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WO2016069949A1 - Compositions et formulations d'inhibiteurs de la voie méthylerthritol phosphate et leurs utilisations - Google Patents

Compositions et formulations d'inhibiteurs de la voie méthylerthritol phosphate et leurs utilisations Download PDF

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Publication number
WO2016069949A1
WO2016069949A1 PCT/US2015/058157 US2015058157W WO2016069949A1 WO 2016069949 A1 WO2016069949 A1 WO 2016069949A1 US 2015058157 W US2015058157 W US 2015058157W WO 2016069949 A1 WO2016069949 A1 WO 2016069949A1
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formula
indole
tetrahydro
nmr
mhz
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Inventor
Paul R. Carlier
Maria Belen CASSERA
Emilio Fernando MERINO
Zhong-ke YAO
Maryam GHAVAMI
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Virginia Tech Intellectual Properties Inc
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Virginia Tech Intellectual Properties Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—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

  • compositions and pharmaceutical formulations thereof where the composition can have a structure according to Formula 209:
  • R-i can be H, COOCH 3 , COOEt, COOH, CONH 2 , CONHCH 3 , a CONHd_ 6 alkyl, CONH(CH) 1 _ 5 (CH 3 ) 2 , CON(C 6 Hi i ), CONHNHCH3, CON(CH 3 ) 2 , or CH 2 OH,
  • R 2 can be H or a C-i-Ce alkyl
  • R 3 can be H, a C1-C6 alkyl group, a benzyl, COCH 3 ,or a diketopiperazine formed between N 2 and R-i ,
  • Xi 2 -Xi 5 can each be independently selected from the group of: H and a halogen
  • R 4 can have a structure according to Formula 210 or 21 1
  • X1-X5 can each be independently selected from the group of H, a halogen, a C C 6 alkyl, a C C 6 alkoxy, NHCH 3 , and C(Xi 6 )3 where Xi 6 can be a halogen,
  • X 6 can be C or N
  • 0 can be selected from the group of O, S, and NXn , where Xn can be selected from the group of: H, a halogen, a C C 6 alkyl, a C C 6 alkoxy, NHCH 3 , and C(Xi 6 )3, where Xi 6 can be a halogen and
  • X7-X9 can each be independently selected from the group of: H, a halogen, a C C 6 alkyl, a C C 6 alkoxy, NHCH 3 , and C(Xi 6 )3 where Xi 6 can be a halogen.
  • the compound does not have a structure according to Formula 60
  • the composition can have (1 R,3S) configuration.
  • the compound can have an R 4 of Formula 210.
  • the halogens specifed in composition can be each independently selected from F, CI, Br, and I.
  • Xi and X 3 are each can each be a halogen.
  • the halogen can be independently selected from F, CI, Br, and I.
  • Xi and X 3 can each be independently selected from a halogen and a C C 6 alkyl.
  • the halogen can be independently selected from F, CI, Br, and I and the C C 6 alkyl is a methyl.
  • Ri can be COOH or CONHCH 3 .
  • compositions can, in some embodiments, inhibit an enzyme of the methylerythritol phosphate pathway.
  • the compositions can, in some embodiments, be toxic to to an organism of the genus Plasmodium.
  • the toxicity at 5 ⁇ of compound is completely eliminated by supplementation with an amount of isopentenyl diphosphate (IPP).
  • IPP isopentenyl diphosphate
  • the toxicity at 5 ⁇ of compsition is completely eliminated by supplementation with an amount of IPP.
  • the composition can be according to Formula 70, 74, 75, 80, 90, 126, 127, 128, 129, 131 , 133, 138, or 140.
  • the composition can be according to Formula 74, 80, 90, 126, 127, 128, 129, 133, 138, or 140.
  • the composition can have an IC 50 for growth inhibition of the organisim of about 880 nM or less. In some embodiments, the composition can have an IC 50 for growth inhibition of the organisim of about 650 nM or less.
  • the pharmaceutial formulations thereof can include a pharmaceutically acceptable carrier.
  • compositions or pharmaceutical formulation thereof can have a structure according to Formula 209:
  • R-i can be H, COOCH 3 , COOEt, COOH, CONH 2 , CONHCH 3 , a CONHd-ealkyl, CONH(CH) 1 _ 5 (CH 3 ) 2 , CON(C 6 Hn), CONHNHCH3, CON(CH 3 ) 2 , or CH 2 OH,
  • R 2 can be H or a C C 6 alkyl
  • R 3 can be H, a C1-C6 alkyl group, a benzyl, COCH 3 ,or a diketopiperazine formed between N 2 and Ri ,
  • Xi 2 -Xis can each be independently selected from the group of: H and a halogen
  • R 4 can have a structure according to Formula 210 or 21 1
  • X1-X5 can each be independently selected from the group of H, a halogen, a C C 6 alkyl, a C C 6 alkoxy, NHCH 3 , and C(Xi 6 )3 where Xi 6 can be a halogen,
  • X 6 can be C or N
  • 0 can be selected from the group of O, S, and NXn , where Xn can be selected from the group of: H, a halogen, a C C 6 alkyl, a C C 6 alkoxy, NHCH 3 , and C(Xi 6 )3, where Xi 6 can be a halogen, and where X 7 -X 9 can each be independently selected from the group of: H, a halogen, a C C 6 alkyl, a C C 6 alkoxy, NHCH 3 , and C(Xi 6 )3 where Xi 6 can be a halogen.
  • the compound does not have a structure according to Formula 60
  • the pharmaceutial formulations thereof can include a pharmaceutically acceptable carrier.
  • the subject can be infected with or can be suspected of being infected with a methylerythritol phosphate (MEP) pathway obligate organism.
  • the composition or pharmaceutical formulation can be administered prophylactically to prevent infection by a methylerythritol phosphate (MEP) pathway obligate organism.
  • the organisim can be a species of the genus Plasmodium, Toxoplasma, Mycobacterium, Baccillus, Vibrio, Clostriduium, Helicobacter, Campylobacter, Chlamydia, Brucella, Eimeria, Klebsiella, Acinetobacter, Pseudomonas, or Neisseria.
  • the organisim can be P. falciparum, P. malariae, P. ovale, P. v/Va or P. knowlesi.
  • the organisim can be T. gondii, M.
  • composition or pharmaceutical formulation can be administered orally, intramuscularly, intravenously, topically or subcutaneously.
  • compositions can have a structure according to Formula 209:
  • R-i can be H, COOCH 3 , COOEt, COOH, CONH 2 , CONHCH 3 , a CONHd-ealkyl, CONH(CH) 1 _ 5 (CH 3 ) 2 , CON(C 6 Hn), CONHNHCH3, CON(CH 3 ) 2 , or CH 2 OH,
  • R 2 can be H or a C C 6 alkyl
  • R 3 can be H, a C1-C6 alkyl group, a benzyl, COCH 3 ,or a diketopiperazine formed between N 2 and Ri ,
  • Xi 2 -Xis can each be independently selected from the group of: H and a halogen
  • R 4 can have a structure according to Formula 210 or 21 1
  • X1-X5 can each be independently selected from the group of H, a halogen, a C C 6 alkyl, a C C 6 alkoxy, NHCH 3 , and C(Xi 6 )3 where Xi 6 can be a halogen,
  • X 6 can be C or N
  • 0 can be selected from the group of O, S, and NXn , where Xn can be selected from the group of: H, a halogen, a C C 6 alkyl, a C C 6 alkoxy, NHCH 3 , and C(Xi 6 )3, where Xi 6 can be a halogen, where X 7 -X 9 can each be independently selected from the group of: H, a halogen, a C C 6 alkyl, a C C 6 alkoxy, NHCH 3 , and C(Xi 6 )3 where Xi 6 can be a halogen.
  • the compound does not have a structure according to Formula 60
  • the organisim can be a methylerythritol phosphate (MEP) pathway obligate organism.
  • the organsim can use the methylerythritol phosphate (MEP) pathway to synthesize isopentenyl diphosphate (IPP).
  • the organism can be a plant.
  • the organism can be a protazoan.
  • the organsim can be a bacterium.
  • a composition according to Formula 60 or a pharmaceutical formulation comprising a composition according to Formula 60 to a subject in need thereof, where the subject in need thereof can be infected with or can be suspected of being infected with a methylerythritol phosphate (MEP) pathway obligate organism.
  • MEP methylerythritol phosphate
  • composition according to Formula 60 or a pharmaceutical formulation comprising a composition according to Formula 60 to a subject in need thereof to prevent infection by a methylerythritol phosphate (MEP) pathway obligate organism.
  • MEP methylerythritol phosphate
  • Fig. 1 shows a cartoon demonstrating nisotropic displacement ellipsoid drawings (50%) of X-ray structure of Formula 80, confirming (1 R, 3S)-absolute configuration.
  • Fig. 2 shows a table demonstrating P. falciparum growth inhibitory activity and effect of isopentenyl diphosphate (IPP) supplementation of MMV08138 stereoisomers and D-ring variants.
  • IPP isopentenyl diphosphate
  • Fig. 3 shows a table demonstrating the synthesis and isolated yields for various embodiments of the compositions described herein.
  • Fig. 4 shows a table demonstrating the effect of C3-substitution on the P. falciparum growth inhibitory activity of a compound according to Formula 60 and some D-ring variants.
  • Fig. 5 shows embodiments of a synthesis scheme for C3 variants of Formula 60.
  • the reagents and conditions were (i) 2,4-dichlorobenzaldehyde, 4 A molecular sieves, CH 2 CI 2 , 24h. (ii) Requisite amine or hydrazine, 25°C or 50°C, 24 h.
  • Figs. 6A and 6B show graphs demonstrating the effects of compounds according to Formula 60 (Fig. 6A) and Formula 80 (Fig. 6B) on P. falciparum Dd2 strain growth in the absence and presence of 200 ⁇ IPP (72h incubation). Data represent the average and standard error of five independent experiments.
  • Fig. 7 shows a table demonstrating in vitro ADME Toxicity of compounds according to Formulas 60 and 80.
  • Fig. 8 shows a graph demonstrating pharmokinetics of a compound according to Formula 60 in the Mouse via oral (PO) (40 mg/kg) or intravenous (IV) (10 mg/kg) administration.
  • Fig. 9 shows a graph demonstrating surviability of E. coli in the presence of various compositions described herein.
  • Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of molecular biology, microbiology, nanotechnology, organic chemistry, chemistry biochemistry, botany and the like, which are within the skill of the art. Such techniques are explained fully in the literature.
  • control is an alternative subject or sample used in an experiment for comparison purposes and included to minimize or distinguish the effect of variables other than an independent variable.
  • a “control” can be positive or negative.
  • pharmaceutical formulation refers to the combination of an active agent, compound, or ingredient with a pharmaceutically acceptable carrier or excipient, making the composition suitable for diagnostic, therapeutic, or preventive use in vitro, in vivo, or ex vivo.
  • pharmaceutically acceptable carrier or excipient refers to a carrier or excipient that is useful in preparing a pharmaceutical formulation that is generally safe, non-toxic, and is neither biologically or otherwise undesirable, and includes a carrier or excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier or excipient” as used in the specification and claims includes both one and more than one such carrier or excipient.
  • pharmaceutically acceptable salt refers to any acid or base addition salt whose counter-ions are non-toxic to the subject to which they are administered in pharmaceutical doses of the salts.
  • subject refers to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets.
  • the term “pet” includes a dog, cat, guinea pig, mouse, rat, rabbit, ferret, and the like.
  • farm animal includes a horse, sheep, goat, chicken, pig, cow, donkey, llama, alpaca, turkey, and the like.
  • therapeutic refers to treating or curing a disease or condition.
  • preventative refers to hindering or stopping a disease or condition before it occurs or while the disease or condition is still in the sub-clinical phase.
  • active agent or “active ingredient” refers to a component or components of a composition to which the whole or part of the effect of the composition is attributed.
  • dose refers to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of the nanoparticle composition or formulation calculated to produce the desired response or responses in association with its administration.
  • antibody refers to a protein produced by B cells that is used by the immune system to identify and neutralize foreign compounds, which are also known as antigens. Antibodies are glycoproteins belonging to the immunoglobulin superfamily. Antibodies, recognize and bind to specific epitopes on an antigen.
  • aptamer refers to single-stranded DNA or RNA molecules that can bind to pre-selected targets including proteins with high affinity and specificity. Their specificity and characteristics are not directly determined by their primary sequence, but instead by their tertiary structure.
  • immunomodulator refers to an agent, such as a therapeutic agent, which is capable of modulating or regulating one or more immune function or response.
  • RNA deoxyribonucleic acid
  • DNA deoxyribonucleic acid
  • RNA ribonucleic acid
  • DNA deoxyribonucleic acid
  • RNA ribonucleic acid
  • RNA may be in the form of a tRNA (transfer RNA), snRNA (small nuclear RNA), rRNA (ribosomal RNA), mRNA (messenger RNA), anti-sense RNA, RNAi (RNA interference construct), siRNA (short interfering RNA), or ribozymes.
  • Anti-infectives include, but are not limited to, antibiotics, antibacterials, antifungals, antivirals, and antiproatozoals.
  • derivative refers to any compound having the same or a similar core structure to the compound but having at least one structural difference, including substituting, deleting, and/or adding one or more atoms or functional groups.
  • derivative does not mean that the derivative is synthesized from the parent compound either as a starting material or intermediate, although this may be the case.
  • derivative can include prodrugs, or metabolites of the parent compound.
  • Derivatives include compounds in which free amino groups in the parent compound have been derivatized to form amine hydrochlorides, p-toluene sulfoamides, benzoxycarboamides, t- butyloxycarboamides, thiourethane-type derivatives, trifluoroacetylamides, chloroacetylamides, or formamides.
  • Derivatives include compounds in which carboxyl groups in the parent compound have been derivatized to form methyl and ethyl esters, or other types of esters or hydrazides.
  • Derivatives include compounds in which hydroxyl groups in the parent compound have been derivatized to form O-acyl or O-alkyl derivatives.
  • Derivatives include compounds in which a hydrogen bond donating group in the parent compound is replaced with another hydrogen bond donating group such as OH, NH, or SH.
  • Derivatives include replacing a hydrogen bond acceptor group in the parent compound with another hydrogen bond acceptor group such as esters, ethers, ketones, carbonates, tertiary amines, imine, thiones, sulfones, tertiary amides, and sulfides.
  • “Derivatives” also includes extensions of the replacement of the cyclopentane ring with saturated or unsaturated cyclohexane or other more complex, e.g., nitrogen-containing rings, and extensions of these rings with side various groups.
  • administering refers to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation, or via an implanted reservoir.
  • parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra- synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques.
  • suitable substituent means a chemically and pharmaceutically acceptable group, i.e., a moiety that does not significantly interfere with the preparation of or negate the efficacy of the inventive compounds. Such suitable substituents may be routinely chosen by those skilled in the art.
  • Suitable substituents include but are not limited to the following: a halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkynyl, C3-C8 cycloalkenyl, (C3-C8 cycloalkyl)C1-C6 alkyl, (C3- C8 cycloalkyl)C2-C6 alkenyl, (C3-C8 cycloalkyl) C1-C6 alkoxy, C3-C7 heterocycloalkyl, (C3- C7 heterocycloalkyl)C1-C6 alkyl, (C3-C7 heterocycloalkyl)C2-C6 alkenyl, (C3-C7 heterocycloalkyl)C1-C6 alkoxyl, hydroxy, carboxy, oxo, sulf
  • optically substituted indicates that a group may be unsubstituted or substituted with one or more substituents as defined herein.
  • alkyl refers to the radical of saturated aliphatic groups (i.e., an alkane with one hydrogen atom removed), including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl- substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C C 3 o for straight chains, and C 3 -C 3 o for branched chains).
  • a straight chain or branched chain alkyl contains 20 or fewer, 15 or fewer, or 10 or fewer carbon atoms in its backbone.
  • cycloalkyls have 3-10 carbon atoms in their ring structure. In some of these embodiments, the cycloalkyl have 5, 6, or 7 carbons in the ring structure.
  • alkyl (or “lower alkyl) as used herein is intended to include both “unsubstituted alkyls” and “substituted alkyls,” the latter of which refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents include, but are not limited to, halogen, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.
  • carbonyl such as a carboxyl, alkoxycarbonyl, formyl, or an acyl
  • thiocarbonyl such as a thioester, a thi
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths.
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include halogen, hydroxy, nitro, thiols, amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN and the like. Cycloalkyls can be substituted in the same manner.
  • heteroalkyl refers to straight or branched chain, or cyclic carbon-containing radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, Se, B, and S, wherein the phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of - S-alkyl, -S-alkenyl, and -S-alkynyl.
  • Representative alkylthio groups include methylthio, ethylthio, and the like.
  • alkylthio also encompasses cycloalkyi groups, alkene and cycloalkene groups, and alkyne groups.
  • Arylthio refers to aryl or heteroaryl groups. Alkylthio groups can be substituted as defined above for alkyl groups.
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkoxyl refers to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl is an ether or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O- alkenyl, and -O-alkynyl.
  • aromatic and aryloxy can be represented by -O-aryl or O-heteroaryl, wherein aryl and heteroaryl are as defined below.
  • alkoxy and aroxy groups can be substituted as described above for alkyl.
  • amine and “amino” (and its protonated form) are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula:
  • R, R', and R" each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2) m -R c or R and R' taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
  • R c represents an aryl, a cycloalkyi, a cycloalkenyl, a heterocycle or a polycycle; and
  • m is zero or an integer in the range of 1 to 8.
  • only one of R or R' can be a carbonyl, e.g., R, R' and the nitrogen together do not form an imide.
  • the term "amine” does not encompass amides, e.g., wherein one of R and R' represents a carbonyl.
  • R and R' each independently represent a hydrogen, an alkyl or cycloakly, an alkenyl or cycloalkenyl, or alkynyl.
  • alkylamine as used herein means an amine group, as defined above, having a substituted (as described above for alkyl) or unsubstituted alkyl attached thereto, i.e., at least one of R and R' is an alkyl group.
  • the term "amido" is art-recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula:
  • R and R' are as defined above.
  • Aryl refers to C 5 -Cio-membered aromatic, heterocyclic, fused aromatic, fused heterocyclic, biaromatic, or bihetereocyclic ring systems.
  • aryl includes 5-, 6-, 7-, 8-, 9-, and 10-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or “heteroaromatics.”
  • the aromatic ring can be substituted at one or more ring positions with one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyi, alkenyl, alkynyl, cycloalkyi, hydroxyl, alkoxyl, amino (or quaternized amino), nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF 3 , -CN, and combinations thereof.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (i.e., "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic ring or rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles.
  • heterocyclic rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H- ⁇ ,5,2-dithiazinyl, dihydrofuro[2,3 bjtetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, ⁇ /-/-indazolyl, indolenyl, indolinyl,
  • aralkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • aralkyloxy can be represented by -O-aralkyl, wherein aralkyl is as defined above.
  • carrier refers to an aromatic or non-aromatic ring(s) in which each atom of the ring(s) is carbon.
  • Heterocycle or “heterocyclic,” as used herein, refers to a monocyclic or bicyclic structure containing 3-10 ring atoms, and in some embodiments, containing from 5-6 ring atoms, wherein the ring atoms are carbon and one to four heteroatoms each selected from the following group of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O, (C1-C10) alkyl, phenyl or benzyl, and optionally containing 1-3 double bonds and optionally substituted with one or more substituents.
  • heterocyclic rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 21-1,61-1-1 ,5, 2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H-indazolyl, indolenyl, indolinyl, indoliziny
  • Heterocyclic groups can optionally be substituted with one or more substituents at one or more positions as defined above for alkyl and aryl, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents at one or more positions as defined above for alkyl and aryl, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydr
  • carbonyl is art-recognized and includes such moieties as can be represented by the general formula:
  • X is a bond or represents an oxygen or a sulfur, and R and R' are as defined above. Where X is an oxygen and R or R' is not hydrogen, the formula represents an "ester”. Where X is an oxygen and R is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R is a hydrogen, the formula represents a "carboxylic acid.” Where X is an oxygen and R' is hydrogen, the formula represents a "formate.” In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiocarbonyl" group.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen.
  • exemplary heteroatoms include, but are not limited to, boron, nitrogen, oxygen, phosphorus, sulfur, silicon, arsenic, and selenium.
  • nitro refers to -N0 2 ;
  • halogen designates -F, -CI, -Br, or -I;
  • sulfhydryl refers to -SH;
  • hydroxyl refers to -OH; and the term “sulfonyl” refers to -S0 2 -.
  • substituted refers to all permissible substituents of the compounds described herein.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic groupings containing any number of carbon atoms, e.g. 1-14 carbon atoms, and optionally include one or more heteroatoms such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats.
  • substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl
  • Heteroatoms such as nitrogen, may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. It is understood that “substitution” or “substituted” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • ⁇ ективное amount refers to the amount of a composition described herein or pharmaceutical formulation described herein that will elicit a desired biological or medical response of a tissue, system, animal, plant, protozoan, bacteria or yeastor human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the desired biological response can be death, growth inhibition, reproductive inhibition, and/or development inhibition.
  • the effective amount will vary depending on the exact chemical structure of the composition or pharmaceutical formulation, the causative agent and/or severity of the infection, disease, disorder, syndrome, or symptom thereof being treated or prevented, the route of administration, the time of administration, the rate of excretion, the drug combination, the judgment of the treating physician, the dosage form, and the age, weight, general health, sex and/or diet of the subject to be treated.
  • falciparum occurs in the apicoplast not via the mevalonate pathway, but rather through the methlerythritol phosphate (MEP) pathway.
  • MEP methlerythritol phosphate
  • IPP isopentenyl diphosphate
  • DMAPP dimethylallyl diphosphate
  • Fosmidomycin was shown to inhibit 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR or IspC), the second enzyme in the MEP pathway, and it cured mice infected with Plasmodium vinckei.
  • DXR or IspC 1-deoxy-D-xylulose 5-phosphate reductoisomerase
  • IspC 1-deoxy-D-xylulose 5-phosphate reductoisomerase
  • FOS was evaluated in clinical trials.
  • FOS is unacceptable as a anti-malarial due to poor oral bioavailability.
  • compositions and formulations thereof containing a MMV008138 derivative or analogue.
  • methods of making and using the compositions, and formulations thereof described herein can, in some embodiments, inhibit the MEP pathway enzyme(s) and thus can be useful for treatment and/or prevention of organisms that utilize the MEP pathway.
  • Other compositions, compounds, methods, features, and advantages of the present disclosure will be or become apparent to one having ordinary skill in the art upon examination of the following drawings, detailed description, and examples. It is intended that all such additional compositions, compounds, methods, features, and advantages be included within this description, and be within the scope of the present disclosure.
  • toxic can refer to a effect that is the result of a composition or pharmaceutical formulation described herein, where the effect is detrimental to the life, growth, development, reproduction, and/or health of an organisim.
  • a composition that can inhibit the growth of an organism can be refered to herein as being toxic to that organism.
  • a MEP-obligate organism refers to an organism that must have a functioning MEP pathway to grow, develop, reproduce, and/or survive.
  • the apicoplast in Plasmodium is essential for both intraerythrocytic and intrahepatic development in a human host.
  • Supply of the isoprenoid precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) is the sole essential function of this organelle in these life stages. Synthesis of these compounds in Plasmodium occurs via the MEP pathway, which is absent in humans. Plasmodium is an MEP-obligate organism as disruption of the MEP pathway results in an inability for the parasite to complete its life cycle.
  • compositions that can inhibit or eliminate isoprenoid biosynthesis in an organism.
  • the compositions can inhibit or ablate isoprenoid biosynthesis by targeting and/or inhibiting one or more enzymes in the methylerthritol phosphate (MEP) pathway.
  • MEP methylerthritol phosphate
  • the compositions can be toxic to an organism.
  • the compositions can selectively inhibit or eliminate isoprenoid biosynthesis in some organisms and not others.
  • composition can have a structure according to formula 209.
  • R-i can be H, COOCH 3 , COOEt, COOH, CONH 2 , CONHCH 3 , a CONHd_ 6 alkyl, CONH(CH) 1 _ 5 (CH 3 ) 2 , CON(C 6 Hi i ), CONHNHCH3, CON(CH 3 ) 2 , or CH 2 OH,
  • R 2 can be H or a C C 6 alkyl
  • R 3 can be H, a C1-C6 alkyl group, a benzyl, COCH 3 ,or a diketopiperazine formed between N 2 and Ri ,
  • Xi 2 -Xi 5 can each be independently selected from the group of: H and a halogen
  • X1-X5 can each be independently selected from the group of H, a halogen, a CrC 6 alkyl, a Ci-C 6 alkoxy, NHCH 3 , and C(Xi 6 )3 where Xi 6 can be a halogen,
  • X 6 can be C or N
  • 0 can be selected from the group of O, S, and NXn , where Xn can be selected from the group of: H, a halogen, a C C 6 alkyl, a C C 6 alkoxy, NHCH 3 , and C(Xi 6 )3, where Xi 6 can be a halogen, and
  • X 7 -X 9 can each be independently selected from the group of: H, a halogen, a C C 6 alkyl, a C C 6 alkoxy, NHCH 3 , and C(Xi 6 )3 where Xi 6 can be a halogen.
  • the compound does not have a structure according to Formula 60.
  • Formula 209 is shown with 4 ring designations: A, B, C, and D. As such, it will be understood that when a portion of the compound of Formula 209 is referred to herein as the "D ring” it is referring to the ring labeled with “D” in formula 209. Some positions are numbered in Formula 209 for reference. As such, it will be understood that when numbers are used to describe a particular feature of a composition according to Formula 9, the numbers are referring to the location of the feature within the compositions. For example, the stereoisomer 1 R, 3S, has the R isomer at the position designated with the "1 " in Formula 209 and is the S isomer at the position designated with the "3" in Formula 209.
  • the composition can have a (1 R,3S)-, (1 S,3S)-, (1 R,3R)-, or a (1 S,3R)- configuration. In some embodiments the composition can have a (1 R,3S)- configuration.
  • R4 is Formula 210.
  • X 1 and X 3 are each a halogen.
  • the halogen can be F, CI, Br, or I.
  • X 1 and X 3 can be the same or different.
  • X 1 and X3 can each be independently selected from a halogen and a d-Ce alkyl.
  • the halogen can be F, CI, Br, or I.
  • the C C 6 alkyl can be methyl.
  • X 1 and X 3 can be the same or different.
  • R 2 and R 3 can both be H.
  • the composition can have a structure according to any one of Formulas 70, 74, 75, 66, 79, 80, 86, 90, 91 , 84, 126,127, 128, 129, 131 , 133, 138, 140, 182, 183, 184, 188, 189, 190, 194, 195, 196, 200, 201 , or 203.
  • the composition can have a structure according to any one of formulas 70, 74, 75, 80, 90, 126, 127, 128, 129, 131 , 133, 138, or 140.
  • the composition can have a structure according to any one of formulas 74, 80, 90, 126, 127, 128, 129, 133, 138, or 140.
  • the composition can have a strucutre according to Formula 60.
  • the compositions described herein can be toxic to an organism.
  • the compositions described herein can inhibit the growth of an organism.
  • the compositions describe herein can disrupt the reproduction cycle of an organism.
  • the organism can be a plant, animal, protazoan bacteria, fungi, or yeast.
  • the organism can synthesize isoprenoids via the MEP pathway.
  • the organism can be a MEP-obligate organism.
  • the organism can be from the genus Plasmoidum.
  • the organism can be P.
  • the organism can be a species of the genus Plasmodium, Toxoplasma, Mycobacterium, Baccillus, Vibrio, Clostriduium, Helicobacter, Campylobacter, Chlamydia, Brucella, Eimeria, Klebisella, Acinetobacter, Pseudomonas, and Neisseria.
  • the organism can be T. gondii, M. tuberculosis, B. anthracis, V. cholera, C. difficile, C. botulinum, H. pylori, C. jejuni, C. trachomatis 434/Bu, C. pneumoniae, B. abortus, E. tenella. K. pneumoniae, A. baumanii, P. aeruginosa, and N. gonorrhoeae.
  • compositions described herein can inhibit or block the growth, development, and/or reproduction of an organism.
  • IC 50 for growth inhibition of the organism can be about 1500 nM or less, about 1200 nM or less, or about 1000 nM or less.
  • the IC 50 for growth inhibition of the organism can be about 880 nM or less.
  • the IC 50 for growth inhibition of the organism can be about 650 nM or less.
  • the organism can be a species of the genus Plasmodium,
  • the organism can be T. gondii, M. tuberculosis, B. anthracis, V. cholera, C. difficile, C. botulinum, H. pylori, C. jejuni, C. trachomatis 434/Bu, C. pneumoniae, B. abortus, E. tenella. K. pneumoniae, A. baumanii, P. aeruginosa, and N. gonorrhoeae.
  • compositions described herein can be provided to a subject alone or as an ingredient, such as an active ingredient, in a pharmaceutical formulation or pharmaceutically acceptable salt thereof.
  • pharmaceutical formulation includes pharmaceutically acceptable salts thereof. Methods of making pharmaceutically acceptable salts are generally known in the art.
  • pharmaceutical formulations that can contain one or more of the compositions described herein.
  • the pharmaceutical formulations can contain an effective amount of a composition described herein.
  • the pharmaceutical formulations can be administered to a subject in need thereof.
  • the subject in need thereof can be infected with or suspected of being infected with an organism that synthesizes isoprenoids via the MEP pathway.
  • the subject in need thereof can be infected with or suspected of being infected with an organism that is a MEP-obligate organism.
  • the compositions and pharmaceutical formulations described herein can be administered prophylactically to a subject in need thereof.
  • the subject in need thereof does not have any known exposure to an MEP-obligate organism.
  • the organism can be from the genus Plasmoidum.
  • the organism can be P. falciparum, P. malariae, P. ovale, P. vivax or P. knowlesi.
  • the organism can be a species of the genus Plasmodium, Toxoplasma, Mycobacterium, Baccillus, Vibrio, Clostriduium, Helicobacter, Campylobacter, Chlamydia, Brucella, Eimeria, Klebisella, Acinetobacter, Pseudomonas, and Neisseria.
  • the organism can be a carbapenem-resistant enterobacteriaceae.
  • the organism can be T.
  • gondii M. tuberculosis, B. anthracis, V. cholera, C. difficile, C. botulinum, H. pylori, C. jejuni, C. trachomatis 434/Bu, C. pneumoniae, B. abortus, E. tenella. K. pneumoniae, A. baumanii, P. aeruginosa, and N. gonorrhoeae.
  • compositions described herein can be included as a pharmaceutical formulation.
  • a composition included in the pharmaceutical formulation can have a structure according to any one of Formulas 60, 70, 74, 75, 66, 79, 80, 86, 90, 91 , 84, 126,127, 128, 129, 131 , 133, 138, 140, 182, 183, 184, 188, 189, 190, 194, 195, 196, 200, 201 , or 203.
  • the pharmaceutical formulations containing an amount of a composition described herein can further include a pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carriers include, but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxyl methylcellulose, and polyvinyl pyrrolidone, which do not deleteriously react with the active composition.
  • the pharmaceutical formulations can be sterilized, and if desired, mixed with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances, and the like which do not deleteriously react with the active composition.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances, and the like which do not deleteriously react with the active composition.
  • the pharmaceutical formulation can also include an effective amount of auxiliary active agents, including but not limited to, DNA, RNA, amino acids, peptides, polypeptides, antibodies, aptamers, ribozymes, guide sequences for ribozymes that inhibit translation or transcription of essential tumor proteins and genes, hormones, immunomodulators, antipyretics, anxiolytics, antipsychotics, analgesics, antispasmodics, anti-inflammatories, anti-histamines, anti-infectives, and chemotherapeutics.
  • auxiliary active agents including but not limited to, DNA, RNA, amino acids, peptides, polypeptides, antibodies, aptamers, ribozymes, guide sequences for ribozymes that inhibit translation or transcription of essential tumor proteins and genes, hormones, immunomodulators, antipyretics, anxiolytics, antipsychotics, analgesics, antispasmodics, anti-inflammatories, anti-histamines, anti
  • Suitable hormones include, but are not limited to, amino-acid derived hormones (e.g. melatonin and thyroxine), small peptide hormones and protein hormones (e.g. thyrotropin- releasing hormone, vasopressin, insulin, growth hormone, luteinizing hormone, follicle- stimulating hormone, and thyroid-stimulating hormone), eiconsanoids (e.g. arachidonic acid, lipoxins, and prostaglandins), and steroid hormones (e.g. estradiol, testosterone, tetrahydro testoste ro n co rtiso I ) .
  • amino-acid derived hormones e.g. melatonin and thyroxine
  • small peptide hormones and protein hormones e.g. thyrotropin- releasing hormone, vasopressin, insulin, growth hormone, luteinizing hormone, follicle- stimulating hormone, and thyroid-stimulating hormone
  • Suitable immunomodulators include, but are not limited to, prednisone, azathioprine, 6-MP, cyclosporine, tacrolimus, methotrexate, interleukins (e.g. IL-2, IL-7, and IL-12), cytokines (e.g. interferons (e.g. I FN-a, I FN- ⁇ , I FN- ⁇ , I FN-K, I FN- ⁇ , and I FN- ⁇ ), granulocyte colony-stimulating factor, and imiquimod), chemokines (e.g. CCL3, CCL26 and CXCL7), cytosine phosphate-guanosine, oligodeoxynucleotides, glucans, antibodies, and aptamers).
  • interleukins e.g. IL-2, IL-7, and IL-12
  • cytokines e.g. interferons (e.g. I FN-a, I FN- ⁇ ,
  • Suitable antipyretics include, but are not limited to, non-steroidal anti-inflammants (e.g. ibuprofen, naproxen, ketoprofen, and nimesulide), aspirin and related salicylates (e.g. choline salicylate, magnesium salicylae, and sodium salicaylate), paracetamol/acetaminophen, metamizole, nabumetone, phenazone, and quinine.
  • non-steroidal anti-inflammants e.g. ibuprofen, naproxen, ketoprofen, and nimesulide
  • aspirin and related salicylates e.g. choline salicylate, magnesium salicylae, and sodium salicaylate
  • paracetamol/acetaminophen metamizole
  • metamizole nabumetone
  • phenazone phenazone
  • quinine quinine
  • Suitable anxiolytics include, but are not limited to, benzodiazepines (e.g. alprazolam, bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam, and tofisopam), serotenergic antidepressants (e.g.
  • selective serotonin reuptake inhibitors tricyclic antidepresents, and monoamine oxidase inhibitors
  • mebicar afobazole
  • selank.bromantane emoxypine
  • azapirones barbituates
  • hyxdroxyzine pregabalin, validol, and beta blockers.
  • Suitable antipsychotics include, but are not limited to, benperidol, bromoperidol, droperidol, haloperidol, moperone, pipaperone, timiperone, fluspirilene, penfluridol, pimozide, acepromazine, chlorpromazine, cyamemazine, dizyrazine, fluphenazine, levomepromazine, mesoridazine, perazine, pericyazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine, trifluoperazine, triflupromazine, chlorprothixene, clopenthixol, flupentixol, tiotixene, zuclopenthixol, clotiapine, loxapine, prothipendyl, car
  • Suitable analgesics include, but are not limited to, paracetamol/acetaminophen, nonsteroidal anti-inflammants (e.g. ibuprofen, naproxen, ketoprofen, and nimesulide), COX-2 inhibitors (e.g. rofecoxib, celecoxib, and etoricoxib), opioids (e.g.
  • morphine morphine, codeine, oxycodone, hydrocodone, dihydromorphine, pethidine, buprenorphine), tramadol, norepinephrine, flupiretine, nefopam, orphenadrine, pregabalin, gabapentin, cyclobenzaprine, scopolamine, methadone, ketobemidone, piritramide, and aspirin and related salicylates (e.g. choline salicylate, magnesium salicylae, and sodium salicaylate).
  • salicylates e.g. choline salicylate, magnesium salicylae, and sodium salicaylate.
  • Suitable antispasmodics include, but are not limited to, mebeverine, papverine, cyclobenzaprine, carisoprodol, orphenadrine, tizanidine, metaxalone, methodcarbamol, chlorzoxazone, baclofen, dantrolene, baclofen, tizanidine, and dantrolene.
  • Suitable anti-inflammatories include, but are not limited to, prednisone, non-steroidal anti-inflammants (e.g. ibuprofen, naproxen, ketoprofen, and nimesulide), COX-2 inhibitors (e.g. rofecoxib, celecoxib, and etoricoxib), and immune selective anti-inflammatory derivatives (e.g. submandibular gland peptide-T and its derivatives).
  • non-steroidal anti-inflammants e.g. ibuprofen, naproxen, ketoprofen, and nimesulide
  • COX-2 inhibitors e.g. rofecoxib, celecoxib, and etoricoxib
  • immune selective anti-inflammatory derivatives e.g. submandibular gland peptide-T and its derivatives.
  • Suitable anti-histamines include, but are not limited to, H receptor antagonists (e.g. acrivastine, azelastine, bilastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine, chlorpromazine, cyclizine, chlorpheniramine, clemastine, cyproheptadine, desloratadine, dexbromapheniramine, dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine, doxylamine, ebasine, embramine, fexofenadine, hydroxyzine, levocetirzine, loratadine, meclozine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, quetiapine, rupata
  • cimetidine famotidine, lafutidine, nizatidine, rafitidine, and roxatidine
  • tritoqualine catechin, cromoglicate, nedocromil, and 32-adrenergic agonists.
  • Suitable anti-infectives include, but are not limited to, amebicides (e.g. nitazoxanide, paromomycin, metronidazole, tnidazole, chloroquine, and iodoquinol), aminoglycosides (e.g. paromomycin, tobramycin, gentamicin, amikacin, kanamycin, and neomycin), anthelmintics (e.g. pyrantel, mebendazole, ivermectin, praziquantel, abendazole, miltefosine, thiabendazole, oxamniquine), antifungals (e.g.
  • amebicides e.g. nitazoxanide, paromomycin, metronidazole, tnidazole, chloroquine, and iodoquinol
  • aminoglycosides e.g. paromomycin
  • azole antifungals e.g. itraconazole, fluconazole, posaconazole, ketoconazole, clotrimazole, miconazole, and voriconazole
  • echinocandins e.g. caspofungin, anidulafungin, and micafungin
  • griseofulvin e.g. nystatin, and amphotericin b
  • antimalarial agents e.g.
  • antituberculosis agents e.g. aminosalicylates (e.g. aminosalicylic acid), isoniazid/rifampin, isoniazid/pyrazinamide/rifampin, bedaquiline, isoniazid, ethanmbutol, rifampin, rifabutin, rifapentine, capreomycin, and cycloserine
  • antivirals e.g.
  • cephalosporins e.g. cefadroxil, cephradine, cefazolin, cephalexin, cefepime, ceflaroline, loracarbef, cefotetan, cefuroxime, cefprozil, loracarbef, cefoxitin, cefaclor, ceftibuten, ceftriaxone, cefotaxime, cefpodoxime, cefdinir, cefixime, cefditoren, cefizoxime, and ceftazidime), glycopeptide antibiotics (e.g.
  • vancomycin vancomycin, dalbavancin, oritavancin, and telvancin
  • glycylcyclines e.g. tigecycline
  • leprostatics e.g. clofazimine and thalidomide
  • lincomycin and derivatives thereof e.g. clindamycin and lincomycin
  • macrolides and derivatives thereof e.g.
  • telithromycin fidaxomicin, erthromycin, azithromycin, clarithromycin, dirithromycin, and troleandomycin
  • linezolid sulfamethoxazole/trimethoprim, rifaximin, chloramphenicol, fosfomycin, metronidazole, aztreonam, bacitracin
  • penicillins amoxicillin, ampicillin, bacampicillin, carbenicillin, piperacillin, ticarcillin, amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, clavulanate/ticarcillin, penicillin, procaine penicillin, oxaxillin, dicloxacillin, and nafcillin
  • quinolones e.g.
  • lomefloxacin norfloxacin, ofloxacin, qatifloxacin, moxifloxacin, ciprofloxacin, levofloxacin, gemifloxacin, moxifloxacin, cinoxacin, nalidixic acid, enoxacin, grepafloxacin, gatifloxacin, trovafloxacin, and sparfloxacin), sulfonamides (e.g. sulfamethoxazole/trimethoprim, sulfasalazine, and sulfasoxazole), tetracyclines (e.g.
  • doxycycline demeclocycline, minocycline, doxycycline/salicyclic acid, doxycycline/omega-3 polyunsaturated fatty acids, and tetracycline
  • urinary anti-infectives e.g. nitrofurantoin, methenamine, fosfomycin, cinoxacin, nalidixic acid, trimethoprim, and methylene blue.
  • Suitable chemotherapeutics include, but are not limited to, paclitaxel, brentuximab vedotin, doxorubicin, 5-FU (fluorouracil), everolimus, pemetrexed, melphalan, pamidronate, anastrozole, exemestane, nelarabine, ofatumumab, bevacizumab, belinostat, tositumomab, carmustine, bleomycin, bosutinib, busulfan, alemtuzumab, irinotecan, vandetanib, bicalutamide, lomustine, daunorubicin, clofarabine, cabozantinib, dactinomycin, ramucirumab, cytarabine, Cytoxan, cyclophosphamide, decitabine, dexamethasone, docetaxel, hydroxyurea, decarbazin
  • the pharmaceutical formulations can contain an effective amount of a composition described herein and/or an effective amount of an auxiliary agent.
  • the effective amount ranges from about 0.001 pg of the composition described herein or auxiliary agent to about 1 ,000 g of the composition described herein or auxiliary agent composition.
  • the effective amount of the composition described herein can be about 5 mg to about 5 g.
  • the effective amount of the composition described herein can be about 7 mg to about 3.5 g.
  • the concentration of the composition amount ranges from about 0.001 nM to about 100 mM.
  • the effective amount of the composition described herein rages from about 0.001 mg/kg body weight to about 1 ,000 mg/kg body weight.
  • the effective amount can be at least 0.001 mg/kg body weight.
  • the effect amount of the composition can range from 0.1 mg/kg body weight to about 50 mg/kg body weight.
  • the effective amount of the auxiliary active agent will vary depending on the auxiliary active agent. In some embodiments, the effective amount of the auxiliary active agent ranges from 0.001 micrograms to about 1 miligrams. In other embodiments, the effective amount of the auxiliary active agent ranges from about 0.01 IU to about 100,00 IU or more. In further embodiments, the effective amount of the auxiliary active agent ranges from 0.001 mL to about 100 mL or more. In yet other embodiments, the effective amount of the auxiliary active agent ranges from about 1 % w/w to about 99% or more w/w of the total pharmaceutical formulation.
  • the effective amount of the auxiliary active agent ranges from about 1 % v/v to about 99% v/v of the total pharmaceutical formulation. In still other embodiments, the effective amount of the auxiliary active agent ranges from about 1 % w/v to about 99% w/v of the total pharmaceutical formulation.
  • the auxiliary active agent can be included in the pharmaceutical formulation or can exist as a stand-alone compound or pharmaceutical formulation that is administered contemporaneously or sequentially with a composition or pharmaceutical formulation described herein.
  • compositions or pharmaceutical formulations described herein may be in a dosage form.
  • the dosage forms can be adapted for administration by any appropriate route.
  • Appropriate routes include, but are not limited to, oral (including buccal or sublingual), rectal, intraocular, inhaled, intranasal, topical (including buccal, sublingual, transdermal, spraying, dusting, pre-emergent application, post-emergent application, and granule application), vaginal, intraurethral, parenteral, intracranial, subcutaneous, intramuscular, intravenous, and intradermal. .
  • Dosage forms adapted for oral administration can be discrete dosage units such as capsules, pellets or tablets, powders or granules, solutions, or suspensions in aqueous or non-aqueous liquids; edible foams or whips, or in oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the bioactive formulations adapted for oral administration also include one or more agents which flavor, preserve, color, or help disperse the bioactive formulation.
  • Dosage forms prepared for oral administration can also be in the form of a liquid solution that can be delivered as a foam, spray, or liquid solution.
  • the oral dosage form can contain at least 1 pg of the complexed compound, and in some embodiments, about 1 pg to about 1000 kg or more of a composition or pharmaceutical formulation described herein. In other embodiments, the oral dosage form can contain about 1 mg to about 1 g of a composition or pharmaceutical formulation described herein.
  • the dosage forms described herein can be microencapsulated.
  • the dosage form can also be prepared to prolong or sustain the release of any ingredient.
  • the complexed active agent can be the ingredient whose release is delayed.
  • the release of an auxiliary ingredient is delayed. Suitable methods for delaying the release of an ingredient include, but are not limited to, coating or embedding the ingredients in material in polymers, wax, gels, and the like. Delayed release dosage formulations can be prepared as described in standard references such as "Pharmaceutical dosage form tablets," eds. Liberman et. al.
  • suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name EUDRAGIT® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.
  • cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate
  • polyvinyl acetate phthalate acrylic acid polymers and copolymers
  • methacrylic resins that are commercially available under the trade name EUDRAGIT® (Roth Pharma, Westerstadt, Germany),
  • Coatings may be formed with a different ratio of water soluble polymer, water insoluble polymers, and/or pH dependent polymers, with or without water insoluble/water soluble non polymeric excipient, to produce the desired release profile.
  • the coating is either performed on the dosage form (matrix or simple) which includes, but is not limited to, tablets (compressed with or without coated beads), capsules (with or without coated beads), beads, particle compositions, "ingredient as is” formulated as, but not limited to, suspension form or as a sprinkle dosage form.
  • Dosage forms adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils, and granules.
  • the bioactive formulations are applied as a topical ointment or cream.
  • the complexed active agent compound, auxiliary active ingredient can be formulated with a paraffinic or water-miscible ointment base.
  • the active ingredient can be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • Dosage forms adapted for topical administration in the mouth include lozenges, pastilles, and mouth washes.
  • the topical formulation of a composition or pharmaceutical formulation described herein can be further formulated as a spray and can include a suitable surfactant, wetting agent, adjuvants/surfactant (stickers, extender, plant penetrant, compatibility agents, buffers, drift control additives, and defoaming agents), or any combination thereof so as to formulated as a spray.
  • a suitable surfactant wetting agent, adjuvants/surfactant (stickers, extender, plant penetrant, compatibility agents, buffers, drift control additives, and defoaming agents), or any combination thereof so as to formulated as a spray.
  • the compounds, any optional auxiliary active ingredient, suitable surfactant, wetting agent, adjuvants, or any combination thereof can be formulated as a solution, suspension, or emulsion.
  • the spray dosage from can be administered through a spraying device.
  • the spraying device can be configured to generate the sprayable formulation as a liquid solution is contacted with the complexed active agent compound or formulation thereof.
  • the sprayable dosage form is pre-made prior to spraying. As such, the spraying device can act solely as an applicator for these embodiments.
  • the topical formulation of composition or pharmaceutical formulation described herein thereof can be further formulated as a dust and can include a suitable dry inert carrier (e.g. talc chalk, clay, nut hull, volcanic ash, or any combination thereof so as to be formulated as a dust.
  • a suitable dry inert carrier e.g. talc chalk, clay, nut hull, volcanic ash, or any combination thereof so as to be formulated as a dust.
  • the dust can contain dust particles of varying sizes.
  • the particle size can be substantially homogenous.
  • the particle size can be heterogeneous.
  • Dosage forms adapted as a dust can contain one or more adjuvants/surfactants (stickers, extender, plant penetrant, compatibility agents, buffers, drift control additives, and defoaming agents).
  • the dosage form for topical administration can be formulated as a bait.
  • the complexed active agent compound or other formulation thereof can be further formulated to include a food or other attractive substance that can attract one or more insect or other pest.
  • the bait dosage form can be formulated as a dust, paste, gel, or granule.
  • Dosage forms adapted as baits can contain one or more adjuvants/surfactants (stickers, extender, plant penetrant, compatibility agents, buffers, drift control additives, and defoaming agents).
  • the dosage form for topical administration can be formulated as granules or pellets that can be applied to the environment. These dosage formulations are similar to dust formulations, but the particles are larger and heavier. The granules can be applied to soil or other environmental area. Dosage forms adapted as granules or pellets can contain one or more adjuvants/surfactants (stickers, extender, plant penetrant, compatibility agents, buffers, drift control additives, and defoaming agents).
  • adjuvants/surfactants stickers, extender, plant penetrant, compatibility agents, buffers, drift control additives, and defoaming agents.
  • the dusts, granules, and pellets described herein can be formulated as wetable dusts, granules, and pellets, soluble dusts granules, and pellets, and/or water-dispersible granules, and/or dry flowables.
  • Dosage forms adapted for nasal or inhalation administration include aerosols, solutions, suspension drops, gels, or dry powders.
  • the composition or pharmaceutical formulation described herein, auxiliary active ingredient, and/or pharmaceutically acceptable salt thereof can be in a dosage form adapted for inhalation can be in a particle-size-reduced form that is obtained or obtainable by micronization.
  • the particle size of the size reduced (e.g. micronized) compound or salt or solvate thereof is defined by a D 50 value of about 0.5 to about 10 microns as measured by an appropriate method known in the art.
  • Dosage forms adapted for administration by inhalation also include particle dusts or mists.
  • Suitable dosage forms wherein the carrier or excipient is a liquid for administration as a nasal spray or drops can include aqueous or oil solutions/suspensions of an active ingredient, which can be generated by various types of metered dose pressurized aerosols, nebulizers, or insufflators.
  • the dosage forms can be aerosol formulations suitable for administration by inhalation.
  • the aerosol formulation can contain a solution or fine suspension of the complexed active agent, auxiliary active ingredient, and/or pharmaceutically acceptable salt thereof a pharmaceutically acceptable aqueous or nonaqueous solvent. Aerosol formulations can be presented in single or multi-dose quantities in sterile form in a sealed container.
  • the sealed container can be a single dose or multi-dose nasal or an aerosol dispenser fitted with a metering valve (e.g. metered dose inhaler), which can be intended for disposal once the contents of the container have been exhausted.
  • the dispenser can contain a suitable propellant under pressure, such as compressed air, carbon dioxide, or an organic propellant, including but not limited to a hydrofluorocarbon.
  • a suitable propellant under pressure such as compressed air, carbon dioxide, or an organic propellant, including but not limited to a hydrofluorocarbon.
  • the aerosol formulation dosage forms in other embodiments are contained in a pump-atomizer.
  • the pressurized aerosol formulation can also contain a solution or a suspension of a composition described herein or pharmaceutical formulation thereof and/or auxilary agent.
  • the aerosol formulation also contains co-solvents and/or modifiers incorporated to improve, for example, the stability and/or taste and/or fine particle mass characteristics (amount and/or profile) of the formulation.
  • Administration of the aerosol formulation can be once daily or several times daily, for example 2, 3, 4, or 8 times daily, in which 1 , 2, or 3 doses are delivered each time.
  • the composition or pharmaceutical formulation described herein can be a dry powder inhalable formulation.
  • a dosage form can contain a powder base such as lactose, glucose, trehalose, manitol, and/or starch.
  • the complexed active agent, auxiliary active ingredient, and/or pharmaceutically acceptable salt thereof is in a particle-size reduced form.
  • a performance modifier such as L-leucine or another amino acid, cellobiose octaacetate, and/or metals salts of stearic acid, such as magnesium or calcium stearate.
  • the aerosol formulations can be arranged so that each metered dose of aerosol contains a predetermined amount of a compound, such as the one or more of the complexed compounds described herein.
  • Dosage forms adapted for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
  • Dosage forms adapted for rectal administration include suppositories or enemas.
  • Dosage forms adapted for parenteral administration and/or adapted for injection can include aqueous and/or non-aqueous sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, solutes that render the composition isotonic with the blood of the subject, and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
  • the dosage forms adapted for parenteral administration can be presented in a single-unit dose or multi-unit dose containers, including but not limited to sealed ampoules or vials.
  • the doses can be lyophilized and resuspended in a sterile carrier to reconstitute the dose prior to administration.
  • Extemporaneous injection solutions and suspensions can be prepared in some embodiments, from sterile powders, granules, and tablets.
  • Dosage forms adapted for ocular administration can include aqueous and/or nonaqueous sterile solutions that can optionally be adapted for injection, and which can optionally contain anti-oxidants, buffers, bacteriostats, solutes that render the composition isotonic with the eye or fluid contained therein or around the eye of the subject, and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
  • the dosage form can be adapted for impregnating (saturating) an object or device, which then can be carried by, worn, or otherwise coupled to an organism in need thereof.
  • the dosage form can be impregnated onto a collar, bracelet, patch, adhesive tape, livestock ear tags, clothing, blankets, plastics, nets, and paints.
  • the composition or pharmaceutical formulation thereof can be formulated and impregnated in the object or device such that the composition or pharmaceutical formulation evaporates over time, which releases the composition and/or pharmaceutical formulation into the air and/or environment surrounding the organism and/or onto the organism, including an organism of the genus Plasmodium and/or an MEP-obligate organism.
  • the dosage form can be adapted as a fumigant, which is a formulation that forms a gas when utilized or applied.
  • the composition and/or pharmaceutical formulation thereof can be supplied as a liquid when packaged under pressure and change to a gas when they are released.
  • the composition and/or pharmaceutical formulation thereof can be supplied as a volatile liquid when enclosed in a container (not under pressure).
  • Others can be formulated as solids that release gases when applied under conditions of high humidity or in the presence of high water vapor.
  • Dosage forms adapted as fumigants can contain one or more adjuvants/surfactants (stickers, extender, plant penetrant, compatibility agents, buffers, drift control additives, and defoaming agents).
  • the dosage form contains a predetermined amount of an the composition and/or pharmaceutical formulation thereof per unit dose.
  • the predetermined amount of the composition and/or pharmaceutical formulation thereof can be an amount of the complexed active agent to treat, prevent, and/or mitigate the symptoms of an infection with an organism described herein (such as, without limitation, a species of the genus Plasmodium or an MEP-obligate organism) or other disease or disorder.
  • the predetermined amount of a composition or pharmaceutical formulation described herein can be an appropriate fraction of the effective amount of the composition or pharmaceutical formulation.
  • Such unit doses may therefore be administered once or more than once a day, more than once per week, more than once per month, or more than once per year.
  • Such dosage forms can be prepared by any of the methods well known in the art.
  • compositions and pharmaceutical formulations described herein can be used to treat and/or prevent infection with and/or infestation of an organism that uses the MEP pathway to generate isoprenoids.
  • the compositions and pharmaceutical formulations described herein can be used to kill an organism that uses the MEP pathway to generate isoprenoids.
  • the compositions and pharmaceutical formulations described herein can be used to inhibit or block the growth, development, and/or reproduction of an organism that uses the MEP pathway to generate isoprenoids.
  • the compositions describe herein can disrupt the reproduction cycle of an organism.
  • the organism that the compositions and pharmaceutical formulations can be used on or used to prevent infection by can be a plant, animal, protazoan bacteria, fungi, or yeast.
  • the organism can synthesize isoprenoids via the MEP pathway.
  • the organism can be a MEP-obligate organism.
  • the organism can be from the genus Plasmoidum.
  • the organism can be P. falciparum, P. malariae, P. ovale, P. vivax or P. knowlesi.
  • the organism can be a species of the genus Plasmodium, Toxoplasma, Mycobacterium, Baccillus, Vibrio, Clostriduium, Helicobacter, Campylobacter, Chlamydia, Brucella, Eimeria, Klebisella, Acinetobacter, Pseudomonas, and Neisseria.
  • the organism can be T. gondii, M.
  • tuberculosis B. anthracis, V. cholera, C. difficile, C. botulinum, H. pylori, C. jejuni, C. trachomatis 434/Bu, C. pneumoniae, B. abortus, E. tenella. K. pneumoniae, A. baumanii, P. aeruginosa, and N. gonorrhoeae.
  • Example 9 (1 S,3S)-methyl 1 -(2,4-dimethylphenyl)-2,3,4,9-tetrahydro-1 H-pyrido[3,4-b]indole-3- carboxylate (Formula 27) and (1 R,3S)-methyl 1-(2,4-dimethylphenyl)-2, 3,4,9- tet
  • Example 12 (1 S,3S)-methyl 1 -(2,4-bis(trifluoromethyl)phenyl)-2,3,4,9-tetrahydro-1 H-pyrido[3,4- b]indole-3-carboxylate (Formula 36) and (1 R,3S)-methyl 1-(2,4- bis(trifluoromethyl)phenyl)-2,3,4,9-tetrahydro-1 H-pyrido[3,4-b]indole-3-carboxylate

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Abstract

La présente invention concerne des composés et des formulations associées qui peuvent inhiber la voie méthylérythritol phosphate (MEP). L'invention concerne également des procédés de production et des utilisations des composés et des formulations associées.
PCT/US2015/058157 2014-10-29 2015-10-29 Compositions et formulations d'inhibiteurs de la voie méthylerthritol phosphate et leurs utilisations Ceased WO2016069949A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019151631A (ja) * 2018-03-02 2019-09-12 国立大学法人 岡山大学 植物病害防除剤及び植物病害の防除方法
US11339162B1 (en) 2020-12-23 2022-05-24 Recurium Ip Holdings, Llc Estrogen receptor modulators

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US20120178707A1 (en) * 2009-05-27 2012-07-12 Liangxian Cao Methods for treating prostrate conditions
WO2012135064A2 (fr) * 2011-03-25 2012-10-04 The Regents Of The University Of California Souches atténuées de plasmodium
US20130065857A1 (en) * 2009-10-12 2013-03-14 Baylor College Of Medicine Novel dxr inhibitors for antimicrobial therapy
WO2013071074A1 (fr) * 2011-11-11 2013-05-16 Invista North America S.A. R.L. Procédés de production de butadiène
US20130171103A1 (en) * 2010-05-27 2013-07-04 Ptc Therapeutics, Inc. Methods for treating viral conditions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120178707A1 (en) * 2009-05-27 2012-07-12 Liangxian Cao Methods for treating prostrate conditions
US20130065857A1 (en) * 2009-10-12 2013-03-14 Baylor College Of Medicine Novel dxr inhibitors for antimicrobial therapy
US20130171103A1 (en) * 2010-05-27 2013-07-04 Ptc Therapeutics, Inc. Methods for treating viral conditions
WO2012135064A2 (fr) * 2011-03-25 2012-10-04 The Regents Of The University Of California Souches atténuées de plasmodium
WO2013071074A1 (fr) * 2011-11-11 2013-05-16 Invista North America S.A. R.L. Procédés de production de butadiène

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019151631A (ja) * 2018-03-02 2019-09-12 国立大学法人 岡山大学 植物病害防除剤及び植物病害の防除方法
US11339162B1 (en) 2020-12-23 2022-05-24 Recurium Ip Holdings, Llc Estrogen receptor modulators
US11999728B2 (en) 2020-12-23 2024-06-04 Recurium Ip Holdings, Llc Estrogen receptor modulators

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