KR101994145B1 - Pharmaceutical composition comprising n1-cyclic amine-n5-substituted biguanide derivatives as an ingredient for preventing or treating jet-lag syndrom - Google Patents

Abstract

The present invention provides a new use of N1-ring amine-N5-substituted-biguanide derivatives for the preparation of medicines for the prevention or treatment of sleep disorders. The composition for preventing or treating sleep disorders according to the present invention can effectively control the sleep disorder by controlling the biorhythmic cycle through an excellent activation effect on AMPK.
[Chemical Formula 1]

Description

[0001] PHARMACEUTICAL COMPOSITION COMPRISING N1-CYCLIC AMINE-N5-SUBSTITUTED BIGUANIDE DERIVATIVES AS AN INGREDIENT FOR PREVENTING OR TREATING JET -LAG SYNDROM}

The present invention relates to a novel use of N1-ring amine-N5-substituted biguanide derivatives for the preparation of medicines for the prevention or treatment of parallax syndrome.

A biological clock is a biological clock which is a functioning organ responsible for periodic rhythms such as diverse physiological, metabolism, development, behavior, and aging of plants and animals. The biological clock of life on earth shows a cycle rhythm of about 24 hours. In mammals, the optic nerve crossing superior nucleus (SCN) in the anterior hypothalamus is the main biological clock region (Panda et al., (2002) Nature 417, 329-335; Reppert, SM and Weaver, DR (1997) Cell, 89, 487 -490). SCN clocks are directly or indirectly 24 hours a day by day-night cycles by light acting through the retinal-SCN pathway (Klein, DC et al. (1991) Suprachiasmatic Nuclei: The Mind's Clock, Oxford Univeristy Press, New York). Within the cell, the biological clock operates by causing the expression of genes regulated by the biological clock and the biological clock to vibrate in a cycle of one day by a transcription translation feedback loop (TTFL) interlocking. CLOCK and BMAL1 bind to the E-box (CACGTG), which is known to begin by moving the circadian locomotor output cycles (CLUT) and BMAL1 (brain and muscle ARNT-like protein 1) Per1 / 2 and Cry1 / 2 genes. The expressed PER1 / 2 And CRY1 / 2 inhibits CLOCK and BMAL1 activity, thereby returning to the starting point. Based on stimuli by an external clock and information of the internal biological clock, SCN produces an integrated time signal and adjusts the peripheral clock in each body part.

Meanwhile, it is known that the wave of the biorhythm, that is, the rhythm does not occur even when the wave is too large, is known to regulate the biorhythm by weakening the wave of the rhythm in which the PER and CRY are excessively amplified. Specifically, PER1, PER2, and CRY1 and CRY2 are negative regulators that inhibit the amplification of biorhythm. They form a negative feedback loop that inhibits CLOCK and BMAL1 from binding to E-box to regulate the transcriptional activity of clock proteins, This again induces the expression of Per genes or genes (Shearman, LP et al. (1997) Neuron 19, 1261-1269). Through such a series of periodic reactions, the human 's biorhythm is maintained. If the control of the biological clock is broken by external stimuli, it can affect physiological phenomena in the body.

AMP-activated protein kinase (AMPK), on the other hand, is known as an 'energy sensor' to detect intracellular energy deficiency. Previous studies have shown that metformin, known as a representative AMPK activator, induces CKIε-dependent degradation of mPER2, a biological clock protein, which in turn affects biological rhythm (Jee Hyun Um, et al., The Journal of Biological Chemistry, vol 282, No. 29, pp. 20794-20798). According to the results of the study, casein kinase Iε (CKIε), one of the regulators of the cycle length of the biorhythm, phosphorylates the biological clock component mPer2 and induces its degradation, shortening the cycle length of the biorhythm, AMPK phosphorylates Ser-389 of CKIε, increasing the activity of CKIε and promoting the degradation of mPer2 by proteasome. It has also been reported that activated AMPK directly induces F-box and leucine-rich repeat protein 3 (FBXL3), known as the E3 ubiquitin ligase, by phosphorylating Ser-71 of CRY1 (see Lamia et al , Science, vol 325 N0.326, pp 437).

Jet lag syndrome is a syndrome caused by the inactivity of biorhythm that is maintained by a sudden change of time, which occurs when passing several time periods over a short period of time. The term parallax syndrome is the first in 1931 when Post and Gatty first described the symptoms of flight attendants and passengers. When the parallax syndrome is common, there are many times when the flight time changes more than when the flight time is long. There may also be differences in symptoms depending on the flight direction. For example, when an airplane moves in the landscape (east-west direction) rather than in the vertical direction (north-south direction), it gets worse and moves to the east (toward Japan) It is known to occur well. Even though the distance is the same, traveling to the east is getting worse because the time delay of the human biological clock is much slower than slowing it down. Symptoms of parallax syndrome include 24-hour periodic rhythm sleep disorder, tiredness, decreased concentration, memory impairment, decreased vitality, slowed reflexes, headache, dizziness, and digestive dysfunction. There have been many research efforts to develop drugs that can alleviate parallax syndrome by appropriately controlling the biological clock, but only melatonin, which is an effective component of the sleep inducer, has been developed as a practical adaptation drug.

24-hour periodic rhythm sleep disorders include airway parallax sleep disorder, shift sleep disorder, progressive sleep disorder, delayed sleep disorder (see J. Wagner, ML Wagner and WA Hening, Annals of Pharmacotherapy (1998) 32, 680-691 ) And the like. In forced depression, individuals explain that they are more likely to be awake when viewed as a percentage of sleep time in a particular period of the 24-hour periodic day (Dijk and Lockley, J. Appl. Physiol. (2002) 92, 852- 862). It is generally recognized that our 24-hour periodic rhythm of sleep is progressive as we age and it is common for sleep quality to decline (see Am J Physiol Endocrinol Metab. (2002) 282, E297-E303). Thus, the sleep that occurs outside the 24-hour periodicity can be both quantitatively and qualitatively painful, for example, due to shifts in sleep due to shift work and airplane parallax. Disruptions in human 24-hour periodic clocks cause sleep disturbances, and substances that regulate 24-hour periodic rhythmicity, such as CKIε and / or CKIδ activators or inhibitors, are helpful in treating sleep disorders, especially 24-hour periodic sleep disorders .

The present invention relates to a compound capable of activating AMPK, which can find a drug that can participate in the regulation of biorhythm and provides a new use of these drugs for use as an active ingredient of medicines for the prevention or treatment of parallax syndrome do.

The present invention relates to a novel use of a N1-ring amine-N5-substituted bi-guanidine derivative compound of the formula 1 for the preparation of a medicament for the prevention or treatment of parallax syndrome, a novel use of N1- A pharmaceutical composition for the prevention or treatment of parallax syndrome comprising a biguanide derivative compound as an active ingredient; And a method of preventing or treating parallax syndrome comprising administering to a subject an N1-ring amine-N5-substituted bi-guanidine derivative compound of Formula 1:

[Chemical Formula 1]

In this formula,

R ₁ and R ₂ are C ₃ together with the nitrogen to which they are connected and _- forming an ₈ heterocycloalkyl, and

R ₃ It is C _{3 - 7} cycloalkyl; C _{3 - 12} aryl; Is _{6-alkyl, -} C _{3 - 12} aryl or C _{3 - 12} substituted with a heteroaryl or unsubstituted C ₁ ring

Here, C _{3 - 8} heterocycloalkyl, C _{3 - 7} cycloalkyl, C _{3 - 12} aryl or C _{3 -} one selected from the group consisting of _4-alkoxy-12 heteroaryl group is halogen, C _{1 - 4} alkyl and C ₁ Or more of the non-hydrogen substituent group, and the non-hydrogen substituent group is further substituted or unsubstituted by halogen.

In the present specification,

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

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

&Quot; Hydroxy " represents -OH.

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

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

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

&Quot; Heterocycloalkyl " refers to a bicyclic and bicyclic hydrocarbon ring in which at least one of the cyclic atoms of the cycloalkyl is composed of elements other than carbon, including heteroatoms, i.e., nitrogen, oxygen or sulfur. Heterocycloalkyl can be attached to a parent group or substrate at any ring atom provided that attachment does not violate the atomic requirement. Likewise, a heterocycloalkyl group may contain one or more non-hydrogen substituents if the attachment does not violate the valence requirements. Examples of heterocycloyl groups include, without limitation, aziridine, azetidine, imidazolyl, pyrroyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, indolyl, indolinyl, and the like .

&Quot; Aryl " refers to a monocyclic or bicyclic aromatic group, and examples of "aryl" groups include phenyl, naphthyl, anthryl and the like. The "aryl" group may be attached to a parent group or substrate at any ring atom provided that attachment does not violate the valence requirements. Likewise, an "aryl" group may include one or more non-hydrogen substituents provided that the substitution does not violate the valence requirements.

&Quot; Heteroaryl " means an aromatic heterocycle of 5 to 10 atoms, including both a ring and a bicyclic ring system. &Quot; Heteroaryl " means that one to four heteroatoms independently selected from nitrogen, oxygen and sulfur are replaced with carbon atoms. Examples of "heteroaryl" groups include, but are not limited to, furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, Pyrimidinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, carbazolyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, triazinyl, phthalazinyl, quinolinyl , Indolyl, benzofuranyl, purinyl, and indolizinyl.

In one embodiment,

R ₁ and R ₂ are C ₃ together with the nitrogen to which they are connected and _- forming an ₈ heterocycloalkyl, and

R ₃ It is C _{3 - 7} cycloalkyl; C _{3 - 12} aryl; Is _{6-alkyl, -} C _{3 - 12} aryl or C _{3 - 12} substituted with a heteroaryl or unsubstituted C ₁ ring

Here, C _{3 - 8} heterocycloalkyl, C _{3 - 7} cycloalkyl, C _{3 - 12} aryl or C _{3 -} one selected from the group consisting of _4-alkoxy-12 heteroaryl group is halogen, C _{1 - 4} alkyl and C ₁ Or more of the non-hydrogen substituent group is unsubstituted or substituted with at least one non-hydrogen substituent group,

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

The C _{3 - 12} heteroaryl is Daily furanyl, thiophenyl, pyridinyl, pyrrolyl, imidazolyl or pyrimidine.

In other embodiments,

R ₁ and R ₂ C ₃ is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholine yl, piperazinyl, and the group consisting of azepanyl, together with the nitrogen that is associated with these _- to form a ₆ membered heterocycloalkyl, and ,

R ₃ It is C _{4 - 7} cycloalkyl; C _{3 - 12} aryl; Is _{4-alkyl, -} C _{3 - 12} aryl or C _{3 - 12} substituted with a heteroaryl or unsubstituted C ₁ ring

Here, C _{3 - 8} heterocycloalkyl, C _{3 - 7} cycloalkyl, C _{3 - 12} aryl or C _{3 -} one selected from the group consisting of _4-alkoxy-12 heteroaryl group is halogen, C _{1 - 4} alkyl and C ₁ Or more, and the non-hydrogen substituent may be further substituted or unsubstituted with halogen.

In another embodiment,

R ₁ and R ₂ C ₃ is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholine yl, piperazinyl, and the group consisting of azepanyl, together with the nitrogen that is associated with these _- to form a ₆ membered heterocycloalkyl Lt; / RTI &

R ₃ It is C _{4 - 7} cycloalkyl; It is selected from phenyl or naphthalenyl C _{3 - 12} aryl; Phenyl, naphthalenyl, furanyl, thiophenyl, pyridinyl, pyrrolyl, and C ₃ is already selected from the group consisting of days _imidazole-12 aryl or C _{3 - 12} substituted with a heteroaryl or unsubstituted C ₁ ring _{- 4} alkyl ,

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

In another embodiment,

R ₁ and R ₂ together with the nitrogen that is associated with these T azepin morpholinyl, pyrrolidinyl, piperidinyl each optionally substituted and selected from the group consisting of azepanyl C ₃ is ₆ intended to form a heterocycloalkyl,

R ₃ It is a C _{5 - 7} cycloalkyl; Phenyl; And _{2-alkyl-substituted} phenyl or thiophen-day or unsubstituted C ₁ ring

Phenyl is halogen, C _{1 - 4} alkyl and C _{1 -} be substituted by one or more non-hydrogen substituents selected from the group consisting of _4-alkoxy or is unsubstituted, and the non-hydrogen substituents or further substituted with a halogen unsubstituted .

In another embodiment,

R ₁ and R ₂ together with the nitrogen that is associated with these T azepin morpholinyl, pyrrolidinyl, piperidinyl each optionally substituted and selected from the group consisting of azepanyl C ₃ is ₆ intended to form a heterocycloalkyl,

R ₃ Is halogen, C _{1 - 2} alkyl and C _{1 -} substituted with one or more non-hydrogen substituents selected from the group consisting of a _2-alkoxy or unsubstituted and unsubstituted phenyl, wherein the non-hydrogen substituents or further substituted by halogen may be one which is unsubstituted .

In another embodiment,

R ₁ and R ₂ together with the nitrogen that is associated with these T azepin morpholinyl, pyrrolidinyl, piperidinyl each optionally substituted and selected from the group consisting of azepanyl C ₃ is ₆ intended to form a heterocycloalkyl,

R ₃ And _{2-alkyl, -} is a substituted C ₁ day phenyl or thiophene

Said phenyl being halogen, C _{1 -} be substituted by one or more non-hydrogen substituents selected from the group consisting of a _2-alkoxy or will unsubstituted, wherein the non-hydrogen substituents or further substituted with a halogen _{unsubstituted-2} alkyl and C ₁ .

In another embodiment,

R ₁ and R ₂ together with the nitrogen that is associated with these T azepin morpholinyl, pyrrolidinyl, piperidinyl each optionally substituted and selected from the group consisting of azepanyl C ₃ is ₆ intended to form a heterocycloalkyl,

R ₃ It is C _{6 -} may be a _{2-alkyl-7-cycloalkyl} or unsubstituted C _1.

In another embodiment,

R ₁ and R ₂ together with the nitrogen that is associated with these T azepin morpholinyl, pyrrolidinyl, piperidinyl each optionally substituted and selected from the group consisting of azepanyl C ₃ is ₆ intended to form a heterocycloalkyl,

R ₃ Is cyclohexyl, cycloheptyl, phenyl, benzyl, phenethyl, thiophenyethyl or methyl,

Wherein the phenyl, benzyl or phenethyl is unsubstituted or substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, methyl, ethyl, methoxy, trifluoromethyl, difluoromethoxy and trifluoromethoxy .

The compound of formula (1)

N1-piperidin-5-phenylbiguanide; N1-piperidin-N5- (3-methyl) phenylbaiguanide; N1-piperidin-N5- (3-ethyl) phenylbaiguanide; N1-piperidin-N5- (3-methoxy) phenylbaiguanide; N1-piperidine-N5- (4-fluoro) phenylbaiguanide; N1-piperidine-N5- (3-fluoro) phenylbaiguanide; N1-Pyrrolidine-N5- (4-chloro) phenylbaiguanide; N1-piperidin-N5- (4-chloro) phenylbaiguanide; N1-piperidin-N5- (3-bromo) phenylbaiguanide; N1-Pyrrolidine-N5- (3-chloro) phenylbaiguanide; N1-piperidin-N5- (3-chloro) phenylbaiguanide; N1-azepan-N5- (3-chloro) phenylbaiguanide; N1-pyrrolidin-N5- (3-trifluoromethyl) phenylbaiguanide; N1-piperidin-N5- (3-trifluoromethyl) phenylbaiguanide; N1-pyrrolidine-N5- (4-trifluoromethyl) phenylbaiguanide; N1-piperidin-N5- (4-trifluoromethyl) phenylbaiguanide; N1-Pyrrolidin-N5- (3-trifluoromethoxy) phenylbaiguanide; N1-piperidin-N5- (3-trifluoromethoxy) phenylbaiguanide; N1-piperidin-N5- (3-difluoromethoxy) phenylbaiguanide; N1-Pyrrolidine-N5- (4-trifluoromethoxy) phenylbaiguanide; N1-piperidin-N5- (4-trifluoromethoxy) phenylbaiguanide; N1-Piperidin-N5- (4-fluoro-3-trifluoromethyl) phenylbaiguanide; N1-piperidine-N5- (4-chloro-3-trifluoromethyl) phenylbaiguanide; N1-Pyrrolidine-N5- (3-fluoro-4-trifluoromethyl) phenylbaiguanide; N1-Piperidine-N5- (3-fluoro-4-trifluoromethyl) phenylbaiguanide; N1-Piperidin-N5- (4-chloro-3-trifluoromethoxy) phenylbaiguanide; N1-azetidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide; N1-Pyrrolidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide; N1-Piperidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide; N1-azetidine-N5- (3-chloro-4-trifluoromethoxy) phenylbaiguanide; N1-Pyrrolidine-N5- (3-chloro-4-trifluoromethoxy) phenylbaiguanide; N1-Piperidin-N5- (3-chloro-4-trifluoromethoxy) phenylbaiguanide; N1-piperidin-N5- (3,4-difluoro) phenylbaiguanide; N1-piperidin-N5- (3,5-difluoro) phenylbaiguanide; N1-Piperidin-N5- (3,5-dichloro) phenylbaiguanide; N1-Pyrrolidin-N5- (3,4-dichloro) phenylbaiguanide; N1-piperidine-N5- (3,4-dichloro) phenylbaiguanide; N1-piperidin-N5- (3-chloro-5-trifluoromethoxy) phenylbaiguanide; N1-Pyrrolidine-N5- (3-bromo-5-trifluoromethoxy) phenylbaiguanide; N1-piperidine-N5- (3-bromo-5-trifluoromethoxy) phenylbaiguanide; N1-piperidin-N5- (3,4,5-trifluoro) phenylbaiguanide; N1-pyrrolidine-N5- (4-trifluoromethyl) phenylbaiguanide; N1-piperidin-N5- (4-trifluoromethyl) phenylbaiguanide; N1-Pyrrolidine-N5- (4-trifluoromethoxy) phenylbaiguanide; N1-piperidin-N5- (4-trifluoromethoxy) phenylbaiguanide; N1-Pyrrolidine-N5- (3-fluoro-4-trifluoromethyl) phenylbaiguanide; N1-Piperidine-N5- (3-fluoro-4-trifluoromethyl) phenylbaiguanide; N1-Pyrrolidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide; N1-Piperidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide; N1-piperidin-N5- (3-trifluoromethyl) benzylbaiguanide; N1-piperidin-5-methylbiguanide; N1-piperidin-5-cyclohexylbaiguanide; N1-pyrrolidine-N5-cycloheptylbaiguanide; N1-piperidin-5-cycloheptylbaiguanide; N1-azepan-N5-cycloheptylbaiguanide; N1-piperidin-N5- (4-methyl) benzylbaiguanide; N1-piperidin-N5- (4-methoxy) benzylbaiguanide; N1-Pyrrolidine-N5- (4-chloro) benzylbaiguanide; N1-azepan-N5- (4-chloro) benzylbaiguanide; N1-Piperidin-N5- (4-trifluoromethyl) benzylbaiguanide; N1-azetidine-N5- (4-trifluoromethoxy) benzylbaiguanide; N1-Pyrrolidine-N5- (4-trifluoromethoxy) benzylbaiguanide; N1-piperidine-N5- (4-trifluoromethoxy) benzylbaiguanide; N1-piperidine-N5- (4-fluoro-3-trifluoromethyl) benzylbaiguanide; N1-piperidin-N5- (4-chloro-3-trifluoromethyl) benzylbaiguanide; N1-piperidin-N5- (3-fluoro-4-trifluoromethyl) benzylbaiguanide; N1-piperidin-N5- (3-chloro-4-trifluoromethyl) benzylbaiguanide; N1-Piperidine-N5- (4-fluoro-3-trifluoromethoxy) benzylbaiguanide; N1-Piperidin-N5- (3-chloro-4-trifluoromethoxy) benzylbaiguanide; N1-piperidin-N5- (2,6-difluoro) benzylbaiguanide; N1-piperidin-N5- (3,4-difluoro) benzylbaiguanide; N1-piperidin-N5- (2,4-dichloro) benzylbaiguanide; N1-Pyrrolidine-N5- (3,4-dichloro) benzylbaiguanide; N1-Piperidin-N5- (3,4-dichloro) benzylbaiguanide; N1-piperidin-N5- (thiophen-2-yl) ethylbiguanide; N1-pyrrolidin-N5- (phenethyl) < / RTI > N1-piperidin-N5- (phenethyl) < / RTI > N1-azepan-N5- (phenethyl) < / RTI > N1-azepan-N5- ((4-fluoro) phenethyl) veguanide or N1-azepan-N5- ((4-chloro) phenethyl) veguanide.

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

In one embodiment, the pharmaceutically acceptable salts of the compounds of formula (I) above are in the form of their salts with formic, acetic, propionic, lactic, butyric, isobutyric, trifluoroacetic, malic, maleic, malonic, Amide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxyacetic acid, It may be a salt with an acid selected from the group consisting of sulfuric acid, phosphoric acid, nitric acid, carbonic acid and boric acid.

As shown in the following examples, the compound of formula (I) or a pharmaceutically acceptable salt thereof exhibits an excellent AMPKa activation effect, and by this, the expression cycle of Per2 is changed to effectively advance the biological clock, Or can be used therapeutically.

Accordingly, the present invention also relates to a pharmaceutical composition for preventing or treating parallax syndrome comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutical composition for preventing or treating paralytic syndrome, Or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined hereinbefore in the manufacture of a medicament for the prevention or treatment of parallax syndrome.

In one embodiment, the parallax syndrome comprises one or more symptoms selected from the group consisting of a 24-hour periodic rhythm sleep disorder, fatigue, decreased concentration, decreased appetite, depression, memory impairment, slowed motor function, headache, .

The 24-hour periodic rhythm sleep disorder may be selected from the group consisting of, for example, alternating sleep sleep disorder, plane parallax sleep disorder, progressive sleep phase syndrome, and delayed sleep phase syndrome.

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

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

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

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

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

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

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

The composition for preventing or treating parallax syndrome according to the present invention can effectively control the symptom according to the parallax syndrome by controlling the biological rhythm cycle through an excellent activation effect on AMPK.

1 shows the effect of AMPK activation by the biguanide derivative, metformin, and an inert compound of Example 44. Fig.
Fig. 2 shows the change in the expression cycle of Per2 gene by the biguanide derivative of Example 44. Fig.
Fig. 3 shows the change of Per2 gene expression cycle by metformin.
FIG. 4 shows changes in the expression period of Per2 gene by an inactive compound.
Figure 5 shows the effect of metformin, a biguanide derivative and an inert compound on the coordination of 6 hour phase shift.

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

[ Example ]

The following compounds synthesized in the manner described in Korean Patent Application No. 10-2012-0086996 and 10-2012-0086999 were tested for the AMPKa activation effect, the effect on Per2 expression and the phase shift acceleration according to the method described in the following test examples The effect on

Test Example  One: AMPK α activation effect measurement

MCF7 cells derived from human breast cancer cells were used and the effect of 5'-AMP-activated protein kinase alpha (AMPKα) activation by a biguanide derivative was confirmed using AMPKα immunoassay kit (Invitrogen, catalog No. KHO0651).

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

The results are shown in Table 1 below.

Example Compound name AMPK  Activation effect AC150
( uM ) 10 uM
(%) 50 uM
(%) Metformin 188.3 130.0 One N1-piperidin-5-phenyl < / RTI >
N - ( N- phenylcarbamimidoyl) piperidine-1-carboximidamide hydrochloride 10.1 347 2 N1-Piperidine-N5- (3-methyl) phenylbaiguanide hydrochloride
N - ( N - m- toluylcarbamimidoyl) piperidine-1-carboximidamide hydrochloride 12.4 149 255 3 N1-Piperidin-N5- (3-ethyl) phenylbaiguanide hydrochloride
N - ( N - (3-ethylphenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 7.3 178 598 4 N1-Piperidine-N5- (3-methoxy) phenylbaiguanide hydrochloride
N - ( N- (3-methoxyphenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 16.0 97 300 5 N1-Piperidine-N5- (4-fluoro) phenylbaiguanide hydrochloride
N - ( N- (4-fluorophenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 4.0 204 429 6 N1-Piperidin-N5- (3-fluoro) phenylbaiguanide hydrochloride
N - ( N- (3-fluorophenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 9.9 378 7 N1-Pyrrolidine-N5- (4-chloro) phenylbaiguanide hydrochloride
N - ( N- (4-chlorophenyl) carbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 8.4 167 512 8 N1-Piperidine-N5- (4-chloro) phenylbaiguanide hydrochloride
N - ( N- (4-chlorophenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 3.4 281 9 N1-Piperidine-N5- (3-bromo) phenylbaiguanide hydrochloride
N - ( N- (3-bromophenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 0.9 526 10 N1-Pyrrolidine-N5- (3-chloro) phenylbaiguanide hydrochloride
N - ( N- (3-chlorophenyl) carbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 4.4 176 586 11 N1-Piperidine-N5- (3-chloro) phenylbaiguanide hydrochloride
N - ( N- (3-chlorophenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 3.2 236 558 12 N1-azepan-N5- (3-chloro) phenylbaiguanide hydrochloride
N - ( N- (3-chlorophenyl) carbamimidoyl) azepane-1-carboximidamide hydrochloride 4.8 211 653 13 N1-Pyrrolidine-N5- (3-Trifluoromethyl) phenylbaiguanide hydrochloride
N - ( N- (3- (trifluoromethyl) phenyl) carbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 4.4 199 578 14 N1-Piperidine-N5- (3-Trifluoromethyl) phenylbaiguanide hydrochloride
N - ( N- (3- (trifluoromethyl) phenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 2.6 388 15 N1-Pyrrolidine-N5- (4-Trifluoromethyl) phenylbaiguanide hydrochloride
N - ( N- (4- (trifluoromethyl) phenyl) carbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 3.1 255 642 16 N1-Piperidine-N5- (4-Trifluoromethyl) phenylbaiguanide hydrochloride
N - ( N- (4- (trifluoromethyl) phenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 2.4 455 17 N1-Pyrrolidine-N5- (3-Trifluoromethoxy) phenylbaiguanide hydrochloride
N - ( N- (3- (trifluoromethoxy) phenyl) carbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 6.9 158 424 18 N1-Piperidine-N5- (3-Trifluoromethoxy) phenylbaiguanide hydrochloride
N - ( N- (3- (trifluoromethoxy) phenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 1.1 400 19 N1-Piperidine-N5- (3-dibromomethoxy) phenylbaiguanide hydrochloride
N - ( N- (3- (difluoromethoxy) phenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 6.4 187 636 20 N1-Pyrrolidine-N5- (4-Trifluoromethoxy) phenylbaiguanide hydrochloride
N - ( N- (4- (trifluoromethoxy) phenyl) carbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 5.1 204 680 21 N1-Piperidine-N5- (4-Trifluoromethoxy) phenylbaiguanide hydrochloride
N - ( N- (4- (trifluoromethoxy) phenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 1.4 538 22 N1-Piperidine-N5- (4-fluoro-3-trifluoromethyl) phenylbaiguanide hydrochloride
N - ( N- (4-fluoro-3- (trifluoromethyl) phenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 1.3 261 23 N1- piperidine-N5- (4-chloro-3-trifluoromethyl) phenylbaiguanide hydrochloride
N - (N - (4- chloro-3- (trifluoromethyl) phenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 7.3 169 24 N1-Pyrrolidine-N5- (3-fluoro-4-trifluoromethyl) phenylbaiguanide hydrochloride
N - ( N- (3-fluoro-4- (trifluoromethyl) phenyl) carbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 2.5 299 25 N1-Piperidine-N5- (3-fluoro-4-trifluoromethyl) phenylbaiguanide hydrochloride
N - ( N- (3-fluoro-4- (trifluoromethyl) phenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 2.7 258 26 N1-Piperidine-N5- (4-chloro-3-trifluoromethoxy) phenylbaiguanide hydrochloride
N - ( N - (4-chloro-3- (trifluoromethoxy) phenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 7.8 160 27 N1-azetidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide hydrochloride
N - ( N- (3-fluoro-4- (trifluoromethoxy) phenyl) carbamimidoyl) azetidine-1-carboximidamide hydrochloride 3.3 265 740 28 N1-Pyrrolidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide hydrochloride
N - ( N - (3-fluoro-4- (trifluoromethoxy) phenyl) carbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 5.0 315 29 N1-Piperidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide hydrochloride
N - ( N- (3-fluoro-4- (trifluoromethoxy) phenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 0.5 400 30 N1-azetidine-N5- (3-chloro-4-trifluoromethoxy) phenylbaiguanide hydrochloride
N - (N - (3- chloro-4- (trifluoromethoxy) phenyl) carbamimidoyl) azetidine-1-carboximidamide hydrochloride 2.6 342 31 N1-Pyrrolidine-N5- (3-chloro-4-trifluoromethoxy) phenylbaiguanide hydrochloride
N - (N - (3- chloro-4- (trifluoromethoxy) phenyl) carbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 2.0 367 32 N1-Piperidine-N5- (3-chloro-4-trifluoromethoxy) phenylbaiguanide hydrochloride
N - (N - (3- chloro-4- (trifluoromethoxy) phenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 3.2 345 33 N1-Piperidine-N5- (3,4-difluoro) phenylbaiguanide hydrochloride
N - ( N- (3,4-difluorophenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 3.6 269 1036 34 N1-Piperidine-N5- (3,5-difluoro) phenylbaiguanide hydrochloride
N - ( N- (3,5-difluorophenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 8.2 144 576 35 N1-Piperidine-N5- (3,5-dichloro) phenylbaiguanide hydrochloride
N - ( N- (3,5-dichlorophenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 3.3 239 36 N1-Pyrrolidine-N5- (3,4-dichloro) phenylbaiguanide hydrochloride
N - ( N- (3,4-dichlorophenyl) carbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 6.2 261 37 N1-Piperidine-N5- (3,4-dichloro) phenylbaiguanide hydrochloride
N - ( N- (3,4-dichlorophenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 0.7 442 38 N1-Piperidine-N5- (3-chloro-5-trifluoromethoxy) phenylbaiguanide hydrochloride
N - (N - (3- chloro-5- (trifluoromethoxy) phenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 5.0 39 N1-Pyrrolidine-N5- (3-Bromo-5-trifluoromethoxy) phenylbaiguanide hydrochloride
N - ( N- (3-bromo-5- (trifluoromethoxy) phenyl) carbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 5.0 521 40 N1-Piperidine-N5- (3-bromo-5-trifluoromethoxy) phenylbaiguanide hydrochloride
N - ( N- (3-bromo-5- (trifluoromethoxy) phenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 5.0 41 N1-Piperidine-N5- (3,4,5-Trifluoro) phenylbaiguanide hydrochloride
N - ( N- (3,4,5-trifluorophenyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 7.2 197 42 N1-Pyrrolidine-N5- (4-Trifluoromethyl) phenylbaiguanide Acetate
N - ( N- (4- (trifluoromethyl) phenyl) carbamimidoyl) pyrrolidine-1-carboximidamide acetate 2.0 554 43 N1-Piperidine-N5- (4-trifluoromethyl) phenylbaiguanide acetic acid salt
N - ( N- (4- (trifluoromethyl) phenyl) carbamimidoyl) piperidine-1-carboximidamide acetate 2.3 313 44 N1-Pyrrolidine-N5- (4-Trifluoromethoxy) phenylbaiguanide Acetate
N - ( N- (4- (trifluoromethoxy) phenyl) carbamimidoyl) pyrrolidine-1-carboximidamide acetate 4.6 186 938 45 N1-piperidin-N5- (4-trifluoromethoxy) phenylbaiguanide acetic acid salt
N - ( N- (4- (trifluoromethoxy) phenyl) carbamimidoyl) piperidine-1-carboximidamide acetate 0.3 270 747 46 N1-Pyrrolidine-N5- (3-fluoro-4-trifluoromethyl) phenylbaiguanide acetic acid salt
N - ( N- (3-fluoro-4- (trifluoromethyl) phenyl) carbamimidoyl) pyrrolidine-1-carboximidamide acetate 3.4 461 47 N1-Piperidine-N5- (3-fluoro-4-trifluoromethyl) phenylbaiguanide acetic acid salt
N - ( N- (3-fluoro-4- (trifluoromethyl) phenyl) carbamimidoyl) piperidine-1-carboximidamide acetate 2.0 710 48 N1-Pyrrolidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide acetic acid salt
N - ( N- (3-fluoro-4- (trifluoromethoxy) phenyl) carbamimidoyl) pyrrolidine-1-carboximidamide acetate 1.3 341 49 N1-Piperidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide acetic acid salt
N - ( N- (3-fluoro-4- (trifluoromethoxy) phenyl) carbamimidoyl) piperidine-1-carboximidamide acetate 0.9 607 50 N1-Piperidine-N5- (3-Trifluoromethyl) benzylbaiguanide hydrochloride
N - ( N- (3- (trifluoromethyl) benzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 1.0 582 677 51 N1-piperidin-5-methylbiguanide hydrochloride
N - ( N- methylcarbamimidoyl) piperidine-1-carboximidamide hydrochloride 9.0 139 500 52 N1-Piperidin-N5-cyclohexylbaiguanide hydrochloride
N - ( N- cyclohexylcarbamimidoyl) piperidine-1-carboximidamide hydrochloride 8.0 167 486 53 N1-Pyrrolidine-N5-cycloheptylbaiguanide hydrochloride
N - ( N -cycloheptylcarbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 7.9 149 612 54 N1-piperidin-5-cycloheptylbaiguanide hydrochloride
N - ( N -cycloheptylcarbamimidoyl) piperidine-1-carboximidamide hydrochloride 2.2 304 719 55 N1-Azepan-N5-cycloheptylbaiguanide hydrochloride
N - ( N -cycloheptylcarbamimidoyl) azepane-1-carboximidamide hydrochloride 5.6 213 325 56 N1-Piperidine-N5- (4-methyl) benzylbaiguanide hydrochloride
N - ( N- (4-methylbenzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 2.3 435 947 57 N1-Piperidine-N5- (4-methoxy) benzylbaiguanide hydrochloride
N - ( N- (4-methoxybenzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 3.9 258 628 58 N1-Pyrrolidine-N5- (4-chloro) benzylbaiguanide hydrochloride
N - ( N- (4-chlorobenzyl) carbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 2.3 304 776 59 N1-azepan-N5- (4-chloro) benzylbau nide hydrochloride
N - ( N- (4-chlorobenzyl) carbamimidoyl) azepane-1-carboximidamide hydrochloride 1.2 443 60 N1-Piperidine-N5- (4-trifluoromethyl) benzylbaiguanide hydrochloride
N - ( N- (4- (trifluoromethyl) benzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 0.9 476 615 61 N1-Azetidine-N5- (4-trifluoromethoxy) benzylbaiguanide hydrochloride
N - ( N- (4- (trifluoromethoxy) benzyl) carbamimidoyl) azetidine-1-carboximidamide hydrochloride 3.9 673 1076 62 N1-Pyrrolidine-N5- (4-Trifluoromethoxy) benzylbaiguanide hydrochloride
N - ( N- (4- (trifluoromethoxy) benzyl) carbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 0.9 242 698 63 N1-Piperidine-N5- (4-trifluoromethoxy) benzylbaiguanide hydrochloride
N - ( N- (4- (trifluoromethoxy) benzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 0.8 472 554 64 N1-Piperidine-N5- (4-fluoro-3-trifluoromethyl) benzylbaiguanide hydrochloride
N - ( N- (4-fluoro-3- (trifluoromethyl) benzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 10.3 180 383 65 N1-Piperidine-N5- (4-chloro-3-trifluoromethyl) benzylbaiguanide hydrochloride
N - ( N- (4-chloro-3- (trifluoromethyl) benzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 1.7 162 232 66 N1-Piperidine-N5- (3-fluoro-4-trifluoromethyl) benzylbaiguanide hydrochloride
N - ( N- (3-fluoro-4- (trifluoromethyl) benzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 1.1 331 389 67 N1-Piperidine-N5- (3-chloro-4-trifluoromethyl) benzylbaiguanide hydrochloride
N - (N - (3- chloro-4- (trifluoromethyl) benzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 4.4 433 384 68 N1-Piperidine-N5- (4-fluoro-3-trifluoromethoxy) benzylbaiguanide hydrochloride
N - ( N- (4-fluoro-3- (trifluoromethoxy) benzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 18.2 244 69 N1-Piperidine-N5- (3-chloro-4-trifluoromethoxy) benzylbaiguanide hydrochloride
N - ( N- (3-chloro-4- (trifluoromethoxy) benzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 8.8 259 70 N1-Piperidine-N5- (2,6-difluoro) benzylbaiguanide hydrochloride
N - ( N- (2,6-difluorobenzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 2.1 179 71 N1-Piperidine-N5- (3,4-difluoro) benzylbaiguanide hydrochloride
N - ( N- (3,4-difluorobenzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 3.8 327 703 72 N1-Piperidine-N5- (2,4-dichloro) benzylbaiguanide hydrochloride
N - ( N- (2,4-dichlorobenzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 3.5 238 831 73 N1-Pyrrolidine-N5- (3,4-dichloro) benzylbaiguanide hydrochloride
N - ( N- (3,4-dichlorobenzyl) carbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 0.8 315 74 N1-Piperidine-N5- (3,4-dichloro) benzylbaiguanide hydrochloride
N - ( N- (3,4-dichlorobenzyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 0.9 443 830 75 N1-Piperidin-N5- (thiophen-2-yl) ethylbaiguanide hydrochloride
N - ( N- (2- (thiophen-2-yl) ethyl) carbamimidoyl) piperidine-1-carboximidamide hydrochloride 9.0 612 76 N1-Pyrrolidin-N5- (phenethyl) valguanide hydrochloride
N - ( N- phenethylcarbamimidoyl) pyrrolidine-1-carboximidamide hydrochloride 8.1 391 77 N1-Piperidin-N5- (phenethyl) < / RTI >
N - ( N- phenethylcarbamimidoyl) piperidine-1-carboximidamide hydrochloride 6.4 167 388 78 N1-azepan-N5- (phenethyl) < / RTI > biguanide hydrochloride
N - ( N- phenethylcarbamimidoyl) azepane-1-carboximidamide hydrochloride 0.7 194 373 79 N1-azepan-N5- ((4-fluoro) phenethyl) valguanide hydrochloride
N - ( N- (4-fluorophenethyl) carbamimidoyl) azepane-1-carboximidamide hydrochloride 0.7 744 721 80 N1-azepan-N5- ((4-chloro) phenethyl) veguanide hydrochloride
N - ( N- (4-chlorophenethyl) carbamimidoyl) azepane-1-carboximidamide hydrochloride 0.5 1130

Test Example  2: Western blot  through AMPK  Observation of activation pattern

The AMPK activating effect was confirmed in Test Example 1, and the compound of Example 44 was selected from among the iguanide derivatives to observe the AMPK activation pattern through Western blotting. As a positive control, metformin, an AMPK activator, was used. As a negative control, an inactive compound (N1-piperidin-N5- (4- (1H-tetra 5-yl)) phenylbaiguanide hydrochloride) was used.

Fibroblast cells (NIH3T3) were plated in 6-well plates in a DMEM medium containing 10% calf serum at a concentration of about 1.5 × 10 ⁵ cells. Cells were incubated for about 24 hours in a 5% CO _2- , And the derivatives were treated with 0.31, 0.62, 1.25, 2.5, 5, 10 or 20 uM. The drug-treated cells were treated in an incubator at 37 ° C for 4 hours. The cell lysate was then confirmed by Western blotting. The concentration of metformin, a positive control, was treated with 0.125, 0.25, 0.5, 1, 2, 4, and 8 mM, which were known to be effective concentrations, and treated with the same concentration as the barguanide derivative that did not activate AMPK as a negative control.

As a result, as shown in Fig. 1, the biguanide derivative induced activation of AMPK to a degree similar to that of metformin at a concentration about 100 to 1000 times lower than that of metformin, and the compound used as a negative control group had an AMPK activation effect .

Test Example  3: Bar iguanade  By a derivative Per2  Change in expression pattern

The effect of a compound of biguanide derivatives on the expression pattern of Per2, a biorhythm-related gene, was examined.

The embryonic fibroblasts were cultured in DMEM medium supplemented with 10% calf serum. The cells were seeded at 6 × 10 ⁵ cells / ml and cultured at 37 ° C. in an incubator supplemented with 5% CO ₂ After 24 hours, the Per2 gene was treated with the retrovirus with luciferase and the cells were cultured for 24 hours in the incubator. Thereafter, dexamethasone, which induces cell synchronization for 2 hours, is treated with 0.31, 0.62, 1.25, 2.5, 5. 10, or 20 uM of biaguanide derivative 2 hours later and at the same time activates luciferase I replaced it with a medium containing luciferin. Then, the expression of Per2 promoter with luciferase in real time was observed for 72 hours using ATTO Kronos machine. As a result, as shown in Fig. 2, the Per2 gene expression cycle was shortened by about 0.5 hour to 1 hour in proportion to the concentration of the biguanide derivative. In particular, the group treated with 2 mM of metformin (FIG. 3) showed a shorter Per2 gene expression cycle to that of the group treated with 3.3 uM of the biguanide derivative, which was not observed by the inactive compound as a negative control (FIG. 4 ).

As in Test Example 2, it was confirmed that the biaguanide derivative can reduce the cycle of Per2, a biorhythm regulating gene, at a concentration lower than that of metformin by about 500 times or less.

Test Example  4: Bar iguanade  Accelerates phase shift by derivatives

To investigate the effect of the biguanide derivatives on the vital rhythm, the changes in the activity of the rats were investigated. The phase shift of 6 hours was performed after about 10 days of entrainment (L: D = 12 hours: 12 hours). Since the phase shift rate may vary from time to time for each individual, the first 6-hour phase shifting step was compared with the 6-hour phase shift after several days without water treatment . The first phase shift was synchronized and a second 6 hour phase shift phase was performed after about 10 days. At this time, instead of the first water, metformin, a biguanide derivative and an inert compound were added to the water. Metformin was dissolved in water at a dose of 300 mg / kg / day, with a biguanide derivative and an inert compound at a dose of 100 mg / kg / day, taking into account the amount of water the rat consumes per day (about 4.5 ml). We then looked at how much time each of the drugs dosed to 6 hour phase shifting compared to the results from the first 6 hour phase shift.

As a result, in the first 6-hour phase shift as shown in Fig. 5, all groups were synchronized over about 5 days. In the second 6-hour phase shift, the mice to which the biguanide derivatives were administered matched faster than the metampin-treated rats as the control. Positive control rats dosed with metformin were synchronized to phase shift over approximately 5 days, while rats receiving the experimental group, the biguanide derivative, were synchronized to a 6 hour phase shift within approximately 3 days. In the case of the inactive compound as the negative control group, the phase shift of the photoperiod was about 5 days to be synchronized with the positive control group.

As in the above Test Examples 1 and 2, it was found that the biguanide derivative controls the biological clock gene more rapidly at a concentration about 500 times lower than that of the control group, metformin, and also affects the behavior of the rat as shown in Fig. 3 . That is, it is shown that the bio-clock cycle can induce faster synchronization when a 6-hour phase shift occurs due to the biguanide derivative.

Claims (13)

1. A pharmaceutical composition for preventing or treating parallax syndrome comprising an N1-ring amine-N5-substituted bi-guanidine derivative represented by the following formula (1) as an active ingredient,
[Chemical Formula 1]

In this formula,
R ₁ and R ₂ together with the nitrogen connected thereto form C _3-8 heterocycloalkyl,
R ₃ is C _3-7 cycloalkyl; C _3-12 aryl; A substituted or unsubstituted C _1-6 alkyl C _3-12 aryl or C _3-12 heteroaryl,
_Wherein C _3-8 heterocycloalkyl, C _3-7 cycloalkyl, C _3-12 aryl or C _3-12 heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, C _1-4 alkyl and C _1-4 alkoxy Or more of the non-hydrogen substituent group is unsubstituted or substituted with at least one non-hydrogen substituent group,
Wherein the parallax syndrome has symptoms of 24-hour periodic rhythm sleep disorder.
The method according to claim 1,
R ₁ and R ₂ are C ₃ together with the nitrogen to which they are connected and _- forming an ₈ heterocycloalkyl, and
R ₃ It is C _{3 - 7} cycloalkyl; C _{3 - 12} aryl; Is _{6-alkyl, -} C _{3 - 12} aryl or C _{3 - 12} substituted with a heteroaryl or unsubstituted C ₁ ring
Here, C _{3 - 8} heterocycloalkyl, C _{3 - 7} cycloalkyl, C _{3 - 12} aryl or C _{3 -} one selected from the group consisting of _4-alkoxy-12 heteroaryl group is halogen, C _{1 - 4} alkyl and C ₁ Or more of the non-hydrogen substituent group is unsubstituted or substituted with at least one non-hydrogen substituent group,
The C _{3 - 12} aryl is phenyl or naphthalenyl,
The C _{3 - 12} heteroaryl is furanyl, thiophenyl, pyridinyl, pyrrolyl, imidazolyl or pyrimidine-day a pharmaceutical composition.
The method according to claim 1,
R ₁ and R ₂ C ₃ is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholine yl, piperazinyl, and the group consisting of azepanyl, together with the nitrogen that is associated with these _- to form a ₆ membered heterocycloalkyl, and ,
R ₃ It is C _{4 - 7} cycloalkyl; C _{3 - 12} aryl; Is _{4-alkyl, -} C _{3 - 12} aryl or C _{3 - 12} substituted with a heteroaryl or unsubstituted C ₁ ring
Here, C _{3 - 8} heterocycloalkyl, C _{3 - 7} cycloalkyl, C _{3 - 12} aryl or C _{3 -} one selected from the group consisting of _4-alkoxy-12 heteroaryl group is halogen, C _{1 - 4} alkyl and C ₁ Hydrogen substituent, wherein the non-hydrogen substituent is further substituted or unsubstituted by halogen.
The method according to claim 1,
R ₁ and R ₂ C ₃ is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholine yl, piperazinyl, and the group consisting of azepanyl, together with the nitrogen that is associated with these _- to form a ₆ membered heterocycloalkyl Lt; / RTI &
R ₃ It is C _{4 - 7} cycloalkyl; It is selected from phenyl or naphthalenyl C _{3 - 12} aryl; Phenyl, naphthalenyl, furanyl, thiophenyl, pyridinyl, pyrrolyl, and C ₃ is already selected from the group consisting of days _imidazole-12 aryl or C _{3 - 12} substituted with a heteroaryl or unsubstituted C ₁ ring _{- 4} alkyl ,
Here, C _{3 - 12} aryl or C _{3 - 12} heteroaryl group is halogen, C _{1 - 4} alkyl and C _{1 -} substituted with one or more non-hydrogen substituents selected from the group consisting of _4-alkoxy or is unsubstituted, and the non-hydrogen substituents Is further substituted or unsubstituted with halogen.
The method according to claim 1,
R ₁ and R ₂ together with the nitrogen that is associated with these T azepin morpholinyl, pyrrolidinyl, piperidinyl each optionally substituted and selected from the group consisting of azepanyl C ₃ is ₆ intended to form a heterocycloalkyl,
R ₃ It is a C _{5 - 7} cycloalkyl; Phenyl; A substituted or unsubstituted C _1-2 alkyl days phenyl or thiophene,
Phenyl is halogen, C _{1 - 4} alkyl and C _{1 -} being substituted with one or more non-hydrogen substituents selected from the group consisting of _4-alkoxy or unsubstituted and ring, the non-hydrogen substituents are optionally substituted further by halogen, ≪ / RTI >
The method according to claim 1,
R ₁ and R ₂ together with the nitrogen that is associated with these T azepin morpholinyl, pyrrolidinyl, piperidinyl each optionally substituted and selected from the group consisting of azepanyl C ₃ is ₆ intended to form a heterocycloalkyl,
R ₃ Is halogen, C _{1 - 2} alkyl and C _{1 -} would substituted with one or more non-hydrogen substituents selected from the group consisting of a _2-alkoxy or an unsubstituted phenyl, wherein the non-hydrogen substituents or further substituted with a halogen unsubstituted pharmaceutical Composition.
The method according to claim 1,
R ₁ and R ₂ together with the nitrogen that is associated with these T azepin morpholinyl, pyrrolidinyl, piperidinyl each optionally substituted and selected from the group consisting of azepanyl C ₃ is ₆ intended to form a heterocycloalkyl,
R ₃ And _{2-alkyl, -} is a substituted C ₁ day phenyl or thiophene
It said phenyl being halogen, C _{1 - 2} alkyl and C _{1 - 2} alkoxy substituted with one or more non-hydrogen substituents selected from the group consisting of or will unsubstituted, in that the non-hydrogen substituents are optionally substituted further by halogen, ≪ / RTI >
The method according to claim 1,
R ₁ and R ₂ together with the nitrogen that is associated with these T azepin morpholinyl, pyrrolidinyl, piperidinyl each optionally substituted and selected from the group consisting of azepanyl C ₃ is ₆ intended to form a heterocycloalkyl,
R ₃ It is C _{6 - 7} cycloalkyl or unsubstituted C _{1 - 2} alkyl pharmaceutical composition.
The method according to claim 1,
R ₁ and R ₂ together with the nitrogen that is associated with these T azepin morpholinyl, pyrrolidinyl, piperidinyl each optionally substituted and selected from the group consisting of azepanyl C ₃ is ₆ intended to form a heterocycloalkyl,
R ₃ Is cyclohexyl, cycloheptyl, phenyl, benzyl, phenethyl, thiophenyethyl or methyl,
Wherein phenyl, benzyl or phenethyl is unsubstituted or substituted with one or more non-hydrogen substituents selected from the group consisting of halogen, methyl, ethyl, methoxy, trifluoromethyl, difluoromethoxy and trifluoromethoxy ≪ / RTI >
The method according to claim 1,
The compound of Formula 1 is N1-piperidin-5-phenylbaiguanide; N1-piperidin-N5- (3-methyl) phenylbaiguanide; N1-piperidin-N5- (3-ethyl) phenylbaiguanide; N1-piperidin-N5- (3-methoxy) phenylbaiguanide; N1-piperidine-N5- (4-fluoro) phenylbaiguanide; N1-piperidine-N5- (3-fluoro) phenylbaiguanide; N1-Pyrrolidine-N5- (4-chloro) phenylbaiguanide; N1-piperidin-N5- (4-chloro) phenylbaiguanide; N1-piperidin-N5- (3-bromo) phenylbaiguanide; N1-Pyrrolidine-N5- (3-chloro) phenylbaiguanide; N1-piperidin-N5- (3-chloro) phenylbaiguanide; N1-azepan-N5- (3-chloro) phenylbaiguanide; N1-pyrrolidin-N5- (3-trifluoromethyl) phenylbaiguanide; N1-piperidin-N5- (3-trifluoromethyl) phenylbaiguanide; N1-pyrrolidine-N5- (4-trifluoromethyl) phenylbaiguanide; N1-piperidin-N5- (4-trifluoromethyl) phenylbaiguanide; N1-Pyrrolidin-N5- (3-trifluoromethoxy) phenylbaiguanide; N1-piperidin-N5- (3-trifluoromethoxy) phenylbaiguanide; N1-piperidin-N5- (3-difluoromethoxy) phenylbaiguanide; N1-Pyrrolidine-N5- (4-trifluoromethoxy) phenylbaiguanide; N1-piperidin-N5- (4-trifluoromethoxy) phenylbaiguanide; N1-Piperidin-N5- (4-fluoro-3-trifluoromethyl) phenylbaiguanide; N1-piperidine-N5- (4-chloro-3-trifluoromethyl) phenylbaiguanide; N1-Pyrrolidine-N5- (3-fluoro-4-trifluoromethyl) phenylbaiguanide; N1-Piperidine-N5- (3-fluoro-4-trifluoromethyl) phenylbaiguanide; N1-Piperidin-N5- (4-chloro-3-trifluoromethoxy) phenylbaiguanide; N1-azetidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide; N1-Pyrrolidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide; N1-Piperidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide; N1-azetidine-N5- (3-chloro-4-trifluoromethoxy) phenylbaiguanide; N1-Pyrrolidine-N5- (3-chloro-4-trifluoromethoxy) phenylbaiguanide; N1-Piperidin-N5- (3-chloro-4-trifluoromethoxy) phenylbaiguanide; N1-piperidin-N5- (3,4-difluoro) phenylbaiguanide; N1-piperidin-N5- (3,5-difluoro) phenylbaiguanide; N1-Piperidin-N5- (3,5-dichloro) phenylbaiguanide; N1-Pyrrolidin-N5- (3,4-dichloro) phenylbaiguanide; N1-piperidine-N5- (3,4-dichloro) phenylbaiguanide; N1-piperidin-N5- (3-chloro-5-trifluoromethoxy) phenylbaiguanide; N1-Pyrrolidine-N5- (3-bromo-5-trifluoromethoxy) phenylbaiguanide; N1-piperidine-N5- (3-bromo-5-trifluoromethoxy) phenylbaiguanide; N1-piperidin-N5- (3,4,5-trifluoro) phenylbaiguanide; N1-pyrrolidine-N5- (4-trifluoromethyl) phenylbaiguanide; N1-piperidin-N5- (4-trifluoromethyl) phenylbaiguanide; N1-Pyrrolidine-N5- (4-trifluoromethoxy) phenylbaiguanide; N1-piperidin-N5- (4-trifluoromethoxy) phenylbaiguanide; N1-Pyrrolidine-N5- (3-fluoro-4-trifluoromethyl) phenylbaiguanide; N1-Piperidine-N5- (3-fluoro-4-trifluoromethyl) phenylbaiguanide; N1-Pyrrolidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide; N1-Piperidine-N5- (3-fluoro-4-trifluoromethoxy) phenylbaiguanide; N1-piperidin-N5- (3-trifluoromethyl) benzylbaiguanide; N1-piperidin-5-methylbiguanide; N1-piperidin-5-cyclohexylbaiguanide; N1-pyrrolidine-N5-cycloheptylbaiguanide; N1-piperidin-5-cycloheptylbaiguanide; N1-azepan-N5-cycloheptylbaiguanide; N1-piperidin-N5- (4-methyl) benzylbaiguanide; N1-piperidin-N5- (4-methoxy) benzylbaiguanide; N1-Pyrrolidine-N5- (4-chloro) benzylbaiguanide; N1-azepan-N5- (4-chloro) benzylbaiguanide; N1-Piperidin-N5- (4-trifluoromethyl) benzylbaiguanide; N1-azetidine-N5- (4-trifluoromethoxy) benzylbaiguanide; N1-Pyrrolidine-N5- (4-trifluoromethoxy) benzylbaiguanide; N1-piperidine-N5- (4-trifluoromethoxy) benzylbaiguanide; N1-piperidine-N5- (4-fluoro-3-trifluoromethyl) benzylbaiguanide; N1-piperidin-N5- (4-chloro-3-trifluoromethyl) benzylbaiguanide; N1-piperidin-N5- (3-fluoro-4-trifluoromethyl) benzylbaiguanide; N1-piperidin-N5- (3-chloro-4-trifluoromethyl) benzylbaiguanide; N1-Piperidine-N5- (4-fluoro-3-trifluoromethoxy) benzylbaiguanide; N1-Piperidin-N5- (3-chloro-4-trifluoromethoxy) benzylbaiguanide; N1-piperidin-N5- (2,6-difluoro) benzylbaiguanide; N1-piperidin-N5- (3,4-difluoro) benzylbaiguanide; N1-piperidin-N5- (2,4-dichloro) benzylbaiguanide; N1-Pyrrolidine-N5- (3,4-dichloro) benzylbaiguanide; N1-Piperidin-N5- (3,4-dichloro) benzylbaiguanide; N1-piperidin-N5- (thiophen-2-yl) ethylbiguanide; N1-pyrrolidin-N5- (phenethyl) < / RTI > N1-piperidin-N5- (phenethyl) < / RTI > N1-azepan-N5- (phenethyl) < / RTI > N1-azepan-N5- ((4-fluoro) phenethyl) veguanide or N1-azepan-N5- ((4-chloro) phenethyl) veguanide.
The method according to claim 1,
Wherein the pharmaceutically acceptable salt is selected from the group consisting of formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid, maleic acid, malonic acid, fumaric acid, succinic acid, succinic monoamide, glutamic acid, tartaric acid, oxalic acid, But are not limited to, glycolic acid, glycolic acid, gluconic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxyacetic acid, ≪ / RTI > wherein the salt is a salt with an acid selected from the group consisting of boric acid.
The method according to claim 1,
Wherein the parallax syndrome further has at least one symptom selected from the group consisting of tiredness, decreased concentration, decreased appetite, depression, memory impairment, slowed motor function, headache, dizziness, and digestive dysfunction.
The method according to claim 1,
Wherein said 24 hour periodic rhythm sleep disorder is selected from the group consisting of shift work sleep disorder, plane parallax sleep disorder, progressive sleep phase syndrome, and delayed sleep phase syndrome.

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