KR20050003905A - Pharmaceutical composition comprising aromatic alkyl sulfone amide derivatives having anti-cancer activity and pharmaceutical composition containing the same - Google Patents

Abstract

PURPOSE: Provided are an aromatic alkylsulfone amide derivative and a pharmaceutical composition containing the same, which show excellent cell death activity against a cancer cell and non-toxicity and thus are useful for preventing and treating a cancer. CONSTITUTION: The aromatic alkylsulfone amide derivative is represented by the formula I, and is prepared by reacting an alkylsulfonyl chloride of the formula III: R3-SO2-Cl, which is obtained by reacting a metal salt of an alkylsulfonic acid of the formula II: R3-SO3-M and a sulfonifying reagent such as SOCl2, with a phenylamine derivative of the formula IV. In the formulas I-IV, R1 is hydroxy group or a C1-C3-alkoxy group, R2 is hydrogen atom, hydroxy group or a C1-C3-alkoxy group, R3 is a C5-C30-alkyl group, and R4 is hydrogen, nitro group, amine group, a halogen atom or a C1-C3-alkyl group. The anti-cancer pharmaceutical composition comprises the aromatic alkylsulfone amide derivative, or a pharmaceutically acceptable salt or isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier.

Description

Pharmaceutical composition comprising aromatic alkyl sulfone amide derivatives having anti-cancer activity and pharmaceutical composition containing the same

OBJECT OF THE INVENTION The present invention relates to aromatic alkyl sulfone amide derivatives compounds having useful novel chemical structures with anticancer activity, pharmaceutical compositions containing them and methods for their preparation.

The mechanism of proliferation and death of cancer cells, which is recognized as the pathogenesis of cancer, is being 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 them, ceramide, is a kind of sphingolipids, a constituent of cell membranes, and has important physiological and chemical functions as factors that regulate cell function.It activates protein kinase and MAP kinase. And inhibiting phospholipase D are reported to be involved in cell growth, differentiation, death, aging and neurodegeneration (Merrill, AHJ, et al., Toxicol. Appl . Pharmcol . 142 , pp208-). 225, 1997). In particular, ceramide is apoptosis (Obeid, Science , 259 , pp1769-1771, 1933), cell differentiation in leukemia cells or other types of cells (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 has been reported as an important secondary transporter, and also Perkinson's disease (Hunot, Proc. Natl. Acade. Sci. USA, 94 , pp7531-7536). , 1997) and Alzheimer's disease (Fiebich., J. Neuroimmunol., 63 , pp207-211, 1995).

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). Increasing the concentration of ceramide has been reported to inhibit the growth of cancer cells.

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.The treatment of ceramides or ceramide degrading enzyme inhibitors with cancer cells increased the concentration of ceramide in cancer cells to promote 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.

In the meantime, many ceramide derivatives have been synthesized. Among them, when the cells are treated with short-chain cell membrane permeable ceramide derivatives such as C ₂ , C ₆ or C ₈ -ceramide, the action is similar to that due to increased ceramide in normal cells. (Witty, JP, et al ., Endocrinology , 137 , pp 5269-5277, 1996). In particular, in recent studies, 6-ethyl-5-tetradecyl-1 H -pyrimidine-2,4-dione and 6-ethyl-5-tetradecyl-2-thioxo-2,3-dihydro-1 H -pyrimidine-4-one has been reported to have better anticancer activity than C ₂ -ceramide when treated on CCRF-CEM human leukemia cells (Macchia, M., et al ., J. Med). Chem. , 44 , pp 3994-4000, 2001). PDMP (Radin, NS, et al ., Adv. Lipid. Res. , 26 , pp183-213, 1993) and De-MAPP (Bielawska, A., et al ., J ), which inhibit enzymes acting at lower ceramide levels Biol. Chem., 271, pp 12646-12654, 1996), all of these compounds have been reported to cause cell death and increase the intracellular concentration of ceramide.

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.

Based on the basic structure of the ceramide, the ceramide derivative of the new structure was studied through a molecular formula strategy. First, the natural ceramide contains C ₁₈ sphingosin group and C ₁₄ -C ₁₆ N -acyl group, so the lipophilic properties are very high and the distribution is not good in vivo. In order to improve the pharmacokinetic properties and improve the pharmacokinetic properties, we designed a ceramide derivative in which the aliphatic group of the sphingosine moiety was substituted with various kinds of phenyl amino alchols. In addition, and conversion of the R-CH ₂ CO-NH- portion of the fatty acid to substitute the CH ₂ CO as part of bio-iso-SO ₂ group cholesteric (bioisosteric group) as R-SO _2. In order to improve the lipophilic properties of ceramides and to synthesize ceramide derivatives having excellent activity, an attempt was made to introduce alkyl groups of various lengths or aromatic rings into the R site, and to view stereochemical specificities of the synthetic compounds. ) The compounds of different carbon stereochemistry were synthesized to compare cytotoxic activity, and the effect of cell death was measured on the synthesized compounds.

The present inventors have completed the present invention by confirming that the novel aromatic alkyl sulfonamide derivative compounds have excellent apoptosis activity against cancer cells.

It is an object of the present invention to provide an aromatic alkyl sulfonamide derivative compound of novel chemical structure with anticancer activity, which is a similar structural form of ceramide.

1a to 1d are measured cytotoxic effects of synthetic compounds having different alkyl groups on various human cancer cell lines,

1A is a diagram measuring the cytotoxic effects of Compounds (1) to (5),

1B is a diagram measuring the cytotoxic effects of Compounds (6) to (10),

1C is a diagram measuring the cytotoxic effect of Compounds (11) to (15),

1D is a diagram measuring the cytotoxic effects of Compounds (16) to (20),

Figure 2a to 2e is a measure of the cytotoxic effect of the synthetic compounds having different alkyl groups and the control group for various human cancer cell lines,

Figure 2a is a diagram measuring the cytotoxic effect on kidney cancer cell line Caki-2,

Figure 2b is a diagram measuring the cytotoxic effect on colon cancer cell line HT-90,

Figure 2c is a diagram measuring the cytotoxic effect on lung cancer cell line A549,

Figure 2d is a diagram measuring the cytotoxic effect on prostate cancer cell line PC-3,

Figure 2e is a diagram measuring the cytotoxic effect on leukemia cell line HL-90.

In order to achieve the above object, the present invention provides a compound represented by the following general formula (I), or a pharmaceutically acceptable salt thereof and isomer thereof as an aromatic alkyl sulfone amide derivative.

(I)

In the above formula,

R ₁ is a hydroxy group or a C ₁ to C ₃ alkoxy group;

R ₂ is a hydrogen atom or a hydroxyl group or a C ₁ to C ₃ alkoxy group;

R ₃ is an alkyl group of C ₅ to C ₃₀ ;

R ₄ is a hydrogen atom, a nitro group, an amine group, a halogen atom or a C ₁ to C ₃ alkyl group.

Preferred compound group of the present invention, in the above general formula (I), R ₁ is a hydroxy group, R ₂ is a hydrogen atom, R ₃ is an alkyl group of C ₇ to C ₁₃ , R ₄ is a hydrogen atom or a nitro group And isomers thereof, and more preferred compounds include

(1R, 2S) 2- (1-heptanesulfonylamido) -1-phenyl-1-propanol,

(1R, 2S) 2- (1-octanesulfonylamido) -1-phenyl-1-propanol,

(1R, 2S) 2- (1-nonanesulfonylamido) -1-phenyl-1-propanol,

(1R, 2S) 2- (1-undecanesulfonylamido) -1-phenyl-1-propanol,

(1R, 2S) 2- (1-tridecanesulfonylamido) -1-phenyl-1-propanol,

(1S, 2R) 2- (1-heptanesulfonylamido) -1-phenyl-1-propanol,

(1S, 2R) 2- (1-octanesulfonyl amido) -1-phenyl-1-propanol,

(1S, 2R) 2- (1-nonanesulfonyl amido) -1-phenyl-1-propanol,

(1S, 2R) 2- (1-undecanesulfonylamido) -1-phenyl-1-propanol,

(1S, 2R) 2- (1-tridecanesulfonylamido) -1-phenyl-1-propanol,

(1R, 2R) 2- (1-heptanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol,

(1R, 2R) 2- (1-octanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol,

(1R, 2R) 2- (1-nonanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol,

(1R, 2R) 2- (1-Undecanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol,

(1R, 2R) 2- (1-tridecanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol,

(1S, 2S) 2- (1-heptanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol,

(1S, 2S) 2- (1-octanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol,

(1S, 2S) 2- (1-nonanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol,

(1S, 2S) 2- (1-Undecanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol,

(1S, 2S) 2- (1-tridecanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol.

In the above general formula (I), the stereochemistry of the chiral centers 1- and 2- of the aromatic alkyl sulfonamides is determined by the rules of can-ingold and prelog (RS Cahn, C. Ingold, and Prelog, Angewandte Chemie , International Edition English, 5 , p385, 1966: 5 , p511, 1966), the compound having the stereochemistry of "S" or "R", the racemic mixture of Formula (I) and the R or S-type stereoisomers of the present invention It is included in a range. The present invention also includes all compounds in the form of pharmaceutically acceptable salts.

In addition, the aromatic alkyl sulfone amide derivative compounds represented by the above general formula (I) according to the present invention can form an acceptable acid addition salt according to a conventional method in the art, such as dissolving the compound in an appropriately selected solvent. It is prepared by treating with an excess of 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 general formula (I) above 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 compound of general formula (I), which will be described in detail below.

The aromatic alkyl sulfonamide derivative represented by the general formula (I) is a general formula (III) obtained by reacting an alkyl sulfonic acid metal salt of general formula (II) with a sulfonation reagent such as SOCl _2. Can be prepared by reacting an alkyl sulfonyl chloride of phenyl amine derivative of formula (IV) corresponding to the definition of R ₁ , R ₂ and R ₄ substituents.

R ₃ -SO ₃ -M (II)

Where

R ₃ is as defined in general formula (I),

M is a heavy metal cation salt such as Na, K, Mg.

R ₃ -SO ₂ -Cl (III)

Where

R ₃ is as defined in general formula (I).

(Ⅳ)

Where

R ₁ , R ₂ and R ₄ are as defined in general formula (I).

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.

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

In order to prepare the compound of the present application, a compound of the general formula (II) may be obtained by a known method, and the compound of the general formula (III) may be dissolved in a suitable solvent after dissolving the compound of the general formula (II). After dropping, slowly adding SOCl ₂ on the ice, refluxing for a predetermined time, and then removing the excess SOCl ₂ with a simple distillation apparatus, the remaining reactant can be prepared by concentrating. Suitable solvents that can be used in the reaction are single or mixed solvents selected from benzene, xylene or toluene, preferably toluene. Typical reaction temperatures range from -20 to 100 ° C., preferably 0 ° C., and reaction times range from a few minutes to one day, preferably 4 hours.

The compound of formula (IV) was dissolved in a weak acid salt such as THF and 30% sodium acetate, and then slowly added dropwise to the compound of formula (III) at an appropriate temperature, followed by stirring for a predetermined time, and then the reaction solution. To this was added an organic solvent such as EtOAc, washed with saturated NaHCO ₃ solution, weak acid such as 5% citric acid and saturated sodium chloride, dried the organic layer with a drying agent such as anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. After purification, the product can be purified by silica gel column chromatography to obtain the pure target compound. Typical reaction temperatures range from -20 to 100 ° C., preferably room temperature, and reaction times range from a few minutes to two days, preferably 24 hours.

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

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

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.

Compounds of formula (I) of the present invention may provide pharmaceutical compositions with pharmaceutically acceptable carriers, adjuvants or diluents, by adding conventional non-toxic pharmaceutically acceptable carriers, adjuvant and excipients 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; 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 100 mg / kg per day, preferably 0.001 to 100 mg / kg, preferably administered once a day, may 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 mammals such as rats, mice, livestock, humans by various routes. 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 illustrative of the present invention, and 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) and thin layer chromatography (TLC) were identified using an ultraviolet (UV) ultra violet (UV) lamp using silica gel 60 F ₂₅₄ (thickness 0.2 μm, Merck), and silica gel column chromatography was used for silica gel. (Merck type 9355, 230-400 mesh), and all reagents were purchased from Aldrich (Aldrich) and used. In addition, optical fluorescence (DIP-370, JASCO) and absorbance (UV-900C, CERES) were measured and analyzed.

Example 1 Preparation of Alkylsulfonylchloride Compounds

Sodium alkylsulfonate (2.5 mM) was dissolved in toluene (50 mL), DMF (5 drops) was added dropwise, SOCl ₂ (5 mM) was added dropwise in an ice bath, and the mixture was refluxed for 4 hours, and then the reaction was simple distillation apparatus. After removing excess SOCl ₂ with, the remaining reaction was concentrated to give alkylsulfonylchloride.

Example 2. Preparation of Thioureido Compound

Phenylaminoalcohol (1.2 mM) was dissolved in THF (20 mL) and 30% sodium acetate (20 mL), and the alkylsulfonyl chloride (2 mM) obtained in Example 1 was slowly added dropwise at room temperature, followed by stirring for 24 hours. After adding ethyl acetate (50 ml) to the reaction solution, the mixture was washed with saturated sodium bicarbonate solution (75 ml x 3), 5% citric acid (75 ml x 3), saturated sodium chloride (75 ml x 3), and the organic layer was washed. After drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure and purification by silica gel column chromatography gave pure thiouride compound.

Example 3. Preparation of (1R, 2S) 2- (1-heptanesulfonylamido) -1-phenyl-1-propanol [1]

1-heptanesulfonylchloride was synthesized according to the preparation method described in Example 1 using 505 mg (2.5 mM) of 1-heptanesulfonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1R, 2S) 181.32 mg (1.2 mM) of 2-amino-1-phenyl-1-propanol and 397.42 mg (2 mM) of 1-heptanesulfonylchloride synthesized above were used in the preparation method described in Example 2. Purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) to synthesize 184.8 mg (yield 49%) of the target compound [1].

TLC (hexane: ethyl acetate = 2: 1), R _f = 0.43

= +14.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.97 (t, 3H, J = 6.6 Hz, CH ₃ ), 1.25 (d, 3H, J = 6.9 Hz, C ₂ -CH ₃ ), 1.26-1.38 (m, 8H, (CH ₂ ) ₄ ), 1.38-1.70 (m, 2H, SO ₂ -CH ₂ CH ₂ ), 2.68-2.74 (m, 2H, SO ₂ -CH ₂ ), 3.60-3.72 (m, 1H, C ₂ -H), 4.67 (d, 1H, J = 5.7 Hz, C ₁ -H), 7.30-7.48 (m, 5H, phenyl)

FABMS ( M + H ) ⁺ for C ₁₆ H ₂₇ NO ₃ S: found 296.15 (314-18); Calculated 313.46

Example 4 Preparation of (1R, 2S) 2- (1-octanesulfonylamido) -1-phenyl-1-propanol [2]

(1R, 2S) was synthesized according to the method described in Example 2 using 181.32 mg (1.2 mM) of 2-amino-1-phenyl-1-propanediol and 425.48 mg (2 mM) of 1-octanesulfonylchloride, Purification by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) yielded 147 mg (yield 37.4%) of the target compound [2].

TLC (hexane: ethyl acetate = 2: 1) R _f = 0.41

= +12.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.95 (t, 3H, J = 6.6 Hz, CH ₃ ), 1.23 (d, 3H, J = 6.3 Hz, C ₂ -CH ₃ ), 1.25-1.44 (m, 10H, (CH ₂ ) 5), 1.44 to 1.68 (m, 2H, SO ₂ -CH ₂ CH ₂ ), 2.58 to 2.80 (m, 2H, SO ₂ -CH ₂ ), 3.58 to 3.72 (m, 1H, C ₂ -H), 4.65 (d, 1H, J = 5.7 Hz, C ₁ -H), 7.25-7.52 (m, 5H, phenyl)

FABMS ( M + H ) ⁺ for C ₁₇ H ₂₉ NO ₃ S: found 310.12 (328-148); Calculated 327.19

Example 5. Preparation of (1R, 2S) 2- (1-nonanesulfonylamido) -1-phenyl-1-propanol [3]

1-nonanesulfonylchloride was synthesized according to the preparation method described in Example 1 using 575.75 mg (2.5 mM) of 1-nonanesulfonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1R, 2S) 181.32 mg (1.2 mM) of 2-amino-1-phenyl-1-propanol and 453.52 mg (2 mM) of 1-nonansulfonyl chloride synthesized above were used in the preparation method described in Example 2. It was synthesized according to the above, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) to synthesize 140 mg (yield 34.1%) of the target compound [3].

TLC (hexane: ethyl acetate = 2: 1) R _f = 0.43

= +12.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.92 (t, 3H, J = 6.9 Hz, CH ₃ ), 1.20 (d, 3H, J = 6.6 Hz, C ₂ -CH ₃ ), 1.22-1.40 (m, 12H, (CH ₂ ) ₆ ), 1.40-1.62 (m, 2H, SO ₂ -CH ₂ CH ₂ ), 2.48-2.71 (m, 2H, SO ₂ -CH ₂ ), 3.54-3.64 (m, 1H, C ₂ -H), 4.59 (d, 1H, J = 6.0 Hz, C ₁ -H), 7.21-7.42 (m, 5H, phenyl)

FABMS ( M + H ) ⁺ for C ₁₈ H ₃₁ NO ₃ S: found 324.19 (342-18); Calculation 341.20

Example 6. Preparation of (1R, 2S) 2- (1-Undecanesulfonylamido) -1-phenyl-1-propanol [4]

1-Undecanesulfonylchloride was synthesized according to the preparation method described in Example 1 using 645.87 mg (2.5 mM) of 1-undecanesulphonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1R, 2S) To the production method described in Example 2 using 181.32 mg (1.2 mM) of 2-amino-1-phenyl-1-propanol and 509.64 mg (2 mM) of 1-undecanesulphonic chloride synthesized above. 107 mg (yield 24%) of the title compound [4] was purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1).

TLC (hexane: ethyl acetate = 2: 1) R _f = 0.45

= +15.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.91 (t, 3H, J = 6.6 Hz, CH ₃ ), 1.19 (d, 3H, J = 6.6 Hz, C ₂ -CH ₃ ), 1.22 to 1.38 (m, 16H, (CH ₂ ) ₈ ), 1.38-1.62 (m, 2H, SO ₂ -CH ₂ CH ₂ ), 2.58-2.75 (m, 2H, SO ₂ -CH ₂ ), 3.54-3.64 (m, 1H, C ₂ -H), 4.59 (d, 1H, J = 5.7 Hz, C ₁ -H), 7.22-7.44 (m, 5H, phenyl)

FABMS ( M + H ) ⁺ for C ₁₉ H ₃₃ NO ₃ S: found 352.32 (370-18); Calculation 369.23

Example 7. Preparation of (1R, 2S) 2- (1-tridecansulfonylamido) -1-phenyl-1-propanol [5]

1-tridecanesulfonylchloride was synthesized according to the preparation method described in Example 1 using 716 mg (2.5 mM) of 1-tridecanesulphonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1R, 2S) To the method described in Example 2 using 181.32 mg (1.2 mM) of 2-amino-1-phenyl-1-propanol and 565.74 mg (2 mM) of 1-tridecanesulfonyl chloride synthesized above. 72 mg (yield 15%) of the target compound [5] was purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1).

TLC (hexane: ethyl acetate = 2: 1) R _f = 0.45

= +15.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.91 (t, 3H, J = 6.6 Hz, CH ₃ ), 1.19 (d, 3H, J = 6.6 Hz, C ₂ -CH ₃ ), 1.22 to 1.38 (m, 20H, (CH ₂ ) ₁₀ ), 1.38-1.62 (m, 2H, SO ₂ -CH ₂ CH ₂ ), 2.58-2.75 (m, 2H, SO ₂ -CH ₂ ), 3.54-3.64 (m, 1H, C ₂ -H), 4.59 (d, 1H, J = 5.7 Hz, C ₁ -H), 7.22-7.44 (m, 5H, phenyl)

FABMS ( M + H ) ⁺ for C ₂₀ H ₃₅ NO ₃ S: found 380.24 (398-18); Calculation 397.27

Example 8. Preparation of (1S, 2R) 2- (1-heptanesulfonylamido) -1-phenyl-1-propanol [6]

1-heptanesulfonylchloride was synthesized according to the preparation method described in Example 1 using 505 mg (2.5 mM) of 1-heptanesulfonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1S, 2R) 181.32 mg (1.2 mM) of 2-amino-1-phenyl-1-propanol and 397.42 mg (2 mM) of 1-heptanesulfonyl chloride synthesized above were used in the preparation method described in Example 2. Purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) to synthesize 200 mg (yield 53%) of the target compound [6].

TLC (hexane: ethyl acetate = 2: 1) R _f = 0.43

= -5.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.92 (t, 3H, J = 6.9 Hz, CH ₃ ), 1.19 (d, 3H, J = 6.9 Hz, C ₂ -CH ₃ ), 1.22 to 1.42 (m, 8H, (CH ₂ ) ₄ ), 1.42 to 1.68 (m, 2H, SO ₂ -CH ₂ CH ₂ ), 2.56 to 2.74 (m, 2H, SO ₂ -CH ₂ ), 3.54 to 3.64 (m, 1H, C ₂ -H), 4.59 (d, 1H, J = 6.0 Hz, C ₁ -H), 7.22-7.42 (m, 5H, phenyl)

FABMS ( M + H ) ⁺ for C ₁₆ H ₂₇ NO ₃ S: found 296.16 (314-18); Calculated 313.46

Example 9 Preparation of (1S, 2R) 2- (1-octanesulfonylamido) -1-phenyl-1-propanol [7]

(1S, 2R) was synthesized according to the preparation method described in Example 2 using 181.32 mg (1.2 mM) of 2-amino-1-phenyl-1-propanol and 425.48 mg (2 mM) of 1-octanesulfonylchloride, Purification by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) yielded 94 mg (yield 23.9%) of the target compound [7].

TLC (hexane: ethyl acetate = 2: 1) R _f = 0.41

= -3.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.92 (t, 3H, J = 6.6 Hz, CH ₃ ), 1.20 (d, 3H, J = 6.6 Hz, C ₂ -CH ₃ ), 1.22 to 1.42 (m, 10H, (CH ₂ ) ₅ ), 1.42-1.68 (m, 2H, SO ₂ -CH ₂ CH ₂ ), 2.48-2.86 (m, 2H, SO ₂ -CH ₂ ), 3.52-3.62 (m, 1H, C ₂ -H), 4.60 (d, 1H, J = 6.0 Hz, C ₁ -H), 7.22-7.48 (m, 5H, phenyl)

FABMS ( M + H ) ⁺ for C ₁₇ H ₂₉ NO ₃ S: found 310.20 (328-18); Calculated 327.19

Example 10. Preparation of (1S, 2R) 2- (1-nonanesulfonylamido) -1-phenyl-1-propanol [8].

1-nonanesulfonylchloride was synthesized according to the preparation method described in Example 1 using 575.75 mg (2.5 mM) of 1-nonanesulfonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1S, 2R) 181.32 mg (1.2 mM) of 2-amino-1-phenyl-1-propanol and 453.52 mg (2 mM) of 1-nonanesulfonyl chloride synthesized above were used in the preparation method described in Example 2. Purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) to synthesize 195 mg (yield 47.5%) of the target compound [8].

TLC (hexane: ethyl acetate = 2: 1) R _f = 0.42

= -5.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.92 (t, 3H, J = 6.6 Hz, CH ₃ ), 1.20 (d, 3H, J = 6.9 Hz, C ₂ -CH ₃ ), 1.22 to 1.42 (m, 12H, (CH ₂ ) ₆ ), 1.42 to 1.64 (m, 2H, SO ₂ -CH ₂ CH ₂ ), 2.58 to 2.78 (m, 2H, SO ₂ -CH ₂ ), 3.56 to 3.68 (m, 1H, C ₂ -H), 4.60 (d, 1H, J = 5.7 Hz, C ₁ -H), 7.22-7.52 (m, 5H, phenyl)

FABMS ( M + H ) ⁺ for C ₁₈ H ₃₁ NO ₃ S: found 324.17 (342-18); Calculation 341.20

Example 11 Preparation of (1S, 2R) 2- (1-Undecanesulfonylamido) -1-phenyl-1-propanol [9]

1-Undecanesulfonylchloride was synthesized according to the preparation method described in Example 1 using 645.87 mg (2.5 mM) of 1-undecanesulphonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1S, 2R) 181.32 mg (1.2 mM) of 2-amino-1-phenyl-1-propanol and 509.64 mg (2 mM) of 1-undecanesulfonyl chloride synthesized above were used in the preparation method described in Example 2. 179 mg (yield 40.4%) of the title compound [9] was purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1).

TLC (hexane: ethyl acetate = 2: 1) R _f = 0.44

= -3.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.91 (t, 3H, J = 6.6 Hz, CH ₃ ), 1.19 (d, 3H, J = 6.6 Hz, C ₂ -CH ₃ ), 1.11 to 1.21 (m, 16H, (CH ₂ ) ₈ ), 1.21-1.62 (m, 2H, SO ₂ -CH ₂ CH ₂ ), 2.56-2.74 (m, 2H, SO ₂ -CH ₂ ), 3.56-3.68 (m, 1H, C ₂ -H), 4.59 (d, 1H, J = 6.0 Hz, C ₁ -H), 7.22-7.42 (m, 5H, phenyl)

FABMS ( M + H ) ⁺ for C ₁₉ H ₃₃ NO ₃ S: found 352.20 (370-18); Calculation 369.23

Example 12. Preparation of (1S, 2R) 2- (1-tridecansulfonylamido) -1-phenyl-1-propanol [10].

1-tridecanesulfonylchloride was synthesized according to the preparation method described in Example 1 using 716 mg (2.5 mM) of 1-tridecanesulphonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1S, 2R) The preparation method described in Example 2 using 181.32 mg (1.2 mM) of 2-amino-1-phenyl-1-propanol and 565.74 mg (2 mM) of 1-tridecanesulfonyl chloride synthesized above. Purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) to synthesize 35 mg (yield 7.5%) of the target compound [10].

TLC (Hexane: EtOAc = 2: 1) R _f = 0.44

= -4.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.91 (t, 3H, J = 6.6 Hz, CH ₃ ), 1.19 (d, 3H, J = 6.6 Hz, C ₂ -CH ₃ ), 1.22 to 1.38 (m, 20H, (CH ₂ ) ₁₀ ), 1.38-1.62 (m, 2H, SO ₂ -CH ₂ CH ₂ ), 2.58-2.75 (m, 2H, SO ₂ -CH ₂ ), 3.54-3.64 (m, 1H, C ₂ -H), 4.59 (d, 1H, J = 5.7 Hz, C ₁ -H), 7.22-7.44 (m, 5H, phenyl)

FABMS ( M + H ) ⁺ for C ₂₀ H ₃₃ NO ₃ S: found 380.25 (398-18); Calculation 397.27

Example 13. Preparation of (1R, 2R) 2- (1-heptanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol [11]

1-heptanesulfonylchloride was synthesized according to the preparation method described in Example 1 using 505 mg (2.5 mM) of 1-heptanesulfonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1R, 2R) 255 mg (1.2 mM) of 2-amino-1- (4'-niphenyl) -1,3-propanediol and 397.42 mg (2 mM) of 1-heptanesulfonylchloride synthesized above were used. It was synthesized according to the preparation method described in Example 2, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) to synthesize 45 mg (yield 10%) of the target compound [11].

TLC (Hexane: EtOAc = 2: 1) R _f = 0.23

= -41.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.90 (t, 3H, J = 6.9 Hz, CH ₃ ), 1.08 to 1.38 (m, 8H, (CH ₂ ) ₄ , 1.38 to 1.48 (m, 2H, SO ₂ -CH ₂ CH ₂ ), 2.54 (t, 2H, J = 8.1 Hz SO ₂ -CH ₂ ), 3.50-3.68 (m, 2H, C ₃ -2H), 3.74 -3.84 (m, 1H, C ₂ -H ), 5.13 (d, 1H, J = 2.4 Hz C ₁ -H), 7.72 (d, 2H, J = 8.7 Hz, 2H-phenyl), 8.24 (d, 2H, J = 8.7 Hz, 2H-phenyl)

FABMS ( M + H ) ⁺ for C ₁₆ H ₂₆ N ₂ 0 ₆ S: found 375.13; Calculated 374.15

Example 14 Preparation of (1R, 2R) 2- (1-octanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol [12]

Example 2 using (1R, 2R) 2-amino-1- (4'-nitrophenyl) -1,3-propanediol 255 mg (1.2 mM) and 425.48 mg (2 mM) of 1-octanesulfonylchloride 60 mg (yield 12.8%) of the target compound was synthesized by purification using silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1).

TLC (hexane: ethyl acetate = 2: 1) R _f = 0.24

= -45.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.91 (t, 3H, J = 6.6 Hz, CH ₃ ), 1.02-1.38 (m, 10H, (CH ₂ ) ₅ ), 1.38-1.48 (m, 2H, SO ₂ -CH ₂ CH ₂ ), 2.53 (t, 2H, J = 8.1 Hz SO ₂ -CH ₂ ), 3.50-3.68 (m, 2H, C ₃ -2H), 3.72-3.88 (m, 1H, C _2- H), 3.13 (d, 1H, J = 2.7 Hz, C ₁ -H), 7.72 (d, 2H, J = 9.0 Hz, 2H-phenyl), 8.24 (d, 2H, J = 6.9 Hz, 2H-phenyl )

FABMS ( M + H ) ⁺ for C ₁₇ H ₂₈ N ₂ O ₆ S: found 389.18; Calculation 388.17

Example 15. Preparation of (1R, 2R) 2- (1-nonanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol [13]

1-nonanesulfonylchloride was synthesized according to the method described in Example 1 using 575.75 mg (2.5 mM) of 1-nonanesulphonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1R, 2R) 255 mg (1.2 mM) of 2-amino-1- (4'-nitrophenyl) -1,3-propanediol and 453.52 mg (2 mM) of 1-nonansulfonyl chloride synthesized above were used Synthesis was carried out according to the preparation method described in Example 2, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) to synthesize 60 mg (yield 10.9%) of the target compound [13].

TLC (hexane: ethyl acetate = 2: 1) R _f = 0.24

= -32.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.90 (t, 3H, J = 6.9 Hz, CH ₃ ), 1.08 to 1.38 (m, 12H, (CH ₂ ) ₆ , 1.38 to 1.48 (m, 2H, SO ₂ -CH ₂ CH ₂ ), 2.54 (t, 2H, J = 8.1 Hz SO ₂ -CH ₂ ), 3.50-3.68 (m, 2H, C ₃ -2H), 3.74 -3.84 (m, 1H, C ₂ -H ), 5.13 (d, 1H, J = 2.4 Hz C ₁ -H), 7.72 (d, 2H, J = 8.7 Hz, 2H-phenyl), 8.24 (d, 2H, J = 8.7 Hz, 2H-phenyl)

FABMS ( M + H ) ⁺ for C ₁₈ H ₃₀ N ₂ O ₆ S: found 403.16; Calculated 402.18

Example 16. Preparation of (1R, 2R) 2- (1-Undecanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol [14]

1-Undecanesulfonylchloride was synthesized according to the general synthesis method A using 645.87 mg (2.5 mM) of 1-undecanesulphonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1R, 2R) 255 mg (1.2 mM) of 2-amino-1- (4'-nitrophenyl) -1,3-propanediol and 509.64 mg (2 mM) of 1-undecanesulfonylchloride synthesized above were used Was synthesized according to the preparation method described in Example 1, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) to synthesize 75 mg (yield 14.5%) of the target compound [14]. .

TLC (Hexane: EtOAc = 2: 1) R _f = 0.21

= -40.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.92 (t, 3H, J = 6.9 Hz, CH ₃ ), 1.20 to 1.40 (m, 16H, (CH ₂ ) ₈ , 1.40 to 1.50 (m, 2H, SO ₂ -CH ₂ CH ₂ ), 2.54 (t, 2H, J = 8.1 Hz SO ₂ -CH ₂ ), 3.50-3.68 (m, 2H, C ₃ -2H), 3.76-3.86 (m, 1H, C ₂ -H ), 5.14 (d, 1H, J = 2.4 Hz C ₁ -H), 7.73 (d, 2H, J = 8.7 Hz, 2H-phenyl), 8.24 (d, 2H, J = 8.7 Hz, 2H-phenyl)

FABMS ( M + H ) ⁺ for C ₁₉ H ₃₂ N ₂ O ₆ S: found 431.20; Calculated 430.21

Example 17. Preparation of (1R, 2R) 2- (1-tridecanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol [15]

1-tridecanesulfonylchloride was synthesized according to the preparation method described in Example 1 using 716 mg (2.5 mM) of 1-tridecanesulphonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1R, 2R) 2-amino-1- (4'-nitorophenyl) -1,3-propanediol 255 mg (1.2 mM) and 565.74 mg (2 mM) of 1-tridecanesulfonyl chloride synthesized above Was synthesized according to the preparation method described in Example 2, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) to give 60 mg (yield 10.9%) of the target compound [15]. Synthesized.

TLC (Hexane: EtOAc = 2: 1) R _f = 0.25

= -42.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.92 (t, 3H, J = 6.9 Hz, CH ₃ ), 1.08 to 1.39 (m, 20H, (CH ₂ ) ₁₀ , 1.39 to 1.50 (m, 2H, SO2- CH ₂ CH ₂ ), 2.55 (t, 2H, J = 8.1 Hz SO2-CH ₂ ), 3.52-3.68 (m, 2H, C ₃ -2H), 3.78-3.86 (m, 1H, C ₂ -H), 5.15 (d, 1H, J = 2.7 Hz C ₁ -H), 7.76 (d, 2H, J = 8.7 Hz, 2H-phenyl), 8.25 (d, 2H, J = 8.7 Hz, 2H-phenyl)

FABMS ( M + H ) ⁺ for C ₂₀ H ₃₄ N ₂ O ₆ S: found 459.19; Calculated 458.25

Example 18. Preparation of (1S, 2S) 2- (1-heptanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol [16]

1-heptanesulfonylchloride was synthesized according to the method described in Example 1 using 505 mg (2.5 mM) of 1-heptanesulfonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1S, 2S) 255 mg (1.2 mM) of 2-amino-1- (4'-nitrophenyl) -1,3-propanediol and 397.42 mg (2 mM) of 1-heptanesulfonylchloride synthesized above were used Synthesis was carried out according to the method described in Example 2, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) to synthesize 58 mg (yield 12.9%) of the target compound [16].

TLC (hexane: ethyl acetate = 2: 1) R _f = 0.23

= +56.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.90 (t, 3H, J = 6.9 Hz, CH ₃ ), 1.08 to 1.38 (m, 8H, (CH ₂ ) 4, 1.38 to 1.48 (m, 2H, SO _2- CH ₂ CH ₂ ), 2.54 (t, 2H, J = 8.1 Hz SO2-CH ₂ ), 3.50-3.68 (m, 2H, C ₃ -2H), 3.74-3.84 (m, 1H, C ₂ -H), 5.13 (d, 1H, J = 2.4 Hz C ₁ -H), 7.72 (d, 2H, J = 8.7 Hz, 2H-phenyl), 8.24 (d, 2H, J = 8.7 Hz, 2H-phenyl)

FABMS ( M + H ) ⁺ for C ₁₆ H ₂₆ N ₂ 0 ₆ S: found 375.15; Calculated 374.15

Example 19. Preparation of (1S, 2S) 2- (1-octanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol [17]

Example 2 using (1S, 2S) 2-amino-1- (4'-nitrophenyl) -1,3-propanediol 255 mg (1.2 mM) and 425.48 mg (2 mM) of 1-octanesulfonylchloride 40 mg (yield 8.5%) of the target compound was synthesized by purification using silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1).

TLC (Hexane: EtOAc = 2: 1) R _f = 0.24

= +42.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.92 (t, 3H, J = 6.9 Hz, CH ₃ ), 1.04 to 1.38 (m, 10H, (CH ₂ ) ₅ , 1.38 to 1.52 (m, 2H, SO2- CH ₂ CH ₂ ), 2.55 (t, 2H, J = 7.9 Hz SO ₂ -CH ₂ ), 3.52-3.68 (m, 2H, C ₃ -2H), 3.78-3.84 (m, 1H, C ₂ -H), 5.15 (d, 1H, J = 2.4 Hz C ₁ -H), 7.74 (d, 2H, J = 9.0 Hz, 2H-phenyl), 8.25 (d, 2H, J = 9.0 Hz, 2H-phenyl)

FABMS ( M + H ) ⁺ for C ₁₇ H ₂₈ N ₂ O ₆ S: found 389.12; Calculation 388.17

Example 20. Preparation of (1S, 2S) 2- (1-nonanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol [18]

1-nonanesulfonylchloride was synthesized according to the preparation method described in Example 1 using 575.75 mg (2.5 mM) of 1-nonanesulfonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1S, 2S) 255 mg (1.2 mM) of 2-amino-1- (4'-nitrophenyl) -1,3-propanediol and 453.52 mg (2 mM) of 1-nonansulfonyl chloride synthesized above were used Was synthesized according to the preparation method described in Example 2, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) to synthesize 30 mg (yield 6.1%) of the target compound [18]. .

TLC (Hexane: EtOAc = 2: 1) R _f = 0.21

= +48.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.91 (t, 3H, J = 6.9 Hz, CH ₃ ), 1.00 to 1.38 (m, 12H, (CH ₂ ) ₆ , 1.38 to 1.50 (m, 2H, SO2- CH ₂ CH ₂ ), 2.53 (t, 2H, J = 7.9 Hz SO ₂ -CH ₂ ), 3.46-3.66 (m, 2H, C ₃ -2H), 3.74-3.84 (m, 1H, C ₂ -H), 5.13 (d, 1H, J = 2.4 Hz C ₁ -H), 7.72 (d, 2H, J = 8.2 Hz, 2H-phenyl), 8.24 (d, 2H, J = 8.6 Hz, 2H-phenyl)

FABMS ( M + H ) ⁺ for C ₁₈ H ₃₀ N ₂ O ₆ S: found 431.31; Calculated 430.21

Example 21. Preparation of (1S, 2S) 2- (1-undecanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol [19]

1-Undecanesulfonylchloride was synthesized according to the preparation method described in Example 1 using 645.87 mg (2.5 mM) of 1-undecanesulphonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1S, 2S) 2-amino-1- (4'-nitrophenyl) -1,3-propanediol 255 mg (1.2 mM) and 509.64 mg (2 mM) of 1-undecanesulfonyl chloride synthesized above were used. Was synthesized according to the preparation method described in Example 2, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) to synthesize 81 mg (yield 15.6%) of the target compound [19]. .

TLC (hexane: ethyl acetate = 2: 1) R _f = 0.22

= +45.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.92 (t, 3H, J = 6.6 Hz, CH ₃ ), 1.04-1.38 (m, 16H, (CH ₂ ) ₈ , 1.38-1.48 (m, 2H, SO2- CH ₂ CH ₂ ), 2.54 (t, 2H, J = 8.1 Hz SO2-CH ₂ ), 3.50-3.68 (m, 2H, C ₃ -2H), 3.78-3.86 (m, 1H, C ₂ -H), 5.14 (d, 1H, J = 2.7 Hz C ₁ -H), 7.72 (d, 2H, J = 9.0 Hz, 2H-phenyl), 8.24 (d, 2H, J = 9.0 Hz, 2H-phenyl)

FABMS ( M + H ) ⁺ for C ₁₉ H ₃₂ N ₂ O ₆ S: found 431.31; Calculated 430.21

Example 22. Preparation of (1S, 2S) 2- (1-tridecanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol [20]

1-tridecanesulfonylchloride was synthesized according to the preparation method described in Example 1 using 716 mg (2.5 mM) of 1-tridecanesulphonic acid and 594.85 mg (5 mM) of SOCl ₂ .

(1S, 2S) 255 mg (1.2 mM) of 2-amino-1- (4'-nitrophenyl) -1,3-propanediol and 565.74 mg (2 mM) of 1-tridecanesulfonyl chloride synthesized above Was synthesized according to the preparation method described in Example 2, and purified by silica gel column chromatography using a developing solvent (hexane: ethyl acetate = 2: 1) to synthesize 32 mg (yield 5.7%) of the target compound [20]. It was.

TLC (Hexane: EtOAc = 2: 1) R _f = 0.24

= +50.000 (c = 0.01, CH ₃ OH)

¹ H-NMR [CD ₃ OD] δ: 0.90 (t, 3H, J = 6.9 Hz, CH ₃ ), 1.06 to 1.38 (m, 20H, (CH ₂ ) ₁₀ , 1.38 to 1.48 (m, 2H, SO2- CH ₂ CH ₂ ), 2.53 (t, 2H, J = 8.1 Hz SO2-CH ₂ ), 3.50-3.66 (m, 2H, C ₃ -2H), 3.74-3.84 (m, 1H, C ₂ -H), 5.13 (d, 1H, J = 2.4 Hz C ₁ -H), 7.72 (d, 2H, J = 9.0 Hz, 2H-phenyl), 8.24 (d, 2H, J = 8.7 Hz, 2H-phenyl)

FABMS ( M + H ) ⁺ for C ₂₀ H ₃₄ N ₂ 0 ₆ S: found 459.16; Calculated 458.25

Experimental Example 1. Toxicity test (MTT test method)

In order to evaluate the cytotoxicity and cell viability of the exemplary compounds of the present invention, human colon cancer cell line HT-29 (Colon cancer cell line, ATCC, HTB-38), renal cancer cell line Caki-2 (Renal cancer cell line, ATCC, HTB-47), 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), human acute bone marrow Human myelocytic leukemia cell line (ATCC, CCL-240), a cell line of leukemia, using MTT (3- (4,5-dimethylthiazol-2-yl) -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 viable and metabolically active cells, which are viable if the concentration of cells in the well to be measured is too low or too high. Since the linear relationship between the concentration and absorbance was not established, the optimal cell concentration was determined.

1-1. Culture of Cell Lines, Preparation of Single Cell Suspensions and Measurement of Cell Concentration

1-1-1. Culture of Cell Lines

Cytotoxicity of Human Colon Cancer Cell Line HT-29, Kidney Cancer Cell Line Caki-2, Lung Cancer Cell Line A549, Prostate Cancer Cell PC-3, and HL-60 Cell Line of Acute Myeloid Leukemia To evaluate the results, all cell lines were thawed in a liquid nitrogen tank and used 2-3 passages in a T flask and RPMI 1640 medium (10% FBS, 0.2% NaHCO ₃ , 0.05 mg / ml gentamicin). ) Were incubated at 37 ° C. and 5% CO ₂ .

1-1-2. Preparation of Single Cell Suspensions

In the case of floating cells, single cell suspensions are obtained by repeated inhalation through sterile pipettes. In the case of adherent cells, trypsin was treated for 3 minutes to separate the cells from the plastic bottom, neutralized with culture medium (10% FBS added to RPMI 1640), and the single cell suspension was repeatedly aspirated through a sterile pipette. Get The suspension was centrifuged at 100 xg for 5 minutes to precipitate the cells, and the suspension was resuspended in an appropriate amount of medium solution. The suspension was diluted 10-fold with PBS (phosphate buffered saline) and hemocytometer (SEQUOIA-TURNER) , UK) to measure the cell density (cell count / ml).

1-1-3. Cell concentration measurement

The cell concentration was directly measured by a microscope using a hemocytometer. After collecting some of the suspended cells, the volume was measured. After that, 10-fold PBS (pH 7.2) buffer solution was added and diluted 10-fold. Cell concentration was measured using a measuring instrument.

1-2. Determination of titration inoculation cell

For each cell line the optimal seeding density of each well to be used for the MTT assay is determined. The number of cells is usually the optimal number of seeding cells that can show a high enough OD ₅₄₀ as the cancer cells proliferate at the time of inoculation and at the end of the MTT experiment after 4 days in the drug-free control group. Represented by / well. To determine the number of cells, inoculate a 96-well plate at several cell densities in the range of 1 to 100 x 10 ³ per well, and incubate for 2 days with only PBS instead of an anticancer agent or sample. Do the same for the law. At the end of the experiment, the absorbance (OD ₅₄₀ ) was measured to determine the most appropriate cell density and then used in subsequent experiments.

1-3. Cell Inoculation, Sample Administration and Culture

After determining the concentration of cells based on the determined appropriate concentration, the test substance to be searched was dissolved in DMSO, diluted with PBS, made into a 10-fold dilution solution, and 20 µl was added to each well. 20 μl of PBS alone is used to make 100% control survival. To the column treated as an untreated group to be used for absorbance measurement, 180 μl of medium was added instead of cell suspension and 20 μl of PBS was added. The appropriate number of cells determined in the preliminary experiments were suspended in 180 μl of medium and inoculated equally into each well of a 96-well plate, and the cells and the plate inoculated with the sample were incubated at 37 ° C. and 5% CO _{2 for} 4 days.

1-4. Measurement of viable cell number

After 4 days, 0.1 mg (50 μl of 2 mg / ml) of MTT (3- [4,5-dimethyl thiazol-2-yl] -2,5-diphenyl tetrazolium bromide, Sigma) was added to each well of the plate. After the addition, the culture was further incubated at 37 ° C. for 4 hours to reduce the MTT.

At the end of the incubation, the formazan crystals formed by centrifuging the plate at 450 × g were precipitated and all were removed using a multidispenser, leaving only about 30 μl of medium, taking care not to disturb the crystals formed in each well.

To dissolve the formazan crystals produced in each well from which the medium was removed. 150 μl of DMSO (dimethyl sulfoxide, Sigma) was added to each well, followed by agitation for about 5 minutes until the formazan crystals melted, and immediately 540 with a 96-well plate micrometer reader (scanning multi well spectrophotometer). Absorbance at nm was measured, which indicates the amount of MTT reduced by the cells and was therefore 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 Equation 1 below.

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. Using the analysis of the pharmacological calculation program, the IC ₅₀ of each sample was obtained, and the 50% inhibitory concentration (IC ₅₀ ) was It is defined as the concentration of drug that results in a 50% survival rate for the control group, and this IC ₅₀ value is used as an indicator of the anticancer effect.

Human Adenocarcinoma cell line HT-29, kidney cancer cell line Caki-2, lung cancer cell line A549, PC-3, prostate cancer cell line PC-3, acute myeloid leukemia To evaluate the cytotoxicity against HL-60, a toxicity test (MTT assay) was performed. The results are as shown in Table 1 below. In cytotoxicity experiments on the renal cancer cell line Caki-2, the longer the length of the aliphatic chain substituted with sulfonamide groups was from C ₇ to C ₁₃ , the higher the cytotoxic effect (see FIGS. 1A to 1D).

In addition, compounds [3], [4], [5], [8], [9], [10], [13], [14], [15], [18], and [19] than the reference drug B13. ] And [20] showed high cytotoxic effects. In particular, compounds [4], [9], [14], [15], and [20] showed 35.6, 46.2, 42.1, 39.4, and 42.9 mM, which were higher than IC ₅₀ 101.8 mM of the control drug B-13 (Fig. 2a).

As a result of cytotoxicity test against colon cancer cell line HT-29, the longer the alkyl group was, the higher the cytotoxic effect was observed (see FIGS. 1A to 1D). Several compounds ([4], [5], [8], [9], [10], [12], [13], [14], [15] than the reference drug B13 (IC ₅₀ = 68.4 mM) , [18], [19], and [20]) showed high cytotoxic effects. In particular, compounds [13], [14], [15], [18], [19], and [20] were about 2.5 times higher (see FIG. 2B).

As a result of cytotoxicity test on lung cancer cell line A549, cytotoxic effect increased as the length of alkyl group generally increased (see FIGS. 1A to 1D). Several compounds ([3], [4], [5], [8], [9], [10], [12], [13], [14] than the reference drug B13 (IC ₅₀ = 94.2 mM) , [15], [17], [18], [19], and [20]) showed high cytotoxic effects. In particular, [4], [13], [14], and [19] showed two times or more, and [15] and [20] showed three times or more higher effects (see FIG. 2C).

As a result of cytotoxicity test on PC-3, a prostate cancer cell line, the cytotoxic effect increased as the alkyl group length increased (see FIGS. 1A to 1D). Compounds [4], [5], [8], [9], [10], [12], [13], [14], [15], [] than the reference drug B13 (IC ₅₀ = 79.3 mM) 17], [18], [19], and [20] showed high cytotoxicity. In particular, [13], [14], [15], and [20] showed a two-fold effect (see FIG. 2D).

As a result of cytotoxicity test on HL-60, a cell line of acute myeloid leukemia, the cytotoxic effect increased as the alkyl group length increased (see FIGS. Compounds [4], [9], [13], [14], [15], and [20] showed higher effects than the control compound B13 (see Fig. 2E).

(Ⅰ)

compound Molecular Composition R ₁ R ₂ R ₃ R ₄ IC _{50 of} human cancer cell lines Kidney cancer Colon cancer Lung cancer Prostate cancer leukemia Caki-2 HT-20 A549 PC-3 HL-60 B13 ^a) 101.8 68.4 94.2 79.3 33.6 One 1R, 2S OH H C ₇ H ₁₅ H 191.5 191.5 207.3 189.3 129.8 2 1R, 2S OH H C ₈ H ₁₇ H 127.6 93.8 148.7 95.3 77.6 3 1R, 2S OH H C ₉ H ₁₉ H 66.6 83.2 90.5 81.7 53.7 4 1R, 2S OH H C ₁₁ H ₂₃ H 35.6 44.2 46.0 44.9 28.5 5 1R, 2S OH H C ₁₃ H ₂₇ H 75.7 35.9 49.3 45.1 34.3 6 1S, 2R OH H C ₇ H ₁₅ H 205.5 183.0 205.7 188.5 130.4 7 1S, 2R OH H C ₈ H ₁₇ H 102.7 96.6 96.6 80.8 62.8 8 1S, 2R OH H C ₉ H ₁₉ H 72.0 60.0 73.0 64.3 44.9 9 1S, 2R OH H C ₁₁ H ₂₃ H 46.2 37.8 74.2 40.5 33.1 10 1S, 2R OH H C ₁₃ H ₂₇ H 78.8 39.2 80.7 67.8 44.4 11 1R, 2R OH OH C ₇ H ₁₅ NO ₂ 233.1 101.0 > 267.3 98.4 116.6 12 1R, 2R OH OH C ₈ H ₁₇ NO ₂ 138.7 53.3 84.6 52.8 54.9 13 1R, 2R OH OH C ₉ H ₁₉ NO ₂ 63.3 27.9 42.7 31.8 27.6 14 1R, 2R OH OH C ₁₁ H ₂₃ NO ₂ 42.1 25.7 41.1 39.1 24.7 15 1R, 2R OH OH C ₁₃ H ₂₇ NO ₂ 39.4 27.0 28.7 29.2 20.7 16 1S, 2S OH OH C ₇ H ₁₅ NO ₂ > 267.3 161.6 267.3 > 267.3 160.6 17 1S, 2S OH OH C ₈ H ₁₇ NO ₂ 141.2 100.3 89.0 75.1 67.6 18 1S, 2S OH OH C ₉ H ₁₉ NO ₂ 75.8 52.2 69.1 51.0 41.4 19 1S, 2S OH OH C ₁₁ H ₂₃ NO ₂ 68.3 61.3 40.9 56.0 37.7 20 1S, 2S OH OH C ₁₃ H ₂₇ NO ₂ 42.9 28.2 30.8 35.9 23.0 ^a) B13: D-Threo-2- (N-myristoylamino) -1- (4'-nitrophenyl) -1,3-propanediol * cell inoculation number-HT-29, Caki-2, A549 , PC-3: 5 × 10 3 cells / well HL-90: 1.5 × 10 ⁴ cells / well - incubation time - 48 hours

The pharmaceutical composition containing the compound of Examples 3 to 22 according to the above production method was formulated and used as follows.

Formulation Example 1 Preparation of Powder

Compound 3 500 mg

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 4 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 5 10 mg

Appropriate amount of 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 9 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, 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.

Aromatic alkyl sulfone derivative compounds having novel chemical structures of the present invention and their isomers and pharmaceutical compositions containing the same have not only excellent cell death activity against cancer cells but also are non-toxic and thus can be used very effectively for the treatment and prevention of cancer. have.

Claims (6)

Aromatic alkyl sulfonamide derivative compounds of the general formula (I) or their pharmaceutically acceptable salts and isomers thereof: (I) In the above formula, R ₁ is a hydroxy group or a C ₁ to C ₃ alkoxy group; R ₂ is a hydrogen atom or a hydroxyl group or a C ₁ to C ₃ alkoxy group; R ₃ is an alkyl group of C ₅ to C ₃₀ ; R ₄ is a hydrogen atom, a nitro group, an amine group, a halogen atom or a C ₁ to C ₃ alkyl group. The compound group and isomer thereof according to claim 1, wherein R ₁ is a hydroxy group, R ₂ is a hydrogen atom, R ₃ is a C ₇ to C ₁₃ alkyl group, and R ₄ is a hydrogen atom or a nitro group. The method of claim 2, (1R, 2S) 2- (1-heptanesulfonylamido) -1-phenyl-1-propanol, (1R, 2S) 2- (1-octanesulfonylamido) -1-phenyl-1-propanol, (1R, 2S) 2- (1-nonanesulfonylamido) -1-phenyl-1-propanol, (1R, 2S) 2- (1-undecanesulfonylamido) -1-phenyl-1-propanol, (1R, 2S) 2- (1-tridecanesulfonylamido) -1-phenyl-1-propanol, (1S, 2R) 2- (1-heptanesulfonylamido) -1-phenyl-1-propanol, (1S, 2R) 2- (1-octanesulfonyl amido) -1-phenyl-1-propanol, (1S, 2R) 2- (1-nonanesulfonyl amido) -1-phenyl-1-propanol, (1S, 2R) 2- (1-undecanesulfonylamido) -1-phenyl-1-propanol, (1S, 2R) 2- (1-tridecanesulfonylamido) -1-phenyl-1-propanol, (1R, 2R) 2- (1-heptanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol, (1R, 2R) 2- (1-octanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol, (1R, 2R) 2- (1-nonanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol, (1R, 2R) 2- (1-Undecanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol, (1R, 2R) 2- (1-tridecanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol, (1S, 2S) 2- (1-heptanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol, (1S, 2S) 2- (1-octanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol, (1S, 2S) 2- (1-nonanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol, (1S, 2S) 2- (1-Undecanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol, (1S, 2S) A compound which is 2- (1-tridecanesulfonylamido) -1- (4'-nitrophenyl) -1,3-propanediol. In formula (Ⅱ) alkylsulfonic acids (alkyl sulfonic acid) salt (M) and an alkyl sulfone chloride (alkyl sulfonyl chloride) of the formula (Ⅲ) obtained by reacting a sulfonation reagent such as SOCl ₂ of R _1, R ₂ And reacting a phenyl amine derivative of formula (IV) corresponding to the definition of R ₄ substituent, wherein the aromatic alkyl sulfonamide derivative compound of claim 1 is represented by formula (I). R ₃ -SO ₃ -M (II) R ₃ -SO ₂ -Cl (III) (Ⅳ) A pharmaceutical composition for the treatment of anticancer drugs comprising the general formula compound of any one of claims 1 to 3 as an active ingredient and a pharmaceutically acceptable carrier. The method of claim 5, 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 adenocarcinoma, 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.