KR101424667B1 - N1-cyclic amine-n2-substituted biguanide derivatives, methods of preparing the same and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention provides an N1-ring amine-N2-substituted biaguanide derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition containing the same. The biguanide derivatives of the present invention exhibit an excellent activating effect of AMPK which is involved in the regulation of energy metabolism even at a small dose compared to conventional drugs, and thus exhibit an anticancer effect including cancer cell proliferation inhibition effect and cancer recurrence and metastasis. In addition, AMPK activation exhibits excellent hypoglycemic action and lipid lowering action and can be useful for the treatment of diabetes, obesity, hyperlipidemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome and metabolic syndrome .

[Chemical Formula 1]

Description

TECHNICAL FIELD The present invention relates to a N1-cyclic amine-N2-substituted biaguanide derivative, a process for producing the same, and a pharmaceutical composition containing the same as an active ingredient. BACKGROUND ART [0002] N1-CYCLIC AMINE-N2- SUBSTITUTED BIGUANIDE DERIVATIVES, METHODS OF PREPARING THE SAME AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME,

The present invention relates to a method for inhibiting the proliferation of cancer cells and inhibiting cancer metastasis and cancer recurrence through the activation of AMPK even at a small dose compared to conventional drugs, and to a method for the treatment of diabetic and metabolic diseases, A derivative thereof, a process for producing the same, and a pharmaceutical composition containing the derivative as an active ingredient.

AMP-activated protein kinases (AMPKs) are enzymes that regulate metabolic pathways to maintain energy homeostasis in cells and throughout the body in order to maintain a balance between nutrient supply and energy demand. AMPK is activated when the ratio of intracellular AMP / ATP increases due to hypoxia or glucose deficiency. Activated AMPK increases fatty acid oxidation to produce more ATP and inhibits anabolism that requires ATP. Activation of AMPK also improves insulin sensitivity, inhibits glucose production in the liver, and increases glucose uptake in muscle. These effects make AMPK a good target for the treatment of type 2 diabetes and metabolic diseases. AMPK inhibits the growth of cancer cells by controlling energy metabolism in normal cells as well as cancer cells. AMPK activated by cancer cells phosphorylates mTORC1, p53 and fatty acid synthetase to regulate cell cycle, cell polarity, autophagy, apoptosis and so on. .

Metformin is used in the treatment of non-insulin dependent diabetes mellitus (type 2 diabetes) because it has the best blood-glucose lowering effect and does not cause hypoglycemia or hyperinsulinemia and can prevent complications. Recently, metformin has been extensively studied. Metformin inhibits the action of mitochondrial electron transport system Complex I to inhibit intracellular energy production, thereby activating AMP-activated protein kinase (AMPK) and producing mTOR / The inhibition of S6K1 signaling pathway inhibits proliferation and tumor growth of cancer cells, and has been widely recognized as an anticancer agent that regulates the metabolism of cancer cells [Mol. Cancer Ther. 9 (5): 1092-1099 (2010)). In addition, epidemiological studies have shown that cancer incidence and mortality from cancer are reduced in patients receiving metformin [BMJ.330: 1304-1305 (2005)].

On the other hand, there is increasing clinical evidence that cancer stem cell involvement causes recurrence and metastasis of cancer. Cancer stem cells are cancer cells that have the ability to regenerate or differentiate into stem cells. In cancer tissues, cancer stem cells are less than 0.2% and are characterized by slow proliferation. Many anticancer drugs developed in the meantime were drugs that targeted rapidly proliferating cancer cells. However, when treated with such an anticancer agent, cancer stem cells showed resistance to conventional chemotherapy, and the prognosis was poor. Metformin, on the other hand, has been shown to selectively act on cancer stem cells in breast cancer cells to eliminate it, thereby preventing cancer recurrence [ Cancer Res . 69 (19): 7507-11 (2009)). In addition, the expression of Snail1, Slug, Twist, ZEB1 / 2, and TGF-β, which are transcription factors involved in epithelial-to-mesenchymal transition (EMT), is inhibited and E-cadherin expression is increased, (Cell Cycle 10: 7, 1144-1151 (2011), Cell Cycle 9:18, < RTI ID = 0.0 > 3807-3814 (2010), Cell Cycle 9: 22,4461-4468 (2010)).

However, metformin is generally dosed three times a day, and since the dose is more than about 500 mg once per day, in order to make it once-daily, a tablet containing about 1,500 mg of metformin is required. In this case, It is difficult to take it, and there is a problem that two or more tablets should be taken at the time of dosing because currently commercially available sustained-release preparations contain about 750 mg of metformin in one tablet. Penformin, which is also the same bioaguanide, was completely banned in the late 1970s due to serious side effects of lactic acidosis. Therefore, there is a need for a bioaguanide-based material which exhibits a pharmacological action superior to that of conventional metformin and has improved physicochemical properties such as phenformin-like side effects.

The present invention is to provide a novel biguanide derivative or a pharmaceutically acceptable salt thereof exhibiting excellent cancer cell proliferation inhibitory effect and an inhibitory effect on cancer metastasis and cancer recurrence in a smaller amount than conventional drugs, and a method for producing the same.

The present invention also relates to a pharmaceutical composition for the treatment of diabetes, obesity, hyperlipidemia, fatty liver, hypercholesterolemia, coronary artery disease, osteoporosis, polycystic ovary syndrome, metabolic syndrome and the like which exhibit excellent hypoglycemic effect and lipid- To provide a pharmaceutical composition.

The present invention provides an N1-cyclic amine-N2-substituted biaguanide derivative compound of the formula 1, or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

  In this formula,

R ₁ and R ₂ form a heterocycloalkyl of 3 to 8 members together with the nitrogen that is associated with these, and

R ₃ is C _{3 - 7} cycloalkyl, or; C _{3 - 12} aryl or C _{3 - 12} substituted with a heteroaryl or unsubstituted C _{1 - 12} alkyl; ₁₂ is an aryl, _- or C ₃

Here, 3 to 8-membered heterocycloalkyl of, C _{3 - 12} aryl or C _{3 -} substituted with one or more non-hydrogen substituents selected from the group consisting of _4-alkoxy-12 heteroaryl group is halogen, C _{1 - 4} alkyl and C ₁ Or not.

In the present specification,

A " substituted " group is one in which one or more hydrogen atoms have been replaced by one or more non-hydrogen atoms, but a valence electron requirement has been met and a chemically stable compound has emerged from substitution. In this specification, unless stated explicitly " unsubstituted ", all substituents are to be construed as being substituted or unsubstituted. The substituents of R ₁ to R ₃ on the biguanide derivative according to the present invention may each be substituted with one or more of the above-defined substituents.

&Quot; Halogen " or " halo " denotes fluoro, chloro, bromo and iodo.

&Quot; Hydroxy " represents -OH.

&Quot; Alkyl " means a straight chain and branched saturated hydrocarbon group generally having the indicated number of carbon atoms (e.g., 1 to 12 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t- butyl, pent- Methylbut-2-yl, 2,2,2-trimethylet-1-yl, n-hexyl, n-heptyl and n-octyl, and the like. Alkyl can be attached to a parent group or substrate at any ring atom provided that attachment does not violate the valence electron requirements. Likewise, the alkyl group may contain one or more non-hydrogen substituents if the attachment does not violate the valence electron requirements. For example, "haloalkyl" refers to -CH ₂ (halo) _, -CH (halo) ₂ or C (halo) ₃ , and means a methyl group in which at least one of the hydrogens of the methyl group is replaced by halogen. Examples of " haloalkyl " groups include, without limitation, trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.

&Quot; Alkoxy " refers to alkyl-O-, wherein alkyl is defined above. Examples of alkoxy groups include, without limitation, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s- do. Alkoxy can be attached to a parent group or substrate at any ring atom provided that the attachment does not violate the valence electron requirements. Likewise, the alkoxy group may include one or more non-hydrogen substituents if the attachment does not violate the valence electron requirements. For example, "haloalkoxy" refers to -O-CH ₂ (halo), -O-CH (halo) ₂ or -OC (halo) ₃ and refers to a methyl group in which at least one of the hydrogens of the methyl group is replaced by a halogen do. Examples of " haloalkoxy " groups include, without limitation, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and triiodomethoxy.

"Cycloalkyl" means a saturated part and bicyclic hydrocarbon ring having a carbon atom number of specified comprises a ring generally (i.e., C _{3 - 8} cycloalkyl is 3, 4, 5, 6, 7 or 8 as ring members Quot; refers to a cycloalkyl group having a carbon atom). Cycloalkyl can be attached to a parent group or substrate at any ring atom provided that attachment does not violate the valence electron requirements. Likewise, a cycloalkyl group can include one or more non-hydrogen substituents if the attachment does not violate the valence electron requirements.

&Quot; Heterocycloalkyl " refers to monocyclic and bicyclic hydrocarbon rings having 3 to 12 membered ring atoms containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. Heterocycloalkyl can be attached to a parent group or substrate at any ring atom provided that attachment does not violate the valence electron requirements. Likewise, the heterocycloalkyl group may contain one or more non-hydrogen substituents if the attachment does not violate the valence electron requirements. Examples of heterocycloyl groups include, without limitation, aziridine, azetidine, imidazolyl, pyrroyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, azepanyl, indolyl, indolinyl, and the like .

&Quot; Aryl " refers to monovalent and divalent aromatic groups, including monovalent and divalent aromatic groups, respectively, of a 5 and 6 membered aromatic group, and " heteroaryl " refers to monovalent and divalent aromatic groups containing 5 to 6 heteroatoms independently selected from nitrogen, - < / RTI > and 6-membered ring aromatic groups, respectively. Examples of "heteroaryl" groups include, but are not limited to, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, Pyrimidinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, carbazolyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, triazinyl, phthalazinyl, quinolinyl , Indolyl, benzofuranyl, purinyl, and indolizinyl.

In one embodiment,

C _{3 - 12} aryl is phenyl or naphthalenyl,

C _{3 - 12} heteroaryl is furanyl, thiophenyl, pyridinyl, pyrrolyl, and imidazolyl, or pyrimidinyl,

The C _{3 - 12} aryl or C _{3 - 12} heteroaryl group is halogen, C _{1 - 4} alkyl and C _{1 -} substituted with one or more non-hydrogen substituents selected from the group consisting of _4-alkoxy or may be unsubstituted.

In another embodiment,

R ₁ and R ₂ together with the nitrogen to which they are attached form a 3 to 8 membered heterocycle selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl and aziridinyl, Alkyl, < / RTI >

R ₃ is C _{3 - 7} cycloalkyl, or; C _{3 - 12} aryl or C _{3 - 12} substituted with a heteroaryl or unsubstituted C _{1 - 12} alkyl; Or C _{3 - 12} aryl, and,

Here, 3 to 8-membered heterocycloalkyl of, C _{3 - 12} aryl or C _{3 -} substituted with one or more non-hydrogen substituents selected from the group consisting of _4-alkoxy-12 heteroaryl group is halogen, C _{1 - 4} alkyl and C ₁ Or may be omitted.

In another embodiment,

R ₁ and R ₂ together with the nitrogen to which they are attached form a 3 to 8 membered heterocycle selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl and aziridinyl, ≪ / RTI > alkyl,

R ₃ is C _{3 - 7} cycloalkyl, or; Phenyl, naphthalenyl, furanyl, thiophenyl, pyridinyl, pyrrolyl, C _{3 -12} aryl or C ₃ which is already jolil and selected from the group consisting of days _{pyrimidin-substituted} with ₁₂ heteroaryl unsubstituted C _{1 - 12} alkyl; ₁₂ is an aryl, _- or C ₃

Here, 3 to 8-membered heterocycloalkyl of, C _{3 - 12} aryl or C _{3 -} substituted with one or more non-hydrogen substituents selected from the group consisting of _4-alkoxy-12 heteroaryl group is halogen, C _{1 - 4} alkyl and C ₁ Or may be omitted.

In another embodiment,

R < ₁ > and R < ₂ > together with the nitrogen to which they are attached form a 4 to 7 membered heterocycloalkyl,

R ₃ is C _{3 - 7} cycloalkyl, or; C _{3 - 12} aryl or C _{3 - 12} substituted with a heteroaryl or unsubstituted C _{1 - 12} alkyl; ₁₂ is an aryl, _- or C ₃

Here, 4 to 7 membered heterocycloalkyl of, C _{3 - 12} aryl or C _{3 -} substituted with one or more non-hydrogen substituents selected from the group consisting of _4-alkoxy-12 heteroaryl group is halogen, C _{1 - 4} alkyl and C ₁ Or may be omitted.

In another embodiment,

R ₁ and R ₂ together with the nitrogen to which they are attached form a 4 to 7 membered heterocycloalkyl selected from the group consisting of pyrrolidinyl, piperidinyl, and azepanyl,

R ₃ is phenyl, naphthalenyl, furanyl, thiophenyl, and C ₃ is selected from the group consisting of date of _{pyridine-substituted} with a C _{1 12-heteroaryl-4-alkyl 12} aryl or C _3; Or C _{3 - 12} aryl, where the C _{3 -} substituted with one or more non-hydrogen substituents selected from the group consisting of _4-alkoxy-12 aryl or C _{3 - 12} heteroaryl group is halogen, C _{1 - 4} alkyl and C ₁ Or may be omitted.

In another embodiment,

R ₁ and R ₂ together with the nitrogen to which they are attached form a 4 to 7 membered heterocycloalkyl selected from the group consisting of pyrrolidinyl, piperidinyl, and azepanyl,

R ₃ is unsubstituted C _{1 - 7} may be a _{cycloalkyl-7-alkyl} and unsubstituted C _3.

In one embodiment, the compound of Formula 1 is N1-piperidin-2-phenylbiguanide; N1-pyrrolidine-N2-methylbiguanide; N1-piperidin-2-methylbiguanide; N1-piperidin-2-isopropyl < / RTI >N1-pyrrolidine-N2-butylbiguanide;N1-piperidin-2-butylvaluanide; N1-piperidin-2- t -butylbiguanide; N1-piperidin-N2- (butan-2-yl) veguanide; N1-pyrrolidine-N2-hexylbaiguanide; N1-piperidin-2-hexylbaiguanide; N1-azepan-2-hexylbaiguanide; N1-pyrrolidine-N2-cyclopentylbaiguanide; N1-piperidin-2-cyclopentylbaiguanide; N1-pyrrolidine-N2-cyclohexylbaiguanide; N1-piperidin-2-cyclohexylbaiguanide; N1-pyrrolidine-N2-cycloheptylbaiguanide; N1-piperidin-2-cycloheptylbaiguanide; N1-azepan-2-cycloheptylbaiguanide; N1-pyrrolidine-N2-phenylbaiguanide; N1-azepan-N2-phenylbaiguanide; N1-piperidin-2- (2-methyl) phenylbaiguanide; N1-piperidin-2- (3-methyl) phenylbaiguanide; N1-piperidin-2- (4-methyl) phenylbaiguanide; N1-piperidin-N2- (4-chloro) phenylbaiguanide; N1-azepan-N2- (4-chloro) phenylbaiguanide; N1-Pyrrolidin-N2-2- (furan-2-ylmethyl) valguanide; N1-piperidin-N2-2- (furan-2-ylmethyl) valguanide; N1-azepan-N2-2- (furan-2-ylmethyl) valguanide; N1-pyrrolidine-N2-benzylbaiguanide; N1-piperidine-N2-benzylbaiguanide; N1-azepan-N2-benzylbaiguanide; N1-piperidin-2- (4-methoxy) benzylbaiguanide; N1-Pyrrolidine-N2- (4-chloro) benzylbaiguanide; N1-azepan-N2- (4-chloro) benzylbaiguanide; N1-pyrrolidin-N2-2- (thiophen-2-ylethyl) veguanide; N1-piperidin-N2-2- (thiophen-2-ylethyl) veguanide; N1-azepan-N2-2- (thiophen-2-ylethyl) veguanide; N1-pyrrolidin-N2- (phenethyl) < / RTI >N1-piperidin-2-phenethylvaluanide; Or N1-azepan-N2- (phenethyl) < / RTI >

The pharmaceutically acceptable salt of the compound of formula (I) according to the present invention may be an acid addition salt formed using an organic acid or an inorganic acid. The organic acid may be selected from the group consisting of formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid, maleic acid, malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, Acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, dichloroacetic acid, aminooxyacetic acid, benzenesulfonic acid, 4-toluenesulfonic acid and methanesulfonic acid salt; The inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and boric acid-based salts. The above-mentioned acid addition salts may be prepared, for example, by a) directly mixing the compound of formula 1 and an acid, or b) dissolving one of them in a solvent or a water solvent, or c) In a solvent or in a hydration solvent.

In one embodiment, the pharmaceutically acceptable salts of the compounds of formula (I) above are in the form of their salts with formic, acetic, propionic, lactic, butyric, isobutyric, trifluoroacetic, malic, maleic, malonic, Amide, glutamic acid, tartaric acid, oxalic acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzenesulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxyacetic acid, Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, and boric acid.

The compound of formula 1 according to the present invention can be prepared by several methods.

In one embodiment,

Reacting a compound of formula (2) with a dicyanoamide in the presence of a base in an organic solvent to obtain a compound of formula (3); There is provided a process for preparing a compound of formula (1), which comprises reacting a compound of formula (3) with a compound of formula (4) in an organic solvent to obtain a compound of formula

[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

In the above formulas, R ₁ , R _{2 ,} and R ₃ are as defined in Formula 1, and in Formula 3, NCS represents isothiocyanate.

In the above preparation process, the base is selected from the group consisting of triethylamine, trimethylamine and diisopropylethylamine, and the organic solvent is selected from the group consisting of dichloromethane, dichloroethane, dimethylformamide, tetrahydrofuran, Nitrile, diethylether, 1,4-dioxane, and the like.

The preparation method can be represented by the following reaction scheme 1, for example, as follows:

[Reaction Scheme 1]

The thiourea compound of formula (4) used as an intermediate in the preparation of the compound of formula (1) can be obtained by reacting the substituted amine of formula (2) with the formula (3) in an organic solvent in the presence of a base. The base used in the preparation of the thiourea compound of Formula 4 may be triethylamine or diisopropylethylamine. The organic solvent may be dichloromethane, dichloroethane or dimethylformamide. The reaction temperature is in the range of 0 占 폚 to room temperature.

The thiourea compound of the formula 4 obtained above is dissolved in a suitable organic solvent (for example, methanol, ethanol, 1,4-dioxane or dimethylformamide) and then an ethanol solution of the formula 5 is added thereto, do. The amount of the silver (II) oxide is about 1 to 2 molar equivalents relative to the compound 4, the amount of the compound (5) is 1 to 2 molar equivalents relative to the compound 4, and the reaction temperature is in a range up to the reflux temperature of the solvent used And from room temperature to 90 DEG C in the case of ethanol). When the reaction is completed, the reaction solution is filtered, and then the pH of the reaction solution is adjusted to about 4 to 5, for example, by using an acid such as hydrochloric acid, and the resultant solution is concentrated and purified to obtain the compound of the formula Lt; RTI ID = 0.0 > acceptable salts. ≪ / RTI >

As shown in the following examples, the compound of the above formula (1) or its pharmaceutically acceptable salt thus obtained can be administered at a lower dose than the conventional drug through the activation of AMPKa to an anticancer activity including cancer metastasis and cancer recurrence inhibition Diabetes, obesity, hyperlipidemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, and metabolic syndrome because they exhibit hypoglycemic action and lipid lowering action.

Accordingly, the present invention provides a medicament comprising the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also relates to a pharmaceutical composition for preventing or treating cancer, diabetes, obesity, hyperlipidemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, metabolic syndrome, , Muscle cell damage and rhabdomyolysis, the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylaxis or treatment of the above diseases, and There is provided a method of preventing or treating a disease comprising administering to a subject a therapeutically effective amount of the compound of formula 1 or a pharmaceutically acceptable salt thereof.

In one embodiment,

The diabetes may be non-insulin dependent diabetes mellitus.

The pharmaceutical composition of the present invention contains at least one pharmaceutically acceptable carrier in addition to the active ingredient. As used herein, " pharmaceutically acceptable carrier " means a known pharmaceutical excipient which is useful when formulating pharmaceutically active compounds for administration and which is substantially non-toxic and non-sensitive under the conditions of use. The exact ratio of such excipients is determined by standard pharmaceutical practice, as well as the solubility and chemical properties of the active compound, the route of administration chosen.

The pharmaceutical composition of the present invention may be formulated into a form suitable for a desired administration method using suitable and physiologically acceptable excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, lubricants, .

The pharmaceutical composition may be formulated in the form of tablets, capsules, pills, granules, powders, injections or solutions, though it is not limited thereto.

Formulations of the pharmaceutical compositions and pharmaceutically acceptable carriers can be appropriately selected according to techniques known in the art and can be found, for example, in the following references: [Urquhart et al., Lancet, 16: 367, 1980 ]; [Lieberman et al., PHARMACEUTICAL DOSAGE FORMS-DISPERSE SYSTEMS, 2nd ed., Vol. 3, 1998]; [Ansel et al., PHARMACEUTICAL DOSAGE FORMS & DRUG DELIVERY SYSTEMS, 7th ed., 2000]; [Martindale, THE EXTRA PHARMACOPEIA, 31st ed.]; [Remington ' s PHARMACEUTICAL SCIENCES, 16th-20th editions]; [THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Goodman and Gilman, eds., 9th ed., 1996]; [Wilson and Gisvolds' TEXTBOOK OF ORGANIC MEDICINAL AND PHARMACEUTICAL CHEMISTRY, Delgado and Remers, eds., 10th ed., 1998]. The principles of formulating pharmaceutical compositions are also described, for example, in Platt, Clin Lab Med, 7: 289-99, 1987; [Aulton, PHARMACEUTICS: THE SCIENCE OF DOSAGE FORM DESIGN, Churchill Livingstone, NY, 1988]; [EXTEMPORANEOUS ORAL LIQUID DOSAGE PREPARATIONS, CSHP, 1998], ["Drug Dosage," J Kans Med Soc, 70 (1): 30-32, 1969).

In one embodiment, the pharmaceutical composition may be for use in combination with a second drug.

In the present invention, the term "second drug" refers to another pharmaceutically active ingredient other than the biguanide derivative of the present invention. The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be used for the treatment of various diseases as described above. Accordingly, the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention can be used in combination with a second drug for the effective treatment of each disease. For example, the second drug may be an anti-hyperglycemic agent, an anti-obesity agent, an anti-cancer agent, or the like.

When the compound of the formula (I) or a pharmaceutically acceptable salt thereof according to the present invention and the second drug are administered in the same manner, the compound of the formula (1) or a pharmaceutically acceptable salt thereof is formulated together with the second drug May also be provided in the form of a combined preparation.

In the present invention, the term 'subject' refers to a warm-blooded animal such as a mammal afflicted with a specific disease, disorder or disease. For example, a human, an orangutan, a chimpanzee, a mouse, a rat, a dog, , Chlorine, and the like, but are not limited to these examples.

Also, " treatment " includes, but is not limited to, alleviating the symptoms, temporarily or permanently eliminating the cause of the symptoms, or preventing or slowing the onset of symptoms and progression of the disease, disorder or disease.

The effective amount of the active ingredient of the pharmaceutical composition of the present invention means the amount required to effect the treatment of the disease. Accordingly, the present invention is not limited to the particular type of the disease, the severity of the disease, the kind and amount of the active ingredient and other ingredients contained in the composition, the type of formulation and the patient's age, body weight, general health status, sex and diet, Rate of administration, duration of treatment, concurrent medication, and the like. For example, in the case of an adult, the compound of the formula (1) may be administered in a total dose of 50 to 3000 mg / kg once to several times a day.

The N1-cyclic amine-N2-substituted biguanide derivatives of formula (I) according to the present invention exhibit excellent cancer cell proliferation inhibition, cancer metastasis and recurrence inhibitory effect even at a small dose compared to conventional drugs, And can be usefully used for the treatment of cancer including diabetes, obesity, hyperlipidemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome and metabolic syndrome.

Advantages and features of the present invention and methods of achieving them will become apparent with reference to the embodiments described in detail below. The present invention may, however, be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Is provided to fully convey the scope of the invention to those skilled in the art, and the invention is only defined by the scope of the claims.

[ Example ]

Example 1: N1-Piperidine-N2-phenylbaiguanide hydrochloride

(1-1) Synthesis of 1-isothiocyanatobenzene

A solution of carbon disulfide (1.34 mL, 22.3 mmol) in dichloromethane (3 mL) was slowly added to a solution of aniline (2.03 mL, 22.3 mmol) in dichloromethane (20 mL) at 0 ° C over 10 minutes. Triethylamine (3.42 mL, 24.5 mmol) was added to the reaction mixture, and the reaction vessel was moved to room temperature and stirred for 1 hour. Ethyl chloroformate (2.13 mL, 22.3 mmol) was added to the mixed solution and stirred for 2 hours. After confirming the completion of the reaction, water (20 mL) was added to the reaction mixture, and 2 N aqueous sodium hydroxide solution (20 mL) was added. After separation of the organic layer, the aqueous layer was extracted with dichloromethane (3 X 20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated to obtain the desired compound (2.44 g, 81%) as a yellow liquid. The compound was used in the next reaction without further purification.

(1-2) Synthesis of N -phenylpiperidine-1-carbothioamide

Piperidine (0.781 mL, 7.91 mmol) and triethylamine (1.65 mL, 11.9 mmol) were added to a solution of 1-isothiocyanato benzene (1.07 g, 7.91 mmol) in dichloromethane . The reaction vessel was moved to room temperature and stirred for 2 hours. After the completion of the reaction was confirmed, distilled water (10 mL) was added to the reaction mixture, and the mixture was neutralized with 1 N HCl aqueous solution. The organic layer was separated, the aqueous layer was extracted with dichloromethane (3 X 10 mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated. The concentrate was purified by flash column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired compound (1.23 g, 71%) as a white solid.

¹ H NMR (600 MHz, DMSO- d ₆ )? 9.19 (br s, 1H), 7.26 (m, 5H), 3.85 (m, 4H), 1.62 (m, 2H), 1.54 (m, 4H); LCMS m / z 221.2 [M + H] < ⁺ >; mp 97-98 [deg.] C.

(1-3) Synthesis of N1-piperidine-N2-phenylbaiguanide hydrochloride salt

(II) (2.39 g, 11.1 mmol) and guanidine hydrochloride (1.06 g, 11.1 mmol) were added to a solution of the compound (1.22 g, 5.53 mmol) obtained in the above step 1-2 in ethanol (10 mL) with stirring. After the mixed solution was refluxed for 6 hours, the reaction mixture was cooled and filtered using Celite 545. The filtrate was concentrated, and the concentrate was purified by flash column chromatography (dichloromethane: methanol = 9: 1). This compound was dissolved in 6 N hydrochloric acid methanol solution (1 mL) and concentrated under reduced pressure to obtain the target compound (0.67 g, 43%) as a white solid.

^{1 H NMR (600 MHz, DMSO-} d 6) δ 9.19 (br s, 1H), 7.27 (m, 2H), 7.11 (t, J = 8.4Hz, 2H), 7.03 (m, 1H), 6.79 (br s, 3H), 3.43 (s, 4H), 1.59 (s, 6H); LCMS m / z 246.2 [M + 1] ^< ^{+ &gt};; mp 220-222 [deg.] C.

The procedure of Example 1 was repeated except for using an amine compound corresponding to the target compound in place of aniline and piperidine in the steps (1-1) and (1-2) of Example 1, respectively, to prepare thiourea , And the objective compounds of the following Examples 2 to 40 were prepared by the same method as in the step (1-3) of Example 1.

Example 2: N1-Pyrrolidine-N2-methylbiguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ7.53 (br s, 1H), 6.59 (br s, 3H), 3.29 (m, 4H), 2.68 (d, J = 4.2Hz, 3H), 1.85 (s, 4H); LC-MS m / z 170.2 [M + 1] ⁺ ; mp 170-172 [deg.] C.

Example 3: N1-Piperidine-N2-methylbiguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ7.75 (br s, 1H), 6.59 (br s, 3H), 3.30 (m, 4H), 2.64 (d, J = 4.2Hz, 3H), 1.53 (m, 2H), 1.48 (m, 4H); LC-MS m / z 184.3 [M + 1] ⁺ ;

Example 4: N1-Piperidine-N2-isopropyl < RTI ID = 0.0 >

^{1 H NMR (400 MHz, DMSO-} d 6) δ7.34 (d, J = 8Hz, 1H), 6.53 (br s, 3H), 3.74 (m, 1H), 3.31 (m, 4H), 1.53 (m , 6H), 1.14 (d, J = 6.4 Hz, 6H). LC-MS m / z 212.2 [M + 1] ⁺ ; mp 265-267 [deg.] C.

Example 5: N1-Pyrrolidine-N2-butylbiguanide Hydrochloric acid

^{1 H NMR (600 MHz, DMSO-} d 6) δ 7.42 (br s, 1H), 6.46 (br s, 1H), 3.28 (m, 4H), 3.09 (m, 2H), 1.89 (s, 4H), 1.46 (m, 2H), 1.28 (m, 2H), 0.87 (t, J = 5.4 Hz, 3H). LC-MS m / z 212.3 [M + 1] ⁺ ; mp 229-231 [

Example 6: N1-Piperidine-N2-butylbiguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ7.74 (br s, 1H), 6.63 (br s, 3H), 3.32 (m, 4H), 3.06 (m, 2H), 1.52 (m, 6H) , 1.46 (m, 2H), 1.26 (m, 2H), 0.86 (t, J = 6.8Hz, 3H); LC-MS m / z 226.3 [M + 1] +; mp157-159 ℃.

Example 7: N1-Piperidine-N2- t -Butylbaiguanide hydrochloride

¹ H NMR (400 MHz, DMSO- d ₆ )? 6.77 (br s, 1H), 6.62 (br s, 3H), 3.18 (m, 4H), 1.50 (m, 6H), 1.26 (s, 9H); LC-MS m / z 226.2 [M + 1] ^< ^{+ &gt};; mp 236-237 [deg.] C.

Example 8: N1-Piperidine-N2- (butan-2-yl) veguanide hydrochloride

¹ H NMR (400 MHz, DMSO- d ₆ )? 7.29 (d, J = 8.4 Hz, 1H), 6.55 (br s, 3H), 3.51 , 2H), 1.12 (d, J = 6.8 Hz, 3H), 0.82 (t, J = 7.2 Hz, 3H); LC-MS m / z 226.2 [M + 1] ^< ^{+ &gt};; mp 275-277 [deg.] C.

Example 9: N1-Pyrrolidine-N2-hexylbaiguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ 7.41 (br s, 1H), 6.44 (br s, 3H), 3.28 (m, 4H), 3.09 (m, 2H), 1.86 (s, 4H), 1.46 (m, 2H), 1.25 (m, 6H), 0.84 (t, J = 6.9 Hz, 3H); LC-MS m / z 240.2 [M + 1] ^< ^{+ &gt};; mp 175-177 [deg.] C.

Example 10: N1-Piperidine-N2-hexylbaiguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ7.63 (br s, 1H), 6.54 (br s, 3H), 3.28 (m, 4H), 3.02 (m, 2H), 1.53 (m, 2H) , 1.48 (m, 4H), 1.43 (m, 2H), 1.20 (m, 6H), 0.82 (t, J = 6.6Hz, 3H); LC-MS m / z 254.3 [m + 1] +; mp182- 183 [deg.] C.

Example 11: N1-Azepan-N2-hexylbaiguanide hydrochloride

^{1 H NMR (400 MHz, DMSO-} d 6) δ 7.48 (br s, 1H), 6.42 (br s, 3H), 3.31 (m, 4H), 3.02 (m, 2H), 1.62 (m, 4H), 1.46 (m, 6H), 1.22 (m, 6H), 0.82 (t, J = 6.8Hz, 3H); LC-MS m / z 268.2 [m + 1] +; mp172-173 ℃.

Example 12: N1-Pyrrolidine-N2-cyclopentylbaiguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ 7.19 (d, J = 6.6Hz, 1H), 6.52 (br s, 3H), 3.91 (m, 1H), 3.31 (m, 4H), 1.85-1.79 (m, 6H), 1.66 (m, 2H), 1.55 (m, 2H), 1.47 (m, 2H); LC-MS m / z 224.2 [M + 1] ^< ^{+ &gt};; mp 235-236 ° C.

Example 13: N1-Piperidine-N2-cyclopentylbaiguanide hydrochloride

¹ H NMR (600 MHz, DMSO- d ₆ )? 7.43 (d, J = 7.8 Hz, 1H), 6.59 (br s, 3H), 3.87 , 2H), 1.65 (m, 2H), 1.55 (m, 8H), 1.47 (m, 2H); LC-MS m / z 238.2 [M + 1] ^< ^{+ &gt};; mp 263-264 [deg.] C.

Example 14: N1-Pyrrolidine-N2-cyclohexylbaiguanide hydrochloride

¹ H NMR (400 MHz, DMSO- d ₆ )? 7.50 (br s, 1 H), 6.94 (br s, 3H), 3.95-3.34 ), 1.56 (m, 1H) , 1.39 (m, 2H), 1.18 (m, 2H), 1.07 (m, 1H); LC-MS m / z 238.3 [m + 1] +; mp169-171 ℃.

Example 15: N1-Piperidine-N2-cyclohexylbaiguanide hydrochloride

¹ H NMR (600 MHz, DMSO- d ₆ )? 7.28 (br s, 1 H), 6.52 (br s, 3H), 3.29-3.26 ), 1.52-1.48 (m, 5H), 1.37 (m, 2H), 1.34 (m, 2H), 1.01 (m, 1H); LC-MS m / z 252.3 [M + 1] ^< ^{+ &gt};; mp 234-235 [deg.] C.

Example 16: N1-Pyrrolidine-N2-cycloheptylbaiguanide hydrochloride

¹ H NMR (600 MHz, DMSO- d ₆ )? 7.16 (br s, 1 H), 6.52 (br s, 3 H), 3.60 1.79 (m, 2H), 1.61 (m, 4H), 1.54 (m, 2H), 1.46 (m, 2H), 1.32 (m, 2H); LC-MS m / z 252.3 [M + 1] ^< ^{+ &gt};; mp245-247 [deg.] C.

Example 17: N1-Piperidine-N2-cycloheptylbaiguanide hydrochloride

¹ H NMR (600 MHz, DMSO- d ₆ )? 7.36 (d, J = 7.8 Hz, 1 H), 6.56 (br s, 3H), 3.55 2H), 1.62 (m, 2H), 1.56 (m, 4H), 1.51 (m, 6H), 1.46 (m, 2H), 1.34 (m, 2H); LC-MS m / z 266.4 [M + 1] ^< ^{+ &gt};; mp 267-269 [deg.] C.

Example 18: N1-Azepan-2-cycloheptylbaiguanide hydrochloride

^{1 H NMR (400 MHz, DMSO-} d 6) δ 7.18 (br s, 1H), 6.39 (br s, 1H), 3.49 (m, 1H), 3.39 (t, J = 5.8Hz, 4H), 1.78 ( m, 2H), 1.62 (m, 8H), 1.50 (m, 8H), 1.32 (m, 2H). LC-MS m / z 280.2 [M + 1] ⁺ ; mp 267-268 [deg.] C.

Example 19: N1-Pyrrolidine-N2-phenylbaiguanide hydrochloride

^{1 H NMR (400 MHz, DMSO-} d 6) δ9.13 (br s, 1H), 7.28 (m, 2H), 7.14 (m, 3H), 6.75 (br s, 3H), 3.48 (m, 4H) , 1.89 (m, 4H); LC-MS m / z 232.2 [M + H] ⁺ ; mp 245-246 [deg.] C.

Example 20: N1-Azepan-N2-phenylbaiguanide hydrochloride

^{1 H NMR (400 MHz, DMSO-} d 6) δ8.89 (br s, 1H), 7.25 (m, 2H), 7.08 (m, 3H), 6.54 (br s, 3H), 3.51 (m, 4H) , 1.71 (m, 4H), 1.53 (m, 4H); LC-MS m / z 252.3 [M + 1] ⁺ ; mp 234-235 [deg.] C.

Example 21: N1-Piperidine-N2- (2-methyl) phenylbaiguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ 8.77 (br s, 1H), 7.15 (m, 4H), 6.62 (br s, 3H), 3.50 (m, 4H), 2.21 (s, 3H), 1.63 (m, 6H); LC-MS m / z 260.2 [M + 1] ⁺ ; mp 234-235 [deg.] C.

Example 22: N1-Piperidine-N2- (3-methyl) phenylbaiguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ 9.12 (br s, 1H), 7.17 (m, 1H), 6.92 (m, 2H), 6.87 (d, J = 7.2Hz, 1H), 6.80 (br 3H), 3.47 (m, 4H), 2.26 (s, 3H), 1.61 (m, 6H); LC-MS m / z 260.2 [M + 1] ⁺ ; mp 194-197 [deg.] C.

Example 23: N1-Piperidine-N2- (4-methyl) phenylbaiguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ 9.10 (br s, 1H), 7.06 (d, J = 8.4Hz, 2H), 6.98 (d, J = 8.4Hz, 2H), 6.72 (br s, 3H), 3.42 (m, 4H), 2.20 (s, 3H), 1.57 (m, 6H). LC-MS m / z 260.2 [M + 1] ⁺ ; mp 218-220 [

Example 24: N1-Piperidine-N2- (4-chloro) phenylbaiguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ7.34 (d, J = 8.4Hz, 2H), 7.34 (d, J = 8.4Hz, 2H), 6.92 (br s, 3H), 3.46 (m, 4H), 1.64 (m, 6H); LC-MS m / z 280.2 [M + H] < ⁺ >; mp 211-212 [deg.] C.

Example 25: N1-Azepan-N2- (4-chloro) phenylbaiguanide hydrochloride

^{1 H NMR (400 MHz, DMSO-} d 6) δ 7.34 (m, 2H), 7.13 (m, 2H), 6.61 (br s, 1H), 3.35 (m, 4H), 1.74 (m, 4H), 1.57 (m, 4H); LC-MS m / z 294.2 [M + H] < ⁺ >; mp 173-174 [deg.] C.

Example 26: N1-Pyrrolidine-N2-2- (furan-2-ylmethyl) valguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ 7.89 (br s, 1H), 7.58 (s, 1H), 6.55 (br s, 3H), 6.41 (s, 1H), 6.31 (s, 1H), LC / MS m / z 236.2 [M + 1] ⁺ ; mp 212-214 [deg.] C.

Example 27: N1-Piperidine-N2-2- (furan-2-ylmethyl) valguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ 8.07 (br s, 1H), 7.54 (m, 1H), 6.62 (br s, 3H), 6.36 (m, 1H), 6.25 (m, 1H), LC-MS m / z 250.2 [M + 1] ⁺ ; mp 216-218 [deg.] C.

Example 28: N1-Azepan-N2-2- (furan-2-ylmethyl) valguanide hydrochloride

¹ H NMR (600 MHz, DMSO- d ₆ )? 7.98 (br s, IH), 7.55 (m, IH), 6.59 (br s, 3H), 6.37 4.23 (d, J = 4.8 Hz , 2H), 3.37 (m, 4H), 1.63 (m, 4H), 1.45 (m, 4H); LC-MS m / z 264.3 [M + 1] ^< ^{+ &gt};; mp 182-184 [deg.] C.

Example 29: N1-Pyrrolidine-N2-benzylbaiguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ 7.98 (br s, 1H), 7.29 (d, J = 5.4Hz, 4H), 7.22 (m, 1H), 6.53 (br s, 3H), 3.31 ( m, 4H), 1.84 (m, 4H); LC-MS m / z 246.2 [M + 1] ^< ^{+ &gt};; mp 206-208 [deg.] C.

Example 30: N1-Piperidine-N2-benzylbaiguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ 8.25 (t, J = 5.7Hz, 1H), 7.30 (m, 5H), 6.66 (br s, 3H), 4.32 (d, J = 5.4Hz, 2H ), 3.35 (m, 4H), 1.55 (m, 6H); LC-MS m / z 260.2 [M + 1] ⁺ ; mp 165-167 [

Example 31: N1-Azepan-2-benzylbaiguanide hydrochloride

^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.04 (br s, 1H), 7.27 (m, 5H), 6.42 (br s, 3H), 4.25 (m, 3H), 3.39 (m, 4H), 1.65 (m, 4H), 1.47 (m, 4H); LC-MS m / z 274.2 [M + H] ⁺ ; mp 175-176 [

Example 32: N1-Piperidine-N2- (4-methoxy) benzylbau nide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ 8.17 (t, J = 6Hz, 1H), 7.23 (d, J = 8.4Hz, 2H), 6.88 (d, J = 9Hz, 2H), 6.93 (br s, 3H), 4.23 (d, J = 6 Hz, 2H), 3.73 (s, 3H), 3.33 (m, 4H), 1.58 (m, 2H), 1.53 (m, 4H); LC-MS m / z 290.2 [M + 1] ^< ^{+ &gt};; mp 102-103 [deg.] C.

Example 33: N1-Pyrrolidine-N2- (4-chloro) benzylbaiguanide hydrochloride

^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.01 (br s, 1H), 7.32 (m, 4H), 6.53 (br s, 3H), 4.28 (s, 2H), 3.30 (m, 4H), 1.84 (m, 4 H); LC-MS m / z 280.2 [M + 1] ^< ^{+ &gt};; mp204-205 [deg.] C.

Example 34: N1-Azepan-N2- (4-chloro) benzylbaiguanide hydrochloride

^{1 H NMR (400 MHz, DMSO-} d 6) δ 8.14 (br s, 1H), 7.35 (d, J = 7.2Hz, 2H), 7.28 (d, J = 7.2Hz, 2H), 6.46 (br s, 3H), 4.23 (d, J = 4.0 Hz, 2H), 3.39 (m, 4H), 1.64 (m, 4H), 1.46 (m, 4H); LC-MS m / z 308.2 [M + 1] ^< ^{+ &gt};; mp 207-208 [deg.] C.

Example 35: N1-Pyrrolidine-N2-2- (thiophen-2-ylethyl) valguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ 7.57 (br s, 1H), 7.32 (d, J = 6.0Hz, 1H), 6.92 (m, 1H), 6.86 (d, J = 3.6Hz, 1H ), 6.53 (br s, 3H), 3.26 (m, 6H), 2.97 (t, J = 7.8 Hz, 2H), 1.83 (s, 4H); LC-MS m / z 266.2 [M + 1] ⁺ ; mp 222-224 [deg.] C.

Example 36: N1-Piperidine-N2-2- (thiophen-2-ylethyl) veguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ 7.81 (br s, 1H), 7.36 (d, J = 4.2Hz, 1H), 6.96 (m, 1H), 6.88 (d, J = 4.2Hz, 1H ), 6.65 (br s, 3H), 3.30 (m, 6H), 3.03 (t, J = 7.5 Hz, 2H), 1.57 (m, 2H), 1.51 (m, 4H); LC-MS m / z 280.2 [M + 1] ^< ^{+ &gt};; mp 206-208 [deg.] C.

Example 37: N1-Azepan-N2-2- (thiophen-2-ylethyl) veguanide hydrochloride

^{1 H NMR (400 MHz, DMSO-} d 6) δ 7.54 (br s, 1H), 7.36 (dd, J = 5.2,1.2Hz, 1H), 6.96 (dd, J = 5.2,3.2Hz, 1H), 6.88 (d, J = 3.2Hz, 1H ), 6.43 (br s, 3H), 3.38 (m, 4H), 3.29 (m, 2H), 3.05 (t, J = 7.2Hz, 2H), 1.64 (m, 4H ), 1.48 (m, 4H); LC-MS m / z 294.2 [M + 1] ^< ^{+ &gt};; mp 233-234 [deg.] C.

Example 38: N1-Pyrrolidine-N2- (phenethyl) valguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ 9.59 (br s, 1H), 7.27 (t, J = 7.2Hz, 2H), 7.18 (t, J = 6.6Hz, 2H), 6.56 (br s, 3H), 3.26 (m, 6H), 2.75 (t, J = 8.4 Hz, 2H), 1.82 (m, 4H); LC-MS m / z 260.2 [M + 1] ^< ^{+ &gt};; mp 206-208 [deg.] C.

Example 39: N1-Piperidine-N2-phenethylbaiguanide hydrochloride

^{1 H NMR (600 MHz, DMSO-} d 6) δ 7.79 (t, J = 5.4Hz, 1H), 7.31 (t, J = 7.5Hz, 2H), 7.21 (t, J = 9.0Hz, 3H), 6.64 (br s, 3H), 3.32 (m, 4H), 3.27 (m, 2H), 2.80 (t, J = 7.5Hz, 2H), 1.57 (m, 2H), 1.50 (m, 4H); LC-MS m / z 274.2 [M + 1] ^< ^{+ &gt};; mp 178-180 [deg.] C.

Example 40: N1-Azepan-N2- (phenethyl) veguanide hydrochloride

^{1 H NMR (400 MHz, DMSO-} d 6) δ7.62 (t, J = 5.0Hz, 1H), 7.28 (m, 2H), 7.21 (m, 3H), 6.52 (br s, 3H), 3.36 ( t, J = 8.0 Hz, 4H), 3.29 (m, 2H), 2.80 (t, J = 7.6 Hz, 2H), 1.62 (m, 4H), 1.46 (m, 4H); LC-MS m / z 288.3 [M + 1] ^< ^{+ &gt};; mp 207-209 [deg.] C.

[ Test Example ]

Compounds synthesized in the manner described in the examples of the present invention were evaluated for the AMPK activation effect and the cancer cell proliferation inhibitory effect according to the method described in the following test examples

Test Example  One: AMPK α activation effect measurement

MCF7 cells (purchased from Korean Cell Line Bank) derived from human breast cancer cells were used, and a 5'-AMP-activated protein kinase alpha immunoassay kit (Invitrogen, catalog No. KHO0651) AMPK activation effect was confirmed.

MCF7 cells were cultured in a DMEM medium containing 10% fetal bovine serum, and placed in a 6-well plate so that the number of cells was about ⁵ × 10 ⁵ cells. Then, cells were cultured in an incubator fed with 5% CO ₂ . Derivatives synthesized in the above examples were treated with 5, 10, and 50 uM and cultured for 24 hours. Metformin hydrochloride was used as a control, and treated with 0.05, 0.5, 1, 2, 5 and 10 mM, and then tested in the same manner as the derivatives synthesized in the examples. Next, the cells were lysed by the method described in the instruction manual of the AMPKα immunoassay kit, 20 ug of the cell lysate was obtained by protein quantification, and then the AMPKα immunoassay kit was used to obtain AMPKα threonine The degree of phosphorylation of 172 residue (Thr172) was confirmed and the result was obtained. The degree of AMPK activation by the biguanide derivative was shown to be phosphorylated AMPKa in the cells cultured in the presence of the compounds synthesized in the above examples, compared to the phosphorylated AMPKa in the cells cultured without treatment with the biguanide derivative . Based on the AMPKa activation result, a graph of AMPK activation curve according to the treatment concentration was prepared, and the concentration of the compound with 150% AMPK activation (activation concentration 150, AC150) was determined using the GraphPad Prism 5.0 program. AMPK activation was measured when the treatment concentration of 10 uM and 50 uM was 50 μM and the concentration of metformin hydrochloride was 50 uM

The results are shown in Table 1 below

AMPK activation effect Example
AMPK activation effect AC150
(uM) 10 uM
(%) 50 uM
(%) Metformin hydrochloride 188.3 130 One > 50 115 2 > 50 85.4 121 3 > 50 97.3 150 4 2.5 205.4 176 5 > 50 116.3 143 6 43.7 104.9 157 7 > 50 94.8 88 8 > 50 77.6 67 9 7.3 159.0 578 10 2.6 321.3 743 11 20.0 87.9 260 12 > 50 96.7 100 13 > 50 86.9 115 14 > 50 102.0 93 15 39.7 90.2 170 16 49.7 103.9 151 17 26.4 131.6 172 18 > 50 94.7 122 19 > 50 78.7 110 20 15.3 121.3 179 21 > 50 92 22 > 50 123 23 22.1 211 24 > 50 88.2 112 25 > 50 98.7 125 26 > 50 102.6 89 27 > 50 86.8 113 28 > 50 72.4 93 29 22.6 118.6 187 30 11.5 322 31 > 50 98.4 111 32 31.8 111.5 179 33 11.7 134.4 276 34 20.9 220 35 > 50 103.3 139 36 39.0 95.1 170 37 22.7 121.3 190 38 19.5 227 39 25.0 200 40 > 50 131.0 143

Test Example  2: Measurement of Cancer Cell Proliferation Inhibitory Effect

HCT116 cells (purchased from Korean Cell Line Bank) derived from human colon cancer were used and cells were cultured in the presence of MTT (3- (4,5-dimethylsazoyl-2-yl) -2,5-ditetrazolium bromide) The cell growth inhibition concentration (GIC50) value at which the growth was inhibited to 50% was measured to confirm the cancer cell proliferation inhibitory effect of the biguanide derivative.

First, HCT116 cells were cultured in a 96-well plate in DMEM medium containing 10% fetal bovine serum for about 5000 cells. Next, to determine the GIC50 value of each compound, the cells were cultured in the above culture medium at 100 uM, 25 uM, 6.25 uM, 1.56 uM and 0.39 uM, respectively, for 48 hours. As a control, metformin hydrochloride was used and treated in the culture broth at 25, 12.5, 2.5, 0.5, 0.1 mM and tested in the same manner as described in the derivatives synthesized in the examples. After treatment of the compound, MTT was added to the culture medium to confirm the living cells and further cultured for 3 hours. The resulting formazane crystal was dissolved using dimethylsulfoxide and the absorbance of the solution was measured at 560 nm. The number of viable cells in the well plate treated with the compounds synthesized in the examples relative to the number of cells cultured in the wells plate after 48 hours of culturing the compound is represented by the cell viability (%) according to each treatment concentration. Using this, a cell viability curve graph was prepared and the inhibitory effect of the cancer cell proliferation was confirmed by calculating the concentration (GIC50) of the compound whose growth was inhibited to 50%. In addition, the percent inhibition of cell growth when the treatment concentration of metformin hydrochloride used as a control group and 100 μM of the biaguanide derivative was indicated.

The results of inhibiting cancer cell growth are shown in Table 2 below.

Cancer cell growth inhibitory effect Example
Cancer cell growth inhibitory effect GI50 (uM) Cell growth inhibition at 100 uM Metformin hydrochloride 2846 1.8 One > 100 12.3 2 > 100 13.6 3 > 100 42.0 4 > 100 14.6 5 > 100 31.7 6 > 100 19.3 7 > 100 35.3 8 > 100 31.3 9 82.1 50.9 10 61.5 52.2 11 > 100 35.6 12 > 100 4.9 13 > 100 5.5 14 > 100 7.7 16 > 100 29.2 17 > 100 28.4 18 > 100 25.3 19 > 100 5.2 20 > 100 11.5 21 > 100 10.0 22 > 100 14.3 23 > 100 9.8 24 > 100 4.1 25 > 100 15.1 26 > 100 11.1 27 > 100 12.0 28 > 100 8.0 29 > 100 28.1 30 > 100 24.0 31 > 100 7.7 32 > 100 17.1 33 > 100 18.6 34 > 100 10.6 35 > 100 19.0 36 > 100 10.6 37 > 100 1.6 38 > 100 1.8 39 > 100 11.4 40 > 100 24.1

Claims (17)

A pharmaceutical composition for treating cancer comprising as an active ingredient a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In this formula,
R ₁ and R ₂ form a heterocycloalkyl of 3 to 8 members together with the nitrogen that is associated with these, and
R ₃ is C _3-7 cycloalkyl; C _1-12 alkyl unsubstituted or substituted with C _3-12 aryl or C _3-12 heteroaryl; Or C _3-12 aryl,
Wherein the 3- to 8-membered heterocycloalkyl, C _3-12aryl or C _{3-12heteroaryl is} optionally substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, C _1-4 alkyl and C _1-4 alkoxy Or not.
The method according to claim 1,
_Wherein said C _3-12 aryl is phenyl or naphthalenyl,
_Wherein said C _3-12 heteroaryl is furanyl, thiophenyl, pyridinyl. Pyrrolyl, imidazolyl, or pyrimidinyl;
_Wherein said C _3-12 aryl or C _3-12 heteroaryl is unsubstituted or substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, C _1-4 alkyl and C _1-4 alkoxy,
A pharmaceutical composition for treating cancer.
The method according to claim 1,
R ₁ and R ₂ together with the nitrogen to which they are attached form a 3 to 8 membered heterocycle selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl and aziridinyl, Alkyl < / RTI >
R ₃ is C _3-7 cycloalkyl; C _1-12 alkyl unsubstituted or substituted with C _3-12 aryl or C _3-12 heteroaryl; Or C _3-12 aryl,
Wherein the 3- to 8-membered heterocycloalkyl, C _3-12aryl or C _{3-12heteroaryl is} optionally substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, C _1-4 alkyl and C _1-4 alkoxy Or not
A pharmaceutical composition for treating cancer.
The method according to claim 1,
R ₁ and R ₂ together with the nitrogen to which they are attached form a 3 to 8 membered heterocycle selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl and aziridinyl, ≪ / RTI > alkyl,
R ₃ is C _3-7 cycloalkyl; Which is unsubstituted or substituted with C _3-12 aryl or C _3-12 heteroaryl selected from the group consisting of phenyl, naphthalenyl, furanyl, thiophenyl, pyridinyl, pyrroyl, imidazolyl and pyrimidinyl, _1-12 alkyl; Or C _3-12 aryl,
Wherein the 3- to 8-membered heterocycloalkyl, C _3-12aryl or C _{3-12heteroaryl is} optionally substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, C _1-4 alkyl and C _1-4 alkoxy Or not
A pharmaceutical composition for treating cancer.
The method according to claim 1,
R ₁ and R ₂ form a heterocycloalkyl of 4 to 7 members together with the nitrogen that is associated with these, and
R ₃ is C _3-7 cycloalkyl; C _1-12 alkyl unsubstituted or substituted with C _3-12 aryl or C _3-12 heteroaryl; Or C _3-12 aryl,
Wherein the 4 to 7 membered heterocycloalkyl, C _3-12 aryl or C _3-12 heteroaryl is optionally substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, C _1-4 alkyl and C _1-4 alkoxy Or not
A pharmaceutical composition for treating cancer.
The method according to claim 1,
R ₁ and R ₂ together with the nitrogen to which they are attached form a 4 to 7 membered heterocycloalkyl selected from the group consisting of pyrrolidinyl, piperidinyl, and azepanyl,
R ₃ is C _1-4 alkyl optionally substituted with C _3-12 aryl or C _3-12 heteroaryl selected from the group consisting of phenyl, naphthalenyl, furanyl, thiophenyl and pyridinyl; Or C _3-12 aryl,
_Wherein said C _3-12 aryl or C _3-12 heteroaryl is unsubstituted or substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, C _1-4 alkyl and C _1-4 alkoxy,
A pharmaceutical composition for treating cancer.
The method according to claim 1,
R ₁ and R ₂ together with the nitrogen to which they are attached form a 4 to 7 membered heterocycloalkyl selected from the group consisting of pyrrolidinyl, piperidinyl, and azepanyl,
R ₃ is unsubstituted C _1-7 alkyl or unsubstituted C _3-7 cycloalkyl
A pharmaceutical composition for treating cancer.
The method according to claim 1,
The compound of formula (1)
N1-piperidin-N2-phenylbaiguanide;
N1-pyrrolidine-N2-methylbiguanide;
N1-piperidin-2-methylbiguanide;
N1-piperidin-2-isopropyl < / RTI >
N1-pyrrolidine-N2-butylbiguanide;
N1-piperidin-2-butylvaluanide;
N1-piperidin-2- t -butylbiguanide;
N1-piperidin-N2- (butan-2-yl) veguanide;
N1-pyrrolidine-N2-hexylbaiguanide;
N1-piperidin-2-hexylbaiguanide;
N1-azepan-2-hexylbaiguanide;
N1-pyrrolidine-N2-cyclopentylbaiguanide;
N1-piperidin-2-cyclopentylbaiguanide;
N1-pyrrolidine-N2-cyclohexylbaiguanide;
N1-piperidin-2-cyclohexylbaiguanide;
N1-pyrrolidine-N2-cycloheptylbaiguanide;
N1-piperidin-2-cycloheptylbaiguanide;
N1-azepan-2-cycloheptylbaiguanide;
N1-pyrrolidine-N2-phenylbaiguanide;
N1-azepan-N2-phenylbaiguanide;
N1-piperidin-2- (2-methyl) phenylbaiguanide;
N1-piperidin-2- (3-methyl) phenylbaiguanide;
N1-piperidin-2- (4-methyl) phenylbaiguanide;
N1-piperidin-N2- (4-chloro) phenylbaiguanide;
N1-azepan-N2- (4-chloro) phenylbaiguanide;
N1-Pyrrolidin-N2-2- (furan-2-ylmethyl) valguanide;
N1-piperidin-N2-2- (furan-2-ylmethyl) valguanide;
N1-azepan-N2-2- (furan-2-ylmethyl) valguanide;
N1-pyrrolidine-N2-benzylbaiguanide;
N1-piperidine-N2-benzylbaiguanide;
N1-azepan-N2-benzylbaiguanide;
N1-piperidin-2- (4-methoxy) benzylbaiguanide;
N1-Pyrrolidine-N2- (4-chloro) benzylbaiguanide;
N1-azepan-N2- (4-chloro) benzylbaiguanide;
N1-pyrrolidin-N2-2- (thiophen-2-ylethyl) veguanide;
N1-piperidin-N2-2- (thiophen-2-ylethyl) veguanide;
N1-azepan-N2-2- (thiophen-2-ylethyl) veguanide;
N1-pyrrolidin-N2- (phenethyl) < / RTI >
N1-piperidin-2-phenethylvaluanide; or
N1-azepan-N2- (phenethyl) < / RTI >
A pharmaceutical composition for treating cancer.
9. The method according to any one of claims 1 to 8,
Wherein said pharmaceutically acceptable salt is selected from the group consisting of formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid, maleic acid, malonic acid, fumaric acid, succinic acid, succinic monoamide, glutamic acid, tartaric acid, oxalic acid, But are not limited to, hydrochloric acid, hydrobromic acid, glycolic acid, gluconic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzenesulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxyacetic acid, A salt with an acid selected from the group consisting of boric acid
A pharmaceutical composition for treating cancer.
9. The method according to any one of claims 1 to 8,
Wherein the treatment of cancer comprises inhibiting cancer recurrence or cancer metastasis.
9. The method according to any one of claims 1 to 8,
Wherein the cancer is selected from the group consisting of cervical cancer, breast cancer, gastric cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, blood cancer and liver cancer.
9. The method according to any one of claims 1 to 8,
Wherein the pharmaceutical composition is formulated in the form of tablets, capsules, pills, granules, powders, injections or solutions.
Reacting a compound of formula (2) with a dicyanoamide in the presence of a base in an organic solvent to obtain a compound of formula (3); Reacting a compound of the formula (3) with a compound of the formula (4) in an organic solvent to obtain a compound of the formula (1): < EMI ID =

[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

In this formula,
R ₁ and R ₂ form a heterocycloalkyl of 3 to 8 members together with the nitrogen that is associated with these, and
R ₃ is C _3-7 cycloalkyl; C _1-12 alkyl unsubstituted or substituted with C _3-12 aryl or C _3-12 heteroaryl; Or C _3-12 aryl,
Wherein the 3- to 8-membered heterocycloalkyl, C _3-12aryl or C _{3-12heteroaryl is} optionally substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, C _1-4 alkyl and C _1-4 alkoxy ≪ / RTI >
In formula (3), NCS represents isothiocyanate.
14. The method of claim 13,
Wherein the base is selected from the group consisting of triethylamine, trimethylamine and diisopropylethylamine and the organic solvent is selected from the group consisting of dichloromethane, dichloroethane, dimethylformamide, tetrahydrofuran, acetonitrile, diethylether, 1,4 - < / RTI > dioxane. delete delete delete