WO2014160034A1 - Modulateurs d'aldéhyde déshydrogénase-1 et leurs procédés d'utilisation - Google Patents

Modulateurs d'aldéhyde déshydrogénase-1 et leurs procédés d'utilisation Download PDF

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WO2014160034A1
WO2014160034A1 PCT/US2014/025679 US2014025679W WO2014160034A1 WO 2014160034 A1 WO2014160034 A1 WO 2014160034A1 US 2014025679 W US2014025679 W US 2014025679W WO 2014160034 A1 WO2014160034 A1 WO 2014160034A1
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cancer
inhibitors
compound
compounds
agents
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PCT/US2014/025679
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English (en)
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Che-Hong Chen
Wenjin Yang
Daria Mochly-Rosen
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The Board Of Trustees Of The Leland Stanford Junior University
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Aldehyde dehydrogenase- 1 (ALDH1A1) is mitochondria nuclear encoded cytosolic enzyme.
  • ALDH1 Al has been widely recognized as a key biomarker for cancer stem cell (CSC). Strong support for the CSC hypothesis, which proposes that a relatively rare subpopulation of tumor cells have the unique ability to initiate and perpetuate tumor growth has been published in the past decade. These cells, called cancer stem cells or tumor-initiating cells, share various characteristics with embryonic and somatic stem cells including self-renewal and multi-potent differentiation. CSCs may be highly resistant to radiation or chemotherapy; therefore, the development of more effective therapies for cancer requires effective targeting of this cell population. These cells can be identified and isolated using biomarkers such as ALDH1A1.
  • ALDHlAl isozymes such as ALDH1A1 metabolize a wide variety of intracellular aldehydes and can thus provide resistance to reactive oxygen species (ROS)-derived products or alkylating agents such as cyclophosphamide.
  • ROS reactive oxygen species
  • High ALDHlAl activity has been reported in CSCs from many cancers including breast, lung, liver, colon, pancreas, ovary, head and neck, prostate cancers and some hematologic cancers.
  • silencing ALDHlAl by siRNA or shRNA leads to cell cycle arrest, apoptosis, decreased ceil viability in vitro, and reduced tumorigenesis in vivo.
  • Silencing ALDHlAl by siRNA also sensitizes cancer cells to drug- induced cell death.
  • silencing ALDHlAl using nanoliposomal siRNA sensitized both taxane- and platinum-resistant cell lines to chemotherapy significantly reducing tumor growth in mice compared with chemotherapy alone (74%-90% reduction; P ⁇ 0.015).
  • ALDHlAl is not only a biomarker of CSCs, but also an attractive therapeutic target for human cancer
  • Antagonists of ALDHlAl are useful for treating disorders such as cancer.
  • Compounds of the present disclosure are antagonist of ALDHlAl, or inhibitors of ALDHlAl and are described herein.
  • the present disclosure provides compounds that function as inhibitors or antagonists of aldehyde dehydrogenase- 1 (ALDHlAl) activity, pharmaceutical compositions containing them, and methods of preparing these compounds.
  • the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) and a cancer
  • R 1 and R 2 are each independently selected from hydrogen and C 1 -C6 alkyl
  • R 3 and R 4 are each independently selected from hydrogen and C 1 -C6 alkyl
  • each R 7 is independently selected from halogen, C 1 -C6 alkyl, and OCH 3 ;
  • n 0, 1, 2, 3, 4, or 5;
  • R 1 and R 2 is hydrogen and the other is Ci-C 6 alkyl.
  • one of R 3 and R 4 is hydrogen and the other is C 1 -C6 alkyl.
  • one of R 3 and R 4 is hydrogen and the other is methyl or ethyl.
  • n is 0, 1, 2, or 3.
  • n is 1, 2, or 3.
  • n is 1.
  • n is 2.
  • each R 7 is C 1 -C6 alkyl.
  • R 7 is methyl, ethyl, or isopropyl.
  • each R 7 is halogen.
  • R 7 is fluoro.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound selected from Table 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a cancer chemotherapeutic agent.
  • the chemotherapeutic agent is selected from non-peptidic (non- proteinaceous) compounds that reduce proliferation of cancer cells, cytotoxic agents, cytostatic agents, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, taxanes, microtubule affecting agents, metal complexes, steroid hormones, tyrosine kinase and/or serine/threonine inhibitors, inhibitors of angiogenesis, colony-stimulating factors, histone- deacetylase inhibitors (HDAC inhibitors), and antagonists of tumor necrosis factor.
  • non-peptidic (non- proteinaceous) compounds that reduce proliferation of cancer cells
  • cytotoxic agents cytostatic agents
  • alkylating agents nitrosoureas
  • antimetabolites antitumor antibiotics
  • taxanes taxanes
  • microtubule affecting agents metal complexes
  • steroid hormones e.g., tyrosine kinase and/
  • the proteinaceous compounds that reduce proliferation of cancer cells is selected from tumor-associated antigen antagonists, antibodies that bind specifically to a tumor antigen, apoptosis receptor agonists, interleukin-2, interferon-alpha (a), interferon-gamma ( ⁇ ), colony-stimulating factors, inhibitors of angiogenesis, and antagonists of tumor necrosis factor.
  • the present disclosure provides a method of treating or preventing cancer comprising administering to a subject a pharmaceutical composition as described herein. In one embodiment, the present disclosure provides a method of treating or preventing cancer comprising administering to a subject a compound as described herein. In one embodiment, the present disclosure provides a method of treating or preventing cancer comprising administering to a subject a compound is selected from Table 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the method as described herein further comprises administering a cancer chemotherapeutic agent.
  • the chemotherapeutic agent is selected from non- peptidic (non-proteinaceous) compounds that reduce proliferation of cancer cells, cytotoxic agents, cytostatic agents, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, taxanes, microtubule affecting agents, metal complexes, steroid hormones, tyrosine kinase and/or serine/threonine inhibitors, inhibitors of angiogenesis, colony-stimulating factors, histone- deacetylase inhibitors (HDAC inhibitors), and antagonists of tumor necrosis factor.
  • HDAC inhibitors histone- deacetylase inhibitors
  • the proteinaceous compounds that reduce proliferation of cancer cells is selected from tumor-associated antigen antagonists, antibodies that bind specifically to a tumor antigen, apoptosis receptor agonists, interleukin-2, interferon-alpha (a), interferon-gamma ( ⁇ ), colony- stimulating factors, inhibitors of angiogenesis, and antagonists of tumor necrosis factor.
  • the compound and the chemotherapeutic agent are administered
  • the method as described herein further comprises administering ionizing radiation.
  • the ionizing radiation is administered via external beam radiation therapy or brachytherapy.
  • the present disclosure provides a method of treating or preventing cancer in a subject comprising administering to the subject a first amount of a compound as described herein in a first treatment procedure, and a second amount of radiation in a second treatment procedure wherein, the first and second amounts together comprise a therapeutically effective amount.
  • the radiation is a radiopharmaceutical agent.
  • the radiation is an ionizing radiation administered via external beam radiation therapy or brachytherapy.
  • the cancer is selected from solid tumors, skin cancers, myeloma, lymphoma, leukemia, ovarian cancer, lung cancer, brain cancer, pancreatic cancer, prostate cancer, colon cancer, colorectal cancer, breast cancer, liver cancer, kidney cancer, oral cancer, head cancer, neck cancer, throat cancer, and thyroid cancer.
  • the method described herein provides a synergistic effect in the treatment of cancer.
  • the present disclosure relates to a method of increasing the sensitivity of a cancerous cells or cancer stem cells to a chemotherapeutic agent comprising administering to a subject a compound as described herein or a pharmaceutical composition as described herein.
  • the chemotherapeutic agent is selected from non-peptidic (non-proteinaceous) compounds that reduce proliferation of cancer cells, cytotoxic agents, cytostatic agents, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, taxanes, microtubule affecting agents, metal complexes, steroid hormones, tyrosine kinase and/or serine/threonine inhibitors, inhibitors of angiogenesis, colony-stimulating factors, histone-deacetylase inhibitors (HDAC inhibitors), and antagonists of tumor necrosis factor.
  • non-peptidic (non-proteinaceous) compounds that reduce proliferation of cancer cells
  • cytotoxic agents cytostatic agents
  • alkylating agents nitrosoureas
  • antimetabolites antitumor antibiotics
  • taxanes taxanes
  • microtubule affecting agents metal complexes
  • steroid hormones e.g., tyrosine kinase and/
  • the proteinaceous compounds that reduce proliferation of cancer cells is selected from tumor-associated antigen antagonists, antibodies that bind specifically to a tumor antigen apoptosis receptor agonists, interleukin-2 interferon-alpha (a), interferon-gamma ( ⁇ ), colony-stimulating factors, inhibitors of angiogenesis, and antagonists of tumor necrosis factor.
  • the compound or pharmaceutical composition is administered by a route selected from topical, intramuscular, intravenous, subcutaneous, and oral. In one embodiment, the compound or pharmaceutical composition is administered to the respiratory tract.
  • the present disclosure provides a use of a pharmaceutical composition as disclosed above for the manufacture of a medicament for treating or preventing cancer.
  • the present disclosure provides a use of a compound of formula (I) for the manufacture of a medicament for treating or preventing cancer.
  • the present disclosure provides a use of a compound selected from Table 1 herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the manufacture of a medicament for treating or preventing cancer.
  • the medicament further comprises a cancer chemotherapeutic agent.
  • the chemotherapeutic agent is selected from non-peptidic (non- proteinaceous) compounds that reduce proliferation of cancer cells, cytotoxic agents, cytostatic agents, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, taxanes, microtubule affecting agents, metal complexes, steroid hormones, tyrosine kinase and/or serine/threonine inhibitors, inhibitors of angiogenesis, colony-stimulating factors, histone- deacetylase inhibitors (HDAC inhibitors), and antagonists of tumor necrosis factor.
  • non-peptidic (non- proteinaceous) compounds that reduce proliferation of cancer cells
  • cytotoxic agents cytostatic agents
  • alkylating agents nitrosoureas
  • antimetabolites antitumor antibiotics
  • taxanes taxanes
  • microtubule affecting agents metal complexes
  • steroid hormones e.g., tyrosine kinase and/
  • the non-proteinaceous compounds that reduce proliferation of cancer cells is selected from tumor-associated antigen antagonists, antibodies that bind specifically to a tumor antigen, apoptosis receptor agonists, interleukin-2, interferon-alpha (a), interferon-gamma ( ⁇ ), colony-stimulating factors, inhibitors of angiogenesis, and antagonists of tumor necrosis factor.
  • the compound and the chemotherapeutic agent are administered
  • the use further comprises administering ionizing radiation.
  • the ionizing radiation is administered via external beam radiation therapy or brachytherapy.
  • the present disclosure provides a use of a first amount of a compound of formula (I) for the manufacture of a medicament for treating or preventing cancer in a first treatment procedure, wherein the use further comprises a second amount of radiation in a second treatment procedure wherein, the first and second amounts together comprise a therapeutically effective amount.
  • the radiation is a radiopharmaceutical agent.
  • the radiation is an ionizing radiation administered via external beam radiation therapy or brachytherapy.
  • the cancer is selected from solid tumors, skin cancers, myeloma, lymphoma, leukemia, ovarian cancer, lung cancer, brain cancer, pancreatic cancer, prostate cancer, colon cancer, colorectal cancer, breast cancer, liver cancer, kidney cancer, oral cancer, head cancer, neck cancer, throat cancer, and thyroid cancer.
  • the use provides a synergistic effect in the treatment of cancer.
  • the present disclosure provides a use of a compound of formula (I) or a pharmaceutical composition as disclosed above for the manufacture of a medicament for increasing the sensitivity of cancerous cells or cancer stem cells to a chemotherapeutic agent.
  • the chemotherapeutic agent is selected from non-peptidic (non- proteinaceous) compounds that reduce proliferation of cancer cells, cytotoxic agents, cytostatic agents, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, taxanes, microtubule affecting agents, metal complexes, steroid hormones, tyrosine kinase and/or serine/threonine inhibitors, inhibitors of angiogenesis, colony-stimulating factors, histone- deacetylase inhibitors (HDAC inhibitors), and antagonists of tumor necrosis factor.
  • non-peptidic (non- proteinaceous) compounds that reduce proliferation of cancer cells
  • cytotoxic agents cytostatic agents
  • alkylating agents nitrosoureas
  • antimetabolites antitumor antibiotics
  • taxanes taxanes
  • microtubule affecting agents metal complexes
  • steroid hormones e.g., tyrosine kinase and/
  • the non-proteinaceous compounds that reduce proliferation of cancer cells is selected from tumor-associated antigen antagonists, antibodies that bind specifically to a tumor antigen apoptosis receptor agonists, interleukin-2 interferon-alpha (a), interferon-gamma ( ⁇ ), colony-stimulating factors, inhibitors of angiogenesis, and antagonists of tumor necrosis factor.
  • the compound or pharmaceutical composition is administered by a route selected from topical, intramuscular, intravenous, subcutaneous, and oral.
  • the compound or pharmaceutical composition is administered to the subject.
  • Figure 1 is a graph showing the selectivity of Compound 5 against different ALDH isozymes.
  • Figure 2A is a graph showing that Compound 5 sensitizes cytotoxic effect of paclitaxel in human multi-drug resistant ovarian NCI/ADR-RES cancer cells.
  • Figure 2B is a graph showing that Compound 5 sensitizes cytotoxic effect of paclitaxel in human multi-drug resistant ovarian TOV-21G-RT cancer cells.
  • Figure 3A is a graph showing that Compound 5 sensitizes cytotoxic effect of doxorubicin in human multi-drug resistant ovarian NCI/ADR-RES cancer cells.
  • Figure 3B is a graph showing that Compound 5 sensitizes cytotoxic effect of doxorubicin in human multi-drug resistant ovarian TOV-21G-RT cancer cells.
  • R 1 and R 2 are each independently selected from hydrogen and Ci-C 6 alkyl
  • R 3 and R 4 are each independently selected from hydrogen and C 1 -C6 alkyl
  • each R 7 is independently selected from halogen, C 1 -C6 alkyl, and OCH 3 ;
  • n 0, 1, 2, 3, 4, or 5;
  • one of R 1 and R 2 is hydrogen and the other is Ci-C 6 alkyl.
  • one of R 1 and R 2 is hydrogen and the other is straight-chain Ci-C 6 alkyl or branched C 3 -C6 alkyl. In one embodiment, one of R 1 and R 2 is hydrogen and the other is straight-chain d- C 4 alkyl or branched C3-C4 alkyl. In one embodiment, one of R 1 and R 2 is hydrogen and the other is straight-chain C 1 -C4 alkyl. In one embodiment, one of R 1 and R 2 is hydrogen and the other is branched C3-C4 alkyl. [0047] In one embodiment, one of R 3 and R 4 is hydrogen and the other is Ci-C 6 alkyl. In one embodiment, one of R 3 and R 4 is hydrogen and the other is methyl or ethyl.
  • one of R 1 and R 2 is hydrogen and the other is straight-chain C 1 -C4 alkyl; and one of R 3 and R 4 is hydrogen and the other is methyl or ethyl. In one embodiment, one of R 1 and R 2 is hydrogen and the other is branched C 3 -C 4 alkyl; and one of R 3 and R 4 is hydrogen and the other is methyl or ethyl.
  • n is 0, 1, 2, or 3. In one embodiment, n is 1, 2, or 3. In one embodiment, n is 1. In one embodiment, n is 2.
  • each R 7 is Ci-C 6 alkyl. In one embodiment, each R 7 is independently methyl, ethyl, or isopropyl. In one embodiment, each R 7 is halogen. In one embodiment, each R 7 is independently chloro or fluoro. In one embodiment, R 7 is chloro. In one embodiment, R 7 is fluoro. In one embodiment, one or more R 7 is Ci-C 6 alkyl and one or more R 7 is halogen. In one embodiment, one or more R 7 is independently methyl, ethyl, or isopropyl and one or more R 7 is independently chloro or fluoro. In one embodiment, one or more R 7 is Ci-C 6 alkyl and one or more R 7 is OCH 3 .
  • one or more R 7 is independently methyl, ethyl, or isopropyl and one or more R 7 is OCH 3 . In one embodiment, one or more R 7 is halogen and one or more R 7 is OCH 3 . In one example, one or more R 7 is independently chloro or fluoro and one or more R 7 is OCH 3 .
  • the present disclosure further provides assays for identifying inhibitors of ALDHlAl.
  • subjects to be treated are humans.
  • a human to be treated according to a subject method is one that has the wild type ALDHlAl allele or a mutated/variant ALDHlAl allele, e.g. a mutated/variant ALDHlAl gene with over-expression of the ALDHlAl transcripts/enzyme, or a mutated/variant ALDHlAl gene which encodes a product with higher enzymatic activity of ALDHlAl.
  • a compound can be readily ascertained whether it is an ALDHlAl inhibitor or not.
  • Assays for dehydrogenase activity of ALDHlAl are known in the art, and any known assay can be used. Examples of dehydrogenase assays are found in various publications, including, e.g., Russo and Hilton, 1998, Cancer Res. 48:2963-8; Ho et al., 2006, Biochemistry 45:9445-53; Sheikh et al., 1997, J. Biol. Chem. 272:18817-18822; Vallari and Pietruszko, 1984, J. Biol. Chem. 259:4922; and Farres et al., 1994, J. Biol. Chem. 269:13854-13860.
  • the assays generally comprise two parts; one is the preparation of human ALDHlAl recombinant enzyme; and the other is the determination of the enzyme inhibition by a compound in the present disclosure.
  • human ALDHlAl recombinant enzyme full-length human ALDHlAl cDNA may be synthesized based on published DNA sequence (e.g., GenBank ID: NM_000689).
  • the synthetic gene may be cloned into the Nhel/EcoRI sites of the His-tag vector, pTrcHis, for protein expression. All the vectors are transformed into BL21 E. coli host cells and subjected to 0.5 niM isopropyl ⁇ -D-l-thiogalactopyranoside (IPTG) induction for protein expression at 30 °C.
  • IPTG isopropyl ⁇ -D-l-thiogalactopyranoside
  • the present disclosure is intended to include all isotopes of atoms occurring in the present
  • isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include C-13 and C-14.
  • a group may optionally be substituted with up to two Ri moieties and Ri at each occurrence is selected independently from the definition of R ⁇
  • substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • N-oxides can be converted to N-oxides by treatment with an oxidizing agent (e.g. , 3-chloroperoxybenzoic acid (ra-CPBA) and/or hydrogen peroxides) to afford other compounds of the present disclosure.
  • an oxidizing agent e.g. , 3-chloroperoxybenzoic acid (ra-CPBA) and/or hydrogen peroxides
  • ra-CPBA 3-chloroperoxybenzoic acid
  • hydrogen peroxides hydrogen peroxides
  • N-hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as ra-CPBA. All shown and claimed nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compound as shown and its N-hydroxy (i.e. , N-OH) and N-alkoxy (i.e. , N-OR, wherein R is substituted or unsubstituted Ci_ 6 alkyl,
  • Ci_6 alkenyl, Ci_ 6 alkynyl, C 3 . i4 carbocycle, or 3-14-membered heterocycle) derivatives
  • Ci_ 6 alkyl is meant to include alkyl groups with 1, 2, 3, 4, 5, 6, 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6 carbons.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Ci-6 alkyl is intended to include Ci , C2, C3, C4, C5, and Cg alkyl groups.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n- hexyl.
  • alkyl also includes alkyl groups that have oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more hydrocarbon backbone carbon atoms, these are known as heteroalkyl,
  • a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone (e.g. , Ci- for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched chain alkyl has four or fewer carbon atoms.
  • cycloalkyls have from three to eight carbon atoms in their ring structure, and in another embodiment, cycloalkyls have five or six carbons in the ring structure.
  • halo or halogen refers to fluoro, chloro, bromo, and iodo.
  • perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
  • the compounds of the present disclosure can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • hydrates include monohydrates, dihydrates, etc.
  • Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
  • Solvates means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 0, such combination being able to form one or more hydrate.
  • Tautomers refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium. It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form.
  • Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present disclosure includes all tautomers of the present compounds [0073]
  • a tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism.
  • a "pharmaceutical composition” is a formulation containing the disclosed compounds in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial.
  • the quantity of active ingredient (e.g. , a formulation of the disclosed compound or salt, hydrate, solvate, or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g. , a formulation of the disclosed compound or salt, hydrate, solvate, or isomer thereof
  • the dosage will also depend on the route of administration.
  • routes of administration A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • a "subject” includes mammals, e.g. , humans, companion animals (e.g. , dogs, cats, birds, and the like), farm animals (e.g. , cows, sheep, pigs, horses, fowl, and the like) and laboratory animals (e.g. , rats, mice, guinea pigs, birds, and the like).
  • the subject is human.
  • the phrase "pharmaceutically acceptable” refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a
  • composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient.
  • “Pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2- acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxy maleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,
  • Other examples include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]- oct-2-ene-l -carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like.
  • the present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used.
  • Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 18th ed. (Mack Publishing Company, 1990).
  • salts can include, but are not limited to, the hydrochloride and acetate salts of the aliphatic amine -containing, hydroxyl amine - containing, and imine
  • esters For example a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g. , a. methyl, ethyl, or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, e.g. , an acetate, propionate, or other ester.
  • the compounds of the present disclosure can also be prepared as prodrugs, for example
  • prodrug and prodrug are used interchangeably.
  • prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g. , solubility, bioavailability, manufacturing, etc.) the compounds of the present disclosure can be delivered in prodrug form.
  • the present disclosure is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same.
  • Prodrugs are intended to include any covalently bonded carriers that release an active parent drug of the present disclosure in vivo when such prodrug is administered to a subject.
  • Prodrugs the present disclosure are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of the present disclosure wherein a hydroxy, amino, sulfhydryl, carboxy, or carbonyl group is bonded to any group that, may be cleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl, free carboxy or free carbonyl group, respectively.
  • prodrugs include, but are not limited to, esters (e.g. , acetate, dialkylaminoacetates, formates, phosphates, sulfates, and benzoate derivatives) and carbamates (e.g. , N,N- dimethylaminocarbonyl) of hydroxy functional groups, esters groups (e.g. ethyl esters, morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (e.g.
  • N-acetyl) N- Mannich bases Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of Formula I, and the like, See Bundegaard, H. "Design of Prodrugs" p. 1-92, Elesevier, New York-Oxford (1985).
  • the term "mitochondrial aldehyde dehydrogenase- 1" or "ALDHlAl” refers to an enzyme that oxidizes an aldehyde (e.g., a xenogenic aldehyde, a biogenic aldehyde, or an aldehyde produced from a compound that is ingested, inhaled, or absorbed) to its corresponding acid in an NAD + -dependent reaction.
  • ALDHlAl oxidizes aldehydes derived from the breakdown of compounds, e.g., toxic compounds that are ingested, that are absorbed, that are inhaled, or that are produced during normal metabolism.
  • ALDHlAl encompasses ALDHlAl from various species. Amino acid sequences of ALDHlAl are publicly available. For example, a human ALDHlAl amino acid sequence is found under GenBank Accession Nos. NM_000689; a mouse ALDHlAl amino acid sequence is found under GenBank Accession No. NM_013467; and a rat ALDHlAl amino acid sequence is found under GenBank Accession No. NM_022407.
  • ALDHlAl as used herein also encompasses fragments, fusion proteins, and variants (e.g., variants having one or more amino acid substitutions, addition, deletions, and/or insertions) that retain ALDHlAl enzymatic activity. Specific enzymatically active ALDHlAl variants, fragments, fusion proteins, and the like can be verified by adapting the methods described herein.
  • An example of an ALDHlAl variant is an ALDHlAl with a 17 base pair (bp) deletion (-416/-432) or a 3 bp insertion (-524) in the
  • ALDHlAl promoter region designated as ALDH1A1*2 and ALDH1A1*3, respectively
  • An ALDHlAl variant retains at least about 1% of the enzymatic activity of a corresponding wild-type ALDHlAl enzyme.
  • Chloride Product D then undergoes thiolation by thiourea (E) to yield Thiourea Compound F.
  • the desired final product G is formed by nucleophilic substitution of Thiourea Compound F with a halide (R 3 X).
  • the present disclosure provides various treatment and prevention methods, generally involving administering to a subject an effective amount of a compound of the present disclosure.
  • Diseases and conditions associated with ALDH1A1 include cancer.
  • Treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc.
  • Treating or “treatment” of a disease state includes: (1) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms; (2) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms; or (3) reducing or lessening the symptoms of the disease state.
  • Preventing refers to causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
  • the present disclosure provides a method of treating or preventing cancer comprising administering to a subject a pharmaceutical composition as described herein. In one embodiment, the present disclosure provides a method of treating or preventing cancer comprising administering to a subject a compound as described herein. In one embodiment, the present disclosure provides a method of treating or preventing cancer comprising administering to a subject a compound is selected from Table 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • the method as described herein further comprises administering a cancer chemotherapeutic agent.
  • the chemotherapeutic agent is selected from non- peptidic (non-proteinaceous) compounds that reduce proliferation of cancer cells, cytotoxic agents, cytostatic agents, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, taxanes, microtubule affecting agents, metal complexes, steroid hormones, tyrosine kinase and/or serine/threonine inhibitors, inhibitors of angiogenesis, colony-stimulating factors, histone- deacetylase inhibitors (HDAC inhibitors), and antagonists of tumor necrosis factor.
  • HDAC inhibitors histone- deacetylase inhibitors
  • the proteinaceous compounds that reduce proliferation of cancer cells is selected from tumor-associated antigen antagonists, antibodies that bind specifically to a tumor antigen, apoptosis receptor agonists, interleukin-2, interferon-alpha (a), interferon-gamma ( ⁇ ), colony- stimulating factors, inhibitors of angiogenesis, and antagonists of tumor necrosis factor.
  • the compound and the chemotherapeutic agent are administered
  • the method as described herein further comprises administering ionizing radiation.
  • the ionizing radiation is administered via external beam radiation therapy or brachytherapy.
  • the present disclosure provides a method of treating or preventing cancer in a subject comprising administering to the subject a first amount of a compound as described herein in a first treatment procedure, and a second amount of radiation in a second treatment procedure wherein, the first and second amounts together comprise a therapeutically effective amount.
  • the radiation is a radiopharmaceutical agent.
  • the radiation is an ionizing radiation administered via external beam radiation therapy or brachytherapy.
  • the cancer is selected from solid tumors, skin cancers, myeloma, lymphoma, leukemia, ovarian cancer, lung cancer, brain cancer, pancreatic cancer, prostate cancer, colon cancer, colorectal cancer, breast cancer, liver cancer, kidney cancer, oral cancer, head cancer, neck cancer, throat cancer, and thyroid cancer.
  • the method described herein provides a synergistic effect in the treatment of cancer.
  • the present disclosure relates to a method of increasing the
  • the chemotherapeutic agent is selected from non-peptidic (non-proteinaceous) compounds that reduce proliferation of cancer cells, cytotoxic agents, cytostatic agents, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, taxanes, microtubule affecting agents, metal complexes, steroid hormones, tyrosine kinase and/or serine/threonine inhibitors, inhibitors of angiogenesis, colony-stimulating factors, histone- deacetylase inhibitors (HDAC inhibitors), and antagonists of tumor necrosis factor.
  • the proteinaceous compounds that reduce proliferation of cancer cells is selected from tumor-associated antigen antagonists, antibodies that bind specifically to a tumor antigen apoptosis receptor agonists, interleukin-2 interferon-alpha (a), interferon-gamma ( ⁇ ), colony- stimulating factors, inhibitors of angiogenesis, and antagonists of tumor necrosis factor.
  • the cancer is ovarian cancer.
  • the present disclosure provides methods of treating or preventing cancer in a subject.
  • the methods generally involve administering to a subject an effective amount of a compound of the present disclosure in conjunction with a standard cancer therapy.
  • Standard cancer therapies include surgery (e.g., surgical removal of cancerous tissue), radiation therapy, bone marrow transplantation, chemotherapeutic treatment, biological response modifier treatment, and certain combinations of the foregoing.
  • Radiation therapy includes, but is not limited to, x-rays or gamma rays that are delivered from either an externally applied source such as a beam, or by implantation of small radioactive sources.
  • Chemotherapeutic agents are compounds that reduce proliferation of cancer cells, and encompass cytotoxic agents and cytostatic agents.
  • Non-limiting examples of chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant (vinca) alkaloids, and steroid hormones.
  • Agents that act to reduce cellular proliferation are known in the art and widely used.
  • Such agents include alkylating agents, such as nitrogen mustards, nitrosoureas, ethylenimine derivatives, alkyl sulfonates, and triazenes, including, but not limited to, mechlorethamine, cyclophosphamide (Cytoxan.TM.), melphalan (L-sarcolysin), carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), streptozocin, chlorozotocin, uracil mustard, chlormethine, ifosfamide, chlorambucil, pipobroman, triethylenemelamine, trie thylenethiophosphor amine, busulfan, dacarbazine, and temozolomide.
  • alkylating agents such as nitrogen mustards, nitrosoureas, ethylenimine derivatives, alkyl sulfon
  • Antimetabolite agents include folic acid analogs, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors, including, but not limited to, cytarabine (CYTOSAR-U), cytosine arabinoside, fluorouracil (5-FU), floxuridine (FudR), 6-thioguanine, 6-mercaptopurine (6-MP), pentostatin, 5 -fluorouracil (5-FU), methotrexate, 10-propargyl-5,8-dideazafolate (PDDF, CB3717), 5,8-dideazatetrahydrofolic acid (DDATHF), leucovorin, fludarabine phosphate, pentostatine, and gemcitabine.
  • CYTOSAR-U cytarabine
  • cytosine arabinoside including, but not limited to, fluorouracil (5-FU), floxuridine (FudR), 6-thioguanine, 6-
  • Suitable natural products and their derivatives e.g., vinca alkaloids, antitumor
  • antibiotics include, but are not limited to, Ara- C, paclitaxel (Taxol®), docetaxel (Taxotere®), deoxycoformycin, mitomycin-C, L-asparaginase, azathioprine; brequinar; alkaloids, e.g. vincristine, vinblastine, vinorelbine, vindesine, etc.;
  • podophyllotoxins e.g. etoposide, teniposide, etc.
  • antibiotics e.g. anthracycline, daunorubicin hydrochloride (daunomycin, rubidomycin, cerubidine), idarubicin, doxorubicin, epirubicin and morpholino derivatives, etc.
  • phenoxizone biscyclopeptides e.g. dactinomycin
  • glycopeptides e.g. bleomycin
  • anthraquinone glycosides e.g. plicamycin (mithramycin)
  • anthracenediones e.g. mitoxantrone
  • azirinopyrrolo indolediones e.g. mitomycin
  • macrocyclic immunosuppressants e.g. cyclosporine, FK-506 (tacrolimus, prograi), rapamycin, etc.; and the like.
  • anti-proliferative cytotoxic agents are navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.
  • Microtubule affecting agents that have antiproliferative activity are also suitable for use and include, but are not limited to, allocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e.g., NSC 33410), dolstatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol®), Taxol® derivatives, docetaxel (Taxotere®), thiocolchicine (NSC 361792), trityl cysterin, vinblastine sulfate, vincristine sulfate, natural and synthetic epothilones including but not limited to, eopthilone A, epothilone B, discodermolide; estramustine, nocodazole, and the like.
  • Hormone modulators and steroids that are suitable for use include, but are not limited to, adrenocorticosteroids, e.g. prednisone, dexamethasone, etc.;
  • estrogens and pregestins e.g. hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, estradiol, clomiphene, tamoxifen; etc.; and adrenocortical suppressants, e.g.
  • estradiosteroids may inhibit T cell proliferation.
  • chemotherapeutic agents include metal complexes, e.g. cisplatin (cis-DDP), carboplatin, etc.; ureas, e.g. hydroxyurea; and hydrazines, e.g. N-methylhydrazine;
  • epidophyllotoxin a topoisomerase inhibitor
  • procarbazine mitoxantrone
  • leucovorin tegafur
  • Other anti-proliferative agents of interest include immunosuppressants, e.g. mycophenolic acid, thalidomide, desoxyspergualin, azasporine, leflunomide, mizoribine, azaspirane (SKF 105685); Iressa® (ZD 1839, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-(4- morpholinyl)propoxy)qu- inazoline); etc.
  • immunosuppressants e.g. mycophenolic acid, thalidomide, desoxyspergualin, azasporine, leflunomide, mizoribine, azaspirane (SKF 105685); Iressa® (ZD 1839, 4-(3-chloro-4-fluorophenylamino)
  • Taxanes include paclitaxel, as well as any active taxane derivative or pro-drug.
  • “Paclitaxel” (which should be understood herein to include analogues, formulations, and derivatives such as, for example, docetaxel, TAXOLTM, TAXOTERETM (a formulation of docetaxel), 10-desacetyl analogs of paclitaxel and 3 'N-desbenzoyl-3 'N-t-butoxycarbonyl analogs of paclitaxel) may be readily prepared utilizing techniques known to those skilled in the art (see also WO 94/07882, WO 94/07881, WO 94/07880, WO 94/07876, WO 93/23555, WO 93/10076; U.S. Pat. Nos.
  • Biological response modifiers suitable for use in connection with the methods of the present disclosure include, but are not limited to, (1) inhibitors of tyrosine kinase (RTK) activity; (2) inhibitors of serine/threonine kinase activity; (3) tumor-associated antigen antagonists, such as antibodies that bind specifically to a tumor antigen; ( 4) apoptosis receptor agonists; (5) interleukin-2; (6) interferon- a.; (7) interferon - ⁇ ; (8) colony-stimulating factors; (9) inhibitors of angiogenesis; and (10) antagonists of tumor necrosis factor.
  • RTK tyrosine kinase
  • the present disclosure provides a use of a pharmaceutical
  • composition as disclosed herein for the manufacture of a medicament for treating or preventing cancer.
  • the present disclosure provides a use of a compound of formula (I) for the manufacture of a medicament for treating or preventing cancer.
  • the present disclosure provides a use of a compound selected from
  • Table 1 herein or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the manufacture of a medicament for treating or preventing cancer.
  • the medicament further comprises a cancer chemotherapeutic agent.
  • the chemotherapeutic agent is selected from non-peptidic (non- proteinaceous) compounds that reduce proliferation of cancer cells, cytotoxic agents, cytostatic agents, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, taxanes, microtubule affecting agents, metal complexes, steroid hormones, tyrosine kinase and/or serine/threonine inhibitors, inhibitors of angiogenesis, colony-stimulating factors, histone- deacetylase inhibitors (HDAC inhibitors), and antagonists of tumor necrosis factor.
  • non-peptidic (non- proteinaceous) compounds that reduce proliferation of cancer cells
  • cytotoxic agents cytostatic agents
  • alkylating agents nitrosoureas
  • antimetabolites antitumor antibiotics
  • taxanes taxanes
  • microtubule affecting agents metal complexes
  • steroid hormones e.g., tyrosine kinase and/
  • the non-proteinaceous compounds that reduce proliferation of cancer cells is selected from tumor-associated antigen antagonists, antibodies that bind specifically to a tumor antigen, apoptosis receptor agonists, interleukin-2, interferon-alpha (a), interferon-gamma ( ⁇ ), colony-stimulating factors, inhibitors of angiogenesis, and antagonists of tumor necrosis factor.
  • the compound and the chemotherapeutic agent are administered simultaneously, staggered, alternating, or sequentially.
  • the use further comprises administering ionizing radiation.
  • the ionizing radiation is administered via external beam radiation therapy or brachytherapy.
  • the present disclosure provides a use of a first amount of a
  • compound of formula (I) for the manufacture of a medicament for treating or preventing cancer in a first treatment procedure, wherein the use further comprises a second amount of radiation in a second treatment procedure wherein, the first and second amounts together comprise a therapeutically effective amount.
  • the radiation is a radiopharmaceutical agent.
  • the radiation is an ionizing radiation administered via external beam radiation therapy or brachytherapy.
  • the cancer is selected from solid tumors, skin cancers, myeloma, lymphoma, leukemia, ovarian cancer, lung cancer, brain cancer, pancreatic cancer, prostate cancer, colon cancer, colorectal cancer, breast cancer, liver cancer, kidney cancer, oral cancer, head cancer, neck cancer, throat cancer, and thyroid cancer.
  • the use provides a synergistic effect in the treatment of cancer.
  • the present disclosure provides a use of a compound of formula (I) or a pharmaceutical composition as disclosed above for the manufacture of a medicament for increasing the sensitivity of cancerous cells or cancer stem cells to a chemotherapeutic agent.
  • the chemotherapeutic agent is selected from non-peptidic (non- proteinaceous) compounds that reduce proliferation of cancer cells, cytotoxic agents, cytostatic agents, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, taxanes, microtubule affecting agents, metal complexes, steroid hormones, tyrosine kinase and/or serine/threonine inhibitors, inhibitors of angiogenesis, colony-stimulating factors, histone- deacetylase inhibitors (HDAC inhibitors), and antagonists of tumor necrosis factor.
  • non-peptidic (non- proteinaceous) compounds that reduce proliferation of cancer cells
  • cytotoxic agents cytostatic agents
  • alkylating agents nitrosoureas
  • antimetabolites antitumor antibiotics
  • taxanes taxanes
  • microtubule affecting agents metal complexes
  • steroid hormones e.g., tyrosine kinase and/
  • the non-proteinaceous compounds that reduce proliferation of cancer cells is selected from tumor-associated antigen antagonists, antibodies that bind specifically to a tumor antigen apoptosis receptor agonists, interleukin-2 interferon-alpha (a), interferon-gamma ( ⁇ ), colony-stimulating factors, inhibitors of angiogenesis, and antagonists of tumor necrosis factor.
  • the compound or pharmaceutical composition is administered by a route selected from topical, intramuscular, intravenous, subcutaneous, and oral.
  • the compound or pharmaceutical composition is administered to the respiratory tract.
  • the present disclosure relates to a pharmaceutical composition
  • R 1 and R 2 are each independently selected from hydrogen and C 1 -C6 alkyl
  • R 3 and R 4 are each independently selected from hydrogen and C 1 -C6 alkyl
  • each R 7 is independently selected from halogen, C 1 -C6 alkyl, and OCH 3 , and
  • n 0, 1, 2, 3, 4, or 5;
  • one of R 1 and R 2 is hydrogen and the other is Ci-C 6 alkyl. In one embodiment, one of R 1 and R 2 is hydrogen and the other is straight-chain Ci-C 6 alkyl or branched C3-C6 alkyl. In one embodiment, one of R 1 and R 2 is hydrogen and the other is straight-chain d- C 4 alkyl or branched C3-C4 alkyl. In one embodiment, one of R 1 and R 2 is hydrogen and the other is straight-chain C 1 -C 4 alkyl. In one embodiment, one of R 1 and R 2 is hydrogen and the other is branched C3-C4 alkyl.
  • one of R 3 and R 4 is hydrogen and the other is Ci-C 6 alkyl. In one embodiment, one of R 3 and R 4 is hydrogen and the other is methyl or ethyl.
  • one of R 1 and R 2 is hydrogen and the other is straight-chain C 1 -C 4 alkyl; and one of R 3 and R 4 is hydrogen and the other is methyl or ethyl. In one embodiment, one of R 1 and R 2 is hydrogen and the other is branched C3-C4 alkyl; and one of R 3 and R 4 is hydrogen and the other is methyl or ethyl.
  • n is 0, 1, 2, or 3. In one embodiment, n is 1, 2, or 3. In one
  • n is 1. In one embodiment, n is 2.
  • each R 7 is Ci-C 6 alkyl. In one embodiment, each R 7 is independently methyl, ethyl, or isopropyl. In one embodiment, each R 7 is halogen. In one embodiment, each R 7 is independently chloro or fluoro. In one embodiment, R 7 is chloro. In one embodiment, R 7 is fluoro. In one embodiment, one or more R 7 is Ci-C 6 alkyl and one or more R 7 is halogen. In one embodiment, one or more R 7 is independently methyl, ethyl, or isopropyl and one or more R 7 is independently chloro or fluoro. In one embodiment, one or more R 7 is Ci-C 6 alkyl and one or more R 7 is OCH 3 .
  • one or more R 7 is independently methyl, ethyl, or isopropyl and one or more R 7 is OCH 3 . In one embodiment, one or more R 7 is halogen and one or more R 7 is OCH 3 . In one example, one or more R 7 is independently chloro or fluoro and one or more R 7 is OCH 3 .
  • a compound of the present disclosure is of one of the following formulae:
  • the present disclosure relates to a pharmaceutical composition
  • the chemotherapeutic agent is selected from non-peptidic (non- proteinaceous) compounds that reduce proliferation of cancer cells, cytotoxic agents, cytostatic agents, alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, taxanes, microtubule affecting agents, metal complexes, steroid hormones, tyrosine kinase and/or serine/threonine inhibitors, inhibitors of angiogenesis, colony-stimulating factors, histone- deacetylase inhibitors (HDAC inhibitors), and antagonists of tumor necrosis factor.
  • non-peptidic (non- proteinaceous) compounds that reduce proliferation of cancer cells
  • cytotoxic agents cytostatic agents
  • alkylating agents nitrosoureas
  • antimetabolites antitumor antibiotics
  • taxanes taxanes
  • microtubule affecting agents metal complexes
  • steroid hormones e.g., tyrosine kinase and/
  • the proteinaceous compounds that reduce proliferation of cancer cells is selected from tumor-associated antigen antagonists, antibodies that bind specifically to a tumor antigen, apoptosis receptor agonists, interleukin-2, interferon-alpha (a), interferon-gamma ( ⁇ ), colony-stimulating factors, inhibitors of angiogenesis, and antagonists of tumor necrosis factor.
  • the compound or pharmaceutical composition is administered by a route selected from topical, intramuscular, intravenous, subcutaneous, and oral. In one embodiment, the compound or pharmaceutical composition is administered to the respiratory tract.
  • the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure (where a compound of the present disclosure is also referred to herein as "active agent” of the present disclosure, or “subject active agent”).
  • the compound of the present disclosure can be formulated with one or more pharmaceutically acceptable excipients.
  • a wide variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein.
  • Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H. C.
  • compositions such as vehicles, adjuvants, carriers or diluents
  • pharmaceutically acceptable auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.
  • a subject ALDH1A1 activity inhibitor may be administered to the host using any convenient means capable of treating cancer.
  • a subject ALDH1A1 activity inhibitor can be incorporated into a variety of formulations for therapeutic administration. More particularly, a subject ALDH1A1 activity inhibitor can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.
  • a subject active agent may be administered in the form of their pharmaceutically acceptable salts, or a subject active agent may be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds.
  • the following methods and excipients are merely exemplary and are in no way limiting.
  • a subject active agent can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.
  • conventional additives such as lactose, mannitol, corn starch or potato starch
  • binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins
  • disintegrators such as corn starch, potato starch or sodium carboxymethylcellulose
  • lubricants such as talc or magnesium stearate
  • a subject active agent can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • an aqueous or nonaqueous solvent such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol
  • solubilizers such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • a subject active agent can be utilized in aerosol formulation to be administered via
  • a subject active agent can be formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like.
  • a subject active agent can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
  • An active agent can be administered rectally via a suppository.
  • the suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycol monomethyl ethers, which melt at body temperature, yet are solidified at room temperature.
  • Unit dosage forms for oral or rectal administration such as syrups, elixirs, and
  • each dosage unit for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the subject active agent.
  • unit dosage forms for injection or intravenous administration may comprise a subject active agent in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of a subject active agent calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle.
  • the specifications for a subject active agent depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.
  • a subject active agent can be formulated for administration by injection.
  • injectable compositions are prepared as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared. The preparation may also be emulsified or the active ingredient encapsulated in liposome vehicles.
  • a subject active agent is delivered by a continuous delivery system.
  • continuous delivery system is used interchangeably herein with “controlled delivery system” and encompasses continuous (e.g., controlled) delivery devices (e.g., pumps) in combination with catheters, injection devices, and the like, a wide variety of which are known in the art.
  • Suitable excipient vehicles are, for example, water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof.
  • the vehicle may contain minor amounts of auxiliary substances such as wetting or emulsifying agents or pH buffering agents.
  • auxiliary substances such as wetting or emulsifying agents or pH buffering agents.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17th edition, 1985.
  • the composition or formulation to be administered will, in any event, contain a quantity of the agent adequate to achieve the desired state in the subject being treated.
  • the subject compounds may be administered in dosages of, for example, 0.1 ⁇ g to 10 mg/kg body weight per day.
  • the range is broad, since in general the efficacy of a therapeutic effect for different mammals varies widely with doses typically being 20, 30 or even 40 times smaller (per unit body weight) in man than in the rat.
  • the mode of administration can have a large effect on dosage.
  • oral dosages may be about ten times the injection dose. Higher doses may be used for localized routes of delivery.
  • a subject ALDH1A1 activity modulator can be administered in an amount of from about 1 mg to about 1000 mg per dose, e.g., from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 75 mg, from about 75 mg to about 100 mg, from about 100 mg to about 125 mg, from about 125 mg to about 150 mg, from about 150 mg to about 175 mg, from about 175 mg to about 200 mg, from about 200 mg to about 225 mg, from about 225 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 750 mg, or from about 750 mg to about 1000 mg per dose.
  • An exemplary dosage may be a solution suitable for intravenous administration; a tablet taken from two to six times daily, or one time -release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient, etc.
  • the time -release effect may be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.
  • dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means.
  • Unit dosage forms for oral or rectal administration such as syrups, elixirs, and
  • each dosage unit for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more compounds of the present disclosure.
  • unit dosage forms for injection or intravenous administration may comprise the compound (s) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.
  • multiple doses of a subject compound are administered.
  • a subject compound is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid).
  • a subject compound is administered continuously.
  • the duration of administration of a subject compound can vary, depending on any of a variety of factors, e.g., patient response, etc.
  • a subject compound can be administered over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
  • a subject compound is administered for the lifetime of the individual.
  • a subject ALDH1A1 activity inhibitor is administered to an individual using any combination
  • Administration can be acute (e.g., of short duration, e.g., a single administration, administration for one day to one week), or chronic (e.g., of long duration, e.g., administration for longer than one week, e.g., administration over a period of time from about 2 weeks to about one month, from about one month to about 3 months, from about 3 months to about 6 months, from about 6 months to about 1 year, or longer than one year).
  • routes of administration include intranasal, intramuscular, intratracheal, subcutaneous, intradermal, transdermal, sublingual, topical application, intravenous, rectal, nasal, oral, and other enteral and parenteral routes of administration. Routes of administration may be combined, if desired, or adjusted depending upon the agent and/or the desired effect. The compound can be administered in a single dose or in multiple doses.
  • An active agent can be administered to a host using any available conventional methods and routes suitable for delivery of conventional drugs, including systemic or localized routes.
  • routes of administration contemplated by the present disclosure include, but are not necessarily limited to, enteral, parenteral, or inhalational routes.
  • Parenteral routes of administration other than inhalation administration include, but are not necessarily limited to, topical, transdermal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, and intravenous routes, i.e., any route of administration other than through the alimentary canal.
  • Parenteral administration can be carried to effect systemic or local delivery of the agent. Where systemic delivery is desired, administration typically involves invasive or systemically absorbed topical or mucosal administration of pharmaceutical preparations.
  • the agent can also be delivered to the subject by enteral administration.
  • Enteral routes of administration include, but are not necessarily limited to, oral and rectal (e.g., using a suppository) delivery.
  • Methods of administration of the agent through the skin or mucosa include, but are not necessarily limited to, topical application of a suitable pharmaceutical preparation, transdermal transmission, injection and epidermal administration.
  • a suitable pharmaceutical preparation for transdermal transmission, absorption promoters or iontophoresis are suitable methods.
  • Iontophoretic transmission may be
  • Example 1 Inhibitory activity of compounds against ALDH1A1
  • NM_000689 The synthetic gene was cloned into the Nhel/EcoRI sites of the His-tag vector, pTrcHis, for protein expression. All the vectors were transformed into BL21 E. coli host cells and subjected to 0.5 mM isopropyl ⁇ -D-l-thiogalactopyranoside (IPTG) induction for protein expression at 30°C. Purifications of the recombinant proteins by affinity nickel columns (HisTrap, GE Healthy Science, USA) were carried out using standard protocols according to manufacturer's instructions (Novagen, USA).
  • ALDH2 ALDH3A1, ALDH4A1, ALDH7A1, and ADH1B1 was determined.
  • Example 3 In vitro anti-cancer activity of the compounds in combination with paclitaxel and doxorubicin
  • Method Cell cultures (5000 cells/well) in medium containing 5% fetal bovine serum
  • FBS fetal bovine serum
  • Basal cells were fixed with 25 ⁇ of 50% (w/v) trichloroacetic acid (TCA) (final 10%) for 30-min as Tz.
  • Compound 5 at various concentrations was added to the cell cultures and then the suction of the basal cells with TCA was performed.
  • the basal wells were washed with phosphate buffer saline (PBS, 100 ⁇ ), and incubated for 48-h or 72-h treatment before reaction was terminated, followed by 30-min incubation at RT. After suction of the cells with TCA, all wells (including basal wells) were washed with PBS (100 ⁇ ) and air-dried for 20 min in the hood.
  • PBS phosphate buffer saline
  • SRB Sulforhodamine B

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Abstract

La présente invention concerne des composés qui fonctionnent comme inhibiteurs de l'activité cytosolique de l'aldéhyde déshydrogénase-1 (ALDHlAl).
PCT/US2014/025679 2013-03-14 2014-03-13 Modulateurs d'aldéhyde déshydrogénase-1 et leurs procédés d'utilisation WO2014160034A1 (fr)

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* Cited by examiner, † Cited by third party
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CN111053778A (zh) * 2019-11-05 2020-04-24 徐州医科大学 咪唑并喹唑啉类衍生物及其盐制备pim1酶抑制剂的应用、pim1酶抑制剂及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010062308A1 (fr) * 2008-10-28 2010-06-03 The Board Of Trustees Of The Leland Stanford Junior University Modulateurs d’aldéhyde déshydrogénase et procédés d’utilisation de ceux-ci
WO2011128407A2 (fr) * 2010-04-16 2011-10-20 Bayer Pharma Aktiengesellschaft Combinaisons contenant une 2,3-dihydroimidazo[1,2-c]quinazoline substituée
WO2012116010A2 (fr) * 2011-02-22 2012-08-30 The General Hospital Corporation Inhibiteurs de la tolérance aux antibiotiques

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010062308A1 (fr) * 2008-10-28 2010-06-03 The Board Of Trustees Of The Leland Stanford Junior University Modulateurs d’aldéhyde déshydrogénase et procédés d’utilisation de ceux-ci
WO2011128407A2 (fr) * 2010-04-16 2011-10-20 Bayer Pharma Aktiengesellschaft Combinaisons contenant une 2,3-dihydroimidazo[1,2-c]quinazoline substituée
WO2012116010A2 (fr) * 2011-02-22 2012-08-30 The General Hospital Corporation Inhibiteurs de la tolérance aux antibiotiques

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DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 25 September 2008 (2008-09-25), XP002727114, Database accession no. 1052659-30-9 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111053778A (zh) * 2019-11-05 2020-04-24 徐州医科大学 咪唑并喹唑啉类衍生物及其盐制备pim1酶抑制剂的应用、pim1酶抑制剂及其应用
CN111053778B (zh) * 2019-11-05 2021-07-23 徐州医科大学 咪唑并喹唑啉类衍生物及其盐制备pim1酶抑制剂的应用、pim1酶抑制剂及其应用

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