EP4452996A1 - Stéroïdes époxy - Google Patents

Stéroïdes époxy

Info

Publication number
EP4452996A1
EP4452996A1 EP22844092.1A EP22844092A EP4452996A1 EP 4452996 A1 EP4452996 A1 EP 4452996A1 EP 22844092 A EP22844092 A EP 22844092A EP 4452996 A1 EP4452996 A1 EP 4452996A1
Authority
EP
European Patent Office
Prior art keywords
mmol
independently
alkyl
cells
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22844092.1A
Other languages
German (de)
English (en)
Inventor
Aram Prokop
Hans-Günther SCHMALZ
Ömer Taspinar
Jennifer WITT
Tobias Wilczek
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Helios Kliniken Schwerin GmbH
Original Assignee
Helios Kliniken Schwerin GmbH
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Filing date
Publication date
Application filed by Helios Kliniken Schwerin GmbH filed Critical Helios Kliniken Schwerin GmbH
Publication of EP4452996A1 publication Critical patent/EP4452996A1/fr
Pending legal-status Critical Current

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Classifications

    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides
    • 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
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • the present invention relates to novel drugs based on steroids.
  • cytotoxic treatment methods such as e.g. B. chemotherapy, radiation therapy and hyperthermia
  • chemotherapeutic agents currently used in clinical practice exert their effects by inducing apoptosis (programmed cell death) (Hannun, 1997).
  • apoptosis programmeed cell death
  • some patients suffering from malignant tumors develop resistance to chemotherapy or radiation at an early stage or are primarily refractory to therapy (Hickman, 1996).
  • primary tumors and metastases often respond quite differently to cytotoxic therapies.
  • the therapies for relapses in childhood leukemia, lymphoma and solid tumors still do not show satisfactory survival rates.
  • ALL acute lymphatic leukemia
  • other tumor diseases some of which are difficult to treat, such as e.g. As brain tumors, lymphomas, sarcomas such as soft tissue sarcomas, Ewing's or osteosarcoma, germ cell tumors, kidney or liver tumors and carcinomas such.
  • B. the thyroid carcinoma or the colon carcinomas and breast carcinomas which are very common in adulthood.
  • difficult rare tumors such.
  • desmoblastic round cell tumors or malignant peripheral nerve sheath tumors in the event of metastasis appropriate chemotherapy is required, since these malignant cells are resistant to cytostatics.
  • psoriasis is one of the most common skin diseases (two to four percent of people suffer from it), and the therapy for it still needs improvement.
  • cytostatic agents which can penetrate into the central nervous system because they show a high volume of distribution. This is of great importance, especially for the treatment of various brain tumors (grade 1 - grade 4), since many conventional cytostatics cannot sufficiently cross the blood-brain barrier, so that the necessary concentration of active substances in the tumor tissue cannot be achieved during chemotherapy.
  • Conventional steroids can easily cross the blood-brain barrier, but they show no or insufficient cytostatic effect in brain tumors, other solid tumors or in steroid-resistant leukemias and lymphomas.
  • the object of the present invention is to provide medicaments which overcome these disadvantages of the prior art.
  • W 1 , W 2 are independently H, OH, CHR 2 OH, CHR 2 R X , CR 2 R X OH or W 1 and W 2 together are 0
  • R 2 saturated or unsaturated, optionally branched alkyl radicals having 4 to 9 carbon atoms, where these alkyl radicals can also have a cyclopropane or cyclobutane substructure;
  • R 3 _ methyl or ethyl
  • X 1 , X 2 independently of one another R x or OR 5 ), or together 0, NOR 4 ;
  • Y 1 , Y 2 independently of one another R x or OR 5 ), or together 0, NOR 4 ; or X 1 and Y 1 together form a double bond or an epoxy group;
  • Z 1 , Z 2 independently of one another R x or OR 5 , or together 0, NOR 4 , CH 2 ;
  • the object is achieved by medicaments based on 7,19-epoxy steroids, containing a compound of the general formula A or a physiologically tolerable salt thereof, in which in the formula:
  • R 2 saturated or unsaturated, optionally branched alkyl radicals having 4 to 9 carbon atoms, it also being possible for these alkyl radicals to have a cyclopropane or cyclobutane substructure;
  • R 3 methyl or ethyl
  • Y 1 , Y 2 (H/OR 5 ), or together 0, NOR 4 ;
  • the formula A therefore includes the basic frameworks A1 and A2:
  • the compounds according to the invention are based on the basic structure of steroids, which have been well researched both synthetically and medically/pharmacologically.
  • Rx in formula I or A has 1 to 10 carbon atoms.
  • Rx in formula I or A has as a substituted alkyl.
  • Preferred protecting groups are carbonate such as tBOC (tert-butyloxycarbonyl) and silyl ethers such as TBDMS (tert-butyldimethylsilyl), esters or acetals such as MOM (methoxymethyl). Additional protecting groups are known to those skilled in the art from Greene's Protective Groups in Organic Synthesis, Fourth Edition, the contents of which are incorporated herein in their entirety.
  • the compounds according to the invention differ from other steroids in particular by the 7,19-epoxy linkage.
  • these substances initiate apoptotic cell death not only in leukemia and lymphoma cells but also in solid tumor cells and in steroid- or polychemotherapy-resistant leukemia or lymphoma cells. Because of their lipophilicity, these compounds of general formula I or A against tumor diseases of the bone marrow, but also against tumors of a different provenance, such as e.g. B. epithelial tumors, sarcomas or malignancies of the skin, etc., are used.
  • malignant brain tumors grade 1 - grade 4
  • malignant brain tumors grade 1 - grade 4
  • gliomas astrocytomas
  • medulloblastomas astrocytomas
  • medulloblastomas astrocytomas
  • apoptosis signaling cascade By investigating the apoptosis signaling cascade, it was possible according to the invention to develop novel steroids which, in contrast to the conventional glucocorticoids, mediate apoptosis in malignant cells via all three known pathways of the apoptosis signaling cascade (receptor-mediated, mitochondrial and via the endoplasmic reticulum). Induce cells and thus destroy glucocorticoid or polycytostatic-resistant leukemia, lymphoma and solid tumor cells. The effect is selective on malignant cells.
  • R x H
  • alkyl and R 2 is 4-methyl-pentyl.
  • Preferred substituents for R 1 are H or methyl.
  • Each R 4 , R 5 and R x independently of one another preferably has up to 10 carbon atoms.
  • R x is alkyl or substituted alkyl.
  • substituents preferably have 1-10 carbon atoms.
  • the invention also relates to a process for the production of
  • step a is carried out under basic conditions.
  • the preferred subject matter of the invention is a process for preparing compounds of the formula A, comprising step a and subsequent conversion of the functional groups: step a being carried out under basic conditions, preferably by heating the substrate in the presence of Li 2 CO 3 and LiBr in N,N-dimethylformamide at temperatures of 80 to 120°C.
  • step a being carried out under basic conditions, preferably by heating the substrate in the presence of Li 2 CO 3 and LiBr in N,N-dimethylformamide at temperatures of 80 to 120°C.
  • the invention also relates to the use of the medicaments according to the invention in the therapy of malignant diseases, benign or semi-malignant skin diseases.
  • Typical malignant diseases are diseases that affect the bone marrow or other blood-forming organs or are solid tumors or epithelial tumors, the solid tumors being in particular brain tumors such as glioblastoma and medulloblastoma.
  • Typical benign or semi-malignant diseases are skin diseases such as psoriasis vulgaris, keloids or basalioma.
  • the medicaments according to the invention are also suitable for use in the therapy of inflammatory and chronically inflammatory diseases, for use in immunosuppressive therapy, for antiviral, antibacterial, antimycotic, antiprotozoal or antihelminthic therapy.
  • the compounds are preferably administered intravenously in the concentration range between 0.1 to 100 pg/ml based on the patient's blood volume.
  • the compounds can also be taken orally.
  • the compounds according to the invention are distinguished by the following properties:
  • the new group of 7,19-epoxy steroids shows a cytostatic effect in solid tumor cells, in various brain tumor cells and in steroid-resistant leukemia and lymphoma cells, which are co-resistant to a wide variety of conventional cytostatics used in therapy .
  • An effect in cytostatic-resistant solid tumor cells is also detectable.
  • the compounds are also effective in pancreatic carcinoma cells.
  • the novel class of steroids specifically induces apoptosis in malignant cells while not damaging primary human leukocytes.
  • novel steroids show a synergistic effect in vitro with conventional cytostatics used in the therapy of malignant diseases.
  • the overcoming of cytostatic drug resistance in connection with the large volume of distribution of the active ingredients in the human body due to their steroid structure are the special new properties of this new class of active ingredients, which promise a good cytostatic effect in malignant diseases that are difficult or impossible to treat today.
  • Figure 1 shows the inhibition of proliferation in Nalm-6 cells.
  • FIG. 2 shows the overcoming of resistance to steroids and polycytostatics in NaKu cells.
  • FIG. 3 shows the overcoming of polycytostatic resistance in BiBo cells.
  • FIG. 4 shows the overcoming of polycytostatic resistance in 7-CCA cells.
  • FIG. 5 shows synergistic effects with cytarabine and vincristine on Nalm-6 cells.
  • FIG. 6 shows the exclusion of non-specific necrosis in Nalm-6 cells.
  • FIG. 7 shows the selectivity for leukemia cells (Nalm-6 cells) and in lymphoma cells (BJAB cells) compared to human leukocytes.
  • FIG. 8 shows the effect in cytostatic-resistant solid tumors.
  • Figure 9 shows the effect in brain tumor cells.
  • Figure 10 shows the effect in primary human glioblastoma cells.
  • Figure 11 shows the effect in primary human pancreatic carcinoma cells.
  • FIG. 12 shows the distribution of the substances according to the invention in the serum.
  • FIG. 13 shows the distribution of the substances according to the invention in the brain.
  • FIG. 14 shows the distribution of the substances according to the invention in the liver. examples
  • the synthesis sequence for the production of the novel steroids according to the invention is explained using the example of the substance WIL-071.
  • the C-19 methyl group of cholesteryl acetate (1) is first hydroxylated according to a method known in principle from the literature before the 19-hydroxycholesteryl acetate (4) in the B ring is oxidatively functionalized and the 7,19-epoxy bridge is closed.
  • Steps a - c Synthesis of 3 ⁇ -acetoxy-cholest- ⁇ 5 -en- -19 ⁇ ol (4) 200 g (0.23 mol, 1.0 eq.) cholesteryl acetate (1) in 1.6 L dioxane were treated with 96 g (0.67 mol, 1.5 eq.) N-bromoacetamide (NBA) and 320 mL HCIO 4 (0.5 N). After 1 hour at 0° C. with the exclusion of light and 1 hour at room temperature, the reaction was stopped by adding saturated NazSO 3 solution (until the reaction mixture became discolored) and water.
  • NBA N-bromoacetamide
  • FT-IR (ATR): v [m 1 ] 3507 (bw), 2944 (s), 2934 (s), 2870 (m), 1734 (m), 1713 (s), 1469 (m), 1444 ( m), 1381 (m), 1370 (m), 1254 (s), 1245 (vs), 1029 (vs), 977 (m), 961 (m), 911 (w), 886 (w), 824 ( f), 807(f), 742(f), 670(f), 610(f).
  • Step d Synthesis of 3 ⁇ -acetoxy-19-methoxymethyloxy-cholestane-A 5 -ene (5)
  • FT-IR (ATR): v [cm- 1 ] 3419 (br w), 2932 (m), 2868 (m), 1733 (m), 1498 (w), 1467 (w), 1444 (w), 1366(m), 1242(s), 1144(m), 1112(m), 1096(m), 1046(s), 1033(s), 986(m), 962(m), 943(m), 915 (m), 881 (f), 845 (f), 824 (f), 814 (f), 727 (f), 703 (f), 679 (f), 630 (f), 607 (m), 580 (w).
  • Step e Synthesis of 3ß-acetoxy-5a-hydroxy-19-methoxymethyloxy-cholestan-6-one (6)
  • FT-IR (ATR): v [cm- 1 ] 3384 (br w), 2939 (m), 2869 (m), 1730 (m), 1713 (s), 1467 (w), 1401 (w), 1382(m), 1365(m), 1236 (s), 1150 (m), 1106 (m), 1034 (s), 1012 (s), 967 (m), 940 (m), 920 (m), 904 (m), 871 (w), 834 (f), 734 (f), 664 (f), 941 (f), 609 (f), 553 (f).
  • Step f Synthesis of 3 ⁇ -acetoxy-7a-bromo-5a,6a-dihydroxy-6 ⁇ ,19-epoxy-cholestane (7)
  • FT-IR (ATR): v [cm- 1 ] 3418 (br w), 2933 (m), 2868 (m), 1726 (s), 1714 (s), 1498 (w), 1466 (w), 1382(m), 1366(m), 1244(s), 1154(m), 1131(m), 1096(m), 1042(s), 984(m), 965(s), 942(s), 906 (m), 846 (m), 814 (f), 727 (f), 703 (m), 680 (m), 666 (m), 629 (m), 609 (m), 583 (m).
  • Step g Synthesis of 3 ⁇ -acetoxy-5a-hydroxy-7 ⁇ ,19-epoxy-cholestan-6-one (8) (WIL-232)
  • FT-IR (ATR): v [cm- 1 ] 3507 (br w), 2944 (s), 2934 (s), 2870 (m), 1734 (m), 1713 (s), 1469 (m), 1444 (m), 1381 (m), 1370 (m), 1254 (s), 1245 (vs), 1029 (vs), 977 (m), 961 (m), 911 (w), 886 (w), 824(f), 807(f), 742(f), 670(f), 610(f).
  • Step h Synthesis of 3 ⁇ ,5a-dihydroxy-7 ⁇ ,19-epoxy-cholestan-6-one (9) (WIL-071)
  • the product 9 (WIL-071) was obtained as a white solid (11.3 g, 26.1 mmol, 98%) and subsequently recrystallized from ca. 400 mL (EtOH/H 2 O, 1:1) (9.7 g highly pure substance) . Melting point: 178°C - 180°C.
  • FT-IR (ATR): v [cm- 1 ] 3463 (br w), 2948 (s), 2868 (m), 1733 (vs), 1497 (w), 1466 (m), 1414 (w), 1382 (m), 1365 (f), 1340 (f), 1296 (f), 1248 (m), 1225 (f), 1153 (m), 1051 (vs), 968 (m), 958 (m), 887 (f), 818 (f), 779 (f), 756 (m), 713 (f), 637 (f), 558 (m), 539 (f).
  • FT-IR (ATR): v [cm- 1 ] 3459 (bw), 2952 (m), 2940 (m), 2918 (m), 2859 (m), 1742 (s), 1714 (s), 1466 (m), 1382 (m), 1345 (f), 1298 (f), 1252 (f), 1238 (m), 1195 (f), 1163 (m), 1145 (m), 1102 (f), 1079 (f), 1051 (s), 980 (f), 948 (m), 913 (f), 903 (f), 891 (f), 854 (f), 822 (f), 797 (f), 752 (m), 723 (m), 663 (f), 631 (m), 594 (f), 559 (m), 525 (m).
  • FT-IR (ATR): v[cm- 1 ] 2954(m), 2933(m), 2857(m), 1724(m), 1688(s), 1632(w), 1465(m), 1453 (m), 1383 (f), 1366 (f), 1328 (f), 1274 (f), 1245 (f), 1231 (m), 1185 (m), 1113 (f), 1074 (f), 1035 (s), 974 (f), 932 (f), 904 (s), 879 (f), 857 (f), 828 (m), 811 (f), 780 (m), 766 (f), 720 (f), 653 (f), 634 (f), 571 (f), 548 (m), 529 (m), 507 (f).
  • FT-IR (ATR): v [cm- 1 ] 3064 (w), 3031 (w), 2949 (s), 2867 (s), 1733 (s), 1496 (w), 1454 (m), 1382 (w), 1364 (w), 1307 (w), 1262 (w), 1228 (w), 1206 (w), 1179 (w), 1142 (w), 1090 (s), 1054 (m), 1001 (f), 953 (f), 873 (f), 842 (f), 803 (f), 734 (s), 693 (s), 557 (f).
  • FT-IR (ATR): v [cm- 1 ] 3444 (bw), 2947 (m), 2868 (m), 1737 (s), 1463 (m), 1381 (m), 1350 (m), 1275 (w), 1261 (w), 1181 (s), 1155 (m), 1082 (m), 1046 (m), 1022 (m), 975 (w), 952 (m), 889 (w), 869 (m), 824 (f), 808 (f), 757 (m), 711 (f), 663 (f), 637 (f), 559 (m).
  • FT-IR (ATR): v [cm- 1 ] 3457 (bw), 2950 (m), 2867 (w), 1743 (s), 1443 (m), 1383 (w), 1320 (w), 1269 (s), 1258 (s), 1227 (m), 1171 (w), 1154 (w), 1046 (m), 1018 (m), 952 (m), 935 (m), 877 (w), 825 (f), 792 (m), 757 (f), 721 (f), 664 (f), 625 (f), 559 (f), 530 (f).
  • FT-IR (ATR): v [cm- 1 ] 3387 (bw), 2951 (m), 2869 (m), 1740 (s), 1720 (s), 1513 (m), 1467 (w), 1384 (m), 1366 (m), 1282 (w), 1251 (m), 1204 (m), 1169 (s), 1051 (m), 970 (w), 918 (w), 867(f), 825(f), 757(f), 734(f), 559(f).
  • the organic phase was washed once each with saturated aqueous NaHCO 3 solution, water and saturated aqueous NaCl solution. The organic phase was then dried over MgSO 4 and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica (20:1, cHex/EtOAc) and the desired product 17 could be obtained as a colorless solid (165 mg, 0.273 mmol, 59%). In addition, the undesired side product 18 could also be obtained as a colorless solid (53 mg, 0.080 mmol, 17 %).
  • FT-IR (ATR): v [cm- 1 ] 3494 (w), 2952 (m), 2931 (m), 2896 (w), 2858 (w), 1741 (m), 1495 (w), 1463 (f), 1441 (f), 1383 (f), 1361 (f), 1252 (m), 1221 (m), 1187 (f), 1147 (s), 1085 (f), 1048 (m), 1021 (m), 977 (f), 961 (f), 888 (f), 835 (s), 780 (s), 755 (m), 712 (m), 663 (f), 636 (f), 602 (f), 559 (f), 474 (f), 434 (f).
  • FT-IR (ATR): v [cm- 1 ] 3523 (w), 2950 (m), 2930 (m), 2885 (w), 2858 (w), 1771 (m), 1754 (m), 1739 (m), 1470 (f), 1444 (f), 1389 (f), 1367 (f), 1255 (f), 1223 (f), 1180 (m), 1141 (s), 1040 (m), 1018 (f), 975 (f), 956 (f), 891 (f), 880 (f), 836 (s), 782 (m), 760 (m), 729 (f), 693 (f), 663 (f), 635 (f), 561 (f), 545 (f), 454 (f), 408 (f).
  • FT-IR (ATR): v [cm- 1 ] 3454 (bw), 2949 (m), 1932 (m), 2867 (m), 1738 (s), 1465 (m), 1446 (m), 1383 (m), 1366 (w), 1223 (s), 1208 (s), 1155 (m), 1097 (s), 1087 (s), 1045 (s), 1020 (m), 973 (m), 961 (m), 920 (f), 888 (f), 824 (m), 780 (f), 757 (m), 716 (f), 663 (f), 637 (f), 559 (m), 522 (m), 477 (m), 431 (m).
  • FT-IR (ATR): v [cm- 1 ] 3423 (bw), 2949 (m), 2867 (m), 1739 (m), 1717 (m), 1603 (w), 1585 (w), 1493 (f), 1451 (f), 1382 (f), 1316 (f), 1273 (s), 1227 (m), 1175 (f), 1152 (f), 1112 (m), 1069 (m), 1046 (m), 1027 (m), 954 (m), 887 (f), 856 (f), 822 (f), 757 (f), 710 (s), 686 (m), 663 (f), 637 (f), 600 (f), 559 (m), 524 (f).
  • the organic phase was washed once each with saturated aqueous NaHCO 3 solution, water and saturated aqueous NaCl solution. The organic phase was then dried over MgSO 4 and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica (10:1 - 8:1; cHex/EtOAc) and the product 21 could be obtained as a colorless solid (65 mg, 0.116 mmol, 69%).
  • FT-IR (ATR): v [cm- 1 ] 3422 (bw), 2951 (w), 2930 (w), 2866 (w), 1731 (s), 1644 (w), 1457 (w), 1434 (f), 1375 (f), 1333 (m), 1301 (f), 1201 (s), 1178 (s), 1146 (m), 1097 (f), 1040 (m), 1033 (m), 1023 (m), 975 (f), 956 (m), 936 (f), 920 (f), 884 (f), 826 (m), 813 (m), 783 (f), 754 (m), 712 (f), 644 (f), 584 (f), 562 (m), 545 (f), 459 (f).
  • FT-IR (ATR): v [cm- 1 ] 3511 (bw), 3290 (bw), 3197 (bw), 3111 (bw), 2954 (m), 2939 (m), 2921 (m), 2867 (m), 1493 (f), 1469
  • FT-IR (ATR): v [cm- 1 ] 3453 (bw), 2951 (m), 2868 (m), 1722 (s), 1645 (w), 1495 (w), 1437 (w), 1383 (f), 1302 (s), 1260 (m), 1227 (f), 1155 (s), 1100 (f), 1086 (f), 1033 (m), 1021 (m), 977 (m), 910 (f), 889 (f), 825 (f), 775 (f), 757 (f), 734 (f), 676 (f), 593 (f), 559 (f), 529 (f).
  • the aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with saturated aqueous NaCl solution, dried over MgSO 4 and freed from solvent under reduced pressure.
  • the residue was purified by column chromatography on silica (1:1; cHex/EtOAc) and the alkene 27 could be obtained as a colorless solid (82 mg, 0.19 mmol, 83 %).
  • FT-IR v [cm- 1 ] 3484 (bw), 2948 (m), 2932 (m), 2866 (m), 1737 (s), (ATR): 1465 (w), 1441 (w), 1375 (m), 1248 (m), 1224 (m), 1157 (m),
  • reaction mixture was terminated by adding saturated NaHCO 3 solution and the aqueous phase was extracted with EtOAc.
  • the combined organic phases were washed with water and saturated NaCl solution.
  • the clear yellow solution was dried over MgSO 4 and the solvent removed under reduced pressure.
  • the desired product 35 was then obtained in the form of a colorless gel (1.51 g, 2.76 mmol, 61%) after purification by column chromatography on silica gel (c-Hex/EtOAc, 3:1).
  • Example 2 Inhibition of proliferation in leukemia cells (Nalm-6 cells).
  • Example 3 Overcoming resistance to steroids and polycytostatics in NaKu cells
  • Bisso cells are lymphoma cells (BJAB cells) that have been made resistant to vincristine and show Bcl-2 overexpression as a resistance mechanism. They show co-resistances for the following cytostatics:
  • Example 5 Overcoming polycytostatic resistance in 7-CCA cells
  • 7-CCA cells are lymphoma cells (BJAB cells) that have been rendered resistant to doxorubin and display caspase-3 underexpression as the mechanism of resistance. They show co-resistance to the following cytostatics:
  • LDH lactate dehydrogenase
  • WIL 071 Treatment with the steroid WIL 071 induces concentration-dependent apoptosis in leukemia cells (Nalm-6 cells) and in lymphoma cells (BJAB cells). WIL 071 acts selectively in malignant cells that are proliferating. In contrast, no apoptosis is induced in human primary leukocytes. The DNA fragmentation was measured by flow cytometry, see FIG. 7. The experiments were carried out three times independently of one another. The error bars show the standard deviations of the measurements from three independent experiments.
  • Example 9 Effect in cytostatic-resistant solid tumors
  • the steroid WIL 071 can also induce apoptosis in solid tumor cells. Resistance to cytostatics is also overcome in neuroblastoma cells (SKNAS cells) (LiOn cells - cisplatin-resistant SKNAS cells with underexpression of caspase-8.
  • SKNAS cells neuroblastoma cells
  • the DNA fragmentation was measured by flow cytometry, see FIG. 8.
  • the experiments were carried out three times independently of one another.
  • the error bars show the standard deviations of the measurements from three independent experiments.
  • the steroid WIL 071 can also induce apoptosis in brain tumor cells.
  • the steroid WIL 071 also significantly induces apoptosis in glioblastoma cells (DBTRG05MG cells).
  • Example 11 Effect in primary human glioblastoma cells
  • the steroid WIL 071 can also induce apoptosis in primary human brain tumor cells.
  • the steroid WIL 071 also significantly induces apoptosis in the primary glioblastoma cells of a patient with glioblastoma (grade 4).
  • the steroid WIL 071 can also induce apoptosis in pancreatic carcinoma cells. In a corresponding cell line (DAN-G), the steroid WIL 071 significantly induces apoptosis.
  • the DNA fragmentation was measured by flow cytometry, see FIG. 11.
  • the experiments were carried out three times independently of one another.
  • the error bars show the standard deviations of the measurements from three independent experiments.
  • Standard treatment for pancreatic cancer includes and 5-fluorouracil. In comparable experiments, these show significantly poorer apoptosis rates (oxaliplatin: 14% apoptosis at 50 pM, 5-fluoro-uracil 24.9% at 30 pM, 21.2% at 50 pM).
  • Example 13 Comparison of the biological effect of different steroid derivatives in leukemia cells (Nalm-6)
  • the cells were incubated in 6-well plates at 1.0-10 5 cells/mL in two milliliters of medium with the respective steroid derivative in various concentrations.
  • the solvent control (DMSO) that was carried along served as a control, which was subtracted from all other measured values in order not to take into account the spontaneous apoptosis of the cells, which takes place independently of the drug concentration.
  • DMSO solvent control
  • the steroid concentration at which apoptosis was triggered in 50% of the leukemia cells tested was read off with the aid of the curve of the dose-response relationship (steroid concentration apoptosis induction) arising from these measured values.
  • Prednisolone resistance overcoming is given.
  • apoptosis induction in prednisolone-resistant leukemia cells is as high as in normal leukemia cells.
  • a stepwise dose increase of the three substances Wil-071, Wil-232 and Wil-369 was carried out in 8-week-old female NOG-F (Taconic) mice. Different mice were given one of up to seven different doses of the test substances. It started on day 1 with the lowest dose of 10 mg/kg. If, after this injection into the animal's tail vein, there were no abnormal behavior or observable health symptoms over the next 24 hours, the next higher dose was continued the next day. In total, doses of 10, 20, 40, 80, 100, 150 and 200 mg/kg were tested as far as possible. The maximum tolerable dose (MTD) was then administered to three other animals and then observed for a week to detect any to observe developing symptoms. The animals were observed and weighed daily. The body weight is considered an indicator of the general condition of the animals.
  • Example 4 The samples obtained in Example 4 were examined for the content of the substances. Since WIL-369 can be hydrolyzed to WIL-071, both WIL-369 and WIL-071 were determined in the samples. To the extent that these substances were detectable in the samples, this is shown in the figures as The distribution is shown in FIGS. 12 to 14.
  • FIG 12 shows that when WIL-369 is administered, WIL-071 is formed but serum levels are rapidly eliminated; Thus, WIL-369 is a prodrug
  • Figure 13 shows relevant levels of WIL-071 after administration of WIL-369 or WIL-071 in the brain, which could be effective for more than 8 hours.
  • Rho-GDI 2 The GDP dissociation inhibitor, D4-GDI (Rho-GDI 2), but not the homologous Rho-GDI 1, is cleaved by caspase-3 during drug-induced apoptosis, Biochem. J. 346, 777-783.
  • Glucocorticoids for the therapy of malignant diseases :
  • Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood, 94, 1209-1217.
  • Proteasome inhibitor-induced apoptosis of B-chronic lymphocytic leukemia cells involves cytochrome c release and caspase activation, accompanied by formation of an approximately 700 kDa Apaf-1 containing apoptosome complex.
  • Leukemia 15 , 1388-1397.

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Abstract

L'invention concerne un médicament à base de 7,19-époxy stéroïdes, contenant un composé de formule générale (I) ou un sel physiologiquement acceptable de celui-ci, où R1 = H; méthyl, aryl-CH2-, Rx-C(=O)- ou Rx-O-C(=O)-; ou R1O est distribué avec s'il y a une double liaison entre 4-5; W1, W2, indépendamment l'un de l'autre, représentent H, OH, CHR2OH, CHR2RX, CR2RXOH ou W1 et W2 représentent ensemble O, R2 = des groupes alkyle saturés ou insaturés, éventuellement ramifiés, ayant 4 à 9 atomes de carbone, lesdits groupes alkyles pouvant également avoir une sous-structure de cyclopropane ou de cyclobutane; R3 = méthyle ou éthyle, X1, X2 représentent indépendamment l'un de l'autre Rx ou OR5), ou ensemble représentent O, NOR4; Y1 et Y2 représentent indépendamment l'un de l'autre Rx ou OR5), ou représentent ensemble O, NOR4; Y1 et Y2 forment ensemble une double liaison ou un groupe époxy; Z1 et Z2 représentent indépendamment l'un de l'autre Rx ou OR5), ou représentent ensemble O, NOR4, CH2; R4 représente indépendamment l'un de l'autre H, alkyle ou aryle; et R5 représente indépendamment l'un de l'autre H; alkyle, aryl-CH2-, Rx-C(=O)- ou Rx- O-C(=O)-, SO3H, SO3CH3, PO(OH)2 ou glycosyl; avec chaque Rx indépendamment l'un de l'autre représentant H groupes alkyles, saturés ou insaturés, éventuellement ramifiés, alkyle, aryle, hétéroaryle, PEG, SO3H, PO(OH)2 ou glycosyle éventuellement substitués, saturés ou insaturés; et jusqu'à 3 atomes d'hydrogène pouvant être substitués par du fluor.
EP22844092.1A 2021-12-22 2022-12-22 Stéroïdes époxy Pending EP4452996A1 (fr)

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EP21217028.6A EP4201950A1 (fr) 2021-12-22 2021-12-22 Stéroïdes époxy
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