Biguanide derivative, a preparation method thereof and a pharmaceutical composition containing the biguanide derivative as an active ingredient
A biguanide derivative compound with N1-N5 substitution, which is represented by Formula 1, or a pharmaceutically acceptable salt thereof, a method of preparing the same, and a pharmaceutical composition containing the same as an active ingredient are provided. The biguanide derivative may exhibit excellent effect on activation of AMPKα and inhibition of cancer cell proliferation in a low dose, compared to conventional drugs, and thus, may be useful to treat diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovarian syndrome, metabolic syndrome, cancer, etc.
1. A compound of Formula 1 or a pharmaceutically acceptable salt thereof:
wherein R 1 is unsubstituted C 1-7 alkyl; C 1-4 alkyl substituted with C 5-12 aryl; or C 5-12 aryl,
R 2 is hydrogen; or unsubstituted C 1-7 alkyl,
R 3 is hydrogen; or C 5-12 aryl,
R 4 is a non-hydrogen substituent selected from the group consisting of unsubstituted C 6-7 alkyl; C 1-4 alkyl substituted with at least one non-hydrogen substituent selected from the group consisting of C 5-12 heteroaryl and C 1-4 alkoxycarbonyl; unsubstituted C 5-7 cycloalkyl; C 5-12 aryl; and C 5-12 heteroaryl, and
the aryl and heteroaryl may be unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of C 1-4 alkoxy, hydroxyl and halogen, and the aryl and heteroaryl may be selected from the group consisting of phenyl, pyridinyl, furanyl and isoquinolinyl.
2. A compound of Formula 1 or a pharmaceutically acceptable salt thereof:
wherein the compound of Formula 1 is N1-hexyl-N5-propyl biguanide; N1-hexyl-N5-cyclopropylmethyl biguanide; N1-hexyl-N5-cyclohexylmethyl biguanide; N1-hexyl-N5-benzyl biguanide; N1,N5-bis(4-chlorophenyl)biguanide; N1,N5-bis(3-chlorophenyl)biguanide; N1-(4-chloro)phenyl-N5-(4-methoxy)phenyl biguanide; N1,N5-bis(3-chloro-4-methoxyphenyl)biguanide; N1,N5-bis(3,4-dichlorophenyl)biguanide; N1,N5-bis(3,5-dichlorophenyl)biguanide; N1,N5-bis(4-bromophenyl)biguanide; N1-benzyl-N5-(pyridine-3-yl)methyl biguanide; N1-(phenethyl)-N5-propyl biguanide; N1-(phenethyl)-N5-cyclopropylmethyl biguanide; N1-(phenethyl)-N5-cycloheptyl biguanide; N1,N1-dimethyl-N5-methoxycarbonylethyl biguanide; N1,N1-dimethyl-N5-cycloheptyl biguanide; N1,N1-dimethyl-N5-cyclopropylmethyl biguanide; N1,N1-dimethyl-N5-(4-bromo)phenyl biguanide; N1,N1-dimethyl-N5-(furan-2-yl)methyl biguanide; N1,N1-dimethyl-N5-(pyridine-3-yl)methyl biguanide; N1,N1-diethyl-N5-(3-chloro)phenyl biguanide; N1,N1-dipropyl-N5-(3-chloro)phenyl biguanide; N1,N1-(ethyl)(propyl)-N5-(4-chloro)phenyl biguanide; N1,N1-dipropyl-N5-(isoquionline-5-yl)biguanide; N1,N1-dihexyl-N5-(3-chloro)phenyl biguanide; N1,N1,N5,N5-tetraethyl biguanide; N1,N1-diethyl-N5,N5-(cyclohexyl)(methyl)biguanide; N1,N1-dipropyl-N5,N5-diethyl biguanide; N1,N1-dipropyl-N5,N5-(methyl)(phenethyl)biguanide; or N1,N1-dipropyl-N5,N5-(4-hydroxylphenyl)(phenyl)biguanide.
3. The compound or a 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, isobutyic 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, anthranyl acid, benzensulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxy acetic acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and boric acid.
4. A compound of Formula 1 or a pharmaceutically acceptable salt thereof:
wherein the compound of Formula 1 is N1-hexyl-N5-benzyl biguanide.
5. The compound or a pharmaceutically acceptable salt thereof of claim 2 , 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, isobutyic 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, anthranyl acid, benzensulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxy acetic acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and boric acid.
6. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.
7. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to claim 2 as an active ingredient.
8. A method of preparing a compound of Formula 1, comprising:
reacting a compound of Formula 2 with dicyanoamide in at least one organic solvent to obtain a compound of Formula 3; and
reacting the compound of Formula 3 with a compound of Formula 4 in at least one organic solvent to obtain the compound of Formula 1:
wherein R 1 is unsubstituted C 1-7 alkyl; C 1-4 alkyl substituted with C 5-12 aryl; or C 5-12 aryl,
R 2 is hydrogen; or unsubstituted C 1-7 alkyl,
R 3 is hydrogen; or C 5-12 aryl,
R 4 is a non-hydrogen substituent selected from the group consisting of unsubstituted C 6-7 alkyl; C 1-4 alkyl substituted with at least one non-hydrogen substituent selected from the group consisting of C 5-12 heteroaryl and C 1-4 alkoxycarbonyl; unsubstituted C 5-7 cycloalkyl; C 5-12 aryl; and C 5-12 heteroaryl, and
the aryl and heteroaryl may be unsubstituted or substituted with at least one non-hydrogen substituent selected from the group consisting of C 1-4 alkoxy, hydroxyl and halogen, and the aryl and heteroaryl may be selected from the group consisting of phenyl, pyridinyl, furanyl and isoquinolinyl.