 1:

[Formula 1]

In Formula 1,

R is C6-C20 aryl or C3-C20 heteroaryl, and the aryl or heteroaryl of R is C1-C7 alkyl, halogen, C1-C7 alkoxy, haloC1-C7 alkyl, C6-C20 aryloxy, cyano and nitro It may be further substituted with one or more selected from the group consisting of;

또는

이고;L is

or

ego;

R ^a is hydrogen or C1-C7 alkyl;

a and b are each independently an integer of 1 to 5;

c is an integer from 0 to 2;

d is an integer from 0 to 4.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating degenerative diseases containing the dibenzooxaphosphinin oxide derivative compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Another aspect of the present invention provides a dietary supplement for improving cognitive ability or improving degenerative diseases containing the dibenzooxaphosphinin oxide derivative compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Another aspect of the present invention provides a composition for selective inhibitory activity of butyrylcholinesterase containing the dibenzooxaphosphinin oxide derivative compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. .

The dibenzooxaphosphinin oxide derivative compound of the present invention is a compound having a novel structure in which various nitrogen-containing substituents are introduced at the 6th position of DOPO.

The dibenzooxaphosphinin oxide derivative compound of the present invention is harmless to the human body and inhibits the activity of cholinesterase, so that it can be used for the prevention and treatment of degenerative diseases, specifically, cranial nerve diseases such as Parkinson's disease and Alzheimer's disease, It can be used as a health supplement that improves degenerative diseases or improves learning ability and memory.

In particular, the dibenzooxaphosphinin oxide derivative compound of the present invention selectively inhibits only BuChE, which has recently been of great interest among the cholinesterase forms, due to its high activity in the brain of Alzheimer's disease patients as well as having few side effects caused by AChE inhibitors. At the same time, since it has a very strong inhibitory activity, it can be used as an active ingredient in a pharmaceutical composition for preventing and treating degenerative diseases and a health supplement for improving cognitive ability or improving degenerative diseases.

Hereinafter, the present invention will be described in more detail. If there are no other definitions in the technical and scientific terms used at this time, they have the meanings commonly understood by those of ordinary skill in the technical field to which this invention belongs, and the following description will unnecessarily obscure the subject matter of the present invention. Description of possible known functions and configurations will be omitted.

Unless otherwise defined, all terms (including technical and scientific terms) used in the present specification may be used with meanings that can be commonly understood by those of ordinary skill in the art to which the present invention belongs. When a part of the specification "includes" a certain component, it means that other components may be further included rather than excluding other components unless specifically stated to the contrary. Also, the singular form includes the plural form unless specifically stated in the text.

The terms "substituent", "radical", "group", "moiety", and "fragment" can be used interchangeably.

The term "C _A -C _B " means "the number of carbons is greater than or equal to A and less than or equal to B", and the terms "A to B" mean "more than A and less than B".

The term "alkyl" refers to a monovalent straight chain or branched saturated hydrocarbon radical composed of only carbon and hydrogen atoms, and may have 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. Examples of such alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.

도 아릴에 포함된다. 구체적인 예로 페닐, 나프틸, 비페닐, 안트릴, 인데닐, 플루오레닐,

등을 포함하지만, 이에 한정되지는 않는다.The term "aryl" is an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen, and includes a single or fused ring system containing 4 to 7, preferably 5 or 6 ring atoms suitably in each ring. In this case, the fused ring may be aromatic or non-aromatic. In addition, aryl includes up to a form in which a plurality of aryls are connected by a single bond. Of the present invention

Also included in aryl. Specific examples of phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl,

And the like, but is not limited thereto.

The term “heteroaryl” refers to an aryl group in which 1 to 4 heteroatoms are selected from N, O and S as an aromatic ring skeleton atom, and the remaining aromatic ring skeleton atoms are carbon, and 5 to 6 membered monocyclic heteroaryl , And polycyclic heteroaryl condensed with one or more benzene rings, and may be partially saturated. In addition, heteroaryl in the present specification includes a form in which one or more heteroaryls are linked by a single bond. Examples of the heteroaryl group include pyrrole, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, benzoimidazole, isoxazole, benzoisooxazole, thiophene, Benzothiophene, furan, benzofuran, and the like, but are not limited thereto.

The term “halo” or “halogen” denotes a halogen element and includes, for example, fluoro, chloro, bromo and iodo.

The term "alkoxy" is an -O-alkyl radical and may have 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. Here,'alkyl' is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and the like.

The term “haloalkyl” refers to an alkyl radical substituted with at least one halogen, wherein “alkyl” is as defined above. Examples of such haloalkyl radicals include, but are not limited to, fluoromethyl, trifluoromethyl, bromomethyl, perfluoroethyl, and the like.

The term "aryloxy" refers to an -O-aryl radical, wherein'aryl' is as defined above. Examples of such aryloxy radicals include, but are not limited to, phenoxy, naphthoxy, and the like.

The term "cyano" means -CN, and "nitro" means -NO ₂ .

The term "pharmaceutically acceptable salt" is any concentration of a compound of the present invention that is relatively non-toxic to the patient and has a harmless effective effect, and side effects due to this salt do not impair the beneficial efficacy of the compound of the present invention itself. It means any organic or inorganic addition salt.

The term “prevention” refers to any action that inhibits or delays the occurrence, spread, and recurrence of a degenerative disease by administration of the composition of the present invention.

The term “improvement” refers to any action that at least reduces the severity of a parameter, such as a symptom, associated with the condition being treated by administration of the composition of the present invention.

The term "treatment" refers to any action in which symptoms of a degenerative disease are improved or beneficially altered by administration of the composition of the present invention.

The term “pharmaceutically acceptable” refers to a property that is not toxic to cells or individuals exposed to the composition, such as humans, and means suitable for use as a pharmaceutical preparation, and is generally regarded as safe for such use. And, for such use, it is officially approved by the national administrative agency or listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

The term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not cause side effects, and the effective dose level is the sex, age, weight, and weight of the patient. Health status, type of disease, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration, and rate of excretion, duration of treatment, factors including drugs used in combination or simultaneously, and other well-known in the medical field. Depending on the factor, it can be readily determined by a person skilled in the art.

The term "food" means meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes , Health functional foods, health foods, etc., and all foods in the usual sense are included.

The term "health functional food" refers to a food manufactured and processed using raw materials or ingredients that have functions useful for the human body pursuant to the Health Functional Food Act No.6727, and the term "functional" refers to the structure and function of the human body. It refers to ingestion for the purpose of obtaining useful effects for health purposes such as controlling nutrients or physiological effects.

The dibenzooxaphosphinin oxide derivative compound according to the present invention is a compound of a novel structure in which various nitrogen-containing substituents are introduced at the 6th position of the DOPO parental nucleus, and has inhibitory activity against (ChE; cholinesterase) to prevent degenerative diseases or It is useful as an active ingredient of a therapeutic pharmaceutical composition, and can also be used as an active ingredient of a health supplement that improves degenerative diseases or improves learning ability and memory.

One aspect of the present invention provides a dibenzooxaphosphinin oxide derivative compound represented by the following Formula 1:

[Formula 1]

In Formula 1,

R is C6-C20 aryl or C3-C20 heteroaryl, and the aryl or heteroaryl of R is C1-C7 alkyl, halogen, C1-C7 alkoxy, haloC1-C7 alkyl, C6-C20 aryloxy, cyano and nitro It may be further substituted with one or more selected from the group consisting of;

또는

이고;L is

or

ego;

R ^a is hydrogen or C1-C7 alkyl;

a and b are each independently an integer of 1 to 5;

c is an integer from 0 to 2;

d is an integer from 0 to 4.

이고; R^a는 수소 또는 C1-C7알킬이고; b는 1 내지 3의 정수일 수 있다.In one embodiment, L is

ego; R ^a is hydrogen or C1-C7 alkyl; b may be an integer of 1 to 3.

이고; c는 0 또는 1의 정수이고; d는 1 내지 3의 정수일 수 있다.In one embodiment, L is

ego; c is an integer of 0 or 1; d may be an integer of 1 to 3.

Specifically, c is an integer of 0, and d may be an integer of 1 to 3.

Specifically, c is an integer of 1, and d may be an integer of 1 to 3.

In one embodiment, the dibenzooxaphosphinin oxide derivative compound may be represented by Formula 2 below.

[Formula 2]

In Formula 2, R and R ^a are the same as defined in Formula 1.

Specifically, R is C6-C12 aryl, and the aryl of R may be further substituted with one or more selected from the group consisting of C1-C4 alkyl, halogen, C1-C4 alkoxy, halo C1-C4 alkyl, and cyano, and ; R ^a may be hydrogen or C1-C4 alkyl.

,

또는

이고; R' 및 R''는 각각 독립적으로 C1-C4알킬, 할로겐, C1-C4알콕시, 할로C1-C4알킬 또는 시아노이고; x는 0 내지 5의 정수이고; y는 0 내지 7의 정수이고; z는 0 내지 4의 정수일 수 있다. More specifically, R is

,

or

ego; R'and R'' are each independently C1-C4 alkyl, halogen, C1-C4 alkoxy, haloC1-C4 alkyl or cyano; x is an integer from 0 to 5; y is an integer from 0 to 7; z may be an integer from 0 to 4.

이고; R'은 C1-C4알킬, 할로겐, C1-C4알콕시, 할로C1-C4알킬 또는 시아노이고; x는 0 내지 3의 정수일 수 있다.More preferably, R is

ego; R'is C1-C4 alkyl, halogen, C1-C4 alkoxy, haloC1-C4 alkyl or cyano; x may be an integer of 0 to 3.

In one embodiment, the dibenzooxaphosphinin oxide derivative compound may be represented by Formula 3 below.

[Formula 3]

In Chemical Formula 3, R is the same as defined in Chemical Formula 1.

Specifically, R is C6-C12 aryl, and the aryl of R may be further substituted with one or more selected from the group consisting of C1-C4 alkyl, halogen, C1-C4 alkoxy, halo C1-C4 alkyl, and cyano. .

,

,

또는

이고; R' 및 R''는 각각 독립적으로 C1-C4알킬, 할로겐, C1-C4알콕시, 할로C1-C4알킬 또는 시아노이고; x는 0 내지 5의 정수이고; y는 0 내지 7의 정수이고; z는 0 내지 4의 정수일 수 있다. More specifically, R is

,

,

or

ego; R'and R'' are each independently C1-C4 alkyl, halogen, C1-C4 alkoxy, haloC1-C4 alkyl or cyano; x is an integer from 0 to 5; y is an integer from 0 to 7; z may be an integer from 0 to 4.

또는

이고; R'은 C1-C4알킬, C1-C4알콕시, 할로C1-C4알킬 또는 시아노이고; x는 0 내지 3의 정수일 수 있다.More preferably, R is

or

ego; R'is C1-C4 alkyl, C1-C4 alkoxy, haloC1-C4 alkyl or cyano; x may be an integer of 0 to 3.

The dibenzooxaphosphinin oxide derivative compound according to an embodiment has excellent inhibitory activity properties against butyrylcholinesterase (BuChE) selectively among cholinesterase (ChE) forms.

In one embodiment, the dibenzooxaphosphinin oxide derivative compound may be selected from the following structures, but is not limited thereto.

The dibenzooxaphosphinin oxide derivative compounds according to the present invention may be prepared by various methods based on known methods and/or techniques in the field of organic synthesis, as will be described later, and the following preparation methods It is only a few examples, and of course, other methods may exist.

Dibenzooxaphosphinin oxide derivative compounds according to an embodiment, as shown in Scheme 1, propagate the 6 position of DOPO and then click-react with various azide compounds, or change the 6 position of DOPO. It can be prepared by reacting with an amine compound:

[Scheme 1]

In Reaction Scheme 1, Hal is halogen, and the rest are the same as defined in Formula 1.

In some cases, the reaction product may be separated and purified using a conventional method, for example, recrystallization and chromatography.

The dibenzooxaphosphinin oxide derivative compound according to an embodiment can be used in the form of prodrugs, hydrates, solvates, and pharmaceutically acceptable salts to enhance absorption or solubility in vivo. Prodrugs, hydrates, solvates and pharmaceutically acceptable salts are also within the scope of the present invention. In the case of salts and solvates, the additional ionic and solvent moieties should also be non-toxic. The dibenzooxaphosphinin oxide compound of the present invention may exist in different heterogeneous forms, and the present invention is intended to include all forms as described above.

The dibenzooxaphosphinin oxide derivative compound, a salt thereof, a solvate or prodrug thereof according to an embodiment exhibits excellent cholinesterase inhibitory action.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating degenerative diseases containing the dibenzooxaphosphinin oxide derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment, the degenerative disease specifically includes a cranial nerve disease such as Parkinson's disease and Alzheimer's disease.

The pharmaceutically acceptable salt can be prepared by a conventional method in the art, for example, a salt with an inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and formic acid. , Acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gastisic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin). Salts with organic acids, salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine and proline, methanesulfonic acid, ethanesulfonic acid, benzenesulfur And salts with sulfonic acids such as phonic acid and toluenesulfonic acid, metal salts obtained by reaction with alkali metals such as sodium and potassium, or salts with ammonium ions.

The pharmaceutical composition according to an embodiment is in the pharmaceutical field by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant, and excipient to the dibenzooxaphosphinin oxide derivative compound or a pharmaceutically acceptable salt thereof. Conventional preparations such as tablets, capsules, troches, solutions, suspensions, etc. can be prepared for oral administration or parenteral administration, and used for the treatment of the degenerative diseases.

Excipients that can be used in the pharmaceutical composition may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, rubber tragacanth, alginic acid, sodium Alginate, methylcellulose, sodium carboxylmethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like. The proportions and properties of these excipients can be determined by the solubility and chemical properties of the tablets chosen, the route of administration chosen and standard pharmaceutical practice.

The dosage of the dibenzooxaphosphinin oxide derivative compound according to an embodiment to the human body may be in a total daily dosage range of 0.01 to 1000 mg/kg/day, but this is the patient's age, weight, and sex. , It may vary depending on the dosage form, health condition, and degree of disease, and may be dividedly administered once a day or several times a day at predetermined time intervals according to the judgment of a doctor or pharmacist.

Another aspect of the present invention provides a dietary supplement for improving cognitive ability or improving Alzheimer's disease or degenerative diseases containing the dibenzooxaphosphinin oxide derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The health functional food composition may be provided in the form of powder, granule, tablet, capsule, syrup, or beverage, and the health functional food is an active ingredient, in addition to the dibenzooxaphosphinin oxide derivative compound, along with other foods or food additives. Used, and can be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined according to the purpose of use, for example, prevention, health or therapeutic treatment.

The health functional food composition includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof. , Organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like. In addition, it may contain flesh for the manufacture of natural fruit juice and fruit juice beverages and vegetable beverages. These components may be used independently or in combination.

In addition, the above health functional food may additionally contain food additives, and the suitability as a'food additive' shall be determined according to the General Regulations of the Food Additive Code approved by the Food and Drug Administration and general test methods, etc. It is judged according to the standards and standards.

Items listed in the'Food Additives Code', for example, chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as red pigment, licorice extract, crystalline cellulose, guar gum, and sodium L-glutamate. Mixed preparations, such as a preparation, an alkali additive for noodles, a preservative preparation, and a tar color preparation, are mentioned.

There is no particular limitation on the type of the food. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, There are alcoholic beverages and vitamin complexes, and all health foods in the usual sense are included.

Another aspect of the present invention provides a composition for selective inhibitory activity of butyrylcholinesterase containing the dibenzooxaphosphinin oxide derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.

Hereinafter, the present invention will be described in detail through examples and experimental examples. However, this is presented as an example of the present invention, and the scope of the present invention is not limited thereto in any sense, and the scope of the present invention is only defined according to the claims to be described later.

[Preparation Example 1] Preparation of 1-(azidomethyl)benzene (Compound B-1)

Benzyl Bromide (0.14 mL, 1.17 mmol) was dissolved in Dimethyl sulfoxide (DMSO, 10 mL). NaN ₃ (114mg, 1.76mmol) was added in subdivided portions and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the resulting filtrate was concentrated under reduced pressure to obtain a colorless liquid compound B-1 (150 mg, 96%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 4.30 (s, 2H), 7.28-7.38 (m, 5H)

[Preparation Example 2] Preparation of 1-(azidomethyl)-2-chlorobenzene (Compound B-2)

2-Chlorobenzyl bromide (0.13 mL, 0.97 mmol) was dissolved in DMSO (10 mL). NaN ₃ (64mg, 1.46mmol) was added in subdivided portions and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the resulting filtrate was concentrated under reduced pressure to obtain a colorless liquid compound B-2 (150 mg, 92%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 4.47 (s, 2H), 7.26-7.28 (m, 2H), 7.36-7.41 (m, 2H)

[Preparation Example 3] Preparation of 1-(azidomethyl)-3-chlorobenzene (Compound B-3)

3-Chlorobenzyl chloride (0.16 mL, 1.24 mmol) was dissolved in DMSO (10 mL). NaN ₃ (120mg, 1.86 mmol) was added in small portions and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the resulting filtrate was concentrated under reduced pressure to obtain a colorless liquid compound B-3 (180 mg, 87%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 4.30 (s, 2H), 7.16-7.19 (m, 1H), 7.29-7.30 (m, 3H)

[Preparation Example 4] Preparation of 1-(azidomethyl)-4-chlorobenzene (Compound B-4)

4-Chlorobenzyl bromide (0.16 mL, 0.97 mmol) was dissolved in DMSO (10 mL). NaN ₃ (95mg, 1.46mmol) was added in subdivided portions and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dried with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure to obtain a yellow liquid compound B-4 (150 mg, 92%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 4.30 (s, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H)

[Preparation Example 5] Preparation of 1-(azidomethyl)-4-methoxybenzene (Compound B-5)

4-Methoxybenzyl bromide (0.14 mL, 0.99 mmol) was dissolved in DMSO (10 mL). NaN ₃ (97 mg, 1.49 mmol) was added in subdivided portions and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the resulting filtrate was concentrated under reduced pressure to obtain a colorless liquid compound B-5 (150 mg, 92%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 3.78 (s, 3H), 4.23 (s, 2H), 6.99 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H)

[Preparation Example 6] Preparation of 1-(azidomethyl)-3-methoxybenzene (Compound B-6)

3-Methoxybenzyl bromide (0.19 mL, 1.27 mmol) was dissolved in DMSO (10 mL). NaN ₃ (124 mg, 1.91 mmol) was added in small portions and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the resulting filtrate was concentrated under reduced pressure to obtain a colorless liquid compound B-6 (150 mg, 92%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 3.80 (s, 3H), 4.29 (s, 2H), 6.85-6.89 (m, 3H), 7.28 (t, J = 8.0 Hz, 1H)

[Preparation Example 7] Preparation of 1-(azidomethyl)-2-methylbenzene (Compound B-7)

2-methylbenzyl bromide (0.14 mL, 1.08 mmol) was dissolved in DMSO (10 mL). NaN ₃ (105 mg, 1.62 mmol) was added in small portions, and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the resulting filtrate was concentrated under reduced pressure to obtain a yellow liquid compound B-7 (132 mg, 83%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.34 (s, 3H), 4.32 (s, 2H), 7.17-7.25 (m, 4H)

[Preparation Example 8] Preparation of 1-(azidomethyl)-3-methylbenzene (Compound B-8)

3-methylbenzyl bromide (0.15 mL, 1.08 mmol) was dissolved in DMSO (10 mL). NaN ₃ (105 mg, 1.62 mmol) was added in subdivided portions and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the resulting filtrate was concentrated under reduced pressure to obtain a colorless liquid compound B-8 (150 mg, 94%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.36 (s, 3H), 4.28 (s, 2H), 7.09-7.15 (m, 3H), 7.26 (t, J = 7.6 Hz, 1H)

[Preparation Example 9] Preparation of 1-(azidomethyl)-4-methylbenzene (Compound B-9)

4-methylbenzyl bromide (0.15 mL, 1.08 mmol) was dissolved in DMSO (10 mL). NaN ₃ (105 mg, 1.62 mmol) was added in subdivided portions and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the resulting filtrate was concentrated under reduced pressure to obtain a yellow liquid compound B-9 (150 mg, 94%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 2.33 (s, 3H), 4.24 (s, 2H), 7.14-7.19 (m, 4H)

[Preparation Example 10] Preparation of 2-(azidomethyl)benzonitrile (Compound B-10)

2-(bromomethyl)benzonitrile bromide (0.2 g, 1.02 mmol) was dissolved in DMSO (10 mL). NaN ₃ (100 mg, 1.53 mmol) was added in small portions and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the resulting filtrate was concentrated under reduced pressure to obtain a clear liquid compound B-10 (130 mg, 81%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 4.61 (s, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 7.6 Hz , 1H), 7.70 (d, J = 8.0 Hz, 1H)

[Production Example 11] Preparation of 3-(azidomethyl)benzonitrile (Compound B-11)

3-(bromomethyl)benzonitrile bromide (0.2 g, 1.02 mmol) was dissolved in DMSO (10 mL). NaN ₃ (100 mg, 1.53 mmol) was added in small portions and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the resulting filtrate was concentrated under reduced pressure to obtain a clear liquid compound B-11 (150 mg, 93%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 4.43 (s, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.61-7.63 (m, 2H)

[Production Example 12] Preparation of 4-(azidomethyl)benzonitrile (Compound B-12)

4-(bromomethyl)benzonitrile chloride (0.2 g, 1.31 mmol) was dissolved in DMSO (10 mL). NaN ₃ (128 mg, 1.97 mmol) was added in small portions and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the resulting filtrate was concentrated under reduced pressure to obtain a clear liquid compound B-12 (200 mg, 96%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 4.46 (s, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H)

[Production Example 13] Preparation of 1-(azidomethyl)-2-(trifluoromethyl)benzene (Compound B-13)

2-(Trifluoromethyl)benzyl bromide (0.13 mL, 0.84 mmol) was dissolved in DMSO (10 mL). NaN ₃ (82 mg, 1.26 mmol) was added in small portions and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dried with anhydrous MgSO ₄ , filtered under reduced pressure, and the resulting filtrate was concentrated under reduced pressure to obtain a clear liquid compound B-13 (130 mg, 77%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 4.55 (s, 2H), 7.43 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0 Hz , 1H), 7.67 (d, J = 8.0 Hz, 1H)

[Preparation Example 14] Preparation of 1-(azidomethyl)-3-(trifluoromethyl)benzene (Compound B-14)

3-(Trifluoromethyl)benzyl bromide (0.13 mL, 0.84 mmol) was dissolved in DMSO (10 mL). NaN ₃ (82 mg, 1.26 mmol) was added in small portions and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dried over anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure to obtain a clear liquid compound B-14 (150 mg, 89%).

¹ H NMR (CDCl ₃ , 400 MHz) δ 4.42 (s, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.58-7.60 (m, 2H)

[Production Example 15] Preparation of 1-(azidomethyl)-4-(trifluoromethyl)benzene (Compound B-15)

4-(Trifluoromethyl)benzyl chloride (0.15 mL, 1.03 mmol) was dissolved in DMSO (10 mL). NaN ₃ (100 mg, 1.55 mmol) was added in subdivided portions and then stirred at room temperature for 24 hours. After the reaction was terminated with H ₂ O, the organic layer was extracted with Ether. The extracted organic layer was dehydrated with anhydrous MgSO ₄ , filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure to obtain a clear liquid compound B-15 (150 mg, 73%).

¹ H NMR (CDCl ₃ , 400MHz) δ 4.40 (s, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H)

[Example 1] 6-(((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amino)-6H-dibenzo[c,e][1,2]oxaphosphinine 6-oxide (compound 1 ) of the manufacture

(1) Preparation of 6-(ethynylamino)-6H-dibenzo[c,e][1,2]oxaphosphinine 6-oxide (Compound A-1)

DOPO (2 g, 9.25 mmol) was dissolved in Dichloromethane (DCM, 10 mL), and then SO ₂ Cl _{2 at 0℃} (0.75 mL, 9.25 mmol) was added dropwise. Then, it was heated to reflux at 80° C. for 3 hours. After cooling to room temperature, Toluene (0.1 mL) was added dropwise, stirred for 10 minutes, concentrated under reduced pressure to remove the solvent, and DCM (10 mL) was added. Triethylamine (TEA, 1.39 mL, 10 mmol) was added dropwise at 0°C, and Propargyl amine (0.97 mL, 10 mmol) was added dropwise, followed by stirring at room temperature for a day. After terminating the reaction with H ₂ O, the organic layer was extracted with DCM. The extracted organic layer was _{filtered under reduced pressure after removing moisture with anhydrous MgSO 4} , and the resulting filtrate was concentrated under reduced pressure and dissolved in a small amount of DCM. After that, hexane (HEX) was added and recrystallized to obtain a white solid compound A-1 (1.5 g, 60% yield).

(2) 6-(((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amino)-6H-dibenzo[c,e][1,2]oxaphosphinine 6-oxide (compound 1) the manufacture of

After dissolving compound A-1 (0.10 g, 0.37 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.04 g, 0.004 mmol) and compound B-1 (0.05 g, 0.4 mmol) were added and microwaved It was reacted with (Microwave) (reaction conditions: 90° C., 4 hours). After concentration under reduced pressure, it was separated by silica gel column chromatography (DCM: MeOH = 40: 1 (v: v)) to obtain Compound 1 as a white solid (80 mg, 52% yield).

Melting point (°C) 45°C; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.08 (d, J = 6.8 Hz, 1H), 4.11 (d, J = 7.2 Hz, 1H), 5.58 (s, 2H), 6.22 (m, 1H) , 7.15 (d, J = 8.0 Hz, 1H), 7.27-7.43 (m, 7H), 7.49 (td, J = 3.2, 7.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.76 ( d, J = 7.2 Hz, 1H), 7.96 (s, 1H), 8.15-8.19 (m, 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 36.29, 53.23, 120.57 (d, J = 6.0 Hz), 122.45 (d, J = 11.0 Hz), 123.38, 124.53 (d, J = 10.0 Hz), 124.75 , 125.91 (d, J = 161.0 Hz), 125.90, 128.48 (2C), 128.60, 128.76 (d, J = 14.0 Hz), 129.22 (2C), 130.04 (d, J = 9.0 Hz), 130.83, 133.24, 136.45 (d, J = 7.0 Hz), 136.61, 149.89 (d, J = 7.0 Hz); ESI-MS: m/z [M+H] ⁺ 403.11 (calcd. 402.12).

[Example 2] 6-(((1-(2-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-6H-dibenzo[c,e][1,2] oxaphosphinine 6-oxide (compound 2 ) of the manufacture

After dissolving compound A-1 (0.15 g, 0.56 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.1 g, 0.11 mmol) and compound B-2 (0.11 g, 0.67 mmol) were added and microwaved It was reacted with (Microwave) (reaction conditions: 90°C, 4 hours). After concentration under reduced pressure, silica gel column chromatography (DCM: MeOH = 49: 1 (v: v)) was used to separate compound 2 (60 mg, 25% yield) as a white solid.

Melting point(℃) 56℃; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.09 (d, J = 6.8 Hz, 1H), 4.13 (d, J, 7.2 Hz, 1H), 5.72 (s, 2H), 6.27 (m, 1H) , 7.18 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.52 (td, J = 2.8, 7.6 Hz, 1H), 7.73-7.79 (m, 2H), 7.88 (d, J = 8.4 Hz, 2H), 8.05 (s, 1H), 8.16-8.21 (m, 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 36.27, 51.01, 120.56 (d, J = 6.0 Hz), 122.45 (d, J = 12.0 Hz), 123.62, 124.54 (d, J = 11.0 Hz), 124.76 , 125.91 (d, J = 162.0 Hz), 125.92, 128.21, 128.76 (d, J = 14.0 Hz), 130.05 (d, J = 10.0 Hz), 130.75, 130.85, 131.03, 133.14, 133.23, 133.25, 133.83, 136.46 (d, J = 7.0 Hz), 149.89 (d, J = 7.0 Hz); ESI-MS: m/z [M+H] ⁺ 437.44 (calcd. 436.09).

[Example 3] 6-(((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-6H-dibenzo[c,e][1,2] oxaphosphinine 6-oxide (compound 3 ) of the manufacture

After dissolving compound A-1 (0.3 g, 1.11 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.2 g, 0.22 mmol) and compound B-3 (0.2 g, 1.2 mmol) were added and microwaved It was reacted with (Microwave) (reaction conditions: 90°C, 4 hours). After concentration under reduced pressure, it was separated by silica gel column chromatography (DCM: MeOH = 49: 1 (v: v)) to obtain a white solid compound 3 (260 mg, 54% yield).

Melting point(℃) 58℃; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.09 (d, J = 6.8 Hz, 1H), 4.12 (d, J = 6.8 Hz, 1H), 5.61 (s, 2H), 6.26 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.28-7.31 (m, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 3.2 Hz, 3H), 7.50 (td, J = 3.2, 7.2 Hz, 1H), 7.72-7.78 (m, 2H), 8.03 (s, 1H), 8.15-8.20 (m, 2H) ; ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 36.28, 52.44, 120.55 (d, J = 6.0 Hz), 122.45 (d, J = 11.0 Hz), 123.51, 124.54 (d, J = 10.0 Hz), 124.75 , 125.90 (d, J = 162.0 Hz), 125.91, 127.24, 127.73, 128.38, 128.61, 128.74 (d, J = 15.0 Hz), 130.09 (d, J = 10.0 Hz), 130.82, 131.17, 133.22, 133.24, 133.77 , 139.02, 149.89 (d, J = 7.0 Hz); ESI-MS: m/z [M+H] ⁺ 437.44 (calcd. 436.09).

[Example 4] 6-(((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-6H-dibenzo[c,e][1,2] oxaphosphinine 6-oxide (compound 4 ) of the manufacture

After dissolving compound A-1 (0.15 g, 0.56 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.1 g, 0.11 mmol) and compound B-4 (0.1 g, 0.67 mmol) were added and microwaved It was reacted with (Microwave) (reaction conditions: 90° C., 4 hours). After concentration under reduced pressure, silica gel column chromatography (DCM: MeOH = 49: 1 (v: v)) was used to separate compound 4 (134 mg, 55% yield) as a white solid.

Melting point(℃) 167℃; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.08 (d, J = 6.8 Hz, 1H), 4.11 (d, J = 6.8 Hz, 1H), 5.59 (s, 2H), 6.27 (m, 1H) , 7.15 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.50 (td, J = 2.8, 7.2 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.97 (s, 1H), 8.15-8.19 (m, 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 36.29, 52.42, 120.56 (d, J = 6.0 Hz), 122.46 (d, J = 12.0 Hz), 123.43, 124.53 (d, J = 11.0 Hz), 124.75 , 125.90 (d, J = 162.0 Hz), 125.91, 128.76 (d, J = 14.0 Hz), 129.22 (2C), 130.05 (d, J = 10.0 Hz), 130.45 (2C), 130.82, 133.22, 133.24, 133.36 , 135.62, 136.46 (d, J = 7.0 Hz), 149.88 (d, J = 7.0 Hz); ESI-MS: m/z [M+H] ⁺ 437.44 (calcd. 436.09).

[Example 5] 6-(((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-6H-dibenzo[c,e][1,2] oxaphosphinine 6-oxide (compound 5 ) of the manufacture

After dissolving compound A-1 (0.20 g, 0.74 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.07 g, 0.074 mmol) and compound B-5 (0.13 g, 0.82 mmol) were added and microwaved It was reacted with (Microwave) (reaction conditions: 90° C., 4 hours). After concentration under reduced pressure, silica gel column chromatography (DCM: MeOH = 40: 1 (v: v)) was used to separate compound 5 (240 mg, 74.7% yield) as a brown solid.

Melting point(℃) 129℃; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.76 (s, 3H), 4.07 (d, J = 6.8 Hz, 1H), 4.10 (d, J = 6.8 Hz, 1H) 5.50 (s, 2H), 6.21 (m, 1H), 6.95 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.28-7.32 (m, 3H), 7.41 (t, J = 7.6 Hz, 1H ), 7.50 (td, J = 2.8, 7.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 6.4 Hz, 1H), 7.90 (s, 1H), 8.15-8.20 (m, 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 36.31, 52.80, 55.65, 114.60 (2C), 120.57 (d, J = 6.0 Hz), 122.45 (d, J = 11.0 Hz), 123.10, 124.53 (d, J = 10.0 Hz), 124.75, 125.90, 125.91 (d, J = 161.0 Hz), 128.49, 128.77 (d, J = 14.0 Hz), 130.05 (d, J = 10.0 Hz), 130.17 (2C), 130.81, 133.22 , 133.23, 136.45 (d, J = 7.0 Hz), 149.88 (d, J = 7.0 Hz), 159.65; ESI-MS: m/z [M+H] ⁺ 433.2 (calcd. 432.14).

[Example 6] 6-(((1-(3-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-6H-dibenzo[c,e][1,2] oxaphosphinine 6-oxide (compound 6 ) of the manufacture

After dissolving compound A-1 (0.20 g, 0.74 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.07 g, 0.074 mmol) and compound B-6 (0.13 g, 0.82 mmol) were added and microwaved It was reacted with (Microwave) (reaction conditions: 90° C., 4 hours). After concentration under reduced pressure, silica gel column chromatography (DCM: MeOH = 40: 1 (v: v)) was used to separate compound 6 (260 mg, 81% yield) as a brown solid.

Melting point(℃) 50℃; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.75 (s, 3H), 4.09 (d, J = 7.2 Hz, 1H), 4.13 (d, J = 7.2 Hz, 1H) 5.55 (s, 2H), 6.24 (m, 1H), 6.89 (d, J = 7.6 Hz, 1H), 6.93 (t, J = 2.4 Hz, 2H), 7.16 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 6.8 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H) 7.42 (t, J = 8.0 Hz, 1H), 7.51 (td J = 2.8, 7.6 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H) 7.98 (s, 1H), 8.16-8.21 (m, 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 36.30, 53.16, 55.61, 113.86, 114.37, 120.56 (d, J = 6.0 Hz), 120.58, 122.46 (d, J = 12.0 Hz), 123.57, 124.53 (d) , J = 10.0 Hz), 124.75, 125.90, 125.92 (d, J = 161.0 Hz), 128.75, 130.04 (d, J = 10.0 Hz), 130.38, 130.82, 133.21, 133.23, 136.45 (d, J = 7.0 Hz) , 138.04, 149.89 (d, J = 7.0 Hz), 159.94; ESI-MS: m/z [M+H] ⁺ 433.2 (calcd. 432.14).

[Example 7] 6-(((1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-6H-dibenzo[c,e][1,2] oxaphosphinine 6-oxide (compound 7 ) of the manufacture

After dissolving compound A-1 (0.10 g, 0.37 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.04 g, 0.004 mmol) and compound B-7 (0.06 g, 0.4 mmol) were added and microwaved It was reacted with (Microwave) (reaction conditions: 90° C., 4 hours). After concentration under reduced pressure, silica gel column chromatography (DCM: MeOH = 40: 1 (v: v)) was used to separate compound 7 (80 mg, 52% yield) as a white solid.

Melting point(℃) 59℃; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.32 (s, 3H) 4.09 (d, J = 7.2 Hz, 1H), 4.12 (d, J = 7.2 Hz, 1H) 5.60 (s, 2H), 6.23 (m, 1H), 7.13-7.15 (m, 2H), 7.22 (td, J = 2.4, 7.6 Hz, 1H), 7.26 (t, J = 2.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.51 (td, J = 2.8, 7.6 Hz, 1H), 7.72-7.77 (m, 2H), 7.84 (s, 1H), 8.15-8.22 (m , 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 21.43, 36.30, 53.25, 120.56 (d, J = 6.0 Hz), 122.46 (d, J = 11.0 Hz), 123.32 124.53 (d, J = 11.0 Hz), 124.75, 125.64, 125.91, 125.92 (d, J = 162.0 Hz), 128.75 (d, J = 14.0 Hz), 129.10, 129.15, 129.24, 130.04 (d, J = 10.0 Hz), 130.82, 133.22, 133.24, 136.45 ( d, J = 7.0 Hz), 136.48, 138.45, 149.89 (d, J = 7.0 Hz); ESI-MS: m/z [M+H] ⁺ 417.08 (calcd. 416.14).

[Example 8] 6-(((1-(3-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-6H-dibenzo[c,e][1,2] oxaphosphinine 6-oxide (compound 8 ) of the manufacture

After dissolving compound A-1 (0.10 g, 0.37 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.04 g, 0.004 mmol) and compound B-8 (0.06 g, 0.4 mmol) were added and microwaved It was reacted with (Microwave) (reaction conditions: 90° C., 4 hours). After concentration under reduced pressure, silica gel column chromatography (DCM: MeOH = 40: 1 (v: v)) was used to separate compound 8 (80 mg, 52% yield) as a white solid.

Melting point(℃) 60.3℃; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.29 (s, 3H) 4.08 (d, J = 7.2 Hz, 1H), 4.11 (d, J = 7.2 Hz, 1H) 5.53 (s, 2H), 6.24 (m, 1H), 7.11-7.16 (m, 4H), 7.27 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 6.8 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H) , 7.50 (td, J = 2.8, 7.6 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 7.6Hz 1H), 7.96 (s, 1H), 8.15-8.20 (m , 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 19.13, 36.29, 51.42, 120.54 (d, J = 5.0 Hz), 122.44 (d, J = 11.0 Hz), 123.28 124.53 (d, J = 11.0 Hz), 124.75, 125.91 (d, J = 163.0 Hz), 125.91 126.73, 128.68, 128.83, 129.30, 130.02 (d, J = 9.0 Hz), 130.84, 130.92, 133.23, 133.25, 134.64, 136.45 (d, J = 7.0 Hz) , 136.87, 149.88 (d, J = 7.0 Hz); ESI-MS: m/z [M+H] ⁺ 417.08 (calcd. 416.14).

[Example 9] 6-(((1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-6H-dibenzo[c,e][1,2] oxaphosphinine 6-oxide (compound 9 ) of the manufacture

After dissolving compound A-1 (0.10 g, 0.37 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.04 g, 0.004 mmol) and compound B-9 (0.06 g, 0.4 mmol) were added and microwaved It was reacted with (Microwave) (reaction conditions: 90° C., 4 hours). After concentration under reduced pressure, silica gel column chromatography (DCM: MeOH = 40: 1 (v: v)) was used to separate compound 9 (80 mg, 52% yield) as a white solid.

Melting point(℃) 72.3℃; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.29 (s, 3H) 4.07 (d, J = 6.8 Hz, 1H), 4.10 (d, J = 6.8 Hz, 1H), 5.52 (s, 2H), 6.19 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.18-7.24 (m, 4H), 7.29 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H ), 7.50 (td, J = 2.8, 7.6 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 8.14-8.19 (m, 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 21.19, 36.30, 53.05, 120.57 (d, J = 6.0 Hz), 122.46 (d, J = 12.0 Hz), 123.19 124.53 (d, J = 10.0 Hz), 124.75, 125.41 (d, J = 161.0 Hz), 125.90, 128.56 (2C), 128.76 (d, J = 14.0 Hz), 129.75 (2C), 130.05 (d, J = 10.0 Hz), 130.82, 133.22, 133.24, 133.57, 133.97, 149.89 (d, J = 7.0 Hz); ESI-MS: m/z [M+H] ⁺ 417.08 (calcd. 416.14).

[Example 10] 2-((4-(((6-oxido-6H-dibenzo[c,e][1,2]oxaphosphinin-6-yl)amino)methyl)-1H-1,2,3- triazol-1-yl)methyl)benzonitrile (compound 10 ) of the manufacture

After dissolving compound A-1 (0.10 g, 0.37 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.04 g, 0.004 mmol) and compound B-10 (0.06 g, 0.4 mmol) were added and microwaved It was reacted with (Microwave) (reaction conditions: 90° C., 4 hours). After concentration under reduced pressure, it was separated by silica gel column chromatography (DCM: MeOH = 40: 1 (v: v)) to obtain a pink solid compound 10 (100 mg, 52% yield).

Melting point(℃) 65℃; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.11 (dd, J = 1.6, 7.2 Hz, 1H), 4.13 (dd, J = 1.6, 7.2 Hz, 1H), 5.81 (s, 2H), 6.29 ( m, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.51 (td, J = 2.8, 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.73-7.79 (m, 3H), 7.94 (d, J = 7.6, 1H), 8.04 (s, 1H), 8.16-8.20 (m, 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 36.26, 51.43, 111.74, 117.51, 120.58 (d, J = 6.0 Hz), 122.45 (d, J = 12.0 Hz), 123.74 124.53 (d, J = 10.0 Hz) ), 124.77, 125.90 (d, J = 162.0 Hz), 125.91, 128.78 (d, J = 14.0 Hz), 129.72, 129.95, 130.06 (d, J = 10.0 Hz), 130.84, 133.23, 133.25, 133.85, 134.31, 136.45 (d, J = 7.0 Hz), 139.39, 149.89 (d, J = 7.0 Hz); ESI-MS: m/z [M+H] ⁺ 428.2 (calcd. 427.12).

[Example 11] 3-((4-(((6-oxido-6H-dibenzo[c,e][1,2]oxaphosphinin-6-yl)amino)methyl)-1H-1,2,3- triazol-1-yl)methyl)benzonitrile (compound 11 ) of the manufacture

After dissolving compound A-1 (0.10 g, 0.37 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.04 g, 0.004 mmol) and compound B-11 (0.06 g, 0.4 mmol) were added and microwaved It was reacted with (Microwave) (reaction conditions: 90° C., 4 hours). After concentration under reduced pressure, silica gel column chromatography (DCM: MeOH = 40: 1 (v: v)) was used to separate compound 11 (130 mg, 82% yield) as a yellow solid.

Melting point(℃) 153℃; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.09 (d, J = 6.8 Hz, 1H), 4.12 (d, J = 6.8 Hz, 1H), 5.67 (s, 2H), 6.27 (m, 1H) , 7.17 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.50 (td, J = 2.8, 7.6 Hz, 1H) , 7.62 (t, J = 7.2 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H) 7.74 (t, J = 7.2 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H) 7.83-7.86 (m, 2H), 8.07 (s, 1H), 8.16-8.20 (m, 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 36.28, 52.25, 112.17, 118.93, 120.55 (d, J = 6.0 Hz), 122.45 (d, J = 12.0 Hz), 123.61 124.55 (d, J = 10.0 Hz) ), 124.76, 125.89 (d, J = 162.0 Hz), 125.92, 128.75 (d, J = 14.0 Hz), 130.04 (d, J = 10.0 Hz), 130.57, 130.82, 132.11, 132.47, 133.22, 133.24, 133.47, 136.46 (d, J = 7.0 Hz), 138.22, 149.89 (d, J = 7.0 Hz); ESI-MS: m/z [M+H] ⁺ 428.2 (calcd. 427.12).

[Example 12] 4-((4-(((6-oxido-6H-dibenzo[c,e][1,2]oxaphosphinin-6-yl)amino)methyl)-1H-1,2,3- triazol-1-yl)methyl)benzonitrile (compound 12 ) of the manufacture

After dissolving compound A-1 (0.10 g, 0.37 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.04 g, 0.004 mmol) and compound B-12 (0.06 g, 0.4 mmol) were added and microwaved It was reacted with (Microwave) (reaction conditions: 90° C., 4 hours). After concentration under reduced pressure, it was separated by silica gel column chromatography (DCM: MeOH = 40: 1 (v: v)) to obtain a yellow solid compound 12 (110 mg, 69% yield).

Melting point(℃) 67℃; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.09 (d, J = 7.2 Hz, 1H), 4.13 (d, J = 7.2 Hz, 1H), 5.72 (s, 2H), 6.27 (m, 1H) , 7.17 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.51 (td, J = 2.4, 7.6 Hz, 1H), 7.73-7.79 (m, 2H), 7.88 (d, J = 8.0 Hz 2H), 8.05 (s, 1H), 8.16-8.20 (m, 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 36.27, 52.58, 119.03, 120.57 (d, J = 5.0 Hz), 122.46 (d, J = 12.0 Hz), 123.77 124.55 (d, J = 11.0 Hz), 124.77, 125.89 (d, J = 161.0 Hz), 125.92, 128.78 (d, J = 14.0 Hz), 129.19 (2C), 130.05 (d, J = 10.0 Hz), 130.83, 133.20 (2C), 133.23, 133.26, 136.45 (d, J = 7.0 Hz), 142.12, 149.89 (d, J = 8.0 Hz); ESI-MS: m/z [M+H] ⁺ 428.1 (calcd. 427.4).

[Example 13] 6-(4-(2,3,4-trimethoxybenzyl)piperazin-1-yl)-6H-dibenzo[c,e][1,2]oxaphosphinine 6-oxide (compound 13 ) of the manufacture

DOPO (200 mg, 0.93 mmol) was dissolved in DCM (10 mL), then SO ₂ Cl _{2 at 0℃} (0.1 mL, 0.93 mmol) was added dropwise at 0°C. Heated to reflux at 80° C. for 3 hours. After cooling to room temperature, Toluene (0.1 mL) was added dropwise, stirred for 10 minutes, concentrated under reduced pressure to remove the solvent, and DCM (10 mL) was added. TEA (1.39 mL, 10 mmol) was added dropwise at 0°C, 1-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride (376 mg, 1.1 mmol) was added dropwise, and then stirred at room temperature for a day. After terminating the reaction with H ₂ O, the organic layer was extracted with DCM. The extracted organic layer was _{filtered under reduced pressure after removing moisture with anhydrous MgSO 4} , and the resulting filtrate was concentrated under reduced pressure and dissolved in a small amount of DCM. Thereafter, silica gel column chromatography (EA: DCM = 9: 1) was performed to obtain a yellow oily liquid compound 13 (80 mg, 18% yield).

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.33 (bs, 4H), 3.05-3.10 (m, 4H), 3.40 (bs, 2H), 3.73 (s, 3H), 3.77 (s, 6H), 6.75 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 7.27-7.33 (m, 2H), 7.45 (t, J = 6.8 Hz, 1H), 7.61 (t, J = 6.8 Hz, 1H), 7.78-7.83 (m, 2H), 8.18-8.25 (m, 2H).

[Example 14] 6-(4-(benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)-6H-dibenzo[c,e][1,2]oxaphosphinine 6-oxide (compound 14 ) of the manufacture

DOPO (200 mg, 0.93 mmol) was dissolved in DCM (10 mL), then SO ₂ Cl _{2 at 0℃} (0.1 mL, 0.93 mmol) was added dropwise. Heated to reflux at 80° C. for 3 hours. After cooling to room temperature, Toluene (0.1 mL) was added dropwise, stirred for 10 minutes, concentrated under reduced pressure to remove the solvent, and DCM (10 mL) was added. TEA (1.39 mL, 10 mmol) was added dropwise at 0°C, and Piperonyl piperazine (293 mg, 1.1 mmol) was added dropwise, followed by stirring at room temperature for a day. After terminating the reaction with H ₂ O, the organic layer was extracted with DCM. The extracted organic layer was _{filtered under reduced pressure after removing moisture with anhydrous MgSO 4} , and the resulting filtrate was concentrated under reduced pressure and dissolved in a small amount of DCM. Thereafter, silica gel column chromatography (EA: DCM = 9: 1) was performed to obtain compound 14 as an oily liquid (70 mg, 17% yield).

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 2.33 (bs, 4H), 3.03-3.15 (m, 4H), 3.40 (s, 2H), 5.98 (s, 2H), 6.74 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 1.2 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.61 (td, J = 3.2, 7.6 Hz, 1H), 7.77 (m, 1H), 7.82 (d, J = 8.0 Hz, 1H), 8.19 ( d, J = 8.0 Hz, 1H), 8.24 (m, 1H).

[Example 15] 6-(((1-(2-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-6H-dibenzo[c,e][1 ,2]oxaphosphinine 6-oxide (compound 15 ) of the manufacture

After dissolving Compound A-1 (0.10 g, 0.37 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.04 g, 0.004 mmol) and Compound B-13 (0.08 g, 0.4 mmol) were added and microwaved It was reacted with (Microwave) (reaction conditions: 80°C, 5 hours). After concentration under reduced pressure, silica gel column chromatography (DCM: MeOH = 40: 1 (v: v)) was used to separate compound 15 (100 mg, 57% yield) as a white solid.

Melting point(℃) 53℃; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.11 (d, J = 7.2 Hz, 1H), 4.14 (d, J = 6.8 Hz, 1H), 5.78 (s, 2H), 6.25 (m, 1H) , 7.17 (t, J = 7.2 Hz, 2H), 7.30 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.51 (td, J = 2.8, 7.2 Hz, 1H) , 7.60 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.72-7.75 (m, 2H), 7.77 (d, J = 7.6 Hz 1H), 7.83 (d, J = 7.6 Hz 1H) 7.94 (s, 1H), 8.16-8.20 (m, 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 36.26, 49.93 (d, J = 2.5 Hz), 120.54 (d, J = 6.0 Hz), 122.45 (d, J = 12.0 Hz), 123.94, 124.05 (d) , J = 156.0 Hz), 124.54 (d, J = 11.0 Hz), 124.77, 125.09, 125.92, 125.99, 126.69 (q, J = 5.0 Hz), 126.92, 127.22, 128.76 (d, J = 14.0 Hz), 129.39 , 130.04, (d, J = 10.0 Hz), 130.81 (d, J = 10.0 Hz), 133.24, 133.26, 134.29, 136.46 (d, J = 7.0 Hz), 149.88 (d, J = 7.0 Hz); ESI-MS: m/z [M+H] ⁺ 470.11 (calcd. 471.42).

[Example 16] 6-(((1-(3-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-6H-dibenzo[c,e][1 ,2]oxaphosphinine 6-oxide (compound 16 ) of the manufacture

After dissolving compound A-1 (0.10 g, 0.37 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.04 g, 0.004 mmol) and compound B-14 (0.08 g, 0.4 mmol) were added and microwaved It was reacted with (Microwave) (reaction conditions: 110° C., 5 hours). After concentration under reduced pressure, silica gel column chromatography (DCM: MeOH = 40: 1 (v: v)) was used to separate compound 16 (110 mg, 69% yield) as a white solid.

Melting point(℃) 53℃; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.09 (d, J = 6.8 Hz, 1H), 4.12 (d, J = 7.2 Hz, 1H), 5.71 (s, 2H), 6.24 (m, 1H) , 7.15 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.48 (td, J = 3.2, 7.6 Hz, 1H) , 7.61 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.71-7.77 (m, 4H), 8.05 (s, 1H), 8.15-8.19 (m, 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 36.27, 52.48, 120.53 (d, J = 6.0 Hz), 122.45 (d, J = 11.0 Hz), 123.56, 124.54 (d, J = 10.0 Hz), 124.75 , 125.21 (q, J = 4.0 Hz), 125.43 (q, J = 4.0 Hz), 125.90 (d, J = 161.0 Hz), 125.91, 128.71 (d, J = 14.0 Hz), 129.72, 130.02 (d, J = 4.0 Hz) = 9.0 Hz), 130.03, 130.43, 130.79, 132.72, 133.21, 133.23, 136.46 (d, J = 7.0 Hz), 138.40, 149.88 (d, J = 7.0 Hz); ESI-MS: m/z [M+H] ⁺ 470.11 (calcd. 471.42).

[Example 17] 6-(((1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-6H-dibenzo[c,e][1 ,2]oxaphosphinine 6-oxide (compound 17 ) of the manufacture

After dissolving compound A-1 (0.10 g, 0.37 mmol) in acetone (10 mL), Cu(PPh ₃ ) ₃ Br (0.04 g, 0.004 mmol) and compound B-15 (0.08 g, 0.4 mmol) were added and microwaved (Reaction conditions: 110° C., 5 hours). After concentration under reduced pressure, silica gel column chromatography (DCM: MeOH = 40: 1 (v: v)) was used to separate compound 17 (60 mg, 34% yield) as a white solid.

Melting point(℃) 190℃; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 4.09 (d, J = 6.8 Hz, 1H), 4.12 (d, J = 6.8 Hz, 1H), 5.71 (s, 2H), 6.24 (m, 1H) , 7.16 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.49 (td, J = 2.8, 7.6 Hz, 1H) , 7.52 (d, J = 8.4 Hz, 2H), 7.71-7.75 (m, 2H), 7.77 (d, J = 8.4 Hz 2H), 8.05 (s, 1H), 8.15-8.20 (m, 2H); ¹³ C NMR (DMSO-d ₆ , 100 MHz) δ 36.26, 52.54, 120.56 (d, J = 6.0 Hz), 122.46 (d, J = 12.0 Hz), 123.65, 124.55 (d, J = 10.0 Hz), 124.76 , 125.89 (d, J = 162.0 Hz), 125.91, 126.15, (q, J = 4.0 Hz), 126.70, 128.76 (d, J = 14.0 Hz), 128.98, 129.19 (2C), 129.29, 130.04, (d, J = 10.0 Hz), 130.79, 133.21, 133.23, 136.44 (d, J = 7.0 Hz), 141.31, 149.87 (d, J = 7.0 Hz); ESI-MS: m/z [M+H] ⁺ 470.11 (calcd. 471.42).

[ Experimental example One] Acetylcholinesterase ( AChE ) And Butyrylcholinesterase ( BuChE ) Inhibition test ( In vitro assay)

For the dibenzooxaphosphinin oxide derivative compound prepared in the above example, the AChE and BuChE inhibitory activities were described in [Ellman, G.L.; Courtney, K.D.; Andres, B.; Featherstone, R.M. Biochem. Pharmacol. 1961, 7, 88-95] was evaluated at 30 ℃ by the colorimetric measurement method reported.

Analytical solutions for AChE inhibitory activity include 0.1M phosphate buffer (pH 8), 0.3 mM 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB, Elman's reagent), and 0.02 units of AChE (Sigma Chemical Co., Ltd., From bovine red blood cells), and 0.5 mM acetylthiocholine iodide as a substrate for the enzymatic reaction. The test compound was added to the assay solution and pre-incubated with the enzyme at 30° C. for 5 minutes. After this period, the substrate was added. The change in absorbance at 412 nm was recorded for 5 minutes using a microplate reader Digiscan 340T, the reaction rates were compared, and the% inhibition due to the presence of the test compound was calculated. The reaction rate was calculated using at least three measurements, and the percent inhibition due to the presence of the test compound was calculated for the control without the compound. The concentration of the compound that produced 50% AChE inhibition (IC ₅₀ ) was determined. The results are shown in Table 1 below.

The assay solution for BuChE inhibitory activity was 0.01 units of butyrylcholinesterase from human serum, 0.1 M sodium phosphate buffer (pH 8), 0.3 mM 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB, Ellman's reagent), and 0.5 mM butyrylthiocholine iodide as a substrate for the enzymatic reaction. Enzyme activity was measured by measuring the absorbance at 412 nm for 5 minutes using a microplate reader Digiscan 340T. The test compound was pre-incubated with the enzyme at 30° C. for 10 minutes. The reaction rate was calculated using at least three measurements. IC ₅₀ is defined as the concentration of each compound that reduces the enzyme activity by 50% relative to the absence of an inhibitor. The results are shown in Table 1 below.

Real compound AChE Inhibitory IC ₅₀ ( μM ) BuChE Inhibitory IC ₅₀ ( μM ) Compound 1 (Example 1) 250> 15.47 ± 0.48 Compound 2 (Example 2) 230> 13.51 ± 0.49 Compound 3 (Example 3) 230> 3.38 ± 1.11 Compound 4 (Example 4) 170> 11.45 ± 0.55 Compound 5 (Example 5) 230> 8.28±0.73 Compound 6 (Example 6) 120> 5.97±0.28 Compound 7 (Example 7) 120> 35.88±1.90 Compound 8 (Example 8) 120> 4.59±0.82 Compound 9 (Example 9) 240> 12.09±0.23 Compound 10 (Example 10) 230> 18.56±0.97 Compound 11 (Example 11) 318.75 ± 0.80 12.21±0.19 Compound 12 (Example 12) 230> 17.95±0.71 Compound 13 (Example 13) 210> 6.06±0.41 Compound 14 (Example 14) 230> 9.93±0.12 Compound 15 (Example 15) 110> 4.07±0.23 Compound 16 (Example 16) 110> 3.14±0.02 Compound 17 (Example 17) 110> 9.41±0.46 Control galantamine 1.70 ± 0.90 9.4 ± 2.50

As shown in Table 1, the dibenzooxaphosphinin oxide derivative compounds prepared in the above Example showed cholinesterase (ChEs) inhibitory activity, and butyrylcholinesterase ( BuChE) showed inhibitory activity. In particular, the compounds of the present invention selectively inhibited butyryl cholinesterase (BuChE) activity among cholinesterases.

Therefore, since the dibenzooxaphosphinin oxide derivative compound of the present invention has a selective inhibitory activity against butyrylcholinesterase (BuChE), it is possible to solve the problem of side effects of acetylcholinesterase (AChE) inhibitors. In addition, a pharmaceutical composition capable of preventing, improving, or treating degenerative diseases such as Parkinson's disease and Alzheimer's disease by targeting butyrylcholinesterase (BuChE), which is highly active in the brain of Alzheimer's disease patients Or it can be very usefully used as an active ingredient of a health supplement composition.

Those of ordinary skill in the art that the present invention is not limited by the above-described embodiments, and that various substitutions, modifications and changes are possible within the scope of the technical spirit of the present invention. It will be clear to you.

Claims (8)

delete Dibenzooxaphosphinin oxide derivative compound represented by the following formula (2) or (3).
[Formula 2]

[Formula 3]

In Formulas 2 and 3,
R is

or

ego;
R'is C1-C4 alkyl, halogen, C1-C4 alkoxy, haloC1-C4 alkyl or cyano;
R ^a is hydrogen or C1-C4 alkyl;
x is an integer from 0 to 3.
delete The method of claim 2,
The dibenzooxaphosphinin oxide derivative compound is a dibenzooxaphosphinin oxide derivative compound selected from the following structures.

A pharmaceutical composition for preventing or treating degenerative diseases containing the dibenzooxaphosphinin oxide derivative compound according to claim 2 or 4 or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 5,
The pharmaceutical composition of the degenerative disease is Parkinson's disease or Alzheimer's disease. A dietary supplement for improving cognitive ability or improving degenerative diseases, containing the dibenzooxaphosphinin oxide derivative compound according to claim 2 or 4 or a pharmaceutically acceptable salt thereof as an active ingredient.
delete