US20200385398A1 - New bicyclic derivatives - Google Patents

New bicyclic derivatives Download PDF

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Publication number
US20200385398A1
US20200385398A1 US16/894,017 US202016894017A US2020385398A1 US 20200385398 A1 US20200385398 A1 US 20200385398A1 US 202016894017 A US202016894017 A US 202016894017A US 2020385398 A1 US2020385398 A1 US 2020385398A1
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Prior art keywords
alkyl
dihydro
carboxamide
benzoxazin
quinoline
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Inventor
Pierre Ducray
Denise RAGEOT
Chouaib Tahtaoui
Francois Pautrat
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Elanco Tiergesundheit AG
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Elanco Tiergesundheit AG
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Priority to US16/894,017 priority Critical patent/US20200385398A1/en
Assigned to ELANCO TIERGESUNDHEIT AG reassignment ELANCO TIERGESUNDHEIT AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PAUTRAT, FRANCOIS, TAHTAOUI, CHOUAIB, DUCRAY, PIERRE, RAGEOT, Denise
Publication of US20200385398A1 publication Critical patent/US20200385398A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • 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 warm-blooded animals.
  • Heartworm Dirofilaria immitis
  • 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.
  • 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.
  • the present invention provides compounds of formula (I) which effectively treat and/or control endoparasites (e.g., heartworm) in warm-blooded animals.
  • endoparasites e.g., heartworm
  • the present invention provides compounds of formula (I):
  • 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.
  • C 1 -C 4 alkyl refers to a straight or branched alkyl chain having from one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, and the like.
  • C 1 -C 4 halogenoalkyl refers to a straight or branched alkyl chain having from one to four carbon atoms and 1 to 5 halogen and includes fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and the like.
  • C 2 -C 4 alkenyl refers to a straight or branched alkenyl chain having from two to four carbon atoms and one carbon-carbon double bond, and includes ethylene, propylene, iso-propylene, butylene, iso-butylene, sec-butylene, and the like.
  • C 2 -C 4 alkynyl refers to a straight or branched alkynyl chain having from two to four carbon atoms and one carbon-carbon triple bond, and includes acetylene, propargyl, and the like.
  • C 1 -C 4 alkoxy refers to a C 1 -C 4 alkyl attached through an oxygen atom and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.
  • C 3 -C 6 cycloalkyl refers to an alkyl ring of three to six carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • halogen and “halogeno” refers to a chloro, fluoro, bromo or iodo atom.
  • C 6 - or C 10 -membered aryl refers to phenyl or naphthyl.
  • C 6 - or C 10 -membered aryloxy refers to phenyl or naphthyl attached through an oxygen atom and includes phenoxy and naphtyloxy.
  • C 6 - or C 10 -membered arylthio-oxy refers to phenyl or naphthyl attached through an sulfur atom and includes phenthio-oxy and naphtylthio-oxy. Further it is understood that the term “C 6 - or C 10 -membered arylthio-oxy” also encompasses in which the sulfur is the —SO 2 — and —S(O)—.
  • 4- to 7-membered heterocycloalkyl refers to a 4 to 7 membered monocyclic saturated or partially (but not fully) unsaturated ring having one or more heteroatoms, preferably one, two, or three heteroatoms, selected from the group consisting of nitrogen, oxygen, and sulfur and the ring optionally includes a carbonyl to form a lactam or lactone. It is understood that where sulfur is included that the sulfur may be either —S—, —SO—, or —SO 2 —.
  • the term includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuryl, hexahydropyrimidinyl, tetrahydropyrimidinyl, dihydroimidazolyl, and the like.
  • 5-membered heteroaryl refers to a five membered, monocyclic, fully unsaturated, ring with one to four carbon atoms and one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the term includes furyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and the like.
  • a 5-membered heteroaryl can be attached as a substituent through a ring carbon or a ring nitrogen atom where such an attachment mode is available, for example for a pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and the like.
  • 6-membered heteroaryl refers to a six membered, monocyclic, fully unsaturated ring with one to five carbon atoms and one or more, typically one to four, heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the term includes pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, and the like. It is understood that a 6-membered heteroaryl can be attached as a substituent through a ring carbon or a ring nitrogen atom where such an attachment mode is available.
  • 5- to 10-membered heteroaryl refers to a five to ten membered, monocyclic or polycyclic fully unsaturated, ring or ring system with one to nine carbon atoms and one or more heteroatoms, preferably one, two, or three heteroatoms, selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the term includes furyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, azepinyl, diazepinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzoxazolyl, benzopyrazinyl, benzopyrazolyl, quinazolyl, thienopyridyl, quinolyl, isoquinolyl benzothiazolyl, and the like. It is understood that a 5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the
  • 5- to 10-membered heteroaryloxy refers to a 5- to 10-membered heteroaryl having one or more heteroatoms, preferably 1, 2, or 3 heteroatoms, selected from the group O, S, and N, attached through an oxygen atom and includes imidazolyloxy, pyrazolyloxy, pyridyloxy, pyrimidyloxy, quinolyloxy, and the like.
  • oxo refers to an oxygen atom doubly bonded to the carbon to which it is attached to form the carbonyl of a ketone or aldehyde.
  • a pryidone radical is contemplated as an oxo substituted 6-membered heteroaryl.
  • C 1 -C 4 alkoxy carbonyl refers the group below:
  • R is a C 1 -C 4 alkyl.
  • nil as used herein with reference to a group, substituent, moiety, or the like, indicates that that group, substituent, or moiety is not present. Wherein a group, substituent, or moiety is ordinarily bonded to two or more other groups, substituents, or moieties, the others are bonded together in lieu of the group, substituent, or moiety which is nil. For example, with a compound having the structure A-B-C; wherein B is nil, then A is directly bonded to C and the compound is A-C. As another example, with a compound having the structure A-B-C; wherein C is nil, then the compound is A-B.
  • 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.
  • 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.
  • a cycloalkyl or heterocycloalkyl ring when a cycloalkyl or heterocycloalkyl ring is substituted with a spiro group, the spiro group can be attached, valency permitting, to any position of the cycloalkyl or heterocycloalkyl, forming an additional ring such that the spiro group is attached to the cycloalkyl or heterocycloalkyl ring through a common atom.
  • spiro substituted rings include 2-oxa-6-azaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 6-oxa-2-azaspiro[3.4]octane, and the like.
  • 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.
  • 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, 41
  • 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 11 C, 18 F, 15 O and 13 N, may be useful in Positron Emission Topography (PET) studies.
  • PET Positron Emission Topography
  • One embodiment relates to a compound of formula (Ia).
  • (b) One embodiment relates to a compound of formula (Ib).
  • (1) One embodiment relates to a compound of formula (Ic).
  • (2) One embodiment relates to a compound of formula (I), embodiments (a), embodiment (b), and (1) wherein at least one of X 1 , X 2 , X 3 , and X 5 is N.
  • (c) One embodiment relates to compounds of formula (I), formula (Ia), formula (Ib), or formula (Ic) wherein X 1 is CR 1 ; X 2 is CR 2 ; X 3 is CR 3 ; X 4 is CR 4 ; X 5 is CR 5 ; and X 6 is N; or a salt thereof.
  • One embodiment relates to compounds of formula (I), formula (Ia), formula (Ib), or formula (Ic) wherein X 1 is CR 1 ; X 2 is CR 2 ; X 3 is CR 3 ; X 4 is CR 4 ; X 5 is N; and X 6 is N; or a salt thereof.
  • One embodiment relates to compounds of formula (I), formula (Ia), or formula (Ib)) wherein X 1 is CR 1 ; X 2 is CR 2 ; X 3 is CR 3 ; X 4 is CR 4 ; X 5 is N; and X 6 is CR 6 ; or a salt thereof.
  • One embodiment relates to compounds of formula (I), formula (Ia), formula (Ib), or formula (Ic) wherein X 1 is CR 1 ; X 2 is CR 2 ; X 3 is CR 3 ; X 4 is N; X 5 is N; and X 6 is N; or a salt thereof.
  • One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f) wherein Q is a 6- or 10 membered aryl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 halogenoalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(C 3 -C 6 cycloalkyl), —N(C 1 -C 4 alkyl)(C 3 -C 6 -cycloalkyl), —NHSO 2 (C 1 -C 4 alkyl), —SC 1 -C 4 alkyl, —S(O)
  • One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f) wherein Q is 6-membered aryl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 halogenoalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(C 3 -C 6 cycloalkyl), —N(C 1 -C 4 alkyl)(C 3 -C 6 -cycloalkyl), —NHSO 2 (C 1 -C 4 alkyl), —SC 1 -C 4 alkyl, —S(O)C 1
  • One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f) wherein Q is a 5- to 10-membered heteroaryl having 1 or 2 heteroatoms selected from the group O, S, and N and wherein the carbons of the heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, —OH, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 halogenoalkyl, C 1 -C 4 alkoxy, —NH 2 , —NH(C 1 -C 4 alkyl), and —N(C 1 -C 4 alkyl) 2 and any N in the heteroaryl is optionally substituted with a substituent selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl;
  • One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f) wherein Q is a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group O, S, N, wherein the heterocycloalkyl is optionally benzo-fused, wherein the carbons of the heterocycloalkyl or optionally benzo-fused heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 halogenoalkyl, C 1 -C 4 alkoxy, —NH 2 , —NH(C 1 -C 4 alkyl), and —N(C 1 -C 4 alkyl) 2 and any N in the heterocycl
  • One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f) wherein Q is a 6- or 10 membered aryloxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 halogenoalkyl, C 1 -C 4 alkoxy, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(C 3 -C 6 cycloalkyl), —N(C 1 -C 4 alkyl)(C 3 -C 6 -cycloalkyl), —NHSO 2 (C 1 -C 4 alkyl), —SC 1 -C 4 alkyl, —S(
  • One embodiment relates to a compound of formula (I) and embodiments (1), (2), (a), (b), (c), (d), (e) and (f) wherein Q is a and 5- to 10-membered heteroaryloxy optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 halogenoalkyl, C 1 -C 4 alkoxy, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(C 3 -C 6 cycloalkyl), C 4 alkyl)(C 3 -C 6 -cycloalkyl), —NHSO 2 (C 1 -C 4 alkyl), —SC 1 -C 4 alkyl, —S(O)
  • One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) (f), (g), (h), (i), (j), (k), and (1) wherein n is 1; or a salt thereof.
  • One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f), (g), (h), (i), (j), (k), (1), and (m) wherein Y 1 is CR 8 R 9 and Y 2 is O; or a salt thereof; (o)
  • One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) (f), (g), (h), (i), (j), (k), (1), (m), and (n) wherein R 4 is selected from the group consisting of C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, —N(C 1 -C 4 alkyl) 2 , and 4- to 7-membered heterocycloalkyl; or a salt thereof.
  • One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (1), (2), (g), (h), (i), (j), (k), (1), (m), and (n) wherein R 4 is —N(C 1 -C 4 alkyl) 2 ; or a salt thereof.
  • R 4 is —N(C 1 -C 4 alkyl) 2 ; or a salt thereof.
  • One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1), (m), (n), (o), and (p) wherein M is O; or a salt thereof.
  • One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1), (m), (n), (o), and (p) wherein M is NR 13 ; or a salt thereof.
  • One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1), (m), (n), (o), and (p) wherein M is S; or a salt thereof.
  • One embodiment relates to a compound of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1), (m), (n), (o), (p), (q), (r), and (s) wherein Z 1 is CR 11 , Z 2 is CR 11 , Z 3 is nil, and Z 4 is S; or a salt thereof.
  • Another embodiment relates to a salt of each of the exemplified compounds.
  • R 1 when present [i.e., when specifically depicted in the formula], is selected from hydrogen, halogen, and cyano.
  • R 1 when present, is selected from hydrogen, fluoro, and cyano.
  • R 1 when present, is hydrogen or fluoro. In another embodiment for formula (Ia-1) through (Ia-8a), R 1 , when present, is hydrogen. In another embodiment for formula (Ia-1) through (Ia-8a), R 1 , when present, is fluoro.
  • R 4 when present, is selected from:
  • R 4 when present, is selected from:
  • R 4 when present, is selected from:
  • R 5 when present, is hydrogen, halogen, C 1 -C 4 alkyl, or C 1 -C 4 halogenoalkyl.
  • R 5 when present, is hydrogen, C 1 -C 4 alkyl, or C 1 -C 4 halogenoalkyl.
  • R 5 when present, is hydrogen, methyl, or trifluoromethyl.
  • R 7 when present, is hydrogen.
  • Q is selected from a 6-membered aryl and a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halogen, C 1 -C 4 halogenoalkyl, and C 1 -C 4 alkoxy.
  • Q is selected from a 6-membered aryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halogen.
  • Q is selected from:
  • Q is selected from:
  • the compound of formula (I), or a salt thereof has formula (Ia-5),
  • R 1 , R 4 , and Q are as defined in the Summary.
  • R 1 is hydrogen, halogen, or cyano. More preferably, R 1 is hydrogen or fluoro.
  • R 4 is 4-morpholino or dimethylamino.
  • Q is a 6-membered aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 halogenoalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(C 3 -C 6 cycloalkyl), —N(C 1 -C 4 alkyl)(C 3 -C 6 -cycloalkyl), —NHSO 2 (C 1 -C 4 alkyl), —SC 1 -C 4 alkyl, —S(O)C 1 -C 4 alkyl, —SO 2 C 1 -C 4 alkyl, —S(O)C 1 -C 4 -hal
  • Q is 6-membered aryl substituted by 1, 2, 3, 4, or 5 substituents independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 halogenoalkyl, and cyano.
  • Q is selected from:
  • 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).
  • AcOH refers to acetic acid
  • aq. refers to aqueous
  • br refers to broad
  • CH 3 CN refers to acetonitrile
  • CH 2 Cl 2 refers to methylene chloride
  • d refers to doublet
  • dd refers to doublet of doublet
  • DIPEA refers to N-diisopropylethylamine
  • DMA refers to N,N-dimethylacetamide
  • DMF refers to N,N-dimethylformamide
  • DMSO refers to dimethylsulfoxide
  • ee refers to enantiomeric excess, eq.
  • ES electrospray ionization
  • EtOAc EtOAc
  • EtOH EtOH
  • HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
  • HPLC high performance liquid chromatography
  • iPrOH isopropanol
  • J coupling constant
  • KOAc potassium acetate
  • K 2 CO 3 refers to potassium carbonate
  • LCMS liquid chromatography-mass spectrometry
  • m/z refers to mass-to-charge ratio
  • M refers to molarity
  • m refers to multiplet
  • MeOH mEtOH, min.
  • NMR nuclear magnetic resonance
  • PEG polethyleneglycol
  • q quartet
  • quint quintet
  • rt rt
  • R t retention time
  • s singlet
  • sat. saturated
  • T temperature
  • t triplet
  • td triplet of doublets
  • THF THF
  • wt weight
  • ⁇ chemical shift
  • Scheme A depicts the reaction of a compound of formula (1) and a compound of formula (2) to give a compound of formula (Ia).
  • the depicted compound of formula (1) is one in which the group A 1 is a hydroxyl group, or an activating groups as is discussed below, and Q, M, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are as desired in the final compound of formula (Ia) or a group that gives rise to Q, M, X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 as desired in the final compound of formula (Ia).
  • a compound of formula (1) can be one in which the depicted group “Q” is a halogen which is further elaborated, in a subsequent step, not shown, to give a compound in which Q is as defined in formula (Ia).
  • a compound in which M is O can be further elaborated to compound in M is S or in which M is NR 13 .
  • the preparation of such compounds of formula (1) is readily appreciated in the art.
  • a compound of formula (2) is one in which R 7 , n, Y 1 , Y 2 , Z 1 , Z 2 , Z 3 , and Z 4 are as desired in the final product of formula (Ia) or a group that gives rise to R 7 , Y 1 , Y 2 , Z 1 , Z 2 , Z 3 , and Z 4 as desired in the final product of formula (Ia).
  • the preparation of such compounds of formula (2) is readily appreciated in the art.
  • Scheme A depicts the reaction of a compound of formula (1) using a compound of formula (2) to give a compound of formula (Ia).
  • Typical groups A 1 are hydroxyl or a leaving group, such as chloro, bromo, or imidazolyl, an activating moiety, a mixed anhydride of another carboxylic acid, such as formic acid, acetic acid, or represents the other part of a symmetrical anhydride formed from two compounds of formula (1).
  • standard amide forming conditions can be used, such as those using coupling agents, including those used in peptide couplings, such as 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (HATU), dicyclohexylcarbodiimide (DCC), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl.
  • an additive such as 4-(dimethylamino)pyridine, 1-hydroxybenzotriazole, and the like may be used to facilitate the reaction.
  • Such reactions are generally carried out using a base, such as N-methylmorpholine or NEt 3 , in a wide variety of suitable solvents such as CH 2 Cl 2 , DMF, NMP, DMA, THF, and the like. Such reactions are well understood and appreciated in the art.
  • a base such as N-methylmorpholine or NEt 3
  • suitable solvents such as CH 2 Cl 2 , DMF, NMP, DMA, THF, and the like.
  • the compounds of formula (Ia) can be converted to salts by methods well known and appreciated in the art.
  • Scheme B depicts the reaction of a compound of formula (3) and a compound of formula (4) to give a compound of formula (Ib).
  • the depicted compound of formula (3) Q, R 7 , X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are as desired in the final compound of formula (I) or a group that gives rise to Q, R 7 , X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 as desired in the final compound of formula (Ib).
  • a compound of formula (3) can be one in which the depicted group “Q” is a halogen which is further elaborated, in a subsequent step, not shown, to give a compound in which Q is as defined in formula (Ib).
  • the preparation of such compounds of formula (3) is readily appreciated in the art.
  • a compound of formula (4) is one in which is one in which the group A 2 is a carboxy group, or an activating groups as is discussed below, and n, Y 1 , Y 2 , Z 1 , Z 2 , Z 3 , and Z 4 are as desired in the final product of formula (Ib) or a group that gives rise to Y 1 , Y 2 , Z 1 , Z 2 , Z 3 , and Z 4 as desired in the final product of formula (Ib).
  • the preparation of such compounds of formula (4) is readily appreciated in the art.
  • Scheme B depicts the reaction of a compound of formula (3) in which using a compound of formula (4) to give a compound of formula (Ib).
  • Typical groups A 2 are carboxy or an acid chloride or acid bromide, or imidazide, an activating moiety, a mixed anhydride of another carboxylic acid, such as formic acid, acetic acid, or represents the other part of a symmetrical anhydride formed from two compounds of formula (4) in which A 2 is carboxy derivative or another activated moiety.
  • Such reactions are generally carried out using a base, such as N-methylmorpholine or triethylamine, in a wide variety of suitable solvents such as CH 2 Cl 2 , DMF, N-methylpyrrolidone (NMP), DMA, THF, and the like.
  • a base such as N-methylmorpholine or triethylamine
  • suitable solvents such as CH 2 Cl 2 , DMF, N-methylpyrrolidone (NMP), DMA, THF, and the like.
  • NMP N-methylpyrrolidone
  • a compound of (Ib) in which M is O can be further elaborated to compound in M is S or in which M is NR 13 .
  • Scheme C depicts the reaction of a compound of formula (5) and a compound of formula (6) to give a compound of formula (Ib).
  • the depicted compound of formula (5) is the same as the a compound of formula (3) described in Scheme B.
  • a compound of formula (6) is one in which is one in which the depicted R 7 and n, Y 1 , Y 2 , Z 1 , Z 2 , Z 3 , and Z 4 are as desired in the final product of formula (Ib) or a group that gives rise to the depicted R 7 , and Y 1 , Y 2 , Z 1 , Z 2 , Z 3 , and Z 4 as desired in the final product of formula (Ib).
  • the preparation of such compounds of formula (6) is readily appreciated in the art.
  • unsymmetrical ureas is well known using phosgene, carbonyldiimidazole, isopropenyl carbamates, and optionally substituted phenoxy carbonyl halides, such as p-nitrophenoxycarbonyl chloride.
  • Such reactions are generally carried out in a sequential manner by adding phosgene, carbonyldiimidazole, isopropenyl carbamates, and optionally substituted phenoxycarbonyl halides to either a compound of formula (5) or a compound of formula (6) using a base, such as N-methylmorpholine or triethylamine, in a wide variety of suitable solvents such as CH 2 Cl 2 , DMF, N-methylpyrrolidone (NMP), DMA, THF, and the like. Then the other of compound (5) or compound (6) is added.
  • a base such as N-methylmorpholine or triethylamine
  • the compounds of formula (Ib) can be converted to salts by methods well known and appreciated in the art.
  • Analyses methods A and B were performed using an Agilent 1200 Infinity Series Liquid Chromatography (LC) system, consisting of a 1260 HiP degasser (G4225A), 1260 Binary Pump (G1312B), 1290 auto-sampler (G4226A), 1290 thermo-stated column compartment (G1316C) and a 1260 Diode Array Detector (G4212B) coupled to an Agilent 6150 single quadrupole mass spectrometry (MS) detector.
  • the injection volume was set to 1 ⁇ L by default.
  • the UV (DAD) acquisition was performed at 40 Hz, with a scan range of 190-400 nm (by 5 nm step). A 1:1 flow split was used before the MS detector.
  • the MS was operated with an electro-spray ionization source (ESI) in both positive & negative ion mode.
  • ESI electro-spray ionization source
  • the nebulizer pressure was set to 50 psi, the drying gas temperature and flow to 350° C. and 12 L/min respectively.
  • the capillary voltages used were 4000V in positive mode and 3500V in negative mode.
  • the MS acquisition range was set to 100-800 m/z with a step size of 0.2 m/z in both polarity modes.
  • Fragmentor voltage was set to 70 (ESI+) or 120 (ESI ⁇ ), Gain to 0.40 (ESI+) or 1.00 (ESI ⁇ ) and the ion count threshold to 4000 (ESI+) or 1000 (ESI ⁇ ).
  • the overall MS scan cycle time was 0.15 s/cycle. Data acquisition was performed with Agilent Chemstation software.
  • Method A Analyses were carried out on a Phenomenex Gemini-NX C18 column of 50 mm length, 2.1 mm internal diameter and 3 ⁇ m particle size.
  • the run was performed at a temperature of 50° C. and a flow rate of 1.2 mL/min, with a gradient elution from 5% to 95% (B1) over 1.5 min followed by a 0.5 min hold at 95% (B1).
  • Method B Analyses were carried out on a Waters)(Bridge C18 column of 50 mm length, 2.1 mm internal diameter and 3.5 ⁇ m particle size.
  • the run was performed at a temperature of 50° C. and a flow rate of 1.2 mL/min, with a gradient elution from 5% to 95% (B2) over 1.5 min followed by a 0.5 min hold at 95% (B2).
  • Method C Analyses were carried out on an Acquity UPLC BEH C18 column of 50 mm length, 2.1 mm internal diameter and 1.7 ⁇ m particle size.
  • the injection volume was 0.1 ⁇ L.
  • the run was performed at a temperature of 40° C. and a flow rate of 0.6 mL/min, with a gradient elution.
  • Method info (Time (min) and B %): 0-5; 0.3-5; 2.5-95; 3.7-95; 4-5; 4.6-5.
  • Method D Analyses were carried out on an Acquity UPLC BEH C18 column of 50 mm length, 2.1 mm internal diameter and 1.7 ⁇ m particle size.
  • the injection volume was 0.1 ⁇ L.
  • the run was performed at a temperature of 45° C. and a flow rate of 0.5 mL/min, with a gradient elution.
  • Method info (Time (min) and A %): 0-98; 0.3-98; 3.2-2; 4.4-2; 4.7-98.
  • Ethyl 8-hydroxy-1-[(4-methoxyphenyl) methyl]-4-oxo-1,5-naphthyridine-3-carboxylate (840 mg, 1.09 mmol) was dissolved in CH 2 Cl 2 (11 mL) and DMF (0.05 mL). To this mixture, oxalyl chloride (0.48 mL, 5.5 mmol) was added and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled down and was quenched by addition of sat. aq. NaHCO 3 solution (50 mL). The layers were separated and the aq. layer was extracted with CH 2 Cl 2 (2 ⁇ 25 mL). The combined organic layers were reduced in vacuo to give ethyl 4,8-dichloro-1,5-naphthyridine-3-carboxylate.
  • Step 1 To a stirred solution of 7-bromoindoline-2,3-dione (2.5 g, 11.06 mmol) and ethyl 4,4,4-trifluorobut-2-ynoate (1.83 g, 11.06 mmol) in DMF (15 mL) was added Na 2 CO 3 (2.34 g, 22.12 mmol) followed by tert-butyl hydroperoxide (TBHP, 0.99 g, 11.06 mmol). The reaction mixture was stirred for 2 h at rt. The reaction mixture was quenched by adding water (20 mL) and extracted with ethy (2 ⁇ 30 mL).
  • Step 2 To a stirred solution of ethyl 8-bromo-4-hydroxy-2-(trifluoromethyl) quinoline-3-carboxylate (1.75 g, 4.80 mmol) in EtOH (10 mL) was added KOH (5.39 g, 96.12 mmol) at rt and heated to 90° C. for 24 h. The reaction mixture was allowed to rt and concentrated. The pH of the residue was adjusted to 1-2 using aqueous 2 N HCl solution and the precipitated solid filtered, washed with water (10 mL), diethyl ether (20 mL) and dried to afford 8-bromo-4-hydroxy-2-(trifluoromethyl)quinoline-3-carboxylic acid.
  • Step 3 A mixture of 8-bromo-4-hydroxy-2-(trifluoromethyl)quinoline-3-carboxylic acid (1 g, 2.97 mmol) and POCl 3 (10 mL) was heated to 90° C. for 2 h. The reaction mixture was allowed to rt and concentrated under reduced pressure to afford 8-bromo-4-chloro-2-(trifluoromethyl)quinoline-3-carbonyl chloride.
  • Step 4 To a stirred solution of 2,3-dihydro-1,4-benzoxazin-4-amine (0.8 g, 5.36 mmol) in THF (5 mL) was added DIPEA and cooled to 0-5° C. A solution of 8-bromo-4-chloro-2-(trifluoromethyl) quinoline-3-carbonyl chloride (1 g, 2.68 mmol) in 4 mL THF was added to the reaction mixture and allowed to stir at rt for 16 h. The reaction was quenched by adding water (20 mL) and extracted with EtOAc (2 ⁇ 30 mL). The combined organic layer was washed with brine (20 mL), dried over Na 2 SO 4 and concentrated under reduced pressure.
  • Step 5 To a stirred solution of 8-bromo-4-chloro-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-2-(trifluoromethyl)quinoline-3-carboxamide (0.844 g, 1.73 mmol) in THF (6 mL) was added morpholine (1.5 mL, 17.34 mmol) at rt and stirred for 16 h. The reaction mixture was concentrated to dryness.
  • Step 6 To a stirred solution of 8-bromo-N-(2,3-dihydro-1,4-benzoxazin-4-yl)-4-morpholino-2-(trifluoromethyl)quinoline-3-carboxamide and (2,3,5-trifluorophenyl) boronic acid (0.687 g, 3.91 mmol) in 1,4-dioxane (15 mL):water (5 mL) was added Cs 2 CO 3 (0.636 g, 1.95 nmmol).
  • the reaction mixture was de-gassed with N2 gas for 10 min followed by the addition of [(t-Bu) 3 PH]BF 4 (0.075 g, 0.26 mmol) and PdCl2(dppf) (0.095, 0.13 mmol).
  • the reaction mixture was heated to 90° C. for 16 h.
  • the reaction mixture was quenched by adding water (150 mL) and extracted with EtOAc (3 ⁇ 50 mL).
  • the combined organic layer was washed with brine (30 mL), dried over Na 2 SO 4 and concentrated under reduced pressure.
  • the crude compound was purified by column chromatography eluting with 0-14% EtOAc in petroleum ether to afford Example 8.2 as a white solid.
  • 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, Ancylostoma, 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.
  • Dipylidiidae especially Dipylidium caninum, Joyeuxiella spp., in particular Joyeuxiella pasquali , and Diplopylidium spp.
  • 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.
  • 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 immitis ).
  • Particular subjects for such treatment are dogs and cats.
  • 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 provides compositions comprising: a compound of invention and at least one acceptable excipient.
  • 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, intraadiposally, 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.
  • acceptable excipient 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the activity of compounds as parasiticides may be determined by a variety of methods, including in vitro and in vivo methods.
  • D. immitis microfilariae are isolated by filtration from beagle blood of an infected donor and allowed to incubate in appropriate media. Test compounds are diluted in DMSO and added to a 96-well plate containing parasites. Plates are incubated for the desired time and motility is assessed using an LCD camera imaging system. Effect of serum is tested by addition of up to 20% fetal bovine serum in the assay. Percent motility inhibition values are generated relative to the average of the DMSO-only wells.
  • the following compounds from the preparation examples showed EC 50 ⁇ 0.1 ⁇ g/mL: 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 3.1, 3.2, 3.3, 3.4, 4.1, 5.1, 5.2, 5.3, 5.4, 5.6, 5.7, 5.8, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.23, 5.24, 6.1, and 7.1.
  • H.c. eggs isolated from lamb fecal matter are allowed to hatch overnight.
  • Test compounds are diluted in DMSO and added to a 96-well plate containing appropriate media.
  • H.c. larvae are added to each well and plates are incubated for the desired time(s).
  • Motility is assessed using an LCD camera imaging system. Percent motility inhibition values are generated relative to the average of the DMSO-only wells.
  • the following compounds from the preparation examples showed EC 50 ⁇ 1 ⁇ g/mL: 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.8, 3.1, 3.2, 3.3, 3.4, 4.1, 5.1, 5.2, 5.3, 5.4, 5.6, 5.7, 5.8, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.23, 5.24, 6.1, and 7.1.
  • Caenorhabditis elegans C. elegans development assay (Ce DA) measures the effect of compounds on developing nematodes. Eggs of C. elegans are deposited in a 384 well plate together with food ( E. coli ) and the treatment formulated in DMSO. Plates are incubated at 25° C. for 48 h to allow the development of nematodes up to the L4-stage. The effect of compounds is measured as motility reduction. Efficacy is expressed in % motility reduction compared to negative controls.
  • Jirds Meriones unguiculatus ), are artificially infected by gavage with third instar larvae each of T. colubriformis and H. contortus . Then treated orally with the test compound formulated in eg DMSO/PEG 2/1, on Day 6 after infection at a dose in a range between 1 ⁇ 3 mg/kg up to 1 ⁇ 32 mg/kg. Three days after treatment, gerbils are euthanized and dissected to recover H. contortus from stomach and T. colubriformis from the small intestine. Efficacy is expressed as a % reduction in worm numbers in comparison with a placebo treated group, using the Abbot's formula.
  • 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 in a range between 1 ⁇ 3 mg/kg up to 5 ⁇ 32 mg/kg (one dose per 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.
  • mice were experimentally infected with 3rd stage larvae of L. sigmodontis , either by subcutaneous injection or by exposure to infected mites. Treatment was done with test article formulated in DMSO/PEG at a ratio 2/1, by oral gavage or subcutaneous injection at a dose in a range between 1 ⁇ 3 mg/kg (single dose) up to 5 ⁇ 32 mg/kg (one dose per day for 5 consecutive days). At necropsy 35 to 37 days after infection, worms are counted in the peritoneum and the pleural cavity. Efficacy is expressed as % reduction in worm numbers in comparison with the placebo treated group, using the Abbot's formula. The compound of examples 3.3, 5.3, 5.41, 5.47, 5.48 and 5.56 were >80% effective against L.s.

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MX2022015038A (es) 2020-05-29 2023-01-04 Boehringer Ingelheim Animal Health Usa Inc Compuestos heterociclicos como anthelminticos.
EP4247809A2 (en) * 2020-11-18 2023-09-27 Elanco Tiergesundheit AG N-(2,3-dihydro-1,4-benzoxazin-4-yl)-3-isopropyl-7-(2,3,5-trifluorophenyl)benzo-thiophene-2-carboxamide derivatives and similar compounds for the treatment of heartworm infections
EP4148052A1 (en) * 2021-09-09 2023-03-15 Bayer Animal Health GmbH New quinoline derivatives
AR127495A1 (es) 2021-11-01 2024-01-31 Boehringer Ingelheim Vetmedica Gmbh Compuestos de pirrolopiridazina como antihelmínticos
WO2023137307A1 (en) * 2022-01-14 2023-07-20 Enko Chem, Inc. Protoporphyrinogen oxidase inhibitors
CN114890920B (zh) * 2022-05-27 2023-12-12 东营施普瑞石油工程技术有限公司 一种防水锁剂及其制备方法

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DE4440193A1 (de) * 1994-11-10 1996-05-15 Bayer Ag Verwendung von Dioxomorpholinen zur Bekämpfung von Endoparasiten, neue Dioxomorpholine und Verfahren zur ihrer Herstellung
JP2001525365A (ja) * 1997-12-11 2001-12-11 バイオケム・フアーマ・インコーポレーテツド 抗ウイルス化合物
WO2000059884A1 (en) * 1999-01-26 2000-10-12 Dana-Farber Cancer Institute, Inc. Pharmaceutically active compounds and methods of use thereof
TW200300140A (en) * 2001-11-14 2003-05-16 Novartis Ag Organic compounds
CN101675056A (zh) * 2007-05-02 2010-03-17 诺瓦提斯公司 杂环化合物及其作为杀虫剂的用途
AU2012273133A1 (en) * 2011-06-20 2013-11-07 E. I. Du Pont De Nemours And Company Heterocyclic compounds for treating helminth infections
US9221835B2 (en) * 2012-09-07 2015-12-29 Zoetis Services Llc Spirocyclic derivatives as antiparasitic agents
CN105164124B (zh) * 2012-11-19 2017-03-15 诺华股份有限公司 用于治疗寄生虫疾病的化合物和组合物
ES2683693T3 (es) * 2014-01-03 2018-09-27 Bayer Animal Health Gmbh Nuevas pirazolil-heteroarilamidas como agentes plaguicidas
JP2017519801A (ja) * 2014-07-11 2017-07-20 インターベット インターナショナル ベー． フェー． 犬糸状虫に対する駆虫薬の使用
RU2769448C2 (ru) * 2016-04-15 2022-03-31 Байер Энимэл Хельс ГмбХ Новые пиразолпиримидиновые производные
AU2017357503B2 (en) * 2016-11-11 2022-02-17 Bayer Animal Health Gmbh New anthelmintic quinoline-3-carboxamide derivatives
SG11201909243TA (en) 2017-04-27 2019-11-28 Bayer Animal Health Gmbh New bicyclic pyrazole derivatives
AU2018293627B2 (en) * 2017-06-30 2022-07-21 Bayer Animal Health Gmbh New azaquinoline derivatives
IL272156B2 (en) * 2017-08-04 2023-09-01 Bayer Animal Health Gmbh History of quinoline for the treatment of worm infections
EP3897843A1 (en) * 2018-12-18 2021-10-27 Elanco Tiergesundheit AG Bicyclic derivatives
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