WO2022128746A1 - Quinoline derivatives as endoparasiticides - Google Patents

Quinoline derivatives as endoparasiticides Download PDF

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Publication number
WO2022128746A1
WO2022128746A1 PCT/EP2021/085059 EP2021085059W WO2022128746A1 WO 2022128746 A1 WO2022128746 A1 WO 2022128746A1 EP 2021085059 W EP2021085059 W EP 2021085059W WO 2022128746 A1 WO2022128746 A1 WO 2022128746A1
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Prior art keywords
compound
salt
formula
compounds
propan
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PCT/EP2021/085059
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French (fr)
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Francois Pautrat
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Elanco Tiergesundheit Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P5/00—Nematocides

Definitions

  • the present invention relates to medicinal chemistry, pharmacology, and veterinary and human medicine. More particularly, the present invention relates to compounds of formula (I) and their use in the control of endoparasites, for example heartworms, in warmblooded animals.
  • Heartworm (Dirofilaria immili.s) is a parasitic roundworm that is spread from host to host through the bites of mosquitoes. The lifecycle starts when a female mosquito takes a blood meal from an infected host. The mosquito ingests immature heartworms which then molt to the infective larvae stage and travel to the mosquitoes’ mouth parts. The mosquito then feeds on a susceptible host, such as a dog or cat, depositing the infective larvae. The larvae then molt to the next larval stage in the new host and then migrate through the body, eventually ending up in the blood vessels. As the larvae migrate through the tissues they molt into juvenile adults. The juvenile adults eventually move into the blood vessels of the lungs where they mature into sexually active adults. The adult heartworms then breed and release immature heartworms completing the cycle. Heartworm infection may result in serious disease for the host.
  • a susceptible host such as a dog or cat
  • Y is CH or N
  • Ri is H or Cl; or a salt thereof.
  • the disclosed compounds show superior properties relative to other compounds. Outside the claimed substitution pattern, equipotent compounds (as antifungal or in vitro anthelmintic) fail to work as antifilarial in vivo (rodent) and even fail to work in dogs at a relevant dose.
  • the chloro-substituted quinolyn seems crucial to reach metabolic stability while retaining in vitro potency (Example C). If substituted-quinolyn is replaced by an unsubstituted quinolyn, in vivo antifilarial efficacy is lost in antifilarial rodent models (Example B). If the quinolyn bromo-substitution is replaced by CCH, tolerability events are observed in mammals.
  • the disclosed (-) enantiomers are significantly more active than the corresponding (+) enantiomers.
  • the present invention also provides compositions, comprising: a compound of formula (I) or a salt thereof and an acceptable excipient, the composition optionally further comprising at least one additional active compound.
  • the present invention also provides a method for treating parasites, comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.
  • the present invention also provides a method for controlling parasites, comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.
  • the present invention also provides a method for treating or controlling parasites, comprising: contacting a subject’s environment with an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.
  • the invention provides for the use of the compounds of the invention as a medicament, including for the manufacture of a medicament.
  • the invention provides the manufacture of a medicament comprising a compound of formula (I) or a salt thereof for treating parasites.
  • the invention provides the manufacture of a medicament comprising a compound of formula (I) or a salt thereof for controlling parasites.
  • the present invention also provides processes from making compounds of the invention and intermediates thereof.
  • acceptable excipient refers to refers to those typically used in preparing veterinary and pharmaceutical compositions and should be pure and non-toxic in the amounts used. They generally are a solid, semi-solid, or liquid material which in the aggregate can serve as a vehicle or medium for the active ingredient.
  • excipients include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and others.
  • administering to a subject includes but is not limited to cutaneous, subcutaneous, intramuscular, mucosal, submucosal, transdermal, oral or intranasal administration. Administration could include injection or topical administration.
  • compounds of the invention and “a compound of the invention” and “compounds of the present invention” and a like include the embodiment of formula (I) and the other more particular embodiments encompassed by formula (I) described herein and the exemplified compounds described herein and a salt of each of these embodiments.
  • control refers to include without limitation decreasing, reducing, or ameliorating the risk of a symptom, disorder, condition, or disease, and protecting an animal from a symptom, disorder, condition, or disease.
  • Controlling may refer to therapeutic, prophylactic, or preventative administration. It is well understood that a larvae or immature heartworm infection may be asymptomatic and infection by mature parasites is symptomatic and/or debilitating. Therefore, for example, a heartworm infection would be controlled by acting on the larvae or immature parasite preventing the infection from progressing to an infection by mature parasites.
  • the term “effective amount” refers to an amount which gives the desired benefit to the subject and includes administration for both treatment and control. The amount will vary from one individual subject to another and will depend upon a number of factors, including the overall physical condition of the subject and the severity of the underlying cause of the condition to be treated, concomitant treatments, and the amount of compound of the invention used to maintain desired response at a beneficial level.
  • an effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
  • the dose a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific condition, disorder, infection, or disease involved; the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • An effective amount of the present invention, the treatment dosage is expected to range from 0.5 mg to 100 mg.
  • Specific amounts can be determined by the skilled person. Although these dosages are based on a subject having a mass of about 1 kg to about 20 kg, the diagnostician will be able to determine the appropriate dose for a subject whose mass falls outside of this weight range.
  • An effective amount of the present invention, the treatment dosage is expected to range from 0.1 mg/kg to 10 mg/kg of the subject.
  • the dosing regimen is expected to be daily, weekly, or monthly administration.
  • salt refers to salts of veterinary or pharmaceutically acceptable organic acids and bases or inorganic acids and bases. Such salts are well known in the art and include those described in Journal of Pharmaceutical Science, 66, 2-19 (1977). An example is the hydrochloride salt.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for about a week.
  • subject and “patient” refers includes humans and non-human mammalian animals, such as dogs, cats, mice, rats, guinea pigs, rabbits, ferrets, cows, horses, sheep, goats, and pigs. It is understood that a more particular subject is a human. Also, a more particular subject are mammalian pets or companion animals, such as dogs and cats and also mice, guinea pigs, ferrets, and rabbits.
  • substituted refers to one or more hydrogen radicals of a group being replaced with non-hydrogen radicals (substituent(s)). It is understood that the substituents may be either the same or different at every substituted position. Combinations of groups and substituents envisioned by this invention are those that are stable or chemically feasible. For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • treating include without limitation restraining, slowing, stopping, reducing, ameliorating, reversing the progression or severity of an existing symptom, or preventing a disorder, condition, or disease.
  • an adult heartworm infection would be treated by administering a compound of the invention.
  • a treatment may be applied or administered therapeutically.
  • Y is CH or N
  • Ri is H or Cl; or a salt thereof.
  • Y is CH. In another embodiment, Y is CH and Ri is H. In another embodiment, Y is CH and Ri is Cl.
  • Y is N. In another embodiment, Y is N and Ri is H. In another embodiment, Y is N and Ri is Cl.
  • a compound of the invention has formula (la), or a salt thereof,
  • a compound of the invention has formula (la- 1), or a salt thereof,
  • a compound of the invention has formula (la-2), or a salt thereof,
  • a compound of the invention has formula (lb), or a salt thereof,
  • a compound of the invention has formula (lb- 1), or a salt thereof,
  • a compound of the invention has formula (Ib-2), or a salt thereof,
  • a compound of the invention has formula (Ic), or a salt thereof,
  • a compound of the invention has formula (Ic-1), or a salt thereof,
  • a compound of the invention has formula (Ic-2), or a salt thereof,
  • a compound of the invention is selected from group consisting of: (-) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyrimidin-2-yl)propan-2- yl)butanamide; (+) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyrimidin-2-yl)propan-2- yl)butanamide; (-) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyridin-2-yl)propan-2- yl)butanamide; (+) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyridin-2-yl)propan-2- yl)butanamide; (+) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyridin
  • a compound of the invention is selected from group consisting of: (S)-2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyrimidin-2-yl)propan-2- yl)butanamide; (7?)-2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyrimidin-2-yl)propan-2- yl)butanamide; (S)-2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyridin-2-yl)propan-2- yl)butanamide; (7?)-2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyridin-2-yl)propan-2- yl)butanamide; (S)-2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-
  • Compounds of the invention also include all isotopic variations, in which at least one atom of the predominant atom mass is replaced by an atom having the same atomic number, but an atomic mass different from the predominant atomic mass.
  • Use of isotopic variations e.g., deuterium, 2 H
  • certain isotopic variations of the compounds of the invention may incorporate a radioactive isotope (e.g., tritium, 3 H, or 14 C), which may be useful in drug and/or substrate tissue distribution studies.
  • Substitution with positron emitting isotopes, such as n C, 18 F, 15 O and 13 N may be useful in Positron Emission Topography (PET) studies.
  • PET Positron Emission Topography
  • Scheme 1 depicts an exemplary process for preparing compounds of formula (I).
  • a compound of formula (a) may undergo substitution reaction with a compound of formula (b) under basic conditions to provide an ester compound of formula (c).
  • the term “LV” in compounds of formula (b) refers to a leaving group, any molecular moiety that departs with a pair of electrons in hydrolytic bond cleavage.
  • a leaving group may include, but is not limited to, a halide (i.e., fluoride, chloride, bromide, or iodide), a tosyl group (i.e., p-toluenesulfonyl), a methanesulfonyl group (i.e., CH3SO2-), a trifluoromethanesulfonyl group (i.e., CF3SO2-), and a trifluoroacetate group (i.e., CF3CO2-), among others.
  • the compound of formula (c) may undergo hydrolysis under basic conditions to provide the carboxylic acid compound of formula (d).
  • the compound of formula (d) may be coupled with the amine compound of formula (e) to provide amide compounds of formula (I).
  • Standard amide forming conditions can be used, such as those using coupling agents, including those used in peptide couplings, such as 2-(lH-7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU), dicyclohexylcarbodiimide (DCC), and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide-HCl.
  • coupling agents including those used in peptide couplings, such as 2-(lH-7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU), dicyclohexylcarbodiimide (DCC), and l-(3- dimethyla
  • an additive such as 4-(dimethylamino)pyridine, 1 -hydroxybenzo triazole, and the like may be used to facilitate the reaction.
  • Such reactions are generally carried out using a base, such as N,N- Diisopropylethylamine, N-methylmorpholine, NEts, in a wide variety of suitable solvents such as CH2CI2, DMF, DMA, THF, and the like.
  • Chiral chromotography may be used to provide the desired enantiomer of the compound of formula (I).
  • Use of chiral intermediates can deliver final desired chiral compound without need of chiral chromatography.
  • the products of each step can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like.
  • the procedures may require protection of certain groups, for example hydroxyl, thiol, amino, or carboxyl groups to minimize unwanted reactions.
  • the selection, use, and removal of protecting groups are well known and appreciated as standard practice, for example T.W. Greene and P. G. M. Wuts in Protective Groups in Organic Chemistry (John
  • Scheme 2 depicts another exemplary process for preparing compounds of formula
  • the compounds of the invention can be administered alone or in the form of a composition.
  • the compounds of the invention are usually administered in the form of compositions, that is, in admixture with at least one acceptable excipient.
  • the proportion and nature of any acceptable excipient(s) are determined by the properties of the selected compound of the invention, the chosen route of administration, and standard practice as in the veterinary and pharmaceutical fields.
  • the present invention also provides compositions, comprising a compound of formula (I) or a salt thereof and an acceptable excipient, the composition optionally further comprising at least one additional active compound.
  • compositions of the invention may be administered to the subject, for example, in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, drenches, solutions, and suspensions.
  • the composition is adapted for oral administration, such as a tablet or a capsule or a liquid formulation, for example, a solution or suspension, adapted for oral administration.
  • the composition is adapted for oral administration, such as chewable formulation, adapted for oral administration.
  • the composition is a liquid or semi-solid formulation, for example, a solution or suspension or a paste, adapted for parenteral administration.
  • compositions for usage on subjects in the treatment and/or control of nematodes/ helminths comprise solutions; emulsions including classical emulsions, microemulsions and self-emulsifying compositions, that are waterless organic, preferably oily, compositions which form emulsions, together with body fluids, upon addition to the subject’s body; suspensions (drenches); pour-on formulations; food additives; powders; tablets including effervescent tablets; boli; capsules including micro-capsules; and chewable treats.
  • Particularly composition forms are tablets, capsules, food additives or chewable treats.
  • Compounds of the invention and compositions thereof can be administered in any form and route which makes the compound bioavailable.
  • the compounds of the invention can be administered by a variety of routes, including orally, in particularly by tablets and capsules.
  • the compounds of the invention can be administered parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, intraarterially, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intraadipo sally, intrathecally and via local delivery for example by catheter or stent.
  • compositions of the present invention are prepared in a manner well known in the veterinary and pharmaceutical art and include at least one of the compounds of the invention as the active ingredient.
  • the amount of a compound of the present invention may be varied depending upon its particular form and may conveniently be between 1% to about 50% of the weight of the unit dose form.
  • the present pharmaceutical compositions are preferably formulated in a unit dose form, each dose typically containing from about 0.5 mg to about 100 mg of a compounds of the invention.
  • One or more unit dose form(s) may be taken to affect the treatment dosage.
  • the compounds of formula (I) of the present invention are useful for the treatment and/or control, in particular helminths, in which the endoparasitic nematodes and trematodes may be the cause of serious diseases of mammals and poultry.
  • Typical nematodes of this indication are: Filariidae, Setariidae, Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostonum, Oesophagostonum, Charbertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris ncylosloma. Uncinaria, Toxascaris and Parascaris.
  • the trematodes include, in particular, the family of Fasciolideae, especially Fasciola hepatica.
  • a particularly notable parasite is the heartworm of the dog, Dirofilaria iminitis.
  • the parasites which may be treated and/or controlled by the compounds of formula (I) also include those from the class of Cestoda (tapeworms), e.g. the families Mesocestoidae, especially of the genus Mesocestoides, in particular M.
  • the compounds of formula (I) are suitable for the treatment and/or control of human pathogenic parasites.
  • typical representatives that appear in the digestive tract are those of the genus Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris and Enterobius.
  • the compounds of the present invention are also against parasites of the genus Wuchereria, Brugia, Onchocerca and Loa from the family of Dracunculus and parasites of the genus Strongyloides and Trichinella, which infect the gastrointestinal tract in particular.
  • a particular parasite to be treated and/or and controlled by the compounds of the invention is the heartworm (Dirofilaria immilis). Particular subjects for such treatment are dogs and cats.
  • the present invention also provides a method for treating parasites, comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.
  • the present invention also provides a method for controlling parasites, comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.
  • the present invention also provides a method for treating or controlling parasites, comprising: contacting a subject’s environment with an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.
  • the invention provides for the use of the compounds of the invention as a medicament, including for the manufacture of a medicament.
  • the invention provides the manufacture of a medicament comprising a compound of formula (I) or a salt thereof for treating parasites.
  • the invention provides the manufacture of a medicament comprising a compound of the invention or a salt thereof for controlling parasites.
  • a compound of the invention can be administered in any form and route which makes the compound bioavailable.
  • the compounds of the invention can be administered by a variety of routes, including orally, in particularly by tablets and capsules.
  • the compounds of the invention can be administered parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, intraarterially, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intraadipo sally, intrathecally and via local delivery for example by catheter or stent.
  • compositions of the invention may be administered to the subject, for example, in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, drenches, solutions, and suspensions.
  • the compounds of the invention may be combined with one or more other active compounds or therapies for the treatment of one or more disorders, diseases or conditions, including the treatment of parasites, for which it is indicated.
  • the compounds of the invention may be administered simultaneously, sequentially or separately in combination with one or more compounds or therapies for treating parasites and other disorders.
  • a compound of the invention when used to treat parasites, including heartworm, may be combined with a macrocyclic lactone such as ivermectin, moxidectin, or milbemycin oxime, or with imidacloprid.
  • a macrocyclic lactone such as ivermectin, moxidectin, or milbemycin oxime
  • imidacloprid particularly combinations for treating parasites include a compound of the invention and ivermectin.
  • Another particular combination for treating parasites include a compound of the invention and milbemycin oxime.
  • compositions and methods of the present invention optionally include comprising an effective amount of at least one additional active compound.
  • activity of compounds as parasiticides may be determined by a variety of methods, including in vitro and in vivo methods.
  • H. contortus nematode Larval Development Assay (He LDA): Freshly harvested and cleaned nematode Haemonchus contortus eggs are used to seed a suitably formatted well plate containing the test substances to be evaluated for antiparasitic activity and media allowing the full development of eggs through to third instar larvae. The plates are incubated for 6 days at 25°C and 60% relative humidity. Egg-hatching and ensuing larval development are recorded to identify a possible nematodicidal activity. Efficacy is expressed in percent reduced egg hatch, reduced development of L3, or paralysis & death of larvae at any stage.
  • Av model Gerbils, injected subcutaneously with infective A. viteae larvae, were subsequently treated with the test article formulated in eg DMSO/PEG 2/1, by oral gavage at a dose of 16 mg/kg (once a day for 5 consecutive days). At necropsy 12 weeks after infection, efficacy is expressed as a % reduction in worm numbers in comparison with the placebo treated group, using the Abbot’s formula.
  • the compounds of Examples 1 & 2 showed respectively 95 and 100% efficacy.
  • CAS RN1450836-43-7 of WO/2013/ 122041 (compound 2.1 p.59) showed no relevant efficacy at 32mg/kg. This result highlights an unexpected superiority of the disclosed substituted quinolynyls in rodent as antifilarials.
  • Examples 1 & 2 showed circulating concentration in dog’s bloodstream treated at 3mg/kg orally of more than lOOOng/ml after 12h.
  • substance CAS RN 1401524-78-4 compound 9 page 41 of WO/2012/130917 showed less than 20ng/ml.
  • This result highlights unexpected ADME properties in dogs for chlorosubstituted quinolyns & ethyl central core.
  • the substitution pattern with acetals, such as CAS RN 1401524-83-1 were not investigated because of related high risks of chemical stability.

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Abstract

The present invention provides compounds of formula (I), which are useful in the control of endoparasites, for example heartworms, in warm-blooded animals.

Description

QUINOLINE DERIVATIVES AS ENDOPARASITICIDES
TECHNICAL FIELD
[0001] The present invention relates to medicinal chemistry, pharmacology, and veterinary and human medicine. More particularly, the present invention relates to compounds of formula (I) and their use in the control of endoparasites, for example heartworms, in warmblooded animals.
BACKGROUND
[0002] Heartworm (Dirofilaria immili.s) is a parasitic roundworm that is spread from host to host through the bites of mosquitoes. The lifecycle starts when a female mosquito takes a blood meal from an infected host. The mosquito ingests immature heartworms which then molt to the infective larvae stage and travel to the mosquitoes’ mouth parts. The mosquito then feeds on a susceptible host, such as a dog or cat, depositing the infective larvae. The larvae then molt to the next larval stage in the new host and then migrate through the body, eventually ending up in the blood vessels. As the larvae migrate through the tissues they molt into juvenile adults. The juvenile adults eventually move into the blood vessels of the lungs where they mature into sexually active adults. The adult heartworms then breed and release immature heartworms completing the cycle. Heartworm infection may result in serious disease for the host.
[0003] Adult heartworm infections may be treated with arsenic-based compounds; the treatment is time consuming, cumbersome, and often only partly successful. Accordingly, treatment is focused on the control of heartworm infection. Heartworm control is currently performed exclusively by year round periodical administration of drugs. Typical treatments include macrocyclic lactones such as ivermectin, moxidectin, and milbemycin oxime. Unfortunately, developing resistance of Dirofilaria immitis to macrocyclic lactones has been observed. Accordingly, there is a need for new compounds which effectively control heartworm infections either by way of prophylaxis or by directly killing heartworms.
[0004] Certain compounds are disclosed in W02006058700; W02008110355; W02009030467; W02009030469; W02009087098; W02012050041; WO2012130798; W02012130917; W02013122041; WO2014044642; W02014048940; W02014130409; WO2015147022; WO2015163280; WO2016013633; WO2017069154; AR102278A1;
Lamberth et al., Bioorganic & Medicinal Chemistry, Vol. 22, No. 15, 1 Aug 2014, pages 3922-3930; Beaudegnies et al., Bioorganic & Medicinal Chemistry, Vol. 24, No. 3, 1 Feb 2016, pages 444-452; Kessabi et al., Synlett, Vol. 27, No. 9, 2016, pages 1375-1378; and Kessabi et al., Tetrahedron Letters, Vol. 57, No. 49, Dec 2016, pages 5511-5513.
DETAILED DESCRIPTION
[0005] The present invention provides compounds of formula (I),
Figure imgf000003_0001
wherein
Y is CH or N; and
Ri is H or Cl; or a salt thereof.
[0006] The disclosed compounds show superior properties relative to other compounds. Outside the claimed substitution pattern, equipotent compounds (as antifungal or in vitro anthelmintic) fail to work as antifilarial in vivo (rodent) and even fail to work in dogs at a relevant dose. The chloro-substituted quinolyn seems crucial to reach metabolic stability while retaining in vitro potency (Example C). If substituted-quinolyn is replaced by an unsubstituted quinolyn, in vivo antifilarial efficacy is lost in antifilarial rodent models (Example B). If the quinolyn bromo-substitution is replaced by CCH, tolerability events are observed in mammals. The disclosed (-) enantiomers are significantly more active than the corresponding (+) enantiomers.
[0007] In one embodiment, the present invention also provides compositions, comprising: a compound of formula (I) or a salt thereof and an acceptable excipient, the composition optionally further comprising at least one additional active compound.
[0008] In one embodiment, the present invention also provides a method for treating parasites, comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.
[0009] In one embodiment, the present invention also provides a method for controlling parasites, comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.
[0010] In one embodiment, the present invention also provides a method for treating or controlling parasites, comprising: contacting a subject’s environment with an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.
[0011] Thus, the invention provides for the use of the compounds of the invention as a medicament, including for the manufacture of a medicament. In one embodiment, the invention provides the manufacture of a medicament comprising a compound of formula (I) or a salt thereof for treating parasites. In one embodiment, the invention provides the manufacture of a medicament comprising a compound of formula (I) or a salt thereof for controlling parasites.
[0012] The present invention also provides processes from making compounds of the invention and intermediates thereof.
1. Definitions
[0013] The term “acceptable excipient” refers to refers to those typically used in preparing veterinary and pharmaceutical compositions and should be pure and non-toxic in the amounts used. They generally are a solid, semi-solid, or liquid material which in the aggregate can serve as a vehicle or medium for the active ingredient. Some examples of acceptable excipients are found in Remington’s Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and others.
[0014] The term, “administering to a subject” includes but is not limited to cutaneous, subcutaneous, intramuscular, mucosal, submucosal, transdermal, oral or intranasal administration. Administration could include injection or topical administration. [0015] The terms “compounds of the invention” and “a compound of the invention” and “compounds of the present invention” and a like include the embodiment of formula (I) and the other more particular embodiments encompassed by formula (I) described herein and the exemplified compounds described herein and a salt of each of these embodiments.
[0016] The terms “control”, “controlling” or “controlled” refers to include without limitation decreasing, reducing, or ameliorating the risk of a symptom, disorder, condition, or disease, and protecting an animal from a symptom, disorder, condition, or disease.
Controlling may refer to therapeutic, prophylactic, or preventative administration. It is well understood that a larvae or immature heartworm infection may be asymptomatic and infection by mature parasites is symptomatic and/or debilitating. Therefore, for example, a heartworm infection would be controlled by acting on the larvae or immature parasite preventing the infection from progressing to an infection by mature parasites.
[0017] The term “effective amount” refers to an amount which gives the desired benefit to the subject and includes administration for both treatment and control. The amount will vary from one individual subject to another and will depend upon a number of factors, including the overall physical condition of the subject and the severity of the underlying cause of the condition to be treated, concomitant treatments, and the amount of compound of the invention used to maintain desired response at a beneficial level.
[0018] An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount, the dose, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific condition, disorder, infection, or disease involved; the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. An effective amount of the present invention, the treatment dosage, is expected to range from 0.5 mg to 100 mg. Specific amounts can be determined by the skilled person. Although these dosages are based on a subject having a mass of about 1 kg to about 20 kg, the diagnostician will be able to determine the appropriate dose for a subject whose mass falls outside of this weight range. An effective amount of the present invention, the treatment dosage, is expected to range from 0.1 mg/kg to 10 mg/kg of the subject. The dosing regimen is expected to be daily, weekly, or monthly administration.
[0019] The term “salt” refers to salts of veterinary or pharmaceutically acceptable organic acids and bases or inorganic acids and bases. Such salts are well known in the art and include those described in Journal of Pharmaceutical Science, 66, 2-19 (1977). An example is the hydrochloride salt.
[0020] The term “stable” refers to compounds that are not substantially altered when subjected to conditions to allow for their production. In a non-limiting example, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for about a week.
[0021] The terms “subject” and “patient” refers includes humans and non-human mammalian animals, such as dogs, cats, mice, rats, guinea pigs, rabbits, ferrets, cows, horses, sheep, goats, and pigs. It is understood that a more particular subject is a human. Also, a more particular subject are mammalian pets or companion animals, such as dogs and cats and also mice, guinea pigs, ferrets, and rabbits.
[0022] The term “substituted,” including when used in “optionally substituted” refers to one or more hydrogen radicals of a group being replaced with non-hydrogen radicals (substituent(s)). It is understood that the substituents may be either the same or different at every substituted position. Combinations of groups and substituents envisioned by this invention are those that are stable or chemically feasible. For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
[0023] The terms “treating”, “to treat”, “treated”, or “treatment”, include without limitation restraining, slowing, stopping, reducing, ameliorating, reversing the progression or severity of an existing symptom, or preventing a disorder, condition, or disease. For example, an adult heartworm infection would be treated by administering a compound of the invention. A treatment may be applied or administered therapeutically.
2. Compounds [0024] The present disclosure provides compounds of formula (I):
Figure imgf000007_0001
wherein
Y is CH or N; and
Ri is H or Cl; or a salt thereof.
[0025] In one embodiment, Y is CH. In another embodiment, Y is CH and Ri is H. In another embodiment, Y is CH and Ri is Cl.
[0026] In another embodiment, Y is N. In another embodiment, Y is N and Ri is H. In another embodiment, Y is N and Ri is Cl.
[0027] The skilled artisan will appreciate that certain of the compounds of the present invention exist as isomers. All stereoisomers of the compounds of the invention, including geometric isomers, enantiomers, and diastereomers, in any ratio, are contemplated to be within the scope of the present invention.
[0028] In certain embodiments, a compound of the invention has formula (la), or a salt thereof,
Figure imgf000007_0002
[0029] In certain embodiments, a compound of the invention has formula (la- 1), or a salt thereof,
Figure imgf000008_0001
[0030] In certain embodiments, a compound of the invention has formula (la-2), or a salt thereof,
Figure imgf000008_0002
[0031] In certain embodiments, a compound of the invention has formula (lb), or a salt thereof,
Figure imgf000008_0003
[0032] In certain embodiments, a compound of the invention has formula (lb- 1), or a salt thereof,
Figure imgf000008_0004
[0033] In certain embodiments, a compound of the invention has formula (Ib-2), or a salt thereof,
Figure imgf000009_0001
[0034] In certain embodiments, a compound of the invention has formula (Ic), or a salt thereof,
Figure imgf000009_0002
[0035] In certain embodiments, a compound of the invention has formula (Ic-1), or a salt thereof,
Figure imgf000009_0003
[0036] In certain embodiments, a compound of the invention has formula (Ic-2), or a salt thereof,
Figure imgf000009_0004
[0037] In certain embodiments, a compound of the invention is selected from group consisting of: (-) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyrimidin-2-yl)propan-2- yl)butanamide; (+) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyrimidin-2-yl)propan-2- yl)butanamide; (-) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyridin-2-yl)propan-2- yl)butanamide; (+) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyridin-2-yl)propan-2- yl)butanamide; (-) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(4-chloro-pyridin-2- yl)propan-2-yl)butanamide; and (+) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(4-chloro- pyridin-2-yl)propan-2-yl)butanamide; or a salt of any of the foregoing compounds.
[0038] In certain embodiments, a compound of the invention is selected from group consisting of: (S)-2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyrimidin-2-yl)propan-2- yl)butanamide; (7?)-2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyrimidin-2-yl)propan-2- yl)butanamide; (S)-2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyridin-2-yl)propan-2- yl)butanamide; (7?)-2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyridin-2-yl)propan-2- yl)butanamide; (S)-2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(4-chloro-pyridin-2- yl)propan-2-yl)butanamide; and (7?)-2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(4-chloro- pyridin-2-yl)propan-2-yl)butanamide; or a salt of any of the foregoing compounds.
[0039] The skilled artisan will also appreciate that certain of the compounds of the present invention exist as tautomers. All tautomeric forms the compounds of the invention are contemplated to be within the scope of the present invention.
[0040] Compounds of the invention also include all isotopic variations, in which at least one atom of the predominant atom mass is replaced by an atom having the same atomic number, but an atomic mass different from the predominant atomic mass. Use of isotopic variations (e.g., deuterium, 2H) may afford greater metabolic stability. Additionally, certain isotopic variations of the compounds of the invention may incorporate a radioactive isotope (e.g., tritium, 3H, or 14C), which may be useful in drug and/or substrate tissue distribution studies. Substitution with positron emitting isotopes, such as nC, 18F, 15O and 13N, may be useful in Positron Emission Topography (PET) studies.
3. Synthetic Methods
[0041] The compounds of the invention can be prepared by a variety of procedures, some of which are described below. All substituents, unless otherwise indicated, are as previously defined.
Figure imgf000011_0001
[0042] Scheme 1 depicts an exemplary process for preparing compounds of formula (I). A compound of formula (a) may undergo substitution reaction with a compound of formula (b) under basic conditions to provide an ester compound of formula (c). The term “LV” in compounds of formula (b) refers to a leaving group, any molecular moiety that departs with a pair of electrons in hydrolytic bond cleavage. A leaving group may include, but is not limited to, a halide (i.e., fluoride, chloride, bromide, or iodide), a tosyl group (i.e., p-toluenesulfonyl), a methanesulfonyl group (i.e., CH3SO2-), a trifluoromethanesulfonyl group (i.e., CF3SO2-), and a trifluoroacetate group (i.e., CF3CO2-), among others. The compound of formula (c) may undergo hydrolysis under basic conditions to provide the carboxylic acid compound of formula (d). The compound of formula (d) may be coupled with the amine compound of formula (e) to provide amide compounds of formula (I). Standard amide forming conditions can be used, such as those using coupling agents, including those used in peptide couplings, such as 2-(lH-7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU), dicyclohexylcarbodiimide (DCC), and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide-HCl. If necessary or desired, an additive such as 4-(dimethylamino)pyridine, 1 -hydroxybenzo triazole, and the like may be used to facilitate the reaction. Such reactions are generally carried out using a base, such as N,N- Diisopropylethylamine, N-methylmorpholine, NEts, in a wide variety of suitable solvents such as CH2CI2, DMF, DMA, THF, and the like. Chiral chromotography may be used to provide the desired enantiomer of the compound of formula (I). Use of chiral intermediates can deliver final desired chiral compound without need of chiral chromatography. [0043] The products of each step can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like. The procedures may require protection of certain groups, for example hydroxyl, thiol, amino, or carboxyl groups to minimize unwanted reactions. The selection, use, and removal of protecting groups are well known and appreciated as standard practice, for example T.W. Greene and P. G. M. Wuts in Protective Groups in Organic Chemistry (John
Wiley and Sons, 1991).
[0044] Scheme 2 depicts another exemplary process for preparing compounds of formula
(I).
Figure imgf000012_0001
4. Compositions
[0045] The compounds of the invention can be administered alone or in the form of a composition. In practice, the compounds of the invention are usually administered in the form of compositions, that is, in admixture with at least one acceptable excipient. The proportion and nature of any acceptable excipient(s) are determined by the properties of the selected compound of the invention, the chosen route of administration, and standard practice as in the veterinary and pharmaceutical fields.
[0046] In certain embodiments, the present invention also provides compositions, comprising a compound of formula (I) or a salt thereof and an acceptable excipient, the composition optionally further comprising at least one additional active compound.
[0047] One skilled in the art can readily select the proper form and route of administration depending upon the particular characteristics of the compound selected, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. The pharmaceutical compositions of the invention may be administered to the subject, for example, in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, drenches, solutions, and suspensions.
[0048] In one embodiment, the composition is adapted for oral administration, such as a tablet or a capsule or a liquid formulation, for example, a solution or suspension, adapted for oral administration. In one embodiment, the composition is adapted for oral administration, such as chewable formulation, adapted for oral administration. In still another embodiment, the composition is a liquid or semi-solid formulation, for example, a solution or suspension or a paste, adapted for parenteral administration.
[0049] Particular compositions for usage on subjects in the treatment and/or control of nematodes/ helminths comprise solutions; emulsions including classical emulsions, microemulsions and self-emulsifying compositions, that are waterless organic, preferably oily, compositions which form emulsions, together with body fluids, upon addition to the subject’s body; suspensions (drenches); pour-on formulations; food additives; powders; tablets including effervescent tablets; boli; capsules including micro-capsules; and chewable treats. Particularly composition forms are tablets, capsules, food additives or chewable treats. [0050] Compounds of the invention and compositions thereof can be administered in any form and route which makes the compound bioavailable. The compounds of the invention can be administered by a variety of routes, including orally, in particularly by tablets and capsules. The compounds of the invention can be administered parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, intraarterially, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intraadipo sally, intrathecally and via local delivery for example by catheter or stent.
[0051] The compositions of the present invention are prepared in a manner well known in the veterinary and pharmaceutical art and include at least one of the compounds of the invention as the active ingredient. The amount of a compound of the present invention may be varied depending upon its particular form and may conveniently be between 1% to about 50% of the weight of the unit dose form. The present pharmaceutical compositions are preferably formulated in a unit dose form, each dose typically containing from about 0.5 mg to about 100 mg of a compounds of the invention. One or more unit dose form(s) may be taken to affect the treatment dosage.
5. Methods of Use
[0052] The compounds of formula (I) of the present invention are useful for the treatment and/or control, in particular helminths, in which the endoparasitic nematodes and trematodes may be the cause of serious diseases of mammals and poultry. Typical nematodes of this indication are: Filariidae, Setariidae, Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostonum, Oesophagostonum, Charbertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris ncylosloma. Uncinaria, Toxascaris and Parascaris. The trematodes include, in particular, the family of Fasciolideae, especially Fasciola hepatica.
[0053] Certain parasites of the species Nematodirus, Cooperia and Oesophagostonum infest the intestinal tract of the host animal, while others of the species Haemonchus and Ostertagia are parasitic in the stomach and those of the species Dictyocaulus are parasitic in the lung tissue. Parasites of the families and may be found in the internal cell tissue and in the organs, e.g. the heart, the blood vessels, the lymph vessels and the subcutaneous tissue. A particularly notable parasite is the heartworm of the dog, Dirofilaria iminitis.
[0054] The parasites which may be treated and/or controlled by the compounds of formula (I) also include those from the class of Cestoda (tapeworms), e.g. the families Mesocestoidae, especially of the genus Mesocestoides, in particular M. lineatus', Dipylidiidae, especially Dipylidium caninum, Joyeuxiella spp., in particular Joyeuxiella pasquali, and Diplopylidium spp., and Taeniidae, especially Taenia pisformis, Taenia cervi, Taenia ovis, Taeneia hydatigena, Taenia multiceps, Taenia taeniaeformis , Taenia serialis, and Echinococcus spp., most particularly Taneia hydatigena, Taenia ovis, Taenia multiceps, Taenia serialis; Echinococcus granulosus and Echinococcus multilocularis .
[0055] Furthermore, the compounds of formula (I) are suitable for the treatment and/or control of human pathogenic parasites. Of these, typical representatives that appear in the digestive tract are those of the genus Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris and Enterobius. The compounds of the present invention are also against parasites of the genus Wuchereria, Brugia, Onchocerca and Loa from the family of Dracunculus and parasites of the genus Strongyloides and Trichinella, which infect the gastrointestinal tract in particular.
[0056] A particular parasite to be treated and/or and controlled by the compounds of the invention is the heartworm (Dirofilaria immilis). Particular subjects for such treatment are dogs and cats.
[0057] In one embodiment, the present invention also provides a method for treating parasites, comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.
[0058] In one embodiment, the present invention also provides a method for controlling parasites, comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.
[0059] In one embodiment, the present invention also provides a method for treating or controlling parasites, comprising: contacting a subject’s environment with an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.
[0060] Thus, the invention provides for the use of the compounds of the invention as a medicament, including for the manufacture of a medicament. In one embodiment, the invention provides the manufacture of a medicament comprising a compound of formula (I) or a salt thereof for treating parasites. In one embodiment, the invention provides the manufacture of a medicament comprising a compound of the invention or a salt thereof for controlling parasites.
[0061] Thus, the use of the compounds of the invention in the treatment and/or control of parasites, in particular helminths, in which the endoparasitic nematodes and trematodes refers to the use of the compounds of the invention to act on the various forms of the parasites throughout its life cycle, independent of whether a subject is manifesting a symptom, including morbidity or mortality, and independently of the phase(s) of the parasitic challenge. [0062] In effecting such treatment and/or control, a compound of the invention can be administered in any form and route which makes the compound bioavailable. The compounds of the invention can be administered by a variety of routes, including orally, in particularly by tablets and capsules. The compounds of the invention can be administered parenteral routes, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, intraarterially, transdermally, intranasally, rectally, vaginally, occularly, topically, sublingually, and buccally, intraperitoneally, intraadipo sally, intrathecally and via local delivery for example by catheter or stent.
[0063] One skilled in the art can readily select the proper form and route of administration depending upon the particular characteristics of the compound selected, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. The pharmaceutical compositions of the invention may be administered to the subject, for example, in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, drenches, solutions, and suspensions.
[0064] The compounds of the invention may be combined with one or more other active compounds or therapies for the treatment of one or more disorders, diseases or conditions, including the treatment of parasites, for which it is indicated. The compounds of the invention may be administered simultaneously, sequentially or separately in combination with one or more compounds or therapies for treating parasites and other disorders.
[0065] For example, when used to treat parasites, including heartworm, a compound of the invention may be combined with a macrocyclic lactone such as ivermectin, moxidectin, or milbemycin oxime, or with imidacloprid. Particular combinations for treating parasites include a compound of the invention and ivermectin. Another particular combination for treating parasites include a compound of the invention and milbemycin oxime.
[0066] Thus, it is understood that the compositions and methods of the present invention optionally include comprising an effective amount of at least one additional active compound. [0067] The activity of compounds as parasiticides may be determined by a variety of methods, including in vitro and in vivo methods.
6. Examples
Example 1
(-) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyrimidin-2-yl)propan-2-yl)butanamide
Figure imgf000017_0001
[0068] To a mixture of 12.7g of 3-Bromo-8-chloro-6-quinolinol CAS registry number 808755-83-1, 160ml DMF and 19.4g K2CO3 is added 10.4ml ethyl 2-bromobutyrate. Mixture is stirred overnight, diluted with ethylacetate, filtered over celite, washed with brine, dried over Na2SO4, concentratated under vacuum then purified by column chromatography. 21g of the desired ester in 140ml THF and 140ml water is stirred overnight, concentrated under vacuum, acidified to pH=l with 2M aq. HC1. The precipitate is collected by filtration then dried to provide the desired carboxylic acid. To a mixture of 15g of the latter, 220ml DMF and 20.5g HATU is added 25ml of EtNiPn then 10g of 2-(pyrimidin-2-yl)propan-2-amine dihydrochloride to afford the desired (-) enantiomer after an addition of further 1.5g HATU, 0.7g amine and 1.8ml EtNiPn, stirred for a day, worked-up with brine and EtOAc, concentrated under vacuum and purification by chiral chromatography. 1 H NMR (400 MHz, DMSO-d6) d 8.91 (d, J=2.34 Hz, 1H), 8.61-8.71 (m, 4H), 7.78(d, J=2.73 Hz, 1H), 7.39 (d, J=2.73 Hz, 1H), 7.31 (t, J=4.88 Hz, 1H), 4.76 (t, J=5.85Hz, 1H), 1.84-1.99 (m, 2H), 1.64 (s, 3H), 1.59 (s, 3H), 1.01 (t,J=7.41 Hz, 3H).
Example 2
(-) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyridin-2-yl)propan-2-yl)butanamide
Figure imgf000018_0001
[0069] Same protocol as in Example 1 using a source of 2-(2-pyridyl)propan-2-amine CAS Registry Number RN 52568-28-2 provides the desired compound. 1 H NMR (400 MHz, DMSO-d6) d 8.91 (d, J=2.34 Hz, 1H), 8.63-8.70 (m, 2H), 8.42(d, J=4.10 Hz, 1H), 7.77 (d, J=2.54 Hz, 1H), 7.59 (dt, J=1.76, 7.71 Hz, 1H), 7.34-7.39 (m, 2H), 7.17 (dd, J=5.07, 7.02 Hz, 1H), 4.80 (t, J=5.95 Hz, 1H), 1.86-2.01(m, 2H), 1.60 (s, 3H), 1.55 (s, 3H), 0.98-1.06 (m, 3H).
Example 3
(-) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(4-chloro-pyridin-2-yl)propan-2- yl)butanamide
Figure imgf000018_0002
[0070] Same protocol as in Example 1 using a source of 2-(4-chloro-2-pyridyl)propan-2- amine CAS Registry Number RN 52568-28-2 provides the desired compound. 1 H NMR (400 MHz, DMSO-d6) d 8.91 (d, J=2.15 Hz, 1H), 8.70 (d, J=2.15 Hz, 1H), 8.63 (s, 1H), 8.38 (d, J=5.27 Hz, 1H), 7.75 (d, J=2.54 Hz, 1H), 7.37 (d, J=2.54 Hz, 1H), 7.29 (s, 1H), 7.27 (d, J=5.36 Hz, 1H), 4.80 (t, J=6.15 Hz, 1H), 1.88-1.99 (m, 2H), 1.58 (s, 3H), 1.54 (s, 3H), 1.02 (t, J=7.41 Hz, 3H). Biological Data
Example A
[0071] H. contortus nematode Larval Development Assay (He LDA)): Freshly harvested and cleaned nematode Haemonchus contortus eggs are used to seed a suitably formatted well plate containing the test substances to be evaluated for antiparasitic activity and media allowing the full development of eggs through to third instar larvae. The plates are incubated for 6 days at 25°C and 60% relative humidity. Egg-hatching and ensuing larval development are recorded to identify a possible nematodicidal activity. Efficacy is expressed in percent reduced egg hatch, reduced development of L3, or paralysis & death of larvae at any stage. In this assay the disclosed (-)-enantiomers of Examples 1, 2 & 3 showed an EC50 below 0.4ppm whereas the (+)-distomers showed ECso>5ppm. This result highlights an unexpected enantio specific effect with the disclosed compounds. Further, in this assay CAS RN1401524-82-0 Compound 13 p.41 of WO/2012/130917 showed EC50>10ppm. This result highlights an unexpected superiority of the polysubstituted substances.
Example B
Filarial nematodes
[0072] Av model: Gerbils, injected subcutaneously with infective A. viteae larvae, were subsequently treated with the test article formulated in eg DMSO/PEG 2/1, by oral gavage at a dose of 16 mg/kg (once a day for 5 consecutive days). At necropsy 12 weeks after infection, efficacy is expressed as a % reduction in worm numbers in comparison with the placebo treated group, using the Abbot’s formula. The compounds of Examples 1 & 2 showed respectively 95 and 100% efficacy. By comparison, CAS RN1450836-43-7 of WO/2013/ 122041 (compound 2.1 p.59) showed no relevant efficacy at 32mg/kg. This result highlights an unexpected superiority of the disclosed substituted quinolynyls in rodent as antifilarials.
Example C
ADME Properties
[0073] Examples 1 & 2 showed circulating concentration in dog’s bloodstream treated at 3mg/kg orally of more than lOOOng/ml after 12h. In these conditions, substance CAS RN 1401524-78-4 compound 9 page 41 of WO/2012/130917 showed less than 20ng/ml. This result highlights unexpected ADME properties in dogs for chlorosubstituted quinolyns & ethyl central core. The substitution pattern with acetals, such as CAS RN 1401524-83-1 were not investigated because of related high risks of chemical stability.

Claims

WE CLAIM:
1. A compound of formula (I):
Figure imgf000021_0001
wherein
Y is CH or N; and
Ri is H or Cl; or a salt thereof.
2. The compound according to claim 1, having formula (la), or a salt thereof,
Figure imgf000021_0002
3. The compound according to claim 2, having formula (la- 1), or a salt thereof,
Figure imgf000021_0003
4. The compound according to claim 2, having formula (la-2), or a salt thereof,
Figure imgf000022_0001
having formula (lb), or a salt thereof,
Figure imgf000022_0002
having formula (Ib-1), or a salt thereof,
Figure imgf000022_0003
having formula (Ib-2), or a salt thereof,
Figure imgf000022_0004
having formula (Ic), or a salt thereof,
Figure imgf000023_0001
9. The compound according to claim 8, having formula (Ic-1), or a salt thereof,
Figure imgf000023_0002
10. The compound according to claim 8, having formula (Ic-2), or a salt thereof,
Figure imgf000023_0003
11. A composition comprising a compound of any one of claims 1 to 10, or a salt thereof, and at least one acceptable carrier.
12. The use of a compound of any one of claims 1 to 10, or a salt thereof, as a medicament.
13. The use of a compound of any one of claims 1 to 10, or a salt thereof, in the manufacture of a medicament for treating endoparasites.
14. The use of a compound of any one of claims 1 to 10, or a salt thereof, in the manufacture of a medicament for treating heartworm. 15. The use of a compound of any one of claims 1 to 10, or a salt thereof, in the manufacture of a medicament for controlling heartworm.
16. A compound that is (-) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyrimidin-2- yl)propan-2-yl)butanamide or a salt thereof.
17. A compound that is (-) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(pyridin-2- yl)propan-2-yl)butanamide or a salt thereof.
18. A compound that is (-) 2-((3-bromo-8-chloroquinolin-6-yl)oxy)-N-(2-(4-chloro- pyridin-2-yl)propan-2-yl)butanamide or a salt thereof.
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