WO2021062168A1 - Molécules inspirees par des sphingolipides synthetiques ayant des groupes pendants heteroaromatiques cytotoxiques, leurs procédés de synthèse et méthodes de traitement - Google Patents

Molécules inspirees par des sphingolipides synthetiques ayant des groupes pendants heteroaromatiques cytotoxiques, leurs procédés de synthèse et méthodes de traitement Download PDF

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WO2021062168A1
WO2021062168A1 PCT/US2020/052742 US2020052742W WO2021062168A1 WO 2021062168 A1 WO2021062168 A1 WO 2021062168A1 US 2020052742 W US2020052742 W US 2020052742W WO 2021062168 A1 WO2021062168 A1 WO 2021062168A1
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cancer
tumor
compound
cell
leukemia
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Aimee EDINGER
Stephen Hanessian
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The Regents Of The University Of California
Université de Montréal
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the disclosure is generally directed to synthetic cytotoxic molecules, medicaments formed from these molecules, methods of synthesis of these molecules, and methods for the treatment of disorders or neoplasms using such therapeutics.
  • Endogenous sphingolipids including ceramide (compound 1 ) and sphingosine- 1 -phosphate are natural components of mammalian cells that have both pro-growth and pro-apoptotic functions (Fig. 1). Sphingolipids modulate a number of signaling processes that regulate the life cycle of cells.
  • SH-BC-893 compound 3
  • SH-BC-893 compound 3
  • Ri is H or alkyl, including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to 14 carbons.
  • R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • R4 and Rs are independently: alkyl including methyl, optionally substituted aryl including optionally substituted phenyl, or optionally substituted heteroaryl including optionally substituted pyridine or optionally substituted pyrimidine
  • n is independently 1, 2, 3, or 4.
  • m is independently 1 or 2.
  • the phenyl moiety can be attached at any available position of the azacycle core.
  • any substituent of R4 or Rs, if present, is independently: halogen, including F, alkyl, terminal alkyne, or azide.
  • the compound is: [0009] In a further embodiment, the compound is:
  • R is connected at its N.
  • X is 0 or S.
  • Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to 14 carbons.
  • R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • n is independently 1, 2, 3, or 4.
  • m is independently 1 or 2.
  • the phenyl moiety can be attached at any available position of the azacycle core.
  • the compound is:
  • R may be further functionalized.
  • R is attached to the azacycle via any of R’s available positions.
  • R’ is H or OH.
  • Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to 14 carbons.
  • R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • n is independently: 1 , 2, 3, or 4.
  • m is independently: 1 or 2.
  • the phenyl moiety can be attached at any available position of the azacycle core. [0013] In yet an even further embodiment, the compound is:
  • Ri and R-T are independently H, alkyl including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to14 carbons.
  • R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • R4 and Rs are independently alkyl including methyl, aryl including phenyl, or heteroaryl including pyridine or pyrimidine n is independently 1, 2, 3, or 4.
  • Ri and R-T are independently H, alkyl including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to 14 carbons.
  • R3 is 1 , 2, 3, or 4 substituents, and each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • n is independently 1 , 2, 3, or 4.
  • the compound is capable of having a cytotoxic or cytostatic effect on human neoplastic cells, and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells.
  • the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (IC50) of less than 100 micromolar, wherein the local IC50 is defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.
  • IC50 50% inhibitory concentration
  • the human neoplastic cells are derived from at least one neoplasm, and wherein the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer
  • ALL acute lymphoblastic leukemia
  • the human neoplastic cells are: fast growing, aggressive, Warburg-phenotypic, malignant, Ras-positive, PTEN-negative, having PI 3-kinase mutations, benign, metastatic, nodular, or a combination thereof.
  • the compound is capable of inhibiting growth of a tumor comprised of human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.
  • a medicament for the treatment of a human disorder that includes a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:
  • Ri is H or alkyl, including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to 14 carbons.
  • R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • R4 and Rs are independently: alkyl including methyl, optionally substituted aryl including optionally substituted phenyl, or optionally substituted heteroaryl including optionally substituted pyridine or optionally substituted pyrimidine
  • n is independently 1, 2, 3, or 4.
  • m is independently 1 or 2.
  • the phenyl moiety can be attached at any available position of the azacycle core.
  • any substituent of R4 or Rs, if present, is independently: halogen, including F, alkyl, terminal alkyne, or azide.
  • the compound is: [0024] In a further embodiment, the compound is:
  • a medicament for the treatment of a human disorder that includes a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:
  • R is connected at its N.
  • X is O or S.
  • Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to 14 carbons.
  • R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • n is independently 1, 2, 3, or 4.
  • m is independently 1 or 2.
  • the phenyl moiety can be attached at any available position of the azacycle core. [0026] In yet a further embodiment, the compound is:
  • a medicament for the treatment of a human disorder that includes a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:
  • R may be further functionalized.
  • R is attached to the azacycle via any of R’s available positions.
  • R’ is H or OH.
  • Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to 14 carbons.
  • R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • n is independently: 1 , 2, 3, or 4.
  • m is independently: 1 or 2.
  • the phenyl moiety can be attached at any available position of the azacycle core. [0028] In yet an even further embodiment, the compound is:
  • a medicament for the treatment of a human disorder that includes a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula: or a pharmaceutically acceptable salt thereof.
  • Ri and R-T are independently H, alkyl including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to14 carbons.
  • R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • R4 and Rs are independently alkyl including methyl, aryl including phenyl, or heteroaryl including pyridine or pyrimidine
  • n is independently 1, 2, 3, or 4.
  • a medicament for the treatment of a human disorder that includes a pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula: or a pharmaceutically acceptable salt thereof.
  • Ri and R-T are independently H, alkyl including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to 14 carbons.
  • R3 is 1 , 2, 3, or 4 substituents, and each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • n is independently 1 , 2, 3, or 4.
  • the human disorder is at least one neoplasm
  • the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell hist
  • ALL acute lymphoblastic leukemia
  • the one or more compounds is capable of having a cytotoxic or cytostatic effect on human neoplastic cells, and wherein the cytotoxic effect is defined by a reduction in the percentage of viable human neoplastic cells and the cytostatic effect is defined by reduction of proliferation of neoplastic cells.
  • the cytotoxic or cytostatic effect is achieved with a local 50% inhibitory concentration (ICso) of less than 100 micromolar, wherein the local ICso is defined by the concentration of the compound that reduces the percentage of viable human neoplastic cells by 50%.
  • the pharmaceutical formulation is capable of inhibiting growth of a tumor comprising human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, and neoplastic cell proliferation.
  • the medicament further includes at least one cytotoxic FDA-approved compound for the treatment of a neoplasm.
  • the compound is capable of inhibiting growth of a tumor comprised of human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.
  • a treatment of a human disorder that includes administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:
  • Ri is H or alkyl, including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to 14 carbons.
  • R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • R4 and Rs are independently: alkyl including methyl, optionally substituted aryl including optionally substituted phenyl, or optionally substituted heteroaryl including optionally substituted pyridine or optionally substituted pyrimidine
  • n is independently 1, 2, 3, or 4.
  • m is independently 1 or 2.
  • the phenyl moiety can be attached at any available position of the azacycle core.
  • any substituent of R4 or Rs, if present, is independently: halogen, including F, alkyl, terminal alkyne, or azide.
  • the compound is: [0040] In a further embodiment, the compound is:
  • a treatment of a human disorder that includes administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:
  • R is connected at its N.
  • X is O or S.
  • Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to 14 carbons.
  • R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • n is independently 1, 2, 3, or 4.
  • m is independently 1 or 2.
  • the phenyl moiety can be attached at any available position of the azacycle core.
  • the compound is:
  • a treatment of a human disorder that includes administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:
  • R may be further functionalized.
  • R is attached to the azacycle via any of R’s available positions.
  • R’ is H or OH.
  • Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to 14 carbons.
  • R3 is 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • n is independently: 1 , 2, 3, or 4.
  • m is independently: 1 or 2.
  • the phenyl moiety can be attached at any available position of the azacycle core.
  • the compound is:
  • a treatment of a human disorder that includes administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula:
  • Ri and R-T are independently H, alkyl including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to14 carbons.
  • R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • R4 and Rs are independently alkyl including methyl, aryl including phenyl, or heteroaryl including pyridine or pyrimidine n is independently 1, 2, 3, or 4.
  • a treatment of a human disorder that includes administering a pharmaceutical formulation to a human subject, the pharmaceutical formulation containing a therapeutically effective amount of one or more small molecule compounds having the formula: or a pharmaceutically acceptable salt thereof.
  • X is O or S.
  • Ri and R-T are independently H, alkyl including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to 14 carbons.
  • R3 is 1 , 2, 3, or 4 substituents, and each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • n is independently 1 , 2, 3, or 4.
  • the human subject is diagnosed with at least one human disorder.
  • the human disorder is at least one neoplasm
  • the at least one neoplasm is: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell hist
  • ALL acute lymphoblastic leukemia
  • the pharmaceutical formulation inhibits growth of a tumor comprising human neoplastic cells, wherein growth is defined by at least one growth assessment, and wherein the at least one growth assessment is: an increase in tumor diameter, an increase in tumor bioluminescence, an increase in tumor volume, an increase in tumor mass, neoplastic cell proliferation, or a combination thereof.
  • the human disorder is characterized by at least one neoplasm characterization, and wherein the at least one neoplasm characterization is: fast-growing, aggressive, Warburg-phenotypic, malignant, Ras- positive, PTEN-negative, having PI 3-kinase mutations, benign, metastatic, nodular, or a combination thereof.
  • the treatment is combined with an FDA- approved standard of care.
  • the pharmaceutical formulation is combined with at least one cytotoxic FDA-approved compound.
  • FIG. 1 provides a molecular structure of ceramide, FTY720, and SH-BC-893 in accordance with the prior art.
  • FIG. 2 provides a molecular structure diagram of a number of therapeutic small molecule analogs in accordance with various embodiments.
  • FIG. 3 provides examples of molecular structures of therapeutic small molecule analogs in accordance with various embodiments.
  • FIG. 4 provides examples of molecular structures of therapeutic small molecule analogs in accordance with various embodiments.
  • FIG. 5 provides a molecular structure of perphenazine and SMAP in accordance with the prior art.
  • FIG. 6 provides examples of molecular structures of therapeutic small molecule analogs in accordance with various embodiments.
  • FIG. 7 provides examples of molecular structures of therapeutic small molecule analogs in accordance with various embodiments.
  • FIG. 8 provides a theoretical depiction of how small therapeutic molecules interact with PP2A in accordance with various embodiments.
  • FIG. 9 provides examples of molecular structures of therapeutic small molecule analogs in accordance with various embodiments.
  • FIG. 10A provides results of cytotoxic activity of compounds 3 and 13 on FL5 cells and the ability of methyl-pyruvate to rescue the cytotoxic effect, generated in accordance with various embodiments.
  • FIG. 10B provides results of cytotoxic activity of compounds 3 and 13 on eight cancer cell lines, generated in accordance with various embodiments.
  • FIG. 10C provides results of cytotoxic activity of compounds 3 and 13, and SMAP on KRAS mutant cancer cell lines, generated in accordance with various embodiments.
  • FIGs. 11 to 14 each provide reaction pathways for the production of therapeutic small molecule analogs in accordance with various embodiments.
  • the molecules are hybrid molecules that include a constrained sphingolipid-like molecule and a heteroaromatic appendage attached thereon.
  • the sphingolipid portion includes a hydrophobic tail inclusive of a phenyl moiety and attached to a pyrrolidine moiety.
  • the phenyl moiety bears further substitution.
  • the sphingolipid portion is SH-BC-893 (Fig. 1 , compound 3).
  • a heteroaromatic appendage is a pyridazine, pyridine, phenoxazine, pyrimidine, or phenothiazine.
  • the heteroaromatic appendage bears further substitution.
  • molecules are prepared and used as pharmaceutically acceptable salts.
  • formulations and medicaments are provided that are directed to the treatment of disorders.
  • these formulations and medicaments target cancers, such as, for example, leukemia, prostate, colon, lung, pancreatic and breast cancer.
  • Therapeutic embodiments contain a therapeutically effective dose of one or more small molecule compounds.
  • Embodiments allow for various formulations, including, but not limited to, formulations for oral, intravenous, or intramuscular administration.
  • Other additional embodiments provide treatment regimens for disorders using therapeutic amounts of the small molecules.
  • Alcohol means a hydrocarbon with an -OH group (ROH).
  • Alkyl refers to the partial structure that remains when a hydrogen atom is removed from an alkane.
  • Alkyl phosphonate means an alkyl group bonded to a phosphate RPO3.
  • Alkane means a compound of carbon and hydrogen that contains only single bonds.
  • Alkene refers to an unsaturated hydrocarbon that contains at least one carbon-carbon double bond.
  • Alkyne refers to an unsaturated hydrocarbon that contains at least one carbon-carbon triple bond.
  • Alkoxy refers to a portion of a molecular structure featuring an alkyl group bonded to an oxygen atom.
  • Aryl refers to any functional group or substituent derived from an aromatic ring.
  • “Amine” molecules are compounds containing one or more organic substituents bonded to a nitrogen atom, RNH2, R2NH, or R3N.
  • amino acid refers to a difunctional compound with an amino group on the carbon atom next to the carboxyl group, RCH(NH2)C02H.
  • Cyanide refers to CN.
  • Ester is a compound containing the -CO2R functional group.
  • Ether refers to a compound that has two organic substituents bonded to the same oxygen atom, i.e. , R-O-R’.
  • Halogen or “halo” means fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • Hydrocarbon means an organic chemical compound that consists entirely of the elements carbon (C) and hydrogen (H).
  • Phosphate means a compound containing the elements phosphorous (P) and oxygen (O).
  • Optionally substituted means substituted or unsubstituted.
  • optionally substituted phenyl is unsubstituted phenyl or substituted phenyl.
  • FIG. 2 A chemical compound in accordance with embodiments described herein is illustrated in FIG. 2 and pictured below.
  • Embodiments comprise the molecules as illustrated in FIG. 2, including an azacycle compound and its salt of a suitable acid: or a pharmaceutically acceptable salt thereof;
  • R is an optionally substituted heteroaromatic moiety such as an optionally substituted pyridazine, optionally substituted pyridine, optionally substituted pyrimidine, phenoxazine, or optionally substituted phenothiazine.
  • Ri is H, alkyl such as C1-6 alkyl or C1-4 alkyl including methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, etc, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to 14 carbons.
  • R3 is a 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is H, halogen, alkyl, alkoxy, N3, NO2, and CN.
  • n is independently 1, 2, 3, or 4.
  • m is independently 1 or 2.
  • R2 is an unsaturated hydrocarbon chain.
  • R2 is Ce-14 alkyl, Ce-io alkyl, C7-9 alkyl, C6H13, C7H15, OdH ⁇ 7, C9H19, C10H21 , Ci 1 H23, C12H25, C13H27, or Ci4H29.
  • R3 is H.
  • n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.
  • n is 1. In some embodiments, m is 2.
  • the R2 and R3 substituents can have different combinations around the phenyl ring with regard to their position.
  • the Ri is an alkyl having 1 to 6 carbons.
  • R is a 1 ,2-pyridazine having the formula (Fig. 2):
  • R4 and R5 are functional groups independently selected from: alkyl including methyl, optionally substituted aryl (i.e. , unsubstituted aryl or substituted aryl) including optionally substituted phenyl, and optionally substituted heteroaryl including optionally substituted pyridine and optionally substituted pyrimidine.
  • the pyridazine moiety is connected to the azacycle at the position 4 or 5 of the pyridazine.
  • any substituents of R4 and R5, if present, are independently halogen including F, alkyl, terminal alkyne, and azide.
  • R4 is C1-6 alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl; unsubstituted aryl or substituted aryl, including unsubstituted phenyl, or phenyl having 1, 2, 3, 4, or 5 substituents; unsubstituted heteroaryl or substituted heteroaryl, including unsubstituted pyridine or pyridine having 1, 2, 3, or 4 substituents, or unsubstituted pyrimidine or pyrimidine having 1 , 2, or 3 substituents.
  • any substituent may be used in the substituted aryl (e.g., substituted phenyl) or substituted heteroaryl (e.g., substituted pyridine or substituted pyrimidine).
  • Rs is Ci-6 alkyl, such as Chta, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl; unsubstituted aryl or substituted aryl, including unsubstituted phenyl, or phenyl having 1, 2, 3, 4, or 5 substituents; unsubstituted heteroaryl or substituted heteroaryl, including unsubstituted pyridine or pyridine having 1, 2, 3, or 4 substituents, or unsubstituted pyrimidine or pyrimidine having 1 , 2, or 3 substituents.
  • any substituent may be used in the substituted aryl (e.g., substituted phenyl) or substituted heteroaryl (e.g., substituted pyridine or substituted pyrimidine).
  • R4 and Rs are the same functional group.
  • R4 and Rs are different functional groups.
  • R4 is C1-6 alkyl, such as methyl, and Rs is optionally substituted phenyl.
  • R4 is C1-6 alkyl, such as methyl, and Rs is optionally substituted pyridine.
  • R4 is C1-6 alkyl, such as methyl, and Rs is optionally substituted pyrimidine.
  • R4 is optionally substituted pyridine and Rs is optionally substituted pyridine.
  • R4 is optionally substituted phenyl and Rs is optionally substituted phenyl.
  • R4 is optionally substituted phenyl and Rs is optionally substituted pyrimidine.
  • an azacycle compound has the formula:
  • R is an optionally substituted phenoxazine or an optionally substituted phenothiazine, such as phenoxazine or phenothiazine having the formula (Fig. 2): which may additionally have substituents on any available ring position.
  • X is selected from: 0 and S.
  • R is attached to the azacycle via R’s nitrogen.
  • Substituents of R may independently include halogen, alkyl (e.g., Ci-6 alkyl, such as Chta, C2 alkyl, C3 alkyl, C4 alkyl, Cs alkyl, or Ce alkyl), alkoxy (e.g., C1-6 alkoxy, such as -OCH3, C2 alkoxy, C3 alkoxy, C4 alkoxy, Cs alkoxy, or Ce alkoxy), N3, NO2, and CN.
  • alkyl e.g., Ci-6 alkyl, such as Chta, C2 alkyl, C3 alkyl, C4 alkyl, Cs alkyl, or Ce alkyl
  • alkoxy e.g., C1-6 alkoxy, such as -OCH3, C2 alkoxy, C3 alkoxy, C4 alkoxy, Cs alkoxy, or Ce alkoxy
  • R is optionally substituted heteroaryl including pyridine and pyrimidine, and a substituted heteroaryl including dimethoxy pyrimidine.
  • These heteroaryl substituents can be attached to the alkyl chain at different positions on the heteroaryl, e.g., the 2-, 3-, or 4- positions on pyridine for example.
  • R’ is H or OH.
  • Ri is H, alkyl including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to14 carbons.
  • R3 is a 1 , 2, 3, or 4 substituents, wherein each substituent, independently, is H, halogen, alkyl, alkoxy, N3, NO2, or CN.
  • n is independently 1 , 2, 3, or 4.
  • m is independently 1 or 2.
  • R is an unsubstituted or substituted pyridine, for example: wherein R is attached to the azacycle via any of R’s available positions.
  • any of the pyridine’s positions 2, 3, or 4 may be used for attachment to the azacycle.
  • the pyridine may additionally have substituents on any available ring.
  • R is an unsubstituted or substituted pyrimidine, for example: wherein R is attached to the azacycle via any of R’s available positions.
  • any of the pyrimidine’s positions 4, 5, or 6 may be used for attachment to the azacycle.
  • the pyrimidine may additionally have substituents on any available ring.
  • R groups that are substituted pyridine and substituted pyrimidine substituents may independently include halogen, alkyl (e.g., C1-6 alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, Cs alkyl, or C6 alkyl), alkoxy (e.g., C1-6 alkoxy, such as -OCH3, C2 alkoxy, C3 alkoxy, C4 alkoxy, Cs alkoxy, or Ob alkoxy), N3, NO2, and CN.
  • alkyl e.g., C1-6 alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, Cs alkyl, or C6 alkyl
  • alkoxy e.g., C1-6 alkoxy, such as -OCH3, C2 alkoxy, C3 alkoxy, C4 alkoxy, Cs alkoxy, or Ob alkoxy
  • N3, NO2 and CN e.g.
  • R2 is Ce-14 alkyl, Ce-io alkyl, C7-9 alkyl, C6H13, C7H15, C8H17, C9H19, C10H21 , Ci 1 H23, C12H25, C13H27, or Ci4H29.
  • R3 is H.
  • n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • n is 1. In some embodiments, m is 2.
  • the R2 and R3 substituents can have different combinations around the phenyl ring with regard to their position.
  • R2 is an unsaturated hydrocarbon chain.
  • the Ri is an alkyl having 1 to 6 carbons.
  • R is a heteroaromatic moiety selected from pyridazine, pyridine, pyrimidine, phenoxazine, or phenothiazine.
  • Ri or Ri‘ is a functional group, each independently selected from: H, alkyl including methyl, Ac, Boc, guanidine moiety.
  • R2 is an aliphatic chain comprising 6 to14 carbons.
  • R3 is 1, 2, 3, or 4 substituents, wherein each substituent, independently, is: H, halogen, alkyl, alkoxy, N3, NO2, CN. n is independently 1, 2, 3, or 4.
  • R2 is Ce-14 alkyl, Ce-io alkyl, C7-9 alkyl, C6H13, C7H15, OdH ⁇ 7, C9H19, C10H21 , Ci 1 H23, C12H25, C13H27, or Ci4H29.
  • R3 is H.
  • n is 1. In some embodiments, n is 2. In some embodiments, n is 3.
  • the R2 and R3 substituents can have different combinations around the phenyl ring with regard to their position.
  • R2 is an unsaturated hydrocarbon chain.
  • Ri or Ri' is an alkyl having 1 to 6 carbons.
  • Ri and Ri' are the same functional group.
  • Ri and Ri' are different functional groups
  • R is a pyridazine having the formula (Fig. 4):
  • R4 and R5 are functional groups independently selected from: alkyl including methyl, optionally substituted aryl (i.e. , unsubstituted aryl or substituted aryl) including optionally substituted phenyl, and optionally substituted heteroaryl including optionally substituted pyridine and optionally substituted pyrimidine.
  • the pyridazine moiety is connected at its position 4 or 5.
  • any substituents of R4 and R5, if present, are independently halogen, including F, alkyl, terminal alkyne, and azide.
  • R4 is C1-6 alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl; unsubstituted aryl or substituted aryl, including unsubstituted phenyl, or phenyl having 1 , 2, 3, 4, or 5 substituents; unsubstituted heteroaryl or substituted heteroaryl, including unsubstituted pyridine or pyridine having 1 , 2, 3, or 4 substituents, or unsubstituted pyrimidine or pyrimidine having 1 , 2, or 3 substituents.
  • any substituent may be used in the substituted aryl (e.g., substituted phenyl) or substituted heteroaryl (e.g., substituted pyridine or substituted pyrimidine).
  • Rs is C1-6 alkyl, such as CH3, C2 alkyl, C3 alkyl, C4 alkyl, Cs alkyl, or C6 alkyl; unsubstituted aryl or substituted aryl, including unsubstituted phenyl, or phenyl having 1 , 2, 3, 4, or 5 substituents; unsubstituted heteroaryl or substituted heteroaryl, including unsubstituted pyridine or pyridine having 1 , 2, 3, or 4 substituents, or unsubstituted pyrimidine or pyrimidine having 1 , 2, or 3 substituents.
  • any substituent may be used in the substituted aryl (e.g., substituted phenyl) or substituted heteroaryl (e.g., substituted pyridine or substituted pyrimidine).
  • R4 and Rs are different functional groups.
  • R4 is C1-6 alkyl, such as methyl, and Rs is optionally substituted phenyl.
  • R4 is C1-6 alkyl, such as methyl, and Rs is optionally substituted pyridine.
  • R4 is C1-6 alkyl, such as methyl, and Rs is optionally substituted pyrimidine.
  • R4 is optionally substituted pyridine and Rs is optionally substituted pyridine.
  • R4 is optionally substituted phenyl and Rs is optionally substituted phenyl.
  • R4 is optionally substituted phenyl and Rs is optionally substituted pyrimidine.
  • R is optionally substituted phenoxazine or optionally substituted phenoxazine, such as a phenoxazine or phenothiazine having the formula (Fig. 4): which may additionaly have substituents on any available ring position.
  • X is selected from: 0 and S.
  • R is connected at its N.
  • the claimed embodiments can also be related to pharmaceutically acceptable salts.
  • a “pharmaceutically acceptable salt” retains the desirable biological activity of the compound without unacceptable toxicological effects.
  • Salts can be salts with a suitable acid, including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, benzoic acid, pamoic acid, alginic acid, methanesulfonic acid, naphthalenesulfonic acid, and the like.
  • incorporated cations can include ammonium, sodium, potassium, lithium, zinc, copper, barium, bismuth, calcium, and the like; or organic cations such as tetraalkylammonium and trialkylammonium cations.
  • organic cations such as tetraalkylammonium and trialkylammonium cations.
  • acidic and cationic salts include salts of other acids and/or cations, such as salts with trifluoroacetic acid, chloroacetic acid, and trichloroacetic acid.
  • Other compounds, as well as modified azacyclic sphingolipid-like molecules, suitable for practice of the present embodiments will be apparent to the skilled practitioner. Furthermore, these molecules may employ several mechanisms of action to inhibit neoplasm growth, even if the molecules are not structurally identical to the compounds shown above.
  • the compounds are administered in a therapeutically effective amount as part of a course of treatment.
  • to "treat” means to ameliorate or prevent at least one symptom of the disorder to be treated or to provide a beneficial physiological effect.
  • one such amelioration of a symptom could be inhibition of neoplastic proliferation.
  • Assessment of neoplastic proliferation can be performed in many ways, including, but not limited to assessing changes in tumor diameter, changes in tumor bioluminescence, changes in tumor volume, changes in tumor mass, or changes in neoplastic cell proliferation rate.
  • an individual to be treated has been diagnosed as having a neoplastic growth or cancer.
  • the neoplasm is characterized as fast-growing, aggressive, Warburg-phenotypic, malignant, Ras-positive, PTEN-negative, having PI 3-kinase mutations, benign, metastatic, or nodular.
  • a number of cancers can be treated, including (but not limited to) acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), anal cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL) chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, hairy cell leukemia, hepatocellular cancer, Hodgkin lymphoma, hypopharyngeal cancer, Kaposi sarcoma, Kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, liver cancer, lung cancer
  • a therapeutically effective amount can be an amount sufficient to prevent reduce, ameliorate or eliminate the symptoms of diseases or pathological conditions susceptible to such treatment, such as, for example, cancers like leukemia, prostate, colon, lung, pancreatic, or breast cancer, or diseases where oncogenic Ras mutations afford multiple metabolic advantages to transformed cells.
  • a therapeutically effective amount is an amount sufficient to reduce the transport of nutrients, such as, for example, glucose, amino acids, nucleotides or lipids, into cells.
  • Dosage, toxicity and therapeutic efficacy of the compounds can be determined, e.g., by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LDso (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compounds that exhibit high therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to non-neoplastic cells and, thereby, reduce side effects.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be form ulated in animal models to achieve a circulating plasma concentration or within the local environment to be treated in a range that includes the IC50 (i.e. , the concentration of the test compound that achieves a half-maximal inhibition of neoplastic growth) as determined in cell culture.
  • a cytotoxic effect is achieved with an IC50 less than 50 mM, 20 pM, 10 pM, 5 pM or 1 pM.
  • an "effective amount” is an amount sufficient to effect beneficial or desired results.
  • a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms.
  • An effective amount can be administered in one or more administrations, applications or dosages.
  • a therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered one from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
  • treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments. For example, several divided doses may be administered daily, one dose, or cyclic administration of the compounds to achieve the desired therapeutic result. A single small molecule compound may be administered, or combinations of various small molecule compounds may also be administered.
  • azacyclic sphingolipid-like small molecule compounds are administered in combination with an appropriate standard of care, such as the standard of care established by the United States Federal Drug Administration (FDA) or the European Medicines Agency (EMA).
  • FDA United States Federal Drug Administration
  • EMA European Medicines Agency
  • azacyclic sphingolipid-like small molecule compounds are administered in combination with other cytotoxic compounds, especially FDA-approved compounds or EMA-approved compounds.
  • FDA-approved or EMA-approved cytotoxic compounds can be utilized, including (but not limited to) methotrexate, gemcitabine, tamoxifen, taxol, docetaxel, and enzalutamide.
  • the claimed compounds can be formulated with one or more adjuvants and/or pharmaceutically acceptable carriers according to the selected route of administration.
  • adjuvants and/or pharmaceutically acceptable carriers for oral applications, gelatin, flavoring agents, or coating material can be added.
  • carriers may include aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles can include sodium chloride and potassium chloride, among others.
  • intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers and the like.
  • the coating agent is one which acts as a coating agent in conventional delayed release oral formulations, including polymers for enteric coating.
  • examples include hypromellose phthalate (hydroxy propyl methyl cellulose phthalate; FIPMCP); hydroxypropylcellulose (FIPC; such as KLUCEL®); ethylcellulose (such as ETFIOCEL®); and methacrylic acid and methyl methacrylate (MAA/MMA; such as EUDRAGIT®).
  • a disintegrating agent is a super disintegrant agent.
  • a diluent is a bulking agent such as a polyalcohol.
  • bulking agents and disintegrants are combined, such as, for example, PEARLITOL FLASFI®, which is a ready to use mixture of mannitol and maize starch (mannitol/maize starch).
  • PEARLITOL FLASFI® which is a ready to use mixture of mannitol and maize starch (mannitol/maize starch).
  • any polyalcohol bulking agent can be used when coupled with a disintegrant or a super disintegrant agent.
  • Additional disintegrating agents include, but are not limited to, agar, calcium carbonate, maize starch, potato starch, tapioca starch, alginic acid, alginates, certain silicates, and sodium carbonate.
  • Suitable super disintegrating agents include, but are not limited to crospovidone, croscarmellose sodium, AMBERLITE (Rohm and Flaas, Philadelphia, Pa.), and sodium starch glycolate.
  • diluents are selected from the group consisting of mannitol powder, spray dried mannitol, microcrystalline cellulose, lactose, dicalcium phosphate, tricalcium phosphate, starch, pregelatinized starch, compressible sugars, silicified microcrystalline cellulose, and calcium carbonate.
  • a formulation further utilize other components and excipients.
  • sweeteners include, but are not limited to, fructose, sucrose, glucose, maltose, mannose, galactose, lactose, sucralose, saccharin, aspartame, acesulfame K, and neotame.
  • flavoring agents and flavor enhancers that may be included in the formulations described herein include, but are not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
  • a formulation also include a surfactant.
  • surfactants are selected from the group consisting of Tween 80, sodium lauryl sulfate, and docusate sodium.
  • binders are selected from the group consisting of povidone (PVP) K29/32, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), corn starch, pregelatinized starch, gelatin, and sugar.
  • PVP povidone
  • HPMC hydroxypropylcellulose
  • HPMC hydroxypropylmethylcellulose
  • EC ethylcellulose
  • corn starch pregelatinized starch
  • gelatin gelatin
  • a formulation also include a lubricant.
  • lubricants are selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, calcium stearate, hydrogenated vegetable oil, mineral oil, polyethylene glycol, polyethylene glycol 4000-6000, talc, and glyceryl behenate.
  • Modes of administration include, but are not limited to, oral, transdermal, transmucosal (e.g., sublingual, nasal, vaginal or rectal), or parenteral (e.g., subcutaneous, intramuscular, intravenous, bolus or continuous infusion).
  • parenteral e.g., subcutaneous, intramuscular, intravenous, bolus or continuous infusion.
  • the actual amount of drug needed will depend on factors such as the size, age and severity of disease in the afflicted individual.
  • the actual amount of drug needed will also depend on the effective concentration ranges of the various active ingredients.
  • a number of embodiments of formulations include those suitable for oral administration. Formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • these methods include the step of bringing into association a compound of at least one embodiment described herein, or a pharmaceutically salt, prodrug, or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients.
  • active ingredient a compound of at least one embodiment described herein, or a pharmaceutically salt, prodrug, or solvate thereof
  • the carrier which constitutes one or more accessory ingredients.
  • Embodiments of formulations disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • Multiple embodiments also compartmentalize various components within a capsule, cachets, or tablets, or any other appropriate distribution technique.
  • compositions include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • Tablets in a number of embodiments, may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • Push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • Preservatives and other additives can also be present. (See generally, Remington's Pharmaceutical Sciences, 16th Edition, Mack, (1980), the disclosure of which is incorporated herein by reference.)
  • Biological data supports the use of the aforementioned sphingolipid-like compounds with heteroaromatic appendage in a variety of embodiments to treat disease. It is noted that embodiments of the compounds described herein, in accordance with the disclosure, kill and/or inhibit the growth of neoplastic cells. Accordingly, embodiments using these compounds to treat various diseases, such as cancer, avoid the pitfalls associated with prior approaches.
  • Activation of PP2A has been reported with a series of tricyclic neuroleptics such as perphenazine (4) and by a synthetic compound incorporating a phenoxazine moiety lacking a basic nitrogen (5) (SMAP) (Fig. 5) (See A Gutierrez, et al., J Clin Invest. 124: 644-655 (2014); and D. B. Kastrinksy, et al., Bioorg Med Chem. 23: 6528-6534 (2015); the disclosures of which are each incorporated herein by reference).
  • SMAP basic nitrogen
  • the pyradizine appendage without the pyrrolidine core and attached hydrophobic tail is unable to confer cytotoxicity, CD98 sequestration, or vacuolation in cancer cells (see compounds 24 and 25).
  • Compound 25, which maintains pyrrolidine core and attached hydrophobic tail but has a basic alkyl in place of the pyradizine appendage did confer cytotoxicity, CD98 sequestration, and vacuolation in cancer cells, albeit at lower levels than molecules having the pyradizine appendage. This suggests that a nitrogen-containing heterocycle rings with a hybrid tail are important for anti-proliferative activity and that a pyradizine appendages can improve that activity.
  • a rescue experiment utilizing pyruvate to increase nutrient uptake was performed, which is presented in Fig. 10.
  • FL5 cells were treated with compound 3 or 13a-13b at each compounds IC50 with and without methyl-pyruvate.
  • the viability of cells was measured utilizing a vital dye that is absorbed into dead cells.
  • the percent viable cells was measured by flow cytometry Approximately half of the cells treated with compound 3 or 13a-13b were viable and treatment with methyl-pyruvate increased this viability up to about 75% (Fig. 10A), demonstrating that nutrient starvation is a major factor in the cytotoxic activity of compounds 13a-13b.
  • Multiplicities are given as multiplet (m), singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin.) and broad (br).
  • Optical rotations were determined on an Anton Paar MCP 300 polarimeter at 589 nm at 25 °C. Specific rotations are given in units of 10 _1 deg cm 2 g -1 .
  • High resolution mass spectra HRMS were performed by the “Centre regional de spectroscopie de masse de I’Universite de Montreal” with electrospray ionisation (ESI) coupled to a quantitative time- of-flight (TOF) detector.
  • Compounds 3 and 5 - 9 were made up at 50 mM in DMSO.
  • Compound 4 perphenazine was purchased from Sigma (P6402-1G) and made up in EtOH.
  • Compounds 10 - 12 were made up at 5 mM in H2O.
  • Calyculin A was purchased from VWR (89157-750) and made up in EtOH
  • Fig. 14 provides an overview of synthesis.
  • arylnitrile (1.0 eq) and zinc trifluoromethanesulfonate (0.25 eq) in acetonitrile (5.0 eq)) was added hydrazine monohydrate (5.0 eq) and the mixture was stirred 18 h at 90 °C.
  • the mixture was added to a solution of sodium nitrate (30 ml_, 1.0 M) and HCI (2.0 M) was added dropwise until pH 3.0.
  • the mixture was extracted with dichloromethane and the organic layer was dried over MgSC , filtered and evaporated to dryness and the crude product was purified by column chromatography.
  • Fig. 14 provides an overview of synthesis.
  • tetrazine derivative 1.0 eq
  • DMSO 0.1 M solution
  • alkene derivative 1.0 eq
  • the solvent was evaporated to dryness and the crude product was purified by column chromatography (MeOH: dichloromethane, 0:1 to 1 :19) to give the Boc protected intermediate.
  • This mixture was dissolved in HCI 4 M in dioxane (0.5 ml_) was added and the mixture was stirred for 2 hours. The solvent was evaporated and the residue was purified by column chromatography.
  • (2S,3R)-3-(4-Octylphenyl)-2-((pent-4-en-1 -yloxy)methyl)pyrrolidin-1 -ium chloride (25): Column chromatography (MeOH: dichloromethane, 1 :19) to give (2S,3R)- 3-(4-octylphenyl)-2-((pent-4-en-1-yloxy)methyl)pyrrolidin-1-ium chloride (4 mg, 52%) as a colorless oil.

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Abstract

L'invention concerne des composés à petites molécules et leurs procédés de synthèse. L'invention concerne également des formulations et des médicaments qui sont destinés au traitement d'une maladie telle que, par exemple, les néoplasmes, les cancers et d'autres maladies. L'invention concerne également des substances thérapeutiques contenant une dose thérapeutiquement efficace d'un ou de plusieurs composés à petites molécules, présents sous forme de sel pharmaceutiquement efficace ou sous forme pure, y compris, sans s'y limiter, des formulations pour l'administration par voie orale, intraveineuse ou intramusculaire.
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US11479530B2 (en) 2015-09-24 2022-10-25 The Regents Of The University Of California Synthetic sphingolipid-like molecules, drugs, methods of their synthesis and methods of treatment
US11999693B2 (en) 2015-09-24 2024-06-04 The Regents Of The University Of California Synthetic sphingolipid-like molecules, drugs, methods of their synthesis and methods of treatment
CN114213351A (zh) * 2021-12-10 2022-03-22 乐威医药（江苏）股份有限公司 1,2,4,5-四嗪化合物的合成方法

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