KR102072245B1 - N1-cyclic amine-n5-substituted biguanide derivatives, methods of preparing the same and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention provides a novel N1-cyclicamine-N5-substituted biguanide derivative of Formula 1, a method for preparing the same, and a use thereof for the manufacture of a medicament for preventing or treating cancer. N1-cyclic amine-N5-substituted biguanide derivatives of the formula (1) according to the present invention shows excellent cancer cell proliferation inhibition and cancer metastasis and recurrence inhibitory effect even at a lower dose compared to conventional drugs, excellent blood sugar lowering action and lipid It exhibits a lowering effect and can be usefully used for the treatment of cancer.
[Formula 1]

Description

N1-Cylicamine-N5-substituted biguanide derivatives, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient {N1-CYCLIC AMINE-N5-SUBSTITUTED BIGUANIDE DERIVATIVES, METHODS OF PREPARING THE SAME AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME}

The present invention is to inhibit the cancer cell proliferation, cancer metastasis and cancer recurrence through the activation of AMPK even at a lower dose than the conventional drug, N1-cyclic amine-N5-substituted biguanide derivative, a method for producing the same and It relates to a pharmaceutical composition containing this as an active ingredient.

AMP-activated protein kinases (AMPKs) are enzymes that maintain energy homeostasis in cells and throughout the body by regulating metabolic pathways to balance 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. AMPK inhibits and kills the proliferation of cancer cells by regulating energy metabolism not only in normal cells but also in cancer cells. AMPK activated in cancer cells regulates cell cycle, cell polarity, autophagy and apoptosis by phosphorylating mTORC1, p53 and fatty acid synthase. Will be displayed.

Metformin is best used in the treatment of insulin-independent diabetes (type 2 diabetes) because it has the best hypoglycemic effect among oral diabetes treatments, does not cause hypoglycemia or hyperinsulinemia, and can prevent complications. Recently, many studies on metformin have been conducted, and metformin inhibits the action of mitochondrial electron transporter Complex I, which inhibits the production of intracellular energy, thereby activating AMPK (AMP-activated protein kinase) and making proteins necessary for survival. It has been spotlighted as an anticancer agent that regulates the metabolism of cancer cells, as a paper published that inhibits the activation of S6K1 signaling pathways inhibits cancer cell proliferation and tumor growth [Mol. Cancer Ther. 9 (5): 1092-1099 (2010)]. In addition, epidemiological investigations confirmed that cancer incidence and mortality from cancer decreased in patients receiving metformin [BMJ.330: 1304-1305 (2005)].

On the other hand, there is increasing clinical evidence that cancer stem cells are involved in cancer recurrence and metastasis. Cancer stem cells are cancer cells that possess stem cell-specific abilities of self-renewal or differentiation, and cancer stem cells are less than 0.2% in cancer tissues. It was a drug targeted to the cells. However, cancer stem cells, which are characterized by proliferating slowly, have become resistant to existing anticancer therapies, and have a poor prognosis. On the other hand, metformin has been found to prevent cancer from recurring by selectively acting on and removing cancer stem cells from breast cancer cells [Cancer Res. 69 (19): 7507-11 (2009)]. It also inhibits the expression of the transcription factors Snail1, Slug, Twist, ZEB1 / 2 and TGF-b, which are involved in epithelial-to-mesenchymal transition (EMT), and increases the expression of E-cadherin in cancer cells. It is also known to prevent the metastasis of cancer by inhibiting the progression of EMT to mobility and invasion [Cell Cycle 10: 7,1144-1151 (2011), Cell Cycle 9:18, 3807-3814 (2010), Cell Cycle 9: 22,4461-4468 (2010)).

There is a need for a biguanide-based material that exhibits better pharmacological action and improved physicochemical properties than conventional metformin.

The present invention is to provide a novel biguanide derivative, or a pharmaceutically acceptable salt thereof, and a method for preparing the same, which exhibit excellent cancer cell proliferation inhibitory effect and cancer metastasis and cancer recurrence inhibitory effect even in a small amount compared to existing drugs.

The present invention provides an N1-ringamine-N5-substituted biguanide derivative compound of Formula 1, or a pharmaceutically acceptable salt thereof:

[Formula 1]

Where

R ₁ and R ₂ are C ₃ having a ring of 4 to 7 atoms with the nitrogen associated with these _- to form a heterocycloalkyl ₆ alkene, and

R ₃ is hydrogen; C _{1 - 6} alkyl; Phenyl; Or a C ₁ is substituted by _phenyl-4 alkyl, and,

The C _{3 - 6} heterocycloalkyl alkene is halogen, hydroxy, and C _{1 -} or substituted with one or more substituents selected from the group consisting of a _6-alkyl is unsubstituted,

Wherein the phenyl is halogen, hydroxy, C _{1 - 6} alkyl, C _{1 - 6} alkoxy, C _{1 - 6} haloalkyl and C _{1 -} substituted with ₆ haloalkoxy of one or more non-hydrogen substituents selected from the group consisting of or is unsubstituted .

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 atom groups, provided that the valence requirements are met and chemically stable compounds must arise from the substitution. Within this specification, all substituents are to be interpreted as being optionally substituted, unless expressly stated to be "unsubstituted." The substituents of R ₁ to R ₃ on the biguanide derivatives according to the present invention may each be substituted with one or more of the above defined substituents.

"Halogen" or "halo" represents fluoro, chloro, bromo and iodo.

"Hydroxy" represents -OH.

"Alkyl" generally refers to straight-chain and branched saturated hydrocarbon groups having the specified number of carbon atoms (eg, 1 to 12 carbon atoms). Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3- 1, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl, n-heptyl and n-octyl and the like. Alkyl may be attached to a parent group or substrate at any ring atom unless the attachment would violate valence requirements. Likewise, an alkyl group may contain one or more non-hydrogen substituents unless the attachment would violate valence requirements. For example, "haloalkyl" means an alkyl group in which at least one of hydrogens in the alkyl group is substituted with halogen. For example, when at least one of the hydrogen of the methyl group is substituted with halogen, it will form -CH ₂ (halo) _, -CH (halo) ₂ or C (halo) ₃ . Examples of "haloalkyl" groups include, without limitation, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl and the like.

"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-pentoxy and the like. do. Alkoxy may be attached to a parent group or substrate at any ring atom if the attachment does not violate valence requirements. Likewise, an alkoxy group may contain one or more non-hydrogen substituents unless the attachment would violate valence requirements. For example, "haloalkoxy" means the alkoxy group in which at least one of hydrogen of the alkoxy group is substituted by halogen. For example, —O—CH ₂ (halo) when at least one of the hydrogens of the methoxy group is substituted with halogen, Form -O-CH (halo) ₂ or -OC (halo) ₃ . Examples of "haloalkoxy" groups include, without limitation, trichloromethoxy, trichloromethoxy, tribromomethoxy, triiodomethoxy, and the like.

"Cycloalkyl alkene" refers to an unsaturated non-aromatic part and polycyclic hydrocarbon ring having a carbon atom number of specified (e.g., C _{3 - 8} cycloalkyl alkene as ring members 3, 4, 5, 6, 7 characters or 8 carbon atoms To cycloalkene group). Cycloalkenes may be attached to a parent group or substrate at any ring atom unless the attachment would violate valence requirements. Likewise, cycloalkene groups may include one or more non-hydrogen substituents unless the attachment would violate valence requirements.

Heterocycloalkenes refer to unsaturated, non-aromatic monocyclic and polycyclic hydrocarbon rings, in which at least one of the ring members of a cycloalkene is composed of heteroatoms, ie, elements other than carbon, including nitrogen, oxygen, or sulfur. Heterocycloalkenes may be attached to a parent group or substrate at any ring atom unless the attachment would violate valence requirements. Likewise, a heterocycloalkene group may contain one or more non-hydrogen substituents unless the attachment would violate valence requirements. Examples of heterocycloalkene groups include without limitation dihydroazine, dihydropyrrole, dihydropyridine, tetrahydropyridine, dihydroazepine, tetrahydroazepine and the like.

In one embodiment,

R ₁ and R ₂ are C ₃ together with the nitrogen to which they are associated with selection from Grundig Troas jetties carbonyl, dihydro-pyrrolinyl, dihydro-pyridinyl, and tetrahydro-pyridinyl group consisting of _- forming a heterocycloalkyl ₆ alkene, and

R ₃ is hydrogen; C _{1 - 6} alkyl; Phenyl; Or a C ₁ is substituted by _phenyl-4 alkyl, and,

The C _{3 - 6} alkene heterocycloalkyl C _{1 - 6} alkyl substituted by or is unsubstituted,

Wherein the phenyl is halogen, hydroxy, C _{1 - 6} alkyl, C _{1 - 6} alkoxy, C _{1 - 6} haloalkyl and C _{1 -} substituted with one or more non-hydrogen substituents selected from the group consisting of _6-haloalkoxy or unsubstituted be ring Can be.

In other embodiments, R ₁ and R ₂ are C ₁ together with the nitrogen that is associated with these _- or substituted with alkyl to form a _4-dihydro unsubstituted pyrrolinyl or tetrahydro-pyridinyl,

R ₃ is hydrogen; C _{1 - 6} alkyl; Phenyl; Or a C ₁ is substituted by _phenyl-4 alkyl, and,

It said phenyl being halogen, C _{1 - 4} alkoxy, C _{1 - 4} haloalkyl, and C _{1 -} substituted with one or more non-hydrogen substituents selected from the group consisting of ₄ haloalkoxy or may be unsubstituted.

In another embodiment, R ₁ and R ₂ together with the nitrogen to which they are attached form C _4-5 heterocycloalkenes having 5 to 6 ring atoms,

R ₃ is hydrogen; C _{1 - 6} alkyl; Phenyl; Or a C ₁ is substituted by _phenyl-2, and alkyl,

The C ₄ alkene _-5 heterocycloalkyl C _{1 -} it is optionally substituted by ₂ alkyl,

It said phenyl being halogen, C _{1 - 2} alkoxy, C _{1 - 2} haloalkyl and C _{1 -} or substituted with one or more non-hydrogen substituents selected from the group consisting of _2-haloalkoxy can be unsubstituted.

In another embodiment, R ₁ and R ₂ are C ₁ together with the nitrogen that is associated with these _- or substituted with ₂ alkyl to form an unsubstituted dihydro-pyrrolinyl or tetrahydro-pyridinyl,

R ₃ is hydrogen; C _{3 - 6} alkyl; Phenyl; Or a C ₁ is substituted by _phenyl-2, and alkyl,

It said phenyl being halogen, C _{1 - 2} alkoxy, C _{1 - 2} haloalkyl and C _{1 -} or substituted with one or more non-hydrogen substituents selected from the group consisting of _2-haloalkoxy can be unsubstituted.

In another embodiment, R ₁ and R ₂ together with the nitrogen to which they are linked form methyl substituted or unsubstituted dihydropyrrolinyl or tetrahydropyridinyl,

R ₃ is hydrogen; Butyl; profile; Hexyl; Phenyl; Or methyl substituted with phenyl,

The phenyl may be unsubstituted or substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, methoxy, trihaloalkyl and trihalomethoxy.

In one embodiment, the compound of Formula 1 may be selected from the group consisting of N1-1,2-dihydropyrrole-N5- (4-trifluoromethoxy) phenyl biguanide; N1-1,2-dihydropyrrole-N5- (4-trifluoromethyl) phenyl biguanide; N1-1,2-dihydropyrrole-N5- (3-trifluoromethyl) phenyl biguanide; N1-1,2-dihydropyrrole-N5- (4-fluoro) phenyl biguanide; N1-1,2-dihydropyrrole-N5- (4-chloro) phenyl biguanide; N1-1,2-dihydropyrrole-N5- (4-bromo) phenyl biguanide; N1-1,2-dihydropyrrole-N5- (3-chloro, 4-trifluoromethoxy) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (3-chloro, 4-trifluoromethoxy) phenyl biguanide; N1-1,2-dihydropyrrole-N5- (3-trifluoromethyl) benzyl biguanide; N1-1,2-dihydropyrrole-N5- (4-trifluoromethyl) benzyl biguanide; N1-1,2-dihydropyrrole-N5- (3-trifluoromethoxy) benzyl biguanide; N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-trifluoromethoxy) phenyl biguanide; N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-trifluoromethyl) phenyl biguanide; N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-chloro) phenyl biguanide; N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-chloro, 3-trifluoromethyl) phenyl biguanide; N1- (3-methyl) -1,2-dihydropyrrole-N5- (3-trifluoromethyl) phenyl biguanide; N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-fluoro) phenyl biguanide; N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-bromo) phenyl biguanide; N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-methoxy) phenyl biguanide; N1- (3-methyl) -1,2-dihydropyrrole-N5- (3,4-dimethoxy) phenyl biguanide; N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-trifluoromethoxy) benzyl biguanide; N1- (3-methyl) -1,2-dihydropyrrole-N5- (3-trifluoromethoxy) phenyl biguanide; N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-trifluoromethyl) benzyl biguanide; N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-chloro, 3-trifluoromethyl) benzyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (4-trifluoromethoxy) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (4-trifluoromethyl) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (3-trifluoromethoxy) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (3-trifluoromethyl) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (4-fluoro, 3-trifluoromethyl) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (4-chloro, 3-trifluoromethoxy) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (3-fluoro, 4-trifluoromethoxy) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (4-chloro) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (4-bromo) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (4-fluoro) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (3,5-dimethoxy) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5-phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (4-methoxy) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (3-methoxy) phenyl biguanide; N1-1,2-dihydropyrrole-N5- (4-methoxy) phenyl biguanide; N1-1,2-dihydropyrrole-N5- (3-methoxy) phenyl biguanide; N1-1,2-dihydropyrrole-N5-phenyl biguanide; N1-1,2-dihydropyrrole-N5- (3,5-dimethoxy) phenyl biguanide; N1-1,2-dihydropyrrole-N5- (4-fluoro, 3-trifluoromethyl) phenyl biguanide; N1-1,2-dihydropyrrole-N5- (3-fluoro, 4-trifluoromethyl) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (4-methyl) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (3-methyl) phenyl biguanide; N1-1,2-dihydropyrrole-N5- (4-methyl) phenyl biguanide; N1-1,2-dihydropyrrole-N5- (3-methyl) phenyl biguanide; N1-1,2-dihydropyrrole-N5- (3-trifluoromethoxy) phenyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5-hexyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (4-trifluoromethoxy) benzyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (3-trifluoromethoxy) benzyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (4-trifluoromethyl) benzyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (3-trifluoromethyl) benzyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5- (4-chloro, 3-trifluoromethyl) benzyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5-butyl biguanide; N1-1,2,3,6-tetrahydropyridine-N5-propyl biguanide; Or N1-1,2,3,6-tetrahydropyridine biguanide.

On the other hand, the pharmaceutically acceptable salt of the compound of Formula 1 according to the present invention may be an acid addition salt formed using an organic acid or an inorganic acid. The organic acid is, for example, 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, citric acid, glycol Acids, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, dichloroacetic acid, aminooxy acetic acid, benzenesulfonic acid, 4-toluenesulfonic acid and methanesulfonic acid salts; Inorganic acids include, for example, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and boric acid salts. The above-mentioned acid addition salts can be, for example, a) directly mixing the compound of formula 1 and acid, b) dissolving one of them in a solvent or a hydrous solvent, or c) compound and acid of formula 1 May be prepared by applying to a general method for preparing a salt in which these are mixed under a solvent or a hydration solvent.

In one embodiment, the pharmaceutically acceptable salt of the compound of Formula 1 is 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 mono Amide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxyacetic acid, hydrochloric acid, bromine Salts with acids selected from the group consisting of acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and boric acid.

The compound of formula 1 according to the present invention may be prepared through several methods.

In one embodiment,

Reacting a compound of formula 2 with dicyanoamide in an organic solvent to obtain a compound of formula 3; There is provided a process for preparing a compound of formula 1 comprising reacting a compound of formula 3 with a compound of formula 4 in an organic solvent to obtain a compound of formula 1

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

Wherein R ₁ , R ₂ and R ₃ are as defined in formula (1).

The preparation method may be represented by, for example, the following Scheme 1, which is described step by step as follows:

Scheme 1

The cyanoguanidine compound of formula 3, which is used as an intermediate in the preparation method of the compound of formula 1, may be obtained by reacting a cyclic amine of formula 2 with dicyanoamide, such as sodium or potassium cyanamide, in an organic solvent in the presence of an acid. Subsequently, the cyanoguanidine compound of Formula 3 obtained above is refluxed with Formula 4 in an organic solvent to obtain a compound of Formula 1.

The amount of dicyanoamide used to prepare the cyanoguanidine compound of Formula 3 is about 1 to 3 molar equivalents based on the compound of Formula 2, and the amount of acid used is about 1 to 2 molar equivalents relative to the compound of Formula 2. In preparing the compound of Formula 2, for example, methanol, ethanol, propanol, butanol, pentanol, acetonitrile, benzene, toluene, 1,4-dioxane, N, N-dimethylamide, etc. may be used. As an acid, hydrochloric acid, sulfuric acid, nitric acid, bromic acid, 4-toluenesulfonic acid, etc. can be used, for example. The reaction temperature of the compound of Formula 2 and dicyanoamide is in the range of 60 to 140 ° C., and the reaction time may be 3 to 24 hours.

The cyanoguanidine compound of Chemical Formula 3 obtained above is dissolved in an organic solvent, and then stirred under reflux after addition of the compound of Chemical Formula 4 and an acid. The amount of the compound of formula 4 used at this time is about 1 to 2 molar equivalents relative to the compound of compound 3, and the acid is about 1 to 2 molar equivalents relative to the compound of formula 3. The organic solvent used in the reaction of the compound of formula 3 with the compound of formula 4 is, for example, methanol, ethanol, propanol, butanol, pentanol, acetonitrile, benzene, toluene, 1,4-dioxane, N, N- Dimethylamide can be used, and examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, bromic acid, 4-toluenesulfonic acid, and the like. At this time, the reaction temperature is in the range up to the reflux temperature of the solvent used (for example, up to 120 to 140 ° C. for butanol), and the reaction time may be 6 to 24 hours. Upon completion of the reaction, the resultant is filtered and then, for example, by adjusting the pH of the reaction solution to about 4 to 5 with an acid such as hydrochloric acid, and concentrating and purifying the resulting solution. Alternatively, acceptable salts can be obtained.

The compound of Formula 1 thus obtained, or a pharmaceutically acceptable salt thereof, is useful for anticancer treatment including cancer metastasis and cancer recurrence at a lower dose than conventional drugs through AMPK activation, as can be seen in the following examples. Can be used.

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

The present invention also provides a pharmaceutical composition for the prevention or treatment of cancer comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, a compound of formula 1 for the manufacture of a medicament for the prevention or treatment of the disease or Provided is a method of preventing or treating the disease, comprising the use of a pharmaceutically acceptable salt thereof and a therapeutically effective amount of the compound of formula 1 or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition of the present invention comprises at least one pharmaceutically acceptable carrier in addition to the active ingredient. As used herein, 'pharmaceutically acceptable carrier' refers to known pharmaceutical excipients that are useful when formulating pharmaceutically active compounds for administration and which are virtually nontoxic and insensitive under the conditions of use. The exact ratio of such excipients is determined by standard pharmaceutical practices, as well as solubility and chemical properties of the active compound, the route of administration chosen.

The pharmaceutical compositions of the present invention may be formulated in a form suitable for the desired method of administration using suitable and physiologically acceptable excipients, disintegrants, sweeteners, binders, coatings, swelling agents, lubricants, lubricants, flavors and the like. Can be.

The pharmaceutical composition may be formulated in the form of, but not limited to, tablets, capsules, pills, granules, powders, injections or solutions.

Formulations of the pharmaceutical compositions and pharmaceutically acceptable carriers can be appropriately selected according to techniques known in the art, for example, see 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, 31 st 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. In addition, 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, and the like.

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

In the present invention, the "second drug" means another pharmaceutically effective ingredient other than the biguanide derivative of the present invention. The compound of formula 1 or a pharmaceutically acceptable salt thereof of the present invention can be used for the treatment of various diseases as described above. Thus, the compound of formula 1 or a pharmaceutically acceptable salt thereof of the present invention may be used in combination with a second drug for the efficient treatment of each disease. For example, the second drug may be an anticancer agent, an antihyperglycemic agent, an anti-obesity agent, or the like comprising an active ingredient different from the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

When the compound of formula 1 according to the present invention or a pharmaceutically acceptable salt thereof and the second drug are administrable in the same manner, the compound of formula 1 or a pharmaceutically acceptable salt thereof is formulated with a second drug It may also be provided in the form of a combination formulation.

Meanwhile, in the present invention, the 'subject' means a warm-blooded animal such as a mammal having a specific disease, disorder or disease, and for example, human, orangutan, chimpanzee, mouse, rat, dog, cow, chicken, pig , Chlorine, sheep, and the like, but are not limited to these examples.

"Treatment" also includes, but is not limited to, alleviating the symptom, removing the cause of the symptom temporarily or permanently, or preventing or slowing the appearance of the symptom and the progression of the disease, disorder or condition described above.

An effective amount of the active ingredient of the pharmaceutical composition of the present invention means an amount required to achieve the treatment of the disease. Thus, the type of disease, the severity of the disease, the type and amount of the active and other ingredients contained in the composition, the type of formulation and the age, weight, general health, sex and diet, sex and diet, time of administration, route of administration and composition of the patient. It can be adjusted according to various factors including the rate of secretion, the duration of treatment, and the drug used concurrently. For example, in adults, the compound of formula 1 may be administered at a dose of 50 to 3000 mg / kg in total, once to several times daily.

N1-cyclic amine-N5-substituted biguanide derivatives of the formula (1) according to the present invention shows excellent cancer cell proliferation inhibition and cancer metastasis and recurrence inhibitory effect even at a lower dose compared to conventional drugs, excellent blood sugar lowering action and lipid It exhibits a lowering effect and can be usefully used for the treatment of cancer.

Advantages and features of the present invention and methods for achieving them will be apparent with reference to the embodiments described below in detail. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various forms, and only the embodiments are intended to complete the disclosure of the present invention, and the general knowledge in the technical field to which the present invention pertains. It is provided to fully convey the scope of the invention to those skilled in the art, and the present invention is defined only by the scope of the claims.

EXAMPLE

Example 1: Synthesis of N1-2,5-dihydropyrrole cyanoguanidine

2,5-dihydropyrrole hydrochloride (0.75 g, 7.104 mmol) and sodium dicyanamide (0.63 g, 7.104 mmol) were dissolved in a butanol (20 mL) solution and stirred under reflux for 3 hours. After completion of the reaction, the reaction mixture was filtered to remove sodium chloride, and the filtrate was concentrated under reduced pressure. The concentrated solution was dissolved in methanol (2 mL), ethyl acetate (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. The resulting solid was filtered and the filtrate was washed with ethyl acetate (2 X 20 mL). The filtrate was dried under reduced pressure to obtain the title compound (0.90 g, 93%) as a white solid.

¹ H NMR (600 MHz, CD3OD) δ 5.89 (m, 2H), 4.16 (m, 4H); LC-MS m / z 137.2 [ M + 1] +;

Example 2: Synthesis of N1-1,2,3,6-tetrahydropyridine cyanoguanidine

Using the 1,2,3,6-tetrahydropyridine instead of the 2,5-dihydropyrrole hydrochloride of Example 1 to obtain the target compound (2.23g, 59.2%) as a white solid by the same method.

¹ H NMR (600 MHz, CD3OD) δ 5.90 (d, 1H), 5.69 (d, 1H), 3.93 (t, 2H), 3.59 (t, 2H), 2.18 (m, 2H); LC-MS m / z 151.2 [M + l] ⁺

Example  3: N1 -3- methyl -2,5- Dihydropyrrole Cyanoguanidine  synthesis

3-methyl-2,5-dihydropyrrole was used in place of the 2,5-dihydropyrrole hydrochloride of Example 1 to obtain the target compound (3.12 g, 83%) as a white solid.

¹ H NMR (600 MHz, CD3OD) δ 5.45 (br s, 1 H), 4.80 (m, 2 H), 4.10 (m, 2 H) 7.16 (s, 3 H); LC-MS m / z 151.2 [ M + 1] +;

Example 4: Preparation of N1-1,2-dihydropyrrole-N5- (4-trifluoromethoxy) phenyl biguanide hydrochloride

At room temperature, (4-trifluoromethoxy) phenylamine (390 mg, 2.20 mmol) was dissolved in a butanol (10 mL) solution, concentrated hydrochloric acid (0.18 mL, 2.20 mmol) was added and stirred for 30 minutes. N1-2,5-dihydropyrrole cyanoguanidine (300 mg, 2.20 mmol) obtained in Example 1 was added to the reaction mixture, and the mixture was stirred under reflux for 1 hour. The reaction mixture was stirred at room temperature for 1 hour, and then the resulting solid was filtered and the filtrate was dried under reduced pressure to give the title compound (265 mg, 34%) as a white solid.

¹ H NMR (600 MHz, CD3OD) δ 3.94 (m, 2H), 3.71 (m, 2H), 3.47 (m, 1H), 3.34 (s, 3H), 2.90 (m, 1H), 2.57 (m, 1H ), 1.71 (m, 10 H), 1.18 (m, 1 H), 0.89 (s, 3 H); LC-MS mlz 282.2 [M + 1] < + >; mp 172 ~ 174 ℃

Instead of the N1-2,5-dihydropyrrole cyanoguanidine synthesized in Example 1 and the (4-trifluoromethoxy) phenylamine used in Example 4 synthesized in Examples 2 to 3 corresponding to the target compound The target compounds of Examples 5 to 61 were prepared by the same method as Example 4 except for using the cyanoguanidine and the amine compound, respectively.

Example  5: N1 -1,2- Dihydropyrrole - N5 -(4- Trifluoromethyl ) Phenyl Biguanide  Preparation of Hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.58 (m, 4H), 5.91 (m, 2H), 4.27 (m, 4H); LC-MS mlz 298.2 [M + 1] < + >; mp 254 ~ 256 ℃

Example  6: N1 -1,2- Dihydropyrrole - N5 -(3- Trifluoromethyl ) Phenyl Biguanide  Preparation of Hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.79 (m, 1H), 7.56 (m, 1H), 7.46 (m, 1H), 7.34 (m, 1H), 5.91 (s, 2H), 4.20 (m, 4H ); LC-MS mlz 298.2 [M + 1] < + >; mp 276 ~ 278 ℃

Example  7: N1 -1,2- Dihydropyrrole - N5 -(4- Floro ) Phenyl Biguanide  Preparation of Hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.33 (m, 2H), 7.04 (m, 2H), 5.90 (m, 2H), 4.17 (m, 4H); LC-MS mlz 248.2 [M + l] < + >; mp 263 ~ 265 ℃

Example 8: N1-1,2-dihydropyrrole-N5- (4-chloro) phenyl biguanide hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.29 (m, 4H), 5.90 (m, 2H), 4.20 (m, 4H); LC-MS mlz 264.2 [M + 1] < + >; mp 264 ~ 266 ℃

Example  9: N1 -1,2- Dihydropyrrole - N5 -(4- Bromo ) Phenyl Biguanide  Hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.42 (m, 2H), 7.30 (m, 2H), 5.90 (m, 2H), 4.24 (m, 4H); LC-MS mlz 309.0 [M + 1] < + >; mp 263 ~ 265 ℃

Example  10: N1 -1,2- Dihydropyrrole - N5 -(3- Chloro ,4- Trifluoromethoxy ) Phenyl Baigu Anide  Hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.79 (m, 1H), 7.42 (m, 2H), 5.99 (m, 2H), 4.30 (m, 4H); LC-MS mlz 348.2 [M + 1] < + >; mp 270 ~ 272 ℃

Example 11: N1-1,2,3,6-tetrahydropyridine-N5- (3-chloro, 4-trifluoromethoxy) phenyl biguanide hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.70 (m, 1H), 7.33 (m, 2H), 5.94 (m, 1H), 5.73 (m, 1H), .3.99 (m, 2H), 3.63 (m, 2H), 2.23 (m, 2H); LC-MS mlz 362.2 [M + 1] < + >; mp 250 ~ 252 ℃

Example  12: N1 -1,2- Dihydropyrrole - N5 -(3- Trifluoromethyl )benzyl Biguanide Hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.70 (m, 4H), 5.89 (m, 2H), 4.52 (m, 2H), 4.23 (m, 4H); LC-MS mlz 312.2 [M + 1] < + >; mp 156 ~ 158 ℃

Example  13: N1 -1,2- Dihydropyrrole - N5 -(4- Trifluoromethyl )benzyl Biguanide Hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.45 (m, 2H), 7.62 (m, 2H), 5.86 (m, 2H), 4.19 (m, 2H), 4.13 (m, 4H); LC-MS mlz 312.2 [M + 1] < + >; mp 268 ~ 270 ℃

Example  14: N1 -1,2- Dihydropyrrole - N5 -(3- Trifluoromethoxy )benzyl Biguanide  Hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.33 (m, 4H), 5.88 (m, 2H), 4.47 (s, 2H), 4.18 (m, 4H); LC-MS mlz 328.2 [M + 1] < + >; mp 218 ~ 220 ℃

Example  15: N1 -(3- methyl ) -1,2- Dihydropyrrole - N5 -(4- Trifluoromethoxy ) Phenyl Baigu Anide  Hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.41 (m, 2H), 7.16 (m, 2H), 5.46 (m, 1H), 4.10 (m, 3H), 1.77 (m, 3H); LC-MS mlz 328.2 [M + 1] < + >; mp 279 ~ 281 ℃

Example  16: N1 -(3- methyl ) -1,2- Dihydropyrrole - N5 -(4- Trifluoromethyl ) Phenyl Baiguaana  Hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.62 (m, 4H), 5.56 (m, 1H), 4.21 (m, 4H), 1.87 (m, 3H); LC-MS mlz 312.2 [M + 1] < + >; mp 272 ~ 274 ℃

Example 17 N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-chloro) phenyl biguanide hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.36 (m, 2H), 7.29 (m, 2H), 5.50 (m, 1H), 4.13 (m, 4H), 1.80 (m, 3H); LC-MS mlz 278.2 [M + 1] < + >; mp 264 ~ 268 ℃

Example  18: N1 -(3- methyl ) -1,2- Dihydropyrrole - N5 -(4- Chloro , 3- Trifluoromethyl ) Phenyl  Biguanide hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.92 (m, 1H), 7.58 (m, 1H), 7.50 (m, 1H), 5.51 (s, 1H), 4.17 (m, 4H), 1.82 (m, 3H ); LC-MS mlz 346.2 [M + 1] < + >; mp 274 ~ 276 ℃

Example  19: N1 -(3- methyl ) -1,2- Dihydropyrrole - N5 -(3- Trifluoromethyl ) Phenyl Baigua Naed  Hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.80 (m, 1H), 7.57 (m, 1H), 7.42 (m, 1H), 7.34 (m, 1H), 5.51 (m, 1H), 4.15 (m, 4H ), 1.81 (m, 3 H); LC-MS mlz 312.2 [M + 1] < + >; mp 282 ~ 284 ℃

Example  20: N1 -(3- methyl ) -1,2- Dihydropyrrole - N5 -(4- Floro ) Phenyl Biguanide Hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.34 (m, 2H), 7.04 (m, 2H), 5.50 (m, 1H), 4.12 (m, 4H), 1.80 (m, 3H); LC-MS mlz 262.1 [M + 1] < + >; mp 270 ~ 272 ℃

Example 21: N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-bromo) phenyl biguanide hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.45 (m, 2H), 7.33 (m, 2H), 5.52 (m, 1H), 4.16 (m, 4H), 1.83 (m, 3H); LC-MS mlz 323.0 [M + 1] < + >; mp 272 ~ 274 ℃

Example 22 N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-methoxy) phenyl biguanide hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.24 (m, 2H), 6.87 (m, 2H), 5.48 (s, 1H), 3.32 (s, 3H), 1.78 (m, 3H); LC-MS mlz 274.2 [M + 1] < + >; mp 263 ~ 265 ℃

Example 23 N1- (3-methyl) -1,2-dihydropyrrole-N5- (3,4-dimethoxy) phenyl biguanide hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 6.58 (m, 2H), 6.26 (m, 1H), 5.52 (m, 1H), 4.18 (m, 4H), 3.30 (s, 3H), 1.83 (m, 3H ); LC-MS mlz 304.2 [M + 1] < + >; mp 261 ~ 263 ℃

Example 24 N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-trifluoromethoxy) benzyl biguanide hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.59 (m, 1H), 7.43 (m, 2H), 7.35 (m, 1H), 7.25 (m, 1H), 5.46 (m, 1H), 4.43 (m, 2H ), 4.15 (m, 2 H), 1.81 (m, 3 H); LC-MS mlz 342.2 [M + 1] < + >; mp 184 ~ 186 ℃

 Example 25 N1- (3-methyl) -1,2-dihydropyrrole-N5- (3-trifluoromethoxy) phenyl biguanide

¹ H NMR (600 MHz, CD3OD) δ 7.59 (m, 1H), 7.46 (m, 2H), 7.23 (m, 1H), 5.88 (s, 1H), 4.45 (m, 2H), 4.16 (m, 2H ), 1.83 (m, 3 H); LC-MS mlz 328.2 [M + 1] < + >; mp 263 ~ 265 ℃

Example  26: N1 -(3- methyl ) -1,2- Dihydropyrrole - N5 -(4- Trifluoromethyl )benzyl Baigua Naed  Hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.74 (m, 1H), 7.64 (m, 2H), 7.51 (m, 1H), 5.56 (s, 1H), 4.48 (s, 2H), 4.19 (m, 4H ), 1.83 (m, 3 H); LC-MS mlz 326.2 [M + 1] < + >; mp 267 ~ 269 ℃

Example 27 N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-chloro, 3-trifluoromethyl) benzyl biguanide hydrochloride

¹ H NMR (600 MHz, CD3OD) δ 7.61 (m, 1H), 7.59 (m, 2H), 7.51 (m, 1H), 5.59 (s, 1H), 4.48 (s, 2H), 4.26 (m, 4H ), 1.85 (s, 3 H); LC-MS mlz 326.2 [M + 1] < + >; mp 230 ~ 232 ℃

Example  28: N1 -1,2,3,6- Tetrahydropyridine - N5 -(4- Trifluoromethoxy ) Phenyl Baigu Anide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.46 (d, 2H), 7.24 (d, 2H), 5.95 (m, 1H), 5.74 (m, 1H), 4.00 (s, 2H), 3.64 (t, 2H) , 2.23 (s, 2 H); LC-MS m / z 328.1 [M + 1] +

Example 29: N1-1,2,3,6-tetrahydropyridine-N5- (4-trifluoromethyl) phenyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.59 (m, 4H), 5.96 (m, 1H), 5.75 (m, 1H), 4.01 (s, 2H), 3.65 (t, 2H), 2.25 (s, 2H) ; LC-MS m / z 312.2 [M + l] +

Example  30: N1 -1,2,3,6- Tetrahydropyridine - N5 -(3- Trifluoromethoxy ) Phenyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.82 (s, 1H), 7.57 (d, 1H), 7.49 (t, 1H), 7.38 (d, 1H), 5.97 (m, 1H), 5.74 (m, 1H) , 4.01 (s, 2H), 3.65 (t, 2H), 2.24 (s, 2H)

Example 31 N1-1,2,3,6-tetrahydropyridine-N5- (3-trifluoromethyl) phenyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.82 (s, 1H), 7.57 (d, 1H), 7.49 (t, 1H), 7.37 (d, 1H), 5.95 (m, 1H), 5.74 (m, 1H) , 4.01 (s, 2H), 3.65 (t, 2H), 2.24 (s, 2H); LC-MS m / z 312.2 [M + l] +

Example  32: N1 -1,2,3,6- Tetrahydropyridine - N5 -(4- Floro , 3- Trifluoromethyl ) Phenyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.80 (m, 1H), 7.60 (m, 1H), 7.28 (t, 1H), 5.95 (m, 1H), 5.73 (m, 1H), 4.00 (s, 2H) , 3.64 (t, 2 H), 2.23 (s, 2 H); LC-MS m / z 330.2 [M + l] +

Example 33: N1-1,2,3,6-tetrahydropyridine-N5- (4-chloro, 3-trifluoromethyl) phenyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.93 (m, 1H), 7.59 (m, 1H), 7.53 (d, 1H), 5.96 (m, 1H), 5.74 (m, 1H), 4.01 (s, 2H) , 3.65 (t, 2 H), 2.24 (s, 2 H); LC-MS m / z 346.0 [M + l] +

Example 34 N1-1,2,3,6-tetrahydropyridine-N5- (3-fluoro, 4-trifluoromethoxy) phenyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.56 (m, 1H), 7.34 (t, 1H), 7.16 (m, 1H), 5.97 (m, 1H), 5.74 (m, 1H), 4.01 (s, 2H) , 3.65 (t, 2 H), 2.25 (s, 2 H); LC-MS m / z 346.2 [M + l] +

Example 35 N1-1,2,3,6-tetrahydropyridine-N5- (4-chloro) phenyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.37 (d, 2H), 7.31 (d, 2H), 5.97 (m, 1H), 5.74 (m, 1H), 3.99 (s, 2H), 3.63 (t, 2H) , 2.23 (s, 2 H); LC-MS m / z 278.2 [M + l] +

Example 36: N1-1,2,3,6-tetrahydropyridine-N5- (4-bromo) phenyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.45 (d, 2H), 7.30 (d, 2H), 5.97 (m, 1H), 5.74 (m, 1H), 3.99 (s, 2H), 3.63 (t, 2H) , 2.23 (s, 2 H); LC-MS m / z 323.0 [M + l] +

Example  37: N1 -1,2,3,6- Tetrahydropyridine - N5 -(4- Floro ) Phenyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.35 (d, 2H), 7.07 (d, 2H), 5.94 (m, 1H), 5.72 (m, 1H), 3.97 (s, 2H), 3.62 (t, 2H) , 2.23 (s, 2 H); LC-MS m / z 262.2 [M + l] +

Example 38: N1-1,2,3,6-tetrahydropyridine-N5- (3,5-dimethoxy) phenyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 6.56 (d, 2H), 6.27 (t, 1H), 5.96 (m, 1H), 5.74 (m, 1H), 4.00 (s, 2H), 3.76 (s, 6H) , 3.64 (t, 2 H), 2.23 (s, 2 H); LC-MS m / z 304.2 [M + 1] +

Example  39: N1 -1,2,3,6- Tetrahydropyridine - N5 - Phenyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.33 (m, 4H), 7.13 (m, 1H), 5.94 (m, 1H), 5.73 (m, 1H), 3.98 (s, 2H), 3.63 (t, 2H) , 2.22 (s, 2 H); LC-MS m / z 244.2 [M + l] +

Example  40: N1 -1,2,3,6- Tetrahydropyridine - N5 -(4- Methoxy ) Phenyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.23 (d, 2H), 6.91 (d, 2H) 5.93 (m, 1H), 5.72 (m, 1H), 3.96 (s, 2H), 3.78 (s, 3H), 3.61 (t, 2 H), 2.21 (s, 2 H); LC-MS m / z 274.2 [M + l] +

Example  41: N1 -1,2,3,6- Tetrahydropyridine - N5 -(3- Methoxy ) Phenyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.22 (t, 1H), 7.00 (t, 1H), 6.88 (m, 1H), 6.71 (m, 1H), 5.95 (m, 1H), 5.74 (m, 1H) , 3.99 (s, 2H), 3.77 (s, 3H), 3.64 (t, 2H), 2.23 (s, 2H); LC-MS m / z 274.2 [M + l] +

Example  42: N1 -1,2- Dihydropyrrole - N5 -(4- Methoxy ) Phenyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.25 (d, 2H), 6.91 (d, 2H), 5.92 (s, 2H), 4.22 (d, 4H), 3.78 (s, 3H); LC-MS m / z 260.2 [M + l] +

Example 43 N1-1,2-dihydropyrrole-N5- (3-methoxy) phenyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.22 (t, 1H), 7.03 (t, 1H), 6.91 (m, 1H), 6.71 (m, 1H), 5.93 (s, 2H), 4.29 (d, 4H) , 3.77 (s, 3 H); LC-MS m / z 260.2 [M + l] +

Example  44: N1 -1,2- Dihydropyrrole - N5 - Phenyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.37 (m, 4H), 7.12 (t, 1H), 5.93 (s, 2H), 4.27 (d, 4H); LC-MS m / z 230.2 [M + l] +

Example  45: N1 -1,2- Dihydropyrrole - N5 -(3,5- Dimethoxy ) Phenyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 6.58 (d, 2H), 6.27 (t, 1H), 5.93 (m, 1H), 4.30 (d, 4H), 3.75 (s, 6H); LC-MS m / z 290.2 [M + l] +

Example 46: N1-1,2-dihydropyrrole-N5- (4-fluoro, 3-trifluoromethyl) phenyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.82 (m, 1H), 7.64 (m, 1H), 7.29 (t, 1H), 5.94 (s, 2H), 4.26 (d, 4H); LC-MS m / z 316.2 [M + l] +

Example 47 N1-1,2-dihydropyrrole-N5- (3-fluoro, 4-trifluoromethyl) phenyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.21 (m, 2H), 7.15 (d, 2H), 5.94 (m, 1H), 5.73 (m, 1H), 3.97 (s, 2H), 3.62 (t, 2H) , 2.30 (s, 3 H), 2.22 (s, 2 H); LC-MS m / z 316.2 [M + l] +

Example 48 N1-1,2,3,6-tetrahydropyridine-N5- (4-methyl) phenyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.21 (m, 2H), 7.15 (d, 2H), 5.94 (m, 1H), 5.73 (m, 1H), 3.97 (s, 2H), 3.62 (t, 2H) , 2.30 (s, 3 H), 2.22 (s, 2 H); LC-MS m / z 258.2 [M + l] +

Example  49: N1 -1,2,3,6- Tetrahydropyridine - N5 -(3- methyl ) Phenyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.21 (m, 3H), 6.96 (d, 2H), 5.95 (m, 1H), 5.73 (m, 1H), 3.98 (s, 2H), 3.63 (t, 2H) , 2.32 (s, 3 H), 2.22 (s, 2 H); LC-MS m / z 258.2 [M + l] +

Example 50 N1-1,2-Dihydropyrrole-N5- (4-methyl) phenyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.24 (d, 2H), 7.15 (d, 2H), 5.92 (s, 2H), 4.26 (d, 4H), 2.31 (s, 3H); LC-MS m / z 244.2 [M + l] +

Example 51 N1-1,2-dihydropyrrole-N5- (3-methyl) phenyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.17 (m, 3H), 6.96 (d, 1H), 5.93 (s, 2H), 4.27 (d, 4H), 2.32 (s, 3H); LC-MS m / z 244.2 [M + l] +

Example  52: N1 -1,2- Dihydropyrrole - N5 -(3- Trifluoromethoxy ) Phenyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.83 (s, 1H), 7.61 (d, 1H), 7.49 (t, 1H), 7.38 (d, 1H), 5.94 (s, 2H), 4.28 (d, 4H)

Example 53 N1-1,2,3,6-tetrahydropyridine-N5-hexyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 5.93 (m, 1H), 5.72 (m, 1H), 3.98 (m, 2H), 3.63 (t, 2H), 3.20 (t, 2H), 2.23 (t, 2H) , 1.70-1.33 (m, 8H), 0.91 (t, 3H); LC-MS m / z 252.4 [M + l] +

Example  54: N1 -1,2,3,6- Tetrahydropyridine - N5 -(4- Trifluoromethoxy )benzyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.43 (d, 2H), 7.25 (d, 2H), 5.91 (m, 1H), 5.68 (m, 1H), 4.43 (s, 2H), 3.90 (m, 2H) , 3.52 (t, 2H), 2.16 (s, 2H); LC-MS m / z 342.2 [M + l] +

Example  55: N1 -1,2,3,6- Tetrahydropyridine - N5 -(3- Trifluoromethoxy )benzyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.43 (t, 1H), 7.33 (d, 1H), 7.25 (s, 1H), 7.18 (d, 1H), 5.91 (m, 1H), 5.68 (m, 1H) , 4.45 (s, 2H), 3.90 (t, 2H), 3.52 (t, 2H), 2.15 (s, 2H); LC-MS m / z 342.2 [M + l] +

Example  56: N1 -1,2,3,6- Tetrahydropyridine - N5 -(4- Trifluoromethyl )benzyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.64 (d, 2H), 7.52 (d, 2H), 5.91 (m, 1H), 5.67 (m, 1H), 4.49 (s, 2H), 3.89 (t, 2H) , 3.51 (t, 2H), 2.14 (s, 2H); LC-MS m / z 326.2 [M + l] +

Example  57: N1 -1,2,3,6- Tetrahydropyridine - N5 -(3- Trifluoromethyl )benzyl Biguanide  Hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.64 (s, 1H), 7.56 (m, 3H), 5.91 (m, 1H), 5.67 (m, 1H), 4.48 (s, 2H), 3.89 (t, 2H) , 3.51 (t, 2H), 2.15 (s, 2H); LC-MS m / z 326.2 [M + l] +

Example 58: N1 -1,2,3,6- tetrahydropyridin-- N5 - (4- chloro, 3-methyl-Access) benzyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 7.74 (s, 1H), 7.56 (m, 2H), 5.91 (m, 1H), 5.68 (m, 1H), 4.45 (s, 2H), 3.89 (t, 2H) , 3.51 (t, 2H), 2.15 (s, 2H); LC-MS m / z 360.2 [M + 1] +

Example 59: N1-1,2,3,6-tetrahydropyridine-N5-butyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 5.94 (m, 1H), 5.73 (m, 1H), 4.19 (t, 1H), 3.98 (m, 2H), 3.64 (t, 2H), 3.20 (t, 1H) , 2.23 (t, 2H), 1.70-1.37 (m, 4H), 0.95 (m, 3H); LC-MS m / z 224.2 [M + l] +

Example 60: N1-1,2,3,6-tetrahydropyridine-N5-propyl biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 5.94 (m, 1H), 5.73 (m, 1H), 3.97 (m, 2H), 3.62 (t, 2H), 3.16 (t, 2H), 2.23 (t, 2H) , 1.58 (m, 2 H), 0.95 (m, 3 H); LC-MS m / z 210.2 [M + l] +

Example 61 N1-1,2,3,6-tetrahydropyridine biguanide hydrochloride

1 H NMR (600 MHz, CD3OD) δ 5.97 (m, 1H), 5.77 (m, 1H), 3.98 (m, 2H), 3.64 (m, 2H), 2.40 (m, 1H), 2.23 (m, 1H) ; LC-MS m / z 168.2 [M + l] +

 [Test Example]

Compounds synthesized in the manner described in the Examples of the present invention were evaluated for the effects of AMPK activation and cancer cell proliferation according to the methods described in the following test examples.

Test Example 1 Measurement of AMPK Activation Effect

MCF7 cells derived from human breast cancer cells (purchased from Korea Cell Line Bank) were used, and AMPK (5'-AMP-activated) induced by biguanide derivatives using the AMPK [pT172] ELISA Kit (Invitrogen, catalog No. KHO0651). protein kinase) activation effect was confirmed.

MCF7 cells were cultured in DMEM (obtained from Gibco Life Technologies (USA)) medium containing 10% calf serum and placed in 6-well plates with approximately ⁵ × 10 ⁵ cells, then cells were incubated in a 5% CO ₂ incubator. Incubated. The derivatives synthesized in Example were treated with 5, 10, and 50 uM in the culture solution and then incubated for 24 hours. Metformin was used as a control, and was treated with 0.05, 0.5, 1, 2, 5 and 10 mM, and then experimented in the same manner as the derivative synthesized in Example. Next, after lysing the cells by the method described in the AMPK [pT172] ELISA Kit instructions, 20 ug of cell lysate was obtained by protein quantification, and according to the method described in the AMPK [pT172] ELISA Kit instructions. From the cell lysate, the degree of phosphorylation of 172 residues of AMPKα threonine (Thr172) was confirmed and the result was obtained. The degree of AMPK activation by the biguanide derivative was expressed as phosphorylated AMPK in the cells cultured in the presence of the compounds synthesized in the above example, compared to the phosphorylated AMPK in the cells cultured without the biguanide derivative. . Based on the AMPK activation results thus obtained, AMPK activation curves were prepared according to the treatment concentrations, and the concentrations of the compounds (activation concentrations 150 and AC150) with 150% AMPK activation were calculated using the GraphPad Prism 5.0 program. The degree of AMPK activation when the treatment concentrations were 10 uM and 50 uM was indicated. Some compounds were unable to measure AMPK activity at 50 uM due to cytotoxicity.

The results are shown in Table 1 below.

Example AMPK activation effect (%) AC150
(uM) 10 uM 50 uM Metformin 188.3 ND 130 4 5.0 201 584 5 2.8 235 223 6 > 50 124 136 7 > 50 94 109 8 8.3 139 515 9 9.0 169 371 10 1.4 408 - 11 1.4 637 - 12 13.8 97 357 13 9.0 135 462 14 8.4 151 507 15 1.6 554 - 16 1.7 398 - 17 4.7 208 - 18 0.81 - - 19 1.5 306 - 20 38.3 83 172 21 11.9 156 - 22 24.5 116 209 23 21.3 57 279 24 5.3 200 421 25 2.2 376 - 26 0.68 443 358 27 13.5 119 316 28 0.15 732 - 29 1.3 551 - 30 0.53 703 - 31 1.8 391 - 32 0.62 837 - 33 0.79 992 - 34 0.29 925 - 35 2.4 314 - 36 0.87 568 - 37 4.2 187 522 38 > 50 97 117 39 67.2 96 138 40 37.8 122 163 41 22.4 125 201 42 14.7 157 210 43 4.7 200 466 44 1.7 289 577 45 4.8 202 299 46 1.6 448 - 47 1.0 758 - 48 4.9 178 691 49 1.9 319 917 50 1.4 317 440 51 3.1 241 409 52 2.7 352 - 53 2.3 311 589 54 0.87 545 650 55 2.1 389 608 56 2.1 389 671 57 2.7 279 579 58 1.8 500 - 59 16.6 104 283 60 12.4 108 338 61 > 50 123 132

Test Example  2: measurement of cancer cell proliferation inhibitory effect

HCT116 cells derived from human colorectal cancer were used, and cell growth was inhibited to 50% using MTT (3- (4,5-dimethylsaazol-2-yl) -2.5-ditetrazolium bromide) reagent. Concentration (cell growth inhibitory concentration, GIC50) value was measured to determine the cancer cell proliferation inhibitory effect of biguanide derivatives.

First, HCT116 cells (purchased from Korea Cell Line Bank) were placed in 96-well plates so that each cell number was approximately 5000 in DMEM (purchased from Gibco Life Technologies (USA)) containing 10% calf serum and incubated for 16 hours. Next, in order to obtain the GIC 50 value of each compound, the culture solution was incubated for 48 hours by treating with 100 uM, 25 uM, 6.25 uM, 1.56 uM and 0.39 uM. MTT (commercially available from AMRESCO (USA)) was added to the cultures to identify living cells after treatment of the compound and incubated for 3 hours. The resulting formazan crystal was dissolved using dimethyl sulfoxide and the absorbance of the solution was measured at 560 nm. After 48 hours of incubation, the number of cells surviving in the well plate treated with the compounds synthesized in Example compared to the number of cells cultured in the well plate not treated with the compound is expressed as% of cell viability according to each treatment concentration. Using this, a graph of cell viability curves was prepared, and the concentration (GIC50) value of the compound whose growth was inhibited to 50% was calculated to confirm the effect of inhibiting cancer cell proliferation. In addition, the percentage of cell growth inhibition when the treatment concentration of the biguanide derivative was 100 uM was indicated.

The results of the cancer cell growth inhibitory effect are shown in Table 2 below.

Example Cancer cell growth inhibitory effect GI50 (uM) Cell growth inhibition (%) at 100 uM Metformin 2172 6.5
(100 uM) 4 19.1 99.7 5 18.0 99.7 6 12.9 99.6 7 > 100 19.8 8 42.8 99.1 9 28.8 99.5 10 8.3 97.9 11 3.0 98.0 12 84.8 53.8 13 77.1 57.8 14 17.5 98.8 15 10.1 99.2 16 10.8 99.3 17 13.9 99.7 18 2.6 99.5 19 9.1 99.6 20 54.8 93.1 21 10.4 99.4 22 18.6 37.1 23 89.9 29.5 24 33.9 99.0 25 4.9 96.6 26 8.2 96.7 27 33.5 96.6 28 8.4 100.5 29 9.5 100.4 30 7.5 99.7 31 7.8 99.5 32 7.9 99.4 33 3.7 99.4 34 6.6 99.4 35 18.4 99.1 36 11.2 99.0 37 135.0 45.3 38 108.5 47.8 39 123.7 39.8 40 > 100 37.4 41 88.2 55.9 42 > 100 14.0 43 114.4 44.9 44 > 100 27.8 45 107.2 47.2 46 12.0 100.1 47 10.8 100.0 48 42.5 97.6 49 57.0 91.8 50 116.8 46.0 51 102.5 48.7 52 15.4 100.1 53 43.7 97.9 54 14.6 98.1 55 22.8 97.9 56 26.9 97.7 57 26.9 97.8 58 7.9 98.4 59 141.4 44.5 60 99.8 50.1 61 > 100 10.5

Claims (13)

A compound of Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

Where
R ₁ and R ₂ together with the nitrogen to which they are attached form C _4-6 heterocycloalkenes having 5 to 7 ring atoms,
R ₃ is C _1-6 alkyl; Phenyl; Or C _1-4 alkyl substituted with phenyl,
The C _4-6 heterocycloalkene is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy and C _1-6 alkyl,
The phenyl is unsubstituted or substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy. .
The method of claim 1,
R ₁ and R ₂ together with the nitrogen to which they are attached form a C _4-6 heterocycloalkene selected from the group consisting of dihydropyrrolinyl, dihydropyridinyl and tetrahydropyridinyl,
R ₃ is C _1-6 alkyl; Phenyl; Or C _1-4 alkyl substituted with phenyl,
The C _4-6 heterocycloalkene is unsubstituted or substituted with C _1-6 alkyl,
The phenyl is unsubstituted or substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy That
A compound of formula 1 or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₁ and R ₂ together with the nitrogen to which they are attached form dihydropyrrolinyl or tetrahydropyridinyl unsubstituted or substituted with C _1-4 alkyl,
R ₃ is C _1-6 alkyl; Phenyl; Or C _1-4 alkyl substituted with phenyl,
The phenyl is unsubstituted or substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, C _1-4 alkoxy, C _1-4 haloalkyl and C _1-4 haloalkoxy
A compound of formula 1 or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₁ and R ₂ together with the nitrogen to which they are attached form C _4-5 heterocycloalkenes having 5 to 6 ring atoms,
R ₃ is C _1-6 alkyl; Phenyl; Or C _1-2 alkyl substituted with phenyl,
The C _4-5 heterocycloalkene is unsubstituted or substituted with C _1-2 alkyl,
The phenyl is unsubstituted or substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, C _1-2 alkoxy, C _1-2 haloalkyl and C _1-2 haloalkoxy
A compound of formula 1 or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₁ and R ₂ together with the nitrogen to which they are linked form dihydropyrrolinyl or tetrahydropyridinyl unsubstituted or substituted with C _1-2 alkyl,
R ₃ is C _3-6 alkyl; Phenyl; Or C _1-2 alkyl substituted with phenyl,
The phenyl is unsubstituted or substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, C _1-2 alkoxy, C _1-2 haloalkyl and C _1-2 haloalkoxy
A compound of formula 1 or a pharmaceutically acceptable salt thereof.
The method of claim 1,
R ₁ and R ₂ together with the nitrogen to which they are attached form a dihydropyrrolinyl or tetrahydropyridinyl unsubstituted or substituted with methyl,
R ₃ is butyl; profile; Hexyl; Phenyl; Or methyl substituted with phenyl,
The phenyl is unsubstituted or substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, methoxy, trihaloalkyl and trihalomethoxy
A compound of formula 1 or a pharmaceutically acceptable salt thereof.
The method of claim 1,
N1-1,2-dihydropyrrole-N5- (4-trifluoromethoxy) phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (4-trifluoromethyl) phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (3-trifluoromethyl) phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (4-fluoro) phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (4-chloro) phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (4-bromo) phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (3-chloro-4-trifluoromethoxy) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (3-chloro-4-trifluoromethoxy) phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (3-trifluoromethyl) benzyl biguanide;
N1-1,2-dihydropyrrole-N5- (4-trifluoromethyl) benzyl biguanide;
N1-1,2-dihydropyrrole-N5- (3-trifluoromethoxy) benzyl biguanide;
N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-trifluoromethoxy) phenyl biguanide;
N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-trifluoromethyl) phenyl biguanide;
N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-chloro) phenyl biguanide;
N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-chloro-3-trifluoromethyl) phenyl biguanide;
N1- (3-methyl) -1,2-dihydropyrrole-N5- (3-trifluoromethyl) phenyl biguanide;
N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-fluoro) phenyl biguanide;
N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-bromo) phenyl biguanide;
N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-methoxy) phenyl biguanide;
N1- (3-methyl) -1,2-dihydropyrrole-N5- (3,4-dimethoxy) phenyl biguanide;
N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-trifluoromethoxy) benzyl biguanide;
N1- (3-methyl) -1,2-dihydropyrrole-N5- (3-trifluoromethoxy) phenyl biguanide;
N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-trifluoromethyl) benzyl biguanide;
N1- (3-methyl) -1,2-dihydropyrrole-N5- (4-chloro-3-trifluoromethyl) benzyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (4-trifluoromethoxy) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (4-trifluoromethyl) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (3-trifluoromethoxy) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (3-trifluoromethyl) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (4-fluoro-3-trifluoromethyl) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (4-chloro-3-trifluoromethoxy) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (3-fluoro-4-trifluoromethoxy) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (4-chloro) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (4-bromo) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (4-fluoro) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (3,5-dimethoxy) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5-phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (4-methoxy) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (3-methoxy) phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (4-methoxy) phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (3-methoxy) phenyl biguanide;
N1-1,2-dihydropyrrole-N5-phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (3,5-dimethoxy) phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (4-fluoro-3-trifluoromethyl) phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (3-fluoro-4-trifluoromethyl) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (4-methyl) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (3-methyl) phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (4-methyl) phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (3-methyl) phenyl biguanide;
N1-1,2-dihydropyrrole-N5- (3-trifluoromethoxy) phenyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5-hexyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (4-trifluoromethoxy) benzyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (3-trifluoromethoxy) benzyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (4-trifluoromethyl) benzyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (3-trifluoromethyl) benzyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5- (4-chloro-3-trifluoromethyl) benzyl biguanide;
N1-1,2,3,6-tetrahydropyridine-N5-butyl biguanide; or
N1-1,2,3,6-tetrahydropyridine-N5-propyl biguanide
A compound of formula 1 or a pharmaceutically acceptable salt thereof.
The method of claim 1,
The pharmaceutically acceptable salts include 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, citric acid, Glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxy acetic acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and Salt with an acid selected from the group consisting of boric acid
Compound of Formula 1 or a pharmaceutically acceptable salt thereof.
Reacting a compound of formula 2 with an alkali metal dicyanoamide in an organic solvent to obtain a compound of formula 3; Method of preparing a compound of formula 1 comprising the step of reacting the compound of formula 3 with a compound of formula 4 in an organic solvent:

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

Where
R ₁ and R ₂ together with the nitrogen to which they are attached form C _4-6 heterocycloalkenes having 5 to 7 ring atoms,
R ₃ is C _1-6 alkyl; Phenyl; Or C _1-4 alkyl substituted with phenyl,
The C _4-6 heterocycloalkene is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy and C _1-6 alkyl,
The phenyl is unsubstituted or substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy. .
A pharmaceutical composition for preventing or treating cancer, comprising as an active ingredient a compound of formula 1 according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.
The method of claim 10,
The treating of the cancer comprises inhibiting cancer recurrence or metastasis of the cancer.
The pharmaceutical composition of claim 10, wherein the cancer is a disease selected from the group consisting of uterine cancer, breast cancer, stomach cancer, brain cancer, rectal cancer, colon cancer, lung cancer, skin cancer, blood cancer, pancreatic cancer, prostate cancer, and liver cancer.
The method of claim 10,
The pharmaceutical composition is formulated in the form of tablets, capsules, pills, granules, powders, injections or solutions.