WO2014123364A1 - N1-cyclic amine-n5-substituted biguanide derivatives, methods of preparing the same and pharmaceutical composition comprising the same - Google Patents

N1-cyclic amine-n5-substituted biguanide derivatives, methods of preparing the same and pharmaceutical composition comprising the same Download PDF

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Publication number
WO2014123364A1
WO2014123364A1 PCT/KR2014/001006 KR2014001006W WO2014123364A1 WO 2014123364 A1 WO2014123364 A1 WO 2014123364A1 KR 2014001006 W KR2014001006 W KR 2014001006W WO 2014123364 A1 WO2014123364 A1 WO 2014123364A1
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Prior art keywords
phenyl
biguanide
methyl
phenyl biguanide
acid
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PCT/KR2014/001006
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French (fr)
Inventor
Chang Hee Min
Yong Eun Kim
Byung Kyu Oh
Ji Sun Lee
Hye Jin Heo
Ju Hoon Oh
Woong Cho
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Hanall Biopharma Co Ltd
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Hanall Biopharma Co Ltd
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Priority claimed from KR1020130014176A external-priority patent/KR102072245B1/en
Priority claimed from KR1020130014175A external-priority patent/KR102034899B1/en
Application filed by Hanall Biopharma Co Ltd filed Critical Hanall Biopharma Co Ltd
Priority to EP14748929.8A priority Critical patent/EP2941418B1/en
Priority to ES14748929T priority patent/ES2797574T3/en
Priority to US14/766,203 priority patent/US9884821B2/en
Publication of WO2014123364A1 publication Critical patent/WO2014123364A1/en
Anticipated expiration legal-status Critical
Priority to US15/841,971 priority patent/US10252996B2/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom

Definitions

  • the present invention relates to an N1-cyclic amine-N5-substituted biguanide derivative that inhibits cancer cell proliferation, cancer metastasis and cancer recurrence by activation of AMPK, even when administered in a small dose compared with conventional drugs, and that exhibits excellent therapeutic effects, a method of preparing the same, and a pharmaceutical composition including the N1-cyclic amine-N5-substituted biguanide derivative as an active ingredient.
  • AMPK AMP-activated protein kinases
  • AMPK is an enzyme that functions to regulate a metabolic pathway so as to maintain balance between supply of nutrients and demand for energy, and thus maintain energy homeostasis in cells and the whole body.
  • AMPK is activated as a ratio of AMP/ATP in the cells increases due to a hypoxemic state or glucose deficiency.
  • the activated AMPK induces fatty acid oxidation to produce a larger amount of ATP and inhibits anabolisms requiring the use of ATP.
  • AMPK inhibits proliferation of cancer cells and kills the cancer cells by regulating energy metabolism in the cancer cells as well as in normal cells.
  • AMPK activated in the cancer cells shows anticancer activities by phosphorylating mTORC1, p53, fatty acid synthase and the like to regulate the cell cycle, cell polarity, autophagy, apoptosis, etc.
  • Metformin has been used to treat insulin-independent diabetes mellitus (i.e., type II diabetes mellitus) since, among oral therapeutic agents for treating diabetes mellitus, it is most effective at lowering blood glucose, does not cause hypoglycemia or hyperinsulinemia and can prevent complications.
  • metformin has been extensively researched. Also, it was reported that metformin activates AMP-activated protein kinase (AMPK) by inhibiting the action of complex 1 of the electron transport system in mitochondria to obstruct intracellular generation of energy, and inhibits activation of the mTOR/S6K1 signaling pathway in which proteins essential for survival are produced to obstruct proliferation of cancer cells and tumor growth (Mol. Cancer Ther.
  • AMPK AMP-activated protein kinase
  • metformin has received considerable attention as an anticancer agent for regulating cancer cell metabolism. Also, an epidemiological survey confirmed that the incidence of cancer and mortality by cancer were lower for patients treated with metformin (BMJ.330: 1304-1305 (2005)).
  • the cancer stem cells refer to cancer cells that have self-regeneration or differentiation activities which are characteristically innate to stem cells.
  • the cancer stem cells are present in the cancer tissues at a content of 0.2% or less, and are characterized by their slow proliferation. Since many anticancer agents developed so far target cancer cells that proliferate rapidly, the cancer stem cells are resistant to conventional anticancer therapy when cancer stem cells are treated with the anticancer agents, thereby causing poor prognoses. On the other hand, it was reported that metformin prevents the recurrence of cancer as it selectively acts only on cancer stem cells among breast cancer cells and removes the cancer stem cells (Cancer Res.
  • metformin prevents the metastasis of cancer by interfering with the motility and invasion of the cancer since it inhibits the expression of Snail1, Slug, Twist, ZEB1/2 and TGF-b, which are transcription factors associated with the epithelial-to-mesenchymal transition (EMT) and promotes the expression of E-cadherin to prevent cancer cells from leading to the EMT (Cell Cycle 10: 7, 1144-1151 (2011), Cell Cycle 9: 18, 3807-3814 (2010), Cell Cycle 9: 22, 4461-4468 (2010)).
  • EMT epithelial-to-mesenchymal transition
  • the present invention is directed to providing a novel biguanide derivative that is highly effective at inhibiting proliferation of cancer cells, cancer metastasis and cancer recurrence, even when administered in a small dose compared with conventional drugs, or a pharmaceutically acceptable salt thereof, and a method of preparing the same.
  • N1-cyclic amine-N5-substituted biguanide derivative compound represented by the following Formula 1, or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are taken together with nitrogen to which they are attached to form C 3-6 heterocycloalkene having 4 to 7 ring atoms; or C 3-6 heterocycloalkyl having 4 to 7 ring atoms, and
  • R 3 is hydrogen; C 1-6 alkyl; phenyl; or C 1-4 alkyl substituted with phenyl, wherein the C 3-6 heterocycloalkene and the C 3-6 heterocycloalkyl are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, hydroxy and C 1-6 alkyl, and the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent 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 substituted group refers to a group in which at least one hydrogen atom is replaced with at least one non-hydrogen atom group, provided that the group satisfies the valence electron requirements and forms a chemically stable compound from the substitution. Unless explicitly described as unsubstituted in this specification, it should be understood that all substituents will be unsubstituted or substituted with another substituent.
  • the substituents R 1 to R 3 on the biguanide derivative according to the present invention may each be re-substituted with at least one of the above-defined substituents.
  • halogen or halo- refers to fluoro, chloro, bromo, and iodo.
  • hydroxy refers to -OH.
  • alkyl refers to a linear and branched saturated hydrocarbon group generally having a specified number of carbon atoms (for example, 1 to 12 carbon atoms).
  • alkyl group 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-yl, 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, etc.
  • the alkyl may be attached to a parent group or a substrate at any ring atom, unless the attachment would violate the valence electron requirements.
  • the alkyl group may include at least one non-hydrogen substituent unless the substitution would violate the valence electron requirements.
  • the term haloalkyl refers to an alkyl group in which at least one hydrogen atom of the alkyl group is substituted with halogen.
  • group such as -CH 2 (halo) , -CH(halo) 2 or C(halo) 3 is formed.
  • haloalkyl group include, without limitation, trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.
  • alkoxy refers to alkyl-O-, provided that the alkyl is the same as defined above.
  • examples of the alkoxy group include, without limitation, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, etc.
  • the alkoxy may be attached to a parent group or a substrate at any ring atom, unless the attachment would violate the valence electron requirements.
  • the alkoxy group may include at least one non-hydrogen substituent unless the attachment would violate the valence electron requirements.
  • haloalkoxy refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is substituted with halogen.
  • group such as -O-CH 2 (halo), -O-CH(halo) 2 or -O-C(halo) 3 is formed.
  • haloalkoxy group include, without limitation, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and triiodomethoxy, etc.
  • cycloalkene refers to a saturated monocyclic and polycyclic hydrocarbon ring generally having the specified number of carbon atoms (for example, C 3-8 cycloalkene refers to cycloalkene group having 3, 4, 5, 6, 7 or 8 carbon atoms as ring members).
  • the cycloalkene may be attached to a parent or substrate at any ring atom, unless the attachment would violate the valence electron requirements.
  • the cycloalkene group may include at least one non-hydrogen substituent unless the substitution would violate the valence electron requirements.
  • heterocycloalkene refers to an unsaturated non-aromatic monocyclic and polycyclic hydrocarbon ring in which at least one of ring members in the cycloalkene is composed of elements rather than carbon, including heteroatoms, for example, nitrogen, oxygen or sulfur.
  • the heterocycloalkene may be attached to a parent or substrate at any ring atom, unless the attachment would violate the valence electron requirements.
  • the heterocycloalkene group may include at least one non-hydrogen substituent unless the attachment would violate the valence electron requirements.
  • heterocycloalkene group examples include, without limitation, dihydroazetine, dihydropyrrole, dihydropyridine, tetrahydropyridine, dihydroazepine, tetrahydroazepine, etc.
  • cycloalkyl refers to a saturated monocyclic and dicyclic hydrocarbon ring generally having the specified number of carbon atoms included in a ring (that is, C 3-8 cycloalkyl refers to cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms as ring members).
  • the cycloalkyl may be attached to a parent or substrate at any ring atom, unless the attachment would violate the valence electron requirements.
  • the cycloalkyl group may include at least one non-hydrogen substituent unless the substitution would violate the valence electron requirements.
  • heterocycloalkyl refers to a monocyclic and dicyclic hydrocarbon ring in which at least one of ring system atoms in the cycloalkyl is composed of elements rather than carbon, including heteroatoms, that is, nitrogen, oxygen or sulfur.
  • the heterocycloalkyl may be attached to a parent or substrate at any ring atom, unless the attachment would violate the valence electron requirements.
  • the heterocycloalkyl group may include at least one non-hydrogen substituent unless the substitution would violate valence electron requirements.
  • heterocycloalkyl group examples include, without limitation, aziridine, azetidine, imidazolyl, pyrrolyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, azepanyl, indolyl, indolinyl, etc.
  • R 1 and R 2 may be taken together with nitrogen to which they are attached to form C 4-5 heterocycloalkene having 5 to 6 ring atoms or C 4-5 heterocycloalkyl having 5 to 6 ring atoms, and
  • R 3 may be hydrogen; C 1-6 alkyl; phenyl; or C 1-4 alkyl substituted with a phenyl,
  • the C 4-5 heterocycloalkyl is substituted with 1 to 4 C 1-6 alkyl groups
  • the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent 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.
  • R 1 and R 2 may be taken together with nitrogen to which they are attached to form C 4-5 heterocycloalkene having 5 to 6 ring atoms or C 4-5 heterocycloalkyl having 5 to 6 ring atoms,
  • R 3 may be hydrogen; C 1-6 alkyl; phenyl; or C 1-2 alkyl substituted with phenyl,
  • the C 4-5 heterocycloalkyl is substituted with one or two C 1-2 alkyl groups
  • the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, C 1-2 alkoxy, C 1-2 haloalkyl, and C 1-2 haloalkoxy.
  • R 1 and R 2 may be taken together with nitrogen to which they are attached to form C 3-6 heterocycloalkene selected from the group consisting of dihydroazetinyl; dihydropyrrolinyl; dihydropyridinyl; and tetrahydropyridinyl, or R 1 and R 2 may be taken together with nitrogen to which they are attached to form C 3-6 heterocycloalkyl selected from the group consisting of azetidinyl; piperidinyl; and pyrrolidinyl, and
  • R 3 may be hydrogen; C 1-6 alkyl; phenyl; or C 1-4 alkyl substituted with phenyl,
  • the C 3-6 heterocycloalkyl is substituted with 1 to 4 C 1-6 alkyl groups
  • the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent 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.
  • R 1 and R 2 may be taken together with nitrogen to which they are attached to form dihydropyrrolinyl or tetrahydropyridinyl which is unsubstituted or substituted with C 1-4 alkyl, or R 1 and R 2 may be taken together with nitrogen to which they are attached to form piperidinyl or pyrrolidinyl which is substituted with C 1-4 alkyl in at least one position thereof, and
  • R 3 may be hydrogen; C 1-6 alkyl; phenyl; or C 1-4 alkyl substituted with phenyl,
  • phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy.
  • R 1 and R 2 may be taken together with nitrogen to which they are attached to form dihydropyrrolinyl or tetrahydropyridinyl which is unsubstituted or substituted with C 1-2 alkyl, or R 1 and R 2 may be taken together with nitrogen to which they are attached to form piperidinyl or pyrrolidinyl substituted with one or two C 1-2 alkyl groups, and
  • R 3 may be hydrogen; C 3-6 alkyl; phenyl; or C 1-2 alkyl substituted with phenyl,
  • phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, C 1-2 alkoxy, C 1-2 haloalkyl, and C 1-2 haloalkoxy.
  • R 1 and R 2 may be taken together with nitrogen to which they are attached to form dihydropyrrolinyl or tetrahydropyridinyl which is unsubstituted or substituted with methyl, or R 1 and R 2 may be taken together with nitrogen to which they are attached to form piperidine, and
  • R 3 may be hydrogen; butyl; propyl; hexyl; phenyl; or methyl substituted with phenyl,
  • piperidine is substituted with one or two methyl groups in at least one of positions 2, 3, 5 and 6, and
  • the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, methoxy, trihalomethyl, and trihalomethoxy.
  • the compound of Formula 1 may include 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-t
  • a 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 may 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, dichloroacetic acid, aminooxy acetic acid, benzensulfonic acid, 4-toluenesulfonic acid and methanesulfonic acid; and the inorganic acid may include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid;
  • the above-described acid addition salt may be prepared by a typical method of preparing a salt, including a) directly mixing the compound of Formula 1 and an acid, b) dissolving one of the compound and an acid in a solvent or a hydrated solvent and mixing the resulting solution, or c) mixing the compound of Formula 1 and the acid in the presence of a solvent or a hydrated solvent.
  • the pharmaceutically acceptable salt of the compound represented by Formula 1 may be a salt of an acid 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, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzensulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxy acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, and boric acid.
  • an acid selected from the group consisting of formic acid, acetic acid, prop
  • the compound of Formula 1 according to the present invention may be prepared by several methods.
  • R 1 , R 2 and R 3 are the same as defined in Formula 1.
  • the preparation method may be illustrated in the following Scheme 1, and will be described by operations, as follows.
  • the cyanoguanidine compound of Formula 3 used as an intermediate may be obtained by reacting the cyclic amine of Formula 2 with a dicyanamide such as sodium or potassium dicyanamide in an organic solvent in the presence of an acid. Then, the compound of Formula 1 may be obtained by refluxing the obtained cyanoguanidine compound of Formula 3 with the compound of Formula 4 in an organic solvent.
  • a dicyanamide such as sodium or potassium dicyanamide
  • An amount of the dicyanamide used for preparation of the cyanoguanidine compound of Formula 3 is equivalent to approximately 1 to 3 moles with respect to the compound of Formula 2, and an amount of the acid used is equivalent to approximately 1 to 2 moles with respect to the compound of Formula 2.
  • methanol, ethanol, propanol, butanol, pentanol, acetonitrile, benzene, toluene, 1,4-dioxane, N,N-dimethylamide, and the like may be, for example, used as the organic solvent, and hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, 4-toluenesulfonic acid, and the like may be, used as the acid.
  • the reaction temperature of the compound of Formula 2 and the dicyanamide may be in a range of 60 to 140°C, and the reaction time may be in a range of 3 to 24 hours.
  • an amount of the compound of Formula 4 is equivalent to approximately 1 to 2 moles with respect to the compound of Formula 3
  • an amount of the acid is equivalent to approximately 1 to 2 moles with respect to the compound of Formula 3.
  • the organic solvent used in reaction of the compound of Formula 3 and the compound of Formula 4 may include methanol, ethanol, propanol, butanol, pentanol, acetonitrile, benzene, toluene, 1,4-dioxane, N,N-dimethylamide, and the like
  • the acid may, for example, include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, 4-toluenesulfonic acid, and the like.
  • the reaction temperature may be in a range of a reflux temperature of the solvent used (i.e., 120 to 140°C for butanol), and the reaction time may be in a range of 6 to 24 hours.
  • the resulting reaction solution is filtered. Thereafter, a pH of the filtered reaction solution may be controlled to approximately 4 to 5 using an acid such as, hydrochloric acid. Then, the resulting reaction solution may be concentrated and purified to yield the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention.
  • the compound of Formula 1 or the pharmaceutically acceptable salt thereof produced in this way may be useful in performing anticancer treatment including inhibition of cancer metastasis and cancer recurrence by AMPK activation, even when administered in a small dose compared with conventional drugs, as will be confirmed in the following Examples.
  • the present invention provides a medicine including the compound of Formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient.
  • Another aspect of the present invention provides a pharmaceutical composition for preventing or treating a cancer, which includes the compound of Formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient, the use of the compound of Formula 1 or the pharmaceutically acceptable salt thereof to prepare a medicine for preventing or treating the disease, and a method of preventing or treating the disease including administering a therapeutically effective amount of the compound of Formula 1 or the pharmaceutically acceptable salt thereof to a subject.
  • the pharmaceutical composition of the present invention includes at least one pharmaceutically acceptable carrier in addition to the active ingredient.
  • pharmaceutically acceptable carrier refers to a known pharmaceutically acceptable excipient, which is useful to formulate a pharmaceutically active compound for administration, and is substantially non-toxic and non-sensitive under the conditions used. An exact ratio of the excipient is determined by standard pharmaceutical practice, as well as solubility, chemical characteristics and selected route for administration of the active compound.
  • the pharmaceutical composition of the present invention may be formulated in a form suitable for a desired administration method using a suitable and physiologically available adjuvant such as an excipient, a disintegrating agent, a sweetening agent, a binder, a coating agent, a swelling agent, a lubricating agent, a glossing agent, a flavoring agent, or the like.
  • a suitable and physiologically available adjuvant such as an excipient, a disintegrating agent, a sweetening agent, a binder, a coating agent, a swelling agent, a lubricating agent, a glossing agent, a flavoring agent, or the like.
  • the pharmaceutical composition may be formulated as a tablet, a capsule, a pill, a granule, a powder, an injection or a liquid, but the present invention is not limited thereto.
  • the formulation and the pharmaceutically acceptable carrier of the pharmaceutical composition may be properly selected according to the techniques known in the related art, and, for example, may be selected with reference to the following documents: (Urquhart et al., Lancet, 16:367, 1980); (Lieberman et al., PHARMACEUTICAL DOSAGE FORMS-DISPERSE SYSTEMS, 2nd ed., vol.
  • the pharmaceutical composition may be used together with a second drug.
  • the term second drug refers to another pharmaceutically active ingredient in addition to the biguanide derivative according to the present invention.
  • the compound of Formula 1 or the pharmaceutically acceptable salt thereof according to the present invention may be used to treat a variety of diseases, as described above.
  • the compound of Formula 1 or the pharmaceutically acceptable salt thereof according to the present invention may be used together with a second drug for effectively treating respective diseases.
  • the second drug may be an anticancer agent, an anti-hyperglycemic agent, an anti-obesity agent, etc., which includes an active ingredient different from the compound of Formula 1 or the pharmaceutically acceptable salt thereof.
  • the compound of Formula 1 or the pharmaceutically acceptable salt thereof according to the present invention and the second drug are able to be administered in the same manner, the compound of Formula 1 or the pharmaceutically acceptable salt thereof may be formulated together with the second drug to be provided in the form of a composite preparation.
  • the term subject refers to a warm-blooded animal such as a mammal with a specific condition, disorder or disease.
  • the subject may be a human, an orangutan, a chimpanzee, a mouse, a rat, a dog, a cow, a chicken, a pig, a goat, a sheep, etc., but the present invention is not limited thereto.
  • treating includes relieving a symptom, temporarily or permanently eliminating causes of the symptom, and preventing or hindering occurrence of the symptom or progression of the above-described condition, disorder or disease, but the present invention is not limited thereto.
  • an effective amount of the active ingredient of the pharmaceutical composition according to the present invention refers to an amount required to treat a disease. Therefore, the effective amount of the active ingredient may be adjusted according to various factors such as kinds and severity of a disease, kinds and contents of an active ingredient and other ingredients included in the composition, kinds of a formulation, age, body weight, general medical conditions, sex and diet of a patient, duration and route of administration, a release rate of the composition, treatment duration, and the number of drugs used together.
  • the compound of Formula 1 may be administered in a total dose of 50 to 3,000 mg/kg when administered once to several times a day.
  • the N1-cyclic amine-N5-substituted biguanide derivative of Formula 1 according to the present invention can be highly useful in treating a cancer since the N1-cyclic amine-N5-substituted biguanide derivative of Formula 1 has an effect of inhibiting cancer cell proliferation, cancer metastasis and recurrence even when administered in a small dose compared with conventional drugs.
  • a white solid target compound (2.23 g, 59.2%) was prepared in the same manner as in Example 1, except that 1,2,3,6-tetrahydropyridine was used instead of the 2,5-dihydropyrrole hydrochloride used in Example 1.
  • a white solid target compound (3.12 g, 83%) was prepared in the same manner as in Example 1, except that 3-methyl-2,5-dihydropyrrole was used instead of the 2,5-dihydropyrrole hydrochloride used in Example 1.
  • Target compounds of the following Examples 5 to 61 were prepared in the same manner as in Example 4, except that the cyanoguanidine and amine compounds synthesized in Examples 2 and 3, which corresponded to the target compounds, were used respectively instead of the N1-2,5-dihydropyrrole cyanoguanidine synthesized in Example 1 and the (4-trifluoromethoxy)phenylamine used in Example 4.
  • a white solid target compound (1.0 g, 37%) was prepared in the same manner as in Example 62, except that N1-(2-methyl)piperidine was used instead of the N1-(3-methyl)piperidine used in Example 62.
  • a white solid target compound (0.75 g, 47.2%) was prepared in the same manner as in Example 62, except that N1-(2,6-dimethyl)piperidine was used instead of the N1-(3-methyl)piperidine used in Example 62.
  • Target compounds of the following Examples 66 to 98 were prepared in the same manner as in Example 65, except that the cyanoguanidine and amine compounds synthesized in Examples 63 and 64, which corresponded to the target compounds, were used respectively instead of the N1-(3-methyl)piperidine cyanoguanidine synthesized in Example 62 and the (3-trifluoromethyl)benzylamine used in Example 65.
  • MCF7 cells derived from human breast cancer cells purchased from the Korean Cell Line Bank (KCLB) were used, and AMPK activation effects of the biguanide derivatives were confirmed using an AMPK [pT172] ELISA kit (Invitrogen, Catalog No. KHO0651).
  • MCF7 cells were cultured in a DMEM medium supplemented with 10% fatal bovine serum (commercially available from Gibco Life Technologies (US)). Thereafter, the cultured MCF7 cells were put into a 6-well plate with approximately 5x10 5 cells per well, and cultured in an incubator supplied with 5% CO 2 . Culture media were treated with the derivatives synthesized in the Examples at concentrations of 5, 10 and 50uM, and then cultured for 24 hours. Metformin was used as the control, and the culture media were treated with 0.05, 0.5, 1, 2, 5 and 10 mM metformin and then tested in the same manner as described for the derivatives synthesized in the Examples.
  • the cells were lysed according to a method presented in the operation manual of the AMPK [pT172] ELISA kit, and 20 ⁇ g of a cell lysate was then yielded through protein assay. Thereafter, the AMPK activation effect was obtained by determining a degree of phosphorylation of a 172 nd threonine residue (Thr172) of the AMPK ⁇ from the cell lysate according to the method presented in the operation manual of the AMPK [pT172] ELISA kit.
  • a degree of AMPK activation by the biguanide derivatives was exhibited as a degree of AMPK ⁇ phosphorylation in cells cultured in the presence of the compounds synthesized in the Examples with respect to a degree of AMPK ⁇ phosphorylation in cells cultured without treatment with the biguanide derivatives.
  • a curve graph showing AMPK activation according to the concentration of the treated compounds was plotted based on the obtained AMPK activation results, and a concentration (activation concentration 150, AC150) value of a compound whose AMPK activation reached 150% was calculated using a GraphPad Prism 5.0 program.
  • degrees of AMPK activation when the concentrations of the treated biguanide derivatives of Examples 4 to 61 were 10 ⁇ M and 50 ⁇ M are listed in the following Table 1
  • degrees of AMPK activation when the concentrations of the treated biguanide derivatives of Examples 65 to 98 were 5 ⁇ M to 10 ⁇ M are listed in the following Table 2.
  • HCT116 cells derived from human colorectal cancer were used, and an effect of inhibiting cancer cell proliferation of the biguanide derivative was confirmed by measuring a concentration value (cell growth inhibition concentration, GIC50) at which cell growth was inhibited by 50% using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reagent.
  • GIC50 cell growth inhibition concentration
  • HCT116 cells purchased from the KCLB
  • a DMEM medium supplemented with 10% fatal bovine serum (commercially available from Gibco Life Technologies (US)) for 16 hours so that approximately 5,000 cells were counted in each well.
  • the culture media were treated with 100 ⁇ M, 25 ⁇ M, 6.25 ⁇ M, 1.56 ⁇ M or 0.39 ⁇ M of the compound, and then cultured for 48 hours.
  • MTT commercially available from AMRESCO (US) was added to the culture media which were then cultured for another 3 hours.
  • DMSO dimethyl sulfoxide
  • a ratio of a living cell count on a well plate treated with the compounds synthesized in the Examples to a cell count cultured on a well plate not treated with the compound was indicated as cell viability (%) according to the concentration of each treated compound.
  • the cell viability (%) was used to plot a cell viability curve graph and calculate a concentration (GIC50) value of the compound at which the growth was inhibited by 50%, thereby confirming the inhibition effect of cancer cell proliferation.
  • Examples 4 to 61 the cell growth inhibitions (%) when the concentration of the treated biguanide derivative and metformin as the control was 100 ⁇ M (Examples 4 to 61) is listed in the following Table 3, and the cell growth inhibitions (%) when the concentration of the treated biguanide derivative and metformin as the control was 25 ⁇ M (Examples 65 to 98) are listed in the following Table 4.

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Abstract

The present invention provides an N1-cyclic amine-N5-substituted biguanide derivative compound represented by Formula 1, a method of preparing the same and a pharmaceutical composition including the biguanide derivative or the pharmaceutically acceptable salt thereof as an actice ingredient. The biguanide derivatives have an effect of inhibiting cancer cell proliferation, cancer metastasis and cancer recurrence by activation of AMPK, even when administered in a small dose compared with conventional drugs.

Description

N1-CYCLIC AMINE-N5-SUBSTITUTED BIGUANIDE DERIVATIVES, METHODS OF PREPARING THE SAME AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
The present invention relates to an N1-cyclic amine-N5-substituted biguanide derivative that inhibits cancer cell proliferation, cancer metastasis and cancer recurrence by activation of AMPK, even when administered in a small dose compared with conventional drugs, and that exhibits excellent therapeutic effects, a method of preparing the same, and a pharmaceutical composition including the N1-cyclic amine-N5-substituted biguanide derivative as an active ingredient.
AMPK (AMP-activated protein kinases) is an enzyme that functions to regulate a metabolic pathway so as to maintain balance between supply of nutrients and demand for energy, and thus maintain energy homeostasis in cells and the whole body. AMPK is activated as a ratio of AMP/ATP in the cells increases due to a hypoxemic state or glucose deficiency. The activated AMPK induces fatty acid oxidation to produce a larger amount of ATP and inhibits anabolisms requiring the use of ATP. AMPK inhibits proliferation of cancer cells and kills the cancer cells by regulating energy metabolism in the cancer cells as well as in normal cells. AMPK activated in the cancer cells shows anticancer activities by phosphorylating mTORC1, p53, fatty acid synthase and the like to regulate the cell cycle, cell polarity, autophagy, apoptosis, etc.
Metformin has been used to treat insulin-independent diabetes mellitus (i.e., type II diabetes mellitus) since, among oral therapeutic agents for treating diabetes mellitus, it is most effective at lowering blood glucose, does not cause hypoglycemia or hyperinsulinemia and can prevent complications. In recent years, metformin has been extensively researched. Also, it was reported that metformin activates AMP-activated protein kinase (AMPK) by inhibiting the action of complex 1 of the electron transport system in mitochondria to obstruct intracellular generation of energy, and inhibits activation of the mTOR/S6K1 signaling pathway in which proteins essential for survival are produced to obstruct proliferation of cancer cells and tumor growth (Mol. Cancer Ther. 9(5): 1092-1099 (2010)). Consequently, metformin has received considerable attention as an anticancer agent for regulating cancer cell metabolism. Also, an epidemiological survey confirmed that the incidence of cancer and mortality by cancer were lower for patients treated with metformin (BMJ.330: 1304-1305 (2005)).
Meanwhile, there is increasing clinical evidence indicating that cancer stem cells take part in recurrence and metastasis of cancer. The cancer stem cells refer to cancer cells that have self-regeneration or differentiation activities which are characteristically innate to stem cells. The cancer stem cells are present in the cancer tissues at a content of 0.2% or less, and are characterized by their slow proliferation. Since many anticancer agents developed so far target cancer cells that proliferate rapidly, the cancer stem cells are resistant to conventional anticancer therapy when cancer stem cells are treated with the anticancer agents, thereby causing poor prognoses. On the other hand, it was reported that metformin prevents the recurrence of cancer as it selectively acts only on cancer stem cells among breast cancer cells and removes the cancer stem cells (Cancer Res. 69(19): 7507-11 (2009)). Also, it was found that metformin prevents the metastasis of cancer by interfering with the motility and invasion of the cancer since it inhibits the expression of Snail1, Slug, Twist, ZEB1/2 and TGF-b, which are transcription factors associated with the epithelial-to-mesenchymal transition (EMT) and promotes the expression of E-cadherin to prevent cancer cells from leading to the EMT (Cell Cycle 10: 7, 1144-1151 (2011), Cell Cycle 9: 18, 3807-3814 (2010), Cell Cycle 9: 22, 4461-4468 (2010)).
For these reasons, there is need for a biguanide-based substance that exhibits better pharmacological action than conventional metformin and has improved physiochemical properties.
The present invention is directed to providing a novel biguanide derivative that is highly effective at inhibiting proliferation of cancer cells, cancer metastasis and cancer recurrence, even when administered in a small dose compared with conventional drugs, or a pharmaceutically acceptable salt thereof, and a method of preparing the same.
One aspect of the present invention provides an N1-cyclic amine-N5-substituted biguanide derivative compound represented by the following Formula 1, or a pharmaceutically acceptable salt thereof:
[Formula 1]
Figure PCTKR2014001006-appb-I000001
In Formula 1, R1 and R2 are taken together with nitrogen to which they are attached to form C3-6 heterocycloalkene having 4 to 7 ring atoms; or C3-6 heterocycloalkyl having 4 to 7 ring atoms, and
R3 is hydrogen; C1-6 alkyl; phenyl; or C1-4 alkyl substituted with phenyl, wherein the C3-6 heterocycloalkene and the C3-6 heterocycloalkyl are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, hydroxy and C1-6 alkyl, and the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.
In this specification, a substituted group refers to a group in which at least one hydrogen atom is replaced with at least one non-hydrogen atom group, provided that the group satisfies the valence electron requirements and forms a chemically stable compound from the substitution. Unless explicitly described as unsubstituted in this specification, it should be understood that all substituents will be unsubstituted or substituted with another substituent. The substituents R1 to R3 on the biguanide derivative according to the present invention may each be re-substituted with at least one of the above-defined substituents.
The term halogen or halo- refers to fluoro, chloro, bromo, and iodo.
The term hydroxy refers to -OH.
The term alkyl refers to a linear and branched saturated hydrocarbon group generally having a specified number of carbon atoms (for example, 1 to 12 carbon atoms). Examples of the alkyl group 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-yl, 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, etc. The alkyl may be attached to a parent group or a substrate at any ring atom, unless the attachment would violate the valence electron requirements. Likewise, the alkyl group may include at least one non-hydrogen substituent unless the substitution would violate the valence electron requirements. For example, the term haloalkyl refers to an alkyl group in which at least one hydrogen atom of the alkyl group is substituted with halogen. For example, when at least one hydrogen atom of methyl group is substituted with halogen, group such as -CH2(halo), -CH(halo)2 or C(halo)3 is formed. Examples of the term haloalkyl group include, without limitation, trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.
The term alkoxy refers to alkyl-O-, provided that the alkyl is the same as defined above. Examples of the alkoxy group include, without limitation, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, etc. The alkoxy may be attached to a parent group or a substrate at any ring atom, unless the attachment would violate the valence electron requirements. Likewise, the alkoxy group may include at least one non-hydrogen substituent unless the attachment would violate the valence electron requirements. For example, the term haloalkoxy refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is substituted with halogen. For example, when at least one hydrogen atom of methoxy group is substituted with halogen, group such as -O-CH2(halo), -O-CH(halo)2 or -O-C(halo)3 is formed. Examples of the term haloalkoxy group include, without limitation, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and triiodomethoxy, etc.
The term cycloalkene refers to a saturated monocyclic and polycyclic hydrocarbon ring generally having the specified number of carbon atoms (for example, C3-8 cycloalkene refers to cycloalkene group having 3, 4, 5, 6, 7 or 8 carbon atoms as ring members). The cycloalkene may be attached to a parent or substrate at any ring atom, unless the attachment would violate the valence electron requirements. Likewise, the cycloalkene group may include at least one non-hydrogen substituent unless the substitution would violate the valence electron requirements.
The term heterocycloalkene refers to an unsaturated non-aromatic monocyclic and polycyclic hydrocarbon ring in which at least one of ring members in the cycloalkene is composed of elements rather than carbon, including heteroatoms, for example, nitrogen, oxygen or sulfur. The heterocycloalkene may be attached to a parent or substrate at any ring atom, unless the attachment would violate the valence electron requirements. Likewise, the heterocycloalkene group may include at least one non-hydrogen substituent unless the attachment would violate the valence electron requirements. Examples of the heterocycloalkene group include, without limitation, dihydroazetine, dihydropyrrole, dihydropyridine, tetrahydropyridine, dihydroazepine, tetrahydroazepine, etc.
The term cycloalkyl refers to a saturated monocyclic and dicyclic hydrocarbon ring generally having the specified number of carbon atoms included in a ring (that is, C3-8 cycloalkyl refers to cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms as ring members). The cycloalkyl may be attached to a parent or substrate at any ring atom, unless the attachment would violate the valence electron requirements. Likewise, the cycloalkyl group may include at least one non-hydrogen substituent unless the substitution would violate the valence electron requirements.
The term heterocycloalkyl refers to a monocyclic and dicyclic hydrocarbon ring in which at least one of ring system atoms in the cycloalkyl is composed of elements rather than carbon, including heteroatoms, that is, nitrogen, oxygen or sulfur. The heterocycloalkyl may be attached to a parent or substrate at any ring atom, unless the attachment would violate the valence electron requirements. Likewise, the heterocycloalkyl group may include at least one non-hydrogen substituent unless the substitution would violate valence electron requirements. Examples of the heterocycloalkyl group include, without limitation, aziridine, azetidine, imidazolyl, pyrrolyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, azepanyl, indolyl, indolinyl, etc.
According to one exemplary embodiment, R1 and R2 may be taken together with nitrogen to which they are attached to form C4-5 heterocycloalkene having 5 to 6 ring atoms or C4-5 heterocycloalkyl having 5 to 6 ring atoms, and
R3 may be hydrogen; C1-6 alkyl; phenyl; or C1-4 alkyl substituted with a phenyl,
wherein the C4-5 heterocycloalkene is unsubstituted or substituted with C1-6 alkyl,
the C4-5 heterocycloalkyl is substituted with 1 to 4 C1-6 alkyl groups, and
the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.
According to another exemplary embodiment, R1 and R2 may be taken together with nitrogen to which they are attached to form C4-5 heterocycloalkene having 5 to 6 ring atoms or C4-5 heterocycloalkyl having 5 to 6 ring atoms,
R3 may be hydrogen; C1-6 alkyl; phenyl; or C1-2 alkyl substituted with phenyl,
wherein the C4-5 heterocycloalkene is unsubstituted or substituted with C1-2 alkyl,
the C4-5 heterocycloalkyl is substituted with one or two C1-2 alkyl groups, and
the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, C1-2 alkoxy, C1-2 haloalkyl, and C1-2 haloalkoxy.
According to still another exemplary embodiment, R1 and R2 may be taken together with nitrogen to which they are attached to form C3-6 heterocycloalkene selected from the group consisting of dihydroazetinyl; dihydropyrrolinyl; dihydropyridinyl; and tetrahydropyridinyl, or R1 and R2 may be taken together with nitrogen to which they are attached to form C3-6 heterocycloalkyl selected from the group consisting of azetidinyl; piperidinyl; and pyrrolidinyl, and
R3 may be hydrogen; C1-6 alkyl; phenyl; or C1-4 alkyl substituted with phenyl,
wherein the C3-6 heterocycloalkene is unsubstituted or substituted with C1-6 alkyl,
the C3-6 heterocycloalkyl is substituted with 1 to 4 C1-6 alkyl groups, and
the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.
According to still another exemplary embodiment, R1 and R2 may be taken together with nitrogen to which they are attached to form dihydropyrrolinyl or tetrahydropyridinyl which is unsubstituted or substituted with C1-4 alkyl, or R1 and R2 may be taken together with nitrogen to which they are attached to form piperidinyl or pyrrolidinyl which is substituted with C1-4 alkyl in at least one position thereof, and
R3 may be hydrogen; C1-6 alkyl; phenyl; or C1-4 alkyl substituted with phenyl,
wherein the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy.
According to still another exemplary embodiment, R1 and R2 may be taken together with nitrogen to which they are attached to form dihydropyrrolinyl or tetrahydropyridinyl which is unsubstituted or substituted with C1-2 alkyl, or R1 and R2 may be taken together with nitrogen to which they are attached to form piperidinyl or pyrrolidinyl substituted with one or two C1-2 alkyl groups, and
R3 may be hydrogen; C3-6 alkyl; phenyl; or C1-2 alkyl substituted with phenyl,
wherein the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, C1-2 alkoxy, C1-2 haloalkyl, and C1-2 haloalkoxy.
According to yet another exemplary embodiment, R1 and R2 may be taken together with nitrogen to which they are attached to form dihydropyrrolinyl or tetrahydropyridinyl which is unsubstituted or substituted with methyl, or R1 and R2 may be taken together with nitrogen to which they are attached to form piperidine, and
R3 may be hydrogen; butyl; propyl; hexyl; phenyl; or methyl substituted with phenyl,
wherein the piperidine is substituted with one or two methyl groups in at least one of positions 2, 3, 5 and 6, and
the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, methoxy, trihalomethyl, and trihalomethoxy.
According to one exemplary embodiment, the compound of Formula 1 may include 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; N1-1,2,3,6-tetrahydropyridine biguanide; N1-(3-methyl)piperidine-N5-(3-trifluoromethyl)benzyl biguanide; N1-(3-methyl)piperidine-N5-(4-chloro)benzyl biguanide; N1-(3-methyl)piperidine-N5-(4-fluoro)phenyl biguanide; N1-(3-methyl)piperidine-N5-(4-bromo)phenyl biguanide; N1-(3-methyl)piperidine-N5-(4-chloro, 3-trifluoromethyl)phenyl biguanide; N1-(3-methyl)piperidine-N5-(3-fluoro, 4-trifluoromethyl)phenyl biguanide; N1-(3-methyl)piperidine-N5-(4-fluoro, 3-trifluoromethyl)phenyl biguanide; N1-(2-methyl)piperidine-N5-(4-trifluoromethoxy)phenyl biguanide; N1-(2-methyl)piperidine-N5-(3-trifluoromethoxy)phenyl biguanide; N1-(2-methyl)piperidine-N5-(4-trifluoromethyl)phenyl biguanide; N1-(3-methyl)piperidine-N5-(3-fluoro, 4-trifluoromethoxy)phenyl biguanide; N1-(2-methyl)piperidine-N5-(3-fluoro, 4-trifluoromethoxy)phenyl biguanide; N1-(2-methyl)piperidine-N5-(4-chloro)phenyl biguanide; N1-(2-methyl)piperidine-N5-(4-fluoro, 3-trifluoromethyl)phenyl biguanide; N1-(2-methyl)piperidine-N5-(3-trifluoromethyl)phenyl biguanide; N1-(2-methyl)piperidine-N5-(4-chloro, 3-trifluoromethyl)phenyl biguanide; N1-(3-methyl)piperidine-N5-(4-trifluoromethyl)phenyl biguanide; N1-(3-methyl)piperidine-N5-(4-trifluoromethoxy)phenyl biguanide; N1-(3-methyl)piperidine-N5-(3-trifluoromethoxy)phenyl biguanide; N1-(3-methyl)piperidine-N5-(4-trifluoromethoxy)benzyl biguanide; N1-(3-methyl)piperidine-N5-(4-fluoro, 3-trifluoromethyl)phenyl biguanide; N1-(3-methyl)piperidine-N5-(4-trifluoromethyl)benzyl biguanide; N1-(3-methyl)piperidine-N5-(4-chloro)phenyl biguanide; N1-(3-methyl)piperidine-N5-(3-trifluoromethyl)phenyl biguanide; N1-(2,6-dimethyl)piperidine-N5-(4-trifluoromethoxy)phenyl biguanide; N1-(2,6-dimethyl)piperidine-N5-(3-trifluoromethoxy)phenyl biguanide; N1-(2,6-dimethyl)piperidine-N5-(4-trifluoromethyl)phenyl biguanide; N1-(2,6-dimethyl)piperidine-N5-(3-trifluoromethyl)phenyl biguanide; N1-(2,6-dimethyl)piperidine-N5-(4-fluoro, 3-trifluoromethyl)phenyl biguanide; N1-(2,6-dimethyl)piperidine-N5-(4-chloro, 3-trifluoromethyl)phenyl biguanide; N1-(2,6-dimethyl)piperidine-N5-(3-fluoro, 4-trifluoromethoxy)phenyl biguanide; N1-(2,6-dimethyl)piperidine-N5-(4-chloro)phenyl biguanide; N1-(2,6-dimethyl)piperidine-N5-(4-bromo)phenyl biguanide; or N1-(2,6-dimethyl)piperidine-N5-(4-fluoro)phenyl biguanide.
Meanwhile, a 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. For example, the organic acid may 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, dichloroacetic acid, aminooxy acetic acid, benzensulfonic acid, 4-toluenesulfonic acid and methanesulfonic acid; and the inorganic acid may include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and boric acid. For example, the above-described acid addition salt may be prepared by a typical method of preparing a salt, including a) directly mixing the compound of Formula 1 and an acid, b) dissolving one of the compound and an acid in a solvent or a hydrated solvent and mixing the resulting solution, or c) mixing the compound of Formula 1 and the acid in the presence of a solvent or a hydrated solvent.
According to one exemplary embodiment, the pharmaceutically acceptable salt of the compound represented by Formula 1 may be a salt of an acid 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, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzensulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxy acetic acid, hydrochloric acid, hydrobromic 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 by several methods.
According to one exemplary embodiment, there is provided a method of preparing a compound represented by the following Formula 1, which includes reacting a compound of the following Formula 2 with a dicyanamide in an organic solvent to obtain a compound of the following Formula 3; and reacting the compound of the following Formula 3 with a compound of the following Formula 4 in an organic solvent to obtain the compound of the following Formula 1:
[Formula 1]
Figure PCTKR2014001006-appb-I000002
[Formula 2]
Figure PCTKR2014001006-appb-I000003
[Formula 3]
Figure PCTKR2014001006-appb-I000004
[Formula 4]
Figure PCTKR2014001006-appb-I000005
In Formulas 1 to 4, R1, R2 and R3 are the same as defined in Formula 1.
For example, the preparation method may be illustrated in the following Scheme 1, and will be described by operations, as follows.
[Scheme 1]
Figure PCTKR2014001006-appb-I000006
In the method of preparing the compound of Formula 1, the cyanoguanidine compound of Formula 3 used as an intermediate may be obtained by reacting the cyclic amine of Formula 2 with a dicyanamide such as sodium or potassium dicyanamide in an organic solvent in the presence of an acid. Then, the compound of Formula 1 may be obtained by refluxing the obtained cyanoguanidine compound of Formula 3 with the compound of Formula 4 in an organic solvent.
An amount of the dicyanamide used for preparation of the cyanoguanidine compound of Formula 3 is equivalent to approximately 1 to 3 moles with respect to the compound of Formula 2, and an amount of the acid used is equivalent to approximately 1 to 2 moles with respect to the compound of Formula 2. Upon preparation of the compound of Formula 2, methanol, ethanol, propanol, butanol, pentanol, acetonitrile, benzene, toluene, 1,4-dioxane, N,N-dimethylamide, and the like may be, for example, used as the organic solvent, and hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, 4-toluenesulfonic acid, and the like may be, used as the acid. The reaction temperature of the compound of Formula 2 and the dicyanamide may be in a range of 60 to 140℃, and the reaction time may be in a range of 3 to 24 hours.
After the cyanoguanidine compound of Formula 3 obtained above is dissolved in an organic solvent, the compound of Formula 4 and an acid are added, and then stirred under reflux. In this case, an amount of the compound of Formula 4 is equivalent to approximately 1 to 2 moles with respect to the compound of Formula 3, and an amount of the acid is equivalent to approximately 1 to 2 moles with respect to the compound of Formula 3. For example, the organic solvent used in reaction of the compound of Formula 3 and the compound of Formula 4 may include methanol, ethanol, propanol, butanol, pentanol, acetonitrile, benzene, toluene, 1,4-dioxane, N,N-dimethylamide, and the like, and the acid may, for example, include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, 4-toluenesulfonic acid, and the like. In this case, the reaction temperature may be in a range of a reflux temperature of the solvent used (i.e., 120 to 140℃ for butanol), and the reaction time may be in a range of 6 to 24 hours. When the reaction is completed, the resulting reaction solution is filtered. Thereafter, a pH of the filtered reaction solution may be controlled to approximately 4 to 5 using an acid such as, hydrochloric acid. Then, the resulting reaction solution may be concentrated and purified to yield the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention.
The compound of Formula 1 or the pharmaceutically acceptable salt thereof produced in this way may be useful in performing anticancer treatment including inhibition of cancer metastasis and cancer recurrence by AMPK activation, even when administered in a small dose compared with conventional drugs, as will be confirmed in the following Examples.
Therefore, the present invention provides a medicine including the compound of Formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient.
Another aspect of the present invention provides a pharmaceutical composition for preventing or treating a cancer, which includes the compound of Formula 1 or the pharmaceutically acceptable salt thereof as an active ingredient, the use of the compound of Formula 1 or the pharmaceutically acceptable salt thereof to prepare a medicine for preventing or treating the disease, and a method of preventing or treating the disease including administering a therapeutically effective amount of the compound of Formula 1 or the pharmaceutically acceptable salt thereof to a subject.
The pharmaceutical composition of the present invention includes at least one pharmaceutically acceptable carrier in addition to the active ingredient. As used in this specification, the term pharmaceutically acceptable carrier refers to a known pharmaceutically acceptable excipient, which is useful to formulate a pharmaceutically active compound for administration, and is substantially non-toxic and non-sensitive under the conditions used. An exact ratio of the excipient is determined by standard pharmaceutical practice, as well as solubility, chemical characteristics and selected route for administration of the active compound.
The pharmaceutical composition of the present invention may be formulated in a form suitable for a desired administration method using a suitable and physiologically available adjuvant such as an excipient, a disintegrating agent, a sweetening agent, a binder, a coating agent, a swelling agent, a lubricating agent, a glossing agent, a flavoring agent, or the like.
The pharmaceutical composition may be formulated as a tablet, a capsule, a pill, a granule, a powder, an injection or a liquid, but the present invention is not limited thereto.
The formulation and the pharmaceutically acceptable carrier of the pharmaceutical composition may be properly selected according to the techniques known in the related art, and, for example, may be selected with reference to the following documents: (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); and (Wilson and Gisvolds' TEXTBOOK OF ORGANIC MEDICINAL AND PHARMACEUTICAL CHEMISTRY, Delgado and Remers, eds., 10th ed., 1998). Also, principals of formulating a pharmaceutical composition may be described, for example, with reference to the following documents: (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); and (Drug Dosage, J Kans Med Soc, 70(1):30-32, 1969).
According to one exemplary embodiment, the pharmaceutical composition may be used together with a second drug.
According to the present invention, the term second drug refers to another pharmaceutically active ingredient in addition to the biguanide derivative according to the present invention. The compound of Formula 1 or the pharmaceutically acceptable salt thereof according to the present invention may be used to treat a variety of diseases, as described above. As a result, the compound of Formula 1 or the pharmaceutically acceptable salt thereof according to the present invention may be used together with a second drug for effectively treating respective diseases. For example, the second drug may be an anticancer agent, an anti-hyperglycemic agent, an anti-obesity agent, etc., which includes an active ingredient different from the compound of Formula 1 or the pharmaceutically acceptable salt thereof.
When the compound of Formula 1 or the pharmaceutically acceptable salt thereof according to the present invention and the second drug are able to be administered in the same manner, the compound of Formula 1 or the pharmaceutically acceptable salt thereof may be formulated together with the second drug to be provided in the form of a composite preparation.
Meanwhile, according to the present invention, the term subject refers to a warm-blooded animal such as a mammal with a specific condition, disorder or disease. For example, the subject may be a human, an orangutan, a chimpanzee, a mouse, a rat, a dog, a cow, a chicken, a pig, a goat, a sheep, etc., but the present invention is not limited thereto.
Also, the term treating includes relieving a symptom, temporarily or permanently eliminating causes of the symptom, and preventing or hindering occurrence of the symptom or progression of the above-described condition, disorder or disease, but the present invention is not limited thereto.
An effective amount of the active ingredient of the pharmaceutical composition according to the present invention refers to an amount required to treat a disease. Therefore, the effective amount of the active ingredient may be adjusted according to various factors such as kinds and severity of a disease, kinds and contents of an active ingredient and other ingredients included in the composition, kinds of a formulation, age, body weight, general medical conditions, sex and diet of a patient, duration and route of administration, a release rate of the composition, treatment duration, and the number of drugs used together. In the case of adults, for example, the compound of Formula 1 may be administered in a total dose of 50 to 3,000 mg/kg when administered once to several times a day.
The N1-cyclic amine-N5-substituted biguanide derivative of Formula 1 according to the present invention can be highly useful in treating a cancer since the N1-cyclic amine-N5-substituted biguanide derivative of Formula 1 has an effect of inhibiting cancer cell proliferation, cancer metastasis and recurrence even when administered in a small dose compared with conventional drugs.
The advantages and features of the present invention and the method of revealing them will be explicit from the following examples described in detail. However, it is to be distinctly understood that the present invention is not limited thereto but may be otherwise variously embodied and practiced. It is obvious that the following examples are to complete the disclosure of the invention and to indicate the scope of the present invention to a skilled artisan completely, and the present invention will be defined only by the scope of the claims.
[EXAMPLES]
Example 1: Synthesis of N1-2,5-dihydropyrrole cyanoguanidine
Figure PCTKR2014001006-appb-I000007
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 then stirred for 3 hours under reflux. After completion of the reaction was confirmed, sodium chloride formed by filtering the reaction mixture was removed, and the filtrate was then concentrated at a reduced pressure. The concentrate was dissolved in methanol (2 mL), and ethyl acetate (5 mL) was then added thereto, and stirred at room temperature for an hour. The formed solid was filtered and the filtrate was washed with ethyl acetate (2x20 mL). The filtrate was dried at a reduced pressure to obtain a white solid target compound (0.90 g, 93%).
1H 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
Figure PCTKR2014001006-appb-I000008
A white solid target compound (2.23 g, 59.2%) was prepared in the same manner as in Example 1, except that 1,2,3,6-tetrahydropyridine was used instead of the 2,5-dihydropyrrole hydrochloride used in Example 1.
1H 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+1]+
Example 3: Synthesis of N1-3-methyl-2,5-dihydropyrrole cyanoguanidine
Figure PCTKR2014001006-appb-I000009
A white solid target compound (3.12 g, 83%) was prepared in the same manner as in Example 1, except that 3-methyl-2,5-dihydropyrrole was used instead of the 2,5-dihydropyrrole hydrochloride used in Example 1.
1H NMR (600 MHz, CD3OD) δ 5.45 (br s, 1H), 4.80 (m, 2H), 4.10 (m, 2H) 7.16 (s, 3H); LC-MS m/z 151.2 [M+1]+
Example 4: Preparation of N1-1,2-dihydropyrrole-N5-(4-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000010
(4-Trifluoromethoxy)phenylamine (390 mg, 2.20 mmol) was dissolved in a butanol (10 mL) solution at room temperature, and concentrated hydrochloric acid (0.18 mL, 2.20 mmol) was added to the resulting solution, and then stirred for 30 minutes. The N1-2,5-dihydropyrrole cyanoguanidine (300 mg, 2.20 mmol) obtained in Example 1 was added to the reaction mixture, and then stirred for an hour under reflux. The reaction mixture was stirred at room temperature for an hour, and the formed solid was filtered. Then, the filtrate was dried at a reduced pressure to obtain a white solid target compound (265 mg, 34%).
1H 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, 10H), 1.18 (m, 1H), 0.89 (s, 3H); LC-MS m/z 282.2 [M+1]+; mp 172-174℃
Target compounds of the following Examples 5 to 61 were prepared in the same manner as in Example 4, except that the cyanoguanidine and amine compounds synthesized in Examples 2 and 3, which corresponded to the target compounds, were used respectively instead of the N1-2,5-dihydropyrrole cyanoguanidine synthesized in Example 1 and the (4-trifluoromethoxy)phenylamine used in Example 4.
Example 5: Preparation of N1-1,2-dihydropyrrole-N5-(4-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000011
1H NMR (600 MHz, CD3OD) δ 7.58 (m, 4H), 5.91 (m, 2H), 4.27 (m, 4H); LC-MS m/z 298.2 [M+1]+; mp 254-256℃
Example 6: Preparation of N1-1,2-dihydropyrrole-N5-(3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000012
1H 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 m/z 298.2 [M+1]+; mp 276-278℃
Example 7: Preparation of N1-1,2-dihydropyrrole-N5-(4-fluoro)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000013
1H NMR (600 MHz, CD3OD) δ 7.33 (m, 2H), 7.04 (m, 2H), 5.90 (m, 2H), 4.17 (m, 4H); LC-MS m/z 248.2 [M+1]+; mp 263-265℃
Example 8: N1-1,2-dihydropyrrole-N5-(4-chloro)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000014
1H NMR (600 MHz, CD3OD) δ 7.29 (m, 4H), 5.90 (m, 2H), 4.20 (m, 4H); LC-MS m/z 264.2 [M+1]+; mp 264-266℃
Example 9: N1-1,2-dihydropyrrole-N5-(4-bromo)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000015
1H NMR (600 MHz, CD3OD) δ 7.42 (m, 2H), 7.30 (m, 2H), 5.90 (m, 2H), 4.24 (m, 4H); LC-MS m/z 309.0 [M+1]+; mp 263-265℃
Example 10: N1-1,2-dihydropyrrole-N5-(3-chloro,4-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000016
1H NMR (600 MHz, CD3OD) δ 7.79 (m, 1H), 7.42 (m, 2H), 5.99 (m, 2H), 4.30 (m, 4H); LC-MS m/z 348.2 [M+1]+; mp 270-272℃
Example 11: N1-1,2,3,6-tetrahydropyridine-N5-(3-chloro,4-trifluoromethoxy) phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000017
1H 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 m/z 362.2 [M+1]+; mp 250-252℃
Example 12: N1-1,2-dihydropyrrole-N5-(3-trifluoromethyl)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000018
1H NMR (600 MHz, CD3OD) δ 7.70 (m, 4H), 5.89 (m, 2H), 4.52 (m, 2H), 4.23 (m, 4H); LC-MS m/z 312.2 [M+1]+; mp 156-158℃
Example 13: N1-1,2-dihydropyrrole-N5-(4-trifluoromethyl)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000019
1H 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 m/z 312.2 [M+1]+; mp 268-270℃
Example 14: N1-1,2-dihydropyrrole-N5-(3-trifluoromethoxy)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000020
1H NMR (600 MHz, CD3OD) δ 7.33 (m, 4H), 5.88 (m, 2H), 4.47 (s, 2H), 4.18 (m, 4H); LC-MS m/z 328.2 [M+1]+; mp 218-220℃
Example 15: N1-(3-methyl)-1,2-dihydropyrrole-N5-(4-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000021
1H 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 m/z 328.2 [M+1]+; mp 279-281℃
Example 16: N1-(3-methyl)-1,2-dihydropyrrole-N5-(4-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000022
1H NMR (600 MHz, CD3OD) δ 7.62 (m, 4H), 5.56 (m, 1H), 4.21 (m, 4H), 1.87 (m, 3H); LC-MS m/z 312.2 [M+1]+; mp 272-274℃
Example 17: N1-(3-methyl)-1,2-dihydropyrrole-N5-(4-chloro)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000023
1H 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 m/z 278.2 [M+1]+; mp 264-268℃
Example 18: N1-(3-methyl)-1,2-dihydropyrrole-N5-(4-chloro, 3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000024
1H 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 m/z 346.2 [M+1]+; mp 274-276℃
Example 19: N1-(3-methyl)-1,2-dihydropyrrole-N5-(3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000025
1H 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, 3H); LC-MS m/z 312.2 [M+1]+; mp 282-284℃
Example 20: N1-(3-methyl)-1,2-dihydropyrrole-N5-(4-fluoro)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000026
1H 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 m/z 262.1 [M+1]+; mp 270-272℃
Example 21: N1-(3-methyl)-1,2-dihydropyrrole-N5-(4-bromo)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000027
1H 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 m/z 323.0 [M+1]+; mp 272-274℃
Example 22: N1-(3-methyl)-1,2-dihydropyrrole-N5-(4-methoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000028
1H 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 m/z 274.2 [M+1]+; mp 263-265℃
Example 23: N1-(3-methyl)-1,2-dihydropyrrole-N5-(3,4-dimethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000029
1H 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 m/z 304.2 [M+1]+; mp 261-263℃
Example 24: N1-(3-methyl)-1,2-dihydropyrrole-N5-(4-trifluoromethoxy)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000030
1H 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, 2H), 1.81 (m, 3H); LC-MS m/z 342.2 [M+1]+; mp 184-186℃
Example 25: N1-(3-methyl)-1,2-dihydropyrrole-N5-(3-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000031
1H 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, 3H); LC-MS m/z 328.2 [M+1]+; mp 263-265℃
Example 26: N1-(3-methyl)-1,2-dihydropyrrole-N5-(4-trifluoromethyl)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000032
1H 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, 3H); LC-MS m/z 326.2 [M+1]+; mp 267-269℃
Example 27: N1-(3-methyl)-1,2-dihydropyrrole-N5-(4-chloro, 3-trifluoromethyl)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000033
1H 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, 3H); LC-MS m/z 326.2 [M+1]+; mp 230-232℃
Example 28: N1-1,2,3,6-tetrahydropyridine-N5-(4-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000034
1H 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, 2H); LC-MS m/z 328.1 [M+1]+
Example 29: N1-1,2,3,6-tetrahydropyridine-N5-(4-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000035
1H 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+1]+
Example 30: N1-1,2,3,6-tetrahydropyridine-N5-(3-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000036
1H 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
Figure PCTKR2014001006-appb-I000037
1H 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+1]+
Example 32: N1-1,2,3,6-tetrahydropyridine-N5-(4-fluoro, 3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000038
1H 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, 2H), 2.23 (s, 2H); LC-MS m/z 330.2 [M+1]+
Example 33: N1-1,2,3,6-tetrahydropyridine-N5-(4-chloro, 3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000039
1H 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, 2H), 2.24 (s, 2H); LC-MS m/z 346.0 [M+1]+
Example 34: N1-1,2,3,6-tetrahydropyridine-N5-(3-fluoro, 4-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000040
1H 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, 2H), 2.25 (s, 2H); LC-MS m/z 346.2 [M+1]+
Example 35: N1-1,2,3,6-tetrahydropyridine-N5-(4-chloro)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000041
1H 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, 2H); LC-MS m/z 278.2 [M+1]+
Example 36: N1-1,2,3,6-tetrahydropyridine-N5-(4-bromo)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000042
1H 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, 2H); LC-MS m/z 323.0 [M+1]+
Example 37: N1-1,2,3,6-tetrahydropyridine-N5-(4-fluoro)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000043
1H 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, 2H); LC-MS m/z 262.2 [M+1]+
Example 38: N1-1,2,3,6-tetrahydropyridine-N5-(3,5-dimethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000044
1H 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, 2H), 2.23 (s, 2H); LC-MS m/z 304.2 [M+1]+
Example 39: N1-1,2,3,6-tetrahydropyridine-N5-phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000045
1H 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, 2H); LC-MS m/z 244.2 [M+1]+
Example 40: N1-1,2,3,6-tetrahydropyridine-N5-(4-methoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000046
1H 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, 2H), 2.21 (s, 2H); LC-MS m/z 274.2 [M+1]+
Example 41: N1-1,2,3,6-tetrahydropyridine-N5-(3-methoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000047
1H 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+1]+
Example 42: N1-1,2-dihydropyrrole-N5-(4-methoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000048
1H 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+1]+
Example 43: N1-1,2-dihydropyrrole-N5-(3-methoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000049
1H 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, 3H); LC-MS m/z 260.2 [M+1]+
Example 44: N1-1,2-dihydropyrrole-N5-phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000050
1H 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+1]+
Example 45: N1-1,2-dihydropyrrole-N5-(3,5-dimethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000051
1H 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+1]+
Example 46: N1-1,2-dihydropyrrole-N5-(4-fluoro, 3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000052
1H 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+1]+
Example 47: N1-1,2-dihydropyrrole-N5-(3-fluoro, 4-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000053
1H 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, 3H), 2.22 (s, 2H); LC-MS m/z 316.2 [M+1]+
Example 48: N1-1,2,3,6-tetrahydropyridine-N5-(4-methyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000054
1H 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, 3H), 2.22 (s, 2H); LC-MS m/z 258.2 [M+1]+
Example 49: N1-1,2,3,6-tetrahydropyridine-N5-(3-methyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000055
1H 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, 3H), 2.22 (s, 2H); LC-MS m/z 258.2 [M+1]+
Example 50: N1-1,2-dihydropyrrole-N5-(4-methyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000056
1H 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+1]+
Example 51: N1-1,2-dihydropyrrole-N5-(3-methyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000057
1H 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+1]+
Example 52: N1-1,2-dihydropyrrole-N5-(3-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000058
1H 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
Figure PCTKR2014001006-appb-I000059
1H 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+1]+
Example 54: N1-1,2,3,6-tetrahydropyridine-N5-(4-trifluoromethoxy)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000060
1H 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+1]+
Example 55: N1-1,2,3,6-tetrahydropyridine-N5-(3-trifluoromethoxy)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000061
1H 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+1]+
Example 56: N1-1,2,3,6-tetrahydropyridine-N5-(4-trifluoromethyl)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000062
1H 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+1]+
Example 57: N1-1,2,3,6-tetrahydropyridine-N5-(3-trifluoromethyl)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000063
1H 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+1]+
Example 58: N1-1,2,3,6-tetrahydropyridine-N5-(4-chloro, 3-trifluoromethyl)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000064
1H 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
Figure PCTKR2014001006-appb-I000065
1H 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+1]+
Example 60: N1-1,2,3,6-tetrahydropyridine-N5-propyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000066
1H 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, 2H), 0.95 (m, 3H); LC-MS m/z 210.2 [M+1]+
Example 61: N1-1,2,3,6-tetrahydropyridine biguanide hydrochloride
Figure PCTKR2014001006-appb-I000067
1H 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+1]+
Example 62: Synthesis of N1-(3-methyl)piperidine cyanoguanidine
Figure PCTKR2014001006-appb-I000068
Concentrated hydrochloric acid (0.9 mL, 0.010 mol) was added to a butanol (10 mL) solution containing 3-methylpiperidine (1.00 g, 0.010 mol), and stirred at 0℃ for 30 minutes. Sodium dicyanamide (0.99 g, 0.011 mol) was added to the mixed solution, and the resulting reaction mixture was stirred for 24 hours under reflux.
After completion of the reaction was confirmed, sodium chloride formed by filtering the reaction mixture was removed, and the filtrate was then concentrated at a reduced pressure. Ethyl acetate (10 mL) was then added to the concentrate, and stirred at room temperature for an hour. The formed solid was filtered, and the filtrate was washed with ethyl acetate (2x20 mL). The filtrate was dried at a reduced pressure to obtain a white solid target compound (1.34 g, 80.0%).
1H NMR (600 MHz, CD3OD) δ 3.97 (m, 2H), 2.85 (m, 1H), 2.52 (m, 1H), 1.84 -1.45 (m, 4H), 1.17 (m, 1H), 0.92 (d, 3H)
Example 63: Synthesis of N1-(2-methyl)piperidine cyanoguanidine
Figure PCTKR2014001006-appb-I000069
A white solid target compound (1.0 g, 37%) was prepared in the same manner as in Example 62, except that N1-(2-methyl)piperidine was used instead of the N1-(3-methyl)piperidine used in Example 62.
1H NMR (600 MHz, CD3OD) δ 3.98 (m, 2H), 2.85 (m, 1H), 2.53 (m, 1H), 1.82 (m, 1H), 1.71 (m, 1H), 1.59 (m, 1H), 1.48 (m, 1H), 1.91 (s, 3H); LC-MS m/z 167.2 [M+1]+
Example 64: Synthesis of N1-(2,6-dimethyl)piperidine cyanoguanidine
Figure PCTKR2014001006-appb-I000070
A white solid target compound (0.75 g, 47.2%) was prepared in the same manner as in Example 62, except that N1-(2,6-dimethyl)piperidine was used instead of the N1-(3-methyl)piperidine used in Example 62.
1H NMR (600 MHz, CD3OD) δ 4.31 (s, 2H), 1.85 (m, 1H), 1.70 (m, 4H), 1.50 (m, 1H), 1.48 (d, 6H); LC-MS m/z 181.2 [M+1]+
Example 65: N1-(3-methyl)piperidine-N5-(3-trifluoromethyl)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000071
Concentrated hydrochloric acid (0.24 mL, 2.71 mmol) was added to a butanol (10 mL) solution containing (3-trifluoromethyl)benzylamine (0.28 mL, 1.99 mmol) at room temperature, and then stirred for 30 minutes. The N1-(3-methyl)piperidine cyanoguanidine (300 mg, 1.81 mmol) obtained in Example 1 was added to the reaction mixture, and then stirred for 2 hours under reflux. The reaction mixture was concentrated at a reduced pressure, and ethyl acetate (3 mL) was added to the concentrated reaction mixture. The formed solid was filtered, and the filtrate was then dried at a reduced pressure to obtain a white solid target compound (0.37 g, 54.7%).
1H NMR (600 MHz, CD3OD) δ 7.63 (m, 1H), 7.55 (m, 3H), 4.47 (s, 2H), 3.85 (dd, 2H), 2.86 (t, 1H), 2.54 (m, 1H), 1.80 (m, 1H), 1.67 (m, 1H), 1.56 (m, 1H), 1.47 (m, 1H), 1.17 (q, 1H), 0.85 (d, 3H); LC-MS m/z 342.2 [M+1]+
Target compounds of the following Examples 66 to 98 were prepared in the same manner as in Example 65, except that the cyanoguanidine and amine compounds synthesized in Examples 63 and 64, which corresponded to the target compounds, were used respectively instead of the N1-(3-methyl)piperidine cyanoguanidine synthesized in Example 62 and the (3-trifluoromethyl)benzylamine used in Example 65.
Example 66: N1-(3-methyl)piperidine-N5-(4-chloro)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000072
1H NMR (600 MHz, CD3OD) δ 7.28 (m, 4H), 4.29 (m, 2H), 3.82 (m, 2H), 2.81 (m, 1H), 2.51 (m, 1H), 1.57 (m, 4H), 1.15 (m, 1H) 0.84 (m, 3H); LC-MS m/z 308.2 [M+1]+; mp 256-258℃
Example 67: N1-(3-methyl)piperidine-N5-(4-fluoro)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000073
1H NMR (600 MHz, CD3OD) δ 7.40 (m, 4H), 4.29 (m, 2H), 3.89 (m, 2H), 2.94 (m, 1H), 2.67 (m, 1H), 1.70 (m, 4H), 1.18 (m, 1H) 0.87 (m, 3H); LC-MS m/z 278.2 [M+1]+; mp 265-267℃
Example 68: N1-(3-methyl)piperidine-N5-(4-bromo)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000074
1H NMR (600 MHz, CD3OD) δ 7.36 (m, 2H), 7.06 (m, 2H), 3.89 (m, 2H), 2.89 (m, 1H), 2.61 (m, 1H), 1.66 (m, 4H), 1.17 (m, 1H), 0.86 (m, 3H); LC-MS m/z 339.2 [M+1]+; mp 252-254℃
Example 69: N1-(3-methyl)piperidine-N5-(4-chloro, 3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000075
1H NMR (600 MHz, CD3OD) δ 7.93 (m, 1H), 7.51 (m, 2H), 3.92 (m, 2H), 2.99 (m, 1H), 2.69 (m, 1H), 1.86 (m, 1H), 1.73 (m, 2H), 1.56 (m, 1H), 1.20 (m, 1H), 0.91 (m, 3H); LC-MS m/z 362.2 [M+1]+; mp 230-232℃
Example 70: N1-(3-methyl)piperidine-N5-(3-fluoro, 4-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000076
1H NMR (600 MHz, CD3OD) δ 7.57 (m, 2H), 7.21 (m, 1H), 3.92 (m, 2H), 3.00 (m, 1H), 2.72 (m, 1H), 1.88 (m, 1H), 1.71 (m, 3H), 1.24 (m, 1H), 0.91 (m, 3H); LC-MS m/z 346.2 [M+1]+; mp 228-230℃
Example 71: N1-(3-methyl)piperidine-N5-(4-fluoro, 3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000077
1H NMR (600 MHz, CD3OD) δ 7.85 (m, 2H), 7.60 (m, 1H), 7.29 (t, J = 9.6Hz, 1H), 3.93 (m, 2H), 3.02 (m, 1H), 2.70 (m, 1H), 1.88 (m, 1H), 1.77 (m, 2H), 1.58 (m, 1H), 1.25 (m, 1H), 0.95 (m, 3H); LC-MS m/z 346.2 [M+1]+; mp 243-245℃
Example 72: N1-(2-methyl)piperidine-N5-(4-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000078
1H NMR (600 MHz, CD3OD) δ 7.42 (m, 2H), 7.20 (m, 2H), 4.35 (m, 1H), 3.88 (m, 1H), 3.06 (m, 1H), 1.71 (m, 3H), 1.59 (m, 2H), 1.48 (m, 1H), 1.22 (s, 3H); LC-MS m/z 344.2 [M+1]+; mp 250-252℃
Example 73: N1-(2-methyl)piperidine-N5-(3-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000079
1H NMR (600 MHz, CD3OD) δ 7.52 (m, 1H), 7.37 (m, 1H), 7.25 (m, 1H), 6.96 (m, 1H), 4.41 (m, 1H), 3.91 (m, 1H), 3.13 (m, 1H), 1.74 (m, 3H), 1.64 (m, 2H), 1.51 (m, 1H) 1.26 (m, 3H); LC-MS m/z 344.2 [M+1]+; mp 246-248℃
Example 74: N1-(2-methyl)piperidine-N5-(4-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000080
1H NMR (600 MHz, CD3OD) δ 7.56 (m, 4H), 4.37 (m, 1H), 3.91 (m, 1H), 3.12 (m, 1H), 1.73 (m, 3H), 1.61 (m, 2H), 1.52 (m, 1H) 1.24 (m, 3H); LC-MS m/z 329.2 [M+1]+; mp 252-254℃
Example 75: N1-(3-methyl)piperidine-N5-(3-fluoro, 4-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000081
1H NMR (600 MHz, CD3OD) δ 7.50 (m, 1H), 7.23 (m, 1H), 7.08 (m, 1H), 2.85 (m, 2H), 2.63 (m, 1H), 1.79 (m, 1H), 1.67 (m, 3H), 1.58 (m, 1H), 1.17 (m, 1H), 0.86 (m, 3H); LC-MS m/z 362.2 [M+1]+; mp 243-245℃
Example 76: N1-(2-methyl)piperidine-N5-(3-fluoro, 4-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000082
1H NMR (600 MHz, CD3OD) δ 7.58 (m, 1H), 7.36 (m, 1H), 7.16 (m, 1H), 4.41 (m, 1H), 3.92 (m, 1H), 3.16 (m, 1H), 1.70 (m, 6H) 1.29 (m, 3H); LC-MS m/z 362.0 [M+1]+; mp 241-243℃
Example 77: N1-(2-methyl)piperidine-N5-(4-chloro)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000083
1H NMR (600 MHz, CD3OD) δ 7.30 (m, 4H), 4.36 (m, 1H), 3.89 (m, 1H), 3.10 (m, 1H), 1.61 (m, 5H), 1.49 (m, 1H), 1.25 (m, 3H); LC-MS m/z 294.0 [M+1]+; mp 251-253℃
Example 78: N1-(2-methyl)piperidine-N5-(4-fluoro, 3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000084
1H NMR (600 MHz, CD3OD) δ 7.84 (m, 1H), 7.56 (m, 1H), 7.28 (m, 1H), 4.39 (m, 1H), 3.90 (m, 1H), 3.13 (m, 1H), 1.73 (m, 5H), 1.51 (m, 1H), 1.25 (m, 3H); LC-MS m/z 346.0 [M+1]+; mp 251-253℃
Example 79: N1-(2-methyl)piperidine-N5-(3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000085
1H NMR (600 MHz, CD3OD) δ 7.83 (m, 1H), 7.48 (m, 2H), 7.32 (m, 1H), 4.39 (m, 1H), 3.92 (m, 1H), 3.13 (m, 1H), 1.73 (m, 6H), 1.20 (m, 3H); LC-MS m/z 328.2 [M+1]+; mp 249-251℃
Example 80: N1-(2-methyl)piperidine-N5-(4-chloro, 3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000086
1H NMR (600 MHz, CD3OD) δ 7.83 (m, 1H), 7.95 (m, 1H), 7.51 (m, 2H), 4.38 (m, 1H), 3.91 (m, 1H), 3.12 (m, 1H), 1.60 (m, 6H), 1.20 (m, 3H); LC-MS m/z 362.3 [M+1]+; mp 316-318℃
Example 81: N1-(3-methyl)piperidine-N5-(4-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000087
1H NMR (600 MHz, CD3OD) δ 7.61 (s, 4H), 3.98 (d, 2H), 3.04 (t, 1H), 2.74 (t, 1H), 1.91 (m, 1H), 1.81-1.73 (m, 2H), 1.63 (m, 1H), 1.27 (q, 1H), 0.98 (d, 3H); LC-MS m/z 328.2 [M+1]+
Example 82: N1-(3-methyl)piperidine-N5-(4-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000088
1H NMR (600 MHz, CD3OD) δ 7.46 (m, 2H), 7.22 (m, 2H), 3.94 (d, 2H), 2.97 (t, 1H), 2.67 (t, 1H), 1.86 (m, 1H), 1.76-1.66 (m, 2H), 1.55 (m, 1H), 1.23 (q, 1H), 0.93 (d, 3H); LC-MS m/z 344.2 [M+1]+
Example 83: N1-(3-methyl)piperidine-N5-(3-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000089
1H NMR (600 MHz, CD3OD) δ 7.54 (s, 1H), 7.38 (t, 1H), 7.26 (d, 1H), 6.98 (d, 1H), 3.97 (s, 2H), 3.00 (s, 1H), 2.70 (t, 1H), 1.88 (m, 1H), 1.78-1.71 (m, 2H), 1.59 (m, 1H), 1.24 (q, 1H), 0.91 (d, 3H); LC-MS m/z 344.2 [M+1]+
Example 84: N1-(3-methyl)piperidine-N5-(4-trifluoromethoxy)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000090
1H NMR (600 MHz, CD3OD) δ 7.42 (d, 2H), 7.25 (d, 2H), 4.41 (s, 2H), 3.84 (dd, 2H), 2.85 (t, 1H), 2.52 (t, 1H), 1.82 (m, 1H), 1.66-1.55 (m, 2H), 1.47 (m, 1H), 1.16 (q, 1H), 0.84 (d, 3H); LC-MS m/z 358.2 [M+1]+
Example 85: N1-(3-methyl)piperidine-N5-(4-fluoro, 3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000091
1H NMR (600 MHz, CD3OD) δ 7.84 (dd, 1H), 7.58 (dt, 1H), 7.29 (t, 1H), 3.95 (s, 2H), 2.99 (s, 1H), 2.96 (t, 1H), 1.88 (m, 1H), 1.77 (m, 1H), 1.69 (m, 1H), 1.57 (m, 1H), 1.24 (q, 1H), 0.94 (d, 3H); LC-MS m/z 346.2 [M+1]+
Example 86: N1-(3-methyl)piperidine-N5-(4-trifluoromethyl)benzyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000092
1H NMR (600 MHz, CD3OD) δ 7.64 (d, 2H), 7.51 (d, 2H), 4.47 (s, 2H), 3.84 (dd, 2H), 2.85 (t, 1H), 2.52 (t, 1H), 1.82 (m, 1H), 1.66 (m, 1H), 1.55 (m, 1H), 1.47 (m, 1H), 1.17 (q, 1H), 0.84 (d, 3H); LC-MS m/z 342.2 [M+1]+
Example 87: N1-(3-methyl)piperidine-N5-(4-chloro)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000093
1H NMR (600 MHz, CD3OD) δ 7.35 (m, 4H), 3.96 (m, 2H), 3.00 (m, 1H), 2.67 (m, 1H), 1.89 (m, 1H), 1.68 (m, 3H) 1.24 (m, 1H), 0.94 (m, 3H); LC-MS m/z 294.2 [M+1]+; mp 252-254℃
Example 88: N1-(3-methyl)piperidine-N5-(3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000094
1H NMR (600 MHz, CD3OD) δ 7.86 (m, 1H), 7.55 (d, 1H), 7.48 t, 1H), 7.37 (d, 1H), 3.97 (s, 2H), 3.01 (t, 1H), 2.71 (t, 1H), 1.89 (m, 1H), 1.77(m, 1H), 1.70 (m, 1H), 1.59 (m, 1H), 1.25 (q, 1H), 0.94 (d, 3H); LC-MS m/z 328.2 [M+1]+
Example 89: N1-(2,6-dimethyl)piperidine-N5-(4-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000095
1H NMR (600 MHz, CD3OD) δ 7.46 (d, 2H), 7.23 (d, 2H), 4.60-4.10 (br s, 2H), 1.90-1.51 (m, 6H), 1.30 (s, 6H); LC-MS m/z 358.4 [M+1]+
Example 90: N1-(2,6-dimethyl)piperidine-N5-(3-trifluoromethoxy)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000096
1H NMR (600 MHz, CD3OD) δ 7.54 (s, 1H), 7.37 (t, 1H), 7.25 (d, 1H), 6.97 (d, 1H), 4.60-4.10 (br s, 2H), 1.91-1.52 (m, 6H), 1.31 (s, 6H); LC-MS m/z 358.4 [M+1]+
Example 91: N1-(2,6-dimethyl)piperidine-N5-(4-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000097
1H NMR (600 MHz, CD3OD) δ 7.58 (s, 4H), 4.60-4.10 (br s, 2H), 1.93-1.52 (m, 6H), 1.32 (s, 6H); LC-MS m/z 342.4 [M+1]+
Example 92: N1-(2,6-dimethyl)piperidine-N5-(3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000098
1H NMR (600 MHz, CD3OD) δ 7.87 (s, 1H), 7.54 (d, 1H), 7.48 (t, 1H), 7.36 (d, 1H), 4.60-4.10 (br s, 2H), 1.93-1.52 (m, 6H), 1.37 (s, 6H); LC-MS m/z 342.4 [M+1]+
Example 93: N1-(2,6-dimethyl)piperidine-N5-(4-fluoro, 3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000099
1H NMR (600 MHz, CD3OD) δ 7.83 (, d, 1H), 7.57 (m, 1H), 7.28 (t, 1H), 4.60-4.10 (br s, 2H), 1.93-1.51 (m, 6H), 1.30 (s, 6H); LC-MS m/z 360.4 [M+1]+
Example 94: N1-(2,6-dimethyl)piperidine-N5-(4-chloro, 3-trifluoromethyl)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000100
1H NMR (600 MHz, CD3OD) δ 7.96 (s, 1H), 7.54 (m, 2H), 4.60-4.10 (br s, 2H), 1.93-1.52 (m, 6H), 1.31 (s, 6H); LC-MS m/z 376.4 [M+1]+
Example 95: N1-(2,6-dimethyl)piperidine-N5-(3-fluoro, 4-trifluoromethoxy)phenyl biguanide
Figure PCTKR2014001006-appb-I000101
1H NMR (600 MHz, CD3OD) δ 7.56 (d, 1H), 7.33 (t, 1H), 7.15 (d, 1H), 4.60-4.10 (br s, 2H), 1.93-1.52 (m, 6H), 1.32 (s, 6H); LC-MS m/z 376.4 [M+1]+
Example 96: N1-(2,6-dimethyl)piperidine-N5-(4-chloro)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000102
1H NMR (600 MHz, CD3OD) δ 7.36 (m, 2H), 7.30 (m, 2H), 4.60-4.10 (br s, 2H), 1.92-1.51 (m, 6H), 1.30 (s, 6H); LC-MS m/z 308.2, 310.2 [M+1]+
Example 97: N1-(2,6-dimethyl)piperidine-N5-(4-bromo)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000103
1H NMR (600 MHz, CD3OD) δ 7.45 (d, 2H), 7.31 (d, 2H), 4.60-4.10 (br s, 2H), 1.93-1.51 (m, 6H), 1.30 (s, 6H); LC-MS m/z 353.2 [M+1]+
Example 98: N1-(2,6-dimethyl)piperidine-N5-(4-fluoro)phenyl biguanide hydrochloride
Figure PCTKR2014001006-appb-I000104
1H NMR (600 MHz, CD3OD) δ 7.37 (m, 2H), 7.05 (m, 2H), 4.60-4.10 (br s, 2H), 1.88-1.50 (m, 6H), 1.29 (s, 6H); LC-MS m/z 292.1 [M+1]+
[EXPERIMENTAL EXAMPLES]
The compounds synthesized by the methods described in the examples of the present invention were evaluated for effects of AMPK activation and inhibition of cancer cell proliferation according to methods described in the following Experimental Examples.
Experimental Example 1: Measurement of AMPK activation effect
MCF7 cells derived from human breast cancer cells (purchased from the Korean Cell Line Bank (KCLB)) were used, and AMPK activation effects of the biguanide derivatives were confirmed using an AMPK [pT172] ELISA kit (Invitrogen, Catalog No. KHO0651).
MCF7 cells were cultured in a DMEM medium supplemented with 10% fatal bovine serum (commercially available from Gibco Life Technologies (US)). Thereafter, the cultured MCF7 cells were put into a 6-well plate with approximately 5x105 cells per well, and cultured in an incubator supplied with 5% CO2. Culture media were treated with the derivatives synthesized in the Examples at concentrations of 5, 10 and 50ｕM, and then cultured for 24 hours. Metformin was used as the control, and the culture media were treated with 0.05, 0.5, 1, 2, 5 and 10 mM metformin and then tested in the same manner as described for the derivatives synthesized in the Examples. Subsequently, the cells were lysed according to a method presented in the operation manual of the AMPK [pT172] ELISA kit, and 20㎍ of a cell lysate was then yielded through protein assay. Thereafter, the AMPK activation effect was obtained by determining a degree of phosphorylation of a 172nd threonine residue (Thr172) of the AMPKα from the cell lysate according to the method presented in the operation manual of the AMPK [pT172] ELISA kit. A degree of AMPK activation by the biguanide derivatives was exhibited as a degree of AMPKα phosphorylation in cells cultured in the presence of the compounds synthesized in the Examples with respect to a degree of AMPKα phosphorylation in cells cultured without treatment with the biguanide derivatives. A curve graph showing AMPK activation according to the concentration of the treated compounds was plotted based on the obtained AMPK activation results, and a concentration (activation concentration 150, AC150) value of a compound whose AMPK activation reached 150% was calculated using a GraphPad Prism 5.0 program. Similarly, degrees of AMPK activation when the concentrations of the treated biguanide derivatives of Examples 4 to 61 were 10μM and 50μM are listed in the following Table 1, and degrees of AMPK activation when the concentrations of the treated biguanide derivatives of Examples 65 to 98 were 5μM to 10μM are listed in the following Table 2. Some of the compounds were not measurable for AMPK activation due to cytotoxicity when the concentrations of the treated compounds were 50μM.
[Corrected under Rule 26 17.02.2014]
Figure WO-DOC-TABLE-1
Table 2
Figure PCTKR2014001006-appb-T000002
Experimental Example 2: Measurement of effect of inhibiting cancer cell proliferation
HCT116 cells derived from human colorectal cancer were used, and an effect of inhibiting cancer cell proliferation of the biguanide derivative was confirmed by measuring a concentration value (cell growth inhibition concentration, GIC50) at which cell growth was inhibited by 50% using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reagent.
First, HCT116 cells (purchased from the KCLB) were put on a 96-well plate and cultured in a DMEM medium supplemented with 10% fatal bovine serum (commercially available from Gibco Life Technologies (US)) for 16 hours so that approximately 5,000 cells were counted in each well. Subsequently, to obtain the GIC50 value of each compound, the culture media were treated with 100μM, 25μM, 6.25μM, 1.56μM or 0.39μM of the compound, and then cultured for 48 hours. In order to determine whether the cells survived after treatment with the compounds, MTT (commercially available from AMRESCO (US)) was added to the culture media which were then cultured for another 3 hours. Formed formazane crystals were dissolved using dimethyl sulfoxide (DMSO) and the absorbance of the resulting solution was measured at 560 nm. After the 48-hour culture, a ratio of a living cell count on a well plate treated with the compounds synthesized in the Examples to a cell count cultured on a well plate not treated with the compound was indicated as cell viability (%) according to the concentration of each treated compound. The cell viability (%) was used to plot a cell viability curve graph and calculate a concentration (GIC50) value of the compound at which the growth was inhibited by 50%, thereby confirming the inhibition effect of cancer cell proliferation. Also, the cell growth inhibitions (%) when the concentration of the treated biguanide derivative and metformin as the control was 100μM (Examples 4 to 61) is listed in the following Table 3, and the cell growth inhibitions (%) when the concentration of the treated biguanide derivative and metformin as the control was 25μM (Examples 65 to 98) are listed in the following Table 4.
[Corrected under Rule 26 17.02.2014]
Figure WO-DOC-TABLE-3
[Corrected under Rule 26 17.02.2014]
Figure WO-DOC-TABLE-4

Claims (20)

  1. A compound of following Formula 1 or a pharmaceutically acceptable salt thereof:
    [Formula 1]
    Figure PCTKR2014001006-appb-I000105
    wherein R1 and R2 are taken together with nitrogen to which they are attached to form C3-6 heterocycloalkene having 4 to 7 ring atoms; or C3-6 heterocycloalkyl having 4 to 7 ring atoms; and
    R3 is hydrogen; C1-6 alkyl; phenyl; or C1-4 alkyl substituted with phenyl,
    wherein the C3-6 heterocycloalkene and the C3-6 heterocycloalkyl are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, hydroxy and C1-6 alkyl,
    the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.
  2. The compound of Formula 1 or the pharmaceutically acceptable salt thereof of claim 1,
    wherein R1 and R2 are taken together with nitrogen to which they are attached to form C4-5 heterocycloalkene having 5 to 6 ring atoms or C4-5 heterocycloalkyl having 5 to 6 ring atoms; and
    R3 is hydrogen; C1-6 alkyl; phenyl; or C1-2 alkyl substituted with phenyl,
    wherein the C4-5 heterocycloalkene is unsubstituted or substituted with C1-6 alkyl,
    the C4-5 heterocycloalkyl is substituted with 1 to 4 C1-6 alkyl groups, and
    the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.
  3. The compound of Formula 1 or the pharmaceutically acceptable salt thereof of claim 1,
    wherein R1 and R2 are taken together with nitrogen to which they are attached to form C4-5 heterocycloalkene having 5 to 6 ring atoms or C4-5 heterocycloalkyl having 5 to 6 ring atoms; and
    R3 is hydrogen; C1-6 alkyl; phenyl; or C1-2 alkyl substituted with phenyl,
    wherein the C4-5 heterocycloalkene is unsubstituted or substituted with C1-2 alkyl,
    the C4-5 heterocycloalkyl is substituted with one or two C1-2 alkyl groups, and
    the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, C1-2 alkoxy, C1-2 haloalkyl, and C1-2 haloalkoxy.
  4. The compound of Formula 1 or the pharmaceutically acceptable salt thereof of claim 1,
    wherein R1 and R2 are taken together with nitrogen to which they are attached to form C3-6 heterocycloalkene selected from the group consisting of dihydroazetinyl; dihydropyrrolinyl; dihydropyridinyl; and tetrahydropyridinyl, or R1 and R2 are taken together with nitrogen to which they are attached to form C3-6 heterocycloalkyl selected from the group consisting of azetidinyl; piperidinyl; and pyrrolidinyl; and
    R3 is hydrogen; C1-6 alkyl; phenyl; or C1-4 alkyl substituted with phenyl,
    wherein the C3-6 heterocycloalkene is unsubstituted or substituted with C1-6 alkyl,
    the C3-6 heterocycloalkyl is substituted with 1 to 4 C1-6 alkyl groups, and
    the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.
  5. The compound of Formula 1 or the pharmaceutically acceptable salt thereof of claim 1,
    wherein R1 and R2 are taken together with nitrogen to which they are attached to form dihydropyrrolinyl or tetrahydropyridinyl which is unsubstituted or substituted with C1-4 alkyl, or R1 and R2 are taken together with nitrogen to which they are attached to form piperidinyl or pyrrolidinyl which is substituted with C1-4 alkyl in at least one position thereof; and
    R3 is hydrogen; C1-6 alkyl; phenyl; or C1-4 alkyl substituted with phenyl,
    wherein the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy.
  6. The compound of Formula 1 or the pharmaceutically acceptable salt thereof of claim 1,
    wherein R1 and R2 are taken together with nitrogen to which they are attached to form dihydropyrrolinyl or tetrahydropyridinyl which is unsubstituted or substituted with C1-2 alkyl, or R1 and R2 are taken together with nitrogen to which they are attached to form piperidinyl or pyrrolidinyl which is substituted with one or two C1-2 alkyl groups; and
    R3 is hydrogen; C3-6 alkyl; phenyl; or C1-2 alkyl substituted with phenyl,
    wherein the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, C1-2 alkoxy, C1-2 haloalkyl, and C1-2 haloalkoxy.
  7. The compound of Formula 1 or the pharmaceutically acceptable salt thereof of claim 1,
    wherein R1 and R2 are taken together with nitrogen to which they are attached to form dihydropyrrolinyl or tetrahydropyridinyl which is unsubstituted or substituted with methyl, or R1 and R2 are taken together with nitrogen to which they are attached to form piperidine; and
    R3 is hydrogen; butyl; propyl; hexyl; phenyl; or methyl substituted with phenyl,
    wherein the piperidine is substituted with one or two methyl groups in at least one of positions 2, 3, 5 and 6, and
    the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, methoxy, trihalomethyl, and trihalomethoxy.
  8. The compound of Formula 1 or the pharmaceutically acceptable salt thereof of claim 1, wherein the compound of Formula 1 is
    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;
    N1-1,2,3,6-tetrahydropyridine biguanide;
    N1-(3-methyl)piperidine-N5-(3-trifluoromethyl)benzyl biguanide;
    N1-(3-methyl)piperidine-N5-(4-chloro)benzyl biguanide;
    N1-(3-methyl)piperidine-N5-(4-fluoro)phenyl biguanide;
    N1-(3-methyl)piperidine-N5-(4-bromo)phenyl biguanide;
    N1-(3-methyl)piperidine-N5-(4-chloro, 3-trifluoromethyl)phenyl biguanide;
    N1-(3-methyl)piperidine-N5-(3-fluoro, 4-trifluoromethyl)phenyl biguanide;
    N1-(3-methyl)piperidine-N5-(4-fluoro, 3-trifluoromethyl)phenyl biguanide;
    N1-(2-methyl)piperidine-N5-(4-trifluoromethoxy)phenyl biguanide;
    N1-(2-methyl)piperidine-N5-(3-trifluoromethoxy)phenyl biguanide;
    N1-(2-methyl)piperidine-N5-(4-trifluoromethyl)phenyl biguanide;
    N1-(3-methyl)piperidine-N5-(3-fluoro, 4-trifluoromethoxy)phenyl biguanide;
    N1-(2-methyl)piperidine-N5-(3-fluoro, 4-trifluoromethoxy)phenyl biguanide;
    N1-(2-methyl)piperidine-N5-(4-chloro)phenyl biguanide;
    N1-(2-methyl)piperidine-N5-(4-fluoro, 3-trifluoromethyl)phenyl biguanide;
    N1-(2-methyl)piperidine-N5-(3-trifluoromethyl)phenyl biguanide;
    N1-(2-methyl)piperidine-N5-(4-chloro, 3-trifluoromethyl)phenyl biguanide;
    N1-(3-methyl)piperidine-N5-(4-trifluoromethyl)phenyl biguanide;
    N1-(3-methyl)piperidine-N5-(4-trifluoromethoxy)phenyl biguanide;
    N1-(3-methyl)piperidine-N5-(3-trifluoromethoxy)phenyl biguanide;
    N1-(3-methyl)piperidine-N5-(4-trifluoromethoxy)benzyl biguanide;
    N1-(3-methyl)piperidine-N5-(4-fluoro, 3-trifluoromethyl)phenyl biguanide;
    N1-(3-methyl)piperidine-N5-(4-trifluoromethyl)benzyl biguanide;
    N1-(3-methyl)piperidine-N5-(4-chloro)phenyl biguanide;
    N1-(3-methyl)piperidine-N5-(3-trifluoromethyl)phenyl biguanide;
    N1-(2,6-dimethyl)piperidine-N5-(4-trifluoromethoxy)phenyl biguanide;
    N1-(2,6-dimethyl)piperidine-N5-(3-trifluoromethoxy)phenyl biguanide;
    N1-(2,6-dimethyl)piperidine-N5-(4-trifluoromethyl)phenyl biguanide;
    N1-(2,6-dimethyl)piperidine-N5-(3-trifluoromethyl)phenyl biguanide;
    N1-(2,6-dimethyl)piperidine-N5-(4-fluoro, 3-trifluoromethyl)phenyl biguanide;
    N1-(2,6-dimethyl)piperidine-N5-(4-chloro, 3-trifluoromethyl)phenyl biguanide;
    N1-(2,6-dimethyl)piperidine-N5-(3-fluoro, 4-trifluoromethoxy)phenyl biguanide;
    N1-(2,6-dimethyl)piperidine-N5-(4-chloro)phenyl biguanide;
    N1-(2,6-dimethyl)piperidine-N5-(4-bromo)phenyl biguanide; and
    N1-(2,6-dimethyl) -N5-(4-fluoro)phenyl biguanide.
  9. The compound of Formula 1 or the pharmaceutically acceptable salt thereof of claim 1,
    wherein the pharmaceutically acceptable salt is a salt with an acid 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, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzensulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxy acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, and boric acid.
  10. A method of preparing a compound of following Formula 1, comprising:
    reacting a compound of the following Formula 2 with a dicyanamide in an organic solvent to obtain a compound of the following Formula 3; and
    reacting the compound of the following Formula 3 with a compound of Formula 4 in an organic solvent to obtain the compound of the following Formula 1:
    [Formula 1]
    Figure PCTKR2014001006-appb-I000106
    [Formula 2]
    Figure PCTKR2014001006-appb-I000107
    [Formula 3]
    Figure PCTKR2014001006-appb-I000108
    [Formula 4]
    Figure PCTKR2014001006-appb-I000109
    wherein R1 and R2 are taken together with nitrogen to which they are attached to form C3-6 heterocycloalkene having 4 to 7 ring atoms or C3-6 heterocycloalkyl having 4 to 7 ring atoms; and
    R3 is hydrogen; C1-6 alkyl; phenyl; or C1-4 alkyl substituted with phenyl,
    wherein the C3-6 heterocycloalkene and the C3-6 heterocycloalkyl are each independently unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, hydroxyl, and C1-6 alkyl, and
    the phenyl is unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy.
  11. A pharmaceutical composition for preventing and treating a cancer, comprising the compound of Formula 1 or the pharmaceutically acceptable salt thereof defined in any one of claims 1 to 9 as an active ingredient.
  12. The pharmaceutical composition of claim 11, wherein the treatment of the cancer includes inhibition of recurrence or metastasis of cancer.
  13. The pharmaceutical composition of claim 11, wherein the cancer is a disease selected from the group consisting of uterine cancer, breast cancer, gastric cancer, brain cancer, rectal cancer, colorectal cancer, lung cancer, skin cancer, blood cancer, pancreatic cancer, prostate cancer, and liver cancer.
  14. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is formulated as a tablet, a capsule, a pill, a granule, a powder, an injection or a liquid.
  15. A use of a compound of Formula 1 or the pharmaceutically acceptable salt thereof defined in any one of claims 1 to 9 in prepararion of a medicine for preventing or treating a cancer.
  16. The use of the compound of Formula 1 or the pharmaceutically acceptable salt thereof of claim 15, wherein the treatment of the cancer includes inhibition of recurrence or metastasis of cancer.
  17. The use of the compound of Formula 1 or the pharmaceutically acceptable salt thereof of claim 15, wherein the cancer is a disease selected from the group consisting of uterine cancer, breast cancer, gastric cancer, brain cancer, rectal cancer, colorectal cancer, lung cancer, skin cancer, blood cancer, pancreatic cancer, prostate cancer, and liver cancer.
  18. A method of preventing or treating a cancer, comprising:
    administering a therapeutically effective amount of the compound of Formula 1 or the pharmaceutically acceptable salt thereof defined in any one of claims 1 to 9 to a subject.
  19. The method of claim 18, wherein the treatment of the cancer includes inhibition of recurrence or metastasis of cancer.
  20. The method of claim 18, wherein the cancer is a disease selected from the group consisting of uterine cancer, breast cancer, gastric cancer, brain cancer, rectal cancer, colorectal cancer, lung cancer, skin cancer, blood cancer, pancreatic cancer, prostate cancer, and liver cancer.
PCT/KR2014/001006 2013-02-07 2014-02-06 N1-cyclic amine-n5-substituted biguanide derivatives, methods of preparing the same and pharmaceutical composition comprising the same Ceased WO2014123364A1 (en)

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