KR101737872B1 - Curcumin derivatives, preparation method thereof and photoacoustic imaging agent for detecting of amyloid plaque having the same - Google Patents

Curcumin derivatives, preparation method thereof and photoacoustic imaging agent for detecting of amyloid plaque having the same Download PDF

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KR101737872B1
KR101737872B1 KR1020150090410A KR20150090410A KR101737872B1 KR 101737872 B1 KR101737872 B1 KR 101737872B1 KR 1020150090410 A KR1020150090410 A KR 1020150090410A KR 20150090410 A KR20150090410 A KR 20150090410A KR 101737872 B1 KR101737872 B1 KR 101737872B1
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박용대
민정준
양승대
허민구
정승진
홍영진
박승환
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Abstract

The present invention relates to a curcumin derivative, a process for producing the same, and a photoacoustic imaging agent for detecting a beta-amyloid plaque comprising the same. The curcumin derivative represented by the formula (1) according to the present invention has excellent selective binding ability to beta-amyloid, It is possible to detect beta-amyloid through an optical-imaging method or a photoacoustic-imaging method, and in particular, it is possible to detect a photoacoustic signal with high efficiency with little noise in response to light of a specific wavelength band, And beta-amyloid and the production of beta-amyloid.

Description

[0001] The present invention relates to a curcumin derivative, a method for producing the same, and a photoacoustic imaging agent for detecting beta-amyloid plaques comprising the same.

The present invention relates to a curcumin derivative, a process for producing the same, and a photoacoustic imaging agent for detecting beta-amyloid plaques comprising the same.

With the advancement of modern medicine, the elderly population of the world is increasing, and the number of senile dementia patients is rapidly increasing. Alzheimer's disease is the most common form of dementia, a progressive neurodegenerative disorder characterized by memory loss, cognitive and behavioral stability. The cause of the disease is not clearly known yet, but the analysis of the posttraumatic brain tissue of the patients revealed that amyloid plaques composed of beta-amyloid peptide (Aβ) between neurons and hyperphosphorylated tau protein filaments in neurons The accumulation of neurofibrillary tangles formed by the nerve fibers has been reported (Ginsberg SD et al., Kluwer Academic / Plenum: New York, 1999: pp 603-654; Lee VM et al., Neuron 1999; 24: 507-510; Selkoe DJ. JAMA 2000; 283: 1615-1617]. 39 to 43 amino acids, including A [beta] peptides, are derived from the larger amyloid precursor protein (APP). In the amyloid production pathway, A [beta] peptides are cleaved from APP by sequential proteolysis of [beta] and [gamma] -secretase. The A [beta] peptide is released as a soluble protein and can be detected at low levels in cerebrospinal fluid (CSF) in normal aged brain. During the course of Alzheimer's, it has been found that A [beta] peptides aggregate and form amyloid deposits in the brain or blood vessels (Blennow et al., Lancet. 2006 Jul 29; 368 (9533): 387-403). It is also known that amyloid deposits play a role in amyloidosis, in which the amyloid protein is abnormally deposited in different organs and / or tissues and causes disease (Chiti et al., Annu Rev Biochem. 2006; 75: 333-66].

Accordingly, in order to diagnose diseases that can be diagnosed by quantitative detection of amyloid aggregates including Alzheimer's disease, many fluorescent compounds having binding to beta amyloid aggregates and easily showing their presence have been studied. A representative of these compounds is Congo red (CR), and a definite diagnosis of Alzheimer's disease is possible by autopsy and staining the brain with Congo red. However, Congo red has a disadvantage in that it can not be used for living people because it can not pass through the brain blood barrier (BBB) due to its strong water solubility, have. In addition to Congo red, one of the earliest developed compounds is derivatives of Chrysamine-G, but this was also too low to pass through the cerebrovascular barrier and could not actually be used [Klunk WE, et al., Neurobiol Aging 1994; 15: 691-8. Klunk WE, et al., Neurobiol Aging 1995; 16: 541-8.]. Derivatives of the 6-dialkylamino-2-naphthylethenylidene (FDDNP) derivative and the thioflavin T (ThT) family have been developed (see Agdeppa ED, et al., J Neuroscience 2001 ; 21: 1-5; Mathisca, et al., Bioorg Med Chem Lett 2002; 12: 295-298.) Further, various benzothiazole derivatives and stilbene derivatives have been patented as radioisotope labeled compounds capable of imaging beta amyloid (Reference US 2002/0133019 A1, US 2003 / 0149250 A1].

However, the conventionally developed beta amyloid detecting fluorescent ligand has a complicated process, has a large molecular weight, and does not show a large change in fluorescence properties after binding with the beta amyloid aggregates. In addition, it is not only selectively binding to beta amyloid selectively but also binds to phosphorylated tau protein fibers, resulting in low detection selectivity, low absorption rate in animal experiments, and easy removal of the ligand from the brain It was difficult to actually use it. Accordingly, there is a continuing need for development of a reagent useful for overcoming the problems of the conventional β-amyloid detecting ligands and specifically detecting and imaging amyloid aggregates only.

Curcumin is a major component of Curie, an Indian stock, and the incidence of Alzheimer's disease among elderly people aged 70-79 is 4.4 times lower than that of Indians (see Arch. Neurol. 2000; 57: 824-830). This suggests the possibility of curcumin for the prevention and treatment of Alzheimer's disease. Indeed, recent literature has shown that when injecting curcumin into a transgenic mouse that has amyloid-accumulated carotid arteries, curcumin binds to the plaque through the blood-brain barrier and decreases the levels of amyloid and plaque when feeding curcumin to transgenic mice [Reference: J. Biol. Chem. 2005; 18: 5892-5901]. Safety due to low toxicity of curcumin has also been reported [J. Neurosci. 2001; 21: 8370-8377; Anticancer Res. 2001; 21: 2895-2900). Studies have been carried out to predict the preventive and therapeutic effect of dementia by performing passive avoidance test or Y-maze test in mice using curcumin or its derivatives and herbal extracts [References: Patent Application No. 2001-0013726 No. 2001-0023065). In addition, novel curcumin derivatives such as hydrazino curcumin have been used for anti-angiogenic activity studies (Reference: Patent Application No. 2005-0010058).

On the other hand, photoacoustic imaging based on photoacoustic effect has attracted much attention as a biomedical imaging modality that provides biological information by visualizing intrinsic biological molecules such as melanin and hemoglobin. The high potential of photoacoustic imaging as biomedical imaging is based on the photoacoustic response of nanomaterials in terms of diagnosis and treatment, including real-time and targeted imaging with high sensitivity, multi-mode imaging and image-guided therapy It is being accelerated by the development of exogenous contrast agents.

In this regard, the development of suitable nanoprobes representing photoacoustic effects is an important technical issue in nanotechnology to improve the efficiency of photoacoustic imaging and optimize various biomedical applications. In addition, the development and artificial manipulation of nanoprobes that exhibit photoacoustic effects can provide another important insight into the fundamental understanding of photoacoustic imaging based on nanomaterials. In principle, the photoacoustic effect is due to the generation of sound waves through the absorption of short-pulsed radiation which causes local expansion of the target resulting in thermal expansion. Although the extinction coefficient and the conversion efficiency of converting the absorbed photons into heat are key factors in generating photoacoustic signals in photoacoustic imaging based on nanomaterials such as molecular level absorbers, Lt; / RTI > Since the photoacoustic effect associated with thermal expansion is generated from a locally heated surrounding medium through thermal conversion from the nanomaterial to the surrounding medium, the surface environment associated with the thermal transfer and dissipative dynamics creates a photoacoustic effect based on the nanomaterial It is a sensitive factor.

Thus, the development and manipulation of new types of photoacoustic diagnostic agents for a basic understanding of photoacoustic reactions based on new photoacoustic diagnostic agents can provide important clues to devising and optimizing contrast agents that cause photoacoustic imaging .

Accordingly, the present inventors have found that the present inventors have found that a compound having excellent selective binding ability to beta-amyloid can be detected through an optical-imaging method or a photoacoustic-imaging method, and in particular, can detect a high photoacoustic signal in response to light irradiation at a specific wavelength band The present inventors completed the present invention by confirming that the curcumin derivative represented by the formula 1 according to the present invention can be useful as a composition for the detection of beta-amyloid and beta-amyloid-induced diseases .

Korean Patent Publication No. 2005-0010058 Korean Patent Registration No. 0719456

It is an object of the present invention to provide a curcumin derivative or a pharmaceutically acceptable salt thereof.

It is still another object of the present invention to provide a method for producing the curcumin derivative.

Another object of the present invention is to provide a composition for detecting beta-amyloid plaques comprising the curcumin derivative or a pharmaceutically acceptable salt thereof.

Yet another object of the present invention is to provide a composition for diagnosing a disease by the production of a beta-amyloid plaque comprising the curcumin derivative or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for detecting optical imaging of a beta-amyloid plaque using the curcumin derivative or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a method for detecting photoacoustic imaging of a beta-amyloid plaque using the curcumin derivative or a pharmaceutically acceptable salt thereof.

In order to achieve the above object,

The present invention provides a curcumin derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

Figure 112015061635539-pat00001

In Formula 1,

R is hydrogen, hydroxy, -B (OH) 2, C 1-10 straight or branched alkyl, a C 1-10 straight or branched chain alkoxy.

Also, as shown in the following Reaction Scheme 1,

A step of coupling a compound represented by formula (2) and a compound represented by formula (3) together with a base in an organic solvent to obtain a compound represented by formula (4) (step 1); And a step (2) of coupling the compound represented by the formula (4) obtained in the step 1 with a compound represented by the formula (5) and a base in an organic solvent to obtain a compound represented by the formula (1) The present invention provides a method for producing a curcumin derivative which is displayed.

[Reaction Scheme 1]

Figure 112015061635539-pat00002

In the above Reaction Scheme 1,

R is as defined above.

Furthermore, the present invention provides a composition for detecting beta-amyloid plaques comprising the curcumin derivative or a pharmaceutically acceptable salt thereof.

The present invention also relates to a pharmaceutical composition for preventing or treating Alzheimer's disease, Down's syndrome, amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, Dutch amyloidosis, inclusion body myositis, Amyloid pneumonitis, amyloid cardiomyopathy, systemic amyloidosis, amyloidosis hereditary cerebral hemorrhage, scrapie, Creutzfeldt-Jakob disease, Kurus disease, Gerstmann-Straussler-Shark Ink Syndrome Amyloid plaques selected from the group consisting of thyroid carcinoma, thyroid carcinoma, muscle weakness disease, and Langerhans' islet type II diabetes mellitus.

Further, the present invention relates to a method for preparing a beta-amyloid plaque, comprising the steps of (1) mixing a sample containing beta-amyloid plaques with a curcumin derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof; And measuring the fluorescence signal for the beta-amyloid plaque (step 2). The present invention also provides a method for detecting an optical imaging of a beta-amyloid plaque.

The present invention also relates to a method for preparing a beta-amyloid plaque, comprising the steps of (1) mixing a sample containing beta-amyloid plaques with a curcumin derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof; And measuring a photoacoustic signal for the beta-amyloid plaque (step 2). The method of detecting photoacoustic imaging of a beta-amyloid plaque comprises the steps of:

The curcumin derivative represented by Formula 1 according to the present invention has excellent selective binding ability to beta-amyloid and can detect beta-amyloid through an optical-imaging method or a photoacoustic-imaging method. In particular, Can detect the photoacoustic signal with high efficiency with little noise in response to the beta-amyloid detection and beta-amyloid production.

1A is an absorption spectrum of the compounds (1a, 1b) of Examples 1 and 2.
FIG. 1B is a graph showing changes in photoacoustic signals according to changes in absorption wavelength of the compounds 1a and 1b of Examples 1 and 2. FIG.
1C is a photoacoustic image obtained by obtaining the compounds 1a and 1b of Examples 1 and 2 at the absorption wavelengths of 680, 700 and 720 nm, respectively.
FIG. 2A is a graph showing changes in photoacoustic signals before and after binding of the beta-amyloid aggregates of the compounds (1a, 1b) of Examples 1 and 2. FIG.
FIG. 2B is a photoacoustic image of the compound (1a, 1b) of Examples 1 and 2 before and after the binding of the beta-amyloid aggregates.
Figure 3 is a beta-amyloid detection photoacoustic imaging image obtained after administration of compound (1a) of Example 1 to wild-type mouse and dementia-induced mouse (5XFAD mouse).
4A is a β-amyloid detection optical image obtained after administering the compound (1a) of Example 1 to a dementia-inducing mouse (5 × FAD mouse).
4B is a beta-amyloid detection optical image obtained after administering the compound (1a) of Example 1 to a general mouse (WT mouse).
FIG. 5A is a β-amyloid detection optical image obtained by extracting the brain after administration of the compound (1a) of Example 1 to a dementia-inducing mouse (5 × FAD mouse).
FIG. 5B is a β-amyloid detection optical image obtained by extracting brain after administration of compound (1a) of Example 1 to a general mouse (WT mouse).

Hereinafter, the present invention will be described in detail.

The present invention provides a curcumin derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

Figure 112015061635539-pat00003

In Formula 1,

R is hydrogen, hydroxy, -B (OH) 2, C 1-10 straight or branched alkyl, a C 1-10 straight or branched chain alkoxy.

Preferably, R is hydroxy or -B (OH) 2 .

More preferably, R is 3-hydroxy or 4-hydroxy.

The chemical structures of the curcumin derivatives represented by the formula (1) according to the present invention are summarized in Table 1 below.

Example Chemical structural formula One
(Compound 1a)

Figure 112015061635539-pat00004
2
(Compound 1b)
Figure 112015061635539-pat00005
 3
(Compound 1c)
Figure 112015061635539-pat00006
 4
(Compound 1d)
Figure 112015061635539-pat00007

The curcumin derivative represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like, which are non-toxic organic acids such as hydrochloric acid, Examples of such pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphate chlorides, bromides, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-diate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, Such as benzene sulfonate, benzene sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene -1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method. For example, the curcumin derivative represented by Formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., The precipitate formed by adding the inorganic acid may be filtered and dried. Alternatively, the precipitate may be dried by evaporating the solvent and excess acid under reduced pressure, followed by crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

Furthermore, the present invention encompasses not only the curcumin derivatives represented by the above formula (1) and pharmaceutically acceptable salts thereof, but also solvates and hydrates which can be prepared therefrom.

Also, as shown in the following Reaction Scheme 1,

A step of coupling a compound represented by formula (2) and a compound represented by formula (3) in a first organic solvent to obtain a compound represented by formula (4) (step 1); And a step (2) of coupling a compound represented by the formula (4) obtained in the step 1 with a compound represented by the formula (5) in a second organic solvent to obtain a compound represented by the formula (1) The present invention provides a method for producing a curcumin derivative which is displayed.

[Reaction Scheme 1]

Figure 112015061635539-pat00008

In the above Reaction Scheme 1,

R is the same as defined in the above formula (1).

Hereinafter, the process for producing a curcumin derivative according to the present invention will be described in detail.

In the preparation method according to the present invention, the step 1 is a step of reacting a compound represented by the formula (2) and a compound represented by the formula (3) together with a base in an organic solvent to obtain a compound represented by the formula (4).

The organic solvent used in step 1 may be ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO) Acetonitrile and the like can be used singly or in combination, and ethyl acetate is preferably used, but not limited thereto.

As the base used in step 1, n-butylamine, piperidine, potassium hydride, sodium hydride, lithium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, rubidium hydroxide and calcium hydroxide may be used , n-butylamine is preferably used, but not limited thereto.

Further, the reaction temperature of step 1 may be 0-50 ° C, preferably 20-30 ° C, but is not limited thereto.

In addition, the reaction time of step 1 can be performed for 1-24 hours, preferably 6-10 hours, but is not limited until all the starting materials have disappeared.

In the preparation method according to the present invention, the step 2 is a step of reacting a compound represented by the formula (4) and a compound represented by the formula (5) together with a base in an organic solvent to obtain a curcumin derivative represented by the formula (1).

The organic solvent used in step 2 may be ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO) Acetonitrile and the like can be used singly or in combination, and it is preferable to use ethyl acetate mixedly, but not limited thereto.

As the base used in step 2, n-butylamine, piperidine, potassium hydride, sodium hydride, lithium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, rubidium hydroxide and calcium hydroxide can be used , And piperidine are preferably used, but the present invention is not limited thereto.

Further, the reaction temperature of step 2 may be 30-120 ° C, preferably 60-100 ° C, but is not limited thereto.

Also, the reaction time of step 2 can be performed for 1-24 hours, preferably 6-10 hours, but is not limited until all the starting materials have disappeared.

Further, the present invention provides a composition for detecting beta-amyloid plaques comprising a curcumin derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof.

The present invention also provides a composition for diagnosing a disease by the production of a beta-amyloid plaque comprising the curcumin derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof.

The "detection composition" and "diagnostic composition" according to the present invention may be used in an optical-imaging method such as single photon emission computed tomography (SPECT) or position emission tomography (PET) Can be used in photoacoustic imaging methods, and preferably in photoacoustic-imaging methods with high detection efficiency.

The term "photoacoustic " used in the present invention means a phenomenon in which a substance absorbs light and locally rises in temperature and propagates through the substance as a pressure. The absorption of minute light is measured with high sensitivity And it is also used in precision spectroscopy because it is possible to measure a sample which is difficult to measure by a general optical method.

As used herein, the term " photoacoustic imaging method "refers to a method of detecting or diagnosing a photoacoustic signal by measuring the photoacoustic signal using the curcumin derivative represented by the formula (1) Which is a hybrid biomedical imaging modality developed on the basis of photoacoustic effect. The photoacoustic imaging irradiates a non-ionizing laser pulse, wherein the energy delivered by the laser is absorbed by the tissue or contrast agent and converted into heat to cause a transient thermoelastic expansion And further induces a wideband (e.g., MHz) ultrasound emission. At this time, the generated ultrasonic waves are detected by an ultrasonic transducer to form an image. The emitted ultrasonic emission, ie the intensity of the photoacoustic signal, is proportional to the local energy deposition. Since the photoacoustic imaging is a phenomenon generated by absorbing the irradiated light, optical absorption is an important factor for the photoacoustic imaging. In biological tissues, optical absorption is by an intrinsic molecule such as hemoglobin or melanin or by a contrast agent introduced from the outside.

As used herein, the term "beta-amyloid plaque " refers to a coagulation state in which various insoluble fibrous proteins are deposited in the tissues of a patient. The beta-amyloid plaque comprises amyloid deposits formed by an aggregate formed by aggregation of the amyloid protein and / or by an additional combination of amyloid proteins.

In the present invention, "beta-amyloid plaque detection" or "beta-amyloid plaque and diagnosis of diseases by the production of beta-amyloid plaques" Wherein the "bond" refers to chemical interactions such as covalent bonds, ionic bonds, hydrophilic-hydrophilic interactions, hydrophobic-hydrophobic interactions, and complex bond bonding.

The term " a disease caused by beta-amyloid plaques and diseases "in the present invention refers to a disease caused by beta-amyloid plaques and diseases such as dementia, Alzheimer's disease, Down's syndrome, amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, Dutch amyloidosis, Weeds syndrome, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic amyloidosis, amyloidosis hereditary cerebral hemorrhage, scrapie, Creutzfeldt-Jakob disease, Kurus disease, Gerstmann-Straussler-Sharkecker syndrome, thyroid carcinoma , Muscle weakness disease, and Langerhans islet type II diabetes.

The diagnostic composition according to the present invention can be administered orally or parenterally at the time of clinical administration and can be used in the form of a general pharmaceutical preparation. The composition may further comprise a pharmaceutically acceptable carrier or an additive. When the composition is formulated, a diluent or excipient such as a filler, a filler, an extender, a binder, a wetting agent, a disintegrant, ≪ / RTI >

Therefore, the curcumin derivative represented by formula (1) according to the present invention has excellent selective binding ability to beta-amyloid, and can detect beta-amyloid through an optical-imaging method or a photoacoustic-imaging method, Since the photoacoustic signal can be detected with high efficiency with little noise in response to light irradiation, it can be useful as a composition for detecting diseases caused by beta-amyloid detection and beta-amyloid production.

The curcumin derivative represented by Chemical Formula 1 according to the present invention has two chemical structural features. The first feature is that two aromatic rings at both ends are conjugated, and the second characteristic is that the two aromatic rings One aromatic ring is substituted with a nitrogen substituent, and the other aromatic ring is substituted with a hydroxy substituent. The present inventors have found that, in the case of a compound having no two chemical structural features, the selective binding ability to beta-amyloid is remarkably lowered.

Specifically, by taking optical-image and photoacoustic-image images of the compounds according to the present invention and comparative compounds having no two chemical structural features, it was found that the concentration of the compound according to the present invention The result of the image was clearer, though remarkably low.

Thus, the present inventors expect that the two chemical structural features significantly improve the selective binding ability to beta-amyloid.

In another aspect of the present invention, there is provided a method for detecting beta-amyloid using the curcumin derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention relates to a method for preparing a beta-amyloid plaque, comprising the steps of: (1) mixing a sample containing a beta-amyloid plaque with a curcumin derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof; And measuring the fluorescence signal for the beta-amyloid plaque (step 2). The present invention also provides a method for detecting an optical imaging of a beta-amyloid plaque.

The present invention also relates to a method for preparing a beta-amyloid plaque, comprising the steps of (1) mixing a sample containing beta-amyloid plaques with a curcumin derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof; And measuring a photoacoustic signal for the beta-amyloid plaque (step 2). The method of detecting photoacoustic imaging of a beta-amyloid plaque comprises the steps of:

Herein, the curcumin derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention exhibits a high binding affinity for a beta-amyloid plaque and forms a specific binding.

The step of administering the composition to a subject can be accomplished by introducing a detectable amount of a composition comprising a curcumin derivative or a pharmaceutically acceptable salt thereof according to the present invention into a tissue or a subject. The introduction into the tissue or subject is administered to the tissue or subject by methods known to those skilled in the art.

The term "tissue" refers to a portion of a subject's body. Examples of tissues include the brain, heart, liver, blood vessels, and arteries. The "detectable amount" is the amount of composition required to be detected by the detection method chosen. The amount of composition to be introduced into a patient to be detected can be readily determined by those skilled in the art. For example, the amount of the composition can be increased and administered to the subject until the active ingredient in the composition is detected by the selected detection method. The term "subject" means a human or other animal. Those skilled in the art can easily determine the time required for the curcumin derivative according to the present invention to bind to the amyloid aggregate by introducing the composition into the subject in a detectable amount and then detecting the label at various points after administration.

Administration of the composition of the present invention in a subject can be by a systemic or local route of administration. For example, the composition may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), in a water bath, intravaginally, intraperitoneally, intravasally, topically (powder, ointment or drip) . The composition may be administered to a subject so as to be able to move through the body. In addition, the composition may be administered to a particular organ or tissue of interest.

In the method for detecting beta amyloid aggregates of the present invention, a composition comprising a curcumin derivative or a pharmaceutically acceptable salt thereof is introduced into a subject in a detectable amount, and after a sufficient time for the compound to bind to the amyloid aggregate, The marker can be detected non-invasively in the subject. Alternatively, the fluorescent label can be detected after a period of time has elapsed for separating the tissue sample from the subject, introducing the composition into the tissue sample, and combining the curcumin derivative or the like in the composition with the amyloid aggregate. The step of detecting the fluorescent label may be performed by an optical-imaging method such as a single nuclear photon emission computed tomography (SPECT) or positron emission tomography (PET) - photoacoustic imaging method, and in particular, photoacoustic imaging method with high detection efficiency.

Imaging beta-amyloid plaques in the brain has several potential advantages. Imaging techniques can improve diagnostic methods by identifying potential patients with excess beta-amyloid plaques accumulated in the brain, and thus likely to develop Alzheimer's disease. The technique will also be useful for monitoring the progression of Alzheimer ' s disease. Once anti-beta amyloid drug treatment is enabled, imaging of the beta-amyloid plaque in the brain can provide an important means for monitoring treatment.

The reason that direct imaging of beta-amyloid plaques in vivo is difficult is because plaque has many of the same physical properties as normal tissue, such as density and moisture content. For this reason, attempts to image beta-amyloid plaques using magnetic resonance imaging (MRI) and computed tomography (CAT) have shown disappointing results, and beta-amyloid plaques have been used as an antibody, serum amyloid P protein, The effort to label with molecules provided some selectivity to the tissue periphery, but provided only poor imaging within the tissue.

However, the curcumin derivatives represented by formula (1) of the present invention can be imaged using fluorescence alone or photoacoustic characteristics without using a radioactive isotope, and there is a large difference in fluorescence characteristics before and after beta-amyloid plaque binding It is possible to detect the beta-amyloid plaque with high sensitivity.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

<Example 1-4> compound 1a (R = 4-OH) , compound 1b (R = 3-OH) , compound 1c (R = 4 - B ( OH) 2) and compound 1d (R = 3-B ( OH) 2 )

Figure 112015061635539-pat00009

Compound 2 (0.5 g, 3.2 mmol) and the corresponding compound 3 (0.5 g, 3.2 mmol) were dissolved in a solution of ethyl acetate (50 ml) and n-butylamine (0.11 g, 1.6 mmol) . The reaction mixture was stirred at room temperature for 8 hours until the starting material disappeared. The solution is dried over and then was extracted with ethyl acetate, washing with water, MgSO 4. After evaporation of the solvent in vacuo, the residue was separated by chromatography (chromatographed) (SiO 2, EtOAc / n -hexane = 3/7 (v / v)), the compound 4 was obtained (0.55 g, 62 %).

Next, the compound 3 (0.1 g, 0.36 mmol) prepared above and the corresponding aldehyde (compound 1a = 4-hydroxylbenzaldehyde compound 1b = 3-hydroxylbenzaldehyde compound 1c = 4-formylphenylboronic acid (Sigma-Aldrich, St. Louis, Mo., USA) was dissolved in a solution of ethyl acetate (50 ml) and piperidine (30 mg, 0.36 mmol). The reaction mixture was stirred at 80 &lt; 0 &gt; C for 8 hours until the starting material disappeared. The solution is dried over and then was extracted with ethyl acetate, washing with water, MgSO 4. The solvent was evaporated in vacuo and the residue was chromatographed (SiO 2 , EtOAc / n -hexane = 1/1 (v / v)) to give compounds 1a and 1b (1a: 37%), (1b: 32%), (1c: 41%), (1d: 38%).

Example  1 (Compound 1a):

1 H NMR (500 MHz, Aceton -d6): 3.09 (. 6H s), 6.24 (1H, s), 6.73 (1H, d, J = 15.3 Hz), 6.78 (2H, d, J = 8.4 Hz), 6.82 (1H, d, J = 16.0 Hz), 6.92 (2H, d, J = 8.4 Hz), 7.65-7.67 (4H, m), 7.83 (1H, d, J = 16.0 Hz), 7.94 (1H, d , &Lt; / RTI &gt; J = 15.3 Hz);

13 C NMR (125 MHz, CDCl 3 , d, ppm): 39.3, 101.0, 112.0, 114.5, 116.2, 118.4, 122.1, 126.5, 131.3, 132.0, 144.6, 147.9, 153.5, 160.9, 177.6, 179.9.

Example  2 (compound 1b):

1 H NMR (500 MHz, Aceton -d6): 3.09 (. 6H s), 6.31 (1H, s), 6.75 (1H, d, J = 15.3 Hz), 6.79 (2H, d, J = 9.1 Hz), D, J = 9.1 Hz), 7.77 (1H, d, J = 16.0 Hz), 7.99 (1H, d, J = 9.1 Hz), 6.92-6.95 (2H, m), 7.20-7.27 15.3 Hz), 8.68 (1 H, OH);

13 C NMR (125 MHz, CDCl 3 , d, ppm): 39.3, 101.5, 112.1, 114.1, 115.1, 118.4, 120.5, 121.9, 122.0, 130.2, 132.4, 136.2, 143.7, 149.0, 153.8, 158.0, 176.6, 180.9 .

Example  3 (Compound 1c):

1 H NMR (500 MHz, Aceton -d6): 3.11 (. 6H s), 6.34 (1H, s), 6.76 (1H, d, J = 15.3 Hz), 6.79 (2H, d, J = 8.4 Hz), 7.06 (1H, d, J = 15.3 Hz), 7.30 (2H, s), 7.69 (2H, d, J = 8.4 Hz), 7.73 (2H, d, J = 7.65 Hz), 7.86 (1H, d, J = 15.3 Hz), 7.93 (2H, d, J = 7.65 Hz), 8.01 (1H, d, J = 15.3 Hz);

13 C NMR (125 MHz, CDCl 3 , d, ppm): 39.3, 101.6, 112.1, 114.1, 121.9, 122.4, 127.9, 132.5, 134.8, 136.4, 143.5, 149.2, 153.8, 176.5, 180.9.

Example  4 (Compound 1d):

1 H NMR (500 MHz, Aceton -d6): 3.10 (. 6H s), 6.31 (1H, s), 6.75 (1H, d, J = 15.3 Hz), 6.79 (2H, d, J = 9.2 Hz), 7.02 (1H, d, J = 15.3 Hz), 7.34 (2H, s), 7.45 (1H, dd, J = 7.5 Hz), 7.68 (2H, d, 9.2 Hz), 7.81 (1H, d, J = 8.4 Hz), 7.87 (1H, d , J = 15.3 Hz), 7.93 (1H, d, J = 7.5 Hz), 7.99 (1H, d, J = 15.3 Hz), 8.23 (1H, s);

13 C NMR (125 MHz, CDCl 3 , d, ppm): 39.3, 101.4, 112.1, 114.1, 121.6, 121.9, 128.4, 130.9, 132.4, 133.9, 134.4, 136.8, 144.0, 149.0, 153.7, 176.7, 180.8.

< Experimental Example  1> Amyloid plaque detection Curcumin  Derivative Photoacoustic  Evaluation of signal amplification

(1) Preparation of A? 42 fibril

Aβ peptide was dissolved in pH 7.4 PBS buffer solution to a final concentration of 100 μM Aβ42 (rPeptide (Bogart, GA, 30622)) and then stirred at room temperature for 3 days using a magnetic bar at 1200 rpm. The formation of A [beta] fibrils was confirmed by the ThT (Thioflavin T) assay.

(2) Example  1 and 2 Curcumin  Absorption of the derivatives (1a, 1b) Spectrum  (Fig. 1A)

The maximum excitation wavelengths of the two curcumin derivative compounds of Examples 1 and 2 according to the present invention were measured with SpectraMax M2 (Molecular Devices). 100 [mu] M curcumin derivatives 1a and 1b compounds of Examples 1 and 2 were used as final concentrations using PBS buffer solution. As a result, both of the two curcumin derivatives showed an absorption wavelength at 450-750 nm (FIG. 1A).

(3) Example  1 and 2 Curcumin  Of the derivatives 1a and 1b Photoacoustic  1b and 1c)

100 [mu] M curcumin derivatives 1a and 1b compounds of Examples 1 and 2 were used as final concentrations. The photoacoustic signal was measured at 680-900 nm, and the strongest acoustic signal was observed at 680 nm (FIGS. 1B and 1C). FIG. 1B shows a change in the photoacoustic signal due to the change of the absorption wavelength, and FIG. 1C shows the change in the photoacoustic image due to the change in the wavelength of 680, 700, and 720 nm.

(4) Amyloid plaque detection Example  1 and 2 Curcumin  Amplification of the photoacoustic signals of the derivatives 1a and 1b (Figs. 2A and 2B)

In-vitro results of the photoacoustic changes of the two curcumin derivatives of Examples 1 and 2 bound to beta-amyloid aggregates. Amplification of the acoustic signals was measured after binding with 100 [mu] M curcumin derivatives (1a, 1b) using 100 [mu] M of aggregated A [beta] 42 peptide. The amplification of photoacoustic signals is closely related to their physical agglomeration. When the curymin derivative binds to the A [beta] 42 aggregate, a single molecule does not bind to the A [beta] 42 aggregate, and many curcumin derivatives bind to the A [beta] 42 aggregate. This leads to the physical aggregation of the curcumin derivative, which leads to amplification of the photoacoustic signal. As a result of the experiment of the present invention, the amplification of the photoacoustic signal was confirmed when it was bound to the A [beta] 42 aggregate as compared to the curcumin derivative not bound to the A [beta] 42 aggregate (Figs. FIG. 2A shows changes in photoacoustic signals before and after binding of the beta-amyloid aggregates of the curcumin derivatives 1a and 1b. FIG. 2B compares photoacoustic images before and after binding of the beta-amyloid aggregates.

< Experimental Example  2> Example  1 and 2 Curcumin  In vivo imaging of Alzheimer's disease model mice using derivatives (1a, 1b)

(One) Example  (Fig. 3) of beta-amyloid detection photoacoustic imaging of general mouse and dementia-induced mice using compound (1a)

Compound 1a (400 μg / kg) of Example 1 was injected into the tail vein of a 13-month old dementia-inducing mouse (5 × FAD mouse) and a wild-type control mouse and 30 minutes later, photoacoustic imaging Respectively. 3, no signal of the compound 1a of Example 1 was detected in the mouse brain after the intravenous injection into the general mouse. However, after intravenous injection into the dementia-induced mouse, Plaque signal could be confirmed (Fig. 3). This indicates that the compound (1a) of Example 1 binds to the beta-amyloid aggregates and shows high photoacoustic signals.

[ Experimental Example  3] Example  1 and 2 Curcumin  In vivo imaging experiments of model mice with Alzheimer's disease using derivatives (1a, 1b)

(One) Example  1 (compound 1a) in comparison with beta-amyloid detection optical imaging of general mouse and dementia-induced mice (FIG. 4).

The curcumin derivative developed by the present invention can be used not only as a photoacoustic diagnostic agent but also as an optical diagnostic agent. The compound 1a (400 μg / kg) of Example 1 was injected into the tail vein of 13-month old dementia-inducing mice (5 × FAD mouse and WT mouse), and then optical imaging was performed for 10-180 minutes . 4A is an experimental result of a dementia-induced mouse, and FIG. 4B is an experimental result of a general mouse. 4, the signal of Compound (1a) of Example 1 rapidly disappeared in the mouse brain after intravenous injection into a general mouse. After intravenous injection into the dementia-induced mouse, Beta-amyloid aggregates that are present in the blood. This indicates that the compound (1a) of Example 1 binds to the beta-amyloid aggregates and shows a high optical signal.

(2) Example  1 (FIG. 5). FIG. 5 is a graph showing the results of comparison of detection of β-amyloid in optical mouse and dementia-induced mouse brain using compound (1a).

In order to evaluate the beta-amyloid binding activity in the brain of a curcumin derivative of the present invention as a photoacoustic and optical diagnostic agent, the compound (1a) of Example 1 was administered intravenously to the tail vein of a 13-month old dementia- (400 μg / kg), and after 30 minutes, the mouse brain was excised and the optical image was measured (FIG. 5). FIG. 5A is an experimental result of a dementia-induced mouse, and FIG. 5B is an experimental result of a normal mouse. As shown in FIG. 5, when a strong optical signal was confirmed by the compound (1a) of Example 1 in the mouse brain and when the central region of the brain was cut and confirmed, a strong signal of the curcumin derivative 1a of Example 1 in the cerebral cortex Respectively. This indicates that the compound (1a) of Example 1 binds to the beta-amyloid aggregates and shows a high optical signal.

Claims (11)

Claims [1] A curcumin derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
Figure 112016123006283-pat00010

(In the formula 1,
R is hydroxy or -B (OH) 2 .
delete The method according to claim 1,
Wherein R is 3-hydroxy or 4-hydroxy, or a pharmaceutically acceptable salt thereof.
As shown in Scheme 1 below,
A step of coupling a compound represented by formula (2) and a compound represented by formula (3) together with a base in an organic solvent to obtain a compound represented by formula (4) (step 1); And
Reacting the compound of formula (4) obtained in step 1 with a compound represented by formula (5) and a base in an organic solvent to obtain a compound represented by formula (1) (step 2);
(1): &lt; EMI ID =
[Reaction Scheme 1]
Figure 112015061635539-pat00011

(In the above Reaction Scheme 1,
R is as defined in claim 1).
A composition for detecting beta-amyloid plaques comprising the curcumin derivative of claim 1 or a pharmaceutically acceptable salt thereof.
6. The method of claim 5,
Wherein the detecting composition is used in an optical-imaging method or a photoacoustic-imaging method.
A composition for diagnosing diseases by the production of a beta-amyloid plaque comprising the curcumin derivative of claim 1 or a pharmaceutically acceptable salt thereof.
8. The method of claim 7,
The disease caused by said beta-amyloid plaques and diseases is selected from the group consisting of dementia, Alzheimer's disease, Down syndrome, amyloid angiopathy, cerebral amyloid angiopathy, systemic amyloidosis, Dutch amyloidosis, inclusion body myositis, Mediterranean fever, Amyloid neuropathy, amyloid cardiomyopathy, systemic amyloidosis, amyloidosis hereditary cerebral hemorrhage, scrapie, Creutzfeldt-Jakob disease, Kurus disease, Gerstmann-Straussler-Shark ink syndrome, thyroid carcinoma, muscle weakness disease , And Langerhans &apos; s type II diabetes mellitus.
8. The method of claim 7,
Wherein the diagnostic composition is used in an opto-imaging method or a photoacoustic-imaging method.
Mixing the curcumin derivative of claim 1 or a pharmaceutically acceptable salt thereof with a sample comprising a beta-amyloid plaque (step 1); And
Measuring the fluorescence signal for the beta-amyloid plaque (step 2);
&Lt; / RTI &gt; wherein the method comprises the steps of:
Mixing the curcumin derivative of claim 1 or a pharmaceutically acceptable salt thereof with a sample comprising a beta-amyloid plaque (step 1); And
Measuring the photoacoustic signal for the beta-amyloid plaque (step 2);
Gt; beta-amyloid plaque. &Lt; / RTI &gt;
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