KR101136045B1 - N1-phenethyl-n2-substituted biguanide derivatives, methods of preparing the same and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention provides a pharmaceutical composition as an N1- (phenethyl) -N2-substituted biguanide derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof, a method for preparing the same, and an active ingredient thereof. N1- (phenethyl) -N2-substituted biguanide derivative of the present invention exhibits excellent hypoglycemic and hypolipidemic activity even at a lower dose than conventional drugs, resulting in diabetes, obesity, hyperlipidemia, hypercholesterolemia, fatty liver, and coronary It can be useful for the treatment of arterial disease, osteoporosis, polycystic ovary syndrome, metabolic syndrome, cancer and the like.

Biguanide derivatives, diabetes, metabolic syndrome

Description

N1- (phenethyl) -N2-substituted biguanide derivatives, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient THE SAME}

The present invention provides a N1- (phenethyl) -N2-substituted biguanide derivative which shows excellent hypoglycemic activity and lipid lowering activity even at a lower dose than a conventional drug, a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient. It is about.

Diabetes mellitus is a disease characterized by persistent hyperglycemic symptoms. Carbohydrate metabolism abnormalities and lipid metabolism abnormalities are major conditions, and systemic complications due to hyperglycemia caused by impaired blood flow and decreased glucose utilization are aggravated. This diabetic condition is caused by insulin deficiency or insulin resistance, and diabetes caused by insulin resistance is called type 2 diabetes.

Type 2 diabetes is caused by a condition in which insulin is unable to carry sugar into the cell due to a decrease in insulin receptors or a deficiency in the signaling system through the receptor, that is, a condition in which insulin develops resistance, It aggravates the direct vascular destruction and metabolic syndrome caused by hyperinsulinemia.

Many types of diabetes drugs have been used to treat this type 2 diabetes. However, drugs other than biguanide metformin have some effects on hypoglycemic effects, but they are not effective in preventing serious complications such as vision loss, heart failure, stroke, kidney failure, peripheral nerve disorders, and foot ulcers. It was. For example, sulfonyurea drugs can be found in the pancreas. It is a drug that lowers blood sugar by forcibly secreting insulin, and the effect of the drug disappears quickly, and abnormal lipid metabolism causes arteriosclerosis, weight gain, and brain damage due to hypoglycemia. In addition, the glitazone-based drug mainly needs to be administered in combination with metformin to solve only the problem of insulin resistance to adipose tissue, causing side effects such as retinal vessel destruction, so there is a disadvantage that requires very careful use.

Metformin, on the other hand, does not cause hypoglycemia, solves insulin resistance in adipose, hepatic and muscle tissues, and has excellent hypoglycemic and It exhibits a glycated hemoglobin level lowering effect. It has also been reported to activate AMP-activated protein kinase (AMPK) to normalize hyperglycemia, improve lipid status, normalize menstrual irregularities, ovulation and pregnancy, treat fatty liver, and even kill cancer stem cells to treat resistant cancer.

However, metformin is generally administered three times a day, and since a single dose is about 500 mg or more, a tablet containing about 1,500 mg or more of metformin is required to sustained release it for a single daily use, in which case the size of the tablet is too large. I have difficulty taking it. In addition, the current long-acting formulations contain only about 750 mg metformin in one tablet, so there is a problem in that two or more tablets should be taken when administering. Accordingly, there is a need for a metformin-based material that exhibits better pharmacological action and improved physicochemical properties than conventional metformin.

The present invention is to provide a novel biguanide derivative, or a pharmaceutically acceptable salt thereof, and a method for preparing the same that exhibit excellent blood glucose lowering and lowering lipid activity even at a lower dose than conventional drugs.

In addition, the present invention is to provide a pharmaceutical composition for treating diabetes, obesity, hyperlipidemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, metabolic syndrome, cancer and the like as the active ingredient.

The present invention provides a N1- (phenethyl) -N2-substituted biguanide derivative compound of Formula 1, or a pharmaceutically acceptable salt thereof:

[Formula 1]

Where

R is C _1-12 alkyl, C _1-12 alkenyl or C _1-12 alkynyl unsubstituted or substituted with one or more substituents selected from the group consisting of C _3-8 cycloalkyl and C _5-12 aryl; Substituted or unsubstituted with one or more substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 alkoxy and C _5-12 aryl Ringed C _3-8 cycloalkyl; Or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 alkoxy and C _3-8 cycloalkyl Or unsubstituted C _5-12 aryl.

Herein, "substituted" groups are those in which one or more hydrogen atoms have been replaced by one or more non-hydrogen atom groups, provided that the valence requirements are met and chemically stable compounds must result from the substitution.

"Alkyl" generally refers to straight-chain and branched saturated hydrocarbon groups having the specified number of carbon atoms (eg, 1 to 12 carbon atoms). Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3- 1, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl, n-heptyl and n-octyl and the like. Alkenyl and alkynyl refer to alkyl groups containing at least one double bond and at least one triple bond. Alkyl, alkenyl or alkynyl may be attached to a parent group or substrate at any ring atom as long as the attachment does not violate valence requirements. Likewise, an alkyl group, alkenyl group, or alkynyl group may include one or more non-hydrogen substituents if the attachment does not violate valence requirements.

"Alkoxy" refers to alkyl-O-, wherein alkyl is defined above. Examples of alkoxy groups include without limitation methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy and the like. do. Alkoxy may be attached to a parent group or substrate at any ring atom if the attachment does not violate valence requirements. Likewise, an alkoxy group may include one or more non-hydrogen substituents unless the attachment would violate valence requirements.

"Halogen" refers to fluoro, chloro, bromo and iodo.

"Cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon rings which generally have a specified number of carbon atoms including the ring (ie, C _3-8 cycloalkyl is a ring member having 3, 4, 5, 6, 7 or 8 Cycloalkyl group having a carbon atom). Cycloalkyls can be attached to a parent group or substrate at any ring atom unless the attachment would violate valence requirements. Likewise, cycloalkyl groups may include one or more non-hydrogen substituents unless the attachment would violate valence requirements.

“Aryl” refers to monovalent and divalent aromatic groups, respectively, including 5- and 6-membered monocyclic aromatic groups containing 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of monocyclic aryl groups include, without limitation, phenyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl , Pyrazinyl, pyridazinyl, pyrimidinyl and the like. Aryl groups also include bicyclic groups, tricyclic groups, etc., including fused 5- and 6-membered rings as defined above. Examples of polycyclic aryl groups include without limitation naphthyl, bifenyl, anthracenyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiopheneyl, quinolinyl , Isoquinolinyl, indolyl, benzofuranyl, furinyl, indolizinyl and the like. The aryl group can be attached to the parent group or substrate at any ring atom as long as the attachment does not violate valence requirements. Likewise, an aryl group may include one or more non-hydrogen substituents if the substitution does not violate valence requirements.

Substituents useful as the “non-hydrogen substituents” mentioned above include, but are not limited to, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, alkoxy, haloalkoxy, Cycloalkoxy, alkanoyl, cycloalkanoyl, cycloalkenoyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryl, aryloxy, carboxy, carbamoyl, halo, hydroxy, mercapto, nitro, cyano, amino, alkylamino , Sulfonic acid, sulfonamido, alkylthio and the like.

In the present invention, R may be substituted or unsubstituted C _1-12 alkyl. For example, substituted C _1-12 alkyl is a “halo C _1-12 alkyl” such as chloromethyl, trifluoromethyl and 1-chloro-2-fluoroethyl; methoxymethyl, methoxyethyl, methoxy “C _1-12 alkoxy C _1-12 alkyl” such as ethoxyethoxyethyl, ethoxymethyl and octyloxymethyl; cyclopropanemethyl, cyclobutanemethyl, cyclopentanemethyl, cyclohexanemethyl, cyclopropaneethyl, cyclobutane C _3-8 cycloalkylC _1-12 alkyl such as ethyl, cyclopentaneethyl, cyclohexaneethyl, cyclopropane propyl, cyclobutanepropyl, cyclopentanepropyl and cyclohexanepropyl; _{PhenylC 1-12} alkyl such as 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl and 3-phenylpropyl, or 1-naphthylmethyl, 2-naphthylmethyl, 1-naphthylethyl and a naphthyl C _5-12 aryl C _1-12 alkyl, including C _1-12 alkyl, such as 2-naphthyl acetate. The substituents may each also be substituted with one or more non-hydrogen substituents.

In the present invention, R may be substituted or unsubstituted C _3-8 cycloalkyl. Preferred examples of “C _3-8 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In the present invention, R may be substituted or unsubstituted C _5-12 aryl. Preferred examples of “aryl” as used herein include substituted or unsubstituted phenyl, pyridinyl or naphthyl.

For example, R is ethyl, methyl, butyl, t-butyl, isobutyl, propyl, isopropyl, hexyl, t-octyl, pentyl, methoxyethyl, benzyl, 4-bromobenzyl, 4-methoxybenzyl, 4-methylbenzyl, cyclopentyl, cyclopropylmethyl, cycloheptyl, cyclohexyl, 1-naphthyl, phenyl, 2-ethylphenyl, 3-trifluoromethylphenyl, 4-methoxyphenyl, 2,5-dimeth Methoxyphenyl, 3,4,5-trimethoxyphenyl, 4-fluorophenyl, 4-methylphenyl, 3-methylphenyl, 4-t-butylphenyl, 3-hexylphenyl, 4-methoxyphenyl, 2,5- Dimethoxyphenyl, 3,5-dimethoxyphenyl, 4-bromophenyl, 3-bromophenyl, 3-phenylphenyl, 3-phenoxyphenyl, 3,5-dichlorophenyl.

In one embodiment, R is C _1-12 alkyl wherein one or more substituents are unsubstituted or substituted with C _5-12 aryl; C _3-8 cycloalkyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy and C _1-6 alkyl; Or C _5-12 aryl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy and C _1-6 alkyl.

In another embodiment, R is C _1-12 alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of phenyl, pyridinyl and naphthyl; C _3-8 cycloalkyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy and C _1-6 alkyl; Or phenyl, pyridinyl or naphthyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy and C _1-6 alkyl.

In another embodiment, R is C _1-12 alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of phenyl, pyridinyl and naphthyl; _{Unsubstituted} C _3-8 cycloalkyl; Or phenyl or naphthyl substituted with one or more halogens.

In another embodiment, the compound of Formula 1 may be a compound selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof:

N1- (phenethyl) -N2-cyclohexyl biguanide;

N1- (phenethyl) -N2-hexyl biguanide;

N1- (phenethyl) -N2-benzyl biguanide;

N1- (phenethyl) -N2-methylphenyl biguanide; or

N1- (phenethyl) -N2- (2,4-dichlorophenyl) biguanide.

In one embodiment,

The pharmaceutically acceptable salt of the compound of Formula 1 according to the present invention may be an acid addition salt. The organic acid is, for example, formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid, maleic acid, malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycol Acids, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, dichloroacetic acid, aminooxy acetic acid, benzenesulfonic acid, p-toluenesulfonic acid and methanesulfonic acid salts; Inorganic acids include, for example, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and boric acid salts. The above-mentioned acid addition salts can be, for example, a) directly mixing the compound of formula 1 and acid, b) dissolving one of them in a solvent or a hydrous solvent, or c) compound of formula 1 and The acid can be prepared by placing it in an acid in a solvent or a hydration solvent and applying it to a general method for preparing a salt thereof.

When the compound of Formula 1 has an acidic group such as a carboxyl group and a sulfonic acid group, the compound is a zwitterionic salt, and such salts are alkali metal salts (such as sodium salts and potassium salts), alkaline earth metal salts (such as calcium salts and Magnesium salts, etc.), inorganic acid salts such as aluminum salts and ammonium salts, and basic addition salts such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexyl Amines and N, N'-dibenzylethylenediamine salts). In addition, the salt of the compound of Formula 1 may be a basic amino acid salt (eg arginine, lysine and ornithine salt) and acidic amino acid salt (eg aspartic acid salt).

Pharmaceutically acceptable salts of the compounds of formula 1 are preferably acetate, hydrochloride, hydrobromide, methanesulfonate, malonate or oxalate salts.

For example, the method for preparing the compound of Formula 1 according to the present invention,

1) reacting a compound of formula 2 with isothiocyanate (RNCS) having a substituent R group in the presence of a base in an organic solvent to obtain a compound of formula 4

2) reacting a compound of formula 4 in a guanidine solution in the presence of mercury oxide:

[Formula 1]

[Formula 2]

[Formula 4]

In the above formula, R is as defined in the formula (1).

As another method, the compound of formula 1 of the present invention

1) reacting a compound of Formula 2 with ethylchloroformate in an organic solvent in the presence of carbon disulfide and a base to obtain a compound of Formula 3;

2) reacting a compound of Formula 3 with NH ₂ R in a solvent in the presence of a base to obtain a compound of Formula 4; And

3) reacting the compound of formula 4 in a guanidine solution in the presence of mercury oxide:

[Formula 1]

[Formula 2]

(3)

[Formula 4]

In the above formulas, R is as defined in Formula 1, and in Formula 3, NCS represents isothiocyanate.

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

The thiourea compound of formula (4), which is used as an intermediate in the preparation method of the compound of formula (1), may be used as a base if 2-isoethyl cyanate (RNCS) having a substituent R group is commercially available. Reacted with RNCS in an organic solvent in the presence of, or (B) when RNCS bearing a substituent R group is not commercially available, 2-phenylethylamine of formula (2) is substituted with ethylchloro in an organic solvent in the presence of carbon disulfide and a base. After reacting with formate to convert the isothiocyanate compound of formula 3, the compound of formula 3 can be obtained by reacting with NH ₂ R in an organic solvent in the presence of a base.

As the base used in the steps (1), (1 ′) and (2) in the preparation of the thiourea compound of Chemical Formula 4, triethylamine, trimethylamine or diisopropylethylamine may be used. Dichloromethane, dichloroethane or dimethylformamide can be used. The reaction temperature is in the range from 0 ° C to room temperature. The amounts of carbon disulfide, base and ethylchloroformate in the above steps (1) and (1 ′) may be used in about 1 to 2 molar equivalents relative to the compound of formula (2), respectively.

In step (3), the thiourea compound of formula 4 obtained above is dissolved in mercury oxide and a suitable organic solvent (for example, ethyl alcohol, methyl alcohol or dimethyl formamide), and then refluxed by adding 1M guanidine ethanol solution. In this case, the amount of mercury oxide is about 1 to 2 molar equivalents relative to compound 8, the 1M guanidine ethanol solution is 1 to 3 molar equivalents relative to compound 8, and the reaction temperature is in the range up to the reflux temperature of the solvent used (for example, dimethyl). In the case of formamide). After completion of the reaction, the resultant is filtered and, for example, by adjusting the pH of the reaction solution to about 4 to 5 using an acid such as hydrochloric acid, and concentrating and purifying the resulting solution. Alternatively, acceptable salts can be obtained.

The compound of Formula 1 or a pharmaceutically acceptable salt thereof obtained as described above exhibits hypoglycemic action and hypolipidemic action even at a lower dose than conventional drugs. Diabetes, obesity, hyperlipidemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, metabolic syndrome and the like can be usefully used.

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

The present invention also provides diabetes, obesity, hyperlipidemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, metabolic syndrome, cancer, myalgia with the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. , A pharmaceutical composition for treating a disease selected from the group consisting of muscle cell damage and rhabdomyolysis, the use of the compound of formula 1 or a pharmaceutically acceptable salt thereof for the treatment of the disease and a therapeutically effective amount of the compound of formula 1 Or a pharmaceutically acceptable salt thereof is provided to the subject.

In one embodiment, the diabetes can be insulin independent diabetes.

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

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

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

Formulations suitable for oral administration include solid formulations, such as capsules containing tablets, particulates, liquids or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates. Agents, gels, solid solutions, liposomes, films (including muco-adhesives), ovules, sprays and liquid formulations. Liquid formulations include, for example, suspensions, solutions, syrups and elixirs.

For tablet dosage forms, depending on the dosage, the drug may comprise from 1% to about 80%, more typically from about 5% to about 60% by weight of the dosage form. Tablets generally contain disintegrants in addition to drugs. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydrides. Oxypropyl cellulose, starch, pregelatinized starch and sodium alginate. In general, the disintegrant will comprise, but is not limited to, about 1% to about 25% by weight of the dosage form, preferably about 5% to about 20% by weight of the dosage form.

Binders are generally used to impart tack to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose . The tablets may also be diluted with diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrides, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. May comprise water.

Tablets may also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. If present, the surfactant may comprise from about 0.2% to about 5% by weight of the tablet, and the lubricant may comprise from about 0.2% to about 1% by weight of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from about 0.25% to about 10%, preferably from about 0.5% to about 3% by weight of the tablet.

Other possible ingredients include antioxidants, colorants, flavors, preservatives and taste-blockers.

Tablet formulations may be compressed directly or by roller to form tablets. Alternatively, the tablet blend, or a portion of the blend, may be wet-, dry-, melt-granulated, melt congealed, or extruded before tableting. The final formulation may comprise one or more layers, may or may not be coated and may be encapsulated.

Tablet formulations are discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).

Solid formulations for oral administration may be formulated in immediate release and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release forms.

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

In one embodiment, the pharmaceutical composition of the present invention may be a tablet. Tablets may optionally be film coated. The total amount of drug per dosage unit can be that amount that provides a dosage form of a convenient size to the patient.

In one embodiment, the pharmaceutical compositions of the present invention may be formulated in the form of sustained release tablets.

For the production of sustained-release tablets, a component selected from an enteric polymer, a hydrophobic substance, a hydrophilic polymer, and the like can be used as the matrix base.

The enteric polymer may be a mixture of one or more selected from polyvinylacetate phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, shellac, cellulose acetate phthalate, cellulose propionate phthalate, Eudragit L, Eudragit S, and the like. May be used, and preferably hydroxypropylmethylcellulose phthalate may be used.

The hydrophobic materials are pharmaceutically acceptable polyvinyl acetate, poly (methacrylate, methyl methacrylate) copolymer, poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate as polymethacrylate copolymers). Acrylates) copolymers, ethyl cellulose and cellulose acetate, fatty acids and fatty acid esters, fatty alcohols, waxes and inorganic substances, and the like, specifically, glyceryl palmitostearate, Fatty acid alcohols such as glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and stearic acid; waxes such as cetostearyl alcohol, cetyl alcohol and stearyl alcohol; carnauba wax, beeswax and microcrystalline wax Talc, precipitated coal as inorganic materials One or two selected from calcium acid, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, and non-gum can be used.

The hydrophilic polymer may be selected from sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives and carboxyvinyl polymers, and specifically, as the sugars, dextrin, polydextrin, dextran, Pectin and pectin derivatives, alginates, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose, amylopectin and the like can be selected and used as cellulose derivatives. , Hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose can be selected and used as a gum , By Custard bean gum, tragacanta, carrageenan, acacia gum, gum arabic, gellan gum, xanthan gum, and the like can be selected. Gelatin, casein, zein, etc. can be selected and used as proteins. Alcohol, polyvinyl pyrrolidone, polyvinyl acetal diethylamino acetate, and the like can be selected and used as the poly methacrylate copolymer, and poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate Rate) copolymer, poly (methacrylic acid, methyl methacrylate) copolymer, poly (methacrylic acid, ethyl acrylate) copolymer, etc. can be selected and used, and polyethylene glycol, polyethylene oxide, etc. are selected as a polyethylene derivative. Carbomer may be used as the carboxyvinyl polymer.

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

In the present invention, the "second drug" means another pharmaceutically effective ingredient other than the metformin acid addition salt of the present invention. The compound of formula 1 or a pharmaceutically acceptable salt thereof of the present invention can be used for the treatment of various diseases as described above. Thus, the compound of formula 1 or a pharmaceutically acceptable salt thereof of the present invention can be used in combination with a second drug for the efficient treatment of each disease. For example, the second drug may be an antihyperglycemic agent, an antiobesity agent, an anticancer agent, or the like.

In one embodiment, the second drug may be an antihyperglycemic agent. Such antihyperglycemic agents may be one or more drugs selected from the group consisting of sulfonylurea-based drugs, thiazolidione-based drugs and alpha-glucosidase inhibitors currently being used in combination with metformin.

In another embodiment, the present invention provides a combination formulation comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof and a second drug.

For convenience of medication, the compound of formula 1 or a pharmaceutically acceptable salt thereof may be provided in the form of a complex formulation formulated with a second drug.

For example, the second drug may be an antihyperglycemic agent, and the antihyperglycemic agent may be one or more drugs selected from the group consisting of sulfonylurea-based drugs, thiazolidione-based drugs, and alpha-glucosidase inhibitors. have.

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

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

An effective amount of the active ingredient of the pharmaceutical composition of the present invention means an amount required to achieve the treatment of the disease. 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 adults, metformin acid addition salt may be administered at a dose of 50 to 3000 mg / kg total, once to several times daily.

N1- (phenethyl) -N2-substituted biguanide derivatives according to the present invention exhibit excellent hypoglycemic and hypolipidemic activity even at low doses compared to conventional drugs, resulting in diabetes, obesity, hyperlipidemia and hypercholesterolemia. Fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, metabolic syndrome, cancer and the like can be usefully used for the treatment.

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

[Example]

Example 1 (KL00369): Preparation of N1- (phenethyl) -N2-cyclohexyl biguanide hydrochloride

(1-1) Synthesis of 1-cyclohexyl-3-phenethylthiourea

Isothiocyanatocyclohexane (1.3 g, 15.0 mmol) was slowly added dropwise to a 2-phenylethylamine (1.3 g, 10.2 mmol) -containing dichloromethane (150 mL) solution. Triethylamine (3.8 mL, 20.4 mmol) was added dropwise to the mixture, followed by stirring at room temperature for 2 hours. After the reaction was completed, the pH of the reaction solution was adjusted to about 7 with 1N HCl, and water was added to extract dimethyl chloride. Flash column chromatography (ethyl acetate: hexane = 1: 3) was used to recover 1-ethyl-3- (2- (thiophen-2yl) ethyl) thiourea (1.6 g, 86%).

(1-2) Synthesis of N1- (phenethyl) -N2-cyclohexyl biguanide hydrochloride

Mercury oxide (II) (2.2 g, 10.2 mmol) was added to a 1-cyclohexyl-3-phenethylthiourea (1.1 g, 5.10 mmol) -containing ethanol (15 mL) solution prepared in step 1-1. Added. To the reaction solution was slowly added dropwise 1M guanidine ethanol solution (15 mL, 15.3 mmol), followed by reflux for 12-24 hours. After the reaction solution was cooled, the reaction solution was filtered using a celite filter, and 2N HCl was added to the filtrate, and the mixture was titrated to pH 4-5. The solution was concentrated, and then recovered using N- (thiophen-2-ylethyl) -N2-ethyl biguanide hydrochloride using flash column chromatography (dichloromethane: methanol = 9: 1) (0.20 g, 14 %).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.33-8.21 (m, 5H, Ph), 3.28 (t, 2H, J = 7.5 Hz, CH ₂ ), 2.78 (t, 2H, J = 7.5 Hz, CH ₂ ), 1.77-1.51 (m, 4H, cyclohexyl), 1.26-1.05 (m, 6H, cyclohexyl); mp 184-186 ° C

Example 2 (KL00370): Preparation of N1- (phenethyl) -N2-hexyl biguanide hydrochloride

(2-1) Synthesis of 2- (2-isothiocyanatoethyl) benzene

The 2-phenylethylamine (4.60 mL, 39.31 mmol) and triethylamine (5.00 mL, 39.31 mmol) -containing 1,2-dichloroethane (25 mL) solutions were cooled to 0 ° C. and then 1,2-di A solution of carbon disulfide (2.36 mL, 39.31 mmol) in chloroethane (50 mL) was added dropwise over 15 minutes. The reaction solution was raised to room temperature and then cooled to 0 ° C., and ethylchloroformate (4.27 mL, 31.39 mmol) was added dropwise. Then, after stirring for 1-2 hours at room temperature, water (150 mL) and 2N sodium hydroxide solution (75 mL) were added, followed by extraction with dichloromethane. The combined extracts were washed with water and brine, dried over sodium sulfate and concentrated to recover 2- (2-isothiocyanatoethyl) benzene as a yellow liquid (5.37 g, yield: 80.75%).

(2-2) Synthesis of 1-hexyl-3-phenethylthiourea

2 (2-Isothiocyanatoethyl) benzene (2.5 g, 15.0 mmol) and hexane-1-amine (1.6 mL, 10.2 mmol) were used in the same manner as in Step 1-1, except that 1 -Hexyl-3-phenethylthiourea was synthesized (2.5 g, 83%).

(2-3) Synthesis of N1- (phenethyl) -N2-hexyl biguanide hydrochloride

1-hexyl-3-phenethylthiourea (1.5 g, 5.10 mmol) prepared in step (2-2) was carried out in the same manner as in step (1-2), to obtain N1- (phenethyl ) -N2-hexyl biguanide hydrochloride was recovered (0.31 g, 17%).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.34-7.20 (m, 5H, Ph), 3.30 (t, 2H, J = 7.6 Hz, CH ₂ ), 3.04 (t, 2H, J = 7.6 Hz, NCH ₂ ), 2.79 (t, 2H, J = 7.6 Hz, CH ₂ ), 1.46-1.41 (m, 2H, CH ₂ ), 1.25 (m, 6H, CH ₂ ), 0.87 (t, 3H, J = 7.6 Hz, CH ₃ ); mp 144-145 ° C

Example 3 (KL00371): N1- (phenethyl) -N2-benzyl biguanide hydrochloride

Example 3 (KL00370) by the same method as Example 2 (KL00370) except for using the amine compound corresponding to the target compound instead of hexane-1-amine in step (2-2) of Example 2 (KL00370) KL00371) was prepared.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.36-7.20 (m, 10H, Ph), 4.31 (s, 2H, CH ₂ ), 3.33 (t, 2H, J = 7.3 Hz, CH ₂ ), 2.79 (t, 2H, J = 7.3 Hz, CH ₂ ); mp 148-151 ℃

Example 4 (KL00372): N1- (phenethyl) -N2-methylphenyl biguanide hydrochloride

Example 4 (KL00370) by the same method as in Example 2 (KL00370) except for using the amine compound corresponding to the target compound instead of hexane-1-amine in step (2-2) of Example 2 (KL00370) KL00372) was prepared.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.34-7.23 (m, 5H, Ph), 7.12 (d, 2H, J = 8.0 Hz, Ph), 7.03 (d, 2H, J = 8.0 Hz, Ph ), 3.38 (t, 2H, J = 7.5 Hz, CH ₂ ), 2.83 (t, 2H, J = 7.5 Hz, CH ₂ ), 2.25 (s, 3H, CH ₃ ); mp 223-225 ° C

Example 5 (KL00373): N1- (phenethyl) -N2- (2,4-dichlorophenyl) biguanide hydrochloride

Except for using the isothiocyanate compound corresponding to the target compound instead of ethyl isothiocyanate in the step (1-1) of Example 1 Example 5 (KL00369) KL00373) was prepared .

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.37-7.18 (m, 8H, Ph), 3.38 (t, 2H, J = 7.1 Hz, CH ₂ ), 2.81 (t, 2H, J = 7.1 Hz, CH ₂ ); mp 205-206 ° C

Test Example 1: Determination of Cholesterol Synthesis Ability

HepG2 cells, a hepatocyte model, were used to measure cholesterol synthesis inhibitory ability, which is an important function of AMPK activated by the compound of the present invention. HepG2 cells, a hepatocyte model, were incubated for 24 hours in a medium containing 1% serum, and then treated with each compound for 24 hours, and then cells were crushed (0.1 M potassium phosphate, pH 7.4, 0.05 M NaCl, 5 mM cholic acid, 0.1% Triton X-100). Reaction was performed at 37 ° C. for 30 minutes by adding the same amount of reaction solution (2 U / ml cholesterol oxidant, 2 U / ml peroxidase, 0.2 U / ml cholesterol esterase, 300uM Amplex red fluorescent factor) to the crushed cells. I was. After the reaction, the amount of cholesterol formed was measured by fluorescence measurement at 560/590 nm (ex / em) wavelength.

compound % Inhibition Metformin (2 mM) 80.37 ± 0.78 Cholesterol (100 uM) Cholesterol (500 uM) Example 1 62.1 ± 3.0 39.2 ± 3.0 Example 2 52.9 ± 3.2 24.5 ± 1.6 Example 3 72.3 ± 6.8 41.0 ± 2.0 Example 4 37.6 ± 0.4 29.7 ± 1.2 Example 5 28.9 ± 0.8 25.6 ± 0.8

Test Example 2 Measurement of Inhibition of Neutral Fatty Acid Synthesis

HepG2 cells, a hepatocyte model, were incubated for 24 hours in a medium containing 1% serum, and then treated with each compound for 24 hours, and then cells were crushed (0.1 M potassium phosphate, pH 7.4, 0.05 M NaCl, 5 mM cholic). acid, 0.1% Triton X-100). The same amount of reaction solution (0.76 U / ml glycerol kinase, 151333 U / ml peroxidase, 22.2 U / ml glycerol oxidant, 300 uM Amplex red, a fluorescence factor) was added to the crushed cells and reacted at 37 ° C. for 30 minutes. After the reaction, the amount of triglyceride formed was measured by fluorescence measurement at 560/590 nm (ex / em) wavelength.

compound % Inhibition Metformin (2 mM) 63.74 ± 1.09 Triglyceride (100 uM) Triglyceride (500 uM) Example 1 91.3 ± 5.6 68.4 ± 2.8 Example 2 85.0 ± 10.9 54.1 ± 2.8 Example 3 97.4 ± 5.2 70.3 ± 1.6 Example 4 76.4 ± 4.3 58.0 ± 2.0 Example 5 57.5 ± 1.2 49.0 ± 0.6

Test Example 3 Measurement of Glucose Formation

HepG2 cells, a hepatocellular model, were cultured in 10% serum hyperglycemic medium, and each compound was treated with serum-free hypoglycemic medium for 24 hours, followed by 0.5 uCi 14C-lactate and 10 mM L-lactate for 4 hours. Cells were cultured. After incubation, the medium of the cells was removed, washed with PBS, 0.1N NaOH was added and left at room temperature for 1 hour. After neutralizing with 1N HCl, the amount of glucose formed in the cells was measured by a liquid scintillation counter.

compound % Inhibition Metformin (2 mM) 38.32 ± 1.06 Glucose Biosynthesis (100 uM) Example 1 100.2 ± 10.8 Example 2 55.4 ± 16.3 Example 3 94.5 ± 3.8 Example 4 66.9 ± 2.6 Example 5 8.3 ± 0.0

Test Example 4 Measurement of Glucose Absorption Capacity

C2C12, a muscle cell model, was used to induce differentiation of muscle cells from 2% calf serum for 6 days. Each compound was treated in serum-free hypoglycemic medium and then incubated with 1 uM of insulin for 24 hours. After incubation, 1uCi 3H-Deoxy-glucose and 10 uM deoxy-glucose were treated at 37 ° C. for 15 minutes. After treatment the medium was removed and washed twice with PBS. Washed cells were treated with 0.1 N NaOH and neutralized with 1N HCl. The amount of glucose absorbed into the cells was measured by a liquid scintillation counter.

compound % Activation Metformin (2 mM) 347.83 ± 13.13 Glucose absorption (100 uM) Example 1 267.0 ± 55.8 Example 2 243.6 ± 21.1 Example 3 339.3 ± 27.4 Example 4 121.5 ± 20.6 Example 5 25.9 ± 5.2

Claims (20)

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

Where R is phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen and C _1-6 alkyl. The method of claim 1, R is phenyl substituted with one or more substituents selected from the group consisting of halogen and C _1-6 alkyl A compound of formula 1 or a pharmaceutically acceptable salt thereof. delete delete The method of claim 1, A compound of formula 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: N1- (phenethyl) -N2-methylphenyl biguanide; And N1- (phenethyl) -N2- (2,4-dichlorophenyl) biguanide. The method of claim 1, The pharmaceutically acceptable salts are formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid, maleic acid, malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, Glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, dichloroacetic acid, aminooxy acetic acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and Salt with an acid selected from the group consisting of boric acid Compound of Formula 1 or a pharmaceutically acceptable salt thereof. Reacting a compound of Formula 2 with an isothiocyanate (RNCS) having a substituent R group in the presence of a base in an organic solvent to obtain a compound of Formula 4; And Reacting a compound of formula 4 in a guanidine solution in the presence of mercury oxide Method for preparing a compound of Formula 1 comprising: [Formula 1]

[Formula 2]

[Formula 4]

Where R is phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen and C _1-6 alkyl. Reacting a compound of Formula 2 with ethylchloroformate in an organic solvent in the presence of carbon disulfide and a base to obtain a compound of Formula 3; Reacting a compound of Formula 3 with NH ₂ R in a solvent in the presence of a base to obtain a compound of Formula 4; And Reacting a compound of formula 4 in a guanidine solution in the presence of mercury oxide Method for preparing a compound of Formula 1 comprising: [Formula 1]

[Formula 2]

(3)

[Formula 4]

Where R is phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogen and C _1-6 alkyl, NCS stands for isothiocyanate. 9. The method according to claim 7 or 8, Wherein said base is selected from the group consisting of triethylamine, trimethylamine and diisopropylethylamine, and the organic solvent is selected from the group consisting of dichloromethane, dichloroethane and dimethylformamide. A pharmaceutical comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. Diabetes, obesity, hyperlipidemia, hypercholesterolemia, fatty liver, coronary artery disease, osteoporosis, polycystic ovary syndrome, metabolic syndrome, cancer, myalgia, muscle cell, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient Pharmaceutical composition for the treatment of a disease selected from the group consisting of injury and rhabdomyolysis. The method of claim 11, Pharmaceutical composition wherein the diabetes is insulin-independent diabetes. The method of claim 11, The pharmaceutical composition is formulated in the form of tablets, capsules, pills, granules, powders, injections or solutions. The method of claim 11, The pharmaceutical composition is formulated in the form of a sustained-release tablet. The method of claim 11, The pharmaceutical composition is for use in combination with a second drug. The method of claim 15, The second drug is an antihyperglycemic agent. The method of claim 16, The antihyperglycemic agent is a pharmaceutical composition which is one or more drugs selected from the group consisting of sulfonylurea-based drugs, thiazolidione-based drugs and alpha-glucosidase inhibitors. A co-formulation comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a second drug: The method of claim 18, The second drug is an antihyperglycemic agent. The method of claim 19, The antihyperglycemic agent is a sulfonylurea-based drug, a thiazolidione-based drug, and an alpha-glucosidase inhibitor.