WO2000026229A1 - Derives de 2-substitues-d-homooxasteroides - Google Patents

Derives de 2-substitues-d-homooxasteroides Download PDF

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Publication number
WO2000026229A1
WO2000026229A1 PCT/JP1999/005828 JP9905828W WO0026229A1 WO 2000026229 A1 WO2000026229 A1 WO 2000026229A1 JP 9905828 W JP9905828 W JP 9905828W WO 0026229 A1 WO0026229 A1 WO 0026229A1
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WIPO (PCT)
Prior art keywords
protein
compound
oxasteroid
angiogenesis
formula
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Application number
PCT/JP1999/005828
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English (en)
Japanese (ja)
Inventor
Naoyuki Koizumi
Shigeki Iwashita
Motohiro Kobayashi
Original Assignee
Teikoku Hormone Mfg. Co., Ltd.
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Publication date
Application filed by Teikoku Hormone Mfg. Co., Ltd. filed Critical Teikoku Hormone Mfg. Co., Ltd.
Priority to AU62282/99A priority Critical patent/AU6228299A/en
Publication of WO2000026229A1 publication Critical patent/WO2000026229A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms

Definitions

  • the present invention relates to novel 2-substituted mono-D-homoxosteroid derivatives.
  • R represents a lower alkoxy group
  • Tubulin is a basic protein that constitutes microtubules, and this tubulin ⁇ 3 heterodimer polymerizes regularly with auxiliary microtubule-associated proteins (MAPs, proteins) to form microtubules.
  • MAPs microtubule-associated proteins
  • Microtubules are tubular protein fibers with a diameter of about 25 nm, which are widely found in eukaryotic cells such as animals and plant fungi, and are destroyed by polymerization and depolymerization in the cell cycle.
  • the formation of the mitotic apparatus, the formation and maintenance of cell morphology, flagella and ciliary motility, substance transport in neurons and pigment cells, hormone secretion, and fluidity of cell membranes are extremely diverse.
  • angiogenesis is mainly the formation of new vascular networks by vascular endothelial cells in venules. This angiogenesis involves the process of solid tumor development, wound healing, inflammation, and intrauterine It has been observed in many diseases, such as meningiosis, rheumatoid arthritis, diabetic retinopathy, ischemic heart disease, arteriosclerosis, and psoriasis vulgaris.
  • angiogenesis In these diseases, various angiogenic factors that induce angiogenesis work in a complex manner to form a new vascular network, which proliferates cells involved in various diseases, including tumor growth and metastasis. It is thought to be one of the causes of worsening the symptoms. Therefore, compounds that can effectively inhibit angiogenesis found in these diseases are useful as preventive or therapeutic agents for malignant tumors, endometriosis, rheumatoid arthritis, diabetic retinopathy, arterial sclerosis, etc. A wide range of effects is expected.
  • the p53 protein is a protein composed of 393 amino acids expressed by the p53 gene, which is a tumor suppressor gene, and has a special role to maintain the integrity of DNA. .
  • This P53 protein is rarely found in normal body cells, but when DNA damage occurs, the level of P53 protein in the cells rises. It blocks the progression to the replicating S phase, during which it repairs DNA, or acts to lead the cell to apoptosis.
  • the P53 protein is a protein with a high rate of turnover that usually has a considerably high molecular degradation rate, and the P53 protein produced in the process of canceration of cells caused by DNA damage is Cancer cells are easily mutated and inactivated, as evidenced by the fact that cancer cells contain large amounts of ineffective mutant p53 protein.
  • a compound exhibiting a p53 protein stabilizing effect can effectively promote the repair of DNA damage, and can be used alone for the prevention or treatment of diseases caused by DNA damage, such as cancer. Alternatively, it is expected to be used as an adjunct in P53 gene therapy.
  • tubulin polymerization inhibitor an angiogenesis inhibitor, or a p53 protein stabilizing agent
  • compounds capable of sufficiently coping with the above-mentioned diseases have not yet been developed.
  • the present invention provides a 2-substituted mono-D-homoxaxasteroid derivative represented by the above formula (I).
  • the term "lower” means that the group or compound to which this term is attached has 6 or less, preferably 4 or less carbon atoms. JP99 / 05828
  • the “lower alkoxy group” represented by the symbol R in the above formula (I) includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert One-butoxy, n -pentyloxy, n -hexyloxy and the like can be mentioned.
  • a particularly preferred group of compounds in the above formula (I) is the compound of the formula (I) wherein R represents a methoxy or ethoxy group.
  • the compound of the formula (I) is, for example,
  • the compound of the above formula (II) is treated with an iodination reagent such as copper (II) iodide monoacetate, thallium (I) iodide monoacetate or the like in a solvent such as acetic acid, dichloromethane or dichloroethane. It can be done by doing.
  • the reaction temperature can be generally from room temperature to the reflux temperature of the reaction mixture, preferably about 40 ° C to 70 ° C.
  • the iodination reagent generally comprises at least 1 mole per mole of compound of formula (II), Preferably, it can be used in a ratio of about 1.1 to 2 mol.
  • the ratio of iodine to the acetic acid compound constituting the iodination reagent is usually preferably about 1: 1 in terms of the molar ratio of iodine to the acetic acid compound.
  • the obtained 2-ode compound can be converted into the desired compound of the above formula (I) by subjecting it to a subsequent alkoxy conversion reaction.
  • the alkoxide conversion reaction is carried out in a solvent such as dimethylformamide, methanol, ethanol, pyridine or the like, in the presence of a catalyst such as copper (II) chloride, by converting the 2-ode compound to an alkoxylation reagent, for example. It can be carried out by treating with sodium methoxide, sodium ethoxide, sodium isopropoxide and the like.
  • the reaction temperature can be generally from room temperature to the reflux temperature of the reaction mixture, preferably from about 50 ° C. to the reflux temperature of the reaction mixture.
  • the ratio of the alkoxylation reagent to the 2-oxide compound can be at least 1 mol, preferably about 2 to 20 mol, of the alkoxylation reagent per 1 mol of the 2-oxide compound.
  • the compound of the above formula (I) aimed at by the present invention is produced.
  • the compound of the formula (I) when one of A or B represents CH 2 is subjected to a reduction reaction. Can also be manufactured.
  • the compound of formula (I) is combined with sodium borohydride and triethylsilane. It can be carried out by treating with a boron trifluoride ether complex, a reducing reagent such as tert-butoxyaluminolithium hydride or diisobutylaluminum hydride.
  • the compound of the formula (I) produced according to the method of the present invention can be obtained from the reaction mixture by a means known per se, for example, a method such as recrystallization, distillation, column chromatography, or thin layer chromatography. It can be separated and purified.
  • the oxasteroid derivative represented by the formula (I) of the present invention described above has an excellent inhibitory action on tubulin polymerization, an inhibitory action on angiogenesis, and a stabilizing action on Z or p53 protein.
  • Diseases involving polymerization, angiogenesis and / or inactivation of P53 protein such as malignant tumors, endometriosis, rheumatoid arthritis, diabetic retinopathy, ischemic heart disease, arterial sclerosis, intractable disease It is useful for the prevention or treatment of skin ulcers, psoriasis, positiosarcoma, Rye nodules, etc.
  • microtubule protein polymerization inhibitory action, tubulin polymerization inhibitory action, angiogenesis inhibitory action and p53 protein stabilizing action of the compound of the formula (I) of the present invention can be measured, for example, as follows. it can.
  • Microtubule proteins were purified according to the method of Shelanski et al. (Shelanski et al., Proc. Natl. Acad. Sci. USA, 70, 765-768, 1973). That is, the microtubule protein polymerizes when heated to 34 ° C in the presence of guanosine triphosphate (GTP) and Mg 2+ , and depolymerizes when heated to 0 ° C in the absence of GTP. Purified from a pig brain homogenate by polymerizing and depolymerizing twice, using buffer-A (10 O mM 2- (N-morpholino) Sulfonic acid (ME S) - N a OH p H 6.
  • buffer-A (10 O mM 2- (N-morpholino) Sulfonic acid (ME S) - N a OH p H 6.
  • Drugs were dissolved or diluted with an initial concentration of 40% dimethylsulfoxide (DMSO) and experiments were performed at a final concentration of 4% DMSO. A drug-free 4% DMSO was used as a control.
  • DMSO dimethylsulfoxide
  • the polymerization was measured according to the method of Bai et al. (Bai et al., Biochem. Pharmacol, 39, 12, 1941-1949, 1990). That is, the buffer B (20 0 mM ME S -N a OH p H 6. 9, 1 mM M g C 1 2) 1 m to 1, Shoyo concentration of the drug 200 meters 1 and microtubule protein solution (final concentration 1. 5 mg / m 1) and made up to 1.98 ml with distilled water.
  • the polymerization reaction was started by heating at 37 ° C in a constant temperature cell holder (EHC-363, JASCO) together with the addition of 20 mM 1 of 50 mM GTP, and the absorbance at 350 nm was measured. Increase (AA 350) was measured with a spectrophotometer (UNIVEC-610C, JASCO) for 30 minutes. A350 at 0 ° C when GTP was not added was defined as A350 of the baseline. The inhibition rate was calculated as a reduction rate of ⁇ A350 of the drug relative to ⁇ 350 of the control after 30 minutes. As a result, 2-methoxy-D-homo 17-oxaestra 1,3,5 (10) —trien 13-total (compound of Example 3) was obtained at a concentration of 100 // M. Shows a% suppression rate
  • tubulin tubulin derived from human brain (lOmgZml, 1001: Lot No. 035 and 036: purchased from Cytoskelton) was used for the experiment.
  • the polymerization was measured according to the method of Bai et al. (Bai et al., Biochem. Pharmacol, 39, 12, 1941-1949, 1990) and the protocol of Cytoskelton. That, 2 X glutamate buffer (2M monosodium grayed Noretame preparative p H 6. 8, 2 mM M g C 1 2, 2mM E GT A) to 0. 9 m 1, Drug 1 Shoyo concentration 80 ⁇ 1 and Buffer A (1 0 OmM MES -N a OH p H 6. 9, 2 mM EGTA, 1 mM Mg S 0 4 ⁇ 7 H 2 0, 2mM DDT) was dissolved in the purified Chuburi emission (final concentration 1.
  • OmgZm 1 To a total volume of 1.62m1, and the polymerization reaction was started by adding 5 OmM GT P18-1 and heating to 37 ° C in a constant temperature cell holder (EHC-363, JASCO). The increase in absorbance at 350 nm ( ⁇ 350) was measured with a spectrophotometer (UVIDEC-610C, Nippon Spectroscopy) for 30 minutes. The A350 immediately after GTP addition in the control was defined as the baseline A350. The inhibition rate was calculated as the reduction rate of the drug ⁇ 350 relative to the control ⁇ 350 after 30 minutes. As a result, the compound of Example 3 showed a 56% inhibition rate at a concentration of 30 ⁇ M.
  • the angiogenesis inhibitory effect was measured using a vascular endothelial cell tube formation model. That is, human umbilical vein vascular endothelial cells (8 ⁇ 104 cells Zm 1) suspension cultured on Matrigel (MATRIGEL TM , Becton Dickinson) using EGM BULLET KIT / EBM basal medium (Clontech) 1 ml of the solution was dispensed into a 24-well plate. Drug 1 00 1 diluted in EGM BULLET KIT / EBM basal medium to each Uweru added, further 37 ° C, 5% C 0 2 incubator The cells were cultured in a beaker, and after 24 hours, the degree of the tube formation was photographed. The lumen of the photograph was traced with a black pen and its length was measured with an image analyzer (Pierce, LA-555). In the present invention, the compound of the present invention exhibits a good angiogenesis inhibitory action.
  • Human breast cancer MC F-7 cells with normal p53 were cultured at 37 ° C in a 5% CO 2 incubator, and the desired concentration (5 M) of the drug and 10 / zg / m 1 cyclohexane were added.
  • a group to which xymid was added (drug-treated cell group) and a group to which only 10 g Zml cycloheximide was added (non-drug-treated cell group) were prepared.
  • nuclear or cytoplasmic fractions were extracted from both cell groups over time.
  • the fractions of drug-untreated cells or drug-treated cells were adjusted to a constant protein level in each lane.
  • the mixture was added to a 10% non-denaturing polyacrylamide gel and subjected to electrophoresis together with the molecular weight.
  • the gel was transferred to a membrane with a 2-trocell mouth and subjected to a membrane blocking treatment. After washing, the required concentration of anti-human p53-secondary antibody was added and shaken for 1 hour. After washing, the required concentration of the secondary antibody was added and shaken for 1 hour.
  • the compound of the present invention exhibits a good p53 protein stabilizing action.
  • oxasteroid derivative of the formula (I) of the present invention can be used as a tulprin polymerization inhibitor, an angiogenesis inhibitor and a stabilizing agent for Z or p53 protein, such as human and other agents.
  • Oral administration or parenteral administration for example, intramuscular injection, intravenous injection, rectal administration, transdermal administration, etc. can be performed for the treatment and treatment of mammals.
  • the compound of the present invention when used as a drug, it may be in a solid form (for example, tablet, hard capsule, soft capsule, granule, powder, fine granule, pill, troche, etc.) depending on the use. It can be prepared and used in either solid form (eg, suppository, ointment, etc.) or liquid form (injection, emulsion, suspension, lotion, spray, etc.).
  • solid form eg, suppository, ointment, etc.
  • liquid form injection, emulsion, suspension, lotion, spray, etc.
  • non-toxic additives that can be used in the above-mentioned preparations include, for example, starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methyl cellulose, carboxymethyl cellulose or the like.
  • Salt gum arabic, polyethylene glycol, alkyl p-hydroxybenzoate, syrup, ethanol, propylene glycol, vaseline, carbowax, glycerin, sodium chloride, sodium sulfite, sodium phosphate, Cunic acid and the like.
  • the agent may also contain other therapeutically useful agents.
  • the content of the compound of the present invention in the drug varies depending on the dosage form and the like. However, in general, it may be contained in a concentration of 0.1 to 50% by weight in the case of the peripheral or semi-solid form, and in a concentration of 0.05 to 10% by weight in the case of the liquid form. desirable.
  • the dose of the compound of the present invention can be varied widely depending on the kind of human or other warm-blooded animals, the administration route, the severity of the symptoms, the diagnosis of a doctor, and the like. From 0.05 per day: L OmgZkg, preferably in the range of 0.1-5 mg / kg. However, as described above, it is of course possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range depending on the severity of the patient's symptoms and the diagnosis of a doctor. The above dosage can be administered once or several times a day.
  • the solvent was distilled off, and 12.6 mg of copper chloride ( ⁇ ), 0.48 ml of 28% sodium methoxide and 0.94 ml of DMF were added to the obtained residue, and the mixture was heated and refluxed for 15 minutes under a nitrogen atmosphere. . After cooling, 0.5 ml of hydrochloric acid was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline. It was washed successively and dried over sodium sulfate.
  • Example 1 the same operation was conducted using 72 mg of sodium methoxide and 0.42 ml of ethanol instead of 28% sodium methoxide to obtain 2-ethoxy-13-hydroxy-1-D-homo-17-. 1,3,5 (10) 1-triene 17 a-one 17 mg was obtained.
  • Example 1 3-hydroxy-D-homo_17-year-old 1,3,5 (10) -triene- 17a-one was replaced by 3-hydroxy-D-homo- 17a.
  • Trien-17-one 63 mg was dissolved in boron trifluoride etherate complex lm1, A mixture of 30 mg of sodium borohydride, 0.25 ml of THF and 0.25 ml of diethylene glycol dimethyl ether was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water, acidified with dilute hydrochloric acid, and the product was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over sodium sulfate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

Dérivés d'oxastéroïdes représentés par la formule (a) exerçant des effets puissants d'inhibition de la polymérisation de tubuline, d'inhibition de la néovascularisation et/ou de stabilisation de la protéine p53. Dans cette formule (a) un de A et B représente C=O ou CH2, tandis que l'autre représente O; R représente alkoxy inférieur. Ces composés sont utiles pour la prévention ou le traitement des tumeurs malignes, de l'endométriose, de la polyarthrite rhumatoïde chronique, de la rétinopathie diabétique, des maladies cardiaques ischémiques, de l'artériosclérose, de l'ulcère de la peau intraitable, du psoriasis, du sarcome de Kaposi ou du léprome.
PCT/JP1999/005828 1998-10-29 1999-10-22 Derives de 2-substitues-d-homooxasteroides WO2000026229A1 (fr)

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Application Number Priority Date Filing Date Title
AU62282/99A AU6228299A (en) 1998-10-29 1999-10-22 2-substituted-d-homooxasteroid derivatives

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JP32293998 1998-10-29
JP10/322939 1998-10-29

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068068A2 (fr) * 2000-03-17 2001-09-20 Institut National De La Sante Et De La Recherche Medicale (I.N.S.E.R.M.) Composes se liant au cytosquelette
US10201623B2 (en) 2013-03-15 2019-02-12 Memorial Sloan Kettering Cancer Center HSP90-targeted cardiac imaging and therapy
US10640508B2 (en) 2017-10-13 2020-05-05 Massachusetts Institute Of Technology Diazene directed modular synthesis of compounds with quaternary carbon centers
WO2020247054A1 (fr) 2019-06-05 2020-12-10 Massachusetts Institute Of Technology Composés, conjugués et compositions d'épipolythiodicétopipérazines et de polythiodicétopipérazines et leurs utilisations
US10918735B2 (en) 2012-12-04 2021-02-16 Massachusetts Institute Of Technology Substituted pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4-diones for cancer treatment
US10918627B2 (en) 2016-05-11 2021-02-16 Massachusetts Institute Of Technology Convergent and enantioselective total synthesis of Communesin analogs
US11932650B2 (en) 2017-05-11 2024-03-19 Massachusetts Institute Of Technology Potent agelastatin derivatives as modulators for cancer invasion and metastasis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5262268A (en) * 1975-11-13 1977-05-23 Shionogi & Co Ltd Novel oxa- and thiasteroids
JPH06340688A (ja) * 1990-08-14 1994-12-13 Roussel Uclaf アミド官能基を含有する炭素鎖を１１β位置に有する新規の１９−ノルステロイド、それらの製造方法、それらの薬剤としての使用及びそれらを含有する製薬組成物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5262268A (en) * 1975-11-13 1977-05-23 Shionogi & Co Ltd Novel oxa- and thiasteroids
JPH06340688A (ja) * 1990-08-14 1994-12-13 Roussel Uclaf アミド官能基を含有する炭素鎖を１１β位置に有する新規の１９−ノルステロイド、それらの製造方法、それらの薬剤としての使用及びそれらを含有する製薬組成物

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068068A2 (fr) * 2000-03-17 2001-09-20 Institut National De La Sante Et De La Recherche Medicale (I.N.S.E.R.M.) Composes se liant au cytosquelette
WO2001068068A3 (fr) * 2000-03-17 2002-06-20 Inst Nat Sante Rech Med Composes se liant au cytosquelette
US10918735B2 (en) 2012-12-04 2021-02-16 Massachusetts Institute Of Technology Substituted pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4-diones for cancer treatment
US10201623B2 (en) 2013-03-15 2019-02-12 Memorial Sloan Kettering Cancer Center HSP90-targeted cardiac imaging and therapy
US10918627B2 (en) 2016-05-11 2021-02-16 Massachusetts Institute Of Technology Convergent and enantioselective total synthesis of Communesin analogs
US11932650B2 (en) 2017-05-11 2024-03-19 Massachusetts Institute Of Technology Potent agelastatin derivatives as modulators for cancer invasion and metastasis
US10640508B2 (en) 2017-10-13 2020-05-05 Massachusetts Institute Of Technology Diazene directed modular synthesis of compounds with quaternary carbon centers
WO2020247054A1 (fr) 2019-06-05 2020-12-10 Massachusetts Institute Of Technology Composés, conjugués et compositions d'épipolythiodicétopipérazines et de polythiodicétopipérazines et leurs utilisations
US11535634B2 (en) 2019-06-05 2022-12-27 Massachusetts Institute Of Technology Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof

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