WO2018076019A1

WO2018076019A1 - Ergot derivative compounds and their use in african sleeping sickness and related disease

Info

Publication number: WO2018076019A1
Application number: PCT/US2017/057917
Authority: WO
Inventors: Martin N. MARTINOV
Original assignee: Far Biotech Inc
Current assignee: Far Biotech Inc
Priority date: 2016-10-21
Filing date: 2017-10-23
Publication date: 2018-04-26
Anticipated expiration: 2019-04-21

Abstract

A novel quantum-based computational process for drug discovery and design was used to identify potential novel liver-stage anti-malarial therapeutic molecules. The approach combined the latest big-data advances in high-throughput bioassay development with fundamental scientific knowledge to generate new pharmaceutical leads. Several indoloquinolines molecules, including nicergoline and structurally related molecules, with no previous association with anti- parasitical activity were identified. These molecules and there use in prevention and/or treatment of Trypanosoma infections are provided.

Description

ERGOT DERIVATIVE COMPOUNDS AND THEIR USE IN AFRICAN SLEEPING SICKNESS AND

RELATED DISEASE

BACKGROUND OF THE INVENTION

[0001] Human African trypanosomiasis ( HAT ), an infectious disease with a large global health burden occurring primarily in central and eastern Africa, is caused by Trypanosoma brucei sp. HAT is 100% fatal if untreated and the current drug therapies suffer from poor safety profiles, difficult treatment regimens, limited effectiveness, and high costs.

[0002] As Human African trypanosomiasis and related Trypanosoma infections are still a global health threat, there continues to exist a need for new and improved therapeutic agents to fight these diseases.

SUMMARY OF THE INVENTION

[0003] Chemical similarity is a central principle in ligand design, and extensive chemoinformatic studies explore multiple methods based on it. However, chemical structure alone does not provide adequate description of bio-molecular interactions, which ate quantum in nature. Through molecular modeling, molecules can be considered as quantum objects: quantum representation of their activity (biological, chemical or pharmacological), not the underlying structure itself, is important. The present inventor's quantum molecular representations exhibit well-defined mathematical characteristics, which afford systematic theoretical treatment and property prediction with methods that would otherwise be computationally impossible (Malar. J., 10:274 (2011); Chem. Biol. Drug Des., 80:810-820 (2012)). Specialized machine-learning algorithms with fuzzy decision-making protocols (Fuzzy Set Syst., 69:125-139 (1995)) are then applied for retrospective data analysis to identify both active compounds and the corresponding quantum features of chemical and biological interest. The modeling data consists either of high-throughput screens of structurally diverse compounds with measured activity (EC 0, IC50, Kd etc.) against the target or phenotype of interest, or of co-crystal structural data of the target and a modulator. Since structurally different entities can exhibit related quantum properties, the quantum representation of biological activity allows the identification of chemically dissimilar compounds, which are similar on a quantum level and vice versa.

[0004] I accordance with one or more embodiments the present inventor used new Human African

Trypanosomiasis (H AT) models based on experimental biochemical and phenotypic data on compounds in a Trypanosoma bioassay for identifying novel Trypanosomiasis drug candidates. [0005] accordance with an embodiment, the present disclosure includes but is not limited to pharmaceutical compositions and methods for the treatment of Trypanosoma infections in which the ergoline

( I ( 8β )- 10-methoxy- 1 ,6-dimethylergolin-8-yl | 5-bromopyridine-3-carboxylate), SMILES

STRUCTURE: CN1 CC(CC2(C1 CC3=CN(C4=CC=CC2=C34)C)OC)COC(=0)C5=CC(=CN=C5)Br; or a salt, solvate, stereoisomer, or prodrug thereof, as well as Nicergoline' s primary metabolites (10-methoxy-l,6- dimethylergoline-8P-methanol ( 1-MMDL), 1 -hydro xymethyl- 10-methoxy-6-methylergoine-8P- methanol (1-OHMMDL), and 10-methoxy-6-methylergoline-8P-methanol (MDL). The 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.

[0006] In accordance with another embodiment, the present disclosure provides a pharmaceutical composition comprising one or more compounds, salts, solvates, stereoisomers, or prodrugs described above, and a pharmaceutically acceptable carrier.

[0007] In accordance with an embodiment, 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. In an embodiment, A compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof:

Formula (I)

wherein

Ri, R₂, R4, R5, R₆, Rs, R9, Rio, R11, Ri₂, R15, R½, R17, Ris, R₂i, R₂₂, R₂6 and R₂ are each independently selected from the group consisting of H, D, Ci-C₆ alkyl, F, CI, Br, and I;

R₃ is selected from the group consisting of H, D, Ci-C₆ alkyl, F, CI, Br, and I;

R is selected from the group consisting of H, D, Ci-C₆ alkyl, F, CI, Br, and I;

Ri₃ and R14 are each independently selected from the group consisting of H, D, Ci-C₆ alkyl, F,

CI, Br, and I;

R19 and R₂o are each selected from the group consisting of H, D, Ci-C₆ alkyl, -0-Ci-C₆ alkyl, F, CI, and Br;

R₂₃ is C, N or S;

R₂₄ is CH, N, O, or S;

R₂₅, is C, N, 0, or S;

provided that if R₂₃ is N, then R₂₆ is not present;

provided that if R₂₄ is O or S, then R is not present;

provided that if R₂5 is N, then Ri₃ is not present;

provided that R_¾ is O, then Ri₃ and Ri₄ are not present, and wherein structure of formula II) is excluded:

wherein Ri, R₂, R4, R5, Re, Rs, R9, Rio, R11, Ri₂, R15, R½, R17, Ris, R₂i, R₂₂, R₂7 are each independently selected from the group consisting of H, D, Ci-C₆ alkyl, F, CI, Br, and I;

Ri₄ is selected from the group consisting of H, D, Ci-C₆ alkyl, F, CI, Br, and I;

R19 and R₂o are each selected from the group consisting of H, D, Ci-C₆ alkyl, -0-Ci-C₆ alkyl, F,

CI, and Br; and

wherein structure of formula II) is excluded:

Formula (II).

In an embodiment of the compound, Ri, R₂, R4, R5, R₆, R₈, R9, Rio, R11, Ri₂, R15, R½, Ri , Ri₈, R₂₁, R₂₂, R₂ are each independently selected from the group consisting of H, D, and d- C₆ alkyl. In an embodiment of the compound, R₃ is selected from the group consisting of CI, Br, and I. In an embodiment of the compound, R is selected from the group consisting of H, D, and Ci-C₆ alkyl. In an embodiment of the compound, R14 is selected from the group consisting of H, D, and Ci-C₆ alkyl. In an embodiment of the compound, R₂o is selected from the group consisting of H, D, Ci-C₆ alkyl, and -0-Ci-C₆ alkyl.

A pharmaceutical composition is disclosed herein. In an embodiment of the

pharmaceutical composition, a pharmaceutically acceptable carrier and a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof:

Formula (I)

wherein

CI, Br, and I;

R₂₃ is C, N or S;

R₂₄ is CH, N, O, or S;

R₂₅, is C, N, 0, or S;

provided that if R₂₃ is N, then R₂₆ is not present;

provided that if R₂₄ is O or S, then R is not present;

provided that if R₂5 is N, then Ri₃ is not present;

Formula (II).

A method of treating a Trypanosoma infection in a subject in need thereof is disclosed herein. In an embodiment, the method includes administering a therapeutically effective dosage of a compound having formula (I):

wherein

CI, Br, and I;

R₂₃ is C, N or S;

R₂₄ is CH, N, O, or S;

R₂₅, is C, N, 0, or S;

provided that if R₂₃ is N, then R₂₆ is not present;

provided that if R₂₄ is O or S, then R is not present;

provided that if R₂5 is N, then Ri₃ is not present; and

provided that R_¾ is O, then Ri₃ and Ri₄ are not present, or a metabolite thereof. In an embodiment of the method, the compound of Formula (I) is a compound of Formula III):

Formula (III)

Ri, R₂, R4, R5, Re, Rs, R9, Rio, R11, Ri₂, R15, R½, R17, Ris, R₂i, R₂₂, R₂7 are each independently selected from the group consisting of H, D, Ci-C₆ alkyl, F, CI, Br, and I;

Ri4 is selected from the group consisting of H, D, Ci-C₆ alkyl, F, CI, Br, and I; and

CI, and Br, or

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.

In an embodiment of the method, the subject is a human or mammal. In an embodiment of the method, the mammal is selected from the group consisting of a horse, dog, and cat. In an embodiment of the method, 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. In an embodiment of the method, 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. In an embodiment of the method, 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. In an embodiment of the method, the treatment is discontinued for a period of days, weeks, one month, two months, three months, or longer. In an embodiment of the method, the compound is [(8P)-10-Methoxy-l,6-dimethylergolin-8-yl]methyl 5-bromonicotinate. In an embodiment of the method, 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. In an embodiment of the method, the Trypanosoma infection is a Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense infection. In an embodiment of the method, a Trypanosoma infection targeting composition according to formula (I) or (III) for use as a medicine or medicament for treating a Trypanosoma infection or alleviating or reducing one or more of the symptoms of a Trypanosoma infection.

A method of treating a Trypanosoma infection in a subject in need thereof is disclosed herein. In an embodiment, the method 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]

In an embodiment of the method, the metabolite of Nicergoline includes 10-methoxy-l,6- dimethylergoline-8P-methanol (also called 1-MMDL), including

l-hydroxymethyl-10-methoxy-6-methylergoine-8P-methanol (also called 1- OHMMDL),

including

-methoxy-6-methylergoline-8P-methanol (also called MDL), including

DETAILED DESCRIPTION OF THE INVENTION

[0008] In accordance with an embodiment, the present disclosure provides pharmaceutical compositions comprising : Nicergoline

( I ( 8β )- 10-rnethoxy- 1.6-dimethyler^«olii>8-yl |methyl 5-bromopyridine-3-carboxylate), SMILES

STRUCTURE:

C 1 CC(CC2(C 1 CC3=CN(C =CC=CC2=C34)C)OC)COC(=0)C5=CC(=CN=C5)Br ; and

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 β- 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.

The term "D" as used in a chemical structure or formula refers to deuterium, which is an isotope of hydrogen.

The term "C_rC„ alkyl" refers to a hydrocarbon substituent group having 1-6 carbons, including methyl, ethyl, propyl, butyl, pentyl, and hexyl groups.

The term "-0-CYC, alkyl" refers to an ester of CVC, alkyl and could be called C,-C_f, alkyl ester.

[0009] 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.

[00010] 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. [00011] For use in medicines, 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.

[00012] In addition, 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.

[00013] As defined herein, in one or more embodiments, "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.

[00014] I an embodiment, the pharmaceutical compositions of the present disclosure comprise the compounds of the present disclosure together with a pharmaceutically acceptable carrier.

[00015] In a further embodiment, the present disclosure provides a method of treating a

Trypanosoma infection in a subject, the method 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.

[00016] It will be understood that the term "Trypanosoma infection" means an infection of the subject with Trypanosoma brucei: Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense.

[00017] Embodiments of the disclosure include a process for preparing pharmaceutical products comprising the compounds, salts, solvates or stereoisomers thereof. The term "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.

[00018] As used herein, 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.

[00019] With respect to pharmaceutical compositions described herein, 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. Examples of 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.

[00020] 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.

[00021] 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.

[00022] For liquid formulations, pharmaceutically acceptable carriers may be, for example, aqueous or non-aqueous solutions, suspensions, emulsions or oils. Examples of 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.

[00023] Examples of 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.

[00024] Parenteral vehicles (for subcutaneous, intravenous, intraarterial, or intramuscular injection) 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.

[00025] Intravenous vehicles include, for example, fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Examples are sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. In general, 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.

[00026] In addition, in an embodiment, 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. sodium lauryl sulfate), permeation enhancers, 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 lauryl sulfate), flow-aids (e.g., colloidal silicon dioxide), plasticizers (e.g., diethyl phthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g., ethyl cellulose, acrylates, polymethacrylates), and/or adjuvants.

[00027] 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.

[00028] Suitable soaps for use i parenteral formulations include, for example, fatty alkali, metal, ammonium, and triethanolamine salts, and 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. and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof. [00029] 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. 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 .

[00030] The 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. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.

[00031] 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)).

[00032] For purposes of the disclosure, 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.

[00033] The dose of the compound of the present disclosure, or a salt, solvate or stereoisomer thereof, also will be determined by the existence, nature and extent of any adverse side effects that might accompany the administration of a particular compound. Typically, 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. By way of example, and not intending to limit the disclosure, the dose of the compound can be about 0.001 to about 100 mg/kg body weight of the subject being treated/day.

[00034] Alternatively, the compound of the present disclosure, or a salt, solvate or stereoisomer thereof, 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.

[00035] In one embodiment, 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). In another embodiment 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.

[00036] In yet another embodiment, the compounds of the present disclosure can be delivered in a controlled release system. For example, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, or other modes of administration. In an embodiment, a pump may be used. In one embodiment, polymeric materials can be used. In yet another embodiment, 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)).

[00037] The compounds of the present disclosure, or salts, solvates or stereoisomers thereof, 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. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance.

[00038] In accordance with the present disclosure, 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. 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. As a result, 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. [00039] Using the quantum similarity modeling approach, 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.

[00040] The newly identified potential anti-HAT compound 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.

EXAMPLES

Quantum Comparison Methods

[00041] Structure representation - localized electron-density descriptors for molecular modeling:

Well-defined chemical subsystems, together with their associated local, spatially resolved properties, are very useful in drug discovery (Zartler, E., and M. Shapiro. 2008. Fragment-Based Drug Discovery. A Practical Approach. John Wiley & Sons). On a theoretical level, these properties serve as powerful descriptors for molecular modeling and design. Notions from Density Functional Theory and Topological Theory of Atoms i Molecules can be combined to rigorously define and compute a complete set of such localized, electron- density descriptors. In general, Non-Relativistic Quantum Mechanics (QM) provides the proper level of physical theory for treatment of molecular and bio-molecular systems. However, many intuitive chemical concepts are not directly related to the corresponding wave function, a state- vector in Hilbert space, which is difficult to partition into chemically meaningful subsystems (J Chem Phys 100:2900-2909 (1994)).

[00042] Density Functional Theory (DFT) provides a systematic framework for inferring chemistry- related information from QM calculations. This is achieved through the use of the electron density, p(r), a real, nonnegative Cartesian function connected to the N-electron molecular wave function ψ by

p(r) = / Ιψ(χ,χ1,..., xN-ll2dsdxl ... dxN-1 , where x={s, r} is the four-dimensional spin-spatial coordinate. As the famous Hohenberg- Kohn theorem shows, p(r) determines all ground-state properties of the entire system, including its chemical and biochemical features.

[00043] Furthermore, the Topological Theory of Atoms in Molecules ( AI )( Malta. C, and R. Boyd.

2007. The Quantum Theory of Atoms in Molecules. Wiley- VCH ) uses p(r) to partition molecules into precise atomic subsystems. These atomic subsystems are bounded by zero-flux surfaces S. which obey the equation where n(r) is the vector normal to S at r and p(r) is the corresponding electron density.

[00044] It is natural to combine DFT and AIM, together with their respective computational algorithms, in a single formalism for studying local molecular properties from first principles. This formalism has yielded meaningful interpretations of many general chemical concepts, such as energy partitioning, atomic softness, electronegativity equalization, atomic reactivity indices, etc. Augmented with the electrostatic potential, this electron density-based methodology has been applied to quantitative structure- activity relationship studies. It also produced the molecular descriptors employed in the modeling effort described here. Importantly, when applied as descriptors, these electron-density transforms define a proper metric (molecular similarity measure) in the modeling space, and allow the use of rigorous mathematical techniques.

[0057] Modelling architecture - fuzzy decision networks: Molecular modeling is a multistep

{Di,j(S), Pi}→P[D(S)].

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. In the first step, descriptor calculation, 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.

[00047] Both powerful descriptors and proper modeling architecture ate crucial for successful molecular modeling and compound discovery. Ideally, the modeling architecture should be chosen i accordance with the underlying fundamental processes of the system, and not with the type of available numerical data. Complex biochemical interactions involve local attributes of distinct and diverse molecular structures, which ate best modeled with discrete combinatorial methods rather than continuous multivariate techniques. Still, inherent weaknesses of traditional molecular descriptors require the use of such continuous multivariate techniques. As sophisticated as some of these techniques are, they cannot al ways compensate for the shortcomings of the underlying molecular-structure representations.

[00048] A straightforward machine-learning algorithm using fuzzy-logic decisions easily discovers the relationship between quantum components and specific interaction patterns. In its simplest implementation, the modeling algorithm produces a model in the form of a fuzzy decision tree. Each tree node corresponds to a single descriptor (interaction constraint). In a fully resolved decision tree, terminal nodes contain only either active or inactive molecules. Furthermore, 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

Nicergoline in vitro assay testing.

[00049] T. brucei (bruceior rhodesiense) were seeded at 4 x 10³ cells/mL in duplicate 24-well plates

(0.5 or 1 mL of culture per well). Cells were incubated for 48 h with 1 or 2 μ L of DMSO (vehicle control) or compound solution in DMSO (at least five final concentrations). The five concentrations used were determined empirically as follows. Trypanosomas were first treated with the following concentrations of drug: 10 μΜ, 1 μΜ, 100 nM, 10 nM, and 1 nM. Cell density was determined with a hemocytometer after 48 h. Mean cell counts were plotted against compound concentration and the GI50 (compound concentration that inhibits T. brucei proliferation by 50%) was determined by fitting curves to the data using GraphPad Prism. Final mean GI50 values were calculated based on two independent experiments.

[00050] 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 10³ 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 < 10⁶/ml) under standard conditions (5% C02 and 37°C), and was subcultured every 1-2 days, by seeding Trypanosomas at 10³/ml.

[00051] Nicergoline inhibited proliferation of T. brucei with GI50 = 6 μ M.

Claims

Claims What is claimed is:

1. A compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof:

Formula (I)

wherein

Ri₃ and R₁₄ are each independently selected from the group consisting of H, D, Ci-C₆ alkyl, F, CI, Br, and I;

R₁₉ and R₂o are each selected from the group consisting of H, D, Ci-C₆ alkyl, -0-Ci-C₆ alkyl, F, CI, and Br;

R₂₃ is C, N or S;

R₂₄ is CH, N, O, or S;

R₂₅, is C, N, 0, or S; provided that if R₂₃ is N, then R₂₆ is not present;

provided that if R₂₄ is O or S, then R is not present;

provided that if R₂5 is N, then Ri₃ is not present;

provided that R_¾ is O, then Ri₃ and Ri₄ are not present, and

wherein structure of formula II) is excluded:

Formula (II).

2. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (III):

wherein

Ri, R₂, R4, R5, R₆, Rs, R9, Rio, R11, Ri₂, R15, R½, R17, Ris, R₂i, R₂₂, R₂7 are each independently selected from the group consisting of H, D, Ci-C₆ alkyl, F, CI, Br, and I;

R19 and R₂o are each selected from the group consisting of H, D, Ci-C₆ alkyl, -0-Ci-C₆ alkyl, F, CI, and Br; and

wherein structure of formula (II) is excluded:

3. The compound of claim 2, wherein Ri, R₂, R4, R5, R₆, Rs, R9, Rio, R11, R12, R15, R16, Ri , Ri8, R21, R22, R27 are each independently selected from the group consisting of H, D, and d- C₆ alkyl.

4. The compound of claim 2, wherein R₃ is selected from the group consisting of CI, Br, and I.

5. The compound of claim 2, wherein R is selected from the group consisting of H, D, and

Ci-C₆ alkyl.

6. The compound of claim 2, wherein R14 is selected from the group consisting of H, D, and

Ci-C₆ alkyl.

7. The compound of claim 2, R₂o is selected from the group consisting of H, D, Ci-C₆ alkyl, and -O-Ci-Ce alkyl.

8. A pharmaceutical composition comprising the compound of claim 1 or a salt, solvate, stereoisomer, or prodrug thereof, and

a pharmaceutically acceptable carrier.

9. A method of treating a Trypanosoma infection in a subject in need thereof, comprising: administering a therapeutically effective dosage of a compound having formula

(I):

Formula (I) wherein

Ri₃ and R14 are each independently selected from the group consisting of H, D, Ci-C₆ alkyl, F, CI, Br, and I; Ri9 and R₂o are each selected from the group consisting of H, D, Ci-C₆ alkyl, -0-Ci-C₆ alkyl, F, CI, and Br;

R₂₃ is C, N or S;

R₂₄ is CH, N, O, or S;

R₂₅, is C, N, 0, or S;

provided that if R₂₃ is N, then R₂₆ is not present;

provided that if R₂₄ is O or S, then R is not present;

provided that if R₂5 is N, then Ri₃ is not present; and

provided that R_¾ is O, then Ri₃ and Ri₄ are not present, or a metabolite thereof.

10. The method of claim 9, wherein the compound of Formula (I) is a compound of Formula (III):

Ri, R₂, R^, R₅, R₆, R₈, R9, Rio, Rii, Ri₂, Ris, R½, Rn, Ris, R₂i, R₂₂, R₂7 are each independently selected from the group consisting of H, D, Ci-C₆ alkyl, F, CI, Br, and I;

Ri₄ is selected from the group consisting of H, D, Ci-C₆ alkyl, F, CI, Br, and I; and Ri9 and R₂o are each selected from the group consisting of H, D, Ci-C₆ alkyl, -0-Ci-C₆ alkyl, F, CI, and Br, or

a metabolite thereof, wherein the metabolite is selected from the group consisting of 10-methoxy-l,6-dimethylergoline-8P-methanol, 1 -hydro xymethyl-10-methoxy-6- methy lergo ine- 8 β- methano 1, and 10- methoxy- 6- methylergo line- 8 β- methano 1.

11. The method of claim 9, wherein the subject is a human or mammal.

12. The method of claim 11, wherein the mammal is selected from the group consisting of a horse, dog, and cat.

13. The method of claim 9, wherein the dosage is from about 1 mg to about 300 mg.

14. The method of claim 9, wherein the dosage is applied from one to four times daily for a period of from 1 to 12 weeks.

15. The method of claim 9, wherein 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.

16. The method of claim 15, wherein the treatment is discontinued for a period of days, weeks, one month, two months, three months, or longer.

17. The method of claim 9, wherein the compound is [(8P)-10-Methoxy-l,6- dimethy lergolin- 8 - y 1] methyl 5 -bro monico tinate .

18. The method of claim 9, wherein 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.

19. The method of claim 1, wherein the Trypanosoma infection is a Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense infection.

20. A Trypanosoma infection targeting composition according to claim 1 or 2 for use as a medicine or medicament for treating a Trypanosoma infection or alleviating or reducing one or more of the symptoms of a Trypanosoma infection.

21. A pharmaceutical combination comprising the compound of any one of claims 1 to 7 and, and a further therapeutically effective compound.

22. A method of treating Trypanosome infection in a subject indeed thereof, comprising administering a therapeutically effective dosage of the compounds of the combination according to claim 21.

23. A pharmaceutical combination of claim 21 for use as a medicine for treating

Trypanosome infection or alleviating or reducing one or more of the symptoms of Trypanosome infection.