EP4255441A1 - PRODROGUE DU 5a-HYDROXY-6ß-[2-(1H-IMIDAZOL-4-YL)ETHYLAMINO]CHOLESTAN-3ß-OL ET COMPOSITIONS PHARMACEUTIQUES LE COMPRENANT POUR UTILISATION DANS LE TRAITEMENT DU CANCER - Google Patents

PRODROGUE DU 5a-HYDROXY-6ß-[2-(1H-IMIDAZOL-4-YL)ETHYLAMINO]CHOLESTAN-3ß-OL ET COMPOSITIONS PHARMACEUTIQUES LE COMPRENANT POUR UTILISATION DANS LE TRAITEMENT DU CANCER

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Publication number
EP4255441A1
EP4255441A1 EP21819893.5A EP21819893A EP4255441A1 EP 4255441 A1 EP4255441 A1 EP 4255441A1 EP 21819893 A EP21819893 A EP 21819893A EP 4255441 A1 EP4255441 A1 EP 4255441A1
Authority
EP
European Patent Office
Prior art keywords
imidazol
cholestan
hydroxy
ethylamino
compound
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
EP21819893.5A
Other languages
German (de)
English (en)
French (fr)
Inventor
Stéphane SILVENTE
Quentin MARLIER
Arnaud RIVES
Nicolas Caron
Dario MOSCA
Hélène MICHAUX
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.)
Dendrogenix
Original Assignee
Dendrogenix
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Dendrogenix filed Critical Dendrogenix
Publication of EP4255441A1 publication Critical patent/EP4255441A1/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • 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
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/36—Arsenic; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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

Definitions

  • the invention relates to the field of sterol compounds and more particularly to prodrugs of the compound 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -ol and pharmaceutical compositions comprising it for use in particular in the treatment of cancer.
  • cancer or "cancerous tumor” encompasses a group of diseases characterized by the uncontrolled growth and spread of abnormal cells. If the cancer cells are not eliminated, the evolution of the disease will more or less quickly lead to the death of the affected person.
  • Cancer management involves surgery, radiotherapy and chemotherapy, which can be used alone or in combination, simultaneously or sequentially.
  • Chemotherapy uses antineoplastic agents which are drugs that prevent or inhibit the maturation and proliferation of neoplasms.
  • Antineoplastic agents work by effectively targeting rapidly dividing cells. Because antineoplastic agents affect cell division, tumors with a high growth rate (such as acute myeloid leukemia and aggressive lymphomas, including Hodgkin's disease) are more susceptible to chemotherapy because a greater proportion of cells targets undergo cell division at any time. Malignant tumors with slower growth rates, such as indolent lymphomas, tend to respond much more modestly to chemotherapy. However, the development of drug resistance is a persistent problem during chemotherapy treatment.
  • AML acute myeloid leukemia
  • anthracycline such as daunorubicin
  • the overall 5-year survival rate is 40% in young adults and about 10% in elderly patients. Response rates vary considerably with aging, from 40% to 55% in patients over 60 and from 24% to 33% in patients over 70. This is even worse for the elderly with unfavorable cytogenetic profiles and death within 30 days of treatment ranges from 10% to 50% with increasing age and worsening.
  • the restriction of the use of these molecules is also due to side effects, and in particular to the emergence of chronic cardiac toxicity (linked to anthracyclines).
  • the toxic mortality rate linked to intensive chemotherapy is 10% to 20% in patients over 60 years of age.
  • Dendrogenin A the compound 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -ol, known as Dendrogenin A, useful for the treatment of chemoresistant tumours.
  • Dendrogenin A (hereafter referred to as DX101) is able to restore the sensitivity of chemoresistant tumors to an antineoplastic agent or to increase the effects of antineoplastic agents on tumors, which in turn makes it possible to reduce the effective cytotoxic dose of antineoplastic agents against chemosensitive tumours.
  • An object of the present invention is to provide new compounds and prodrugs or prodrugs of the compound Dendrogenin A, useful in particular for treating cancerous tumours, chemosensitive and/or chemoresistant tumours.
  • the first subject of the invention is a compound of formula (I); or a pharmaceutically acceptable salt of such a compound, in which R1 is chosen from:
  • R 2 , R3 are equivalent or different and are chosen from H and a saturated or unsaturated, linear or branched C1 to C8 carbon chain optionally containing one or more substituents chosen from allyl, carbonyl and aromatic heterocycle groups,
  • R 4 being chosen from -CH 2 CH 3 and -C 5 H 11 ,
  • R 5 is a C1 to C8 carbon chain; saturated or unsaturated, linear or branched,
  • R 6 is the side chain of the amino acids chosen from -CH 2 -C 3 N 2 H 2 , CH 2 CH(CH 3 ) 2 , - CH(CH 3 )CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 C 6 H 5 , -CH 2 C 8 NH 6 , -(CH 2 ) 4 NH 2 , -CH 2 C 6 OH 5 , -C 3 H 5 N, for its use as a medicament for regressing a mammalian cancerous tumor.
  • a second subject of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising, in a pharmaceutically acceptable vehicle, at least one compound of formula (I) for its use as a medicament for regressing a mammalian cancerous tumour.
  • solvate is used herein to describe a molecular complex comprising a compound of the invention and containing stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecules such as ethanol.
  • solvent molecules such as ethanol.
  • hydrate refers when said solvent is water.
  • carbonyl refers to a double bond between a carbon atom and an oxygen atom.
  • aromatic heterocycle refers to monocyclic and polycyclic aromatic compounds comprising as cyclic elements one or more heteroatoms among O, S and/or N.
  • aromatic heterocycles mention may be made of imidazole, furan, thiophene, pyrole, purine, pyrimidine, indole and benzofuran.
  • human refers to a subject of either sex and at any stage of development (i.e. newborn, infant, juvenile, adolescent, adult).
  • patient refers to a warm-blooded animal, more preferably a human, who is awaiting reception or receiving medical treatment and/or who will be the subject of a medical procedure.
  • pharmaceutical vehicle means an inert carrier or medium used as a solvent or diluent in which the pharmaceutically active agent is formulated and/or administered.
  • pharmaceutical carriers include creams, gels, lotions, solutions and liposomes.
  • administration means to deliver, the active agent or the active ingredient (for example the compound of formula (I)), in a pharmaceutically acceptable, to the patient in which a condition, symptom and/or disease is to be treated.
  • treat and “treatment” as used herein include alleviating, alleviating, stopping, curing a condition, symptom and/or disease.
  • prodrug or "prodrug” as used in the present description refers to pharmacologically acceptable derivatives of the compounds of formula (I), which can be administered to a patient without undue toxicity, irritation, allergic reaction, etc. ., which are convertible in vivo by metabolic means (eg hydrolysis) and whose in vivo biotransformation product generates the biologically active drug.
  • Most of the prodrugs described in this specification are characterized by increased bioavailability and are readily metabolized to biologically active compounds in vivo.
  • the prodrug is administered in a form that is inactive or much less active than its metabolite.
  • the prodrugs have identical, similar or superior pharmacological properties to the compound 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -ol.
  • Certain prodrugs described in the present invention when they do not show a higher bioavailability than the reference compound, show a faster penetration and potentially a faster effect for their use to treat cancer.
  • drug in this description means any compound or composition presented as having curative or preventive properties with regard to human or animal diseases.
  • a medicine includes any compound or any composition that can be used in humans or animals or that can be administered to them, with a view to establishing a medical diagnosis or restoring, correcting or modifying their physiological functions by exerting a pharmacological, immunological or metabolic action.
  • the drug is composed of two kinds of substances, an active principle and one or more excipients.
  • active ingredient refers to a compound having a pharmacological effect and a therapeutic effect.
  • excipient refers to any substance other than the active ingredient in a medicine.
  • chemoresistant cancer we mean a cancer in a patient where the proliferation of cancerous cells cannot be prevented or inhibited by means of an antineoplastic agent or a combination of antineoplastic agents commonly used to treat this cancer, at a dose acceptable to the patient.
  • Tumors may be inherently resistant prior to chemotherapy, or resistance may be acquired during treatment by tumors initially responsive to chemotherapy.
  • chemosensitive cancer is meant a cancer in a patient which responds to the effects of an antineoplastic agent, i.e. where the proliferation of cancer cells can be prevented by means of said antineoplastic agent at a dose acceptable to the patient.
  • the compound of formula (I) belongs to the group of steroids.
  • the numbering of the carbon atoms of the compound of formula (I) therefore follows the nomenclature defined by the IUPAC in Pure & Appl. Chem., Vol.61, No.10, pp.1783-1822,1989.
  • the numbering of the carbon atoms of a compound belonging to the group of steroids according to IUPAC is shown below:
  • AML acute myeloid leukemia
  • Dendrogenin A 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -ol;
  • MCF-7 Michigan Cancer Foundation-7
  • DMEM Dulbecco's Modified Eagle Medium
  • FCS fetal calf serum
  • ChEH Cholesterol Epoxide Hydrolase
  • Neuro2a murine glioblastoma
  • PBS phosphate buffered saline
  • DMSO dimethyl sulfoxide
  • OD optical density or absorbance
  • CT cholestane-3 ⁇ ,5 ⁇ ,6 ⁇ -triol
  • OCDO 6-oxo-cholestan-3 ⁇ ,5 ⁇ -diol
  • 5,6 ⁇ -EC 5,6 ⁇ -epoxycholesterol
  • Tam Tamoxifen
  • the first subject of the invention is a compound of formula (I); or a pharmaceutically acceptable salt of such a compound, in which R1 is chosen from:
  • R 2 , R 3 are equivalent or different and are chosen from H and a saturated or unsaturated, linear or branched C1 to C8 carbon chain optionally containing one or more chosen substituents from allyl, carbonyl and aromatic heterocycle groups,
  • R 4 being chosen from -CH 2 CH 3 and -C 5 H 11 ,
  • R 5 is a C1 to C8 carbon chain; saturated or unsaturated, linear or branched,
  • the invention relates to a compound of formula (I); or a pharmaceutically acceptable salt of such a compound, in which R 1 is chosen from:
  • R 2 , R 3 are equivalent or different and are chosen from H and a saturated or unsaturated, linear or branched C1 to C8 carbon chain optionally containing one or more chosen substituents from allyl, carbonyl and aromatic heterocycle groups, a group - C(O)R 4 , with R 4 is chosen from -CH 2 CH 3 and -C 5 H 11 ,
  • R 5 is a C1 to C8 carbon chain; saturated or unsaturated, linear or branched, a group - C(O)CHNH(COCH 2 CH 3 )R61 where Re is the side chain of the amino acids chosen from -CH 2 -C 3 N 2 H 2 , CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 C 6 H 5 , -CH 2 C 8 NH 6 , -(CH 2 ) 4 NH 2 , -CH 2 C 6 OH 5 , -C 3 H 5 N, for its use as a medicament for regressing a cancerous mammalian tumour.
  • the R 1 radical is a -C(O)R 4 group (acyl group) with R 4 being the radical chosen from -CH 2 CH 3 and -C 5:11 a.m.
  • the R 4 radical is preferably the -CH 2 CH 3 radical, it is the compound 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4- yl)-ethylamino]-cholestan-3 ⁇ -propionate. Propionate is interchangeably propanoate.
  • the R 4 radical is C 5 H 11 , it is the compound 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl) -ethylamino]-cholestan-3 ⁇ -hexanoate.
  • the R 1 radical is a -C(O)OR 5 group (carbonate group), where R 5 is a C1 to C8 carbon chain.
  • the R 5 radical is preferably an ethyl or butyl carbon chain, very preferably an ethyl carbon chain.
  • the R 1 radical is a -C(O)NR 2 R 3 group (carbamate group) in which R 2 and R 3 are equivalent or different and are selected from H and a saturated, linear C1 to C8 carbon chain optionally containing an aromatic heterocycle substituent.
  • R 2 and R 3 are chosen from two ethyl radicals or the 1-H-imidazole-4yl group.
  • R 2 and R 3 is an aromatic heterocycle substituent such as the 1-H-imidazole-4yl group.
  • R 1 is a group - C(O)CHNH(COCH 2 CH 3 )R 6 where R 6 is the side chain of the amino acids chosen from - CH 2 -C 3 N 2 H 2 , CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 C 6 H 5 , -CH 2 C 8 NH 6 , - (CH 2 ) 4 NH 2 , -CH 2 C 6 OH 5 , -C 3 H 5 N.
  • R 1 radical is the -C(O)CHNH(COCH 2 CH 3 )CH(CH 3 )CH 2 CH 3 group
  • R 1 radical is the -C(O)CHNH(COCH 2 CH 3 )CH(CH 3 )CH 2 CH 3 group
  • it is of the compound N-propionate-L-Isoleucine 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -yl ester.
  • R 1 radical is the -C(O)CHNH(COCH 2 CH 3 )CH 2 C6H 5 group
  • it is the N-propionate compound -L-Phenylalanine 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -yl ester.
  • R 1 radical is the -C(O)CHNH(COCH 2 CH 3 )CH 2 C 8 NH 6 group
  • R 1 radical is the -C(O)CHNH(COCH 2 CH 3 )CH 2 C 8 NH 6 group
  • it is the compound N -propionate-L-Tryptophan 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -yl ester.
  • R 1 radical is the -C(O)CHNH(COCH 2 CH 3 )CH 2 C 6 H 4 OH group
  • R 1 radical is the -C(O)CHNH(COCH 2 CH 3 )CH 2 C 6 H 4 OH group
  • it is the compound N-propionate-L-Tyrosine 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -yl ester.
  • R 1 radical is the -C(O)CHNH(COCH 2 CH 3 )CH(CH 3 )2 group
  • R 1 radical is the -C(O)CHNH(COCH 2 CH 3 )CH(CH 3 )2 group
  • it is the compound N -propionate-L-Valine 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -yl ester.
  • R 1 radical is the -C(O)CHNH(COCH 2 CH 3 )C 3 H 5 N group
  • R 1 radical is the -C(O)CHNH(COCH 2 CH 3 )C 3 H 5 N group
  • it is the compound N- Propionate-L-Proline a-hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -yl ester.
  • N-propionate-L-Tryptophan 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -yl ester
  • N-propionate-L-Lysine 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -yl ester
  • the compound of formula (I) is intended for use as a drug in the treatment of breast, prostate, colorectal, lung, bladder, skin, uterus, cervix, mouth, brain, stomach, liver, throat, larynx, esophagus, bone, ovary, pancreas, kidney, retina, sinus, nasal cavity, testis, thyroid, vulva, in the treatment of lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, leukemia, acute myeloid leukemia or acute lymphocytic leukemia, multiple myeloma, Merkel cell carcinoma or mesothelioma.
  • the cancer is acinar adenocarcinoma, acinar carcinoma, acrolentiginous melanoma, actinic keratosis, adenocarcinoma, adenoid cystic carcinoma, adenosquamous carcinoma, adnexal carcinoma, rest tumor adrenal cell carcinoma, adrenocortical carcinoma, aldosterone-secreting carcinoma, alveolar soft tissue sarcoma, ameloblastic thyroid carcinoma, angiosarcoma, apocrine carcinoma, Askin tumor, astrocytoma, basal cell carcinoma, carcinoma basaloid, basosquamous carcinoma, bile duct cancer, bone marrow cancer, botryoid sarcoma, bronchioalveolar carcinoma, bronchogenic adenocarcinoma, bronchogenic carcinoma, carcinoma ex pleomorphic adenoma, chloroma, carcinoma cholangiocellular, chondrosarcom
  • the compound of formula (I) is for use as a medicament in the treatment of breast cancer, myeloid leukemia and melanoma in mammals.
  • the compound is for use as a drug in the treatment of chemosensitive cancer.
  • the compound of formula (I) is intended for use as a medicament in the treatment of a chemoresistant cancer.
  • the chemoresistant cancer is a hematological or blood cancer, such as leukemia, in particular acute myeloid leukemia or acute lymphocytic leukemia, lymphoma, in particular non-Hodgkin's lymphoma and myeloma multiple.
  • leukemia in particular acute myeloid leukemia or acute lymphocytic leukemia
  • lymphoma in particular non-Hodgkin's lymphoma and myeloma multiple.
  • the cancer is chemoresistant to daunorubicin, cytarabine, fluorouracil, cisplatin, all-trans-retinoic acid, arsenic trioxide, bortezomib, or one of of their combinations.
  • the C3-specific prodrugs of the compound Dendrogenin A described in this specification exhibit comparable or superior pharmacological activity to Dendrogenin A.
  • Dendrogenin A is eliminated rapidly in vivo from the body.
  • the C3-specific prodrugs according to the invention have a higher bioavailability than Dendrogenin A and are easily metabolized into biologically active compounds in vivo. Therefore, the therapeutic effect of Dendrogenin A is prolonged in the patient's body when a specific C3 prodrug described in this description is used in vivo.
  • All references to compounds of formula (I) include references to salts, multi-component complexes and their liquid crystals. All references to compounds of formula (I) also include references to polymorphs and their usual crystals. [59]
  • the compound according to the invention may be in the form of pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt of the compound of formula (I) comprises the acid addition thereof.
  • Suitable acid salts are formed from acids that form non-toxic salts.
  • the salts are chosen from: acetate, adipate, benzoate, bicarbonate, carbonate, bisulfate, sulfate, camphorsulfonate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, furamate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, chloride hydrochloride, hydrobromide, bromide, hydroiodide, iodide, isethionate, lactate, malate, maleate, malonate mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate , pyrogluta
  • compositions of formula (I) can be prepared by one or more of the following three methods:
  • the salt obtained can precipitate and be collected by filtration or can be recovered by evaporation of the solvent.
  • the degree of ionization of the salt obtained can vary from completely ionized to almost non-ionized.
  • the second subject of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, in a pharmaceutically acceptable vehicle, at least one compound according to the invention, as described above for its use as a medicament for regressing a cancerous mammalian tumour.
  • the pharmaceutical composition further comprises at least one other therapeutic agent.
  • this other therapeutic agent is an antineoplastic agent.
  • the antineoplastic agent is a DNA damaging agent such as camptothecin, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, cisplatin, carboplatin, oxaliplatin, cyclophosphamide, chlorambucil, chlormethine, busulfan, treosulfan or thiotepa, an antitumor antibiotic such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, actinomycin D, mitomycin, bleomycin or plicamycin, an antimetabolite such as 5-fluorouracil, cytarabine, fludarabine or methotrexate, an antimitotic such as paclitaxel
  • the pharmaceutical composition is used in the treatment of cancer in a patient suffering from a tumor which is chemoresistant to said antineoplastic agent when it is not administered in combination with a compound according to the invention .
  • the pharmaceutical composition is used in the treatment of cancer in a patient suffering from a tumor which is chemosensitive to said antineoplastic agent, and the dose of the antineoplastic agent administered to said patient in combination with a compound according to the invention or one of its pharmaceutically acceptable salts is lower than the dose of the antineoplastic agent when it is not administered in combination with a compound according to the invention.
  • the dose of the antineoplastic agent administered to said patient in combination with a compound according to the invention or one of its pharmaceutically acceptable salts is lower than the dose of the antineoplastic agent administered alone, without any other active ingredient.
  • composition according to the invention may also also comprise other active therapeutic compounds commonly used in the treatment of the pathology set out above.
  • the pharmaceutical composition comprises the compound according to the invention as the sole therapeutic agent.
  • the pharmaceutical composition comprises the compound of formula (I) administered to the patient as an active therapeutic agent.
  • the pharmaceutical composition comprises the compound of formula (I) administered to the patient in combination with at least one other active therapeutic agent.
  • the pharmaceutical composition of the invention can be administered by any route, in particular by route: intradermal, intramuscular, intraperitoneal, intravenous or subcutaneous, pulmonary, transmucosal (oral, intranasal, intravaginal, rectal ), nasal spray inhalation, using tablet, capsule, solution, powder, gel, particle formulation; and contained in a syringe, an implanted device, an osmotic pump, a cartridge, a micropump; or any other means appreciated by the skilled artisan well known in the art.
  • Site-specific administration can be performed, for example, intratumoral, intra-articular, intrabronchial, intra-abdominal, intracapsular, intra-cartilaginous, intracavitary, intracerebellar, intracerebroventricular, intracolonic, intracervical, intragastric, intrahepatic, intracardiac , intraosteal, intrapelvic, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravascular, intravesical, intralesional, vaginal, rectal, buccal, sublingual, intranasal or transdermal in a suitable dosage comprising the usual non-toxic and pharmaceutically acceptable vehicles.
  • the pharmaceutical composition is in a form suitable for being administered intravenously, subcutaneously, intraperitoneally or orally.
  • the oral route is particularly preferred.
  • the compound of the invention is also effective on humans.
  • compositions for the administration of the compounds of this invention may be presented in unit dose form and may be prepared by any of the methods well known in the state of the art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • pharmaceutical compositions are prepared by bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect on the disease process or state.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, capsules, syrups, elixirs, solutions, mouth patches, oral gel, chewing gum, chewable tablets, effervescent powder and effervescent tablets.
  • the essays Pharmaceuticals containing the active ingredient can be in the form of an aqueous or oily suspension.
  • the aqueous suspensions contain the active materials mixed with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;
  • the dispersing or wetting agents may be a natural phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of alkylene oxide ethylene with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as polyoxyethylene monooleate sorbitol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.
  • the oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example peanut, olive, sesame or coconut oil, or in a mineral such as liquid paraffin.
  • Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those mentioned above and flavoring agents can be added to obtain a palatable oral preparation. These compositions can be preserved by adding an antioxidant such as ascorbic acid.
  • Dispersible powders and granules which are suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives.
  • Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. These formulations may also contain emollient, preservative, flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose. These formulations may also contain emollient, preservative, flavoring and coloring agents.
  • the pharmaceutical compositions according to the invention may be in the form of an aqueous or oleaginous suspension which can be injected in a sterile manner. This suspension can be formulated according to the known art using the appropriate dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic diluent or solvent acceptable parenterally, for example a solution in 1,3-butane diol.
  • Acceptable vehicles and solvents include; water, Ringer's fluid and isotonic sodium chloride solution.
  • sterile fixed oils are traditionally used as a solvent or suspending medium. For this purpose, any fixed oil can be used, including synthetic mono- or diglycerides. Also, fatty acids such as oleic acid are used in the preparation of injectables.
  • compositions according to the invention can also be administered in the form of suppositories for the rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and which will therefore melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and which will therefore melt in the rectum to release the drug.
  • materials include cocoa butter and polyethylene glycols.
  • compositions according to the invention can be administered via the ocular route by means of solutions or ointments.
  • transdermal delivery of the compounds in question can be achieved by means of iontophoretic and other patches.
  • creams, ointments, jellies, solutions or suspensions are used.
  • a suitable dosage of the pharmaceutical composition according to the invention can generally be from about 0.1 to 50,000 micrograms ( ⁇ g) per kg of body weight. of the patient per day, which can be administered in single or multiple doses.
  • the dosage level will preferably be from about 1000 to about 40,000 ⁇ g/kg per day, depending on many factors such as the severity of the cancer to be treated, the age and relative state of health of the subject, the route and the form of administration.
  • this composition may be supplied in the form of tablets containing 1000 to 100000 micrograms of each of the active ingredients, in particular 1000, 5000, 10000, 15000, 20000, 25000, 50000, 75000, 100000 micrograms of each active ingredient .
  • This composition can be administered on a 1 to 4 times daily schedule, for example once or twice daily.
  • the dosage regimen may be adjusted to provide an optimal therapeutic response.
  • the invention also discloses below processes for the manufacture of the compounds of formula (I).
  • Figure 1 illustrates the pharmacokinetic profile of the compound 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -yl propionate (DX107) in comparison with the compound Dendrogenin A (DX101).
  • Figure 2 illustrates the pharmacokinetic profile of the compound 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]-cholestan-3 ⁇ -yl-(2-(1 H-imidazol-4-yl)ethyl)carbamate (DX117) in comparison with the compound Dendrogenin A (DX101).
  • Figure 3 illustrates the pharmacokinetic profile of the compound 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -ethyl-carbonate (DX121) in comparison with the compound Dendrogenin A (DX101).
  • Figure 4A illustrates the comparison of activity between DX107 and DX101 on the reduction of tumor growth.
  • Figure 4B illustrates the activity comparison between DX107 and DX101 on animal survival
  • Figure 5 shows the results of a cytotoxicity study of the compound, 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -yl propionate on Neuro2a cells via a trypan blue test.
  • Figure 6 illustrates the results of an MTT cell viability test carried out on MCF-7 mammary tumor cells in the presence of the compound 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino ]-cholestan-3 ⁇ -yl propionate.
  • Figure 7 illustrates the results of Cholesterol Epoxide Hydrolase (ChEH) activity in MCF-7 cells in the presence of the compound 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)- ethylamino]-cholestan-3 ⁇ -yl propionate.
  • ambient temperature used in the following examples must be interpreted as being a temperature between 10 and 40 degrees Celsius (°C), for example between 15°C and 30°C and preferably around 20°C.
  • Example 1 Synthesis of the compound of formula (I) 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]cholestan-3 ⁇ -yl propionate (named DX107, in basic form):
  • the first step is a synthesis of the compound cholestan-3 ⁇ -propionate comprising the following steps:
  • the second step consists in synthesizing from cholestan-3 ⁇ -propionate the compound 5,6 ⁇ -Epoxycholestan-3 ⁇ -propionate as follows:
  • the third step consists in synthesizing 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]cholestane-3 ⁇ -propionate (DX107 in basic form) as follows:
  • Histamine in its basic form (1.44 g, 13.0 mmol) is added after complete dissolution of 3.00 g of 5,6 ⁇ -Epoxycholestan-3 ⁇ -propionate (at 73%, 4.6 mmol) in 30 ml of butanol.
  • the reaction mixture is kept under stirring and at reflux for 48 hours.
  • the progress of the reaction is monitored by thin layer chromatography (TLC) to monitor the conversion of 5,6 ⁇ -Epoxycholestan-3 ⁇ -propionate.
  • TLC thin layer chromatography
  • the reaction medium is diluted in 24 mL of methyl tert-butyl ether, the organic phase is washed twice with 24 mL of water then twice with a saturated NaCl solution.
  • the organic phase is dried over anhydrous MgSO 4 .
  • the reaction crude is purified by chromatography column on silica gel on a purification automaton.
  • the eluent used is a mixture of dichloromethane/ethyl acetate 100-0% to 0-100%.
  • a white powder of 1.20 g of 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]cholestan-3 ⁇ -yl propionate is obtained, corresponding to 46% yield.
  • Example 2 Preparation of a dilactate salt of 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino1cholestan-3 ⁇ -yl propionate (DX107 in dilatact form):
  • a dilactate salt of compound 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]cholestan-3 ⁇ -yl propionate was prepared as follows:
  • Example 3 Synthesis of the compound of formula (I) 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylaminol-cholestan-38-yl hexanoate (named DX113, in basic form) :
  • the first step is a synthesis of the compound cholestan-3 ⁇ -hexanoate comprising the following steps:
  • the second step consists in synthesizing from cholestan-3 ⁇ -hexanoate the compound 5,6 ⁇ -Epoxycholestan-3 ⁇ -hexanoate as follows:
  • Vacuum evaporation of the organic solvent allows 5.06 g of a white powder to be obtained, corresponding to 5,6 ⁇ -Epoxycholestan-3 ⁇ -hexanoate (70%) and 5,6 ⁇ -Epoxycholestan-3 ⁇ -hexanoate (30%). 5,6 ⁇ -Epoxycholestan-3 ⁇ -hexanoate is used as is without further purification.
  • the third step consists in synthesizing 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]-cholestane-3 ⁇ -hexanoate as follows (DX1 13 in basic form):
  • Histamine in its basic form (1.25 g, 11.2 mmol) is added to a butanol solution (40 mL) of a 5,6 ⁇ -Epoxycholestan-3 ⁇ -hexanoate (at 70% purity, 4.0 g, 5.6 mmol ).
  • the reaction mixture is kept under stirring and at reflux for 48 hours.
  • the progress of the reaction is monitored by thin layer chromatography (TLC) to monitor the conversion of 5,6 ⁇ -Epoxycholestan-3 ⁇ -hexanoate.
  • TLC thin layer chromatography
  • the reaction medium is diluted in 40 mL of methyl tert-butyl ether, the organic phase is washed three times with 40 mL of water then once with 40 mL of saturated NaCl solution.
  • the organic phase is dried over anhydrous MgSO 4 .
  • the reaction crude is purified by chromatography column on silica gel on a purification automaton.
  • the eluent used is a dichloromethane/ethyl acetate mixture 100-0% to 0-100%.
  • a white powder of 1.71 g of 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]cholestane-3 ⁇ -hexanoate (50% yield) is obtained.
  • Example 4 Preparation of a dilactate salt of the compound 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]cholestan-3 ⁇ -yl hexanoate (DX113 in dilactate form): [107] A dilactate salt of the compound 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -yl hexanoate was prepared as follows:
  • Example 5 Synthesis of the compound of formula (I) 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]cholestan-3 ⁇ -yl ethyl carbonate (named DX121, in basic form) :
  • the first step consists in synthesizing from the commercial product cholestan-3 ⁇ -yl ethyl carbonate the compound 5,6 ⁇ -Epoxycholestan-3 ⁇ -yl ethyl carbonate as follows:
  • Meta-chloro-peroxybenzoic acid (m-CPBA) (77%, 1.31 g, 5.8 mmol) is dissolved in dichloromethane (30 mL) and added dropwise over 30 minutes to a mixture of cholestan-3 ⁇ -yl ethyl carbonate (2.02 g, 4.4 mmol) dissolved in dichloromethane (15 mL). Stirring is maintained at room temperature for three hours. The reaction medium is washed twice with an aqueous solution of sodium sulphite (10% by weight), twice with a saturated solution of NaHCO 3 and once with a saturated solution of NaCl. The organic phase is dried over anhydrous MgSO 4 .
  • the second step consists of synthesizing 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]-cholestan-3 ⁇ -yl ethyl carbonate as follows:
  • Histamine in its basic form (754.5 mg, 6.8 mmol) is added after complete dissolution of 2.09 g of 5,6 ⁇ -Epoxycholestan-3 ⁇ -yl ethyl carbonate (at 76%, 3.4 mmol) in 20 ml of butanol.
  • the reaction mixture is kept under stirring and at reflux for 48 hours.
  • the progress of the reaction is monitored by thin layer chromatography (TLC) to monitor the conversion of 5,6 ⁇ -Epoxycholestan-3 ⁇ -yl ethyl carbonate.
  • TLC thin layer chromatography
  • the reaction medium is diluted in 20 mL of methyl tert-butyl ether, the organic phase is washed 3 times with 20 mL of a saturated NaCl solution.
  • the organic phase is dried over anhydrous MgSO 4 .
  • the reaction crude is purified by chromatography column on silica gel on a purification automaton.
  • the eluent used is a mixture of dichloromethane/ethyl acetate 100-0% to 0-100%.
  • a white powder of 480 mg of 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]-cholestan-3 ⁇ -yl ethyl carbonate is obtained, corresponding to 24% yield.
  • Example 6 Preparation of a dilactate salt of 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino1-cholestan-3 ⁇ -yl ethyl carbonate (DX121 in dilactate form):
  • a dilactate salt of the compound 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]-cholestan-3 ⁇ -yl ethyl carbonate was prepared as follows:
  • Example 7 Synthesis of the compound of formula (I) 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino1cholestane-3 ⁇ -yl butyl carbonate (named DX119, in basic form):
  • the first step consists in synthesizing from the commercial product cholestan-3 ⁇ -yl butyl carbonate the compound 5,6 ⁇ -Epoxycholestan-3 ⁇ -yl butyl carbonate as follows:
  • Vacuum evaporation of the organic solvent yields 2.21 g of a white powder corresponding to the mixture of the two isomers: 5,6 ⁇ -Epoxycholestan-3 ⁇ -yl butyl carbonate (77%) and 5,6 ⁇ -Epoxycholestan-3 ⁇ -yl butyl carbonate (23%).
  • the white powder is used as is without further purification.
  • the second step consists of synthesizing 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]-cholestan-3 ⁇ -yl butyl carbonate (DX119 in basic form) as follows:
  • Histamine in its basic form (759.8 mg, 6.8 mmol) is added after complete dissolution of 2.21 g of 5,6 ⁇ -Epoxycholestan-3 ⁇ -yl butyl carbonate (at 77%, 3.4 mmol) in 20 ml of butanol .
  • the reaction mixture is kept under stirring and at reflux for 48 hours.
  • the progress of the reaction is monitored by thin layer chromatography (TLC) to monitor the conversion of 5,6 ⁇ -Epoxycholestan-3 ⁇ -yl butyl carbonate.
  • TLC thin layer chromatography
  • the reaction medium is diluted in 20 mL of methyl tert-butyl ether, the organic phase is washed 3 times with 20 mL of a saturated NaCl solution.
  • the organic phase is dried over anhydrous MgSO 4 .
  • the reaction crude is purified by chromatographic column on a purification automaton.
  • the eluent used is a mixture of dichloromethane/ethyl acetate 100-0% to 0-100%.
  • a white powder of 814 mg of 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]-cholestan-3 ⁇ -yl butyl carbonate is obtained, corresponding to 39% yield.
  • Example 8 Preparation of a dilactate salt of 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino1-cholestan-3 ⁇ -yl butyl carbonate (DX1 19 in dilactate form):
  • a dilactate salt of the compound 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]-cholestan-3 ⁇ -yl butyl carbonate was prepared as follows:
  • Example 9 Synthesis of the compound of formula (I) 5 ⁇ -Hydroxy-6 ⁇ -[2-(1 H-imidazol-4-yl)ethylamino]-cholestane-3 ⁇ -yl-(2-(1 H-imidazol -4-yl)ethyl)carbamate (named DX1 17, in basic form):
  • the first step is a synthesis of the compound cholestan-3 ⁇ -yl phenyl carbonate comprising the following steps: [132] In a 100mL ground-in flask, 20 mL of dichloromethane are added to dissolve 7.58 g of cholesterol (19.6 mmol) and 1.0 g of 4-Dimethylaminopyridine (DMAP, 8.2 mmol). Then 15 mL of anhydrous pyridine (185.5 mmol) and 3.4 mL of phenyl chloroformate (24.1 mmol) are added and the whole is mixed at room temperature for 1 hour.
  • DMAP 4-Dimethylaminopyridine
  • the reaction is diluted by adding 35 mL of dichloromethane and the reaction medium is washed three times with 70 mL of an aqueous solution of HCl (1 M).
  • the organic phase is dried over anhydrous MgSO 4 . Vacuum evaporation of the organic solvent makes it possible to obtain 8.79 g of a white powder corresponding to the desired product, corresponding to 98% yield.
  • the second step consists in synthesizing from cholestan-3 ⁇ -yl phenyl carbonate the compound 5,6 ⁇ -Epoxycholestan-3 ⁇ -yl phenyl carbonate as follows:
  • Meta-chloro-peroxybenzoic acid (77%, 5.08 g, 22.7 mmol) is dissolved in dichloromethane (70 mL) and added dropwise for 1 hour to a mixture of cholestan-3 ⁇ -yl phenyl carbonate (8.79 g , 17.3 mmol) dissolved in dichloromethane (70 mL). Stirring is maintained at room temperature for three hours. The reaction medium is washed twice with an aqueous solution of Na 2 S 2 O 3 (10% by weight), twice with a saturated solution of NaHCO 3 and once with a saturated solution of NaCl. The organic phase is dried over anhydrous MgSO 4 .
  • Vacuum evaporation of the organic solvent makes it possible to obtain 9.04 g of transparent oil corresponding to the mixture of the two isomers: 5,6 ⁇ -epoxycholestan-3 ⁇ -yl phenyl carbonate and 5,6 ⁇ -epoxycholestan-3 ⁇ -yl phenyl carbonate.
  • the mixture was redissolved in 10 mL of Et 2 O and 40 mL of EtOH were added to obtain a white precipitate.
  • the solution was filtered and the precipitate washed with EtOH.
  • the procedure makes it possible to obtain 7.23 g of a white powder rich in 5,6 ⁇ -epoxy-cholestan-3 ⁇ -yl phenyl carbonate corresponding to 88% yield 89% (76% enantiomeric excess).
  • the third step is to synthesize 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]-cholestan-3 ⁇ -yl-(2-(1H-imidazol-4-yl )ethyl)carbamate (DX1 17 in basic form) as follows:
  • Histamine in its basic form (1.13 g, 10.2 mmol) is added after complete dissolution of 1.0 g of 5,6 ⁇ -epoxy-cholestan-3 ⁇ -yl phenyl carbonate (88%, 1.7 mmol) with 30 mL of butanol.
  • the reaction mixture is kept under stirring and at reflux for 48 hours.
  • the progress of the reaction is monitored by thin layer chromatography (TLC) to monitor the conversion of 5,6 ⁇ -epoxycholestan-3 ⁇ -yl phenyl carbonate.
  • TLC thin layer chromatography
  • the mixture was transferred to a separatory funnel and the organics were extracted twice with 15 mL of methyl tert-butyl ether and twice more with 15 mL of ethyl acetate.
  • the organic phases were combined, dried over anhydrous MgSO 4 .
  • the reaction crude is purified by chromatography column on silica gel on a purification automaton.
  • the eluent used is a mixture of ethyl acetate-MeOH 95-5% up to 80-20% and finally DCM-MeOH-NH 4 OH 75-20-5%.
  • a white powder of 530 mg of 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]-cholestan-3 ⁇ -yl-(2-(1H-imidazol-4-yl)ethyl) carbamate is obtained, correspond to 48% yield.
  • Example 10 Preparation of a trilactate salt of 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]-cholestan-3 ⁇ -yl-(2-(1H-imidazol- 4-yl)ethyl)carbamate (DX1 17 in trilactate form):
  • a trilactate salt of the compound 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]-cholestan-3 ⁇ -yl-(2-(1H-imidazol-4-yl)ethyl)carbamate a was prepared as follows:
  • Example 11 Synthesis of the compound of formula (I) 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino1cholestan-3 ⁇ -yl-diethyl carbamate (named DX131, in basic form):
  • the first step is a synthesis of the compound cholestan-3 ⁇ -diethyl carbamate comprising the following steps:
  • the white solid was dissolved with 100 mL of Et 2 O and made precipitate with 100 ml of MeOH, then the solution was filtered and the precipitate is washed with cold MeOH.
  • the procedure makes it possible to obtain 9.30 g of a white powder corresponding to cholestan-3 ⁇ -diethyl carbamate (yield of 95%).
  • the second step consists in synthesizing from cholestan-3 ⁇ -diethyl carbamate the compound 5,6 ⁇ -Epoxycholestan-3 ⁇ -diethyl carbamate as follows:
  • Meta-chloro-peroxybenzoic acid (77%, 4.47 g, 19.9 mmol) is dissolved in dichloromethane (100 mL) and added dropwise for 1 h to a mixture of cholestan-3 ⁇ -diethyl carbamate (7.45 g, 15.3 mmol) dissolved in dichloromethane (50 mL). Stirring is maintained at room temperature for three hours. The reaction medium is washed twice with an aqueous solution of Na 2 S 2 O 3 (10% by weight), twice with a saturated solution of NaHCO 3 and once with a saturated solution of NaCl. The organic phase is dried over anhydrous MgSO 4 .
  • the third step is to synthesize 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]cholestane-3 ⁇ -diethyl carbamate (DX131 in basic form) as follows: [148]
  • Histamine in its basic form (756.3 mg, 6.8 mmol) is added after complete dissolution of 2.00 g of 5,6 ⁇ -Epoxycholestan-3 ⁇ -diethyl carbamate (at 86%, 3.4 mmol) with 7 ml of butanol.
  • the reaction mixture is kept under stirring and at reflux for 48 hours.
  • the progress of the reaction is monitored by thin layer chromatography (TLC) to monitor the conversion of 5,6 ⁇ -Epoxycholestan-3 ⁇ -diethyl carbamate.
  • TLC thin layer chromatography
  • the reaction medium is diluted in 7 mL of methyl tert-butyl ether, the organic phase is washed 3 times with 7 mL of a saturated NaCl solution.
  • the organic phase is dried over anhydrous MgSO 4 .
  • the reaction crude is purified by column chromatography on silica gel.
  • the eluent used is a mixture of hexane-ethyl acetate 90-10% up to 0-100%, then ethyl acetate-methanol 90-10% up to 70-30%.
  • a white powder of 0.45 g of 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]cholestane-3 ⁇ -yl-diethylcarbamate is obtained, corresponding to a 22% yield.
  • Example 12 Preparation of a dilactate salt of 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino1cholestan-3 ⁇ -yl-diethylcarbamate (DX131 in dilactate form):
  • a dilactate salt of the compound 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]cholestan-3 ⁇ -yl-diethyl carbamate was prepared as follows:
  • Example 13 Synthesis of the compound of formula (I) 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]cholestan-3 ⁇ -yl propionyltyrosine (named DX133, in basic form):
  • the first step is the synthesis of N-propionyltyrosine from the amino acid tyrosine:
  • the second step is the esterification reaction between cholesterol and N-propionyltyrosine to obtain the compound cholestan-3 ⁇ -yl propionyltyrosine
  • the organic phases thus obtained were combined and dried over MgSO 4 then evaporated, allowing a white-brownish solid to be obtained.
  • the reaction crude is purified by column chromatography on silica gel.
  • the eluent used is a mixture of hexane/ethyl acetate 90-10% up to 30-70%.
  • a brownish-white solid of 7.83 g of cholestane-3 ⁇ -yl propionyltyrosine is obtained, corresponding to 96% yield.
  • the third step consists in synthesizing from cholestan-3 ⁇ -yl propionyltyrosine the compound 5,6 ⁇ -Epoxycholestan-3 ⁇ -yl propionyltyrosine as follows:
  • Meta-chloro-peroxybenzoic acid (77%, 1.79 g, 8.0 mmol) is dissolved in dichloromethane (45 mL) and added dropwise over 30 minutes to a mixture of cholestan-3 ⁇ -yl propionyltyrosine (4.66 g, 7.7 mmol) dissolved in dichloromethane (20 mL). Stirring is maintained at room temperature for three hours. The reaction medium is washed twice with an aqueous solution of Na 2 S 2 O 3 (10% by weight), twice with a saturated solution of NaHCO 3 and once with a saturated solution of NaCl. The organic phase is dried over anhydrous MgSO 4 .
  • Vacuum evaporation of the organic solvent makes it possible to obtain 6.29 g of an oil corresponding to the mixture of the two isomers: 5,6 ⁇ -Epoxycholestan-3 ⁇ -yl propionylglycine and 5,6 ⁇ -Epoxycholestan-3 ⁇ -yl propionylglycine.
  • the mixture was redissolved in 20 mL of dichloromethane and 80 mL of EtOH was added to obtain a brownish-white precipitate. The brownish-white precipitate obtained was filtered and washed with MeOH.
  • the fourth step is to synthesize 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino]cholestan-3 ⁇ -yl propionyltyrosine as follows (DX133 in basic form):
  • Histamine in its basic form (449 mg, 4.0 mmol) is added after complete dissolution of 1.0 g of 5,6 ⁇ -Epoxycholestan-3 ⁇ -yl propionyltyrosine (at 63%, 1.0 mmol) under 5 ml of butanol.
  • the reaction mixture is kept under stirring and under reflux for 24 hours.
  • the progress of the reaction is monitored by thin layer chromatography (TLC) to monitor the conversion of 5,6 ⁇ -Epoxycholestan-3 ⁇ -yl propionyltyrosine.
  • reaction medium is diluted in 5 mL of methyl tert-butyl ether, the organic phase is washed twice with 5 mL of a saturated solution of NaCl and once with 5 mL of a saturated solution of NaHCO 3 .
  • the organic phase is dried over anhydrous MgSO 4 .
  • the reaction crude is purified by column chromatography on silica gel.
  • the eluent used is a mixture of ethyl acetate-methanol 100-0% up to 70-30%.
  • Example 14 Preparation of a dilactate salt of 5 ⁇ -Hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)ethylamino1cholestan-3 ⁇ -yl propionyltyrosine (DX133 in lactate form):
  • 3-yl propionyltyrosine was prepared as follows:
  • Example 15 Synthesis of the compounds (N-propionyl)-L-Histidine 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylaminol-cholestan-3 ⁇ -yl ester, (N- propionyl)-L-Isoleucine 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylaminol-cholestan-3 ⁇ -yl ester. (N-propionyl)-L-Leucine 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylaminol-cholestan-3 ⁇ -yl ester.
  • Example 19 Study of the cytotoxicity of compounds and 5 ⁇ -hydroxy-6 ⁇ -[2-(1 H-imidazol-4-yl)-ethylamino1-cholestan-3 ⁇ -yl propionate or DX107:
  • the culture medium consists of Dulbecco's Modified Eagle Medium (DMEM) marketed by Westburg under the reference LO BE12-604F), comprising 4.5 g/L Glucose with L-Glutamine, to which 10% serum is added. of fetal calf (SVF). Neuro2a cells (murine neuroblastoma) are introduced into this culture medium.
  • DMEM Dulbecco's Modified Eagle Medium
  • LO BE12-604F fetal calf
  • 24-well dishes were seeded with 10,000 Neuro2a cells per well. After 72 hours (h) of culture under normal conditions, i.e. in an incubator at a temperature of 37°C at 5% CO2, the Neuro2a cells were treated for 48 hours with 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -yl-propionate and 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]- cholestan-3 ⁇ -ol at 100 nM, 1 ⁇ M and 10 ⁇ M.
  • a control (CTL) is also carried out using the protocol described previously without the treatment with the aforementioned compounds.
  • FIG. 5 illustrates the ordinate of the percentage of cell survival relative to the control group.
  • the cell survival percentage is respectively 43.25% ⁇ 2.44, and 30, 46 ⁇ 5.22%.
  • a cytotoxic activity of the compounds of formula (I) is observed towards Neuro2a tumor cells for concentrations of 1 ⁇ M for 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -yl propanoate and 10 ⁇ m for 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4- yl)-ethylamino]-cholestan-3 ⁇ -yl propionate.
  • Example 20 Effect of the compound 5 ⁇ -hvdroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino1-cholestan-3 ⁇ -yl propionate or DX107 on the viability of MCF-7 cells:
  • MCF-7 Moichigan Cancer Foundation-7
  • HER2 ER(+) cells
  • the MCF-7 cells are in a cell culture medium identical to example 14 and are seeded in 12-well plates at 50,000 cells per well for 24 h. 24 hours after seeding, the cells are treated with the vehicle solvate comprising water and ethanol with a ratio of 1 ⁇ of ethanol and comprising 5 ⁇ -hydroxy-6 ⁇ -[2-(1 H-imidazol-4 -yl)-ethylamino]-cholestan-3 ⁇ -yl propionate or 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -ol at 1, 2.5 or 5 ⁇ M .
  • the cells are observed under an inverted microscope and photographed via the microscope camera at 24 h and 48 h.
  • the white vesicles reflect cell death by cytotoxic autophagy; - Rounding cells indicate cell death;
  • the supernatant cells reflect cell death; and - Refractory cells reflect cell death.
  • a cell viability test is measured by MTT labeling at 48 hours. This test is based on the use of the tetrazolium salt MTT (bromide of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium). Tetrazolium is reduced by active living cell mitochondrial succinate dehydrogenase to formazan, a violet-colored precipitate. The quantity of precipitate formed is proportional to the quantity of living cells but also to the metabolic activity of each cell. Thus, a simple assay of the optical density at 540 nm by spectroscopy makes it possible to know the relative quantity of living and metabolically active cells.
  • the medium is aspirated, the cells washed with phosphate buffered saline (PBS) then incubated with MTT (0.5 mg/ml in PBS) for approximately 2 hours.
  • the MTT solution is aspirated and then the purple crystals are dissolved in dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • Figure 6 illustrates the ordinate of the percentage of cell viability compared to the control group.
  • the control group is made in a similar way to the groups studied without the addition of the molecules studied in this text.
  • a 5 ⁇ -hydroxy-6 ⁇ -[2-(1 H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -ethoxyl dose-dependent decrease in cell viability in MTT for 5 ⁇ -hydroxy is measured.
  • Example 21 Effect of the compound 5 ⁇ -hydroxy-6 ⁇ -[2-(1 H-imidazol-4-yl)-ethylamino1-cholestan-38-yl propionate or DX107 on the activity of Cholesterol Epoxide Hydrolase (ChEH ) in MCF-7 cells:
  • the compounds 5,6 ⁇ -epoxycholesterol (5,6 ⁇ -EC) and 5,6[3-epoxycholesterol (5,6 ⁇ -EC) are oxysterols implicated in the anticancer pharmacology of tamoxifen, a widely used antitumor drug. They are both metabolized to cholestane-3 ⁇ ,5 ⁇ ,6 ⁇ -triol (CT) by the enzyme cholesterol-5,6-epoxide hydrolase (ChEH), and CT is metabolized by the enzyme HSD11 B2 (1 ip-Hydroxysteroid dehydrogenase 2) to 6-oxo-cholestan-3 ⁇ ,5 ⁇ -diol (OCDO), a tumor-promoting oncosterone.
  • CT cholesterol-5,6-epoxide hydrolase
  • the following experiment aims to demonstrate the ability of the compound 5 ⁇ -hydroxy-6 ⁇ -[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3 ⁇ -yl propionate to block ChEH and therefore to limit the metabolism of oncosterone, a tumor promoting metabolite.
  • MCF-7 cells are in a cell culture medium identical to Example 20 and are seeded in 6-well plates at 150,000 cells per well with 3 wells per treatment condition. 24 h after seeding, the MCF-7 cells are treated with [ 14 C]5,6 ⁇ -EC (stock solution 1000X: 0.6 mM; 20 ⁇ Ci/ ⁇ mol; final concentration 0.6 ⁇ M) alone or in combination with Tamoxifen (tam) . Tamoxifen is used as a positive control for the compounds studied. The treatment with the compound according to the invention is carried out at a concentration of 1 ⁇ M.
  • lipid extracts are prepared from the cell pellets by extraction with 100 pL of chloroform, 400 pL of methanol and 300 ⁇ L of water. Lipid extracts are analyzed by thin layer chromatography (TLC) using ethyl acetate (EtOAc) as eluent. The analysis is carried out using a plate reader and then by autoradiography.
  • TLC thin layer chromatography
  • EtOAc ethyl acetate
  • Example 22 Study of the cytotoxicity of DX101 prodrugs on 4T1 cells
  • the culture medium consists of Dulbecco's Modified Eagle Medium (DMEM, marketed by Westburg under the reference LO BE12-604F), comprising 4.5 g/L Glucose with L-Glutamine, to which 10% serum is added. of fetal calf (FCS) and 50 U/mL penicillin/streptomycin.
  • DMEM Dulbecco's Modified Eagle Medium
  • FCS fetal calf
  • the 4T 1 cells are introduced into this culture medium.
  • 96-well dishes were seeded with 2,000 4T 1 cells per well. After 72 hours (h) of culture under normal conditions, i.e. in an incubator at a temperature of 37°C at 5% CO2, the 4T1 cells are treated for 48 hours with DX101, DX107, DX113, DX117, DX1 19, DX121 or DX131 at 100 nM, 1 ⁇ M, 2.5 ⁇ M and 10 ⁇ M.
  • a control condition (CTL) is also carried out in parallel using the protocol described previously without treatment with the molecules DX101, DX107, DX113, DX1 17, DX1 19, DX121, DX131 or DX133.
  • [190] Cell viability is measured by three different methods.
  • MTT labeling is carried out at 48 hours. This test is based on the use of the tetrazolium salt MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide). Tetrazolium is reduced by active living cell mitochondrial succinate dehydrogenase to formazan, a violet-colored precipitate. The quantity of precipitate formed is proportional to the quantity of living cells but also to the metabolic activity of each cell. Thus, a simple assay of the optical density at 550 nm by spectroscopy makes it possible to know the relative quantity of living and metabolically active cells.
  • the medium is aspirated, and the cells are incubated with MTT (0.5 mg/ml in culture medium) for about 3 hours.
  • MTT 0.5 mg/ml in culture medium
  • the MTT solution is aspirated and the purple crystals are dissolved in dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • the OD optical density
  • the percentage of viability is then determined in each well compared to the CTL and the IC 50 (concentration for which 50% of living cells remain) is determined for each molecule with the Prism software using a regression line nonlinear (log(inhibitor) vs. Response).
  • the percentage of viability is determined using the assay of the activity of the enzyme LDH (lactate dehydrogenase) in the cell supernatants using the non-radioactive cytotoxicity assay kit (Promega ).
  • LDH lactate dehydrogenase
  • LDH is an enzyme released in the supernatant of dead cells. The higher the LDH activity in the supernatant, the greater the cell death.
  • the released LDH converts a purple tetrazolium salt to a red-colored formazan, absorbing at 490 nm. The intensity of the red color is proportional to the number of dead cells.
  • the supernatants are transferred to a new 96-well plate and are incubated for 30 minutes in the presence of the substrate mix at room temperature.
  • the reaction is stopped using the stop buffer and the absorbance is determined at 490 nm.
  • the percentage of cell death is determined here using a 100% control of maximum LDH activity (made from untreated cells incubated in the presence of the lysis solution for 45 minutes at 37°C just before adding of the substrate mix), and the cell viability in each well is then deduced from this percentage.
  • the IC 50 is then determined as explained in the previous paragraph.
  • the percentage of viability is determined using the CelITox Green Cytotoxicity Assay kit (Promega). This test measures cell death via a change in membrane integrity. This test uses a cyanine-type probe which does not penetrate cells when they are alive, but which binds to the DNA of dead cells, making them permeable to the probe, causing it to fluoresce. Accordingly, the higher the fluorescence in the wells, the greater the cell death. After 48 hours of treatment, the cells are incubated for a minimum of 15 minutes in the presence of Celltox green reagent at room temperature and the fluorescence is read at ⁇ emission 485 nm/ ⁇ excitation 590 nm.
  • the percentage of cell death is determined using the 100% cell death control (made from untreated cells incubated in the presence of the lysis solution for 30 minutes at 37°C before adding the Celltox green reagent), and the cell viability in each well is then deducted from this percentage.
  • the IC 50 is then determined as explained above.
  • Example 23 Study of the cytotoxicity of DX101 prodrugs on BT-474 cells
  • BT-474 human mammary tumor cells characterized as being triple positive HER2+, ER+, PR+.
  • the BT-474 cells are in a cell culture medium identical to the previous example and are seeded in 24-well plates at 70,000 cells per well, for the determination of cell viability using Trypan blue, or in 96-well plates at 13,000 cells per well for determining cell viability using the MTT or LDH assay. After 96 hours (h) of culture under normal conditions, i.e.
  • the Biorad TC20 cell counting device counts the proportion of blue and non-blue cells, and reports the percentage of cells. The percentage of viability is then determined in each well relative to the untreated cells and the IC 50 is determined as explained in the preceding example. The results are shown in Table 2. Also, the percentage viability of BT-474 cells was determined using the MTT and LDH assay, performed as described in the previous example. The results are also shown in Table 2.
  • n b represents the number of independent tests with 4 to 10 replicates for each condition.
  • Example 24 Effect of prodrug DX107 on tumor growth in vivo
  • All animal procedures were conducted according to our institution's guidelines after being approved by the ethics committee.
  • 4T1 cells were cultured as before, and were dissociated in trypsin and washed twice in cold PBS and resuspended in 1.5 million/mL PBS.
  • 4T1 tumors were obtained by subcutaneous transplantation of 0.150 million cells in 100 ⁇ L into the flank of female Balb/c mice (9 weeks, January). When the tumors had reached a volume of 50-100 mm 3 , the mice were force-fed with 40 mg/kg of DX101 or 40 mg/kg of DX11 1 or of the control vehicle (water).
  • the treatment was carried out every day until the end of the experiment (tumor volume > 1000 mm 3 ).
  • the tumor volume was determined daily using a caliper and calculated using the formula: 1 /z X (Length * Width 2 ).
  • the percentage of tumor growth inhibition was determined according to the following formula: 100 X (1 - (Tumor volume, day 8 / tumor volume day 0) DX107 ) / (1- (tumor volume, day 8 / tumor volume day 0) vehicle ).
  • DX107 has a greater effect than DX101 in reducing tumor growth (***p ⁇ 0.001, one-way ANOVA test and Tukey's post-test). Tumor growth inhibition was further determined to be 78% for DX107-treated animals and 58% for DX101-treated animals.

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EP21819893.5A 2020-12-03 2021-12-03 PRODROGUE DU 5a-HYDROXY-6ß-[2-(1H-IMIDAZOL-4-YL)ETHYLAMINO]CHOLESTAN-3ß-OL ET COMPOSITIONS PHARMACEUTIQUES LE COMPRENANT POUR UTILISATION DANS LE TRAITEMENT DU CANCER Pending EP4255441A1 (fr)

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