KR20230094996A - Substituted thiazolidinedione derivative compounds and pharmaceutical composition for preventing or treating cancer comprising the same - Google Patents

Abstract

The present invention provides a substituted thiazolidinedione derivative compound with a novel structure that acts as a sterol regulatory element-binding protein-1 (SREBP1) inhibitor, a hydrate thereof or pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient.

Description

Substituted thiazolidinedione derivative compound and pharmaceutical composition for preventing or treating cancer containing the same

The present invention relates to a substituted thiazolidinedione derivative compound having a novel structure acting as a sterol regulatory element-binding protein-1 (SREBP1) inhibitor, a hydrate thereof or a pharmaceutically acceptable salt thereof, and a cancer treatment comprising the same as an active ingredient. It relates to a pharmaceutical composition for prevention or treatment.

SREBP1 (sterol regulatory element-binding protein-1) is an important transcriptional regulator in fat synthesis and metabolism, an enzyme required for the synthesis of endogenous cholesterol, fatty acids (FAs), triacylglycerols, and/or phospholipids. precisely regulate the expression of

Recently, SREBP1 has been reported in many literatures to play a very important role in cancer metabolism and tumor signaling. According to recent research results, it has been reported that SREBP1 is required for the survival of brain tumor cells with an EGF (epidermal growth factor) signal-dependent anticancer drug resistance mechanism. and increased fatty acid synthesis. As a result, it is known that brain tumor cells promote survival and proliferation through the EGFR/PI3K/Akt/SREBP1 signaling pathway.

Brain tumor is a collective term for primary brain cancer that occurs in the brain tissue and the meninges surrounding the brain, and secondary brain cancer that has metastasized from cancer that has occurred in the skull or other parts of the body. Cancers that occur in the lung, stomach, breast, etc. are limited to one or two types for each organ, and their properties are the same or similar. cancer occurs.

Brain tumors found in adults include glioma, glioblastoma, meningioma (meningioma), pituitary adenoma (adenoma), and schwannoma. Of these, glioblastoma starts from glial cells in brain tissue. It accounts for 12-15% of all brain tumors and is known to be the most common primary brain tumor in adults. These brain tumors are typical intractable solid cancers in which the improvement in survival rate by treatment is insignificant, and a fundamental therapeutic effect cannot be derived by conventional cancer treatment methods.

Accordingly, there is a need to develop an inhibitor capable of selectively inhibiting SREBP1, which plays a very important link in cancer metabolism and tumor signaling.

Curr Pharm Des. 2014;20(15):2619-26. Tumor Biol. 2015 Jun;36(6):4133-41. Cell Death Dis. 2018 Feb 15;9(3):265. Front Oncol. 2022 Jul 14;12:952371. Curr Pharm Des. 2014;20(15):2619-26.

Therefore, the present inventors synthesized compounds with novel structures that can act as inhibitors for SREBP1, and confirmed that they can be used as new anticancer agents by showing anticancer effects in cancer, especially brain tumor models, in vitro and in vivo, and the present invention completed.

An object of the present invention is to provide a substituted thiazolidinedione derivative compound having a novel structure, a hydrate thereof, or a pharmaceutically acceptable salt thereof, which can act as an SREBP1 inhibitor.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising the substituted thiazolidinedione derivative compound, a hydrate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a health functional food composition for preventing or improving cancer, comprising the substituted thiazolidinedione derivative compound, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a method for treating cancer, comprising administering the substituted thiazolidinedione derivative compound, a hydrate thereof or a pharmaceutically acceptable salt thereof to an individual or subject in need thereof .

Another object of the present invention is to provide the substituted thiazolidinedione derivative compound, a hydrate thereof or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

Another object of the present invention is to provide a use of the substituted thiazolidinedione derivative compound, a hydrate thereof or a pharmaceutically acceptable salt thereof for use in the preparation of a drug for the treatment of cancer.

In order to achieve the above purpose,

One aspect of the present invention provides a substituted thiazolidinedione derivative compound represented by Formula 1, a hydrate thereof, or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

는 단일결합 또는 이중결합이고;

is a single bond or a double bond;

또는

이고;Ar ¹ is

or

ego;

R ¹ is C1-C10 alkyl;

R ² is haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy;

R ³ is C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, haloC1-C10 alkoxy or C6-C12 arylalkyloxy;

X ¹ is CH or N;

R ^A is hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C6-C12 arylC1-C10 alkyl or -L ¹ -Het ¹ ;

L ¹ is C1-C10 alkylene;

Het ¹ is C3-C10 heterocycloalkyl;

a1 is an integer from 0 to 3;

b1 and c1 are each independently an integer of 0 to 5.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer comprising a substituted thiazolidinedione derivative compound represented by Formula 2 below, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 2]

In Formula 2,

는 단일결합 또는 이중결합이고;

is a single bond or a double bond;

또는

이고;Ar ² is

or

ego;

R ¹¹ is C1-C10 alkyl;

R ¹² is C1-C10 alkyl, hydroxy, haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy;

R ¹³ is C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, haloC1-C10 alkoxy or C6-C12 arylalkyloxy;

X ² is CH or N;

R ^B is hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C6-C12 arylC1-C10 alkyl or -L ² -Het ² ;

L ² is C1-C10 alkylene;

Het ² is C3-C10 heterocycloalkyl;

a2 is an integer from 0 to 3;

b2 and c2 are each independently an integer of 0 to 5;

Another aspect of the present invention provides a health functional food composition comprising a substituted thiazolidinedione derivative compound represented by Formula 2, a hydrate thereof, or a food chemically acceptable salt thereof as an active ingredient.

Another aspect of the present invention is a treatment of cancer comprising the step of administering a substituted thiazolidinedione derivative compound represented by Formula 2, a hydrate thereof or a pharmaceutically acceptable salt thereof to a subject or subject in need thereof. provides a way

Another aspect of the present invention provides a substituted thiazolidinedione derivative compound represented by Formula 2, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

Another aspect of the present invention provides a use of the substituted thiazolidinedione derivative compound represented by Formula 2, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug for cancer treatment.

The present disclosure relates to a novel substituted thiazolidinedione derivative compound and a pharmaceutical composition for preventing or treating cancer containing the same as an active ingredient, and the compound according to an embodiment has high biocompatibility and high selectivity and can be taken orally. Since it can act as an effective bioavailable SREBP1 inhibitor, it can be usefully used as a pharmaceutical composition for preventing or treating cancer.

The compound according to one embodiment acts as an SREBP1 inhibitor without being toxic to normal cells and can specifically induce apoptosis in cancer cell lines, especially brain tumors, and thus EGF (epidermal growth factor) signal-dependent It can be usefully used without side effects as an efficient improvement, prevention, and treatment for brain tumors with anticancer drug resistance mechanisms.

Figure 1 - Measurement of the activity of derivatives using a cell based-assay system [(a) a cell-based assay system using a 6xSRE reporter vector; (b) Changes in the expression levels of activated forms of SREBP1a and SREBP1c and GFP expression in (c) isolated GFP-low cells; (d) Changes in GFP expression when treated with DMSO, a control group, and fatostatin and FGH10019, which are known to inhibit SREBP activity, respectively]
Figure 2 - Cell viability comparison experiment according to compound treatment in brain tumor stem cell HOG-GSC
Figure 3 - Western blot assay results of Compound 11 (Example 11)
Figure 4 - A graph showing the cell viability of brain tumor stem cells HOG-GSC according to the concentration of Compound 11 (Example 11)
Figure 5 - Graph showing drug concentration in plasma after oral administration (25 mg/kg)
Figure 6 - A graph showing drug concentration in brain tissue after oral administration (25 mg/kg)
Figure 7 - Schematic diagram for in vivo efficacy evaluation test
Figure 8 - Graph showing survival rate over time
Figure 9 - Photograph of the brain tissue of the final surviving mouse on day 66 after tumor transplantation
Figure 10 - Photograph of mouse brain tissue on day 16 after tumor implantation

Hereinafter, the present invention will be described in more detail. At this time, if there is no other definition in the technical terms and scientific terms used, they have meanings commonly understood by those of ordinary skill in the art to which this invention belongs, and will unnecessarily obscure the gist of the present invention in the following description. Descriptions of possible known functions and configurations are omitted.

The embodiments described in this specification may be modified in many different forms, and a technology according to an embodiment is not limited to the embodiment described below. In addition, embodiments of one embodiment are provided to more completely explain the present invention to those skilled in the art. Furthermore, "include" a certain component throughout the specification means that other components may be further included without excluding other components unless otherwise stated.

Numerical ranges, as used herein, include lower and upper limits and all values within that range, increments logically derived from the form and breadth of the range being defined, all values defined therein, and the upper and lower limits of the numerical range defined in different forms. includes all possible combinations of As an example, when the content of the composition is limited to 10% to 80% or 20% to 50%, the numerical range of 10% to 50% or 50% to 80% should also be construed as described in this specification. Unless otherwise specifically defined herein, values outside the numerical range that may occur due to experimental errors or rounding of values are also included in the defined numerical range.

Unless otherwise specified herein, "about" may be considered a value within 30%, 25%, 20%, 15%, 10% or 5% of the specified value.

The following terms used herein are defined as follows, but these are only illustrative and are not intended to limit the present invention, application or use.

The singular form used herein may be intended to include the plural form as well, unless the context dictates otherwise.

As used herein, the terms "substituent", "radical", "group", "moiety", and "fragment" may be used interchangeably.

As used herein, the term "C _A -C _B " means "more than A and less than B", and the term "A to B" means "more than A and less than B".

As used herein, the term "hydrocarbyl" refers to a radical having one binding site derived from hydrocarbon, and "aromatic hydrocarbyl" refers to a radical having one binding site derived from an aromatic hydrocarbon compound.

In the context of "substituted or unsubstituted" as used herein, 'substitution' refers to a group or moiety having one or more substituents attached to the structural backbone of the group or moiety. It means, but not limited to, substitution of a group other than hydrogen in a stated group or structural backbone.

As used herein, the term "alkyl" refers to a monovalent straight-chain or branched saturated hydrocarbon radical composed only of carbon and hydrogen atoms. The alkyl may have 1 to 10 carbon atoms, or 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Examples of the alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethylhexyl, and the like.

As used herein, the term "cycloalkyl" refers to a monovalent saturated carbocyclic radical composed of a single ring. Examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

As used herein, the term "alkoxy" refers to an -O-alkyl radical, where 'alkyl' is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, and the like.

As used herein, the term "halo" or "halogen" refers to a halogen group element and includes, for example, fluoro, chloro, bromo and iodo.

As used herein, the term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group wherein each of one or more hydrogen atoms is replaced by a halogen atom, wherein alkyl, alkoxy and halogen are as defined above. For example, haloalkyl includes fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, perfluoroethyl, etc., and haloalkoxy is fluoromethoxy, difluoromethyl oxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, perfluoroethoxy and the like.

As used herein, the term "aryl" is an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen, either singly or fused, each ring containing preferably 4 to 7, preferably 5 or 6, ring atoms. It includes a ring system, and even includes a form in which a plurality of aryls are connected by single bonds. Examples include, but are not limited to, phenyl, naphthyl, biphenyl, terphenyl, anthryl, fluorenyl, and the like.

As used herein, the term "heterocycloalkyl" is a monovalent radical of a saturated heterocycle containing 1 to 4 heteroatoms selected from N, O and S, and the saturated heterocycle is a monocyclic, multicyclic or spirocyclic ring. It includes not only the form, but also the form fused with an aromatic hydrocarbon ring such as benzene, and may be bonded through a heteroatom or a carbon atom. In addition, a carbon atom in the saturated heterocycle may be substituted with oxo. Examples of such heterocycloalkyl radicals include aziridine, oxetane, pyrrolidine, tetrahydrofuran, dioxolane, dithiolane, imidazolidine, tetrahydropyran, pyrazolidine, pyrrolidinone, azetidine, piperi Dean, piperazine, morpholine, thiomorpholine, dioxane, hexahydroazepine, thiolane, dihydroisoindole, benzodioxole, dihydrobenzodioxin, isoindolinone, indolinone, dihydroisoquinolinone, tetra Hydrobenzoazepinone, 3-azabicyclo[3.1.0]hexane, octahydropyrrolo[3,4-c]pyrrole, 2,7-diazaspiro[4.4]nonane, 2-azaspiro[4.4]nonane It may contain monovalent radicals of saturated heterocycles such as

As used herein, the term "pharmaceutically acceptable" means that it exhibits characteristics that are not toxic to objects such as cells or humans exposed to the composition, and is suitable for use as a pharmaceutical preparation, and generally refers to such use. It is considered safe for such use and is officially approved by a national regulatory authority for such use or is listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

As used herein, the term "pharmaceutically acceptable salt" is a concentration that has a relatively non-toxic and harmless effective effect on patients, and the side effects caused by the salt do not reduce the beneficial effects of the compound itself of the present invention. means any and all organic or inorganic addition salts of a compound.

As used herein, the terms "pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids administration of an active agent and absorption by a subject.

As used herein, the term "prevention" refers to any activity that inhibits or delays the occurrence, spread, and recurrence of cancer.

As used herein, the term "improvement" refers to any activity that at least reduces a parameter related to the condition being treated, for example, the severity of a symptom.

As used herein, the term "treatment" refers to any activity that improves or beneficially changes the symptoms of cancer.

As used herein, the term "individual" refers to all animals, including humans, who have or are likely to develop cancer. The animal may be not only humans but also mammals such as cattle, horses, sheep, pigs, goats, camels, antelopes, dogs, and cats that require treatment for similar symptoms, but are not limited thereto.

As used herein, the term "administration" means introducing the pharmaceutical composition of the present invention to a subject by any appropriate method, and the administration route of the composition of the present invention is various oral or parenteral routes as long as it can reach the target tissue. can be administered through

As used herein, the term "pharmaceutically effective amount" means an amount that is sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is dependent on the patient's gender, Factors including age, weight, health condition, type and severity of disease, activity of drug, sensitivity to drug, method of administration, time of administration, route of administration, and excretion rate, duration of treatment, combinations or drugs used concurrently, and other medical It can be readily determined by a person skilled in the art according to factors well known in the art.

As used herein, the term "food" means meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcohol Beverages, vitamin complexes, health functional foods and health foods, etc., include all foods in a conventional sense.

As used herein, the term "functional health food" refers to food manufactured and processed using raw materials or ingredients having useful functionalities for the human body according to the Act on Health Functional Foods No. 6727, and "functional" refers to the human body. It refers to intake for the purpose of obtaining useful effects for health purposes such as regulating nutrients for the structure and function of food or physiological functions.

As used herein, the term "acceptable food salt" means a formulation of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound.

One embodiment provides a substituted thiazolidinedione derivative compound represented by Formula 1 below, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Formula 1,

는 단일결합 또는 이중결합이고;

is a single bond or a double bond;

또는

이고;Ar ¹ is

or

ego;

R ¹ is C1-C10 alkyl;

R ² is haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy;

R ³ is C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, haloC1-C10 alkoxy or C6-C12 arylalkyloxy;

X ¹ is CH or N;

R ^A is hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C6-C12 arylC1-C10 alkyl or -L ¹ -Het ¹ ;

L ¹ is C1-C10 alkylene;

Het ¹ is C3-C10 heterocycloalkyl;

a1 is an integer from 0 to 3;

b1 and c1 are each independently an integer of 0 to 5.

The substituted thiazolidinedione derivative compound represented by Chemical Formula 1 according to the present invention is a compound having a novel structure and can be used as an active ingredient for preventing or treating cancer by inhibiting SREBP1 essential for the survival of cancer stem cells. Cancer stem cells, which are responsible for the growth and metastasis of cancer cells and resistance to anticancer drugs, are highly dependent on the regulation of lipid metabolism by SREBP1, a transcription factor protein that promotes lipid synthesis. Therefore, since the compound according to the present invention acts as an SREBP1 inhibitor and selectively inhibits SREBP1 to eliminate cancer stem cells and cancer cells, it can be useful as a target anticancer agent for cancer.

In addition, since the compound of the present invention has high biocompatibility, high selectivity, is orally bioavailable, and acts as an SREBP1 inhibitor without showing toxicity to normal cells, it can specifically induce apoptosis only in cancer cell lines. It can be used effectively without side effects as an effective preventive and therapeutic agent. Cancer diseases that can be prevented, treated, or ameliorated by treatment with the compound according to the present invention are intractable solid cancers, specifically, glioma, glioblastoma, meningioma (meningioma), pituitary adenoma (adenoma) , brain tumors such as schwannoma, etc.

In one embodiment, a1 is an integer from 0 to 2; b1 may be an integer from 0 to 2.

In one embodiment, c1 may be an integer of 0 to 2.

는 이중결합이고; Ar¹은

이고; R²은 할로C1-C4알킬옥시 또는 C6-C12아릴C1-C4알킬옥시이고; a1는 0 내지 2의 정수이며; b1은 0 내지 2의 정수이고; R^A는 수소, C1-C4알킬, C3-C8사이클로알킬 또는 -L¹-Het¹이고; L¹은 C1-C4알킬렌이고; Het¹는 C3-C8헤테로사이클로알킬일 수 있다.In one embodiment,

is a double bond; Ar ¹ is

ego; R ² is haloC1-C4alkyloxy or C6-C12arylC1-C4alkyloxy; a1 is an integer from 0 to 2; b1 is an integer from 0 to 2; R ^A is hydrogen, C1-C4alkyl, C3-C8cycloalkyl or -L ¹ -Het ¹ ; L ¹ is C1-C4alkylene; Het ¹ may be C3-C8 heterocycloalkyl.

는 이중결합이고; Ar¹은

,

또는

이고; R^a 및 R^b는 각각 독립적으로 C1-C4알킬이고; R²은 할로C1-C4알킬옥시 또는 C6-C12아릴C1-C4알킬옥시이고; b1은 0 내지 2의 정수이고; R^A는 수소, C1-C4알킬, C3-C8사이클로알킬 또는

이고; Z은 O 또는 S이고; d는 1 내지 4의 정수일 수 있다.In one embodiment,

is a double bond; Ar ¹ is

,

or

ego; R ^a and R ^b are each independently C1-C4 alkyl; R ² is haloC1-C4alkyloxy or C6-C12arylC1-C4alkyloxy; b1 is an integer from 0 to 2; R ^A is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl or

ego; Z is O or S; d may be an integer from 1 to 4.

는 단일결합 또는 이중결합이고; Ar¹은

이고; X¹는 CH 또는 N이고; R³은 C1-C4알킬, 할로C1-C4알킬, C1-C4알콕시, 할로C1-C4알콕시 또는 C6-C12아릴C1-C4알킬옥시이고; c1는 0 내지 2의 정수이고; R^A는 수소, C1-C4알킬, C3-C8사이클로알킬 또는 -L¹-Het¹이고; L¹은 C1-C4알킬렌이고; Het¹는 C3-C8헤테로사이클로알킬일 수 있다.In one embodiment,

is a single bond or a double bond; Ar ¹ is

ego; X ¹ is CH or N; R ³ is C1-C4alkyl, haloC1-C4alkyl, C1-C4alkoxy, haloC1-C4alkoxy or C6-C12arylC1-C4alkyloxy; c1 is an integer from 0 to 2; R ^A is hydrogen, C1-C4alkyl, C3-C8cycloalkyl or -L ¹ -Het ¹ ; L ¹ is C1-C4alkylene; Het ¹ may be C3-C8 heterocycloalkyl.

는 단일결합 또는 이중결합이고; Ar¹은

,

,

,

또는

이고; R³은 C1-C4알킬, 할로C1-C4알킬, C1-C4알콕시, 할로C1-C4알콕시 또는 C6-C12아릴C1-C4알킬옥시이고; c1는 0 내지 2의 정수이고; R^A는 수소, C1-C4알킬, C3-C8사이클로알킬 또는

이고; Z은 O 또는 S이고; d는 1 내지 4의 정수일 수 있다.In one embodiment,

is a single bond or a double bond; Ar ¹ is

,

,

,

or

ego; R ³ is C1-C4alkyl, haloC1-C4alkyl, C1-C4alkoxy, haloC1-C4alkoxy or C6-C12arylC1-C4alkyloxy; c1 is an integer from 0 to 2; R ^A is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl or

ego; Z is O or S; d may be an integer from 1 to 4.

In one embodiment, the Ar ¹ may be selected from the following structure.

일 수 있다.In one embodiment, R ^A is hydrogen, methyl, ethyl or

can be

In one embodiment, the substituted thiazolidinedione derivative compound may be any one selected from the group of compounds below, but is not limited thereto:

( Z )-5-((1-(4-(trifluoromethoxy)phenyl)-1 H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((1-(4-(benzyloxy)phenyl)-1 H -pyrrole-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((1-(4-(benzyloxy)phenyl)-1 H -pyrrol-3-yl)methylene)thiazolidine-2,4-dione;

(Z)-5-((2-( p -tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-(4-( t -butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-(4-(trifluoromethyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-(4-methoxyphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-(4-(trifluoromethoxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-(4-(benzyloxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-( o -tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

(Z)-5-((2-( m -tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-(3-( t -butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-(3,5-dimethylphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

5-((2-(4-( t -butyl)phenyl)pyridin-4-yl)methyl)thiazolidine-2,4-dione;

( Z )-5-((2-(4-( t -butyl)phenyl)pyridin-4-yl)methylene)-3-methylthiazolidine-2,4-dione;

( Z )-5-((2-(4-( t -butyl)phenyl)pyridin-4-yl)methylene)-3-(2-morpholinoethyl)thiazolidine-2,4-dione;

( Z )-5-((6-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((6-(4-methoxyphenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((5-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((5-( p -tolyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((5-(4-( t -butyl)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((4-phenylpyridin-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((4-( p -tolyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((4-(4-( t -butyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione; and

( Z )-5-((6-(4-( t -butyl)phenyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione.

The above-mentioned compounds can be prepared based on the examples described below. Representative examples are described in the following examples, but substituents may be added or excluded, and the position of the substituent may be changed, if necessary. In addition, based on techniques known in the art, starting materials, reactants, reaction conditions, and the like can be changed. Changing the type or position of the substituents at the remaining positions, if necessary, can be performed by those skilled in the art using techniques known in the art. Further details are described in the Examples below.

The substituted thiazolidinedione derivative compound according to an embodiment includes not only pharmaceutically acceptable salts thereof, but also hydrates and solvates that can be prepared therefrom.

Since the substituted thiazolidinedione derivative compound may be used in the form of a prodrug, hydrate, solvate, or pharmaceutically acceptable salt in order to enhance absorption in vivo or increase solubility, the scope of the present invention includes the above formula Not only the compound of 1, but also a prodrug thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt form thereof also fall within the scope of the present invention.

The substituted thiazolidinedione derivative compound according to an embodiment may be used in the form of a pharmaceutically acceptable salt, and the pharmaceutically acceptable salt is a salt prepared according to a conventional method in the art. Methods are known to those skilled in the art. Specifically, the pharmaceutically acceptable salt includes, but is not limited to, pharmacologically or physiologically acceptable salts derived from free acids and bases.

Acid addition salts formed by pharmaceutically acceptable free acids include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, Fluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorb It is obtained from organic acids such as acid, carbonic acid, vanillic acid, and hydroiodic acid. Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, Bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succi nate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxy Benzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxy oxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt can be prepared by a conventional method, for example, dissolving the substituted thiazolidinedione derivative compound according to one embodiment in a water-miscible organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc. Alternatively, it may be prepared by filtering and drying the precipitate produced by adding an inorganic acid, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.

In addition, a pharmaceutically acceptable metal salt may be prepared using a base. An alkali metal salt or alkaline earth metal salt, for example, by dissolving a substituted thiazolidinedione derivative compound according to an embodiment in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating the filtrate , obtained by drying At this time, as the metal salt, it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt, but is not limited thereto. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

The hydrate of the substituted thiazolidinedione derivative compound according to an embodiment contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. It means a compound containing or a pharmaceutically acceptable salt thereof.

A solvate of a substituted thiazolidinedione derivative compound according to an embodiment refers to a compound containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces or a pharmaceutically acceptable salt thereof. do. Solvents that can be used include those that are volatile and non-toxic.

That is, the substituted thiazolidinedione derivative compound according to one embodiment is dissolved in a water-miscible solvent such as methanol, ethanol, acetone, or 1,4-dioxane, and then crystallized after adding a free acid or base. Alternatively, it may be recrystallized to form solvates including hydrates.

Another embodiment provides a pharmaceutical composition for preventing or treating cancer comprising a substituted thiazolidinedione derivative compound represented by Formula 2, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 2]

In Formula 2,

는 단일결합 또는 이중결합이고;

is a single bond or a double bond;

또는

이고;Ar ² is

or

ego;

R ¹¹ is C1-C10 alkyl;

R ¹² is C1-C10 alkyl, hydroxy, haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy;

R ¹³ is C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, haloC1-C10 alkoxy or C6-C12 arylalkyloxy;

X ² is CH or N;

R ^B is hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C6-C12 arylC1-C10 alkyl or -L ² -Het ² ;

L ² is C1-C10 alkylene;

Het ² is C3-C10 heterocycloalkyl;

a2 is an integer from 0 to 3;

b2 and c2 are each independently an integer of 0 to 5;

In one embodiment, the pharmaceutical composition can be used for the purpose of treatment, prevention and alleviation of cancer diseases caused by abnormal cell growth. A cancer disease that can be prevented, treated, or alleviated by treatment with the pharmaceutical composition may be a brain tumor.

Specifically, the pharmaceutical composition can selectively inhibit sterol regulatory element-binding protein 1 (SREBP1), and by selectively inhibiting SREBP1, it can exert a preventive or therapeutic effect on cancer. Accordingly, the pharmaceutical composition can act as an SREBP1 inhibitor to specifically induce apoptosis in cancer cell lines, particularly brain tumors, thereby efficiently improving brain tumors having an epidermal growth factor (EGF) signal-dependent anticancer drug resistance mechanism. , it can be usefully used as a preventive and therapeutic agent without side effects.

According to one embodiment, treatment with the substituted thiazolidinedione derivative compound suppressed SREBP1 and inhibited the proliferation of brain tumor cells. Accordingly, the substituted thiazolidinedione derivative compound according to the present invention may be useful for treating or preventing cancer diseases by inhibiting proliferation of cancer cells by selectively inhibiting SREBP1 in cancer tissues such as brain tumors.

In Chemical Formula 2 according to an embodiment, a2 is an integer of 0 to 2; b2 may be an integer from 0 to 2.

In Chemical Formula 2 according to an embodiment, c2 may be an integer of 0 to 2.

는 이중결합이고; Ar²은

이고; R¹²은 C1-C10알킬, 하이드록시, 할로C1-C10알킬옥시 또는 C6-C12아릴C1-C10알킬옥시이고; a2는 0 내지 2의 정수이며; b2은 0 내지 2의 정수이고; R^B는 수소, C1-C4알킬, C3-C8사이클로알킬 또는 -L²-Het²이고; L²은 C1-C4알킬렌이고; Het²는 C3-C8헤테로사이클로알킬일 수 있다.In Formula 2 according to an embodiment,

is a double bond; Ar ² is

ego; R ¹² is C1-C10 alkyl, hydroxy, haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy; a2 is an integer from 0 to 2; b2 is an integer from 0 to 2; R ^B is hydrogen, C1-C4alkyl, C3-C8cycloalkyl or -L ² -Het ² ; L ² is C1-C4 alkylene; Het ² may be C3-C8 heterocycloalkyl.

는 이중결합이고; Ar²은

,

또는

이고; R^c 및 R^d는 각가 독립적으로 C1-C4알킬이고; R¹²은 C1-C4알킬, 하이드록시, 할로C1-C4알킬옥시 또는 C6-C12아릴C1-C4알킬옥시이고; b2는 0 내지 2의 정수이며; R^B는 수소, C1-C4알킬, C3-C8사이클로알킬 또는

이고; Z은 O 또는 S이고; e는 1 내지 4의 정수일 수 있다.In Formula 2 according to an embodiment,

is a double bond; Ar ² is

,

or

ego; R ^c and R ^d are each independently C1-C4 alkyl; R ¹² is C1-C4alkyl, hydroxy, haloC1-C4alkyloxy or C6-C12arylC1-C4alkyloxy; b2 is an integer from 0 to 2; R ^B is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl or

ego; Z is O or S; e may be an integer from 1 to 4.

는 단일결합 또는 이중결합이고; Ar²은

이고; X²는 CH 또는 N이고; R¹³은 C1-C4알킬, 할로C1-C4알킬, C1-C4알콕시, 할로C1-C4알콕시 또는 C6-C12아릴C1-C4알킬옥시이고; c2는 0 내지 2의 정수이고; R^B는 수소, C1-C4알킬, C3-C8사이클로알킬 또는 -L²-Het²이고; L²은 C1-C4알킬렌이고; Het²는 C3-C8헤테로사이클로알킬일 수 있다.In Formula 2 according to an embodiment,

is a single bond or a double bond; Ar ² is

ego; X ² is CH or N; R ¹³ is C1-C4alkyl, haloC1-C4alkyl, C1-C4alkoxy, haloC1-C4alkoxy or C6-C12arylC1-C4alkyloxy; c2 is an integer from 0 to 2; R ^B is hydrogen, C1-C4alkyl, C3-C8cycloalkyl or -L ² -Het ² ; L ² is C1-C4 alkylene; Het ² may be C3-C8 heterocycloalkyl.

는 단일결합 또는 이중결합이고; Ar²은

,

,

,

또는

이고; R¹³은 C1-C4알킬, 할로C1-C4알킬, C1-C4알콕시, 할로C1-C4알콕시 또는 C6-C12아릴C1-C4알킬옥시이고; c2는 0 내지 2의 정수이고; R^B는 수소, C1-C4알킬, C3-C8사이클로알킬 또는

이고; Z은 O 또는 S이고; e는 1 내지 4의 정수일 수 있다.In Formula 2 according to an embodiment,

is a single bond or a double bond; Ar ² is

,

,

,

or

ego; R ¹³ is C1-C4alkyl, haloC1-C4alkyl, C1-C4alkoxy, haloC1-C4alkoxy or C6-C12arylC1-C4alkyloxy; c2 is an integer from 0 to 2; R ^B is hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl or

ego; Z is O or S; e may be an integer from 1 to 4.

In Chemical Formula 2 according to an embodiment, Ar ² may be selected from the following structures.

일 수 있다.In Formula 2 according to an embodiment, R ^B is hydrogen, methyl, ethyl or

can be

According to an embodiment, the substituted thiazolidinedione derivative compound represented by Chemical Formula 2 may be any one selected from the group of compounds below, but is not limited thereto:

( Z )-5-((1-phenyl- 1H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((1-( p -tolyl)-1 H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((1-(4-( t -butyl)phenyl)-1 H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((1-(4-hydroxyphenyl)-1 H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((1-(4-(trifluoromethoxy)phenyl)-1 H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((1-(4-(benzyloxy)phenyl)-1 H -pyrrole-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((3,4-dimethyl-1-phenyl-1 H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((1-phenyl- 1H -pyrrol-3-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((1-(4-(benzyloxy)phenyl)-1 H -pyrrol-3-yl)methylene)thiazolidine-2,4-dione;

(Z)-5-((2-( p -tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-(4-( t -butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-(4-(trifluoromethyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-(4-methoxyphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-(4-(trifluoromethoxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-(4-(benzyloxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-( o -tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

(Z)-5-((2-( m -tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-(3-( t -butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((2-(3,5-dimethylphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;

5-((2-(4-( t -butyl)phenyl)pyridin-4-yl)methyl)thiazolidine-2,4-dione;

( Z )-5-((2-(4-( t -butyl)phenyl)pyridin-4-yl)methylene)-3-methylthiazolidine-2,4-dione;

( Z )-5-((2-(4-( t -butyl)phenyl)pyridin-4-yl)methylene)-3-(2-morpholinoethyl)thiazolidine-2,4-dione;

( Z )-5-((6-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((6-(4-methoxyphenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((5-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((5-( p -tolyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((5-(4-( t -butyl)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((4-phenylpyridin-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((4-( p -tolyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((4-(4-( t -butyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione;

( Z )-5-((4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione; and

( Z )-5-((6-(4-( t -butyl)phenyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione.

The pharmaceutical composition according to an embodiment further includes a conventional non-toxic pharmaceutically acceptable carrier and/or excipient in addition to the active ingredient, and is a conventional preparation in the pharmaceutical field, that is, a preparation for oral administration or a preparation for parenteral administration. It can be formulated as In addition, diluents such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants may be further included.

Examples of the pharmaceutically acceptable carrier, excipient or diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, dextrins, cyclodextrins such as α-, β and γ cyclodextrins, hydroxyalkylcyclo dextrin (including 2- and 3-hydroxypropyl-β cyclodextrin), talc, magnesium stearate, or mineral oil, but is not limited thereto.

The pharmaceutical composition is formulated in various forms such as oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and sterile injection solutions according to conventional methods according to the purpose of use. It can be used and can be administered orally or through various routes including intravenous, intraperitoneal, subcutaneous, rectal, topical, and the like.

The formulation for oral administration may optionally be enteric coated, and may exhibit a delayed or sustained release through the enteric coating. That is, the preparation for oral administration may be a dosage form having an immediate or modified release pattern.

The formulation for parenteral administration may be a formulation having an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.

The pharmaceutical composition according to one embodiment may further include fillers, anti-agglomerating agents, lubricants, wetting agents, flavoring agents, emulsifiers, preservatives, and the like.

Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, etc. One or more diluents or excipients such as extenders, wetting agents, disintegrants, lubricants, binders, and surfactants may be used. As the disintegrant, agar, starch, alginic acid or sodium salt thereof, calcium monohydrogen phosphate anhydrous salt, etc. may be used, and as the lubricant, silica, talc, stearic acid or magnesium salt or calcium salt thereof, polyethylene glycol, etc. may be used. , Magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low-substituted hydroxypropyl cellulose and the like may be used as the binder. In addition, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, etc. may be used as diluents, and in some cases, generally known boiling mixtures, absorbents, coloring agents, flavoring agents, sweetening agents, etc. may be used together.

Examples of preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspensions. As a base for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerol, gelatin, etc. may be used. Meanwhile, conventional additives such as solubilizers, tonicity agents, suspending agents, emulsifiers, stabilizers, and preservatives may be included in the injection. In order to formulate an injection, the active ingredient may be mixed in water with a stabilizer or buffer to prepare a solution or suspension, which may be prepared in unit dosage form in an ampoule or vial.

The pharmaceutical composition according to one embodiment may be sterilized or may further contain adjuvants such as preservatives, stabilizers, thickeners, hydration agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful compositions. It may further contain substances, and may be formulated according to conventional methods such as dissolution, dispersion, mixing, granulation, gelation, or coating.

In the pharmaceutical composition according to an embodiment, the pharmaceutically effective amount of the substituted thiazolidinedione derivative compound, which is an active ingredient, depends on the patient's health condition, disease type, severity, drug activity, drug sensitivity, administration method, It may be determined according to factors including time of administration, route of administration and excretion rate, duration of treatment, drugs used in combination or concomitantly, and other factors well known in the medical arts. Specifically, the effective amount of the substituted thiazolidinedione derivative compound in the pharmaceutical composition may vary depending on the patient's age, sex, and weight, and is generally about 0.001 to 500 mg/kg/day, preferably 0.01 to 100 mg/kg/day, may be administered daily or every other day, or divided into once to several times a day. However, since it may increase or decrease depending on the route of administration, severity of disease, sex, weight, age, etc., the dosage is not limited to the scope of the present invention in any way.

The pharmaceutical composition according to one embodiment can be administered orally or parenterally, and the substituted thiazolidinedione derivative compound enters the gastrointestinal tract by oral administration as an anticancer agent for oral administration to treat cancer, or , can be directly absorbed from the mouth into the bloodstream, for example by buccal or sublingual administration.

The pharmaceutical composition according to one embodiment may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, or may be administered singly or in multiple doses. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.

Another embodiment provides a health functional food composition for preventing or improving cancer using the substituted thiazolidinedione derivative compound, a hydrate thereof, or a food chemically acceptable salt thereof.

The food chemically acceptable salt is a compound of the present invention hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, inorganic acids such as phosphoric acid, sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, tartaric acid, formic acid, citric acid, acetic acid , trichloroacetic acid, trifluoroacetic acid, capric acid, isobutanoic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and the like. In addition, by reacting the compound of the present invention with a base, salts such as alkali metal salts such as ammonium salts, sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, dicyclohexylamine, N-methyl-D-glucamine , It may also be obtained by forming salts of organic bases such as tris (hydroxymethyl) methylamine, and amino acid salts such as arginine and lysine, but is not limited thereto.

The health functional food composition may be provided in the form of a powder, granule, tablet, capsule, syrup or beverage. can be used appropriately. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use thereof, for example, prevention, health or therapeutic treatment.

The health functional food composition includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, colorants and enhancers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts , organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, and the like. In addition, it may contain fruit flesh for the manufacture of natural fruit juice, fruit juice beverages and vegetable beverages. These components may be used independently or in combination.

In addition, the health functional food may additionally contain food additives, and the suitability as a 'food additive' is determined according to the general rules of the Food Additive Code and general test methods approved by the Korea Food and Drug Administration unless otherwise specified. It is judged according to standards and standards.

Examples of items listed in the 'Food Additive Code' include chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as dark pigment, licorice extract, crystalline cellulose, and guar gum, sodium L-glutamate Mixed preparations such as preparations, noodle-added alkali preparations, preservative preparations, and tar color preparations may be mentioned.

The substituted thiazolidinedione derivative compound of the present invention contained in the health functional food composition can be used according to the effective dose of the pharmaceutical composition, but long-term for the purpose of health and hygiene or health control In the case of ingestion, it may be less than the above range, and the active ingredient may be used in an amount greater than the above range because there is no problem in terms of safety.

The health functional food composition is meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages and vitamin complexes It can be formulated into various formulations such as the like.

Another embodiment provides a selective inhibitor of SREBP1 comprising the substituted thiazolidinedione derivative compound, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Another embodiment is a cancer treatment comprising the step of administering the substituted thiazolidinedione derivative compound, a hydrate thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to a subject having or at risk of developing cancer. A method for preventing or treating is provided.

In addition, the present invention provides the substituted thiazolidinedione derivative compound, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

In addition, the present invention provides a use of the substituted thiazolidinedione derivative compound, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in the preparation of a drug for cancer treatment.

Hereinafter, Examples and Experimental Examples will be specifically exemplified and described. However, the examples and experimental examples to be described below are merely illustrative of a part, and the technology described herein is not limited thereto.

Example I: Synthesis of Phenyl-Pyrrole Backbone Compound

[Example 1] Preparation of ( Z )-5-((1-Phenyl- 1H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 1)

Step 1: 1-Phenyl-1 H Preparation of -pyrrole-2-carbaldehyde (compound a-1)

After adding 1 H -Pyrrole-2-carbaldehyde (200 mg, 2.1 mmol), copper(II) acetate hydrate (840 mg, 4.2 mmol), and triethylamine (851 mg, 8.4 mmol) to dichloromethane (15 ml), phenylboronic acid (769 mg, 6.31 mmol) was added dropwise and stirred at room temperature for 48 hours. After completion of the reaction, extraction was performed using EtOAc and water, and the resulting organic layer was washed with brine, dried over magnesium sulfate, and filtered. The residue obtained by distilling the filtered solution under reduced pressure was separated and purified by medium pressure liquid chromatography to obtain 1-phenyl-1 H -pyrrole-2-carbaldehyde (compound a-1) (158 mg, 44% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 7.50 - 7.37 (m, 3H), 7.37 - 7.31 (m, 2H), 7.16 (dd, J = 4.0, 1.7 Hz, 1H), 7.06 (t, J = 1.9 Hz, 1H), 6.39 (dd, J = 4.0, 2.6 Hz, 1H).

Step 2: ( Z )-5-((1-Phenyl-1 H Preparation of -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 1)

Compound a-1 obtained in step 1 (50 mg, 0.292 mmol), thiazolidine-2,4-dione (37 mg, 0.321 mmol), piperidine (0.029 ml, 0.292 mmol), and acetic acid (0.017 ml, 0.292 mmol) After dissolving in toluene (5 ml), react by stirring at 100 ° C. for 2 hours. After completion of the reaction, extraction was performed using EtOAc and water, and the obtained organic layer was washed with brine, dried over magnesium sulfate, and filtered. The residue obtained by distilling the filtered solution under reduced pressure is separated and purified using medium pressure liquid chromatography (silica gel, 0-30% EtOAc/Hexane) to obtain a compound. The obtained compound was recrystallized using EtOAc to obtain a solidified final target compound, ( Z )-5-((1-phenyl- 1H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 1). (28 mg, 35% yield).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.37 (br s, 1H), 7.65 - 7.52 (m, 3H), 7.46 - 7.41 (m, 3H), 7.30 (s, 1H), 6.72 (d, J = 3.8 Hz, 1H), 6.57 - 6.53 (m, 1H); LCMS (ESI), m/z = 270.95 [M+H] ⁺ .

[Example 2] Preparation of ( Z )-5-((1-( p -Tolyl) -1H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 2)

Step 1: 1-( p -Tolyl)-1 H Preparation of -pyrrole-2-carbaldehyde (compound a-2)

1-( p -tolyl) was prepared in the same manner as in Step 1 of Example 1, except that 4,4,5,5-tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane was used instead of phenylboronic acid. ) -1H -pyrrole-2-carbaldehyde (Compound a-2) was obtained (180 mg, 30% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.55 (s, 1H), 7.27 - 7.20 (m, 4H), 7.15 (dd, J = 4.0, 1.6 Hz, 1H), 7.05 - 7.02 (m, 1H), 6.38 (dd, J = 3.9, 2.6 Hz, 1H), 2.41 (s, 3H).

Step 2: ( Z )-5-((1-( p -Tolyl)-1 H Preparation of -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 2)

The target compound, ( Z )-5-((1-( p -tolyl) -1H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 2) was obtained (25 mg, 53% yield).

¹ H NMR (400 MHz, (CD ₃ ) ₂ CO) δ 10.88 (br s, 1H), 7.44 (s, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.34 - 7.29 (m, 2H) , 7.27 (dd, J = 2.7, 1.4 Hz, 1H), 6.74 (dd, J = 4.1, 0.9 Hz, 1H), 6.56 - 6.49 (m, 1H), 2.44 (s, 3H); LCMS (ESI), m/z = 284.93 [M+H] ⁺ .

[Example 3] Preparation of ( Z )-5-((1-(4-( tert -Butyl)phenyl) -1H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 3)

Step 1: 1-(4-( tert -Butyl)phenyl)-1 H Preparation of -pyrrole-2-carbaldehyde (compound a-3)

1 H -Pyrrole-2-carbaldehyde (300 mg, 3.15 mmol), copper(II) acetate hydrate (1.26 g, 6.3 mmol), and triethylamine (1.59 g, 15.7 mmol) were added to dichloroethane (15 ml) (4 After adding -( tert -butyl)phenyl)boronic acid (1.12 g, 3.15 mmol) dropwise, the mixture was stirred at 80 °C for 48 hours. After completion of the reaction, extraction was performed using EtOAc and water, and the resulting organic layer was washed with brine, dried over magnesium sulfate, and filtered. The residue obtained by distillation of the filtered solution under reduced pressure was separated and purified by medium pressure liquid chromatography to obtain 1-(4-( tert -butyl)phenyl)-1 H -pyrrole-2-carbaldehyde (compound a-3) (130 mg, 18% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.57 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.17 (dd, J = 4.0, 1.6 Hz, 1H), 7.07 (t, J = 1.9 Hz, 1H), 6.40 (dd, J = 3.9, 2.7 Hz, 1H), 1.37 (s, 9H).

Step 2: ( Z )-5-((1-(4-( tert -Butyl)phenyl)-1 H Preparation of -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 3)

The reaction was carried out with stirring at 100° C. for 3 hours in the same manner as in Step 2 of Example 1, except that compound a-3 (30 mg, 0.132 mmol) was used instead of compound a-1. After completion of the reaction, extraction was performed using EtOAc and water, and the obtained organic layer was washed with brine, dried over magnesium sulfate, and filtered. The residue obtained by distillation of the filtered solution under reduced pressure was separated by medium pressure liquid chromatography (silica gel, 0-30% EtOAc/Hexane) and then separated by preparative liquid chromatography (30-50% water/MeCN with 0.1% TFA). Further purification yielded the target compound, ( Z )-5-((1-(4-( tert -butyl)phenyl) -1H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 3) (20 mg, 46% yield, TFA salt).

^1H NMR (400 MHz, MeOD) δ 7.61 (d, J = 8.5 Hz, 2H), 7.47 (s, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.21 (dd, J = 2.3, 1.5 Hz, 1H), 6.75 (d, J = 3.4 Hz, 1H), 6.53 - 6.47 (m, 1H), 1.40 (s, 9H); LCMS (ESI), m/z = 326.97 [M+H] ⁺ .

[Example 4] Preparation of ( Z )-5-((1-(4-Hydroxyphenyl)-1H - pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 4)

Step 1: 1-(4-Hydroxyphenyl)-1 H Preparation of -pyrrole-2-carbaldehyde (compound a-4)

1-(4-hydroxyphenyl) -1H -pyrrole-2-carbaldehyde (Compound a-4) was obtained in the same manner as in Step 1 of Example 1, except that (4-hydroxyphenyl)boronic acid was used instead of phenylboronic acid. (110 mg, 18% yield).

Step 2: ( Z )-5-((1-(4-Hydroxyphenyl)-1 H Preparation of -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 4)

The target compound, ( Z )-5-((1-(4-hydroxyphenyl) -1 H -pyrrol-2-yl) methylene) thiazolidine-2,4-dione (Compound 4) was obtained (7 mg, 15% yield).

^1H NMR (400 MHz, MeOD) δ 7.42 (s, 1H), 7.21 - 7.13 (m, 3H), 6.93 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 3.9 Hz, 1H), 6.49 - 6.45 (m, 1H); LCMS (ESI), m/z = 286.91 [M+H] ⁺ .

[Example 5] Preparation of ( Z )-5-((1-(4-(Trifluoromethoxy)phenyl) -1H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 5)

Step 1: 1-(4-(Trifluoromethoxy)phenyl)-1 H Preparation of -pyrrole-2-carbaldehyde (compound a-5)

1-(4-(trifluoromethoxy)phenyl) -1H- pyrrole-2-carbaldehyde (compound a-5) was obtained (130 mg, 16% yield).

Step 2: ( Z )-5-((1-(4-(Trifluoromethoxy)phenyl)-1 H Preparation of -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 5)

The target compound, ( Z )-5-((1-(4-(trifluoromethoxy) )phenyl) -1H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 5) was obtained (15 mg, 27% yield).

¹ H NMR (400 MHz, MeOD) δ 7.55 - 7.46 (m, 4H), 7.42 (s, 1H), 7.27 (dd, J = 2.4, 1.3 Hz, 1H), 6.78 (d, J = 3.9 Hz, 1H) ), 6.57 - 6.51 (m, 1H); LCMS (ESI), m/z = 354.87 [M+H] ⁺ .

[Example 6] Preparation of ( Z )-5-((1-(4-(Benzyloxy)phenyl) -1H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 6)

Step 1: 1-(4-(Benzyloxy)phenyl)-1 H Preparation of -pyrrole-2-carbaldehyde (compound a-6)

1-(4-(benzyloxy)phenyl)-1 H -pyrrole-2-carbaldehyde (compound a-6) was obtained (160 mg, 18% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.54 (s, 1H), 7.49 - 7.38 (m, 4H), 7.36 (d, J = 7.0 Hz, 1H), 7.30 - 7.26 (m, 2H), 7.14 ( dd, J = 4.0, 1.6 Hz, 1H), 7.04 (dd, J = 9.4, 2.6 Hz, 3H), 6.38 (dd, J = 3.9, 2.6 Hz, 1H), 5.11 (s, 2H).

Step 2: ( Z )-5-((1-(4-(Benzyloxy)phenyl)-1 H Preparation of -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 6)

The target compound, ( Z )-5-((1-(4-(benzyloxy) )phenyl) -1H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 6) was obtained (28 mg, 41% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 7.51 (s, 1H), 7.50 - 7.32 (m, 5H), 7.22 (d, J = 8.8 Hz, 2H), 7.13 - 7.03 (m, 3H), 6.74 ( d, J = 3.8 Hz, 1H), 6.54 - 6.46 (m, 1H), 5.13 (s, 2H); LCMS (ESI), m/z = 377.02 [M+H] ⁺ .

[Example 7] Preparation of ( Z )-5-((3,4-Dimethyl-1-phenyl- 1H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 7)

Step 1: 3,4-Dimethyl-1-phenyl-1 H Preparation of -pyrrole-2-carbaldehyde (compound a-7)

3,4-dimethyl-1-phenyl-1 was prepared in the same manner as in Step 1 of Example 1, except that 3,4-dimethyl - 1 H -pyrrole-2-carbaldehyde was used instead of 1 H -Pyrrole-2-carbaldehyde. H -pyrrole-2-carbaldehyde (compound a-7) was obtained (210 mg, 65% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.62 (s, 1H), 7.48 - 7.34 (m, 3H), 7.34 - 7.27 (m, 2H), 6.80 (s, 1H), 2.38 (s, 3H), 2.06 (s, 3H).

Step 2: ( Z )-5-((3,4-Dimethyl-1-phenyl-1 H Preparation of -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 7)

The target compound, ( Z )-5-((3,4-dimethyl-1 -phenyl-1 H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione (Compound 7) was obtained (10 mg, 17% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18 (s, 1H), 7.73 (s, 1H), 7.45 - 7.38 (m, 2H), 7.37 - 7.31 (m, 1H), 7.22 (d, J = 7.7 Hz, 2H), 6.88 (s, 1H), 2.17 (s, 3H), 2.06 (s, 3H); LCMS (ESI), m/z = 299.03 [M+H] ⁺ .

[Example 8] Preparation of ( Z )-5-((1-Phenyl- 1H -pyrrol-3-yl)methylene)thiazolidine-2,4-dione (Compound 8)

Step 1: 1-Phenyl-1 H Preparation of -pyrrole-3-carbaldehyde (compound a-8)

1 - phenyl-1 H -pyrrole-3-carbaldehyde (compound a-8 ) was obtained (158 mg, 44% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.86 (s, 1H), 7.67 (t, J = 1.9 Hz, 1H), 7.52 - 7.45 (m, 2H), 7.42 (dd, J = 8.6, 1.3 Hz, 2H), 7.36 (ddd, J = 8.3, 2.4, 1.2 Hz, 1H), 7.09 (dd, J = 3.7, 1.5 Hz, 1H), 6.81 (dd, J = 2.9, 1.6 Hz, 1H).

Step 2: ( Z )-5-((1-Phenyl-1 H Preparation of -pyrrol-3-yl)methylene)thiazolidine-2,4-dione (Compound 8)

The target compound, ( Z )-5-((1-phenyl-1 H - pyrrol-3-yl) methylene) thiazolidine-2,4-dione (Compound 8) was obtained (25 mg, 52% yield).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.31 (s, 1H), 7.93 (t, J = 1.8 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J = 7.6 Hz, 2H) , 7.61 - 7.59 (m, 1H), 7.52 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 6.55 (dd, J = 2.9, 1.7 Hz, 1H); LCMS (ESI), m/z = 271.00 [M+H] ⁺ .

[Example 9] Preparation of ( Z )-5-((1-(4-(Benzyloxy)phenyl) -1H -pyrrol-3-yl)methylene)thiazolidine-2,4-dione (Compound 9)

Step 1: 1-(4-(Benzyloxy)phenyl)-1 H Preparation of -pyrrole-3-carbaldehyde (compound a-9)

1- ( 4-(benzyloxy)phenyl)-1 H -pyrrole-3-carbaldehyde (compound a-9) was obtained (20 mg, 3% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 9.83 (s, 1H), 7.57 (t, J = 1.9 Hz, 1H), 7.47 - 7.29 (m, 7H), 7.07 - 7.03 (m, 2H), 6.99 ( t, J = 2.3 Hz, 1H), 6.77 (dt, J = 5.4, 2.2 Hz, 1H), 5.11 (s, 2H).

Step 2: ( Z )-5-((1-(4-(Benzyloxy)phenyl)-1 H Preparation of -pyrrol-3-yl)methylene)thiazolidine-2,4-dione (Compound 9)

The target compound, ( Z )-5-((1-(4-(benzyloxy) )phenyl) -1H -pyrrol-3-yl)methylene)thiazolidine-2,4-dione (Compound 9) was obtained (33 mg, 77% yield).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.29 (br s, 1H) _, 7.82 (s, 1H), 7.71 (d, J = 4.0 Hz, 1H), 7.55 (dd, J = 8.9, 4.2 Hz , 2H), 7.51 - 7.44 (m, 2H), 7.44 - 7.37 (m, 2H), 7.37 - 7.31 (m, 1H), 7.14 (dd, J = 8.9, 4.2 Hz, 2H), 6.51 (s, 1H) ), 5.16 (d, J = 3.6 Hz, 2H); LCMS (ESI), m/z = 376.95 [M+H] ⁺ .

Example II: Synthesis of Phenyl-Pyridine or Phenyl-Pyrimidine Backbone Compounds

[Example 10] Preparation of ( Z )-5-((2-( p -Tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 10)

Step 1: 2-( p -Preparation of Tolyl)isonicotinaldehyde (Compound b-1)

2-Bromoisonicotinaldehyde (0.390 g, 2.1 mmol) and 4,4,5,5-tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane (0.916 g, 4.2 mmol), Pd(PPh ₃ ) ₄ (0.242 g, 0.210 mmol) was added to toluene (5 ml) under nitrogen, and then 2 M Na ₂ CO ₃ (5.3 ml) was added dropwise, followed by stirring at 100 °C for 3 hours. After completion of the reaction, the mixture was cooled at room temperature, extracted using EtOAc and water, and the obtained organic layer was washed with brine, dried over magnesium sulfate, and filtered. The residue obtained by distilling the filtered solution under reduced pressure was separated and purified by medium pressure liquid chromatography to obtain 2-( p -tolyl)isonicotinaldehyde (compound b-1) (151 mg, 36% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.14 (s, 1H), 8.93 (d, J = 4.9 Hz, 1H), 8.12 (s, 1H), 8.01 - 7.93 (m, 2H), 7.61 (dd, J = 5.0, 1.2 Hz, 1H), 7.36 - 7.29 (m, 2H), 2.43 (s, 3H).

Step 2: (Z)-5-((2-( p Preparation of -Tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 10)

After dissolving compound b-1 (100 mg, 0.507 mmol), thiazolidine-2,4-dione (71.3 mg, 0.608 mmol), and piperidine (60.2 μl, 0.608 mmol) in ethanol (3 ml), a microwave reactor was used. React by stirring at 100 ° C. for 1.5 hours. After completion of the reaction, extraction was performed using EtOAc and water, and the obtained organic layer was washed with brine, dried over magnesium sulfate, and filtered. The residue obtained by distilling the filtered solution under reduced pressure is separated and purified using medium pressure liquid chromatography (silica gel, 0-50% EtOAc/Hexane) to obtain a compound. The obtained compound was recrystallized using EtOAc to obtain a solidified final target compound, ( Z )-5-((2-( p -Tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 10). (6 mg, 4% yield).

^1H NMR (400 MHz, MeOD) δ 8.71 (d, J = 5.2 Hz, 1H), 7.95 - 7.87 (m, 3H), 7.81 (s, 1H), 7.46 (d, J = 5.2 Hz, 1H), 7.36 (d, J = 7.9 Hz, 2H), 2.44 (s, 3H); LCMS (ESI), m/z = 297.01 [M+H] ⁺ .

[Example 11] Preparation of ( Z )-5-((2-(4-( tert -Butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 11)

Step 1: 2-(4-( tert Preparation of -Butyl)phenyl)isonicotinaldehyde (Compound b-2)

Step 1 of Example 10 except for using 4-( tert -butyl)phenyl)boronic acid instead of 4,4,5,5-Tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane (2-(4-( tert -butyl)phenyl)isonicotinaldehyde) (compound b-2) was obtained in the same manner (2.1 g, 82% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ10.14 (s, 1H), 8.93 (d, J = 4.9 Hz, 1H), 8.12 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.61 (dd, J = 4.9, 1.3 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 1.38 (s, 9H).

Step 2: ( Z )-5-((2-(4-( tert Preparation of -Butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 11)

The target compound, ( Z )-5-((2-(4-( tert) -Butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 11) was obtained (159 mg, 27% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.80 (d, J = 5.1 Hz, 1H), 8.43 (br s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.83 (s, 1H), 7.75 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.26 - 7.23 (m, 1H), 1.38 (s, 9H); LCMS (ESI), m/z = 339.09 [M+H] ⁺ .

[Example 12] Preparation of ( Z )-5-((2-(4-(Trifluoromethyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 12)

Step 1: Preparation of 2-(4-(Trifluoromethyl)phenyl)isonicotinaldehyde (compound b-3)

4,4,5,5-Tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane was replaced with (4-(trifluoromethyl)phenyl)boronic acid, but the same as in step 1 of Example 10. 2-(4-(trifluoromethyl)phenyl) isonicotinaldehyde (compound b-3) was obtained (219 mg, 41% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 10.17 (s, 1H), 9.00 (d, J = 4.8 Hz, 1H), 8.21 (s, 1H), 8.20 - 8.15 (m, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.72 (dd, J = 4.8, 1.1 Hz, 1H).

Step 2: ( Z Preparation of )-5-((2-(4-(Trifluoromethyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 12)

The target compound, ( Z )-5-((2-(4-(trifluoromethyl) )phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 12) was obtained (9 mg, 13% yield).

^1H NMR (400 MHz, MeOD) δ 8.83 (d, J = 5.3 Hz, 1H), 8.23 (d, J = 8.2 Hz, 2H), 8.11 (s, 1H), 7.92 - 7.82 (m, 3H), 7.61 (dd, J = 5.3, 1.3 Hz, 1H); LCMS (ESI), m/z = 350.95 [M+H] ⁺ .

[Example 13] Preparation of ( Z )-5-((2-(4-Methoxyphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 13)

Step 1: Preparation of 2-(4-Methoxyphenyl)isonicotinaldehyde (compound b-4)

2 in the same manner as in Step 1 of Example 10, except that (4-methoxyphenyl)boronic acid was used instead of 4,4,5,5-Tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane. -(4-methoxyphenyl)isonicotinaldehyde (compound b-4) was obtained (364 mg, 79% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.13 (s, 1H), 8.90 (d, J = 4.9 Hz, 1H), 8.08 (s, 1H), 8.06 - 7.98 (m, 2H), 7.58 (dd, J = 4.9, 1.3 Hz, 1H), 7.08 - 6.97 (m, 2H), 3.89 (s, 3H).

Step 2: ( Z Preparation of )-5-((2-(4-Methoxyphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 13)

The target compound, ( Z )-5-((2-(4-methoxyphenyl) Pyridin-4-yl) methylene) thiazolidine-2,4-dione (Compound 13) was obtained (5 mg, 2% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.77 (d, J = 5.1 Hz, 1H), 8.00 - 7.92 (m, 2H), 7.81 (s, 1H), 7.70 (s, 1H), 7.22 (dd, J = 5.2, 1.4 Hz, 1H), 7.06 - 7.00 (m, 2H), 3.89 (s, 3H); LCMS (ESI), m/z = 312.96 [M+H] ⁺ .

[Example 14] Preparation of ( Z )-5-((2-(4-(Trifluoromethoxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 14)

Step 1: Preparation of 2-(4-(Trifluoromethoxy)phenyl)isonicotinaldehyde (compound b-5)

4,4,5,5-Tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane was replaced with (4-(trifluoromethoxy)phenyl)boronic acid, but the same as in step 1 of Example 10. In this way, 2-(4-(trifluoromethoxy)phenyl)isonicotinaldehyde (compound b-5) was obtained (345 mg, 60% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 10.16 (s, 1H), 8.96 (d, J = 4.9 Hz, 1H), 8.14 - 8.09 (m, 3H), 7.67 (dd, J = 4.9, 1.3 Hz, 1H), 7.40 - 7.32 (m, 2H).

Step 2: ( Z Preparation of )-5-((2-(4-(Trifluoromethoxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 14)

The target compound, ( Z )-5-((2-(4-(trifluoromethoxy) )phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 14) was obtained (11 mg, 11% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.91 (br s, 1H), 8.83 (d, J = 5.1 Hz, 1H), 8.09 - 7.99 (m, 2H), 7.83 (s, 1H), 7.74 (s , 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.32 (dd, J = 5.1, 1.4 Hz, 1H); LCMS (ESI), m/z = 366.98 [M+H] ⁺ .

[Example 15] Preparation of ( Z )-5-((2-(4-(Benzyloxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 15)

Step 1: Preparation of 2-(4-(Benzyloxy)phenyl)isonicotinaldehyde (compound b-6)

4,4,5,5-Tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane was replaced with (4-(benzyloxy)phenyl)boronic acid, but the same as in step 1 of Example 10. In this way, 2-(4-(benzyloxy)phenyl)isonicotinaldehyde (compound b-6) was obtained (532 mg, 86% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.07 (s, 1H), 8.86 (d, J = 4.9 Hz, 1H), 8.04 - 8.02 (m, 1H), 8.02 - 7.98 (m, 2H), 7.56 - 7.49 (m, 1H), 7.47 - 7.42 (m, 2H), 7.42 - 7.36 (m, 2H), 7.36 - 7.32 (m, 1H), 7.11 - 7.03 (m, 2H), 5.11 (s, 2H).

Step 2: ( Z Preparation of )-5-((2-(4-(Benzyloxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 15)

The target compound, ( Z )-5-((2-(4-(benzyloxy) )phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 15) was obtained (3 mg, 4.5% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.77 (d, J = 5.1 Hz, 1H), 8.33 (br s, 1H), 7.97 (d, J = 8.7 Hz, 2H), 7.81 (s, 1H), 7.70 (s, 1H), 7.51 - 7.31 (m, 5H), 7.22 (dd, J = 5.1, 1.0 Hz, 1H), 7.11 (d, J = 8.8 Hz, 2H), 5.15 (s, 2H); LCMS (ESI), m/z = 388.98 [M+H] ⁺ .

[Example 16] Preparation of ( Z )-5-((2-( o -Tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 16)

Step 1: 2-( o -Preparation of Tolyl)isonicotinaldehyde (Compound b-7)

2- ( o -tolyl)isonicotinaldehyde (compound b-7) was obtained (82.5 mg, 78% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.14 (s, 1H), 8.96 (d, J = 4.9 Hz, 1H), 7.82 (s, 1H), 8.01 (dd, J = 4.9, 1.4 Hz, 1H), 7.43 (d, J = 7.5 Hz, 1H) ), 7.37 - 7.29 (m, 3H), 2.39 (s, 3H).

Step 2: ( Z )-5-((2-( o Preparation of -Tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 16)

The target compound, ( Z )-5-((2-( o -tolyl) Pyridin-4-yl) methylene) thiazolidine-2,4-dione (Compound 16) was obtained (5.0 mg, 17% yield).

^1H NMR (400 MHz, MeOD) δ 8.72 (d, J = 5.2 Hz, 1H), 7.81 (s, 1H), 7.59 (s, 1H), 7.53 (d, J = 4.9 Hz, 1H), 7.38 - 7.31 (m, 4H), 2.33 (s, 3H); LCMS (ESI), m/z = 297.00 [M+H] ⁺ .

[Example 17] Preparation of ( Z )-5-((2-( m -Tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 17)

Step 1: 2-( m -Preparation of Tolyl)isonicotinaldehyde (Compound b-8)

2- ( m -tolyl)isonicotinaldehyde (compound b-8) was obtained (97.8 mg, 92% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.15 (s, 1H), 8.94 (d, J = 4.8 Hz, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 4.9, 1.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 2.46 (s, 3H).

Step 2: (Z)-5-((2-( m Preparation of -Tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 17)

The target compound, ( Z )-5-((2-( m -tolyl) Pyridin-4-yl) methylene) thiazolidine-2,4-dione (Compound 17) was obtained (8.1 mg, 18% yield).

^1H NMR (400 MHz, MeOD) δ 8.70 (d, J = 5.2 Hz, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.78 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.46 (dd, J = 5.2, 1.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 2.45 (s, 3H); LCMS (ESI), m/z = 297.00 [M+H] ⁺ .

[Example 18] Preparation of ( Z )-5-((2-(3-( tert -Butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 18)

Step 1: 2-(3-( tert Preparation of -Butyl)phenyl)isonicotinaldehyde (Compound b-9)

Step 1 of Example 10 except that (3-( tert -butyl)phenyl)boronic acid was used instead of 4,4,5,5-Tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane 2-(3-( tert -butyl)phenyl)isonicotinaldehyde (compound b-9) was obtained in the same manner as in (135 mg, 99% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.16 (s, 1H), 8.95 (d, J = 4.8 Hz, 1H), 8.12 (s, 1H), 8.10 (t, J = 1.8 Hz, 1H), 7.84 (dt, J = 7.5, 1.4 Hz, 1H) ), 7.63 (dd, J = 4.9, 1.4 Hz, 1H), 7.53 - 7.51 (m, 1H), 7.45 (t, J = 7.7 Hz, 1H), 1.41 (s, 9H).

Step 2: ( Z )-5-((2-(3-( tert Preparation of -Butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 18)

The target compound, ( Z )-5-((2-(3-( tert) -butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 18) was obtained (7.0 mg, 17% yield).

^1H NMR (400 MHz, MeOD) δ 8.72 (d, J = 5.2 Hz, 1H), 8.05 (s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.48 - 7.43 (m, 2H), 1.40 (s, 9H); LCMS (ESI), m/z = 339.02 [M+H] ⁺ .

[Example 19] Preparation of ( Z )-5-((2-(3,5-Dimethylphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 19)

Step 1: Preparation of 2-(3,5-Dimethylphenyl)isonicotinaldehyde (compound b-10)

2- (3,5-dimethylphenyl)isonicotinaldehyde (compound b-10) was obtained (247.5 mg, 44% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.15 (s, 1H), 8.93 (d, J = 4.9 Hz, 1H), 8.12 (s, 1H), 7.68 (s, 2H), 7.62 (dd, J = 4.9, 1.3 Hz, 1H), 7.12 (s , 1H), 2.42 (s, 6H).

Step 2: ( Z Preparation of )-5-((2-(3,5-Dimethylphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 19)

The target compound, ( Z )-5-((2-(3,5- dimethylphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione (Compound 19) was obtained (16.5 mg, 22% yield).

^1H NMR (400 MHz, MeOD) δ 8.61 (d, J = 5.3 Hz, 1H), 7.88 (s, 1H), 7.55 (s, 2H), 7.50 (s, 1H), 7.46 (dd, J = 5.3 , 1.4 Hz, 1H), 7.12 (s, 1H), 2.40 (s, 6H); LCMS (ESI), m/z = 311.02 [M+H] ⁺ .

[Example 20] Preparation of 5-((2-(4-( tert -Butyl)phenyl)pyridin-4-yl)methyl)thiazolidine-2,4-dione (Compound 20)

After dissolving compound 11 (50 mg, 0.148 mmol) in ethanol (3 ml), Pd/C (31.4 mg, 0.030 mmol) and 37% HCl (0.121 ml, 1.477 mmol) were added dropwise. The reaction mixture was stirred for 12 hours at 75 °C under hydrogen gas. After completion of the reaction, it was filtered using a filter syringe, and the filtrate was distilled under reduced pressure to obtain a residue. The residue was separated and purified using medium pressure liquid chromatography (silica gel, 0-50% EtOAc/Hexane) to obtain the target compound, 5-((2-(4-( tert -butyl)phenyl)pyridin-4-yl) methyl)thiazolidine-2,4-dione (Compound 20) was obtained (8 mg, 16% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.66 (d, J = 5.1 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.59 (s, 1H), 7.51 (d, J = 8.5 Hz , 2H), 7.12 (dd, J = 5.1, 1.4 Hz, 1H), 4.59 (dd, J = 9.4, 4.0 Hz, 1H), 3.56 (dd, J = 14.1, 4.0 Hz, 1H), 3.25 (dd, J = 14.1, 9.4 Hz, 1H), 1.36 (s, 9H); LCMS (ESI), m/z = 341.05 [M+H] ⁺ .

[Example 21] Preparation of ( Z )-5-((2-(4-( tert -Butyl)phenyl)pyridin-4-yl)methylene)-3-methylthiazolidine-2,4-dione (Compound 21)

After dissolving Compound 11 (10 mg, 0.030 mmol) and K ₂ CO ₃ (4.9 mg, 0.035 mmol) in DMF (0.3 ml), Iodomethane (2.2 μl, 0.035 mmol) was added and stirred for 4 hours. When the reaction is complete, extraction is performed using EtOAc and water, and the obtained organic layer is washed with water and brine, dried over anhydrous magnesium sulfate, and filtered. The residue obtained by distillation of the filtered solution under reduced pressure was separated and purified by medium pressure liquid chromatography (silica gel, 0-50% EtOAc/Hexane) to obtain the target compound, ( Z )-5-((2-(4-( tert- ) Butyl) phenyl) pyridin-4-yl) methylene) -3-methylthiazolidine-2,4-dione (Compound 21) was obtained (6 mg, 58% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.79 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.87 (s, 1H), 7.76 (s, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.26 - 7.24 (m, 1H), 3.28 (s, 3H), 1.38 (s, 9H); LCMS (ESI), m/z = 353.08 [M+H] ⁺ .

[Example 22] ( Z )-5-((2-(4-( tert -Butyl)phenyl)pyridin-4-yl)methylene)-3-(2-morpholinoethyl)thiazolidine-2,4-dione (compound 22) Manufacturing

The target compound, ( Z )-5-((2-(4-( tert -butyl)phenyl)pyridin, was prepared in the same manner as in Example 22, except that 4-(2-chloroethyl)morpholine·HCl salt was used instead of iodomethane. -4-yl)methylene)-3-(2-morpholinoethyl)thiazolidine-2,4-dione (Compound 22) was obtained (10 mg, 38% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.79 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.85 (s, 1H), 7.77 (s, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.30 - 7.24 (m, 1H), 3.91 (t, J = 6.3 Hz, 2H), 3.72 - 3.58 (m, 4H), 2.64 (t, J = 6.3 Hz, 2H), 2.56 - 2.45 (m, 4H), 1.38 (s, 9H); LCMS (ESI), m/z = 452.22 [M+H] ⁺ .

[Example 23] Preparation of ( Z )-5-((6-Phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 23)

Step 1: Preparation of 6-Phenylnicotinaldehyde (Compound b-11)

2-Bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane were used in the same steps as in Example 10, step 1, except that 6-bromonicotinaldehyde and phenylboronic acid were used. 6-phenylnicotinaldehyde (compound b-11) was obtained by the method (425 mg, 86% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 10.13 (s, 1H), 9.13 (d, J = 1.9 Hz, 1H), 8.23 (dd, J = 8.3, 2.2 Hz, 1H), 8.09 (dd, J = 7.8, 1.8 Hz, 2H), 7.90 (d, J = 8.3 Hz, 1H), 7.57 - 7.44 (m, 3H).

Step 2: ( Z Preparation of )-5-((6-Phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 23)

The target compound, ( Z )-5-((6-phenylpyridin-3-yl) was prepared in the same manner as in Step 2 of Example 10, except that compound b-1 (40 mg, 0.218 mmol) was used instead of compound b-1. )methylene)thiazolidine-2,4-dione (Compound 23) was obtained (10 mg, 16% yield).

¹ H NMR (400 MHz, (CD ₃ ) ₂ CO) δ 11.35 (br s, 1H), 8.83 (d, J = 5.1 Hz, 1H), 8.24 - 8.14 (m, 2H), 8.10 (s, 1H) , 7.85 (s, 1H), 7.58 - 7.43 (m, 4H); LCMS (ESI), m/z = 283.01 [M+H] ⁺ .

[Example 24] Preparation of ( Z )-5-((6-(4-Methoxyphenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 24)

Step 1: Preparation of 6-(4-Methoxyphenyl)nicotinaldehyde (Compound b-12)

Example 10 except that 6-bromonicotinaldehyde and (4-methoxyphenyl)boronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane 6-(4-methoxyphenyl)nicotinaldehyde (compound b-12) was obtained in the same manner as in step 1 (382 mg, 83% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 10.11 (s, 1H), 9.08 (d, J = 1.9 Hz, 1H), 8.19 (dd, J = 8.3, 2.1 Hz, 1H), 8.13 - 7.93 (m, 2H), 7.84 (d, J = 8.3 Hz, 1H), 7.09 - 6.90 (m, 2H), 3.89 (s, 3H).

Step 2: ( Z Preparation of )-5-((6-(4-Methoxyphenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 24)

The target compound, ( Z )-5-((6-(4-methoxyphenyl) Pyridin-3-yl) methylene) thiazolidine-2,4-dione (Compound 24) was obtained (15.4 mg, 21% yield).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.72 (br s, 1H) _, 8.87 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 8.9 Hz, 2H), 8.08 (d, J = 8.5 Hz, 1H), 7.98 (dd, J = 8.5, 2.3 Hz, 1H), 7.85 (s, 1H), 7.08 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H); LCMS (ESI), m/z = 313.09 [M+H] ⁺ .

[Example 25] Preparation of ( Z )-5-((6-(4-(Trifluoromethoxy)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 25)

Step 1: Preparation of 6-(4-(Trifluoromethoxy)phenyl)nicotinaldehyde (Compound b-13)

Except for using 6-bromonicotinaldehyde and (4-(trifluoromethoxy)phenyl)boronic acid instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane. 6-(4-(trifluoromethoxy)phenyl)nicotinaldehyde (compound b-13) was obtained in the same manner as in step 1 of Example 10 (332 mg, 58% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 10.16 (s, 1H), 9.14 (d, J = 1.6 Hz, 1H), 8.26 (dd, J = 8.2, 2.1 Hz, 1H), 8.19 - 8.07 (m, 2H), 7.90 (d, J = 8.2 Hz, 1H), 7.41 - 7.30 (m, 2H).

Step 2: ( Z Preparation of )-5-((6-(4-(Trifluoromethoxy)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 25)

The target compound, ( Z )-5-((6-(4-(trifluoromethoxy) )phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 25) was obtained (15 mg, 21% yield).

^1H NMR (400 MHz, DMSO- d6 ) δ 8.91 (d, J = 2.1 Hz, 1H), _8.28 (d, J = 8.9 Hz, 2H), 8.16 (d, J = 8.4 Hz, 1H), 8.04 (dd, J = 8.5, 2.2 Hz, 1H), 7.72 (s, 1H), 7.51 (d, J = 8.2 Hz, 2H); LCMS (ESI), m/z = 366.99 [M+H] ⁺ .

[Example 26] Preparation of ( Z )-5-((5-Phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 26)

Step 1: Preparation of 5-Phenylnicotinaldehyde (Compound b-14)

The same steps as in Example 10, step 1, except that 5-bromonicotinaldehyde and phenylboronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane. 5-phenylnicotinaldehyde (compound b-14) was obtained by the method (430 mg, 87% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 10.19 (s, 1H), 9.08 (dd, J = 12.8, 1.9 Hz, 2H), 8.36 (t, J = 2.1 Hz, 1H), 7.66 - 7.59 (m, 2H), 7.55 - 7.38 (m, 3H).

Step 2: ( Z Preparation of )-5-((5-Phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 26)

The target compound, ( Z )-5-((5-phenylpyridin-3-yl )methylene)thiazolidine-2,4-dione (Compound 26) was obtained (16 mg, 21% yield).

^1H NMR (400 MHz, DMSO- d6 ) δ 8.95 (d, J = 2.1 Hz, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.20 (t, J = 2.1 Hz _, 1H), 7.91 (s, 1H), 7.81 - 7.75 (m, 2H), 7.55 (t, J = 7.4 Hz, 2H), 7.52 - 7.43 (m, 1H); LCMS (ESI), m/z = 282.95 [M+H] ⁺ .

[Example 27] Preparation of ( Z )-5-((5-( p -Tolyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 27)

Step 1: 5-( p -Tolyl) Preparation of nicotinaldehyde (compound b-15)

Step 1 of Example 10 except that 5-bromonicotinaldehyde and p -tolylboronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane 5-( p -tolyl)nicotinaldehyde (compound b-15) was obtained in the same manner as in (468 mg, 88% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ10.19 (s, 1H), 9.05 (d, J = 2.3 Hz, 1H), 9.00 (d, J = 1.8 Hz, 1H), 8.31 (t, J = 2.1 Hz, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 3.88 (s, 3H).

Step 2: ( Z )-5-((5-( p Preparation of -Tolyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 27)

The target compound, ( Z )-5-((5-( p -tolyl) Pyridin-3-yl) methylene) thiazolidine-2,4-dione (Compound 27) was obtained (33 mg, 45% yield).

^1H NMR (400 MHz, MeOD) δ 8.82 (d, J = 2.1 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.16 (t, J = 2.1 Hz, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H); LCMS (ESI), m/z = 296.99 [M+H] ⁺ .

[Example 28] Preparation of ( Z )-5-((5-(4-( tert -Butyl)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 28)

Step 1: 5-(4-( tert Preparation of -Butyl)phenyl)nicotinaldehyde (Compound b-16)

Except that 5-bromonicotinaldehyde and 4-( tert -butyl)phenyl)boronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane. 5-(4-( tert -butyl)phenyl)nicotinaldehyde (compound b-16) was obtained in the same manner as in step 1 of Example 10 (689 mg, 99% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ10.19 (s, 1H), 9.08 (d, J = 2.2 Hz, 1H), 9.03 (d, J = 1.8 Hz, 1H), 8.34 (t, J = 2.1 Hz, 1H), 7.60 - 7.53 (m, 4H), 1.38 (s, 9H).

Step 2: ( Z )-5-((5-(4-( tert Preparation of -Butyl)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 28)

The target compound, ( Z )-5-((5-(4-( tert) -butyl)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione (Compound 28) was obtained (1.9 mg, 3% yield).

^1H NMR (400 MHz, MeOD) δ 8.82 (d, J = 2.0 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.18 (t, J = 2.0 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 1.38 (s, 9H); LCMS (ESI), m/z = 338.93 [M+H] ⁺ .

[Example 29] Preparation of ( Z )-5-((4-Phenylpyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 29)

Step 1: Preparation of 4-Phenylpicolinaldehyde (Compound b-17)

2-Bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane were replaced with 4-bromopicolinaldehyde and phenylboronic acid, but the same steps as in Example 10, step 1. In this way, 4-phenylpicolinaldehyde (compound b-17) was obtained (361 mg, 73% yield).

Step 2: ( Z Preparation of )-5-((4-Phenylpyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 29)

The target compound, ( Z )-5-((4-phenylpyridin-2-yl )methylene)thiazolidine-2,4-dione (Compound 29) was obtained (30 mg, 38% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.43 (br s, 1H), 8.80 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 7.90 (s, 1H), 7.87 (d , J = 7.5 Hz, 2H), 7.75 (d, J = 5.1 Hz, 1H), 7.62 - 7.45 (m, 3H); LCMS (ESI), m/z = 282.90 [M+H] ⁺ .

[Example 30] Preparation of ( Z )-5-((4-( p -Tolyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 30)

Step 1: 4-( p -Preparation of Tolyl)picolinaldehyde (Compound b-18)

Step 1 of Example 10 except for using 4-bromopicolinaldehyde and p -tolylboronic acid instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane 4-( p -tolyl)picolinaldehyde (compound b-18) was obtained in the same manner as in (200 mg, 47% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 10.14 (s, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.73 (dd, J = 5.1, 1.8 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H).

Step 2: ( Z )-5-((4-( p Preparation of -Tolyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 30)

The target compound, ( Z )-5-((4-( p -tolyl) Pyridin-2-yl) methylene) thiazolidine-2,4-dione (Compound 30) was obtained (25 mg, 33% yield).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.46 (s, 1H) _, 8.76 (d, J = 5.2 Hz, 1H), 8.24 (d, J = 1.2 Hz, 1H), 7.89 (s, 1H) , 7.77 (d, J = 8.2 Hz, 2H), 7.73 (dd, J = 5.2, 1.8 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 2.37 (s, 3H); LCMS (ESI), m/z = 296.96 [M+H] ⁺ .

[Example 31] Preparation of ( Z )-5-((4-(4-( tert -Butyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 31)

Step 1: 4-(4-( tert- Preparation of Butyl) phenyl) picolinaldehyde (Compound b-19)

Except that 4-bromopicolinaldehyde and 4-( tert -butyl)phenyl)boronic acid were used instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane. (4-( tert -butyl)phenyl)boronic acid (compound b-19) was obtained in the same manner as in step 1 of Example 10 (496 mg, 77% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 10.14 (s, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.19 (d, J = 1.2 Hz, 1H), 7.73 (dd, J = 5.1, 1.9 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.56 - 7.51 (m, 2H), 1.37 (s, 9H).

Step 2: ( Z )-5-((4-(4-( tert Preparation of -Butyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 31)

The target compound, ( Z )-5-((4-(4-( tert) -butyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 31) was obtained (16 mg, 23% yield).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.45 (s, 1H) _, 8.78 (d, J = 5.2 Hz, 1H), 8.23 (d, J = 1.1 Hz, 1H), 7.90 (s, 1H) , 7.79 (d, J = 8.5 Hz, 2H), 7.73 (dd, J = 5.2, 1.7 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H), 1.33 (s, 9H); LCMS (ESI), m/z = 339.07 [M+H] ⁺ .

[Example 32] Preparation of ( Z )-5-((4-(4-(Trifluoromethyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 32)

Step 1: Preparation of 4-(4-(Trifluoromethyl)phenyl)picolinaldehyde (Compound b-20)

Except for using 4-bromopicolinaldehyde and (4-(trifluoromethyl)phenyl) boronic acid instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-( p- tolyl)-1,3,2-dioxaborolane. 4-(4-(trifluoromethyl)phenyl)picolinaldehyde (compound b-20) was obtained in the same manner as in step 1 of Example 10 (150 mg, yield 37%).

^1H NMR (400 MHz, CDCl ₃ ) δ 10.16 (s, 1H), 8.89 (d, J = 5.0 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.80 (d, J = 2.2 Hz) , 3H), 7.77 (d, J = 1.8 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H).

Step 2: ( Z Preparation of )-5-((4-(4-(Trifluoromethyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 32)

The target compound, ( Z )-5-((4-(4-(trifluoromethyl) )phenyl)pyridin-2-yl) methylene)thiazolidine-2,4-dione (Compound 32) was obtained (24 mg, 43% yield).

^1H NMR (400 MHz, DMSO- d6 ) δ 12.48 (s, 1H), 8.86 ( _d , J = 5.2 Hz, 1H), 8.32 (s, 1H), 8.08 (d, J = 8.2 Hz, 2H) , 7.93 (d, J = 8.6 Hz, 2H), 7.91 (s, 1H), 7.82 (dd, J = 5.2, 1.7 Hz, 1H); LCMS (ESI), m/z = 351.00 [M+H] ⁺ .

[Example 33] Preparation of ( Z )-5-((4-(4-(Trifluoromethoxy)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 33)

Step 1: Preparation of 4-(4-(Trifluoromethoxy)phenyl)picolinaldehyde (Compound b-21)

Except for using 4-bromopicolinaldehyde and (4-(trifluoromethoxy)phenyl)boronic acid instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane. 4-(4-(trifluoromethoxy)phenyl)picolinaldehyde (compound b-21) was obtained in the same manner as in step 1 of Example 10 (337 mg, 47% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 10.15 (s, 1H), 8.85 (d, J = 5.1 Hz, 1H), 8.21 - 8.14 (m, 1H), 7.77 - 7.70 (m, 3H), 7.37 ( d, J = 8.1 Hz, 2H).

Step 2: ( Z Preparation of )-5-((4-(4-(Trifluoromethoxy)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 33)

The target compound, ( Z )-5-((4-(4-(trifluoromethoxy) )phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (Compound 33) was obtained (16 mg, 29% yield).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.81 (d, J = 5.1 Hz, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.71 - 7.63 (m, 3H), 7.47 (dd, J = 5.1, 1.7 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H); LCMS (ESI), m/z = 367.02 [M+H] ⁺ .

[Example 34] Preparation of ( Z )-5-((6-(4-( tert -Butyl)phenyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Compound 34)

Step 1: Preparation of 4-(4-(Trifluoromethyl)phenyl)picolinaldehyde (Compound b-20)

Instead of 2-bromoisonicotinaldehyde and 4,4,5,5-tetramethyl-2-( p -tolyl)-1,3,2-dioxaborolane, 6-bromopyrimidine-4-carbaldehyde and 4-( tert -butyl)phenyl)boronic acid were used. 6-(4-( tert -butyl)phenyl)pyrimidine-4-carbaldehyde (compound b-22) was obtained in the same manner as in step 1 of Example 10, except that the mixture was used (26 mg, 41% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.11 (s, 1H), 9.50 - 9.41 (m, 1H), 8.26 - 8.19 (m, 1H), 8.17 - 8.07 (m, 2H), 7.61 - 7.53 (m , 2H), 1.38 (s, 9H).

Step 2: ( Z )-5-((6-(4-( tert Preparation of -Butyl)phenyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Compound 34)

The target compound, ( Z )-5-((6-(4-( tert) -butyl)phenyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Compound 34) was obtained (3 mg, 8% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.68 (s, 1H), 9.34 (s, 1H), 8.50 (s, 1H), 8.17 (d, J = 8.5 Hz, 2H), 7.81 (s, 1H), 7.61 (d, J = 8.5 Hz, 2H), 1.34 (s, 9H); LCMS (ESI), m/z = 340.10 [M+H] ⁺ .

<Experimental Example 1> Measurement of activity of derivatives using a cell based-assay system

After confirming that the cell-based assay system (Fig. 1a) using a 6xSRE reporter vector showed copGFP changes specific to SREBP protein activity changes, the activity of the compound of the present invention was measured as follows.

First, as shown in (a) of FIG. 1, 6 copies of SRE (5'-ATCACCCCAC-3'), a DNA sequence to which the transcriptional regulator SREBP active form binds, was transferred to the minimal CMV promoter of the pGreenfire-Lenti-reporter vector. A 6xSRE reporter vector was constructed by inserting it at the 5' end. The 6xSRE reporter vector is a vector system that activates the minimal CMV promoter and expresses copGFP only when the activated form of SREBP binds to 6xSRE. After introducing the vector into brain tumor stem cells, HOG-GSC, FACS sorting It was separated into GFP high cell and GFP low cell. Active forms of SREBP1a and SREBP1c were overexpressed in the isolated GFP-low cells (Fig. 1b), and the increase in GFP expression was measured. As a result, it was confirmed that overexpression of SREBP1a and SREBP1c active forms in the isolated GFP-low cells increased GFP expression to 43.30% and 93.49% (Fig. 1c). The isolated GFP-high cells were treated with DMSO as a control and fatostatin and FGH10019 known to inhibit SREBP activity, respectively, to measure the change in GFP expression level. As a result, the expression of GFP when treated with known fatostatin and FGH10019 It was confirmed that this was inhibited by about 50% (Fig. 1 d).

From the above results, it was confirmed that the cell-based assay system using a 6xSRE reporter vector exhibited copGFP changes specific to SREBP protein activity changes, and this was used for derivative screening below.

HOG-GSC-6xSRE-copGFP_HIGH cells were dispensed in a 96-well plate (Corning) at 5000 cells/well, and after 24 hours, the compound of the present invention was treated three times in each well at a concentration of 1 μM, and then real-time cell Using imaging equipment (Incucyte), all wells were photographed every 3 hours for 72 hours in an incubator (ThermoFisher) at 37° C., 5% CO ₂ to photograph the intensity change of copGFP. Thereafter, the intensity of copGFP treated with DMSO as a control in HOG-GSC-6xSRE-copGFP_HIGH cells was set as 1, the activity for each compound was normalized, and then the activity of 11 compounds showing excellent efficacy was normalized So, it is described in Table 1 below.

[Table A]

<Experimental Example 2> Comparison of cell viability in brain tumor stem cells (MTS assay)

Injecting 11 compounds into HOG-GSC cells, which are brain tumor stem cells, After 72 hours of treatment with μM and DMSO as a control, the number of surviving cells was evaluated by MTS assay.

Brain tumor stem cells, HOG-GSC, were seeded in 96-well plate at 5,000 per well, and 37℃, 5% CO ₂ for 24 hours to stabilize the cells. cultured in an incubator (ThermoFisher). Thereafter, 11 compounds of the present invention were treated at a concentration of 5 μM, respectively, and DMSO as a control was treated with the same volume as that of each compound. 37° C., 5% CO ₂ for 72 hours after treatment with compounds of the present invention and controls. cultured in an incubator. Thereafter, cell viability was quantified using a Cell viability assay kit (LPS solution), in which the color development becomes darker according to the amount of living cells in each well. Cell viability assay solution was treated and 37℃, 5% CO ₂ for 3 hours The reaction was performed in an incubator to develop color, and the absorbance at 450 nm was measured using a microplate reader (BioTek). The absorbance intensity of the control group was set to 1 to normalize the absorbance of cells treated with each compound, as shown in FIG. 2 did

As a result, the compounds exhibiting a normalized MTS value of less than 0.5 showed a decrease in cell viability by 50% or more compared to the control group, and compounds 3, 10, 11, 12, 14, 15, 18, 19, 25, and 28 of the present invention , 31 was confirmed to have a significant cell survival inhibitory effect on brain tumor stem cells (FIG. 2).

<Experimental Example 3> Western blot assay

HOG-GSC-6xSRE-copGFP_HIGH cells were treated with compound 11 (Example 11) at 5 μM, 2.5 μM, 1.25 μM, 0.625 μM, 0.312 μM, 0.156 μM, 0.078 μM and control DMSO, respectively, and 24, 48, 72 After an hour, each cell sample was obtained.

Equal amounts of proteins extracted from each cell sample were run on 8% SDS-PAGE gel electrophoresis. The proteins developed on the SDS-PAGE gel were transferred to a PVDF (Millipore, Billerica, MA, USA) membrane, and the non-protein portion of the membrane was 5% skim milk-Tris-Buffered Saline 0.1% Tween-20 (TBS-T) solution. was blocked by reacting at room temperature for 1 hour.

As primary antibodies, anti-SREBP1 (BD Bioscience) and anti-SREBP2 (R&D systems) were diluted 1:1500 in 1% bovine serum albumin (BSA)-TBST solution, and anti-ACTIN (Sigma) was diluted with 1% BSA. - It was diluted 1:20000 in TBS-T solution and reacted at 4℃ for 16 hours.

After washing the PVDF membrane by rocking three times in TBS-T solution at room temperature at 30 rpm for 10 minutes, goat anti-rabbit IgG HRP (horseradish peroxidase) antibody and goat anti-mouse IgG HRP secondary antibody were degreased by 5%. It was diluted 1:10000 in a milk-TBS-T solution, rocked slowly at room temperature, and allowed to react at room temperature for 1 hour. The film was washed with TBS-T by rocking three times for 10 minutes at 30 rpm at room temperature, and then luminescent using an HRP substrate and imaged using a film. The results are shown in FIG. 3 .

When Compound 11 (Example 11) was exposed to HOG-GSC-6xSRE-copGFP-HIGH cells at various concentrations for 24 hours, 48 hours, and 72 hours, Compound 11 (Example 11) dose-dependently expressed SREBP1 was suppressed (FIG. 3). SREBP2 was also inhibited, but it was confirmed that SREBP1 was mainly inhibited (FIG. 3).

<Experimental Example 4> Cell viability analysis

Brain tumor stem cells, HOG-GSC, were seeded with 5000 cells per well in a 96-well plate, and after 24 hours, compound 11 (Example 11) 20 μM, 10 μM, 5 μM, 2.5 μM, 1.25 μM, 0.625 μM , 0.312 μM, 0.156 μM, 0.078 μM concentrations were repeatedly treated three times, and DMSO as a control was repeatedly treated with the same volume three times. 37°C, 5% CO ₂ for 72 hours after treatment cultured in an incubator (ThermoFisher). Thereafter, cell viability was compared according to the concentration of Compound 11 (Example 11) using a Cell viability assay kit (LPS solution) in which the color development becomes darker according to the amount of living cells in each well. In addition, the absorbance at 450 nm was measured using a microplate reader (BioTek), and the absorbance at each concentration was normalized based on the absorbance intensity of the control group as 1, and is shown in FIG. 4 .

As a result of measuring cell viability after treating brain tumor stem cells HOG-GSC with Compound 11 (Example 11) at various doses, cell viability of HOG-GSC was significantly reduced compared to control DMSO, and Compound 11 (Example 11) The cell viability of HOG-GSC decreased in proportion to the concentration of (FIG. 4).

From this, it can be seen that the compound of the present invention has an excellent apoptotic effect on brain tumor stem cells and can be used as a brain tumor treatment targeting brain tumor stem cells.

<Experimental Example 5> In vivo pharmacokinetics (in vivo PK) test and in vivo brain tissue distribution test

I. In vivo PK test

1.1. Experimental drugs and excipients

Test Drug: Compound 11

Excipient: 10% DMSO, 75% PEG400, 15% Saline

1.2. experimental system

Mice, CRljOri:CD1 (ICR), SPF 6 weeks old (7 weeks old when administered)

1.3. route of administration

Oral administration (PO), intravenous administration (IV)

1.4. Administration method and frequency of administration

After obtaining the mouse, it was used in the experiment after a 5-day acclimatization period. The administration dose was 25 mg/kg for oral administration and 5 mg/kg for intravenous administration. The amount of the administered liquid for each individual was calculated based on the body weight after fasting (on the day of administration), and was orally administered once to the oral administration group (PO) using a disposable syringe (1 mL) attached with a zonde for oral administration, The intravenous administration group (IV) was administered intravenously through the tail vein using a disposable syringe (1 mL).

1.5. Blood collection and plasma separation

About 0.3mL of blood is collected from the jugular vein with a 1mL syringe (25G) treated with sodium citrate 3.8% (about 30~40 μl), put into one microtube (QSP, 1.5mL), and centrifuged at 12,000RPM /3min Plasma was collected by separation. Plasma was stored frozen at -80 ° C until analysis, and all animals in the pharmacokinetic experiment group were euthanized after blood collection was completed.

The blood sampling time points are as follows.

1.6. Concentration analysis and evaluation

experimental material

Mouse blank plasma (Biochemed, 029-APSC-MP-ICR, Sodium citrate)

Internal standard compound: Chlorpropamide (TRC, C424800)

sample preparation

580 μl of acetonitrile (including internal standard) was added to 20 μl of plasma/tissue, followed by vortexing and centrifugation at 4°C at 15,000 rpm for 5 minutes. The supernatant obtained after centrifugation was analyzed by LC-MS/MS.

1.7. Analysis of results

PK parameters were calculated using the phoenix WinNonlin 6.4 version (Pharsight, USA) program and a non-compartmental analysis model.

1.8. Experiment result

Table 1 and FIG. 5 show drug concentrations in plasma after oral administration (25 mg/kg).

[Table 1]

Table 2 below shows drug concentrations in plasma after intravenous administration (5 mg/kg).

[Table 2]

When administered orally at 25 mg/kg, the half-life was 3.9 hours, Tmax was 1.6 hours, Cmax was 5042.5 ng/ml, and AUClast was 39412.0 hr*ng/ml. In addition, in the case of oral administration of 25 mg/kg, BA (bioavailability) was 62.4% compared to the case of intravenous administration of 5 mg/kg. Therefore, it was confirmed that the compound according to the present invention exhibits a level of exposure in the body suitable for oral administration.

II. In vivo brain tissue distribution test

2.1. Experimental drugs and excipients

Test Drug: Compound 11

Excipient: 20% hydroxypropyl-β-cyclodextrin aqueous solution with 1% DMSO

2.2. experimental system

Mouse, Hsd:ICR (CD-1®, SPF 4 weeks old (7 weeks old when administered)

2.3. route of administration

Oral Administration (PO)

2.4. Administration method and frequency of administration

After obtaining the mice, they were used in the experiment after going through a two-week quarantine and acclimatization period. The administered dose was 25 mg/kg. The amount of each individual dose was calculated based on body weight after fasting for 15 hours (day of administration), and was administered orally once using a disposable syringe (1 mL) attached with a sonde for oral administration.

2.5. Blood collection and brain tissue collection

After respiratory anesthesia, blood was collected through cardiac blood sampling with a 1 mL syringe, placed in a K2-EDTA-treated tube, and centrifuged at 8,000 RPM, 4 ° C. for 20 minutes to obtain plasma from the supernatant. After blood collection was completed, heart perfusion was performed on the animals, and brain tissue was extracted, and the olfactory bulb, cerebellum, pons, and medulla were removed from the extracted brain tissue. Collected plasma and brain tissue were stored frozen at -80 ° C until analysis.

The timing of blood collection and brain tissue collection is as follows.

In order to secure a sufficient amount of samples for analysis, brain tissue and blood samples obtained from two individuals were pooled and used (three repeated samples were obtained from six animals at one time collection). Plasma and brain tissue were collected in the same way from mice of the same age that were not administered with the compound, and were used as donated plasma and blank tissue, respectively, for material concentration analysis.

2.6. Concentration analysis and evaluation

experimental material

Internal standard compound: Verapamil hydrochloride (TCI, V0118)

sample preparation

190 μL of acetonitrile containing 200 ng/mL of internal standard was added to 10 μL of plasma sample and vortexed at 2,500 RPM for 60 seconds. Thereafter, centrifugation was performed at 12,000 RPM for 5 minutes, and 50 μL of the supernatant was taken and mixed with 50 μL of acetonitrile. Of this, 2 μL was injected into LC-MS/MS.

After weighing the brain tissue, tertiary distilled water corresponding to 4 times the weight (w/v = 1/4) was added and homogenized using a homogenizer. 10 µL of the homogenized tissue mixture was added with 190 µL of acetonitrile containing 50 ng/mL of the internal standard, and vortexed at 2,500 RPM for 60 seconds. Thereafter, centrifugation was performed at 12,000 RPM for 10 minutes, and 2 μL of the supernatant was taken and injected into LC-MS/MS.

2.7. Analysis of results

PK parameters were calculated with a non-compartmental analysis model using PKSolver2.0 software.

2.8. Experiment result

6 shows concentrations in blood and brain tissue after oral administration (25 mg/kg) of Compound 11, and PK parameters calculated therefrom are shown in Table 3 below.

[Table 3]

As a result of analyzing the concentration of the drug in brain tissue after oral administration, the ratio of concentration in brain tissue to blood was confirmed to be 0.470 on average and 0.777 at maximum. The area under the curve (AUC) ratio of brain tissue to blood was confirmed to be 0.543.

<Experimental Example 6> In vivo efficacy evaluation

The following anticancer efficacy was evaluated to confirm the tumor growth inhibitory efficacy of the example compounds according to the present invention in an animal model (FIG. 7).

First, HOG-GSC, a brain tumor stem cell line, was transplanted into the caudate putamen in the brain of a BALB/c nude mouse to establish an orthotopic xenograft model. From the 7th day after brain tumor stem cell transplantation, the practice compound of the present invention was orally administered for 3 weeks on a schedule of 5 days of administration and 2 days of withdrawal, and only the excipient was administered to the control group in the same manner. Then, by examining the survival period of the mouse based on the clinical findings as the brain tumor grows in the animal, it was confirmed whether the death of the animal caused by the tumor was delayed by administering the compound of the present invention. In addition, on the 16th day after the tumor transplantation, control mice and mice administered with an exemplary compound of the present invention were euthanized at the same time, and brain tissues were removed, and the sizes of brain tumors were compared on the same day.

The results of this anticancer efficacy evaluation are shown in FIGS. 8, 9 and 10.

Figure 8 is a graph showing the survival rate of mice over time, it can be seen that the animals administered with the exemplary compound of the present invention survive for a long time compared to the control animals.

9 is a photograph of the brain tissue of a mouse that finally survived on day 66 after tumor transplantation, and no tumor was observed.

10 is a photograph of mouse brain tissue on day 16 after tumor transplantation, and Table 4 quantifies the experimental results of FIG. 10 as a ratio of tumor cross-sectional area to total brain tissue cross-sectional area. When administering the compound of the present invention compared to the control group, it was confirmed that the size of the tumor was reduced or no tumor was found compared to the control group. From this, it can be seen that the compound according to the present invention has an excellent tumor growth inhibitory effect and can be used as a new brain tumor treatment targeting brain tumor stem cells.

[Table 4]

Although the present invention has been described in detail only for the described embodiments, it is obvious to those skilled in the art that various changes and modifications are possible within the scope of the technical idea of the present invention, and it is natural that these changes and modifications fall within the scope of the appended claims. .

Claims (10)

A substituted thiazolidinedione derivative compound represented by Formula 1, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,

is a single bond or a double bond;
Ar ¹ is

or

ego;
R ¹ is C1-C10 alkyl;
R ² is haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy;
R ³ is C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, haloC1-C10 alkoxy or C6-C12 arylalkyloxy;
X ¹ is CH or N;
R ^A is hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C6-C12 arylC1-C10 alkyl or -L ¹ -Het ¹ ;
L ¹ is C1-C10 alkylene;
Het ¹ is C3-C10 heterocycloalkyl;
a1 is an integer from 0 to 3;
b1 and c1 are each independently an integer of 0 to 5. According to claim 1,
remind

is a double bond; Ar ¹ is

ego; R ² is haloC1-C4alkyloxy or C6-C12arylC1-C4alkyloxy; a1 is an integer from 0 to 2; b1 is an integer from 0 to 2; R ^A is hydrogen, C1-C4alkyl, C3-C8cycloalkyl or -L ¹ -Het ¹ ; L ¹ is C1-C4alkylene; A substituted thiazolidinedione derivative compound, a hydrate thereof, or a pharmaceutically acceptable salt thereof, wherein Het ¹ is C3-C8 heterocycloalkyl. According to claim 1,
The Ar ¹ is

ego; X ¹ is CH or N; R ³ is C1-C4alkyl, haloC1-C4alkyl, C1-C4alkoxy, haloC1-C4alkoxy or C6-C12arylC1-C4alkyloxy; c1 is an integer from 0 to 2; R ^A is hydrogen, C1-C4alkyl, C3-C8cycloalkyl or -L ¹ -Het ¹ ; L ¹ is C1-C4alkylene; A substituted thiazolidinedione derivative compound, a hydrate thereof, or a pharmaceutically acceptable salt thereof, wherein Het ¹ is C3-C8 heterocycloalkyl. According to claim 1,
A substituted thiazolidinedione derivative compound, a hydrate thereof, or a pharmaceutically acceptable salt thereof, wherein Ar ¹ is selected from the following structures.

According to claim 1,
Wherein R ^A is hydrogen, methyl, ethyl or

A phosphorus-substituted thiazolidinedione derivative compound, a hydrate thereof, or a pharmaceutically acceptable salt thereof. According to claim 1,
The compound represented by Formula 1 is any one selected from the group of compounds below, a compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
( Z )-5-((1-(4-(trifluoromethoxy)phenyl)-1 H -pyrrol-2-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((1-(4-(benzyloxy)phenyl)-1 H -pyrrole-2-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((1-(4-(benzyloxy)phenyl)-1 H -pyrrol-3-yl)methylene)thiazolidine-2,4-dione;
(Z)-5-((2-( p -tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((2-(4-( t -butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((2-(4-(trifluoromethyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((2-(4-methoxyphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((2-(4-(trifluoromethoxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((2-(4-(benzyloxy)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((2-( o -tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;
(Z)-5-((2-( m -tolyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((2-(3-( t -butyl)phenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((2-(3,5-dimethylphenyl)pyridin-4-yl)methylene)thiazolidine-2,4-dione;
5-((2-(4-( t -butyl)phenyl)pyridin-4-yl)methyl)thiazolidine-2,4-dione;
( Z )-5-((2-(4-( t -butyl)phenyl)pyridin-4-yl)methylene)-3-methylthiazolidine-2,4-dione;
( Z )-5-((2-(4-( t -butyl)phenyl)pyridin-4-yl)methylene)-3-(2-morpholinoethyl)thiazolidine-2,4-dione;
( Z )-5-((6-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((6-(4-methoxyphenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((6-(4-(trifluoromethoxy)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((5-phenylpyridin-3-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((5-( p -tolyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((5-(4-( t -butyl)phenyl)pyridin-3-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((4-phenylpyridin-2-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((4-( p -tolyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((4-(4-( t -butyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((4-(4-(trifluoromethyl)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione;
( Z )-5-((4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione; and
( Z )-5-((6-(4-( t -butyl)phenyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione. A pharmaceutical composition for preventing or treating cancer comprising a substituted thiazolidinedione derivative compound represented by Formula 2, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
[Formula 2]

In Formula 2,

is a single bond or a double bond;
Ar ² is

or

ego;
R ¹¹ is C1-C10 alkyl;
R ¹² is C1-C10 alkyl, hydroxy, haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy;
R ¹³ is C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, haloC1-C10 alkoxy or C6-C12 arylalkyloxy;
X ² is CH or N;
R ^B is hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C6-C12 arylC1-C10 alkyl or -L ² -Het ² ;
L ² is C1-C10 alkylene;
Het ² is C3-C10 heterocycloalkyl;
a2 is an integer from 0 to 3;
b2 and c2 are each independently an integer of 0 to 5; According to claim 7,
The cancer is a brain tumor, the pharmaceutical composition. According to claim 7,
The pharmaceutical composition is to selectively inhibit SREBP1 (sterol regulatory element-binding protein-1), the pharmaceutical composition. A health functional food composition for preventing or improving cancer comprising a substituted thiazolidinedione derivative compound represented by Formula 2, a hydrate thereof, or a food chemically acceptable salt thereof as an active ingredient.
[Formula 2]

In Formula 2,

is a single bond or a double bond;
Ar ² is

or

ego;
R ¹¹ is C1-C10 alkyl;
R ¹² is C1-C10 alkyl, hydroxy, haloC1-C10 alkyloxy or C6-C12 arylC1-C10 alkyloxy;
R ¹³ is C1-C10 alkyl, haloC1-C10 alkyl, C1-C10 alkoxy, haloC1-C10 alkoxy or C6-C12 arylalkyloxy;
X ² is CH or N;
R ^B is hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C6-C12 arylC1-C10 alkyl or -L ² -Het ² ;
L ² is C1-C10 alkylene;
Het ² is C3-C10 heterocycloalkyl;
a2 is an integer from 0 to 3;
b2 and c2 are each independently an integer of 0 to 5;

Images