KR100555655B1 - Ureido or thioureido ceramide derivatives having potent anti-cancer activity and the pharmaceutical compositions containing the same - Google Patents

Abstract

The present invention relates to a ureido or thioureido derivative compound of ceramide having a novel chemical structure capable of mediating cancer and inflammatory diseases, and a pharmaceutical composition containing the compound. Provided are pharmaceutical compositions useful for the prevention and treatment of cancer and inflammatory diseases.

 Ceramides, ureido, thioureido, derivatives, cancer, inflammatory diseases, pharmaceutical compositions

Description

Ureido or thioureido ceramide derivatives having potent anti-cancer activity and the pharmaceutical compositions containing the same

OBJECT OF THE INVENTION The present invention relates to a ureido or thioureido ceramide derivative compound of useful novel chemical structure having anticancer activity, a pharmaceutical composition containing the same, and a preparation method thereof.

The mechanism of proliferation and death of cancer cells and the activation of inflammatory cells, which are recognized as the pathogenesis of cancer and inflammatory diseases, have recently been actively studied at the molecular level due to the rapid development of biology.

Lipids and their degradation products, which are components of cell membranes, have important biochemical functions as factors involved in cell function regulation. One of these, ceramide, acts as a lipid messenger that mediates many biological actions, ie, ceramide is apoptosis in leukemia cells and many other types of cells (Obeid, Science , 259 , pp1769-). 1771, 1933), cell differentiation (Okazaki, J. Biol. Chem., 264 , pp19076-19086, 1989), cell growth inhibition (Jayadev, J. Biol. Chem. , 269 , pp5757-5763, 1995) and cell aging (Venable, J. Biol. Chem. , 270 , pp30701-30708, 1995: Kim, Biochem. Biophys. Res. Commun. , 28 , 583-587, 1997), and are reported as important secondary delivery agents. Degenerative brain diseases such as Perkinson's disease (Hunot, Proc. Natl. Acade. Sci. USA, 94 , pp7531-7536, 1997) and Alzheimer's disease (Fiebich., J. Neuroimmunol., 63 , pp207-211, 1995) The relationship with is also known.

Apoptosis is a very important and tightly regulated cell function among the various physiological actions associated with increased intracellular concentrations of ceramides. It has been found that this is achieved (Obeid, Science , 259 , pp 1769-1771, 1993).

When dysfunction comes in the physiological mechanism of apoptosis, it promotes cancer cell differentiation and differentiation of cancer cells, and normalizing these defects is not toxic to normal cells and selectively promotes cancer cell death only (Selzner., Cancer Research , 61 , pp1233-1240, 2001). The concentration of ceramide was less than 50% in cancer cells than in normal cells. Treatment of ceramides or ceramide degrading enzyme inhibitors with cancer cells increased the concentration of ceramide in cancer cells, facilitating the release of cytochrome c. This activated caspase and caused cell death. No toxicity was reported for normal cells (Selzner, Cancer Research , 61 , pp1233-1240, 2001).

Therefore, ceramide-based compounds or compounds capable of increasing ceramide concentrations may be compounds that enable new therapeutic strategies that show selective toxicity to cancer cells only. Natural ceramide is a compound in which a sphingosine and an acyl group are bonded by an amide bond, and have one hydroxy group on carbon 1 and 3 carbon and one amine group on carbon 2, respectively, as shown in Formula 1 below. It is a compound of (2S, 3R) -D-erythro structure having a trans double bond to carbon.

The ceramide derivative was invented by applying a molecular formula strategy based on the structure of such ceramide. By changing the length of the N-acyl group, the lipophilic properties of the compound were controlled, and the aliphatic group of the sphingosine moiety was converted to an aryl group to increase the cell membrane permeability and improve the pharmacokinetic properties of the compound. The cell death effect was measured.

The present inventors have confirmed that the novel ureido or thioureido ceramide derivative compounds have excellent apoptosis activity against cancer cells to complete the present invention.

It is an object of the present invention to provide useful ureido or thioureido derivative compounds of novel novel chemical structures with anticancer activity, which are analogous to ceramides.

In order to achieve the above object, the present invention provides a compound represented by the following general formula (I), pharmaceutically acceptable salts and isomers thereof as ureido or thioureido derivatives. .

( I )

(I)

In the above formula,

Y is an oxygen atom or a sulfur atom;

R ₁ and R ₂ is a hydrogen atom or a hydroxyl group;

R ₃ is an aromatic ring or a substituent in which a heterocycle having a hetero atom selected from N, O, or S is fused or unfused with each other;

R ₄ is a hydrogen atom or an alkyl group having 1 to 20 carbon atoms.

In the present invention, in the general formula (I), R ₃ is

ego,

X includes at least one hydrogen atom, a halogen atom, a hydroxy group, an alkyl group having 1 to 5 carbon atoms, an alkoxy group or an alkyl group having 1 to 5 carbon atoms or an alkoxy group substituted with a halogen atom, which may be substituted at any position of the ring.

In the general formula (I), Y is an oxygen atom, R ₁ and R ₂ are hydroxy groups, and R ₃ is An aryl group including a phenyl group, a para chlorophenyl group and a para fluorophenyl group, R ₄ is an alkyl group having 1 to 20 carbon atoms including a hydrogen atom, a butyl group, a hexyl group, an octyl group, a nonyl group, a dodecyl group, and a tetradecyl group R ₅ and X include a compound represented by the following general formula (II) which is a substituent as defined above, and an isomer thereof, preferably

(2S, 3R, 4E) -2- (3-n-butyl ureido) -5-phenyl-4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-hexyl ureido) -5-phenyl-4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-octyl ureido) -5-phenyl-4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-nonyl ureido) -5-phenyl-4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-dodecyl ureido) -5-phenyl-4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-tetradecyl ureido) -5-phenyl-4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-butyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-hexyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-octyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-nonyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-dodecyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-tetradecyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-butyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-hexyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-octyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-nonyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-dodecyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-tetradecyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol.

(Ⅱ)

(Ⅱ)

In the general formula (I), Y is a sulfur atom, R ₁ and R ₂ are hydroxy groups, and R ₃ is An aryl group including a phenyl group, a para chlorophenyl group and a para fluorophenyl group, R ₄ is an alkyl group having 1 to 20 carbon atoms including a hydrogen atom, a butyl group, a hexyl group, an octyl group, a decyl group, a dodecyl group, and a tetradecyl group R ₅ and X include a compound represented by the following general formula (III) which is a substituent as defined above, and an isomer thereof, preferably

(2S, 3R, 4E) -2- (3-n-butyl thioureido) -5-phenyl-4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-hexyl thioureido) -5-phenyl-4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-octyl thioureido) -5-phenyl-4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-decyl thioureido) -5-phenyl-4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-dodecyl thioureido) -5-phenyl-4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-tetradecyl thioureido) -5-phenyl-4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-butyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-hexyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-octyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-decyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-dodecyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-tetradecyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-butyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-hexyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-octyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-decyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-dodecyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol,

(2S, 3R, 4E) -2- (3-n-tetradecyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol.

(Ⅲ)

(Ⅲ)

In the above general formula (I), the stereochemistry of chiral centers 2- and 3- of ureido or thioureido is the rule of Can-Ingold and Prelog (RS Cahn, C. Ingold, and Prelog, Angewandte Chemie , International Edition). English, 5, p385, 1966: 5, p511, 1966) is a compound having a stereochemistry of "S" or "R", so the racemic mixture and the R or S-type stereoisomers of the general formula (I) It is included in the scope of the invention. The present invention also includes compounds in the form of pharmaceutically acceptable salts.

In addition, the ureido or thioureido derivative compounds represented by the general formula (I) according to the present invention may form an acceptable acid addition salt according to a conventional method in the art, for example, in an appropriately selected solvent. Prepared by dissolving the compound and treating it with excess inorganic or organic acid. Pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid or nitric acid; And organic acid salts such as acetic acid, methanesulfonic acid, citric acid, fumaric acid, maleic acid, ascorbic acid, succinic acid, tartaric acid, benzenesulfonic acid and the like.

Pharmaceutically acceptable salts of the above general formula (I) include salts of acidic or basic groups which may be present in compounds of general formula (I), unless otherwise indicated. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, and methods or processes for preparing salts known in the art It can be prepared through.

The compounds of formula (I) have asymmetric centers and therefore may exist in different enantiomeric forms, and all optical isomers and stereoisomers of compounds of formula (I) and mixtures thereof are also included within the scope of the present invention. Shall be. The present invention encompasses the use of racemates, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof, and includes methods or processes for the separation of isomers known in the art.

Another object of the present invention is to provide a method for preparing the general formula (I) compounds as follows.

The above method for preparing ureido or thioureido derivatives is obtained by reacting the compound of formula (VII) with chlorotitanium triethoxide and aldehyde to hydrolyze the compound of formula (VII). The ureido of formula (IV) characterized by preparing a compound of formula (I), reducing the compound to prepare a compound of formula (V), and subsequently reacting an isocyanate or isothiocyanate reactant under lower alcohol solvent. Alternatively, thioureido derivative compounds can be prepared.

(Ⅳ)

(Ⅳ)

(Ⅴ)

(Ⅴ)

(Ⅵ)

(Ⅵ)

(Ⅶ)

(Ⅶ)

(Ⅷ)

(Ⅷ)

Where

R ₃ is

ego;

R ₄ is a hydrogen atom or an alkyl group having 1 to 20 carbon atoms.

The isocyanate reactant includes a manufacturing method selected from butyl isocyanate, hexyl isocyanate, octyl isocyanate, nonyl isocyanate, dodecyl isocyanate and tetradecyl isocyanate.

The thioisocyanate reactive agent includes a preparation method selected from butyl thioisocyanate, hexyl thioisocyanate, octyl thioisocyanate, decyl thioisocyanate, dodecyl thioisocyanate and tetradecyl thioisocyanate.

In addition, the lower alcohol solvent means a manufacturing method of the alcohol selected from methanol, ethanol or a mixed solvent thereof.

The compounds of the present invention may be chemically synthesized by the method shown in the following schemes, but are not limited to these examples. The following schemes represent the preparation steps of representative compounds of the present invention, and other compounds may be prepared by appropriate changes in reagents and starting materials known to those skilled in the art.

The process for preparing the compound of general formula (I) is described in detail as described in Scheme 1 below.

The compound of formula (VII), which is used as a starting material in the first step of preparing the compound of the present application, may be obtained by a known method, and the compound of formula (VII) may be a suitable compound of formula (VII). After dissolving in a solvent, chlorotitanium ethoxide (ClTi (OEt) ₃ ) can be dissolved in a suitable solvent, added slowly, and reacted with the corresponding aldehyde in the presence of a suitable base to prepare. Suitable solvents that can be used are single or mixed solvents selected from methylene chloride (CH ₂ Cl ₂ ), N, N-dimethylformamide (DMF), tetrahydrofuran (THF), chloroform, methanol or acetone. Suitable bases are triethylamine (TEA) or pyridine and the like, typical reaction temperatures range from -20 to 100 ° C, preferably 0 ° C, and reaction times range from minutes to 3 days.

The compound of formula (VI) may be prepared by dissolving the compound of formula (VII) in a suitable solvent and then hydrolyzing in the presence of an acid of an appropriate concentration. Suitable solvents that may be used include tetrahydrofuran (THF), It is a single or mixed solvent selected from methanol, ethanol or water, the typical reaction temperature ranges from -20 to 200 ℃, preferably 25 ℃, the reaction time ranges from several minutes to 10 days.

The compound of Formula (V) may be prepared by dissolving the compound of Formula (VI) in a suitable solvent and then reducing with an appropriate reducing agent. Suitable solvents that may be used include tetrahydrofuran (THF), methanol, ethanol or Single or mixed solvent selected from water, suitable reducing agent is sodium borohydride (NaBH ₄ ), sodium hydride (NaH) or lithium aluminum hydride (LiAlH ₄ ), etc., typical reaction temperature range from -20 to 100 ℃ Preferably, it is 0 degreeC, and reaction time is a range from several minutes to 10 days.

The compound of formula (IV) may be prepared by dissolving the compound of formula (V) in a suitable solvent and then slowly adding the corresponding isocyanate or isothiocyanate, and suitable solvents that may be used include tetrahydrofuran (THF). ), Methanol, ethanol or water alone or mixed solvent. Typical reaction temperatures range from -20 to 100 ° C., preferably 25 ° C., and reaction times range from a few minutes to 10 days.

It is still another object of the present invention to provide a pharmaceutical composition containing, as an active ingredient, an amount of the compound of formula (I) and a pharmaceutically acceptable carrier effective in the treatment of cancer and inflammatory diseases.

Pharmaceutical compositions comprising the compounds of the present invention as active ingredients can be used for the treatment and prevention of cancer diseases.

The cancer may include lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, anal muscle cancer, colon cancer, breast cancer, fallopian tube carcinoma, endometrial carcinoma and cervical cancer. Species, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penis cancer, prostate cancer, chronic or acute leukemia, lymphocyte Lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, or a combination of one or more of these cancers It means to include.

In addition, pharmaceutical compositions containing the compounds of the present invention as active ingredients can be used for the treatment and prevention of inflammatory diseases.

The compounds of the present invention have anti-cancer and anti-inflammatory activities, and the pharmaceutical compositions of the present invention can be used for inhibiting and treating inflammation such as alleviating or alleviating anti-cancer or acute, chronic, inflammatory pain.

The compound of formula (I) of the present invention may provide a pharmaceutical composition together with a pharmaceutically acceptable carrier, adjuvant or diluent, by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient. Formulations (e.g., oral, parenteral, intravenous, intraperitoneal, subcutaneous, topical) in conventional formulations in the art may be administered in solid or liquid form, particularly preferably administered orally and intravenously. will be. For example, the compounds of the present invention can be dissolved in oil, propylene glycol or other solvents commonly used in the preparation of injectable solutions, and are not particularly limited as suitable carriers, for example, physiological saline, polyethylene glycol, Ethanol, vegetable oil and isopropyl myristate, and the like, and the compounds of the present invention may be formulated into ointments or creams for topical application.

Hereinafter, the formulation method and the excipient will be described, but are not limited only to these examples.

Pharmaceutical dosage forms of the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.

In clinical use of the pharmaceutical composition of the present invention, it is conventionally combined with a carrier in the pharmaceutical field, and oral administration such as tablets, capsules, troches, elixirs, solutions, suspensions, etc. Preparations for use; Injectable preparations, such as injectable solutions, injectable lyophilized powders or suspensions v; It may be formulated into various forms such as topical preparations such as ointments, creams, and liquids. Carriers that can be used in the pharmaceutical compositions of the present invention should be non-toxic as is commonly applied in the pharmaceutical art.

The compounds of the present invention can be prepared by dissolving, suspending or emulsifying the compound in a conventional saline solution, a water-soluble solvent such as 5% dextrose or a non-aqueous solvent such as vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester or propylene glycol. It can be formulated as. Formulations of the present invention may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.

In the case of preparations for oral administration, binders such as microcrystalline cellulose, gumtragacanth or gelatin; Disintegrants such as alginic acid, Prinogel ^™ and corn starch; Lubricants such as magnesium stearate and steotes ^™ ; Glidants, such as colloidal silica; Sweeteners such as sugar, saccharin, and seasonings such as peppermint, methyl salicylate, orange flavor, and the like may be applied. When the unit dosage form is a capsule, in addition to the additives described above, it may include a liquid carrier such as fatty oil, and in other forms, the unit dosage form may include a material that may improve the physical form of the dosage unit, such as a kuting agent. May contain Thus, in the case of tablets or pills, it may be coated with sugar shellac or coated with other enteric skin. In the case of syrup, in addition to the active compound, it may contain sugars, traditional preservatives, dyes, colorants, seasonings and the like as a sweetener.

Formulations for parenteral administration can be used by preparing the active ingredient in solution or as a lyophilized powder or suspension. Ingredients that may be included in such solutions or lyophilized powders or suspensions include sterile diluents such as water for injection, saline, hardened oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; Antibacterial agents such as benzyl alcohol or methylparabens; Antioxidants such as ascorbic acid or sodium bisulfide; Chelating agents such as ethylene diaminetetraacetic acid (EDTA); Buffers such as acetate, citrate or phosphate; And reagents that control tonicity, such as sodium chloride, dextrose, and mannose. Parenteral preparations may be used in ampoules, disposable syringes, or multiple dose vials made of glass or plastic.

Preferred dosages of the compounds of the present invention vary depending on the condition and weight of the patient, the severity of the disease, the form of the drug, the route of administration and the duration of administration, and may be appropriately selected by those skilled in the art and for particularly preferred effects, the compounds of the present invention Silver is 0.0001 to 100mg / kg per day, preferably 0.001 to 100mg / kg, preferably administered once a day, can be administered several times divided. The compound of the present invention in the composition should be present in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight relative to the total weight of the total composition.

The pharmaceutical composition of the present invention can be administered to various mammals such as rats, mice, livestock, humans, and the like. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection. The present invention provides pharmaceutical compositions for the prevention and treatment of anticancer and acute, chronic, inflammatory diseases.

Hereinafter, the present invention will be described in detail by way of examples.

However, the following reference examples, examples and experimental examples are merely to illustrate the present invention, the content of the present invention is not limited to the following reference examples, examples and experimental examples.

Reference Example 1. Laboratory Instruments and Reagents

Analytical instruments for the compounds prepared herein include ¹ H-NMR (300 MHz, Varian Gemini 2000, USA) and mass spectrometers (Autospec M363, Micromass, UK), and the internal standard of NMR is tetramethyl silane (tetramethyl). silane, TMS), thin layer chromatography (TLC) was identified using a silica gel 60 F254 (thickness 0.2 ㎛, Merck) spots with an ultraviolet lamp, silica gel column chromatography was silica gel (Merck type 9355, 230 ~) 400 mesh) and all reagents were purchased from Aldrich (Aldrich). In addition, infrared measurement (Nicolet, Magna 750), melting point measurement (Buchi, Melting point B-540), photoluminescence (JASCO, DIP-370) and absorbance (CERES, UV-900C) Was done.

Example 1. [(R, R, R, R)-(+)-3-hydroxy-2- (2-hydroxy-2,6,6-trimethyl-bicyclo

[3.1.1] Preparation of hept-3-ideneamino) -5-phenyl-pentene-4-acid ethyl ester (1)

[(1R, 2R, 5R)-(+)-2-hydroxy-2,6,6-trimethyl-bicyclo [3.1.1] hept-3-ideneamino] acetic acid ethyl ester (2.5 g, 10 mmol) The solution dissolved in methylene chloride (10 mL) was cooled to 0 ° C., and chlorotitanium ethoxide (2.18 g, 10 mmol) was dissolved in methylene chloride (10 mL) and slowly added dropwise to this mixture, followed by trans-cinnamaldehyde (1.45 g). , 11 mmol) was added dropwise in methylene chloride (10 mL) and anhydrous triethylamine (2.02 g, 20 mmol) was added dropwise. After further reacting at 0 ° C. for 4 hours, the reaction solution was added to a cold brine solution, stirred, extracted with ethyl acetate (4 × 30 mL), the organic layers were collected, dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. Was purified by silica gel column chromatography using a developing solvent (eluent: ethyl acetate: hexane = 1: 4), and 1.85 g (yield 48%) of [(R, R, R, R)-(+)-3 -Hydroxy-2- (2-hydroxy-2,6,6-trimethyl-bicyclo [3.1.1] hept-3-ideneamino) -5-phenyl-penten-4-ic acid ethyl ester was obtained ( See Table 1).

TLC (ethyl acetate: hexane = 1: 1): R _f = 0.24

= + 14.3 (c=0.65, 메탄올)

= + 14.3 (c = 0.65, methanol)

IR (CHCl ₃ ) cm ^-1 : 3540 (OH), 1740 (C = O), 1655 (C = N), 1520 (arom, C = C)

¹ H-NMR [CDCl ₃ ] δ: 0.88 (s, 3H, CH ₃ ), 1.26 (t, 3H, J = 7.2 Hz, CH ₃ ), 1.32 (s, 3H, CH ₃ ), 1.54 (d, 1H , J = 11.1Hz, H CH), 1.64 (s, 3H, CH ₃ ), 2.02 ~ 2.10 (m, 2H, CH + CH), 2.30 ~ 2.40 (m, 1H, HC H ), 2.43 ~ 2.50 (m , 2H, CH ₂ ), 4.19-4.23 (m, 3H, CH ₂ O + CH-N), 4.80-4.91 (m, 1H, H C-OH), 6.22 (dd, 1H, J = 15.2 and 6.0 Hz , = CH-), 6.71 (d, 1H, J = 15.2Hz, ph-CH =), 7.00 ~ 7.36 (m, 5H, arom)

Example 2. [(R, R, R, R)-(+)-5- (4-Chloro phenyl) -3-hydroxy-2- (2-hydroxy-2,6,6-trimethyl-bi Preparation of cyclo [3.1.1] hept-3-ideneamino) -pentene-4-acid ethyl ester (2006.01)

[(1R, 2R, 5R)-(+)-2-hydroxy-2,6,6-trimethyl-bicyclo [3.1.1] hept-3-ideneamino] acetic acid ethyl ester (2.5 g, 10 mmol) The solution dissolved in methylene chloride (10 ml) was cooled to 0 ° C., and chlorotitanium ethoxide (2.18 g, 10 mmol) was dissolved in methylene chloride (10 ml) and slowly added dropwise to the mixture, followed by 3- (4-chlorophenyl) ) -Propenal (1.45 g, 11 mmol) is added dropwise in methylene chloride (10 mL) and anhydrous triethylamine (2.02 g, 20 mmol) is added dropwise. After further reacting at 0 ° C. for 4 hours, the reaction solution was added to a cold brine solution, stirred, extracted with ethyl acetate (4 × 30 mL), the organic layers were collected, dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The obtained compound was purified by silica gel column chromatography using a developing solvent (ethyl acetate: hexane = 1: 4), and 1.64 g (yield 39%) of [(R, R, R, R)-(+)-5 -(4-Chloro phenyl) -3-hydroxy-2- (2-hydroxy-2,6,6-trimethyl-bicyclo [3.1.1] hept-3-ideneamino) -pentene-4- acid ethyl An ester was obtained (see Table 1).

TLC (ethyl acetate: hexane = 1: 1): R _f = 0.22

= + 17.4 (c=0.95, 메탄올)

= + 17.4 (c = 0.95, methanol)

IR (CHCl ₃ ) cm ^-1 : 3540 (OH), 1745 (C = O), 1655 (C = N), 1510 (arom, C = C)

¹ H-NMR [CDCl ₃ ] δ: 0.86 (s, 3H, CH ₃ ), 1.26 (t, 3H, J = 7.2 Hz, CH ₃ ), 1.32 (s, 3H, CH ₃ ), 1.51 (s, 3H , CH ₃ ), 1.56 (d, 1H, J = 10.8 Hz, H CH) 2.02-2.13 (m, 2H, CH + CH), 2.31-2.39 (m, 1H, HC H ), 2.48 (bro s, 2H , CH ₂ ), 4.12-4.21 (m, 3H, CH ₂ O + CH-N), 4.70-4.81 (m, 1H, H C-OH), 6.21 (dd, 1H, J = 15.3 and 6.2 Hz, = CH-), 6.65 (d, 1H, J = 15.3 Hz, ph-CH =), 7.01 to 7.30 (m, 5H, arom)

Example 3. [(R, R, R, R)-(+)-5- (4-fluorophenyl) -3-hydroxy-2- (2-hydroxy-2,6,6-trimethyl- Preparation of bicyclo [3.1.1] hept-3-ideneamino) -pentene-4-acid ethyl ester (2006.01)

[(1R, 2R, 5R)-(+)-2-hydroxy-2,6,6-trimethyl-bicyclo [3.1.1] hept-3-ideneamino] acetic acid ethyl ester (2.5 g, 10 mmol) The solution dissolved in methylene chloride (10 mL) was cooled to 0 ° C., and chlorotitanium ethoxide (2.18 g, 10 mmol) was dissolved in methylene chloride (10 mL) and slowly added dropwise to the mixture, followed by 3- (4-fluoro Phenyl) -propenal (1.45 g, 11 mmol) was added dropwise in methylene chloride (10 mL) and anhydrous triethylamine (2.02 g, 20 mmol) was added dropwise. The reaction solution was further reacted at 0 ° C. for 4 hours, the reaction solution was added to a cold brine solution, stirred, extracted with ethyl acetate (4 × 30 mL), the organic layers were collected, dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. Was purified by silica gel column chromatography using a developing solvent (ethyl acetate: hexane = 1: 4), and 2.3 g (yield 58%) of [(R, R, R, R)-(+)-5- ( 4-Fluorophenyl) -3-hydroxy-2- (2-hydroxy-2,6,6-trimethyl-bicyclo [3.1.1] hept-3-ideneamino) -pentene-4- acid ethyl ester Was obtained (see Table 1).

TLC (ethyl acetate: hexane = 1: 1): R _f = 0.27

= + 12.5 (c=0.75, 메탄올)

= + 12.5 (c = 0.75, methanol)

IR (CHCl ₃ ) cm ^-1 : 3550 (OH), 1740 (C = O), 1650 (C = N), 1540 (arom, C = C)

¹ H-NMR [CDCl ₃ ] δ: 0.86 (s, 3H, CH ₃ ), 1.22 (t, 3H, J = 7.2 Hz, CH ₃ ), 1.31 (s, 3H, CH ₃ ), 1.45 (d, 1H , J = 10.8 Hz, H CH), 1.51 (s, 3H, CH ₃ ), 2.01-2.15 (m, 2H, CH + CH), 2.34-2.40 (m, 1H, HC H ), 2.52-2.60 (m , 2H, CH ₂ ), 4.20-4.29 (m, 3H, CH ₂ O + CH-N), 4.70-4.81 (m, 1H, H C-OH), 6.13 (dd, 1H, J = 15.6 and 6.3 Hz , = CH-), 6.67 (d, 1H, J = 15.6Hz, ph-CH =), 6.90 ~ 7.10 (m, 2H, arom), 7.29 ~ 7.30 (m, 2H, arom)

(Ⅶ)

(Ⅶ)

compound R ₃ One -CH = CH-ph 2

3

Example 4 Preparation of (2R, 3R, 4E) -2-Amino-3-hydroxy-5-phenyl-penten-4-acid (4)

The compound of Example 1 (1.1 g, 2.94 mmol) was dissolved in 1.2 N hydrochloric acid (20 mL) and tetrahydrofuran (5 mL) and reacted at 25 ° C. for 3 days. After completion of the reaction, the tetrahydrofuran was concentrated under reduced pressure. The aqueous layer was extracted with ethyl ether (4 × 20 mL), the aqueous layer was neutralized with sodium bicarbonate (pH = 7 to 7.5), extracted with ethyl acetate (4 × 20 mL), and the organic layer was dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained compound was purified by silica gel column chromatography using a developing solvent (chloroform: methanol = 7: 1) to obtain 0.44 g (yield 63%) of (2R, 3R, 4E) -2. Amino-3-hydroxy-5-phenyl-pentene-4-acid was obtained (see Table 2).

TLC (chloroform: methanol = 7: 1): R _f = 0.53

= +16.0 (c=0.25, 메탄올)

= +16.0 (c = 0.25, methanol)

IR (CHCl ₃ ) cm ^-1 : 1740 (C = O), 1520 (arom, C = C)

¹ H-NMR [CDCl ₃ ] δ: 1.24 (t, 3H, J = 7.2 Hz, CH ₂ C H ₃ ), 3.66 (d, 1H, J = 5.1 Hz, H C-NH ₂ ), 4.17-4.28 ( m, 2H, CH ₂ O), 4.49-4.59 (m, 1H, H C-OH), 6.25 (dd, 1H, J = 15.9 and 6.6 Hz, = CH-), 6.69 (d, 1H, J = 15.9 Hz, ph-CH =), 7.24 ~ 7.40 (m, 5H, arom)

Example 5 Preparation of (2R, 3R, 4E) -2-Amino-5- (4-chlorophenyl) -3-hydroxy-5-phenyl-penten-4-acid (5)

The compound of Example 2 (1.1 g, 2.94 mmol) was dissolved in 1.2 N hydrochloric acid (20 mL) and tetrahydrofuran (5 mL) and reacted at 25 ° C. for 3 days. After completion of the reaction, tetrahydrofuran was concentrated under reduced pressure. The aqueous layer was extracted with ethyl ether (4 × 20 mL), the aqueous layer was neutralized with sodium bicarbonate (pH = 7 to 7.5), extracted with ethyl acetate (4 × 20 mL), the organic layer was dried over anhydrous magnesium sulfate and filtered. One filtrate was concentrated under reduced pressure, and the obtained compound was purified by silica gel column chromatography using a developing solvent (chloroform: methanol = 7: 1), and 0.24 g (yield 30%) of (2R, 3R, 4E) -2- Amino-5- (4-chlorophenyl) -3-hydroxy-5-phenyl-pentene-4-acid was obtained (see Table 2).

TLC (chloroform: methanol = 7: 1): R _f = 0.49

= + 24.0 (c=0.75, 메탄올)

= + 24.0 (c = 0.75, methanol)

IR (CHCl ₃ ) cm ^-1 : 1750 (C = O), 1520 (arom, C = C)

¹ H-NMR [CDCl ₃ ] δ: 1.23 (t, 3H, J = 7.2 Hz, CH ₂ C H ₃ ), 4.06 (d, 1H, J = 4.2 Hz, H C-NH ₂ ), 4.19-4.28 ( m, 2H, CH ₂ O), 4.62 to 4.73 (m, 1H, H C-OH), 6.28 (dd, 1H, J = 15.9 and 6.6 Hz, = CH-), 6.68 (d, 1H, J = 15.9 Hz, ph-CH =), 7.28-7.41 (m, 4H, arom)

Example 6 Preparation of (2R, 3R, 4E) -2-Amino-5- (4-fluorophenyl) -3-hydroxy-5-phenyl-penten-4-acid (6)

The compound of Example 3 (1.1 g, 2.94 mmol) was dissolved in 1.2 N hydrochloric acid (20 mL) and tetrahydrofuran (5 mL) and reacted at 25 ° C. for 3 days. After completion of the reaction, tetrahydrofuran was concentrated under reduced pressure. The aqueous layer was extracted with ethyl ether (4 × 20 mL), the aqueous layer was neutralized with sodium bicarbonate (pH = 7 to 7.5), extracted with ethyl acetate (4 × 20 mL), the organic layer was dried over anhydrous magnesium sulfate and filtered. One filtrate was concentrated under reduced pressure, and the obtained compound was purified by silica gel column chromatography using a developing solvent (chloroform: methanol = 7: 1) to give 0.60 g (yield 80%) of (2R, 3R, 4E) -2-. Amino-5- (4-fluorophenyl) -3-hydroxy-5-phenyl-pentene-4-acid was obtained (see Table 2).

TLC (chloroform: methanol = 7: 1): R _f = 0.47

= + 23.0 (c=0.45, 메탄올)

= + 23.0 (c = 0.45, methanol)

IR (CHCl ₃ ) cm ^-1 : 1740 (C = O), 1540 (arom, C = C)

¹ H-NMR [CDCl ₃ ] δ: 1.25 (t, 3H, J = 7.2 Hz, CH ₂ C H ₃ ), 4.22 (d, 1H, J = 4.2 Hz, H C-NH ₂ ), 4.20-4.30 ( m, 2H, CH ₂ O), 4.69 to 4.71 (m, 1H, H C-OH), 6.20 (dd, 1H, J = 15.6 and 6.6 Hz, = CH-), 6.72 (d, 1H, J = 15.6 Hz, ph-CH =), 7.05 (t, 2H, J = 8.7 Hz, arom), 7.42-7.45 (m, 2H, arom)

(Ⅵ)

(Ⅵ)

compound R ₃ 4 -CH = CH-ph 5

6

Example 7 Preparation of (2S, 3R, 4E) -2-Amino-5-phenyl-4-pentene-1,3-diol (7)

The compound of Example 4 (0.14 g, 0.6 mmol) was dissolved in 5 ml of a mixed solution (ethanol: water = 3: 1), cooled to 0 ° C., and sodium borohydride (0.9 g, 2.4 mol) was added at once. It was. The reaction solution was stirred at 0 ° C. for 4 days to confirm the reaction progress by thin layer chromatography. After completion of the reaction, the reaction solution was extracted with ethyl acetate (4 × 5 mL). The extracted organic layer was collected, dried over anhydrous magnesium sulfate, and concentrated to obtain a compound. The compound was purified by silica gel column chromatography using a developing solvent (chloroform: methanol: water = 6: 4: 0.5) to yield 0.06 g (yield 55). %) Of (2S, 3R, 4E) -2-amino-5-phenyl-4-pentene-1,3-diol (see Table 3).

TLC (chloroform: methanol: water = 6: 4: 0.5): R _f = 0.17

= + 30.1 (c=0.35, 메탄올)

= + 30.1 (c = 0.35, methanol)

IR (KBr) cm ^-1 : 3500 (OH), 1520 (arom, C = C)

¹ H-NMR [CD ₃ OD] δ: 2.94 (td, 1H, J = 6.0 and 4.9 Hz, H C-NH ₂ ), 3.56 (dd, 1H, J = 11.3 and 6.0 Hz, H CH-OH), 3.73 (dd, 1H, J = 11.3 and 5.8 Hz, HC H- OH), 4.24 (t, 1H, J = 6.4 Hz, H C-OH), 6.3 (dd, 1H, J = 15.9 and 6.9 Hz, = CH-), 6.66 (d, 1H, J = 15.9 Hz, ph-CH =), 7.20-7.45 (m, 5H, arom)

Example 8 Preparation of (2S, 3R, 4E) -2-Amino-5- (4-chlorophenyl) -4-pentene-1,3-diol (8)

The compound of Example 5 (0.14 g, 0.6 mmol) was dissolved in 5 ml of a mixed solution (ethanol: water = 3: 1), cooled to 0 ° C., and sodium borohydride (0.9 g, 2.4 mol) was added at once. It was. The reaction solution was stirred at 0 ° C. for 4 days to confirm the reaction by thin layer chromatography. After completion of the reaction, the mixture was extracted with ethyl acetate (4 × 5 mL). The extracted organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to obtain a compound. This compound was purified by silica gel column chromatography using a developing solvent (chloroform: methanol: water = 6: 4: 0.5) to give 0.08 g (59% yield) of (2S, 3R, 4E) -2-amino-. 5- (4-chlorophenyl) -4-pentene-1,3-diol was obtained (see Table 3).

TLC (chloroform: methanol: water = 6: 4: 0.5): R _f = 0.20

= + 25.0 (c=0.38, 메탄올)

= + 25.0 (c = 0.38, methanol)

IR (KBr) cm ^-1 : 3550 (OH), 1520 (arom, C = C)

¹ H-NMR [CD ₃ OD] δ: 2.98 (m, 1H, H C-NH ₂ ), 3.59 (dd, 1H, J = 11.1 and 6.3 Hz, H CH-OH), 3.70 (dd, 1H, J = 11.1 and 6.0 Hz, HC H- OH), 4.27 (t, 1H, J = 6.3 Hz, H C-OH), 6.32 (dd, 1H, J = 16.5 and 6.9 Hz, = CH-), 6.65 (d , 1H, J = 16.5Hz, ph-CH =), 7.25 ~ 7.42 (m, 4H, arom)

Example 9 Preparation of (2S, 3R, 4E) -2-Amino-5- (4-fluorophenyl) -4-pentene-1,3-diol (9)

The compound of Example 6 (0.14 g, 0.6 mmol) was dissolved in a mixed solution (5 mL) of a mixed solution (ethanol: water = 3: 1), cooled to 0 ° C., and sodium borohydride (0.9 g, 2.4 mol). ) Was added at a time. The reaction solution was stirred at 0 ° C. for 4 days to confirm the progress of the reaction by thin layer chromatography. After completion of the reaction, the mixture was extracted with ethyl acetate (4 × 5 mL). The extracted organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated to obtain a compound. The compound was purified by silica gel column chromatography using a developing solvent (chloroform: methanol: water = 6: 4: 0.5) to give 0.08 g (66%) of (2S, 3R, 4E) -2-amino. -5- (4-fluorophenyl) -4-pentene-1,3-diol was obtained (see Table 3).

TLC (chloroform: methanol: water = 6: 4: 0.5): R _f = 0.22

= + 30.0 (c=0.50, 메탄올)

= + 30.0 (c = 0.50, methanol)

IR (KBr) cm ^-1 : 3500 (OH), 1540 (arom, C = C)

¹ H-NMR [CD ₃ OD] δ: 3.10 (m, 1H, H C-NH ₂ ), 3.73 (dd, 1H, J = 11.4 and 6.1 Hz, H CH-OH), 3.77 (dd, 1H, J = 11.4 and 6.0 Hz, HC H- OH), 4.42 (t, 1H, J = 7.5 Hz, H C-OH), 6.22 (dd, 1H, J = 15.6 and 6.3 Hz, = CH-), 6.72 (d , 1H, J = 15.6Hz, ph-CH =), 6.98 ~ 7.05 (m, 2H, arom), 7.38 ~ 7.49 (m, 2H, arom)

(Ⅴ)

(Ⅴ)

compound R ₃ 7 -CH = CH-ph 8

9

Example 10. General Preparation of Ureido Compounds

Pentene diol (1.29 mmol) was dissolved in ethanol (50 mL), and slowly reacted with alkyl isocyanate (1.68 mmol) at room temperature for 4 hours, and then the reaction solution was diluted with ethyl acetate (200 mL) and water (30 mL). ), Saturated aqueous sodium bicarbonate solution (30 ml), 5% citric acid (30 ml) and brine (30 ml), combined organic layers, dried over anhydrous sodium sulfate, and the resulting compound was concentrated on silica gel column chromatography (Merck type 9355). , 230-400 mesh) to obtain a pure ureido compound.

Example 11 Preparation of (2S, 3R, 4E) -2- (3-n-butyl ureido) -5-phenyl-4-pentene-1,3-diol (10)

(2S, 3R, 4E) -2-Amino-5-phenyl-4-pentene-1,3-diol (7) (100 mg, 0.52 mmol) and n-butyl isocyanate (67 mg, 0.67 mmol) It synthesize | combined according to the preparation method described in Example 10, and refine | purified by silica gel column chromatography using the developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E) -2- (3-n- Butyl ureido) -5-phenyl-4-pentene

55 mg (36% yield) of -1,3-diol compound (10) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1), R _f = 0.35

= 16 (C=0.1 , 메탄올)

= 16 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3350 (NH), 1650 (C = O), 1520 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.85 (t, 3H, J = 7.2 Hz, CH ₃ CH ₂ ), 1.28 to 1.35 (m, 4H, (CH ₂ ) ₂ ), 3.08 (m, 2H, CH ₂ -NH), 3.62-3.65 (m, 2H, HO-CH ₂ ), 3.76-3.79 (t, 1H, HC-NH), 4.13-4.17 (m, 1H, HC-OH), 6.31 (d, d , 1H, J = 15.9 and 6.9HZ, = CH-), 6.60 (d, 1H, J = 15.9Hz, ph-CH =), 7.13-7.42 (m, 5H, arom)

FABMS (M + Na) ⁺ for C ₁₆ H ₂₄ N ₂ O ₃ Na: calc. 315.26; Found 315.12

Example 12. Preparation of (2S, 3R, 4E) -2- (3-n-hexyl ureido) -5-phenyl-4-pentene-1,3-diol (11)

(2S, 3R, 4E) -2-Amino-5-phenyl-4-pentene-1,3-diol (7) (100 mg, 0.52 mmol) and n-hexyl isocyanate (85 mg, 0.67 mmol) It was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to give (2S, 3R, 4E) -2- (3-n- 107 mg (yield 65%) of hexyl ureido) -5-phenyl-4-pentene-1,3-diol compound (11) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.33

= 9 (C=0.1 , 메탄올)

= 9 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3340 (NH), 1640 (C = O), 1520 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.89 (t, 3H, J = 6.6 Hz, CH ₃ CH ₂ ), 1.26-1.40 (m, 8H, (CH ₂ ) ₄ ), 3.10 (m, 2H, CH ₂ -NH), 3.69 (m, 2H, HO-CH ₂ ), 3.80 (m, 1H, HC-NH), 4.32 (t, 1H, HC-OH), 6.32 (d, d, 1H, J = 15.9 and 6.6 HZ, = CH-), 6.61 (d, 1H, J = 15.9 Hz, ph-CH =), 7.14-7.43 (m, 5H, arom)

FABMS (M + H) ⁺ for C ₁₈ H ₂₉ N ₂ O ₃ : calcd 321.21; Found 321.11

Example 13. Preparation of (2S, 3R, 4E) -2- (3-n-octyl ureido) -5-phenyl-4-pentene-1,3-diol (12)

Example using (2S, 3R, 4E) -2-amino-5-phenyl-4-pentene-1,3-diol (7) (250 mg, 1.29 mmol) and n-octyl isocyanate (260 mg, 1.68 mmol) It was synthesized according to the preparation method described in 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to give (2S, 3R, 4E) -2- (3-n-octyl Ureido) -5-phenyl-4-pentene-1,3-diol compound (12) 250 mg (yield 56%) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.15

= 42 (C=0.1 , 메탄올 )

= 42 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3320 (NH), 1640 (C = O), 1530 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.90 (t, 3H, J = 6.6 Hz, CH ₃ CH ₂ ), 1.25-1.39 (m, 12H, (CH ₂ ) ₆ ), 3.07 (m, 2H, CH ₂ -NH), 3.75 (m, 2H, HO-CH ₂ ), 3.77-3.83 (m, 1H, HC-NH), 4.30-4.32 (t, 1H, HC-OH), 6.27 (d, d, 1H , J = 15.9 and 6.6HZ, = CH-), 6.61 (d, 1H, J = 15.9Hz, ph-CH =), 7.21-7.43 (m, 5H, arom)

FABMS (M + H) ⁺ for C ₂₀ H ₃₃ N ₂ 0 ₃ : calcd. 349.25; Found 349.27

Example 14 Preparation of (2S, 3R, 4E) -2-nonyl ureido-5-phenyl-4-pentene-1,3-diol (13)

Example using (2S, 3R, 4E) -2-amino-5-phenyl-4-pentene-1,3-diol (7) (100 mg, 0.52 mmol) and n-nonyl isocyanate (113 mg, 0.67 mmol) It was synthesized according to the preparation method described in 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to give (2S, 3R, 4E) -2-nonyl ureido-5-. 170 mg (yield 91%) of phenyl-4-pentene-1,3-diol compound (13) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.30

= 18 (C=0.1 , 메탄올)

= 18 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3300 (NH), 1660 (C = O), 1540 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.80 (t, 3H, J = 7.2 Hz, CH ₃ CH ₂ ), 1.14 to 1.28 (m, 14H, (CH ₂ ) ₇ ), 2.98 (m, 2H, CH ₂ -NH), 3.58 (m, 2H, HO-CH ₂ ), 3.69-3.71 (m, 1H, HC-NH), 4.20 (m, 1H, HC-OH), 6.15-6.23 (d, d, 1H) , J = 15.9 and 6.9HZ, = CH-), 6.50 to 6.55 (d, 1H, J = 15.9 Hz, ph-CH =), 7.10 to 7.32 (m, 5H, arom)

FABMS (M + H) ⁺ for C ₂₁ H ₃₅ N ₂ O ₃ : calcd. 363.26; Found 363.29

Example 15. Preparation of (2S, 3R, 4E) -2- (3-n-dodecyl ureido) -5-phenyl-4-pentene-1,3-diol (14)

(2S, 3R, 4E) -2-amino-5-phenyl-4-pentene-1,3-diol (7) (100 mg, 0.52 mmol) and n-dodecyl isocyanate (142 mg, 0.67 mmol) It was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to give (2S, 3R, 4E) -2- (3-n-dode 122 mg (yield 58%) of silureido) -5-phenyl-4-pentene-1,3-diol compound (14) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.34

= 13 (C=0.1 , 메탄올)

= 13 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3310 (NH), 1650 (C = O), 1550 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.91 (t, 3H, J = 6.0 Hz, CH ₃ CH ₂ ), 1.24 to 1.41 (m, 20H, (CH ₂ ) ₁₀ ), 3.07 (m, 2H, CH ₂ -NH), 3.68 (m, 2H, HO-CH ₂ ), 3.80 (m, 1H, HC-NH), 4.30 (m, 1H, HC-OH), 6.26-6.34 (d, d, 1H, J = 16.2 and 7.2HZ, = CH-), 6.60 to 6.66 (d, 1H, J = 16.2 Hz, ph-CH =), 7.21 to 7.42 (m, 5H, arom)

FABMS (M + H) ⁺ for C ₂₄ H ₄₁ N ₂ O ₃ : calcd 405.30; Found 405.15

Example 16. Preparation of (2S, 3R, 4E) -2- (3-n-tetradecyl ureido) -5-phenyl-4-pentene-1,3-diol (15)

(2S, 3R, 4E) -2-amino-5-phenyl-4-pentene-1,3-diol (7) (250 mg, 1.29 mmol) and n-tetradecyl isocyanate (402 mg, 1.68 mmol) It was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E) -2- (3-n 257 mg (yield 46%) of -tetradecyl ureido) -5-phenyl-4-pentene-1,3-diol compound (15) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.24

= 17 (C=0.1 , 메탄올)

= 17 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3320 (NH), 1630 (C = O), 1565 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.85 (t, 3H, J = 6.3 Hz, C H ₃ CH ₂ ), 1.14 to 1.28 (m, 24H, (CH ₂ ) ₁₂ ), 2.94 (m, 2H, C H ₂ -NH), 3.55 (m, 2H, HO-C H ₂ ), 3.71 (t, 1H, H C-NH), 4.20 (m, 1H, H C-OH), 6.21 (d, d, 1H, J = 16.8 and 6.6H _Z , = CH-), 6.62 (d, 1H, J = 16.8 Hz, ph-CH =), 7.10-7.31 (m, 5H, arom)

FABMS (M + H) ⁺ for C ₂₆ H ₄₅ N ₂ 0 ₃ : calc. 433.34; Found 433.27

Example 17. Preparation of (2S, 3R, 4E) -2- (3-n-butyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol (16)

(2S, 3R, 4E) -2-amino-5- (4-chlorophenyl) -4-pentene-1,3-diol (8) (100 mg, 0.44 mmol) and n-butyl isocyanate (57 mg, 0.57 mmol) Was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to obtain (2S, 3R, 4E) -2- (3). 100 mg (yield 70%) of -n-butyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol compound (16) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.22

= 4 (C=0.1 , 메탄올)

= 4 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3330 (NH), 1660 (C = O), 1550 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.89 (t, 3H, J = 7.2 Hz, C H ₃ CH ₂ ), 1.28 to 1.39 (m, 4H, (CH ₂ ) ₂ ), 3.08 (m, 2H, C H ₂ -NH), 3.61 to 3.67 (m, 2H, HO-C H ₂ ), 3.80 (m, 1H, H C-NH), 4.52 (m, 1H, H C-OH), 6.31 (d, d, 1H, J = 15.9 and 6.0H _Z , = CH-), 6.61 (d, 1H, J = 15.9 Hz, ph-CH =), 7.28-7.40 (m, 4H, arom)

FABMS (M + Na) ⁺ for C ₁₆ H ₂₄ ClN ₂ O ₃ Na: calc. 349.12; Found 349.12

Example 18. Preparation of (2S, 3R, 4E) -2- (3-n-hexyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol (17)

(2S, 3R, 4E) -2-amino-5- (4-chlorophenyl) -4-pentene-1,3-diol (8) (200 mg, 0.88 mmol) and n-hexyl isocyanate (163 mg, 1.14 mmol) Was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to obtain (2S, 3R, 4E) -2- (3). 100 mg (yield 31%) of -n-hexyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol compound (17) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.20

= 37 (C=0.1 , 메탄올)

= 37 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3350 (NH), 1640 (C = O), 1530 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.90 (t, 3H, J = 7.2 Hz, C H ₃ CH ₂ ), 1.25 to 1.39 (m, 8H, (CH ₂ ) ₄ ), 3.04 to 3.09 (m, 2H, C H ₂ -NH), 3.66 (m, 2H, HO-C H ₂ ), 3.81 (m, 1H, H C-NH), 4.35 (m, 1H, H C-OH), 6.35 (d, d, 1H, J = 14.1 and 7.2H _Z , = CH-), 6.59 (d, 1H, J = 14.1 Hz, ph-CH =), 7.29-7.42 (m, 4H, arom)

FABMS (M + H) ⁺ for C ₁₈ H ₂₈ ClN ₂ O ₃ : calcd 355.17; Found 355.12

Example 19. Preparation of (2S, 3R, 4E) -2- (3-n-octyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol (18)

(2S, 3R, 4E) -2-amino-5- (4-chlorophenyl) -4-pentene-1,3-diol (8) (200 mg, 0.88 mmol) and n-octyl isocyanate (177 mg, 1.14 mmol) Was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to obtain (2S, 3R, 4E) -2- (3). 120 mg (36% yield) of -n-octyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol compound (18) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.13

= 32 (C=0.1 , 메탄올)

= 32 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3400 (NH), 1650 (C = O), 1540 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.89 (t, 3H, J = 7.2 Hz, C H ₃ CH ₂ ), 1.24 to 1.33 (m, 12H, (CH ₂ ) ₆ ), 3.04 (m, 2H, C H ₂ -NH), 3.64 (m, 2H, HO-C H ₂ ), 3.79 (m, 1H, H C-NH), 4.30 (t, 1H, H C-OH), 6.33 (d, d, 1H, J = 15.6 and 6.6H _Z , = CH-), 6.57 (d, 1H, J = 15.6Hz, ph-CH =), 7.27-7.40 (m, 4H, arom)

FABMS (M + H) ⁺ for C ₂₀ H ₃₂ ClN ₂ O ₃ : calcd. 383.20; Found 383.12

Example 29. Preparation of (2S, 3R, 4E) -2- (3-n-nonyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol (19)

(2S, 3R, 4E) -2-amino-5- (4-chlorophenyl) -4-pentene-1,3-diol (8) (250 mg, 1.09 mmol) with n-nonyl isocyanate (235 mg, 1.28 mmol) Was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to obtain (2S, 3R, 4E) -2- (3). 69 mg (yield 16%) of -n-nonyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol compound (19) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1), R _f = 0.15

= 25 (C=0.1 , 메탄올)

= 25 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3500 (NH), 1640 (C = O), 1550 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.92 (t, 3H, J = 6.9 Hz, C H ₃ CH ₂ ), 1.26 to 1.38 (m, 14H, (CH ₂ ) ₇ ), 3.07 (m, 2H, C H ₂ -NH), 3.65 (m, 2H, HO-C H ₂ ), 3.78 (m, 1H, H C-NH), 4.30 (m, 1H, H C-OH), 6.32 (d, d, 1H, J = 15.6 and 6.6H _Z , = CH-), 6.62 (d, 1H, J = 15.6 Hz, ph-CH =), 7.30-7.42 (m, 4H, arom)

FABMS (M + H) ⁺ for C ₂₁ H ₃₄ ClN ₂ O ₃ : calcd 397.22; Found 397.18

Example 21.Preparation of (2S, 3R, 4E) -2- (3-n-dodecyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol (20)

(2S, 3R, 4E) -2-amino-5- (4-chlorophenyl) -4-pentene-1,3-diol (8) (200 mg, 0.88 mmol) and n-dodecyl isocyanate (270 mg, 1.28 mmol) ) Was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to give (2S, 3R, 4E) -2- ( 184 mg (yield 48%) of 3-n-dodecyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol compound (20) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.17

= 29 (C=0.1 , 메탄올)

= 29 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3400 (NH), 1650 (C = O), 1540 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.91 (t, 3H, J = 6.9 Hz, C H ₃ CH ₂ ), 1.29 to 1.38 (m, 20H, (CH ₂ ) ₁₀ ), 3.08 (m, 2H, C H ₂ -NH), 3.68 (m, 2H, HO-C H ₂ ), 3.78 (m, 1H, H C-NH), 4.29 (t, 1H, H C-OH), 6.30 (d, d, 1H, J = 15.9 and 7.2H _Z , = CH-), 6.57 (d, 1H, J = 15.9 Hz, ph-CH =), 7.29-7.41 (m, 4H, arom)

FABMS (M + H) ⁺ for C ₂₄ H ₄₀ ClN ₂ O ₃ : calcd 439.26; Found 439.16

Example 22. Preparation of (2S, 3R, 4E) -2- (3-n-tetradecyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol (21)

(2S, 3R, 4E) -2-amino-5- (4-chlorophenyl) -4-pentene-1,3-diol (8) (250 mg, 1.10 mmol) with n-tetradecyl isocyanate (342 mg, 1.43 mmol ) Was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to give (2S, 3R, 4E) -2- ( 134 mg (yield 26%) of 3-n-tetradecyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol compound (21) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.22

= 18 (C=0.1 , 메탄올)

= 18 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3350 (NH), 1660 (C = O), 1560 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.90 (t, 3H, J = 7.2 Hz, C H ₃ CH ₂ ), 1.28 to 1.37 (m, 24H, (CH ₂ ) ₁₂ ), 3.07 (m, 2H, C H ₂ -NH), 3.64 (m, 2H, HO-C H ₂ ), 3.77 (m, 1H, H C-NH), 4.28 (m, 1H, H C-OH), 6.32 (d, d, 1H, J = 15.6 and 6.9H _Z , = CH-), 6.62 (d, 1H, J = 15.6 Hz, ph-CH =), 7.27-7.40 (m, 4H, arom)

FABMS (M + H) ⁺ for C ₂₆ H ₄₄ ClN ₂ O ₃ : calcd 467.30; Found 467.25

Example 23. Preparation of (2S, 3R, 4E) -2- (3-n-butyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol (22)

(2S, 3R, 4E) -2-amino-5- (4-fluorophenyl) -4-pentene-1,3-diol (9) (160 mg, 0.76 mmol) with n-butyl isocyanate (97 mg, 0.98 mmol ) Was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to give (2S, 3R, 4E) -2- ( 120 mg (yield 51%) of 3-n-butyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol compound (22) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.25

= 8 (C=0.1 , 메탄올)

= 8 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3360 (NH), 1650 (C = O), 1540 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.85 (t, 3H, J = 6.0 Hz, C H ₃ CH ₂ ), 1.27 to 1.35 (m, 4H, (CH ₂ ) ₂ ), 3.15 (m, 2H, C H ₂ -NH), 3.61 (m, 2H, HO-C H ₂ ), 3.79 (m, 1H, H C-NH), 4.35 (m, 1H, H C-OH), 6.10 (d, d, 1H, J = 15.9 and 6.9H _Z , = CH-), 6.60 (d, 1H, J = 15.9 Hz, ph-CH =), 7.00 (m, 2H, arom), 7.40 (m, 2H, arom)

FABMS (M + H) ⁺ for C ₁₆ H ₂₄ FN ₂ O ₃ : calcd 311.17; Found 311.15

Example 24. Preparation of (2S, 3R, 4E) -2- (3-n-hexyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol (23)

(2S, 3R, 4E) -2-amino-5- (4-fluorophenyl) -4-pentene-1,3-diol (9) (250 mg, 1.18 mmol) and n-hexyl isocyanate (220 mg, 1.54 mmol ) Was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to give (2S, 3R, 4E) -2- ( 200 mg (yield 48%) of 3-n-hexyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol compound (23) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.16

= 36 (C=0.1 , 메탄올)

= 36 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3340 (NH), 1640 (C = O), 1550 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.90 (t, 3H, J = 6.7 Hz, C H ₃ CH ₂ ), 1.26 to 1.36 (m, 8H, (CH ₂ ) ₄ ), 3.07 (m, 2H, C H ₂ -NH), 3.63 (m, 2H, HO-C H ₂ ), 3.77 (m, 1H, H C-NH), 4.35 (m, 1H, H C-OH), 6.20 (d, d, 1H, J = 15.9 and 6.9H _Z , = CH-), 6.63 (d, 1H, J = 15.9 Hz, ph-CH =), 7.01-7.7.0 (m, 2H, arom), 7.42-7.45 (m, 2H , arom)

FABMS (M + H) ⁺ for C ₁₈ H ₂₈ FN ₂ O ₃ : calcd 339.20; Found 339.20

Example 25. Preparation of (2S, 3R, 4E) -2- (3-n-octyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol (24)

(2S, 3R, 4E) -2-amino-5- (4-fluorophenyl) -4-pentene-1,3-diol (9) (250 mg, 1.18 mmol) with n-octyl isocyanate (239 mg, 1.54 mmol ) Was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to give (2S, 3R, 4E) -2- ( 250 mg (yield 58%) of 3-n-octyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol compound (24) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.16

= 22 (C=0.1 , 메탄올)

= 22 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3350 (NH), 1660 (C = O), 1540 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.91 (t, 3H, J = 6.9 Hz, C H ₃ CH ₂ ), 1.27 to 1.36 (m, 12H, (CH ₂ ) ₆ ), 3.09 (m, 2H, C H ₂ -NH), 3.70 (m, 2H, HO-C H ₂ ), 3.81 (m, 1H, H C-NH), 4.32 (m, 1H, H C-OH), 6.24 (d, d, 1H, J = 15.9 and 6.9H _Z , = CH-), 6.63 (d, 1H, J = 15.9 Hz, ph-CH =), 7.01 to 7.07 (m, 2H, arom), 7.40 to 7.46 (m, 2H , arom)

FABMS (M + H) ⁺ for C ₂₀ H ₃₂ FN ₂ O ₃ : calcd. 367.23; Found 367.20

Example 26. Preparation of (2S, 3R, 4E) -2- (3-n-nonyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol (25)

(2S, 3R, 4E) -2-amino-5- (4-fluorophenyl) -4-pentene-1,3-diol (9) (250 mg, 1.18 mmol) with n-nonyl isocyanate (260 mg, 1.54 mmol ) Was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to give (2S, 3R, 4E) -2- ( 220 mg (yield 45%) of 3-n-nonyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol compound (25) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.12

= 14 (C=0.1 , 메탄올)

= 14 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3360 (NH), 1650 (C = O), 1560 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.92 (t, 3H, J = 7.2 Hz, C H ₃ CH ₂ ), 1.26 to 1.39 (m, 14H, (CH ₂ ) ₇ ), 3.05 (m, 2H, C H ₂ -NH), 3.67 (m, 2H, HO-C H ₂ ), 3.78 (m, 1H, H C-NH), 4.31 (m, 1H, H C-OH), 6.27 (d, d, 1H, J = 15.9 and 6.9H _Z , = CH-), 6.60 (d, 1H, J = 15.9 Hz, ph-CH =), 7.01-7.7.0 (m, 2H, arom), 7.40-7.47 (m, 2H , arom)

FABMS (M + H) ⁺ for C ₂₁ H ₃₄ FN ₂ O ₃ : calcd 381.25; Found 381.20

Example 27. Preparation of (2S, 3R, 4E) -2- (3-n-dodecyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol (26)

(2S, 3R, 4E) -2-amino-5- (4-fluorophenyl) -4-pentene-1,3-diol (9) (100 mg, 0.47 mmol) with n-dodecyl isocyanate (130 mg, 0.62 mmol) was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to obtain (2S, 3R, 4E) -2-. Dodecyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol compound (26) 128 mg (yield 64%) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.26

= 15 (C=0.1 , 메탄올)

= 15 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3370 (NH), 1650 (C = O), 1550 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.80 (t, 3H, J = 7.2 Hz, C H ₃ CH ₂ ), 1.13 to 1.30 (m, 22H, (CH ₂ ) ₁₁ ), 2.95 (m, 2H, C H ₂ -NH), 3.53 (m, 2H, HO-C H ₂ ), 3.69 (m, 1H, H C-NH), 4.18 (m, 1H, H C-OH), 6.15 (d, d, 1H, J = 15.9 and 6.9H _Z , = CH-), 6.52 (d, 1H, J = 15.9 Hz, ph-CH =), 6.88 to 6.95 (m, 2H, arom), 7.28 to 7.74 (m, 2H , arom)

FABMS (M + H) ⁺ for C ₂₄ H ₄₀ FN ₂ O ₃ : calcd 423.29; Found 423.32

Example 28. Preparation of (2S, 3R, 4E) -2- (3-n-tetradecyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol (27)

(2S, 3R, 4E) -2-amino-5- (4-fluorophenyl) -4-pentene-1,3-diol (9) (250 mg, 1.18 mmol) with n-tetradecyl isocyanate (368 mg, 1.54 mmol) was synthesized according to the preparation method described in Example 10, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to obtain (2S, 3R, 4E) -2-. 125 mg (yield 23%) of (3-n-tetradecyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol compound (27) were synthesized (see Table 4).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.12

= 9 (C=0.1 , 메탄올)

= 9 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3340 (NH), 1640 (C = O), 1540 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.92 (t, 3H, J = 6.0 Hz, C H ₃ CH ₂ ), 1.30 to 1.42 (m, 26H, (CH ₂ ) ₁₃ ), 3.04 (m, 2H, C H ₂ -NH), 3.62 (m, 2H, HO-C H ₂ ), 3.75 (m, 1H, H C-NH), 4.30 (m, 1H, H C-OH), 6.23 (d, d, 1H, J = 15.9 and 6.9H _Z , = CH-), 6.64 (d, 1H, J = 15.9 Hz, ph-CH =), 7.01-7.06 (m, 2H, arom), 7.39-7.45 (m, 2H , arom)

FABMS (M + H) ⁺ for C ₂₆ H ₄₄ FN ₂ O ₃ : calcd 451.33; Found 451.31

(Ⅱ), R₃ =

(II), R ₃ =

Compound group compound R R ₄ Ⅱ 10 H C ₄ H ₉ 11 H C ₆ H ₁₃ 12 H C ₈ H ₁₇ 13 H C ₉ H ₁₉ 14 H C ₁₂ H ₂₅ 15 H C ₁₄ H ₂₉ 16 Cl C ₄ H ₉ 17 Cl C ₆ H ₁₃ 18 Cl C ₈ H ₁₇ 19 Cl C ₉ H ₁₉ 20 Cl C ₁₂ H ₂₅ 21 Cl C ₁₄ H ₂₉ 22 F C ₄ H ₉ 23 F C ₆ H ₁₃ 24 F C ₈ H ₁₇ 25 F C ₉ H ₁₉ 26 F C ₁₂ H ₂₅ 27 F C ₁₄ H ₂₉

Example 29. Preparation of Thioureido Compounds

Pentene diol (1.29 mmol) was dissolved in ethanol (50 mL), and alkyl isothiocyanate (1.68 mmol) was slowly added at room temperature and reacted for 4 hours. The reaction solution was diluted with ethyl acetate (200 mL) and water ( 30 ml), saturated aqueous sodium bicarbonate solution (30 ml), 5% citric acid (30 ml), brine (30 ml), organic layers were combined, dried over anhydrous sodium sulfate, and the obtained compound was concentrated by silica gel column chromatography (Merck type). 9355, 230-400 mesh) to obtain a pure thioureido compound.

Example 30. Preparation of (2S, 3R, 4E) -2- (3-n-butyl thioureido) -5-phenyl-4-pentene-1,3-diol (28)

(2S, 3R, 4E) -2-amino-5-phenyl-4-pentene-1,3-diol (7) (150 mg, 0.78 mmol) and n-butyl isothiocyanate (107 mg, 0.93 mmol) were used Was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to obtain (2S, 3R, 4E) -2- (3-n). 100 mg (yield 41%) of -butyl thioureido) -5-phenyl-4-pentene-1,3-diol compound (28) were synthesized (see Table 5).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.34

= 25 (C=0.1 , 메탄올)

= 25 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3400 (NH), 1560 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.88 (t, 3H, J = 7.2 Hz, C H ₃ CH ₂ ), 1.28 to 1.51 (m, 4H, (CH ₂ ) ₂ ), 3.45 (m, 2H, C H ₂ -NH), 3.75 (m, 2H, HO-C H ₂ ), 3.82 (t, 1H, H C-NH), 4.45 (m, 1H, H C-OH), 6.38 (d, d, 1H, J = 15.9 and 6.3H _Z , = CH-), 6.62 (d, 1H, J = 15.9 Hz, ph-CH =), 7.21-7.43 (m, 5H, arom)

FABMS (M + Na) ⁺ for C ₁₆ H ₂₅ N ₂ O ₃ S: calcd 309.16; Found 309.13

Example 31. Preparation of (2S, 3R, 4E) -2- (3-n-hexyl thioureido) -5-phenyl-4-pentene-1,3-diol (29)

(2S, 3R, 4E) -2-amino-5-phenyl-4-pentene-1,3-diol (7) (150 mg, 0.78 mmol) and n-hexyl isothiocyanate (133 mg, 0.93 mmol) were used Was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to obtain (2S, 3R, 4E) -2- (3-n). 160 mg (yield 61%) of -hexyl thioureido) -5-phenyl-4-pentene-1,3-diol compound (29) were synthesized (see Table 5).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.35

= 24 (C=0.1 , 메탄올)

= 24 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3340 (NH), 1550 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.87 (t, 3H, J = 7.2 Hz, C H ₃ CH ₂ ), 1.30 to 1.49 (m, 8H, (CH ₂ ) ₄ ), 3.42 (m, 2H, C H ₂ -NH), 3.77 (m, 2H, HO-C H ₂ ), 3.85 (m, 1H, H C-NH), 4.42 (t, 1H, H C-OH), 6.35 (d, d, 1H, J = 15.9 and 6.6H _Z , = CH-), 6.62 (d, 1H, J = 15.9 Hz, ph-CH =), 7.21-7.43 (m, 5H, arom)

FABMS (M + H) < + > for C ₁₈ H ₂₉ N ₂ 0 ₂ S: calcd 337.19; Found 337.15

Example 32. Preparation of (2S, 3R, 4E) -2- (3-n-octyl thioureido) -5-phenyl-4-pentene-1,3-diol (30)

(2S, 3R, 4E) -2-amino-5-phenyl-4-pentene-1,3-diol (7) (150 mg, 0.77 mmol) and n-octyl isothiocyanate (160 mg, 0.93 mmol) were used Was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to obtain (2S, 3R, 4E) -2- (3). 130 mg (yield 46%) of -n-octyl thioureido) -5-phenyl-4-pentene-1,3-diol compound (30) were synthesized (see Table 5).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.28

= 29 (C=0.1 , 메탄올)

= 29 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3350 (NH), 1540 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.91 (t, 3H, J = 6.6 Hz, C H ₃ CH ₂ ), 1.26 to 1.49 (m, 12H, (CH ₂ ) ₆ ), 3.42 (m, 2H, C H ₂ -NH), 3.72 (m, 2H, HO-C H ₂ ), 3.83 (m, 1H, H C-NH), 4.44 (t, 1H, H C-OH), 6.32 (d, d, 1H, J = 15.9 and 6.9H _Z , = CH-), 6.64 (d, 1H, J = 15.9 Hz, ph-CH =), 7.21-7.42 (m, 5H, arom)

FABMS (M + H) ⁺ for C ₂₀ H ₃₃ N ₂ 0 ₂ S: calc. 365.22; Found 365.24

Example 33. Preparation of (2S, 3R, 4E) -2- (3-n-decyl thioureido) -5-phenyl-4-pentene-1,3-diol (31)

(2S, 3R, 4E) -2-amino-5-phenyl-4-pentene-1,3-diol (7) (150 mg, 0.77 mmol) and n-decyl isothiocyanate (177 mg, 0.85 mmol) were used Was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to give (2S, 3R, 4E) -2- (3-). 130 mg (yield 43%) of n-decyl thioureido) -5-phenyl-4-pentene-1,3-diol compound (31) were synthesized (see Table 5).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.40

= 16 (C=0.1 , 메탄올)

= 16 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3350 (NH), 1540 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.87 (t, 3H, J = 7.2 Hz, C H ₃ CH ₂ ), 1.26 to 1.55 (m, 16H, (CH ₂ ) ₈ ), 3.42 (m, 2H, C H ₂ -NH), 3.75 (m, 2H, HO-C H ₂ ), 3.82 (m, 1H, H C-NH), 4.42 (m, 1H, H C-OH), 6.32 (d, d, 1H, J = 15.9 and 6.9H _Z , = CH-), 6.61 (d, 1H, J = 15.9 Hz, ph-CH =), 7.20-7.42 (m, 5H, arom)

FABMS (M + H) ⁺ for C ₂₂ H ₃₇ N ₂ 0 ₂ S: calcd 393.25; Found 393.32

Example 34. Preparation of (2S, 3R, 4E) -2- (3-n-dodecyl thioureido) -5-phenyl-4-pentene-1,3-diol (32)

(2S, 3R, 4E) -2-amino-5-phenyl-4-pentene-1,3-diol (7) (150 mg, 0.77 mmol) and n-dodecyl isothiocyanate (215 mg, 0.85 mmol) Was synthesized according to the preparation method described in Example 29 above, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E) -2- (3-). 105 mg (yield 32%) of 5-phenyl-4-pentene-1,3-diol compound (32) were synthesized (see Table 5).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.30

= 21 (C=0.1 , 메탄올)

= 21 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3410 (NH), 1550 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.90 (t, 3H, J = 6.9 Hz, C H ₃ CH ₂ ), 1.28 to 1.49 (m, 20H, (CH ₂ ) ₁₀ ), 3.42 (m, 2H, C H ₂ -NH), 3.75 (m, 2H, HO-C H ₂ ), 3.82 (m, 1H, H C-NH), 4.45 (m, 1H, H C-OH), 6.35 (d, d, 1H, J = 15.9 and 7.2H _Z , = CH-), 6.61 (d, 1H, J = 16.2Hz, ph-CH =), 7.20-7.42 (m, 5H, arom)

FABMS (M + H) ⁺ for C ₂₄ H ₄₁ N ₂ O ₂ S: calcd 421.28; Found 421.31

Example 35. Preparation of (2S, 3R, 4E) -2- (3-n-tetradecyl thioureido) -5-phenyl-4-pentene-1,3-diol (33)

(2S, 3R, 4E) -2-amino-5-phenyl-4-pentene-1,3-diol (7) (250 mg, 1.29 mmol) and n-tetradecyl isothiocyanate (402 mg, 1.68 mmol) Was synthesized according to the preparation method described in Example 29 above, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E) -2- (3-). 267 mg (yield 46%) of n-tetradecyl thioureido) -5-phenyl-4-pentene-1,3-diol compound (33) were synthesized (see Table 5).

TLC (hexane: ethyl acetate = 1: 1), R _f = 0.24

= 17 (C=0.1 , 메탄올)

= 17 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3320 (NH), 1565 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.85 (t, 3H, J = 6.3 Hz, C H ₃ CH ₂ ), 1.14 to 1.28 (m, 24H, (CH ₂ ) ₁₂ ), 2.94 (m, 2H, C H ₂ -NH), 3.55 (m, 2H, HO-C H ₂ ), 3.71 (t, 1H, H C-NH), 4.20 (m, 1H, H C-OH), 6.21 (d, d, 1H, J = 16.8 and 6.6H _Z , = CH-), 6.62 (d, 1H, J = 16.8 Hz, ph-CH =), 7.10-7.31 (m, 5H, arom)

FABMS (M + H) ⁺ for C ₂₆ H ₄₅ N ₂ 0 ₃ : calc. 433.34; Found 433.27

Example 36. Preparation of (2S, 3R, 4E) -2- (3-n-butyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol (34)

(2S, 3R, 4E) -2-amino-5- (4-chlorophenyl) -4-pentene-1,3-diol (8) (100 mg, 0.44 mmol) and n-butyl isothiocyanate (57 mg, 0.48 mmol) was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E) -2. 95 mg (yield 63%) of-(3-n-butyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol compound (34) were synthesized (see Table 5). .

TLC (hexane: ethyl acetate = 1: 1), R _f = 0.36

= 9 (C=0.1 , 메탄올)

= 9 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3400 (NH), 1570 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.88 (t, 3H, J = 7.2 Hz, C H ₃ CH ₂ ), 1.29 to 1.53 (m, 4H, (CH ₂ ) ₂ ), 3.44 (m, 2H, C H ₂ -NH), 3.74 (d, 2H, HO-C H ₂ ), 4.52 (m, 1H, H C-NH), 4.62 (m, 1H, H C-OH), 6.29 (d, d, 1H, J = 15.9 and 5.7H _Z , = CH-), 6.63 (d, 1H, J = 15.9 Hz, ph-CH =), 7.28-7.40 (m, 4H, arom)

FABMS (M + H) ⁺ for C ₁₆ H ₂₄ ClN ₂ O ₂ S: calcd 343.13; Found 343.11

Example 37. Preparation of (2S, 3R, 4E) -2- (3-n-hexyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol (35)

(2S, 3R, 4E) -2-amino-5- (4-chlorophenyl) -4-pentene-1,3-diol (8) (100 mg, 0.44 mmol) and n-hexyl isothiocyanate (69 mg, 0.48 mmol) was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E) -2. 90 mg (yield 56%) of-(3-n-hexyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol compound (35) were synthesized (see Table 5). .

TLC (hexane: ethyl acetate = 1: 1), R _f = 0.35

= 25 (C=0.1 , 메탄올)

= 25 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3350 (NH), 1530 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.89 (t, 3H, J = 7.2 Hz, C H ₃ CH ₂ ), 1.257 to 1.51 (m, 8H, (CH ₂ ) ₄ ), 3.42 (m, 2H, C H ₂ -NH), 3.74 (m, 2H, HO-C H ₂ ), 4.50 (m, 1H, H C-NH), 4.65 (m, 1H, H C-OH), 6.31 (d, d, 1H, J = 15.6 and 5.7H _Z , = CH-), 6.63 (d, 1H, J = 15.6Hz, ph-CH =), 7.28 (d, 2H, arom), 7.38 (d, 2H, arom)

FABMS (M + H) ⁺ for C ₁₈ H ₂₈ ClN ₂ O ₂ S: calcd 371.15; Found 371.11

Example 38. Preparation of (2S, 3R, 4E) -2- (3-noctyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol (36)

(2S, 3R, 4E) -2-amino-5- (4-chlorophenyl) -4-pentene-1,3-diol (8) (100 mg, 0.44 mmol) and n-octyl isothiocyanate (83 mg, 0.48 mmol) was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E) -2. 120 mg (yield 30%) of-(3-noctyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol compound (36) were synthesized (see Table 5).

TLC (hexane: ethyl acetate = 1: 1), R _f = 0.42

= 12 (C = 0.1 , 메탄올)

= 12 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3450 (NH), 1560 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.90 (t, 3H, J = 7.2 Hz, C H ₃ CH ₂ ), 1.26 to 1.50 (m, 12H, (CH ₂ ) ₆ ), 3.36 (m, 2H, C H ₂ -NH), 3.72 (d, 2H, HO-C H ₂ ), 4.55 (m, 1H, H C-NH), 4.65 (t, 1H, H C-OH), 6.29 (d, d, 1H, J = 15.9 and 6.0H _Z , = CH-), 6.57 (d, 1H, J = 15.9 Hz, ph-CH =), 7.28-7.40 (m, 4H, arom)

FABMS (M + H) ⁺ for C ₂₀ H ₃₂ ClN ₂ O ₂ S: calc. 399.18; Found 399.16

Example 39. Preparation of (2S, 3R, 4E) -2- (3-n-decyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol (37)

(2S, 3R, 4E) -2-amino-5- (4-chlorophenyl) -4-pentene-1,3-diol (8) (100 mg, 0.44 mmol) and n-decyl isothiocyanate (96 mg, 0.48 mmol) was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E) -2. 130 mg (yield 69%) of-(3-n-decyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol compound (37) were synthesized (see Table 5).

TLC (hexane: ethyl acetate = 1: 1), R _f = 0.45

= 11 (C=0.1 , 메탄올)

= 11 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3480 (NH), 1560 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.91 (t, 3H, J = 7.2 Hz, C H ₃ CH ₂ ), 1.26 to 1.50 (m, 16H, (CH ₂ ) ₈ ), 3.42 (m, 2H, C H ₂ -NH), 3.72 (d, 2H, HO-C H ₂ ), 4.50 (m, 1H, H C-NH), 4.62 (m, 1H, H C-OH), 6.29 (d, d, 1H, J = 16.2 and 5.7H _Z , = CH-), 6.62 (d, 1H, J = 16.2Hz, ph-CH =), 7.28-7.40 (m, 4H, arom)

FABMS (M + H) ⁺ for C ₂₁ H ₃₆ ClN ₂ O ₂ S: calcd 427.21; Found 427.19

Example 40. (2S, 3R, 4E) -2- (3-n-dodecyl thioureido) -5- (4-chloro phenyl) -4-pentene

Preparation of -1,3-diol (38)

(2S, 3R, 4E) -2-amino-5- (4-chlorophenyl) -4-pentene-1,3-diol (8) (100 mg, 0.44 mmol) with n-dodecyl isothiocyanate (110 mg , 0.48 mmol) was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E)-. 120 mg (yield 60%) of 2- (3-n-dodecyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol compound (38) were synthesized (see Table 5). ).

TLC (hexane: ethyl acetate = 1: 1), R _f = 0.25

= 10 (C=0.1 , 메탄올 )

= 10 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3450 (NH), 1550 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.91 (t, 3H, J = 6.9 Hz, C H ₃ CH ₂ ), 1.26 to 1.51 (m, 20H, (CH ₂ ) ₁₀ ), 3.42 (m, 2H, C H ₂ -NH), 3.72 (m, 2H, HO-C H ₂ ), 4.50 (m, 1H, H C-NH), 4.65 (t, 1H, H C-OH), 6.29 (d, d, 1H, J = 16.2 and 5.7H _Z , = CH-), 6.57 (d, 1H, J = 16.2Hz, ph-CH =), 7.28-7.41 (m, 4H, arom)

FABMS (M + H) ⁺ for C ₂₄ H ₄₀ ClN ₂ O ₂ S: calcd 455.24; Found 455.20

Example 41.Preparation of (2S, 3R, 4E) -2- (3-n-tetradecyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol (39)

(2S, 3R, 4E) -2-amino-5- (4-chlorophenyl) -4-pentene-1,3-diol (8) (250 mg, 1.10 mmol) and n-tetradecyl isothiocyanate (342 mg , 1.43 mmol) was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E)-. 134 mg (yield 26%) of 2- (3-n-tetradecyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol compound (39) were synthesized (Table 5 Reference).

TLC (hexane: ethyl acetate = 1: 1), R _f = 0.22

= 18 (C=0.1 , 메탄올)

= 18 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3350 (NH), 1660 (C = O), 1560 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.90 (t, 3H, J = 7.2 Hz, C H ₃ CH ₂ ), 1.28 to 1.37 (m, 24H, (CH ₂ ) ₁₂ ), 3.07 (m, 2H, C H ₂ -NH), 3.64 (m, 2H, HO-C H ₂ ), 3.77 (m, 1H, H C-NH), 4.28 (m, 1H, H C-OH), 6.32 (d, d, 1H, J = 15.6 and 6.9HZ, = CH-), 6.62 (d, 1H, J = 15.6Hz, ph-CH =), 7.27-7.40 (m, 4H, arom)

FABMS (M + H) ⁺ for C ₂₆ H ₄₄ ClN ₂ O ₃ : calcd 467.30; Found 467.25

Example 42. (2S, 3R, 4E) -2- (3-n-butyl thioureido) -5- (4-fluorophenyl) -4-pentene

Preparation of -1,3-diol (40)

(2S, 3R, 4E) -2-amino-5- (4-fluorophenyl) -4-pentene-1,3-diol (9) (100 mg, 0.47 mmol) and n-butyl isothiocyanate (60 mg , 0.52 mmol) was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E)-. 100 mg (yield 65%) of 2- (3-n-butyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol compound (40) were synthesized (see Table 5). ).

TLC (hexane: ethyl acetate = 1: 1): R _f = 0.40

= 2 (C=0.1 , 메탄올)

= 2 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3440 (NH), 1540 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.87 (t, 3H, J = 6.0 Hz, C H ₃ CH ₂ ), 1.25 to 1.53 (m, 4H, (CH ₂ ) ₂ ), 3.44 (m, 2H, C H ₂ -NH), 3.72 (d, 2H, HO-C H ₂ ), 4.40 (m, 1H, H C-NH), 4.59 (m, 1H, H C-OH), 6.21 (d, d, 1H, J = 15.9 and 5.7H _Z , = CH-), 6.60 (d, 1H, J = 15.9 Hz, ph-CH =), 7.03 (m, 2H, arom), 7.42 (m, 2H, arom)

FABMS (M + H) ⁺ for C ₁₆ H ₂₄ FN ₂ O ₂ S: calcd 327.15; Found 327.08

Example 43. (2S, 3R, 4E) -2- (3-n-hexyl thioureido) -5- (4-fluorophenyl) -4-pentene

Preparation of -1,3-diol (41)

(2S, 3R, 4E) -2-amino-5- (4-fluorophenyl) -4-pentene-1,3-diol (9) (150 mg, 0.71 mmol) and n-hexyl isothiocyanate (112 mg , 0.78 mmol) was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E)-. 85 mg (yield 34%) of 2- (3-n-hexyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol compound (41) were synthesized (see Table 5). ).

TLC (hexane: ethyl acetate = 1: 1), R _f = 0.42

= 25 (C=0.1 , 메탄올)

= 25 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3420 (NH), 1550 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.88 (t, 3H, J = 6.7 Hz, C H ₃ CH ₂ ), 1.24 to 1.56 (m, 8H, (CH ₂ ) ₄ ), 3.50 (m, 2H, C H ₂ -NH), 3.80 (m, 2H, HO-C H ₂ ), 4.42 (m, 1H, H C-NH), 4.60 (m, 1H, H C-OH), 6.20 (d, d, 1H, J = 15.9 and 6.9H _Z , = CH-), 6.65 (d, 1H, J = 15.9 Hz, ph-CH =), 7.01-7.08 (m, 2H, arom), 7.42-7.46 (m, 2H , arom)

FABMS (M + H) ⁺ for C ₁₈ H ₂₈ FN ₂ 0 ₂ S: calcd 355.18; Found 355.16

Example 44. (2S, 3R, 4E) -2- (3-n-octyl thioureido) -5- (4-fluorophenyl) -4-pentene

Preparation of -1,3-diol (42)

(2S, 3R, 4E) -2-amino-5- (4-fluorophenyl) -4-pentene-1,3-diol (9) (100 mg, 0.47 mmol) and n-octyl isothiocyanate (89 mg , 0.52 mmol) was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E)-. 105 mg (yield 37%) of 2- (3-n-octyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol compound (42) were synthesized (see Table 5). ).

TLC (hexane: ethyl acetate = 1: 1), R _f = 0.56

= 5 (C=0.1 , 메탄올)

= 5 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3450 (NH), 1560 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.90 (t, 3H, J = 6.9 Hz, C H ₃ CH ₂ ), 1.27 to 1.52 (m, 12H, (CH ₂ ) ₆ ), 3.42 (m, 2H, C H ₂ -NH), 3.74 (d, 2H, HO-C H ₂ ), 4.50 (m, 1H, H C-NH), 4.61 (m, 1H, H C-OH), 6.21 (d, d, 1H, J = 16.5 and 6.0H _Z , = CH-), 6.63 (d, 1H, J = 16.5Hz, ph-CH =), 7.00 to 7.06 (m, 2H, arom), 7.41 to 7.44 (m, 2H , arom)

FABMS (M + H) ⁺ for C ₂₀ H ₃₂ FN ₂ O ₂ S: calcd 383.21; Found 383.15

Example 45. (2S, 3R, 4E) -2- (3-n-decyl thioureido) -5- (4-fluorophenyl) -4-pentene

Preparation of -1,3-diol (43)

(2S, 3R, 4E) -2-amino-5- (4-fluorophenyl) -4-pentene-1,3-diol (9) (100 mg, 0.47 mmol) and n-decyl isothiocyanate (104 mg , 0.52 mmol) was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) to obtain (2S, 3R, 4E) -2. 82 mg (yield 42%) of-(3-n-decyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol compound (43) were synthesized (see Table 5). ).

TLC (hexane: ethyl acetate = 1: 1), R _f = 0.32

= 7 (C=0.1 , 메탄올)

= 7 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3380 (NH), 1560 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.90 (t, 3H, J = 6.6 Hz, C H ₃ CH ₂ ), 1.19 to 1.51 (m, 16H, (CH ₂ ) ₈ ), 3.43 (m, 2H, C H ₂ -NH), 3.72 (d, 2H, HO-C H ₂ ), 4.43 (m, 1H, H C-NH), 4.60 (m, 1H, H C-OH), 6.21 (d, d, 1H, J = 15.9 and 6.9H _Z , = CH-), 6.63 (d, 1H, J = 15.9 Hz, ph-CH =), 6.99 to 7.06 (m, 2H, arom), 7.40 to 7.47 (m, 2H , arom)

FABMS (M + H) ⁺ for C ₂₂ H ₃₆ FN ₂ O ₂ S: calcd 411.24; Found 411.20

Example 46. Preparation of (2S, 3R, 4E) -2- (3-n-dodecyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol (44 )

(2S, 3R, 4E) -2-amino-5- (4-fluorophenyl) -4-pentene-1,3-diol (9) (100 mg, 0.47 mmol) and n-dodecyl isothiocyanate ( 118 mg, 0.52 mmol) was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E). 75 mg (yield 37%) of 2- (3-n-dodecyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol compound (44) were synthesized (Table 5).

TLC (hexane: ethyl acetate = 1: 1), R _f = 0.25

= 4 (C=0.1 , 메탄올)

= 4 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3400 (NH), 1550 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.91 (t, 3H, J = 6.9 Hz, C H ₃ CH ₂ ), 1.27 to 1.52 (m, 22H, (CH ₂ ) ₁₁ ), 3.42 (m, 2H, C H ₂ -NH), 3.72 (d, 2H, HO-C H ₂ ), 4.45 (m, 1H, H C-NH), 4.59 (m, 1H, H C-OH), 6.27 (d, d, 1H, J = 15.9 and 6.9H _Z , = CH-), 6.63 (d, 1H, J = 15.9 Hz, ph-CH =), 7.00 to 7.05 (m, 2H, arom), 7.40 to 7.44 (m, 2H , arom)

FABMS (M + H) ⁺ for C ₂₄ H ₄₀ FN ₂ O ₂ S: calc. 439.27; Found 439.25

Example 47. Preparation of (2S, 3R, 4E) -2- (3-n-tetradecyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol (45 )

(2S, 3R, 4E) -2-amino-5- (4-fluorophenyl) -4-pentene-1,3-diol (9) (250 mg, 1.18 mmol) and n-tetradecyl isothiocyanate ( 368 mg, 1.54 mmol) was synthesized according to the preparation method described in Example 29, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 1: 1) (2S, 3R, 4E). 125 mg (yield 23%) of 2- (3-n-dodecyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol compound (45) were synthesized (Table 23). 5).

TLC (hexane: ethyl acetate = 1: 1), R _f = 0.12

= 4 (C=0.1 , 메탄올)

= 4 (C = 0.1, methanol)

IR (KBr) cm ^-1 : 3340 (NH), 1640 (C = O), 1540 (arom, C = C)

¹ H-NMR (CD ₃ OD) δ: 0.92 (t, 3H, J = 6.0 Hz, C H ₃ CH ₂ ), 1.30 to 1.42 (m, 26H, (CH ₂ ) ₁₃ ), 3.04 (m, 2H, C H ₂ -NH), 3.62 (m, 2H, HO-C H ₂ ), 3.75 (m, 1H, H C-NH), 4.30 (m, 1H, H C-OH), 6.23 (d, d, 1H, J = 15.9 and 6.9HZ, = CH-), 6.64 (d, 1H, J = 15.9 Hz, ph-CH =), 7.01 to 7.06 (m, 2H, arom), 7.39 to 7.45 (m, 2H, arom)

FABMS (M + H) ⁺ for C ₂₆ H ₄₄ FN ₂ O ₃ : calcd 451.33; Found 451.31

(Ⅲ), R₃ =

(III), R ₃ =

Compound group compound R R ₄           Ⅲ 28 H C ₄ H ₉ 29 H C ₆ H ₁₃ 30 H C ₈ H ₁₇ 31 H C ₁₀ H ₂₁ 32 H C ₁₂ H ₂₅ 33 H C ₁₄ H ₂₉ 34 Cl C ₄ H ₉ 35 Cl C ₆ H ₁₃ 36 Cl C ₈ H ₁₇ 37 Cl C ₁₀ H ₂₁ 38 Cl C ₁₂ H ₂₅ 39 Cl C ₁₄ H ₂₉ 40 F C ₄ H ₉ 41 F C ₆ H ₁₃ 42 F C ₈ H ₁₇ 43 F C ₁₀ H ₂₁ 44 F C ₁₂ H ₂₅ 45 F C ₁₄ H ₂₉

Experimental Example 1. Toxicity test (MTT test method)

In order to evaluate the cytotoxicity and cell viability of the ureido and thioureido ceramide derivative compounds 10 to 45 of the present application, human kidney cancer cell line Caki-2 (Renal cancer cell line (ATCC, HTB-47), colon cancer) Cell line HT-29 (Colon cancer cell line, ATCC, HTB-38), lung cancer cell line A549 (Lung cancer cell line, ATCC, CCL-185), prostate cancer cell line PC-3 (Prostate cancer cell line, ATCC, CRL-1435), MTT (3- (4,5-dimethylthiazol-2-yl)-using human myelocytic leukemia cell line (ATCC, CCL-240), a cell line of human acute myeloid leukemia. 2,5-diphenyltetrazolium bromide thiazolyl blue; Sigma, USA) test method was used.

The MTT assay is a method of measuring the cytotoxicity as a percentage of the control group by measuring the absorbance of formazan produced by the reduction of MTT by live and metabolically active intracellular mitochondrial dehydrogenase. And reflects the concentration of metabolically active cells. 2,3,5-triphenyl tetrazolium chloride (TTC) is reduced to formazan in living cells, which shows insoluble purple color and can measure respiration rate to a degree of color. The absorbance of formazan is maximum at a wavelength of 540 nm, and the absorbance measured at this wavelength reflects the concentration of living and metabolically active cells. If the concentration of cells in the well to be measured is too low or in a high range, Since the linear relationship between concentration and absorbance was not established, the optimal cell concentration was determined.

Preparation of single cell suspension and examination of cell concentration

Suspension cells were centrifuged at 1000 rpm for 5 minutes, 10 ml of cell culture was added to pellets of remaining cells, and repeatedly absorbed through a sterile pipette to obtain single cell suspensions. Monolayer cells Treated with trypsin, the cells were removed from the bottom of the flask, neutralized with cell culture medium, centrifuged at 1000 rpm for 5 minutes, 10 ml of cell culture solution was added to the remaining cell pellet, and repeatedly aspirated through a sterile pipette. Single cell suspensions were obtained.

Cell concentration was directly measured by a microscope using a hemocytometor (Hemocytometor, SEQUOIA-TURNER, UK), a portion of the suspended cells were taken to measure the volume, 10 times PBS (Phosphate buffered saline, pH 7.2) After adding the buffer solution and diluting it 10 times, the cell concentration was measured using a hemocytometer.

Determination of titration inoculation cell

In order to measure the absorbance, the first was used as an untreated group containing only 80 μl of medium and 20 μl of PBS buffer. Second, 90 μl of medium was added, followed by 90 μl of cell suspension (400 × 10 ³ cell density). Inoculate well, mix, and transfer 90 μl of cell suspension from the second compartment to the third compartment. Inoculate while diluting the cell density in half in this manner, and then add 90 μl of medium and 20 μl of PBS buffer from the second cell containing the last cell. After incubating the pellets inoculated with cells for 4 days at 37 ° C. and 5% carbon dioxide, the absorbance was measured at 540 nm, and the values obtained therefrom are graphically shown with the vertical axis representing the absorbance of the cells and the horizontal axis representing the concentration of the cells. When the absorbance of the proportional part is found in the curve, the appropriate cell number obtained by calculating the appropriate cell density in the exponential growth phase of the part is used in the following experiment.

Cell Inoculation, Sample Administration and Culture

After determining the concentration of cells based on the determined titer, the single cell suspension was mixed well in a wide glass tube, and each well was inoculated with 180 μl of cell suspension using a multichannel pipette. After dissolving in, 20 μl of each concentration was added to each well. In one column, 20 μl of PBS buffer solution was added as a control group to make a 100% surviving group. Also, one column was used as a non-treated group for absorbance measurement, and 180 μl of medium and 20 μl of PBS buffer were used instead of cell suspension. Was added. Plates inoculated with cancer cells and specimens were incubated at 37 ° C. and 5% carbon dioxide for 4 days.

Measurement of viable cell number

After 4 days, 0.1 mg (50 μl of 2 mg / ml) of MTT was added to each well of the plate, and again incubated for 4 hours at 37 ° C. and 5% carbon dioxide to allow MTT to be reduced.

At the end of the incubation, the formazan crystals formed by separating the glass plates from 450 g x centrifugation for 5 minutes were precipitated, and all of them were removed using a multi-dispenser, leaving only about 30 μl of medium, taking care not to disturb the crystals formed in each well.

To dissolve the formazan crystals formed in each well from which the medium was removed, 150 µl of dimethyl sulfoxide (DMSO, dimethyl sulforoxide, Aldrich) was added and shaken for about 15 minutes to dissolve the formazan crystals. Absorbance was measured at 540 nm using a photometer for plate (ELISA reader, Molecular devices, USA), which absorbed the amount of MTT reduced by the cells and was proportional to the number of viable cells present in each well.

In the test group, the average OD ₅₄₀ value of one column was obtained from each well to calculate a percentage value of the average value of the control group (100% surviving group), and the average value was calculated by the following formula.

Mean = (average optical density of test group / average optical density of control group) × 100

This percentage corresponds to the cell viability of the test group compared to the control group. The IC ₅₀ of each sample was obtained using the pharmaceutical calculation program, and the 50% inhibitory concentration (IC ₅₀ ) was 50% of the control group. It is defined as the concentration of the drug to be used, and this IC ₅₀ value is used as an indicator of the anticancer effect.

As a result, of 36 ureido or thiourei ceramide derivative compounds, thioureido compounds showed higher apoptosis effect than ureido compounds, and the substituent effect on the aromatic ring of the ureido ceramide derivative compound was not substituted. Chloro-substituted 16-21 compounds showed higher apoptosis effects than 10-15 compounds, and fluoro-substituted 22-27 compounds showed lower apoptosis effects. The difference in cell killing effect according to the chain length of the alkyl ureido group was greater, and the length of the alkyl chain was higher at C ₈ ~ C ₁₂ , and the longer the C ₁₄ was, the lower the cell killing effect. Among the cancer cells, the effect of apoptosis on colon cancer cell line HT-29 (colon cancer) and lung cancer cell line A549 (lung cancer) was high, and apoptosis effect on kidney cancer cell line Caki-2 (renal cancer) was low. . Compound 12 showed 3.50 mM IC ₅₀ apoptosis effect against HT-29 (colon cancer), compared to the control drug C ₆ -ceramide, Compound 19 showed 10.51 IC ₅₀ against HT-29 (colon cancer) The IC ₅₀ was 16.69 mM for mM, HL-60 (leukemia), showing a higher apoptosis effect than the reference C ₆ -ceramide (see Table 6).

Thioureido ceramide derivatives showed higher cytotoxicity than ureido compounds. Compounds of alkyl chain lengths of alkyl thioureido groups with C ₈ ~ C ₁₂ showed high cytotoxicity. Same as the ceramide derivative. Compound 30 showed higher cytotoxicity than the control compound C ₆ -ceramide, with IC ₅₀ of 13.94 mM for prostate cancer PC-3 (prostate cancer) and IC ₅₀ of 22.6 mM for Caki-2 (renal cancer), Compound 43 showed higher cytotoxicity than the control compound C ₆ -ceramide, with IC ₅₀ of 28.95 mM for prostate cancer and PC ₅₀ of 34.03 mM for Caki-2 (renal cancer) (Table 7 Reference).

For Caki-2 (renal cancer) cells, the IC ₅₀ of compounds 30, 31, 36 and 43 showed high cytotoxicity at 22.60, 33.39, 40.52 and 28.95 mM, respectively, and against HT-29 (colon cancer) cells. IC ₅₀ of 12 and 17 showed high cytotoxicity at 3.61 and 4.56 mM, respectively, and IC ₅₀ of compounds 15, 30, 36 and 43 were as high as 23.77, 18.32, 28.41 and 29.71 mM for A549 (lung cancer) cells. It was a compound having cytotoxicity, and the IC ₅₀ of compounds 15, 26, 29, 30, 31, 36, 37, 42 and 43 was 35.8, 37.22, 38.41, 13.94, 37.71, for PC-3 (prostate cancer) cells. 30.35, 31.64, 50.97 and 34.03 mM showed high cytotoxicity. For leukemia cell line HL-60 (leukemia), the IC ₅₀ of compounds 19, 31, 32, 36, 43 were 16.69, 25.32, 23.88, 24.89 and It was a compound with high cytotoxicity at 26.97 mM (see Table 6 and Table 7).

Since ceramide causes cell death and increased intracellular inflammation, cytotoxicity experiments were performed on cancer cells in order to synthesize ceramide derivatives having more potent cell death.

Since cancer cells have lower ceramide concentrations than normal cells, adding a compound that can increase intracellular ceramide concentrations, such as ceramide analogues or ceramidase inhibitors, increases the lower intracellular ceramide concentrations, thereby not causing toxicity to normal cells. Has been reported to cause cell death. Based on this, compounds showing high apoptosis effect in the cytotoxicity test against cancer cells are expected to play the role of compounds with anti-cancer activity that is selective only for cancer cells, and developed as a new type of anti-cancer substance showing strong cytotoxicity. It was found to play the role of a possible leading compound.

(Ⅱ), R₃ =

(II), R ₃ =

Compound group compound R R ₄ IC _{50 of} human cancer cell lines Kidney cancer Colon cancer Lung cancer Prostate cancer leukemia Caki-2 HT-29 A549 PC-3 HL-60 B13 109.43 95.63 64.11 83.18 28.00 C ₆ -ceramide 42.53 8.48 28.04 55.78 26.11 Ⅱ 10 H C ₄ H ₉ > 342.03 > 342.03 > 342.03 > 342.03 > 342.03 11 H C ₆ H ₁₃ 219.85 158.19 > 275.85 175.69 161.85 12 H C ₈ H ₁₇ 136.49 3.61 34.38 58.12 35.52 13 H C ₉ H ₁₉ 64.18 26.62 80.69 81.93 29.39 14 H C ₁₂ H ₂₅ > 247.16 33.78 110.15 130.49 33.42 15 H C ₁₄ H ₂₉ 120.16 29.87 23.77 35.81 45.12 16 Cl C ₄ H ₉ > 305.98 > 305.98 > 305.98 > 305.98 199.12 17 Cl C ₆ H ₁₃ > 281.79 4.56 106.89 132.34 75.82 18 Cl C ₈ H ₁₇ > 261.15 > 261.15 > 261.15 > 261.15 171.37 19 Cl C ₉ H ₁₉ 51.52 10.51 39.52 60.03 16.69 20 Cl C ₁₂ H ₂₅ 198.46 44.05 87.93 97.24 29.28 21 Cl C ₁₄ H ₂₉ > 214.10 65.38 66.70 80.48 132.64 22 F C ₄ H ₉ > 322.21 > 322.21 > 322.21 > 322.21 > 322.21 23 F C ₆ H ₁₃ > 295.49 235.45 > 295.49 > 295.49 170.33 24 F C ₈ H ₁₇ > 272.87 200.16 > 272.87 > 272.87 136.89 25 F C ₉ H ₁₉ > 262.81 > 262.81 > 262.81 > 262.81 155.43 26 F C ₁₂ H ₂₅ 38.20 14.11 37.85 37.22 35.42 27 F C ₁₄ H ₂₉ 120.49 52.97 43.73 63.61 30.01 ^* B13: D-Threo-2- (N-myristoylamino) -1- (4'-nitrophenyl) -1,3-propanediol

(Ⅲ), R₃ =

(III), R ₃ =

Compound group compound R R ₄ IC _{50 of} human cancer cell lines Kidney cancer Colon cancer Lung cancer Prostate cancer leukemia Caki-2 HT-29 A549 PC-3 HL-60 B13 109.43 95.63 64.11 83.18 28.00 C ₆ -ceramide 42.53 8.48 28.04 55.78 26.11 Ⅲ 28 H C ₄ H ₉ > 324.21 197.63 > 324.21 > 324.21 231.29 29 H C ₆ H ₁₃ 51.28 18.80 53.86 38.41 149.46 30 H C ₈ H ₁₇ 22.60 27.66 18.32 13.94 29.82 31 H C ₁₀ H ₂₁ 33.39 23.02 31.83 37.71 25.32 32 H C ₁₂ H ₂₅ 56.77 27.44 55.88 78.84 23.88 33 H C ₁₄ H ₂₉ 34 Cl C ₄ H ₉ 168.12 123.96 183.70 161.99 118.74 35 Cl C ₆ H ₁₃ 64.72 55.43 67.90 61.24 61.69 36 Cl C ₈ H ₁₇ 40.52 14.30 28.41 30.35 24.86 37 Cl C ₁₀ H ₂₁ 51.67 51.24 33.16 31.64 40.93 38 Cl C ₁₂ H ₂₅ 148.82 149.65 123.23 70.01 105.25 39 Cl C ₁₄ H ₂₉ 40 F C ₄ H ₉ 197.90 189.48 253.58 203.96 161.92 41 F C ₆ H ₁₃ 167.62 181.66 164.57 169.69 168.53 42 F C ₈ H ₁₇ 54.96 48.71 53.09 50.97 47.91 43 F C ₁₀ H ₂₁ 28.95 25.55 29.71 34.03 26.97 44 F C ₁₂ H ₂₅ 68.12 68.24 65.84 71.47 51.65 45 F C ₁₄ H ₂₉ ^* B13: D-Threo-2- (N-myristoylamino) -1- (4'-nitrophenyl) -1,3-propanediol

The pharmaceutical composition containing the compound of Examples 1 to 47 according to the above production method was formulated and used as follows.

Formulation Example 1 Preparation of Powder

Compound 12 500mg

Corn Starch 100mg

Lactose 100mg

Talc 10mg

The above ingredients are mixed and filled in an airtight cloth to prepare a powder.

Formulation Example 2 Preparation of Tablet

Compound 19 100mg

Corn Starch 100mg

Lactose 100mg

2 mg magnesium stearate

After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.

Formulation Example 3 Preparation of Capsule

Compound 30 50 mg

Lactose 50mg

1 mg magnesium stearate

The above ingredients are mixed and compressed into tablets according to a conventional method for preparing capsules to fill gelatin capsules.

Formulation Example 4 Preparation of Injection

Compound 36 10mg

Appropriate sterile distilled water for injection

pH adjuster

According to the conventional method for preparing an injectable drug, the active ingredient is dissolved in distilled water for injection, the pH is adjusted to about 7.5, and the whole is filled with 2 ml of ampoules with injectable distilled water for sterilization.

Formulation Example 5 Preparation of Liquid

Compound 43 1 g

10 g of isomerized sugar

10g per book

Lemon flavor

Purified water

According to the conventional method for preparing a liquid solution, each component is added to the purified water, dissolved, and lemon flavor is added, and then purified water is added to adjust the total amount to 100 ml, and then filled into a brown bottle to prepare a liquid solution.

Although the composition ratio is mixed with a component suitable for a favorite beverage in a preferred embodiment, the composition ratio may be modified according to regional and ethnic preferences such as demand hierarchy, demand country, and use purpose.

Ureido or thioureido ceramide derivatives and their isomers and pharmaceutical compositions containing the same having a novel chemical structure of the present invention increase the concentration of intracellular ceramides, thereby killing cancer cells as well as non-toxic and thus acute as well as cancer. And the treatment and prevention of chronic inflammatory diseases and the like.

Claims (13)

A ureido or thioureido derivative compound of the general formula (I) or a pharmaceutically acceptable salt thereof or an isomer thereof:

(I) In the above formula, Y is an oxygen atom or a sulfur atom; R ₁ and R ₂ is a hydrogen atom or a hydroxyl group; R ₃ is an aromatic ring or a substituent in which a heterocycle having a hetero atom selected from N, O, and S is mutually fused or unfused; R ₄ is a hydrogen atom or an alkyl group having 1 to 20 carbon atoms. The compound of claim 1, wherein R ₃ is

ego; X is a compound substituted with at least one hydrogen atom, a halogen atom, a hydroxy group, an alkyl group having 1 to 5 carbon atoms, an alkoxy group or an alkyl group having 1 to 5 carbon atoms or an alkoxy group substituted with a halogen atom, which may be substituted at any position of the ring. The ureido derivative compound of the general formula (II) below, or a pharmaceutically acceptable salt thereof, or an isomer thereof according to claim 1, wherein Y is an oxygen atom, and R ₁ and R ₂ are hydroxy groups.

(Ⅱ) Where R ₃ is

ego; X is one or more hydrogen atoms, halogen atoms, hydroxy groups, alkyl groups having 1 to 5 carbon atoms, alkoxy groups or alkyl groups having 1 to 5 carbon atoms or alkoxy groups substituted with halogen atoms, which may be substituted at any position of the ring; R ₄ is a hydrogen atom or an alkyl group having 1 to 20 carbon atoms. The method of claim 3, wherein (2S, 3R, 4E) -2- (3-n-butyl ureido) -5-phenyl-4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-hexyl ureido) -5-phenyl-4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-octyl ureido) -5-phenyl-4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-nonyl ureido) -5-phenyl-4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-dodecyl ureido) -5-phenyl-4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-tetradecyl ureido) -5-phenyl-4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-butyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-hexyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-octyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-nonyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-dodecyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-tetradecyl ureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-butyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-hexyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-octyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-nonyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-dodecyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-tetradecyl ureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol. The thiouureido derivative compound of formula (III) or a pharmaceutically acceptable salt thereof or isomer thereof according to claim 1, wherein Y is a sulfur atom and R ₁ and R ₂ are hydroxy groups.

(Ⅲ) Where R ₃ is

ego; X is one or more hydrogen atoms, halogen atoms, hydroxy groups, alkyl groups having 1 to 5 carbon atoms, alkoxy groups or alkyl groups having 1 to 5 carbon atoms or alkoxy groups substituted with halogen atoms, which may be substituted at any position of the ring; R ₄ is a hydrogen atom or an alkyl group having 1 to 20 carbon atoms. The method of claim 5, (2S, 3R, 4E) -2- (3-n-butyl thioureido) -5-phenyl-4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-hexyl thioureido) -5-phenyl-4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-octyl thioureido) -5-phenyl-4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-decyl thioureido) -5-phenyl-4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-dodecyl thioureido) -5-phenyl-4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-tetradecyl thioureido) -5-phenyl-4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-butyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-hexyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-octyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-decyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-dodecyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-tetradecyl thioureido) -5- (4-chlorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-butyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-hexyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-octyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-decyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-dodecyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol, (2S, 3R, 4E) -2- (3-n-tetradecyl thioureido) -5- (4-fluorophenyl) -4-pentene-1,3-diol. A pharmaceutical composition for anticancer treatment, comprising the general formula compound of any one of claims 1 to 6 as an active ingredient and a pharmaceutically acceptable carrier. According to claim 7, wherein the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, anal muscle cancer, colon cancer, breast cancer, fallopian tube carcinoma, uterus Endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic Or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma, pituitary adenoma, or these A pharmaceutical composition comprising one or more combinations of cancers. delete The compound of formula (VII) prepared by reacting the following compound of formula (VII) with chlorotitanium triethoxide and aldehyde was hydrolyzed to prepare a compound of formula (VI), and the compound was reduced to reduce general compound. A process for preparing the ureido or thioureido derivative compounds of the general formula (IV), characterized in that the compound of (V) is prepared and subsequently isocyanate or isothiocyanate reactant is reacted in an ethanol solvent.

(Ⅳ)

(Ⅴ)

(Ⅵ)

(Ⅶ)

(Ⅷ) In the above formula: R ₃ is

ego; R ₄ is a hydrogen atom or an alkyl group having 1 to 20 carbon atoms. The method of claim 10, wherein the isocyanate reactant is selected from octyl isocyanate, nonyl isocyanate, dodecyl isocyanate and tetradecyl isocyanate. The method of claim 10, wherein the thioisocyanate reactant is selected from octyl thioisocyanate, decyl thioisocyanate, dodecyl thioisocyanate and tetradecyl thioisocyanate. delete