WO2018076019A1 - Composés dérivés de l'ergot et leur utilisation dans la trypanosomiase africaine et les maladies associées - Google Patents

Composés dérivés de l'ergot et leur utilisation dans la trypanosomiase africaine et les maladies associées Download PDF

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WO2018076019A1
WO2018076019A1 PCT/US2017/057917 US2017057917W WO2018076019A1 WO 2018076019 A1 WO2018076019 A1 WO 2018076019A1 US 2017057917 W US2017057917 W US 2017057917W WO 2018076019 A1 WO2018076019 A1 WO 2018076019A1
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Prior art keywords
alkyl
group
compound
formula
infection
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PCT/US2017/057917
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English (en)
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Martin N. MARTINOV
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Far Biotech, Inc.
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Publication of WO2018076019A1 publication Critical patent/WO2018076019A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
    • C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8
    • 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
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • HAT Human African trypanosomiasis
  • Trypanosomiasis H AT
  • H AT Trypanosomiasis
  • the present disclosure includes but is not limited to pharmaceutical compositions and methods for the treatment of Trypanosoma infections in which the ergoline
  • compositions ate contemplated to be particularly useful in formulation of a medicament, preferably for use in the prevention or treatment of a Human African trypanosomiasis infection in a subject.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds, salts, solvates, stereoisomers, or prodrugs described above, and a pharmaceutically acceptable carrier.
  • the present disclosure provides a method of preventing or treating a Trypanosoma infection in a subject comprising administering an effective amount of a compound, salt, solvate, stereoisomer, or prodrugs described above, or the pharmaceutical compositions described above.
  • a pharmaceutically active molecule is disclosed herein.
  • Ri, R 2 , R4, R5, R 6 , Rs, R9, Rio, R11, Ri 2 , R15, R1 ⁇ 2, R17, Ris, R 2 i, R 22 , R 2 6 and R 2 are each independently selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • R 3 is selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • R is selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • Ri 3 and R14 are each independently selected from the group consisting of H, D, Ci-C 6 alkyl, F,
  • R19 and R 2 o are each selected from the group consisting of H, D, Ci-C 6 alkyl, -0-Ci-C 6 alkyl, F, CI, and Br;
  • R 23 is C, N or S
  • R 24 is CH, N, O, or S
  • R 25 is C, N, 0, or S
  • R 23 is N, then R 26 is not present
  • R 24 is O or S, then R is not present
  • R 3 ⁇ 4 is O, then Ri 3 and Ri 4 are not present, and wherein structure of formula II) is excluded:
  • Ri, R 2 , R4, R5, Re, Rs, R9, Rio, R11, Ri 2 , R15, R1 ⁇ 2, R17, Ris, R 2 i, R 22 , R 2 7 are each independently selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • R 3 is selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • R is selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • Ri 4 is selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • R19 and R 2 o are each selected from the group consisting of H, D, Ci-C 6 alkyl, -0-Ci-C 6 alkyl, F,
  • Ri, R 2 , R4, R5, R 6 , R 8 , R9, Rio, R11, Ri 2 , R15, R1 ⁇ 2, Ri , Ri 8 , R 21 , R 22 , R 2 are each independently selected from the group consisting of H, D, and d- C 6 alkyl.
  • R 3 is selected from the group consisting of CI, Br, and I.
  • R is selected from the group consisting of H, D, and Ci-C 6 alkyl.
  • R14 is selected from the group consisting of H, D, and Ci-C 6 alkyl.
  • R 2 o is selected from the group consisting of H, D, Ci-C 6 alkyl, and -0-Ci-C 6 alkyl.
  • a pharmaceutical composition is disclosed herein. In an embodiment of the disclosure,
  • composition a pharmaceutically acceptable carrier and a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof:
  • Ri, R 2 , R4, R5, R 6 , Rs, R9, Rio, R11, Ri 2 , R15, R1 ⁇ 2, R17, Ris, R 2 i, R 22 , R 2 6 and R 2 are each independently selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • R 3 is selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • R is selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • Ri 3 and R14 are each independently selected from the group consisting of H, D, Ci-C 6 alkyl, F,
  • R19 and R 2 o are each selected from the group consisting of H, D, Ci-C 6 alkyl, -0-Ci-C 6 alkyl, F, CI, and Br;
  • R 23 is C, N or S
  • R 24 is CH, N, O, or S
  • R 25 is C, N, 0, or S
  • R 23 is N, then R 26 is not present
  • R 24 is O or S, then R is not present
  • R 3 ⁇ 4 is O, then Ri 3 and Ri 4 are not present, and wherein structure of formula II) is excluded:
  • a method of treating a Trypanosoma infection in a subject in need thereof includes administering a therapeutically effective dosage of a compound having formula (I):
  • Ri, R 2 , R4, R5, R 6 , Rs, R9, Rio, R11, Ri 2 , R15, R1 ⁇ 2, R17, Ris, R 2 i, R 22 , R 2 6 and R 2 are each independently selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • R 3 is selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • R is selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • Ri 3 and R14 are each independently selected from the group consisting of H, D, Ci-C 6 alkyl, F,
  • R19 and R 2 o are each selected from the group consisting of H, D, Ci-C 6 alkyl, -0-Ci-C 6 alkyl, F, CI, and Br;
  • R 23 is C, N or S
  • R 24 is CH, N, O, or S
  • R 25 is C, N, 0, or S
  • R 23 is N, then R 26 is not present
  • R 24 is O or S, then R is not present
  • the compound of Formula (I) is a compound of Formula III):
  • Ri, R 2 , R4, R5, Re, Rs, R9, Rio, R11, Ri 2 , R15, R1 ⁇ 2, R17, Ris, R 2 i, R 22 , R 2 7 are each independently selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • R 3 is selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • R is selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • Ri4 is selected from the group consisting of H, D, Ci-C 6 alkyl, F, CI, Br, and I;
  • R19 and R 2 o are each selected from the group consisting of H, D, Ci-C 6 alkyl, -0-Ci-C 6 alkyl, F,
  • a metabolite thereof wherein the metabolite is selected from the group consisting of 10- methoxy-l,6-dimethylergoline-8P-methanol,l-hydroxymethyl-10-methoxy-6-methylergoine-8P- methanol, and 10-methoxy-6-methylergoline-8P-methanol.
  • the subject is a human or mammal.
  • the mammal is selected from the group consisting of a horse, dog, and cat.
  • the dosage is from about 1 mg to about 300 mg, including from about 1 mg to about 200 mg, including from about 5 mg to about 100 mg, including from about 10 mg to about 50 mg.
  • the dosage is applied from one to four times daily, including 1, 2, 3, and 4, for a period of from 1 to 12 weeks, including.
  • the dosage is applied for a first course of treatment, treatment is discontinued for a period of time, and the treatment is resumed for at least a second course of treatment.
  • the treatment is discontinued for a period of days, weeks, one month, two months, three months, or longer.
  • the compound is [(8P)-10-Methoxy-l,6-dimethylergolin-8-yl]methyl 5-bromonicotinate.
  • the compound is ((6aR,9R,10aS)-10a-methoxy-4,7-dimethyl- 4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-yl)methyl 5-bromonicotinate.
  • the Trypanosoma infection is a Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense infection.
  • a method of treating a Trypanosoma infection in a subject in need thereof includes administering a therapeutically effective dosage of a compound that is a metabolite of Nicergoline [((6aR,9R,10aS)-10a-methoxy-4,7-dimethyl- -octahydroindolo[4,3-fg]quinolin-9-yl)methyl 5-bromonicotinate]
  • the metabolite of Nicergoline includes 10-methoxy-l,6- dimethylergoline-8P-methanol (also called 1-MMDL), including
  • the present disclosure provides pharmaceutical compositions comprising : Nicergoline
  • Nicergoline's primary metabolites (10-methoxy- l,6-dimethylergoline-8P-methanol (1-MMDL), 1- hydroxymethyl- 10-methoxy-6-methylergoine-8P-methanol (1-OHMMDL), and 10-methoxy-6- nict h y lcrgo 1 i nc- 8 ⁇ - met ha no 1 (MDL), or their pharmaceutically acceptable acid addition salts including but not limited to such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid, and such organic acids as maleic acid, succinic acid and citric acid.
  • Other pharmaceutically acceptable salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium and magnesium, or with organic bases, such as dicyclohexylamine.
  • D as used in a chemical structure or formula refers to deuterium, which is an isotope of hydrogen.
  • C r C Pain alkyl refers to a hydrocarbon substituent group having 1-6 carbons, including methyl, ethyl, propyl, butyl, pentyl, and hexyl groups.
  • -0-CYC, alkyl refers to an ester of CVC, alkyl and could be called C,-C f , alkyl ester.
  • Suitable pharmaceutically acceptable salts of the compounds of the present disclosure include, for example, acid addition salts which may, for example, be formed by mixing a solution of the compound according to the disclosure with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fu marie acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. All of these salts may be prepared by conventional means by reacting, for example, the appropriate acid or base with the corresponding compounds of the present disclosure.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fu marie acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. All of these salts may be prepared by conventional means by reacting
  • Salts formed from free caiboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • organic bases such as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • the salts of the compounds of the present disclosure should be pharmaceutically acceptable salts.
  • Other salts may, however, be useful i the preparation of the compounds according to the disclosure or of their pharmaceutically acceptable salts.
  • embodiments of the disclosure include hydrates of the compounds of the present disclosure.
  • the term "hydrate” includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like. Hydrates of the compounds of the present disclosure may be prepared by contacting the compounds with water under suitable conditions to produce the hydrate of choice.
  • contacting means that the one or more compounds of the present disclosure are introduced into a sample having at least one Trypanosoma organism, including for example, Trypanosoma brucei, and appropriate enzymes or reagents, in a test tube, flask, tissue culture, chip, array, plate, microplate, capillary, or the like, and incubated at a temperature and time sufficient to permit binding of the at least one compounds of the present disclosure to interact with the organism.
  • Contacting can also refer to contacting human or animal bodily fluids either in vitro or in vivo.
  • compositions of the present disclosure comprise the compounds of the present disclosure together with a pharmaceutically acceptable carrier.
  • the present disclosure provides a method of treating a
  • Trypanosoma infection in a subject comprising administering to the subject, a pharmaceutical composition comprising at least one compound of the present disclosure suitable for use in treating a Trypanosoma infection, with a pharmaceutically acceptable carrier, in an effective amount to inhibit, suppress or treat symptoms of the Trypanosoma infection.
  • Trypanosoma infection means an infection of the subject with Trypanosoma brucei: Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense.
  • Embodiments of the disclosure include a process for preparing pharmaceutical products comprising the compounds, salts, solvates or stereoisomers thereof.
  • pharmaceutical product means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined herein.
  • Pharmaceutical compositions formulated for particular applications comprising the Trypanosoma inhibitors of the present disclosure are also part of this disclosure, and are to be considered an embodiment thereof.
  • the term “treat,” as well as words stemming therefrom, includes preventative as well as disorder remitative treatment.
  • the terms “reduce”, “suppress” and “inhibit,” as well as words stemming therefrom, have their commonly understood meaning of lessening or decreasing. These words do not necessarily imply 100% or complete treatment, reduction, suppression, or inhibition.
  • the pharmaceutically acceptable carrier can be any of those conventionally used, and is limited only by physico-chemical considerations, such as solubility and lack of reactivity with the active compound(s), and by the route of administration.
  • the pharmaceutically acceptable carriers described herein for example, vehicles, adjuvants, excipients, and diluents, are well known to those skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active agent(s), and one which has little or no detrimental side effects or toxicity under the condi tions of use.
  • the pharmaceutically acceptable carriers include soluble carriers such as known buffers which can be physiologically acceptable (e.g., phosphate buffer) as well as solid compositions such as solid-state carriers or latex beads.
  • the carriers or diluents used herein may be solid carriers or diluents for solid formulations, liquid carriers or diluents for liquid formulations, or mixtures thereof.
  • Solid carriers or diluents include, but are not limited to, gums, starches (e.g., corn starch, pregelatinized starch), sugars (e.g., lactose, mannitol, sucrose, dextrose), cellulosic materials (e.g., macrocrystalline cellulose), acrylates (e.g., polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
  • pharmaceutically acceptable carriers may be, for example, aqueous or non-aqueous solutions, suspensions, emulsions or oils.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.
  • Aqueous earners include, for example, water, alcoholic/aqueous solutions, cyclodextrins, emulsions or suspensions, including saline and buffered media.
  • oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, fish-liver oil, sesame oil, cottonseed oil, corn oil, olive, petrolatum, and mineral.
  • Suitable fatty acids for use in parenteral formulations include, for example, oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Parenteral vehicles for subcutaneous, intravenous, intraarterial, or intramuscular injection
  • parenteral vehicles include, for example, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
  • Formulations suitable for parenteral administration include, for example, aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and nonaqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservati ves.
  • Intravenous vehicles include, for example, fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like.
  • sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
  • water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • the compounds of the present disclosure may further comprise, for example, binders (e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g., cornstarch, potato starch, alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g., Tris- HC1, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g.
  • binders e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar
  • solubilizing agents e.g., cremophor, glycerol, polyethylene glycerol, benzlkonium chloride, benzyl benzoate, cyclodextrins, sorbitan esters, stearic acids
  • anti-oxidants e.g., ascorbic acid, sodium metabisuliite, butylated hydroxyanisole
  • stabilizers e.g., hydroxypropyl cellulose, hyroxypropylmethyl cellulose
  • viscosity increasing agents e.g., carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum
  • sweetners e.g., aspartame, citric acid
  • preservatives e.g., thimerosal, benzyl alcohol, parabens
  • lubricants e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lau
  • the choice of carrier will be determined, in part, by the particular compound, as well as by the particular method used to administer the compound. Accordingly, there are a variety of suitable formulations of the pharmaceutical composition of the disclosure.
  • the following formulations for parenteral, subcutaneous, intravenous, intramuscular, intraarterial, intrathecal and interperitoneal administration are exemplary, and are in no way limiting. More than one route can be used to administer the compounds of the present disclosure, and in certain instances, a particular route can provide a more immediate and more effective response than another route.
  • Suitable soaps for use i parenteral formulations include, for example, fatty alkali, metal, ammonium, and triethanolamine salts
  • suitable detergents include, for example, (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-(Vaminoptopionates.
  • the parenteral formulations will typically contain from about 0.5% to about 25% by weight of the compound of the present disclosure or a salt, solvate or stereoisomer thereof, in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants, for example, having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight.
  • HLB hydrophile-lipophile balance
  • Suitable surfactants include, for example, polyethylene glycol sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide wi th propylene glycol .
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
  • injectable formulations are in accordance with the disclosure.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well-known to those of ordinary skill i the art (see, e.g., Pharmaceutics and Pharmacy Practice, .I B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Trissel, 15th ed., pages 622-630 (2009)).
  • the amount or dose of the compound of the present disclosure, or a salt, solvate or stereoisomer thereof, administered should be sufficient to effect, e.g., a therapeutic or prophylactic response, in the subject over a reasonable time frame.
  • the dose will be determined by the efficacy of the particular compound and the condition of a human, as well as the body weight of a human to be treated.
  • the dose of the compound of the present disclosure also will be determined by the existence, nature and extent of any adverse side effects that might accompany the administration of a particular compound.
  • an attending physician will decide the dosage of the compound with which to treat each individual patient, taking into consideration a variety of factors, such as age, body weight, general health, diet, sex, compound to be administered, route of administration, and the severity of the condition being treated.
  • the dose of the compound can be about 0.001 to about 100 mg/kg body weight of the subject being treated/day.
  • the compound of the present disclosure can be modified into a depot form, such that the manner in which the compound is released into the body to which it is administered is controlled with respect to time and location within the body (see, for example, U.S. Patent No. 4,450,150).
  • Depot forms of compound can be, for example, an implantable composition comprising the compound and a porous or non-porous material, such as a polymer, wherein compound is encapsulated by or diffused throughout the material and/or degradation of the non-porous material.
  • the depot is then implanted into the desired location within the body and the compounds are released from the implant at a predetermined rate.
  • the compounds of the present disclosure, or salts, solvates or stereoisomers thereof, provided herein can be controlled release compositions, i.e., compositions in which the one or more compounds are released over a period of time after administration.
  • Controlled or sustained release compositions include formulation in lipophilic depots (e.g., fatty acids, waxes, oils).
  • the composition is an immediate release composition, i.e., a composition in which all or substantially all of the active compound is released immediately after administration.
  • the compounds of the present disclosure can be delivered in a controlled release system.
  • the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, or other modes of administration.
  • a pump may be used.
  • polymeric materials can be used.
  • a controlled release system can be placed in proximity to the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemi dose (see, e.g., Design of Controlled Release Drug Delivery Systems, Xiaoling Li and Bhaskara R. Jasti eds. (McGraw-Hill, 2006)).
  • the compounds of the present disclosure may also include incorporation of the active ingredients into or onto particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, hydrogels, etc., or onto liposomes, microemulsions, micelles, unilamellar- or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.
  • polymeric compounds such as polylactic acid, polyglycolic acid, hydrogels, etc.
  • liposomes such as polylactic acid, polyglycolic acid, hydrogels, etc.
  • microemulsions such as polylactic acid, polyglycolic acid, hydrogels, etc.
  • micelles such as unilamellar- or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.
  • Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance.
  • the compounds may be modified by, for example, the covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline.
  • water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or polyproline.
  • the modified compounds are known to exhibit substantially longer half-lives in blood following intravenous injection, than do the corresponding unmodified compounds.
  • Such modifications may also increase the compounds' solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, and greatly reduce the immunogenic! ty and reactivity of the compound.
  • the desired in vivo biological activity may be achieved by the administration of such polymer- compound abducts less frequently, or in lower doses than with the unmodified compound.
  • the present inventors discovered a drug, ready to be evaluated in humans for Trypanosoma elimination and identified several additional orally bioa variable lead molecules that inhibited the parasite in an in vitro test model.
  • Nicergoline is an ergot alkaloid derivative that has been clinically available since the 1970s. It has a broad spectrum of action: (1) as a al- adrenoceptor antagonist, it induces vasodilation and increases arterial blood flow; (2) it enhances cholinergic and catecholaminergic neurotransmitter function; (3) it inhibits platelet aggregation; (4) it promotes metabolic activity, resulting in increased utilization of oxygen and glucose; and (5) it has neurotrophic and antioxidant properties.
  • Nicergoline has been in clinical use for over three decades for conditions such as cerebral infarction, acute and chronic peripheral circulation disorders, vascular dementia, and Alzheimer's disease and has been found to be beneficial in a variety of other conditions. Nicergoline is used to treat senile dementia and other vascular conditions such as thrombosis and atherosclerosis, arterial blockages in the limbs, Raynaud's disease, vascular migraines, and retinopathy.
  • DFT Density Functional Theory
  • p(r) determines all ground-state properties of the entire system, including its chemical and biochemical features.
  • the starting point, ⁇ Si, Pi ⁇ . called a training set is a set of molecular structures Si for which a particular property of interest P has been measured.
  • every structure is reduced to some form, typically a list of real numbers ⁇ D j ) , which can be modeled statistically.
  • the second step actual modeling, attempts to find a model - a general mapping between property P and structure S through descriptors D. I successful, the model would have predictive power that can be applied to structures for which no measurement exists. Naturally, the predictive power of the model depends on the quality (accuracy, diversity, etc.) of the training set as well as descriptor properties and modeling architecture.
  • a straightforward machine-learning algorithm using fuzzy-logic decisions easily discovers the relationship between quantum components and specific interaction patterns.
  • the modeling algorithm produces a model in the form of a fuzzy decision tree.
  • Each tree node corresponds to a single descriptor (interaction constraint).
  • terminal nodes contain only either active or inactive molecules.
  • each terminal node is fully characterized statistically - if a molecule belongs to it, the prediction is qualified by associated confidence intervals and other statistical parameters.
  • a model in the form of a decision tree is easy to interpret.
  • Each tree path that contains an active terminal node also contains a set of nodes (quantum components) that define the interaction pattern common to all training-set molecules belonging to this terminal.
  • the fuzzy decision tree formalism can be generalized to more powerful fuzzy decision algorithms. Given a diverse training set of structures with known inhibition, the modeling effort produces a decision network characterizing all present interaction patterns in terms of activity-controlling descriptors, which can be visualized
  • T. brucei (bruceior rhodesiense) were seeded at 4 x 10 3 cells/mL in duplicate 24-well plates
  • GI50 compound concentration that inhibits T. brucei proliferation by 50%
  • T. brucei and HeLa cells In vitro culture of T. brucei and HeLa cells. Bloodstream form T. brucei CA427 strain were used for experiments. Parasites were seeded at a density of 2 x 10 3 cells/ml, and cultured in HMI-9 medium, containing 10% FBS, 10% Serum Plus (heat inactivated) and an antibiotic/antimycotic solution with a final concentration of 100 I.U./ml penicillin, 100 ug/ml streptomycin, 0.25 ug/ml Amphotericin B. The cultures was maintained in log phase growth (density ⁇ 10 6 /ml) under standard conditions (5% C02 and 37°C), and was subcultured every 1-2 days, by seeding Trypanosomas at 10 3 /ml.

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Abstract

La présente invention concerne un nouveau processus de calcul à base quantique pour la découverte et la conception de médicament, ledit processus ayant été utilisé pour identifier de nouvelles molécules thérapeutiques potentielles contre la malaria en phase hépatique. L'approche utilisée a combiné les avancées les plus récentes en termes de données massives dans le développement de dosage biologique à haut rendement avec des connaissances scientifiques fondamentales pour générer de nouvelles têtes de série pharmaceutiques. Plusieurs molécules d'indoloquinolines, y compris la nicergoline et des molécules structurellement associées, sans association précédente avec une activité anti-parasitaire ont été identifiées. Ces molécules et leur utilisation dans la prévention et/ou le traitement d'infections par Trypanosoma sont proposées.
PCT/US2017/057917 2016-10-21 2017-10-23 Composés dérivés de l'ergot et leur utilisation dans la trypanosomiase africaine et les maladies associées WO2018076019A1 (fr)

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CN115181090A (zh) * 2022-08-12 2022-10-14 青岛农业大学 二氢吲哚3,4并萘环骨架化合物的新用途及一种植物杀菌剂

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115093395A (zh) * 2022-08-12 2022-09-23 青岛农业大学 二氢吲哚3,4并萘环骨架化合物、其制备方法及应用
CN115181090A (zh) * 2022-08-12 2022-10-14 青岛农业大学 二氢吲哚3,4并萘环骨架化合物的新用途及一种植物杀菌剂

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