WO2023068322A1 - Ｃｄ環側鎖置換ビタミンｄ誘導体 - Google Patents

Ｃｄ環側鎖置換ビタミンｄ誘導体 Download PDF

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WO2023068322A1
WO2023068322A1 PCT/JP2022/039059 JP2022039059W WO2023068322A1 WO 2023068322 A1 WO2023068322 A1 WO 2023068322A1 JP 2022039059 W JP2022039059 W JP 2022039059W WO 2023068322 A1 WO2023068322 A1 WO 2023068322A1
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French (fr)
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敦史 橘▲高▼
文裕 川越
利之 榊
佳織 安田
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Teikyo University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation

Definitions

  • the present invention relates to CD ring side chain-substituted vitamin D derivatives and pharmaceutical compositions containing them.
  • Active vitamin D 3 (1,25-dihydroxyvitamin D 3 ) is known to have many physiological activities such as calcium metabolism regulation, tumor cell proliferation inhibition, differentiation induction, and immunoregulation. .
  • the present inventors synthesized 2-substituted vitamin derivatives (MART-10, MART-11) and demonstrated that they have a high ability to induce differentiation of human leukemia cells HL-60 (Patent Document 1, Non-Patent Document 1). .
  • MART-10 and MART-11 are not included in the compounds of the present invention.
  • the present inventor synthesized a novel vitamin D derivative in which a halogen atom was introduced into the CD ring side chain of MART-10 and MART-11, and found that it has a therapeutic effect on psoriasis-induced model mice, and human breast cancer (MCF -7) Newly found that it has cancer cell growth inhibitory effect in cells.
  • An object of the present invention is to provide novel vitamin D derivatives useful for treating or preventing psoriasis or cancer.
  • X is a linear or branched alkyl group having 1 to 4 carbon atoms which may be substituted with a hydroxyl group, or a linear or branched chain having 1 to 4 carbon atoms which may be substituted with a hydroxyl group; an alkenyl group of 4,
  • Y is an optionally hydroxyl-substituted linear or branched C5-C8 alkyl group substituted with at least one halogen atom.
  • X is a linear or branched C3 alkyl group optionally substituted with a hydroxyl group, or a linear or branched C3 alkenyl group optionally substituted with a hydroxyl group and The compound of [1], wherein Y is a 4-hydroxyl-4-methylpentyl group substituted with at least one halogen atom.
  • Y is (Wherein, Z is a hydrogen atom or a hydroxyl group, R1, R2, R3, R4, R7, and R8 are each independently a hydrogen atom or a halogen atom, R5 and R6 are each independently a methyl group or an ethyl group optionally substituted with 1 to 3 halogen atoms)
  • a compound according to any one of [1] to [4], which is a group represented by [6] A pharmaceutical composition containing the compound of any one of [1] to [5] as an active ingredient.
  • [7] A pharmaceutical composition for treating or preventing psoriasis, containing the compound of any one of [1] to [5] as an active ingredient.
  • a pharmaceutical composition for treating or preventing cancer containing the compound of any one of [1] to [5] as an active ingredient.
  • novel vitamin D derivatives useful for treating or preventing psoriasis or cancer can be provided.
  • FIG. 10 is a graph showing the effect of application of vitamin D derivatives on imiquimod (IMQ)-induced psoriasis model mice.
  • FIG. 1 shows the auricle thickness when IMQ alone or IMQ plus vitamin D derivative (calcipotriol or MART10-F2) ethanol solutions of various concentrations were dripped and treated for 3 days.
  • 4 is a graph showing a comparison of cell numbers after 3 days of culture in the presence of 100 nmol/L of various derivatives.
  • 4 is a graph showing a comparison of cell numbers after culturing for 7 days in the presence of various derivatives at 1, 10, and 100 nmol/L.
  • FIG. 10 is a graph showing the effect of 24F2-MART-10 on the growth of cancer cells in terms of changes over time in the area of three-dimensional cultured cells.
  • FIG. 1 shows the auricle thickness when IMQ alone or IMQ plus vitamin D derivative (calcipotriol or MART10-F2) ethanol solutions of various concentrations were d
  • the term "optionally substituted with a hydroxyl group, linear or branched alkyl group having 1 to 8 carbon atoms” means unsubstituted or substituted with a hydroxyl group. means a linear or branched alkyl group having 1 to 8 carbon atoms.
  • the number of carbon atoms in the alkyl group is preferably 1-5, more preferably 1-4, still more preferably 3.
  • the unsubstituted C 1-8 linear or branched alkyl group includes, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i -butyl group, t-butyl group, linear and branched pentyl group, hexyl group, heptyl group, octyl group and the like.
  • linear or branched alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group means any one of the above unsubstituted linear or branched alkyl groups having 1 to 8 carbon atoms or More hydrogen atoms are substituted with hydroxyl groups, for example, hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, hydroxybutyl group, hydroxypentyl group, hydroxyhexyl group, hydroxyheptyl group, hydroxyoctyl group etc. can be mentioned.
  • the term "optionally substituted with a hydroxyl group, linear or branched C 1-8 alkenyl group” means unsubstituted or substituted with a hydroxyl group. means a linear or branched alkenyl group having 1 to 8 carbon atoms.
  • the alkenyl group preferably has 1 to 5 carbon atoms, more preferably 1 to 4 carbon atoms, and still more preferably 3 carbon atoms.
  • unsubstituted C 1-8 linear or branched alkenyl groups examples include methylene, vinyl, allyl, n-butenyl, sec-butenyl, pentenyl, heptenyl and octenyl groups. etc. can be mentioned.
  • linear or branched alkenyl group having 1 to 8 carbon atoms substituted with a hydroxyl group means any one of the above unsubstituted linear or branched alkenyl groups having 1 to 8 carbon atoms or Further hydrogen atoms are substituted with hydroxyl groups, and examples include hydroxymethylene group, hydroxyallyl group, hydroxybutenyl group, hydroxypentenyl group, hydroxyheptenyl group, hydroxyoctenyl group and the like. .
  • the configuration of the group X at the 2-position of the general formula (I) in this specification may be either the R configuration or the S configuration.
  • those in which the group X at the 2-position of the general formula (I) has the S configuration are named MART-10, and those in the R configuration are named MART-11.
  • a linear or branched alkyl group having 1 to 12 carbon atoms which may be substituted with a hydroxyl group and which is substituted with at least one halogen atom means an unsubstituted or hydroxyl-substituted linear or branched alkyl group having 1 to 12 carbon atoms, wherein any one or more hydrogen atoms in the alkyl group are substituted with halogen atoms.
  • the number of carbon atoms in the alkyl group is preferably 3-10, more preferably 5-8, still more preferably 6 or 8.
  • Halogen atoms include, for example, fluorine, chlorine, bromine, iodine and the like, preferably fluorine.
  • the group Y is particularly preferably (Wherein, Z is a hydrogen atom or a hydroxyl group, R1, R2, R3, R4, R7, and R8 are each independently a hydrogen atom or a halogen atom, R5 and R6 are each independently a methyl group or an ethyl group optionally substituted with 1 to 3 halogen atoms) is a group represented by
  • the halogen atom substitution in the CD ring side chain is not limited to the following, but for example, 26,27-hexahalide ( Production Example 1 described later), 26,27-tetrahalide (Production Example 8) in which two halogen atoms were introduced into each of the carbon atoms at positions 26 and 27, for a total of four halogen atoms, at positions 26 and 27 26,27-dihalide in which one halogen atom was introduced to each carbon atom and two halogen atoms in total (Production Example 9), 24-dihalide in which two halogen atoms were introduced to the carbon atom at position 24 (manufacturing implementation Example 2), 24R-monohalide with one halogen atom introduced at the 24-position carbon atom, 24S-monohalide (Preparation Example 3), with two halogen atoms introduced at the 23-position carbon atom 23-dihalide (Production Example 4), 23R-monohalide in which one halogen atom is introduced at the carbon
  • the pharmaceutical composition of the present invention is used as a medicament for treating subjects (for example, animals, preferably mammals, particularly humans) with an active ingredient alone, or preferably together with a pharmaceutically acceptable carrier or diluent. It can be administered in an amount effective for the body or can be provided in the form of food or drink.
  • the pharmaceutical composition of the present invention when provided as a medicament, it can be administered as an oral or parenteral formulation, preferably an oral formulation.
  • oral formulation include liquid formulations such as suspensions, emulsions, syrups and extracts, and solid formulations such as tablets, capsules, powders, fine granules and granules.
  • parenteral agents include injections.
  • Pharmaceutically acceptable carriers or diluents include, for example, excipients, disintegrants, binders, flavoring agents, foaming agents, sweeteners, flavors, lubricants, buffers, antioxidants, Surfactants, fluidizing agents and the like can be mentioned.
  • the dosage of the pharmaceutical composition of the present invention can be appropriately selected according to, for example, the target disease, patient condition, body weight, age, sex, route of administration, etc.
  • the lower limit of the dosage is 0.000 mg/day for an adult.
  • the upper limit of dosage can be selected within the range of 100 ⁇ g to 10000 ⁇ g per day for adults, and can be administered in 1 to 3 divided doses per day.
  • the pharmaceutical composition of the present invention can be used for treating or preventing psoriasis or cancer.
  • PPTS pyridinium p-toluenesulfonic acid
  • N,N-dimethyl-4-aminopyridine 464.5 mg, 3.68 mmol
  • nBu 3 P 345.5 mg, 427.0 ⁇ L, 1 .77 mmol
  • Acetyl 44 (201.8 mg, 0.43 mmol) was dissolved in dioxane (1.5 mL) and the solution was added to the mixture. After stirring for 17 hours at the same temperature, the reaction mixture was quenched with H 2 O at room temperature. The mixture was extracted with EtOAc three times. The organic layer was washed with brine , dried over Na2SO4 , filtered and concentrated.
  • LiAlH 4 (14.0 mg, 0.37 mmol) was added to a solution of above crude 46 in Et 2 O (3 mL) at 0° C. and the mixture was stirred at the same temperature for 15 minutes and at room temperature for 20 minutes. After the reaction was quenched with MeOH, water, and saturated aqueous sodium potassium tartrate, the mixture was extracted three times with EtOAc. The organic layer was washed with brine , dried over Na2SO4 , filtered and concentrated. Crude alcohol 47 was used in the next reaction without further purification.
  • p-Toluenesulfonic acid monohydrate (1.14 g, 6.0 mmol) was added to a solution of the above coupling compound in MeOH (50 mL) and CH 2 Cl 2 (10 mL). The mixture was stirred in air at room temperature for 17 hours. After the reaction was quenched with H 2 O and saturated aqueous NaHCO 3 at room temperature, the mixture was extracted with CH 2 Cl 2 three times. The organic layer was dried over Na2SO4 , filtered and concentrated. The residue was purified on a preparative silica gel TLC plate (EtOAc only) to give 23RF-MART-10 and 23RF-MART-11 as a mixture.
  • p-Toluenesulfonic acid monohydrate (1.24 g, 6.52 mmol) was added to a solution of the above coupling compound in MeOH (50 mL) and CH 2 Cl 2 (10 mL). The mixture was stirred in air at room temperature for 17 hours. After the reaction was quenched with H 2 O and saturated aqueous NaHCO 3 at room temperature, the mixture was extracted with CH 2 Cl 2 three times. The organic layer was dried over Na2SO4 , filtered and concentrated. The residue was purified on a preparative silica gel TLC plate (EtOAc only) to give 23SF-MART-10 and 23SF-MART-11 as a mixture.
  • Ref. 1 Grzywacz, P.; Plum, L. A.; Sicinski, R. R.; Clagett-Dame, M.; 3 (2MD) reduces potency but allows bone selectivity.
  • MeMgCl (1.3 mL, 3.0 mol/L THF solution, 3.93 mmol) was added to a THF (10 mL) solution of the crude product 121 at -78°C, and the mixture was stirred at -78°C for 5 minutes and then at 0°C. Stirred for 1 hour. After the reaction was quenched with H 2 O and saturated aqueous NH 4 Cl at 0° C., the mixture was extracted with EtOAc three times. The organic layer was dried over Na2SO4 , filtered and concentrated. The crude residue was used for the next reaction without further purification.
  • Ph 3 P (1.75 g, 6.67 mmol) and N,N′-dimethylpropylene urea (DMPU) (1.3 mL, 1.34 g, 10.5 mmol) were added to a solution of the crude residue in CH 3 CN (2 mL). and the mixture was cooled to 0°C.
  • TMSCF 2 Br (1.2 mL, 1.60 g, 7.68 mmol) was added to the mixture at 0°C. After the mixture was stirred at 0° C. for 10 minutes and at room temperature for 5 hours, H 2 O (1 mL) and pyridine (423 ⁇ L, 414.5 mg, 5.24 mmol) were added and stirred at 80° C. for 1 hour.
  • n-BuLi (2.9 mL, 1.59 mol/L in hexane, 4.63 mmol) was added to a solution of trimethylsilyldiazomethane (8.3 mL, 0.6 mol/L in hexane, 4.96 mmol) in THF (15 mL). °C and the mixture was stirred at the same temperature for 15 minutes.
  • aldehyde 101 [see Ref. 1 above] (1.12 g, 3.31 mmol) in THF (15 mL) and the solution was stirred at the same temperature for 30 min. After the reaction was quenched with H 2 O and AcOH at ⁇ 78° C., the mixture was extracted with EtOAc three times. The organic layer was dried over Na2SO4 , filtered and concentrated. The residue was purified by flash column chromatography on silica gel (hexane only) to give compound 158 (110.1 mg, 10%) as a colorless oil.
  • DIBAL-H (2.5 mL, 1.0 mol/L hexane solution, 2.5 mmol) was added to a solution of crude ethyl ester 163 (230.0 mg) in THF (7 mL) at ⁇ 78° C., and the mixture was stirred at the same temperature for 30 minutes. Stir for a minute. After diluting the reaction with MeOH at ⁇ 78° C., H 2 O and saturated aqueous sodium potassium tartrate were added at room temperature. The mixture was extracted with EtOAc three times. The organic layer was washed with brine , dried over Na2SO4 , filtered and concentrated.
  • MART10-F2 24F 2 -MART-10 (hereinafter also referred to as MART10-F2) produced in Production Example 2 was selected as the vitamin D derivative, and calcipotri, a compound already used as a therapeutic agent, was selected. It was compared with oar (Sigma-Aldrich). The above treatment was performed for 3 days, and the auricle thickness was measured after 3 days. The results are shown in FIG. It can be seen that the thickness of the auricle, which had thickened due to inflammation due to imiquimod, was reduced by applying calcipotriol.
  • MART10-F2 the thickness was significantly thinner than when the same amount of calcipotriol was applied, and MART10-F2 showed a high effect even with 1/5 the amount of calcipotriol.
  • vitamin D derivatives other than MART10-F2 were also found to have a certain degree of therapeutic effect, although the effect was stronger or weaker.
  • MCF-7 cells were grown using E-MEM (containing L-glutamine and phenol red) medium containing 1% NEAA (Non-essential Amino Acids Solution) and 10% FBS (fetal bovine serum), 5% CO 2 , 37 It was cultured under conditions of °C. The cultured MCF-7 cells were suspended in a medium to a concentration of 2.0 ⁇ 10 4 cells/mL, and 100 ⁇ L of each suspension was seeded in a 96-well plate. After culturing at 37° C.
  • E-MEM containing L-glutamine and phenol red
  • NEAA Non-essential Amino Acids Solution
  • FBS fetal bovine serum
  • the supernatant was removed and replaced with a medium containing 100 nmol/L of each vitamin D derivative.
  • This medium was prepared by adding a 50 ⁇ mol/L ethanol solution of each vitamin D derivative in an amount of 1/500 of the medium, and contained 0.5% ethanol. After replacing the medium with a vitamin D derivative-added medium, the cells were further cultured for 3 days.
  • the number of cells 3 days after the addition of vitamin D derivatives was measured by the MTT assay method.
  • the MTT assay method is as follows. The medium in each well was removed and 100 ⁇ L of fresh medium without vitamin D derivatives was added. 10 ⁇ L of MTT (3-(4,5-Dimethylthial-2-yl)-2,5-Diphenyltetrazalium Bromide: Dojindo) 5 mg/mL) dissolved in PBS(-) (phosphate buffered saline) in each well were added one by one and cultured at 37° C. for 4 hours. After 4 hours, the medium was removed from each well, 200 ⁇ L of DMSO was added to each well, and the wells were well stirred, and then the absorbance at 535 nm was measured.
  • FIG. 2 shows the number of cells cultured for 3 days in the presence of 100 nmol/L of each derivative.
  • the vertical axis in FIG. 2 is the relative number of cells when the number of cells in the derivative-free medium is set to 1.
  • Each derivative had a higher cancer cell proliferation inhibitory effect than natural 1 ⁇ ,25D3 and EB1089 (a vitamin D derivative for which a phase II clinical trial was conducted as a therapeutic drug for pancreatic cancer).
  • 24F 2 -MART-10 MART10-F2 in FIG. 2
  • 24F 2 -MART-11 MART11-F2 in FIG. 2 produced in Production Example 2
  • Production Example 1 MART-10-F 6 (same MART-10-F6) and MART-11-F 6 (same MART-11-F6) manufactured by the company were selected.
  • MART10-F2, MART10-F6, MART11-F2, and MART11-F6 were cultured for 7 days in media containing each compound at final concentrations of 1, 10, and 100 nmol/L in order to examine efficacy at lower concentrations. The number of cells after the treatment was compared. The results are shown in FIG. It was found that all of the four derivatives evaluated exhibited cancer cell growth inhibitory effects at lower concentrations than the natural type 1 ⁇ ,25D3. In addition, vitamin D derivatives other than the four evaluated derivatives were also found to have a certain degree of inhibitory effect on cancer cell proliferation, although the effect was stronger or weaker.
  • MCF-7 cells Human breast cancer (MCF-7) cells were three-dimensionally cultured by the method described below, and the cancer cell growth inhibitory effect of vitamin D derivatives was investigated.
  • MCF-7 cells cultured under the conditions described in Evaluation Example 2 were suspended in a medium to 5.0 ⁇ 10 4 cells/mL, and placed in a U-bottom 96-well plate (Cell Carrier) treated with an ultra-low adhesion polymer. 100 ⁇ L each was seeded on a Spheroid ULA Plate, Perkin Elmer). After culturing at 37° C. for 3 days, the supernatant was removed and replaced with a medium containing 100 nmol/L of active vitamin D (1,25D3) or 24F2-MART-10.
  • This medium was prepared by adding a 50 ⁇ mol/L ethanol solution of each compound to be evaluated in an amount of 1/500 of the medium, and contained 0.5% ethanol. Only the same amount of ethanol was added to the control group. 4, 7, and 10 days after addition of each evaluation compound, the medium was replaced with a medium containing only each evaluation compound or ethanol at the same concentration as above at 50 ⁇ L/well, and culture was continued until 14 days later. 0, 4, 7, 10 and 14 days after the addition of each evaluation compound, bright-field photography was performed using an imaging analyzer (Operetta CLS, Perkin Elmer) to obtain the area value of the three-dimensional cultured cells.
  • an imaging analyzer Operetta CLS, Perkin Elmer
  • Fig. 7 shows the changes over time in the area of three-dimensional cultured cells cultured in media supplemented with each evaluation compound. Also in this evaluation system, 24F2-MART-10 exerted a higher cancer cell growth inhibitory effect than active vitamin D (1,25D3). In addition, 24F2-MART-10 exerted the effect earlier than active vitamin D.
  • the present invention can be used to provide a pharmaceutical composition for treating or preventing psoriasis or cancer.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025108575A1 (en) * 2023-11-21 2025-05-30 Roche Diagnostics Gmbh Methods of selective deprotection and synthesis of transhydrindane- skeleton-based compounds

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WO2004033420A1 (ja) * 2002-10-10 2004-04-22 Chugai Pharmaceutical Co Ltd ２,２−ジ置換−１α，２５−ジヒドロキシ−１９−ノルビタミンＤ誘導体
WO2004067504A1 (ja) * 2003-01-31 2004-08-12 Chugai Seiyaku Kabushiki Kaisha ２位置換ビタミンｄ誘導体
JP2018521010A (ja) * 2015-05-26 2018-08-02 ウイスコンシン アラムニ リサーチ ファンデーション １α，２５−ジヒドロキシ−２４，２４−ジフルオロ−１９−ノルビタミンＤ３類似体およびそれらの薬学的使用法

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WO2004033420A1 (ja) * 2002-10-10 2004-04-22 Chugai Pharmaceutical Co Ltd ２,２−ジ置換−１α，２５−ジヒドロキシ−１９−ノルビタミンＤ誘導体
WO2004067504A1 (ja) * 2003-01-31 2004-08-12 Chugai Seiyaku Kabushiki Kaisha ２位置換ビタミンｄ誘導体
JP2018521010A (ja) * 2015-05-26 2018-08-02 ウイスコンシン アラムニ リサーチ ファンデーション １α，２５−ジヒドロキシ−２４，２４−ジフルオロ−１９−ノルビタミンＤ３類似体およびそれらの薬学的使用法

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IWASAKI, H. HOSOTANI, R. MIYAMOTO, Y. NAKANO, Y. YAMAMOTO, K. YAMADA, S. SHINKI, T. SUDA, T. YAMAGUCHI, K. KONNO, K. TAKAYAMA, H.: "Stereoselective Synthesis and Structural Establishment of (25S)-24,24-Difluoro-1@a,25,26-trihydroxyvitamin D"3, a Major Metabolite of 24,24-Difluoro-1@a,25-dihydroxyvitamin D"3", TETRAHEDRON, vol. 54, no. 49, 3 December 1998 (1998-12-03), AMSTERDAM, NL , pages 14705 - 14724, XP004142596, ISSN: 0040-4020, DOI: 10.1016/S0040-4020(98)00949-1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025108575A1 (en) * 2023-11-21 2025-05-30 Roche Diagnostics Gmbh Methods of selective deprotection and synthesis of transhydrindane- skeleton-based compounds

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