Classifications

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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
• • 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
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • A—HUMAN NECESSITIES
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  • 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
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • 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
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
  • C07D215/52—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4 with aryl radicals attached in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2896—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• a disclosed DHODH inhibitor can be any DHODH inhibitor as disclosed in Intl. Pat. Appl. No. PCT/US19/38622, which is incorporated herein by reference.
• An exemplary DHODH inhibitor as disclosed there is: 2-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd3)
• Disclosed DHODH inhibitors can have a formula represented by a structure: , wherein each of Z 1 , Z 2 , Z 3 , and Z 4 is independently selected from CH and N; wherein R 1 is selected from hydrogen, halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CF 3 , and ⁇ CF 2 CF 3 ; wherein one of R 5a , R 5b , R 5c , R 5d , and R 5e is selected from a group having formula represented by a structure:
• kits comprising a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, or a disclosed pharmaceutical composition; and: (a) at least one agent known to treat a cancer, a host- versus-graft-disease, and/or a disorder associated with T-cell proliferation; and (b) instructions for treating a cancer, a host-versus-graft-disease, and/or a disorder associated with T-cell proliferation.
• FIGs. 1A-1B show representative data for the effect of a representative DHODH inhibitor on the expression of CD38 in AML cells.
• the Cpd 3 and daratumumab combination treatment comprised dosing with 50 mg/kg Cpd 3 on a dosing scheduled of Monday/Wednesday/Friday and dosing with 1 ⁇ g/g daratumumab on a dosing schedule of Tuesday and Friday (TF). Mice were monitored until reaching early/end removal criteria (ERC) and overall survival was calculated using Kapler Meyer analysis. The arrow indicates start of treatment.
• FIG. 2B shows representative photographic images of spleens isolated from the animals from each treatment group as they reached ERC. The treatment type is indicated below each photographic image as outlined for FIG.2A.
• the data show that Cpd3 in combination with the CD38 antibody daratumumab decreased tumor burden, i.e., a smaller spleen size, compared to other treatment groups.
• FIGs.4A-4B show plots of data obtained from the flow cytometry studies of the type shown in FIGs.3A-3C. Briefly, primary AML cells were treated with vehicle (DMSO), brequinar (BRQ, 1 ⁇ M), BAY2402234 (BAY), or Cpd3 (1 ⁇ M) for 72 hours, and then the CD11b and CD38 surface expression were determined by flow cytometry. Mean fluorescence intensity (MFI) plots were normalized to vehicle (DMSO).
• FIG. 4A shows expression levels of CD11b after three and seven days of treatment with the indicated agent.
• FIG.4B shows expression levels of CD38 after three and seven days of treatment with the indicated agent.
• FIG. 4A shows expression levels of CD11b after three and seven days of treatment with the indicated agent.
• FIG.4B shows expression levels of CD38 after three and seven days of treatment with the indicated agent.
• FIG. 5 shows representative data obtained from treatment of six AML cell-lines with different mutational backgrounds. The cell lines were treated with the indicated compound at the indicated concentrations for three days.
• BRQ Brequinar
• BAY BAY2402234.
• FIGs. 6A-6B show representative data for the effect of a representative DHODH inhibitor in combination with an anti-CD38 antibody in a mouse xenograft model using a TIWK (MWF) dosing regiment for the DHODH inhibitor, Cpd 4, as described herein belo.
• FIG. 6A shows data for the indicated therapeutic agents, including combination treatment with DHODH inhibitor, Cpd 4, with daratumumab (Dara).
• FIG.6B shows data for the indicated therapeutic agents, including combination treatment with DHODH inhibitor, Cpd 4, with isatuximab (Isa).
• FIGs. 7A-7B show representative data for the effect of a representative DHODH inhibitor in combination with an anti-CD38 antibody in a mouse xenograft model using a daily dosing regiment for the DHODH inhibitor, Cpd 4, as described herein belo.
• FIG. 7A shows data for the indicated therapeutic agents, including combination treatment with DHODH inhibitor, Cpd 4, with daratumumab (Dara).
• FIG.7B shows data for the indicated therapeutic agents, including combination treatment with DHODH inhibitor, Cpd 4, with isatuximab (Isa).
• a unimolecular nanoparticle “a nanocluster,” or “a biomimetic vesicle,” including, but not limited to, two or more such unimolecular nanoparticles, nanoclusters, or biomimetic vesicles, including combinations of unimolecular nanoparticles, nanoclusters, or biomimetic vesicles, and the like.
• ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
• the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’.
• the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values includes “about ‘x’ to about ‘y’”.
• ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
• a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.
• an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.
• dihydroorotate dehydrogenase and “DHODH” can be used interchangeably, and refer to an enzyme encoded by a gene in humans with a cytogenetic location of 16q22.2 and a molecular location of base pairs 72,008,744 to 72,025,417 on chromosome 16 (Homo sapiens Annotation Release 109, GRCh38.p12). The gene structure in humans comprises 9 exons.
• Brequinar can also be referred to by the IUPAC chemical name, or 6-fluoro-2-(2'-fluoro-1,1'- biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid.
• Common salt forms are brequinar potassium and brequinar sodium (also referred to herein as BQR Na), which are the alkali metal salts of the conjugate base of the carboxylic acid.
• Brequinar is sometimes referred as DuP-785 or NSC-368390.
• administering can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavernous, intrathecal, intravireal, intracerebral, intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g.
• the amount of a treatment may be varied for example by increasing or decreasing the amount of a disclosed compound and/or pharmaceutical composition, by changing the disclosed compound and/or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on.
• Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.
• Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.
• an effective amount or dose of a disclosed compound is the amount of the composition that is capable of inhibiting DHODH to provide a clinically meaningful decrease in the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system, as a result of inhibiting DHODH.
• the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
• Illustrative substituents include, for example, those described below.
• the permissible substituents can be one or more and the same or different for appropriate organic compounds.
• the heteroatoms, such as nitrogen can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds.
• aliphatic or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic.
• aliphatic groups contain 1-20 carbon atoms.
• Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
• heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
• Heteroaryl groups can be monocyclic, or alternatively fused ring systems.
• Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl.
• hydroxyl or “hydroxy” as used herein is represented by the formula —OH.
• nitro as used herein is represented by the formula —NO 2 .
• nitrile or “cyano” as used herein is represented by the formula —CN.
• organic residue defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove.
• Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc.
• Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together.
• examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals.
• the inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical.
• Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.
• the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds.
• bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula.
• bonds to the chiral carbon when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
• the Cahn-Ingold- Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
• Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance.
• the disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
• isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, and 36 Cl, respectively.
• A-D a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B- D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the disclosure.
• aqueous solutions are suitable for intravenous administration provided the pH is appropriately adjusted and the solution is made isotonic, for example with a sufficient amount of sodium chloride or glucose.
• the sterilization may be carried out by heating or by any other means which does not adversely affect the composition.
• the combinations may also take the form of liposomes or the form of an association with carriers as cyclodextrins or polyethylene glycols.
• Anti-CD38 Therapeutic Agents [0140] In the disclosed pharmaceutical compositions and methods of treating a clinical condition, a DHODH inhibitor is used with an anti-CD38 therapeutic agent.
• the anti-CD38 therapeutic agent comprises a therapeutic agent that decreases the number of CD38 expressing cells and/or level of cell membrane concentration of CD38 protein.
• the anti-CD38 therapeutic agent can comprise a cellular therapy, e.g., an antigen-specific adoptive cell therapy, including, but not limited to, T cells expressing CAR (i.e., a CAR T based cellular therapy comprising a CAR T cell having at least partial specificity for an antigen such as CD-38).
• the anti-CD38 therapeutic agent comprises a CAR-T therapeutic agent target CD38 expressing cells.
• the CAR-T therapeutic agent induces apoptosis of CD38 positive cells.
• CD4 are 55-kD glycoproteins originally defined as differentiation antigens on T-lymphocytes, but also found on other cells including monocytes/macrophages.
• CD4 antigens are members of the immunoglobulin supergene family and are implicated as associative recognition elements in MHC (major histocompatibility complex) class II-restricted immune responses.
• MHC major histocompatibility complex
• the Dimeric Antigen Receptor can utilize a Fab instead of the scFv used by traditional Chimeric Antigen Receptor (CAR) T cells.
• anti-CD38 therapeutic agents useful in the disclosed pharmaceutical compositions and methods include those listed herein below in Tables 1-3. Table 1. Anti-CD38 Therapeutic Agents.
• ADCC antibody dependent cell-mediated cytotoxicity
• ADCC the cell-mediated reaction wherein nonspecific cytotoxic cells that express Fc ⁇ Rs recognize bound antibody on a target cell and subsequently cause lysis of the target cell.
• ADCC is correlated with binding to Fc ⁇ RIIIa; increased binding to Fc ⁇ RIIIa leads to an increase in ADCC activity.
• ADCP antibody dependent cell-mediated phagocytosis as used herein is meant the cell-mediated reaction wherein nonspecific cytotoxic cells that express Fc ⁇ Rs recognize bound antibody on a target cell and subsequently cause phagocytosis of the target cell.
• hybridoma cell lines producing the 38SB13, 38SB18, 38SB19, 38SB30, 38SB31, and 38SB39 murine anti-CD38 antibodies have been deposited at the American Type Culture Collection (10801 University Bld, Manassas, Va., 20110-2209, USA), on Jun. 21, 2006, under the deposit numbers PTA-7667, PTA-7669, PTA-7670, PTA-7666, PTA-7668, and PTA-7671, respectively (as described in WO2008/047242).
• Further exemplary useful antibodies for the disclosed pharmaceutical combinations include those disclosed in United States Patent Application No.2018/0066069.
• Antibodies against CD38 such as daratumumab, MOR202, or SAR650984, have been, and are currently being evaluated in the clinic for their efficacy to treat hematological malignancies and plasma cell disorders, including multiple myeloma. Each antibody has been found to bind to a different portion of the extracellular region of CD38, and each demonstrates different clinical responses (e.g. , anti -tumor effects).
• Daratumumab available from Johnson & Johnson (Janssen Biotech)/Genmab as Darzalex® is described in the publication to de Weers et.
• Table 1 lists a number of antibodies, or fragments thereof, that bind CD38, and their epitope (binding site) on the CD38 molecule, some or all of which may be useful according to various aspects of the present disclosure.
• the disclosed anti-CD38 antibody used in the disclosed pharmaceutical combinations is capable of killing a CD38+ cell by antibody dependent cell-mediated phagocytosis (ADCP), cellular fratricide, apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
• the anti-CD38 antibody can be selected from daratumumab, isatuximab (SAR650984), MOR202 (MorphoSys AG), and TAK-079.
• a suitable anti-CD38 antibody useful in the disclosed pharmaceutical compositions and methods comprise thos0e described herein above in Tables 1 and 2.
• a suitable anti-CD38 antibody useful in the disclosed pharmaceutical compositions and methods comprise trispecific antibodies such as those described in Sanofi Phase 1 : CD3xCD28xCD38 asset SAR442257 “ClinicalTrials.gov Identifier: NCT04401020”.
• the present disclosure provides isolated anti-CD38 antibodies that specifically bind human CD38 protein (and, as described below, additionally and preferably specifically bind primate CD38 protein).
• reference to an anti-CD38 antibody is an antibody as defined in the foregoing that is capable of binding CD38.
• An “antibody” includes monoclonal, polyclonal, bispecific, multispecific, murine, chimeric, fragments, humanized and human antibodies.
• a “naked antibody” is an antibody or antigen binding fragment thereof that is not attached to a therapeutic or diagnostic agent.
• the Fc portion of an intact naked antibody can provide effector functions, such as complement fixation and ADCC (see, e.g., Markrides, Pharmacol Rev 50:59-87, 1998). Other mechanisms by which naked antibodies induce cell death may include apoptosis.
• a “human antibody” is an antibody obtained from transgenic mice that have been genetically engineered to produce specific human antibodies in response to antigenic challenge.
• elements of the human heavy and light chain locus are introduced into strains of mice derived from embryonic stem cell lines that contain targeted disruptions of the endogenous heavy chain and light chain loci.
• the transgenic mice can synthesize human antibodies specific for human antigens, and the mice can be used to produce human antibody- secreting hybridomas.
• Methods for obtaining human antibodies from transgenic mice are described by Green et al., Nature Genet.7:13 (1994), Lonberg et al., Nature 368:856 (1994), and Taylor et al., Int. Immun. 6:579 (1994).
• Bispecific antibodies and bispecific antibody fragments (bsFab) may have at least one arm that specifically binds to, for example, a T cell, an NK cell, a monocyte or a neutrophil, and at least one other arm that specifically binds to an antigen produced by or associated with a diseased cell, tissue, organ or pathogen, for example a tumor-associated antigen.
• a variety of bispecific antibodies can be produced using molecular engineering.
• An antibody preparation, or a composition described herein, is said to be administered in a “therapeutically effective amount” if the amount administered is physiologically significant.
• An agent is physiologically significant if its presence results in a detectable change in the physiology of a recipient subject.
• “Camelids” comprise old-world camelids (Camelus bactrianus and Camelus dromaderius) and new world camelids (for example, Lama paccos, Lama glama and Lama vicugna).
• the term “nanobody” as used herein in its broadest sense is not limited to a specific biological source or to a specific method of preparation.
• the nanobodies hereof can generally be obtained: (1) by isolating the V H H domain of a naturally occurring heavy chain antibody; (2) by expression of a nucleotide sequence encoding a naturally occurring V H H domain; (3) by “humanization” of a naturally occurring V H H domain or by expression of a nucleic acid encoding a such humanized V H H domain; (4) by “camelization” of a naturally occurring VH domain from any animal species and, in particular, from a mammalian species, such as from a human being, or by expression of a nucleic acid encoding such a camelized VH domain; (5) by “camelization” of a “domain antibody” or “Dab” as described in the art, or by expression of a nucleic acid encoding such a camelized VH domain; (6) by using synthetic or semi-synthetic techniques for preparing proteins, polypeptides or other amino acid sequences known per se; (7) by preparing a nucleic acid
• Such humanized nanobodies of the invention can be obtained in any suitable manner known per se (i.e., as indicated under points (1)-(8) above) and, thus, are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring V H H domain as a starting material.
• the VH sequence that is used as a starting material or starting point for generating or designing the camelized nanobody is preferably a VH sequence from a mammal, more preferably, the VH sequence of a human being, such as a VH3 sequence.
• the camelized nanobodies of the invention can be obtained in any suitable manner known per se (i.e., as indicated under points (1)-(8) above) and, thus, are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring VH domain as a starting material.
• Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.
• an antibody that specifically binds an antigen will have a KD that is 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for a control molecule relative to the antigen or epitope.
• specific binding for a particular antigen or an epitope found in CD38 can be exhibited, for example, by an antibody having a KA or Ka for an antigen or epitope of at least 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for the epitope relative to a control, where KA or Ka refers to an association rate of a particular antibody-antigen interaction.
• modifications or moieties include, but are not limited to, methylated, acetylated, glycosylated, sulfated, phosphorylated, carboxylated, and amidated moieties and other moieties that are well known in the art.
• Moieties include any chemical group or combinations of groups commonly found on immunoglobulin molecules in nature or otherwise added to antibodies by recombinant expression systems, including prokaryotic and eukaryotic expression systems. [0199] Covalent modifications of antibodies are included within the scope of this disclosure, and are generally, but not always, done post-translationally.
• covalent modifications of the antibody are introduced into the molecule by reacting specific amino acid residues of the antibody with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C-terminal residues.
• side chain modifications contemplated by the disclosure include modifications of amino groups such as by reductive alkylation by reaction with an aldehyde followed by reduction with NaBH 4 ; amidination with methylacetimidate; acylation with acetic anhydride; carbamoylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2, 4, 6-trinitrobenzene sulphonic acid (TNBS); acylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; and pyridoxylation of lysine with pyridoxal-5-phosphate followed by reduction with NaBH 4 .
• Engineered glycoforms may be generated by a variety of methods known in the art (Uma ⁇ a et al., 1999, Nat Biotechnol 17:176-180; Davies et al., 2001, Biotechnol Bioeng 74:288-294; Shields et al., 2002, J Biol Chem 277:26733-26740; Shinkawa et al., 2003, J Biol Chem 278:3466-3473; U.S. Pat. No. 6,602,684; U.S. Ser. No. 10/277,370; U.S. Ser. No.
• the antibody may bind to a CD38-positive cell with an EC50 value of less than about 15 nM.
• the antibody may bind to a CD38-positive cell with an EC50 value of less than about 13 nM.
• the antibody may bind to a CD38-positive cell with an EC50 value of less than about 10 nM.
• Variants of such anti-CD38 antibodies can be engineered and expressed such that the antibodies have reduced immunogenicity, enhanced stability, and enhanced half life in circulation without a significant loss of specificity or affinity of the antibody to the CD38 antigen. These variant antibodies can be fused to an attenuated interferon.
• Antibodies can be humanized using a variety of other techniques including CDR-grafting (EP 0239400; WO 91/09967; U.S. Pat. Nos.5,530,101; and 5,585,089), veneering or resurfacing (EP 0592106; EP 0519596; Padlan E. A., 1991, Molecular Immunology 28(4/5): 489-498; Studnicka G. M. et al., 1994, Protein Engineering, 7(6): 805-814; Roguska M. A.
• DHODH Inhibitor Compounds [0213] In the disclosed pharmaceutical compositions and methods of treating a clinical condition, a DHODH inhibitor is used with an anti-CD38 antibody.
• a suitable DHODH inhibitor can be one of the DHODH inhibitors as disclosed herein, or any other DHODH inhibitor as know to the skilled artisan.
• DHODH inhibitors can have a formula represented by a structure: wherein Z 1 is a five-membered heterocyclic diyl; wherein R 1 is selected from hydrogen, halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CF 3 , and ⁇ CF 2 CF 3 ; wherein one of R 5a , R 5b , R 5c , R 5d , and R 5e is selected from a group having formula represented by a structure: ⁇ R 20 , ⁇ R 30 ⁇ A 1 ⁇ R 40 , ⁇ A 1 ⁇ R 40 , ⁇ A 1 ⁇ R 30 ⁇ A 2 ⁇ R 40 , or ⁇ A 1 ⁇ R 30 ⁇ A 2 ⁇ R 31 ⁇ A 3 ⁇ R 40 ; wherein A 1 is selected from ⁇ O ⁇ and ⁇ NR 50 ⁇ ; wherein R 50 is selected from hydrogen, ⁇ C 1 -C 10
• Further exemplary disclosed DHODH inhibitors can have a formula represented by a structure: , wherein R 1 is selected from hydrogen, halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CF 3 , and ⁇ CF 2 CF 3 ; wherein one of R 5a , R 5b , R 5c , R 5d , and R 5e is selected from a group having formula represented by a structure: ⁇ R 20 , ⁇ R 30 ⁇ A 1 ⁇ R 40 , ⁇ A 1 ⁇ R 40 , ⁇ A 1 ⁇ R 30 ⁇ A 2 ⁇ R 40 , or ⁇ A 1 ⁇ R 30 ⁇ A 2 ⁇ R 31 ⁇ A 3 ⁇ R 40 ; wherein A 1 is selected from ⁇ O ⁇ and ⁇ NR 50 ⁇ ; wherein R 50 is selected from hydrogen, ⁇ C 1 -C 10 alkyl, ⁇ C 1 -C 10 aminoalkyl, and ⁇ C
• Aspect 88 The compound of Aspect 88, wherein R 5a is R 20 .
• Aspect 90 The compound of any one of Aspect 88 or Aspect 89, wherein R 20 is selected from ⁇ C2-C7 alkylamino and ⁇ C2-C7 alkoxy.
• Aspect 91 The compound of any one of Aspect 88 or Aspect 89, wherein R 20 is halogen.
• Aspect 92 The compound of any one of Aspect 87-Aspect 91, wherein each of R 5b , R 5c , R 5d , and R 5e is selected from halogen and hydrogen.
• Aspect 93 The compound of Aspect 92, wherein each of R 5b , R 5c , R 5d , and R 5e is hydrogen.
• Aspect 9 The compound of any one of 1-Aspect 8, wherein R 5c is halogen, C 1 -C 7 haloalkyl, or –O(C 1 -C 7 haloalkyl).
• Aspect 10 The compound of Aspect 9, wherein R 5c is halogen.
• Aspect 11 The compound of Aspect 10, wherein R 5c is F.
• Aspect 12 The compound of Aspect 9, wherein R 5c is –OCF 3 , –OCH 2 CF 3 , or – OCF 2 CF 3 .
• Aspect 3 The compound of Aspect 1 or Aspect 2, wherein R 1 is selected from halogen, –SF 5 , –CF 3 , and –CF 2 CF 3 .
• Aspect 4 The compound of Aspect 3, wherein R 1 is halogen or –SF 5 .
• Aspect 5. The compound of Aspect 4, wherein R 1 is –F or –Cl.
• Aspect 6. The compound of Aspect 4, wherein R 1 is –F.
• Aspect 7. The compound of Aspect 4, wherein R 1 is –Cl.
• Aspect 8. The compound of Aspect 4, wherein R 1 is –SF 5 .
• Aspect 16 wherein R 5c is –O(C 1 -C 7 alkyl), –(C 1 -C 7 alkanediyl)–OH, –O(C 1 -C 7 alkanediyl)–OH, –CH2O(C 1 -C 7 alkyl), or –(CH2)2O(C 1 -C 7 alkyl).
• Aspect 18 The compound of Aspect 17, wherein R 5c is ⁇ OCH 3 or ⁇ OCH2CH 3 .
• Aspect 19 The compound of any one of Aspect 16-Aspect 18, wherein each of R 5a , R 5b , R 5d , and R 5e is hydrogen. [0345] Aspect 20.
• Aspect 39 The compound of Aspect 38, wherein R 6a and R 6b are independently selected from hydrogen, halogen, ⁇ SF 5, ⁇ CN, ⁇ N 3, ⁇ OH, ⁇ NH 2, ⁇ CHF 2, ⁇ CH 2F, and ⁇ CF 3.
• Aspect 40 The compound of Aspect 39, wherein R 6a and R 6b are independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 41 Aspect 41.
• Aspect 44 The compound of Aspect 43, wherein R 6a and R 6c are independently selected from ⁇ F, ⁇ Cl, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 45 The compound of Aspect 43, wherein R 6a and R 6c are independently selected from ⁇ F, ⁇ Cl, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 46 The compound of Aspect 45, wherein R 6a and R 6d are independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 46 The compound of Aspect 45, wherein R 6a and R 6d are independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 47 Aspect 47.
• Aspect 54 The compound of any one of Aspect 1-Aspect 37, wherein R 6a is selected from hydrogen, halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 aminoalkyl, and C 1 -C 3 hydroxyalkyl; and wherein each of R 6b , R 6c , and R 6d is hydrogen. [0379] Aspect 54.
• each of R 6a and R 6b is independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , C 1 -C 3 alkyl, C1- C3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 aminoalkyl, and C 1 -C 3 hydroxyalkyl; and wherein each of R 6c and R 6d is hydrogen.
• each of R 6a and R 6c is independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 67 The compound of Aspect 39, wherein each of R 6a and R 6c is independently selected from ⁇ F, ⁇ Cl, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 68 The compound of Aspect 40, wherein each of R 6a and R 6c is ⁇ F.
• each of R 6b and R 6c is independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 75 The compound of Aspect 39, wherein each of R 6b and R 6c is independently selected from ⁇ F, ⁇ Cl, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 76 The compound of Aspect 40, wherein each of R 6b and R 6c is ⁇ F.
• Aspect 82 The compound of any one of Aspect 1-Aspect 76, wherein R 20 is selected from hydrogen, ⁇ C 4 -C 10 alkyl, ⁇ C 4 -C 10 aminoalkyl, and ⁇ C 4 -C 10 hydroxyalkyl.
• Aspect 83 The compound of any one of Aspect 1-Aspect 76, wherein R 20 is selected from hydrogen, ⁇ C 4 -C 10 alkyl, ⁇ C 4 -C 10 aminoalkyl, and ⁇ C 4 -C 10 hydroxyalkyl.
• Aspect 88 The compound of any one of Aspect 1-Aspect 76, wherein R 20 is selected from hydrogen, ⁇ C 3 -C 8 alkyl, ⁇ C 3 -C 8 aminoalkyl, and ⁇ C 3 -C 8 hydroxyalkyl.
• Aspect 89 The compound of any one of Aspect 1-Aspect 76, wherein R 20 is selected from hydrogen, ⁇ C 3 -C 6 alkyl, ⁇ C 3 -C 6 aminoalkyl, and ⁇ C 3 -C 6 hydroxyalkyl.
• Aspect 91 The compound of any one of Aspect 1-Aspect 76, wherein R 20 is selected from hydrogen, ⁇ C 3 -C 5 alkyl, ⁇ C 3 -C 5 aminoalkyl, and ⁇ C 3 -C 5 hydroxyalkyl.
• Aspect 90 The compound of any one of Aspect 1-Aspect 76, wherein R 20 is selected from hydrogen, ⁇ C 3 -C 4 alkyl, ⁇ C 3 -C 4 aminoalkyl, and ⁇ C 3 -C 4 hydroxyalkyl.
• Aspect 91 Aspect 91.
• Aspect 98 The compound of any one of Aspect 1-Aspect 76, wherein each of R 30 and R 31 is independently selected from hydrogen, ⁇ C 6 -C 8 alkanediyl, ⁇ C 6 -C 8 aminoalkanediyl, and ⁇ C 6 -C 8 hydroxyalkanediyl.
• Aspect 99 The compound of any one of Aspect 1-Aspect 76, wherein each of R 30 and R 31 is independently selected from hydrogen, ⁇ C 6 -C 8 alkanediyl, ⁇ C 6 -C 8 aminoalkanediyl, and ⁇ C 6 -C 8 hydroxyalkanediyl.
• Aspect 102 The compound of any one of Aspect 1-Aspect 76, wherein each of R 30 and R 31 is independently selected from hydrogen, ⁇ C 5 -C 6 alkanediyl, ⁇ C 5 -C 6 aminoalkanediyl, and ⁇ C 5 -C 6 hydroxyalkanediyl.
• Aspect 102 The compound of any one of Aspect 1-Aspect 76, wherein each of R 30 and R 31 is independently selected from hydrogen, ⁇ C 4 -C 10 alkanediyl, ⁇ C 4 -C 10 aminoalkanediyl, and ⁇ C 4 -C 10 hydroxyalkanediyl.
• Aspect 103 Aspect 103.
• Aspect 114 The compound of any one of Aspect 1-Aspect 76, wherein each of R 30 and R 31 is independently selected from hydrogen, ⁇ C 2- C 6 alkanediyl, ⁇ C 3- C 6 aminoalkanediyl, and ⁇ C 2 -C 6 hydroxyalkanediyl.
• Aspect 114 The compound of any one of Aspect 1-Aspect 76, wherein each of R 30 and R 31 is independently selected from hydrogen, ⁇ C 2 -C 5 alkanediyl, ⁇ C 2 -C 5 aminoalkanediyl, and ⁇ C 2 -C 5 hydroxyalkanediyl.
• Aspect 116 The compound of any one of Aspect 1-Aspect 76, wherein each of R 30 and R 31 is independently selected from hydrogen, ⁇ C 2 -C 4 alkanediyl, ⁇ C 2 -C 4 aminoalkanediyl, and ⁇ C 2 -C 4 hydroxyalkanediyl.
• Aspect 116 The compound of any one of Aspect 1-Aspect 76, wherein each of R 30 and R 31 is independently selected from hydrogen, ⁇ C 2 -C 3 alkanediyl, ⁇ C 2 -C 3 aminoalkanediyl, and ⁇ C 2 -C 3 hydroxyalkanediyl.
• Aspect 116 The compound of any one of Aspect 1-Aspect 116, wherein R 40 is selected from hydrogen, ⁇ C 5 -C 10 alkyl, ⁇ C 5 -C 10 aminoalkyl, and ⁇ C 5 -C 10 hydroxyalkyl.
• Aspect 120 The compound of any one of Aspect 1-Aspect 116, wherein R 40 is selected from hydrogen, ⁇ C 5 -C 8 alkyl, ⁇ C 5 -C 8 aminoalkyl, and ⁇ C 5 -C 8 hydroxyalkyl.
• Aspect 121 Aspect 121.
• Aspect 124 The compound of any one of Aspect 1-Aspect 116, wherein R 40 is selected from hydrogen, ⁇ C 4 -C 8 alkyl, ⁇ C 4 -C 8 aminoalkyl, and ⁇ C 4 -C 8 hydroxyalkyl.
• Aspect 124 The compound of any one of Aspect 1-Aspect 116, wherein R 40 is selected from hydrogen, ⁇ C 4 -C 6 alkyl, ⁇ C 4 -C 6 aminoalkyl, and ⁇ C 4 -C 6 hydroxyalkyl.
• Aspect 125 The compound of any one of Aspect 1-Aspect 116, wherein R 40 is selected from hydrogen, ⁇ C 4 -C 6 alkyl, ⁇ C 4 -C 6 aminoalkyl, and ⁇ C 4 -C 6 hydroxyalkyl.
• Aspect 188 The compound of any one of Aspect 1-Aspect 176, wherein R 70 is selected from hydrogen, ⁇ C 3 -C 6 alkyl, ⁇ C 3 -C 6 aminoalkyl, and ⁇ C 3 -C 6 hydroxyalkyl.
• Aspect 189 The compound of any one of Aspect 1-Aspect 176, wherein R 70 is selected from hydrogen, ⁇ C 3 -C 6 alkyl, ⁇ C 3 -C 6 aminoalkyl, and ⁇ C 3 -C 6 hydroxyalkyl.
• Aspect 208 The compound of any one of Aspect 1-Aspect 208, wherein A 3 is selected from ⁇ O ⁇ , ⁇ NH ⁇ , ⁇ NCH 3 ⁇ , ⁇ NCH 2 CH 3 ⁇ , ⁇ N(CH2)2CH 3 ⁇ , ⁇ NCH(CH 3 )2 ⁇ , ⁇ N(CH2)3CH 3 ⁇ , and ⁇ N(CH2)4CH 3 ⁇ .
• Aspect 210 The compound of Aspect 209, wherein A 3 is selected from ⁇ O ⁇ , ⁇ NH ⁇ , ⁇ NCH 3 ⁇ , and ⁇ NCH 2 CH 3 ⁇ .
• Aspect 211 The compound of Aspect 209, wherein A 3 is ⁇ O ⁇ .
• Aspect 212 The compound of Aspect 209, wherein A 3 is ⁇ O ⁇ .
• Aspect 217 The compound of Aspect 216, wherein Ar 1 is a phenyl group substituted with one group selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ OCH 3 , ⁇ NHCH 3 , ⁇ N(CH 3 ) 2 , ⁇ CH 2 OH, ⁇ CH 3 , ⁇ CH 2 Cl, ⁇ CHCl 2 , ⁇ CCl 3 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Ar 1 is a phenyl group substituted with one group selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ OCH 3 , ⁇ NHCH 3 , ⁇ N(CH 3 ) 2 , ⁇ CH 2 OH, ⁇ CH 3 , ⁇ CH 2 Cl, ⁇ CHCl 2 , ⁇ CCl 3 , ⁇ CHF 2
• Aspect 253 wherein R 6a and R 6d are independently selected from ⁇ F, ⁇ Cl, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 255 The compound of Aspect 245, wherein R 6a is selected from ⁇ F, ⁇ Cl, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, and ⁇ NH 2 .
• Aspect 256 The compound of Aspect 245, wherein R 6a is selected from ⁇ F, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, and ⁇ NH 2 .
• Aspect 262 The compound of Aspect 260, wherein R 6a is selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 262 The compound of Aspect 261, wherein R 6a is selected from ⁇ F, ⁇ Cl, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 263. The compound of Aspect 262, wherein R 6a is ⁇ F.
• Aspect 264 The compound of Aspect 264.
• a disclosed DHODH inhibitor can be other DHODH inhibitors as disclosed herein below and referred to as DHODH Inhibitor Compounds – Group V.
• an exemplary DHODH inhibitor of DHODH Inhibitor Compounds – Group V disclosed herein is selected from the group consisting of brequinar, leflunomide, redoxal, vidofludimas, S-2678, 2-(3,5-difluoro-3′methoxybiphenyl-4-ylamino)nicotinic acid (also known as ASLAN003), BAY-2402234 (-N-(2-chloro-6-fluorophenyl)-4-(4-ethyl-3- (hydroxymethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-5-fluoro-2-((1,1,1-trifluoropropan-2- yl)oxy)benzamide), AG-636 (1-
• an exemplary DHODH inhibitor of DHODH Inhibitor Compounds – Group V disclosed herein is selected from the group consisting of teriflunomide, leflunomide a compound of formula (II) (disclosed in WO2008/077639 incorporated herein by reference): wherein: ⁇ one of the groups G 1 represents a nitrogen atom or a group CR c and the other group represents CR c ; ⁇ G 2 represents a nitrogen atom or a group CR d ; ⁇ R 1 represents a group selected from hydrogen, halogen, C 1-4 alkyl which may be optionally substituted with 1, 2 or 3 substituents selected from the group comprising halogen, hydroxy, and C 3-8 cycloalkyl which may be optionally substituted with 1, 2 or 3 substituents selected from halogen and hydroxyl; ⁇ R 2 represents a group selected from hydrogen, halogen, hydroxyl, C 1-4 alkyl which may be optionally substituted
• Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this disclosure.
• Certain isotopically-labelled compounds of the present disclosure for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
• the disclosed compounds can be isolated as solvates and, in particular, as hydrates of a disclosed compound, which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
• solvates and hydrates can be obtained, for example, by crystallization from a solvent or from aqueous solution.
• one, two, three or any arbitrary number of solvate or water molecules can combine with the compounds according to the disclosure to form solvates and hydrates.
• the disclosed compounds can be used in the form of salts derived from inorganic or organic acids.
• Pharmaceutically acceptable salts include salts of acidic or basic groups present in the disclosed compounds.
• Suitable pharmaceutically acceptable salts include base addition salts, including alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts, which may be similarly prepared by reacting the drug compound with a suitable pharmaceutically acceptable base.
• alkali metal salts e.g., sodium or potassium salts
• alkaline earth metal salts e.g., calcium or magnesium salts
• suitable organic ligands e.g., quaternary ammonium salts
• DHODH inhibitors for use in the present disclosure can alternatively be based on antisense oligonucleotide constructs.
• Anti-sense oligonucleotides including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of DHODH mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level DHODH protein, and thus activity, in a cell.
• antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding DHODH can be synthesized, e.g., by conventional phosphodiester techniques and administered by e.g., intravenous injection or infusion.
• Methods for using antisense techniques for specifically inhibiting gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos.6,566,135; 6,566,131; 6,365,354; 6,410,323; 6,107,091; 6,046,321; and 5,981,732).
• siRNAs Small inhibitory RNAs
• DHODH gene expression can be reduced by contacting the tumor, subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that expression of DHODH is specifically inhibited (i.e. RNA interference or RNAi).
• dsRNA small double stranded RNA
• RNAi RNA interference or RNAi
• anti-sense RNA molecules can be generated by in vitro or in vivo transcription of DNA sequences encoding the RNA molecule.
• DNA sequences can be incorporated into a wide variety of vectors that incorporate suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters.
• suitable RNA polymerase promoters such as the T7 or SP6 polymerase promoters.
• Various modifications to the oligonucleotides of the disclosure can be introduced as a means of increasing intracellular stability and half-life.
• Step 2 the compound of Formula 3, isolated from Step 1, is reacted with compounds of Formula 4 to yield the desired disclosed compound of Formula 5 as shown above. Briefly, a mixture of the appropriate isatin, i.e., a compound of Formula 4, e.g., 5- fluoroisatin (5-fluoroindoline-2,3-dione), and a suitable base, e.g., aqueous potassium hydroxide solution (33%), are stirred and heated gently.
• a compound of Formula 4 e.g., 5- fluoroisatin (5-fluoroindoline-2,3-dione
• a suitable base e.g., aqueous potassium hydroxide solution (33%
• Step 2 Pfitzinger Reaction.
• compounds of the present disclosure e.g. compounds of Formula 5 can be prepared in a two-step reaction as shown above. Briefly, the synthesis of compound of Formula 5 begins in Step 1 with reaction of compounds of Formulas 1 and 2 to yield compounds of Formula 3.
• Compounds of Formula 1, i.e., halosubstituted heteroaryl ethanone analogs, e.g., 1-(4-bromothiophen-2-yl)ethan-1-one, and Formula 2, i.e., appropriately substituted phenylboronic acids, e.g., 4-ethoxyphenylboronic acid, can be obtained from commercial sources or can be readily prepared by one skilled in the art according to methods described in the literature. For example, both 1-(4-bromothiophen-2-yl)ethan-1-one and 4- ethoxyphenylboronic acid are available commercially.
• Compounds of Formula 1, i.e., 4-halosubstituted phenone analogs, e.g., 3-fluoro-4-bromoacetophenone, and Formula 2, i.e., appropriately substituted phenylboronic acids, e.g., 4-ethoxyphenylboronic acid, can be obtained from commercial sources or can be readily prepared by skilled in the art according to methods described in the literature. For example, both 3-fluoro-4-bromophenone and 4-ethoxyphenylboronic acid are available commercially.
• the reaction of reaction of compounds of Formulas 1 and 2 is typically carried at a molar ratio of Formula 1 compound to Formula 2 compound of about 25:1 to about 1:1 in a suitable solvent, e.g., 1-propanol, in the presence of palladium acetate and triphenylphosphine, at a suitable temperature, e.g. about 75 oC to about 200 oC, for a suitable period of time, e.g. about 10 minutes to about 2 hours, in order to ensure that the reaction is complete.
• the reaction is then cooled to a suitable temperature, e.g., room temperature, and then can be further cooled, e.g., to about 0 °C to obtain suitable crystals, which can be collected by filtration.
• Step 2 the compound of Formula 3, isolated from Step 1, is reacted with compounds of Formula 4 to yield the desired disclosed compound of Formula 5 as shown above. Briefly, a mixture of the appropriate isatin, i.e., a compound of Formula 4, e.g., 5- fluoroisatin (5-fluoroindoline-2,3-dione), and a suitable base, e.g., aqueous potassium hydroxide solution (33%), are stirred and heated gently.
• a compound of Formula 4 e.g., 5- fluoroisatin (5-fluoroindoline-2,3-dione
• a suitable base e.g., aqueous potassium hydroxide solution (33%
• the slurry of a compound of Formula 3, e.g., 1-(4’-ethoxy-[1,1’-biphenyl]-4-yl)ethan-1-one, in an amount of about equimolar to the compound of Formula 4, and a suitable solvent is used to prepare the slurry, e.g., ethanol.
• a suitable temperature e.g., reflux or about 70 °C to about 200 °C
• a suitable period of time e.g., about 10 minutes to about 3 hours
• the slurry of a compound of Formula 3, e.g., 1-(4’-ethoxy-[1,1’-biphenyl]-4-yl)ethan-1-one, in an amount of about equimolar to the compound of Formula 4, and a suitable solvent is used to prepare the slurry, e.g., ethanol.
• a suitable temperature e.g., reflux or about 70 °C to about 200 °C
• a suitable period of time e.g., about 10 minutes to about 3 hours
• “pharmaceutically-acceptable carriers” means one or more of a pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, and adjuvants.
• the disclosed pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy and pharmaceutical sciences. [0662]
• the disclosed pharmaceutical compositions comprise a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agent, and optionally one or more adjuvant.
• the disclosed pharmaceutical compositions include those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
• the disclosed pharmaceutical composition can be formulated to allow administration orally, nasally, via inhalation, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitonealy, intraventricularly, intracranially and intratumorally.
• parenteral administration includes administration by bolus injection or infusion, as well as administration by intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
• the present disclosure also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof.
• a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes.
• Bases which can be used to prepare the pharmaceutically acceptable base-addition salts of the base compounds are those which can form non-toxic base-addition salts, i.e., salts containing pharmacologically acceptable cations such as, alkali metal cations (e.g., lithium, potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine- (meglumine), lower alkanolammonium and other such bases of organic amines.
• pharmacologically acceptable cations such as, alkali metal cations (e.g., lithium, potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine- (meglumine), lower alkanolammonium and other such bases of organic amines.
• a disclosed compound comprising a protonatable group or moiety, e.g., an amino group
• a pharmaceutically acceptable salt can be used to prepare a pharmaceutically acceptable salt.
• such a disclosed compound may comprise an isolation step comprising treatment with a suitable inorganic or organic acid.
• Acid addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding basic compounds with an aqueous solution containing the desired pharmacologically acceptable anions and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they also can be prepared by treating the free base form of the disclosed compound with a suitable pharmaceutically acceptable non-toxic inorganic or organic acid.
• Acids which can be used to prepare the pharmaceutically acceptable acid-addition salts are those which can form non-toxic acid-addition salts, i.e., salts containing pharmacologically acceptable anions formed from their corresponding inorganic and organic acids.
• Exemplary, but non-limiting, inorganic acids include hydrochloric hydrobromic, sulfuric, nitric, phosphoric and the like.
• Exemplary, but non-limiting, organic acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, isethionic, lactic, maleic, malic, mandelicmethanesulfonic, mucic, pamoic, pantothenic, succinic, tartaric, p-toluenesulfonic acid and the like.
• the acid-addition salt comprises an anion formed from hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
• a pharmaceutical carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
• the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
• compositions disclosed herein comprise a compound of the present disclosure (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents.
• the disclosed pharmaceutical compositions can include a pharmaceutically acceptable carrier and a disclosed compound, or a pharmaceutically acceptable salt thereof.
• a disclosed compound, or pharmaceutically acceptable salt thereof can also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds.
• the instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
• water particularly sterile water, or physiologically acceptable organic solvents, such as alcohols (ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives, fatty alcohols, partial esters of glycerol), oils (for example peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soya bean oil, castor oil, bovine hoof oil), paraffins, dimethyl sulphoxide, triglycerides and the like.
• alcohols ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives, fatty alcohols, partial esters of glycerol
• oils for example peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soya bean oil, castor oil, bovine hoof oil
• paraffins dimethyl sulphoxide, triglycerides and the like.
• a liquid dosage form such as a drinkable solutions
• the following substances may be used as stabilizers or solubilizers: lower aliphatic mono- and multivalent alcohols with 2-4 carbon atoms, such as ethanol, n-propanol, glycerol, polyethylene glycols with molecular weights between 200-600 (for example 1 to 40% aqueous solution), diethylene glycol monoethyl ether, 1,2-propylene glycol, organic amides, for example amides of aliphatic C1-C6-carboxylic acids with ammonia or primary, secondary or tertiary C 1 -C 4 -amines or C1- C4-hydroxy amines such as urea, urethane, acetamide, N-methyl acetamide, N,N-diethyl acetamide, N,N-dimethyl acetamide, lower aliphatic amines and diamines with 2-6 carbon atoms, such
• solubilizers and emulsifiers such as the following non-limiting examples can be used: polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolizated oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols or fatty acids or also 1-methyl-3-(2-hydroxyethyl)imidazolidone-(2).
• solubilizers and emulsifiers such as the following non-limiting examples can be used: polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such
• polyoxyethylated means that the substances in question contain polyoxyethylene chains, the degree of polymerization of which generally lies between 2 and 40 and in particular between 10 and 20.
• Polyoxyethylated substances of this kind may for example be obtained by reaction of hydroxyl group-containing compounds (for example mono- or diglycerides or unsaturated compounds such as those containing oleic acid radicals) with ethylene oxide (for example 40 mole ethylene oxide per 1 mole glyceride).
• hydroxyl group-containing compounds for example mono- or diglycerides or unsaturated compounds such as those containing oleic acid radicals
• ethylene oxide for example 40 mole ethylene oxide per 1 mole glyceride.
• oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil. See also Dr. H. P.
• compositions of the present disclosure may be formulated into any form typically employed for topical application.
• a topical pharmaceutical composition can be in a form of a cream, an ointment, a paste, a gel, a lotion, milk, a suspension, an aerosol, a spray, foam, a dusting powder, a pad, and a patch.
• the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the present disclosure, or pharmaceutically acceptable salts thereof, via conventional processing methods.
• the base in a fatty paste is generally petrolatum, hydrophilic petrolatum and the like.
• the pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base. Additional reference may be made to Remington: The Science and Practice of Pharmacy, for further information. [0705]
• Gel formulations are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil.
• Foam compositions are typically formulated in a single or multiple phase liquid form and housed in a suitable container, optionally together with a propellant which facilitates the expulsion of the composition from the container, thus transforming it into a foam upon application.
• Other foam forming techniques include, for example the “Bag-in-a-can” formulation technique.
• Compositions thus formulated typically contain a low-boiling hydrocarbon, e.g., isopropane. Application and agitation of such a composition at the body temperature cause the isopropane to vaporize and generate the foam, in a manner similar to a pressurized aerosol foaming system.
• Skin patches may further comprise a removable cover, which serves for protecting it upon storage.
• patch configuration which can be utilized with the present disclosure include a single-layer or multi-layer drug-in-adhesive systems which are characterized by the inclusion of the drug directly within the skin-contacting adhesive.
• the adhesive not only serves to affix the patch to the skin, but also serves as the formulation foundation, containing the drug and all the excipients under a single backing film.
• a membrane is disposed between two distinct drug- in-adhesive layers or multiple drug-in-adhesive layers are incorporated under a single backing film.
• Examples of pharmaceutically acceptable carriers that are suitable for pharmaceutical compositions for topical applications include carrier materials that are well-known for use in the cosmetic and medical arts as bases for e.g., emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, milks, foams, suspensions, aerosols and the like, depending on the final form of the composition.
• suitable carriers according to the present disclosure therefore include, without limitation, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin and lanolin derivatives, and like materials commonly employed in cosmetic and medicinal compositions.
• Topical compositions of the present disclosure can, if desired, be presented in a pack or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient.
• the dispenser device may, for example, comprise a tube.
• the pack or dispenser device may be accompanied by instructions for administration.
• the pack or dispenser device may also be accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration.
• Such notice for example, may include labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
• compositions of the present disclosure can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
• compositions containing a compound of the present disclosure, and/or pharmaceutically acceptable salts thereof can also be prepared in powder or liquid concentrate form.
• the pharmaceutical composition (or formulation) may be packaged in a variety of ways. Generally, an article for distribution includes a container that contains the pharmaceutical composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, foil blister packs, and the like. The container may also include a tamper proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container typically has deposited thereon a label that describes the contents of the container and any appropriate warnings or instructions.
• the disclosed pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
• the pack may for example comprise metal or plastic foil, such as a blister pack.
• the pack or dispenser device may be accompanied by instructions for administration.
• the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
• Such notice for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
• compositions comprising a disclosed compound formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
• the exact dosage and frequency of administration depends on the particular disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, solvate, or polymorph thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof; the particular condition being treated and the severity of the condition being treated; various factors specific to the medical history of the subject to whom the dosage is administered such as the age; weight, sex, extent of disorder and general physical condition of the particular subject, as well as other medication the individual may be taking; as is well known to those skilled in the art.
• the pharmaceutical composition will comprise from 0.05 to 99 % by weight, preferably from 0.1 to 70 % by weight, more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % by weight, preferably from 30 to 99.9 % by weight, more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
• the present disclosure provides methods of treatment comprising administration of a therapeutically effective amount of a disclosed compound or pharmaceutical composition as disclosed herein above to a subject in need thereof.
• the disclosed compounds and disclosed pharmaceutical compositions can be used in methods of treating a disease or disorder that are associated with increased, aberrant, or dysfunctional levels of dihydroorotate dehydrogenase (DHODH) activity in a cell, tissue, or organism.
• DHODH dihydroorotate dehydrogenase
• the disclosed compounds and disclosed pharmaceutical compositions can be used to inhibit DHODH activity in a cell, tissue or organism to provide a clinical or therapeutic benefit to a subject which has been determined to or been diagnosed to have with increased, aberrant, or dysfunctional levels of dihydroorotate dehydrogenase (DHODH) activity.
• DHODH dihydroorotate dehydrogenase
• the subject has been diagnosed with a need for treatment prior to the administering step.
• the subject has been diagnosed with a disorder treatable by inhibition of DHODH and/or a need for inhibition of DHODH prior to the administering step.
• the subject has been diagnosed with a cancer, a disorder associated with T-cell proliferation, or a may be at risk for graft-versus-host disease or organ rejection following transplantation prior to the administering step.
• the subject has been identified with a need for treatment prior to the administering step.
• the disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which compounds of formula I or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone.
• the other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound.
• DHODH is an enzyme that catalyzes the fourth step in the de novo biosynthesis of pyrimidine. It converts dihydroorotate (DHO) to orotate (ORO). Human DHODH is a ubiquitous flavine mononucleotide (FMN) moiety flavoprotein.
• FMN flavine mononucleotide
• DHODH is anchored at the inner mitochondrial leaflet and catalyzes the conversion of DHO to ORO, which represents the rate limiting step in the de novo pyrimidine biosynthesis.
• Kinetic studies indicate a sequential ping-pong mechanism for the conversion of DHO to ORO (e.g., see Knecht et al., Chem. Biol. Interact.2000, 124, 61-76).
• the first half-reaction comprises the reduction of DHO to ORO. Electrons are transferred to the FMN which becomes oxidized to dihydroflavin mononucleotide (FMNH2).
• the human enzyme dihydroorotate dehydrogenase represents a well-characterized target for small molecular weight Disease Modifying Antirheumatic Drugs (DMARDs).
• DHODH dihydroorotate dehydrogenase
• DMARDs small molecular weight Disease Modifying Antirheumatic Drugs
• autoimmune diseases that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited, to rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis, ankylosing spondilytis, Wegener's granulomatosis, polyarticular juvenile idiopathic arthritis, inflammatory bowel disease such as ulcerative colitis and Crohn's disease, Reiter's syndrome, fibromyalgia and type-1 diabetes.
• Immune and inflammatory diseases that can be treated by the disclosed compounds or disclosed pharmaceutical compositions include, but are not limited, to asthma, COPD, respiratory distress syndrome, acute or chronic pancreatitis, graft versus-host disease, chronic sarcoidosis, transplant rejection, contact dermatitis, atopic dermatitis allergic rhinitis, allergic conjunctivitis, Behçet's syndrome, inflammatory eye conditions such as conjunctivitis and uveitis.
• the present disclosure pertains to methods for treating organ rejection diseases or ameliorating and/or preventing organ rejection diseases in patients pre- disposed to organ rejection by administering to a patient in need of such treatment an effective amount of at least one disclosed compound or disclosed pharmaceutical composition.
• Carcinoma including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including a
• the disclosed compounds or disclosed pharmaceutical compositions can act as modulators of apoptosis, and accordingly, can be useful in the treatment of cancer (including but not limited to those types mentioned herein above), viral infections (including but not limited to herpes virus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer's disease, AIDS- related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infar
• the disclosed compounds and disclosed pharmaceutical compositions can be used in inhibiting tumor angiogenesis and metastasis.
• the disclosed compounds and disclosed pharmaceutical compositions can also be combined with other active compounds in the treatment of diseases wherein the inhibition of DHODH is known to show beneficial effect.
• immune disorders that can be treated using the disclosed compounds and disclosed pharmaceutical compositions include psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepati
• psoriasis
• Chronic graft-versus-host disease is a primary cause of nonrelapse mortality after allogeneic hematopoietic stem cell transplantation (HSCT) (Baird K, Pavletic SZ. Curr Opin Hematol.2006; 13(6):426–435; Lee SJ, Vogelsang G, Flowers ME. Biol Blood Marrow Transplant.2003; 9(4):215–233; Pidala J, et al. Blood.2011; 117(17):4651–4657; and Arai S, et al. Blood. 2011; 118(15):4242–4249).
• HSCT allogeneic hematopoietic stem cell transplantation
• kits whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient.
• Such kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient.
• a kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc.
• Aspect 6 wherein the antigen-specific adoptive cell therapy comprises a CAR T cell directed to recognize a CD38 epitope or antigen.
• Aspect 8 The pharmaceutical composition of any one of Aspect 1-Aspect 7, wherein the DHODH inhibitor compound is a compound of DHODH inhibitor compound Group I as disclosed herein.
• the pharmaceutical composition of Aspect 17, wherein R 20 is ⁇ C2-C7 alkylamino. Aspect 19.
• the pharmaceutical composition of Aspect 17, wherein R 20 is ⁇ C2-C7 alkoxy.
• Aspect 20 The pharmaceutical composition of Aspect 17, wherein each of R 5a , R 5b , R 5d , and R 5e is selected from halogen and hydrogen.
• Aspect 21 The pharmaceutical composition of Aspect 17, wherein each of R 5a , R 5b , R 5d , and R 5e is hydrogen.
• Aspect 22. The pharmaceutical composition of Aspect 17, wherein R 1 is halogen.
• the pharmaceutical composition of Aspect 22, wherein R 1 is fluoro.
• Aspect 24 The pharmaceutical composition of Aspect 8, wherein the DHODH inhibitor compound is present as:
• Aspect 32 The pharmaceutical composition of Aspect 30, wherein the DHODH inhibitor compound is a compound having a formula represented by a structure: or a subgroup thereof.
• Aspect 33 The pharmaceutical composition of any one of 1-Aspect 7, wherein the DHODH inhibitor compound is a compound of DHODH inhibitor compound Group IV as disclosed herein.
• Aspect 35 The pharmaceutical composition of Aspect 34, wherein the DHODH inhibitor compound is a compound having a formula represented by a structure: or combinations thereof.
• Aspect 36 The pharmaceutical composition of Aspect 34, wherein the DHODH inhibitor compound is a compound having a formula represented by a structure: or combinations thereof.
• Aspect 37 The pharmaceutical composition of Aspect 34, wherein the DHODH inhibitor compound is a compound having a formula represented by a structure:
• Aspect 53 The pharmaceutical composition of Aspect 52, wherein R 6a and R 6b are independently selected from hydrogen, halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 54 The pharmaceutical composition of Aspect 53, wherein R 6a and R 6b are independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 55 The pharmaceutical composition of Aspect 52, wherein R 6a and R 6b are independently selected from hydrogen, halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 56 wherein R 6a and R 6c are independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 58 The pharmaceutical composition of Aspect 57, wherein R 6a and R 6c are independently selected from ⁇ F, ⁇ Cl, ⁇ SF5, ⁇ CN, ⁇ N3, ⁇ OH, ⁇ NH2, ⁇ CHF2, ⁇ CH2F, and ⁇ CF 3 .
• Aspect 59 Aspect 59.
• Aspect 73 The pharmaceutical composition of Aspect 72, wherein R 6b is selected from ⁇ F, ⁇ Cl, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 74 The pharmaceutical composition of Aspect 73, wherein R 6b is ⁇ F.
• Aspect 75 The pharmaceutical composition of Aspect 73, wherein R 6b is ⁇ F.
• each of R 6a and R 6b is independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 aminoalkyl, and C 1 -C 3 hydroxyalkyl; and wherein each of R 6c and R 6d is hydrogen.
• Aspect 76 is independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 aminoalkyl, and C 1 -C 3 hydroxyalkyl; and wherein each of R 6c and R 6d is hydrogen.
• each of R 6a and R 6c is independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 81. The pharmaceutical composition of Aspect 80, wherein each of R 6a and R 6c is independently selected from ⁇ F, ⁇ Cl, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 82. The pharmaceutical composition of Aspect 81, wherein each of R 6a and R 6c is ⁇ F.
• each of R 6a and R 6d is independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 aminoalkyl, and C 1 -C 3 hydroxyalkyl; and wherein each of R 6b and R 6c is hydrogen.
• Aspect 84 is independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 aminoalkyl, and C 1 -C 3 hydroxyalkyl; and wherein each of R 6b and R 6c is hydrogen.
• each of R 6a and R 6d is independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 85. The pharmaceutical composition of Aspect 84, wherein each of R 6a and R 6d is independently selected from ⁇ F, ⁇ Cl, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 86. The pharmaceutical composition of Aspect 85, wherein each of R 6a and R 6d ⁇ F.
• each of R 6b and R 6c is independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 aminoalkyl, and C 1 -C 3 hydroxyalkyl; and wherein each of R 6a and R 6d is hydrogen.
• Aspect 88 is independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 aminoalkyl, and C 1 -C 3 hydroxyalkyl; and wherein each of R 6a and R 6d is hydrogen.
• each of R 6b and R 6c is independently selected from halogen, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 89. The pharmaceutical composition of Aspect 88, wherein each of R 6b and R 6c is independently selected from ⁇ F, ⁇ Cl, ⁇ SF 5 , ⁇ CN, ⁇ N 3 , ⁇ OH, ⁇ NH 2 , ⁇ CHF 2 , ⁇ CH 2 F, and ⁇ CF 3 .
• Aspect 90. The pharmaceutical composition of Aspect 89, wherein each of R 6b and R 6c is ⁇ F.
• Aspect 91. The pharmaceutical composition of Aspect 34, wherein the DHODH inhibitor compound is a compound having a formula represented by a structure:
• Aspect 92 The pharmaceutical composition of Aspect 34, wherein the DHODH inhibitor compound is a compound having a formula represented by a structure:
• Aspect 93 The pharmaceutical composition of Aspect 34, wherein the DHODH inhibitor compound is a compound having a formula represented by a structure: , or a combination thereof.
• Aspect 94 The pharmaceutical composition of any one of Aspect 6- Aspect 87, wherein the the DHODH inhibitor compound is a pharmaceutically acceptable salt thereof comprising the conjugate base form of the compound, and a counter ion selected from Li + , K + , Na + , ammonium, tetramethylammonium, tetraethylammonium, Fe +2 , Cu +2 , Zn +2 , Mg +2 , Ca +2 , Al +3 , Fe +3 , and combinations thereof.
• Aspect 95 Aspect 95.
• Aspect 88 The pharmaceutical composition of Aspect 88, wherein the counter ion is Na + .
• Aspect 96 The pharmaceutical composition of any one of Aspect 1-Aspect 7, wherein the DHODH inhibitor compound is a compound of DHODH inhibitor compound Group V as disclosed herein.
• Aspect 97 The pharmaceutical composition of any one of Aspect 1-Aspect 7, wherein the DHODH inhibitor compound is a compound of DHODH inhibitor compound Group V as disclosed herein.
• Aspect 98 The pharmaceutical combination of any one of Aspect 1-Aspect 97, further comprising at least one agent known to treat a cancer.
• Aspect 99. The pharmaceutical combination of Aspect 98, wherein the at least one agent is a DNA methyltransferase inhibitor, an HDAC-inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or combinations thereof.
• Aspect 100. The pharmaceutical combination of Aspect 99, wherein the DNA methyltransferase inhibitor is 5-aza-2 ′ -deoxycytidine, 5-azacytidine, zebularin, epigallocatechin-3-gallate, procaine, or combinations thereof.
• Aspect 99 wherein the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or combinations thereof.
• Aspect 103 The pharmaceutical combination of Aspect 99, wherein the mTor inhibitor is BEZ235, everolimus, temsirolimus, rapamycin, AZD8055, or cobminations thereof.
• Aspect 104 The pharmaceutical combination of Aspect 99, wherein the mTor inhibitor is BEZ235, everolimus, temsirolimus, rapamycin, AZD8055, or cobminations thereof.
• alkylating agent is selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
• the alkylating agent is selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a
• Aspect 114 The pharmaceutical combination of Aspect 113, wherein the least one agent known to treat GVHD is a steroid, an mTor inhibitor, a tyrosine kinase inhibitor, or other agent known to treat GVHD.
• Aspect 115 The pharmaceutical combination of Aspect 114, wherein the steroid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or combinations thereof.
• Aspect 116 The pharmaceutical combination of Aspect 114, wherein tyrosine kinase inhibitor is imatinib, ruxolitinib, or a combination thereof.
• Aspect 117 The pharmaceutical combination of Aspect 114, wherein tyrosine kinase inhibitor is imatinib, ruxolitinib, or a combination thereof.
• Aspect 120 wherein the disease modifying antirheumatic drug is selected from methotrexate, gold salts, D-penicillamine, hydroxychloroquine, auranofin, sulfasalazine, and combinations thereof.
• Aspect 122. The pharmaceutical combination of Aspect 120, wherein the nonsteroidal anitinflammatory drug is selected from indomethacin, naproxen, diclofenac, ibuprofen, aspirin and aspirin analogs, acetaminophen, and combinations thereof.
• Aspect 123 wherein the disease modifying antirheumatic drug is selected from methotrexate, gold salts, D-penicillamine, hydroxychloroquine, auranofin, sulfasalazine, and combinations thereof.
• Aspect 122. The pharmaceutical combination of Aspect 120, wherein the nonsteroidal anitinflammatory drug is selected from indomethacin, naproxen, diclofenac, ibuprofen
• Aspect 120 wherein the COX-2 selective inhibitor is selected from celecoxib, rofecoxib, etoricoxib, valdecoxib, lumiracoxib, and combinations thereof.
• Aspect 124. The pharmaceutical combination of Aspect 120, wherein the immunosuppressive drug is selected from a calcineurin inhibitor such as cyclosporin and FK506;a p70S6 kinase inhibitor such as sirolimus and rapamycin; an inosine monophosphate dehydrogenase inhibitor such as mycophenolate; leflunomide, cyclophosphamide, azathioprine, and combinations thereof.
• Aspect 120 wherein the steroid is selected from prednisone, betamethasone, budesonide and dexamethasone, and combinations thereof.
• Aspect 126. The pharmaceutical combination of Aspect 120, wherein the biological response modifier is selected from TNF ⁇ antagonists such as infliximab, adalimmab and etanercept; IL-1 receptor antagonists such as anakinra; humanized or chimeric antibodies or fusion proteins such as alefacept, efalizumab, daclizumab; anti-chemokine antibodies; anti- interleukin antibodies; and combinations thereof.
• TNF ⁇ antagonists such as infliximab, adalimmab and etanercept
• IL-1 receptor antagonists such as anakinra
• humanized or chimeric antibodies or fusion proteins such as alefacept, efalizumab, daclizumab
• anti-chemokine antibodies anti- interleukin antibodies
• the other agent useful for the treatment of autoimmune disorder is selected from hemokine receptor antagonists or modulators, cannabinoid receptor antagonists or modulators, inhibitors of matrix metalloproteinases, TNF ⁇ -converting enzymes, nitric oxide synthetases or phosphodiesterase IV, such as roflumilast or cilomilast; inhibitors of p38 MAP-kinase, the NF- kappa ⁇ , pathway or IL-1 receptor associated kinase or inhibitors of interactions involving adhesion molecules such as LFA-1, VLA-4, ICAM-1, VCAM-1, ⁇ 4 ⁇ 7 , MAdCAM-1, and ⁇ v ⁇ 3 ; and combinations thereof.
• hemokine receptor antagonists or modulators cannabinoid receptor antagonists or modulators, inhibitors of matrix metalloproteinases, TNF ⁇ -converting enzymes, nitric oxide synthetases or phosphodiesterase IV, such as roflumilast or cilomilast
• a method for the treatment of a disease or disorder in a mammal comprising the step of administering to the mammal either: (a) a therapeutically effective amount of a pharmaceutical combination of any of Apsect 1-Aspect 127; or (b) co-administering an anti- CD38 therapeutic agent as disclosed herein and at least one DHODH inhibitor compound as disclosed herein.
• Aspect 129. The method of Aspect 128, wherein the mammal is a human.
• Aspect 130 wherein the disorder or disease is associated with abnormal, increased, or aberrant dihydroorotate dehydrogenase (DHODH) activity.
• Aspect 132 The method of Aspect 131, wherein the disorder or disease can be treated by inhibition of dihydroorotate dehydrogenase (DHODH) activity.
• Aspect 133 The method of any one of Aspect 128-Aspect 132, further comprising the step of identifying a mammal in need of treatment of the disorder or disease.
• Aspect 134 The method of Aspect 133, wherein the disorder or disease is associated with abnormal, increased, or aberrant dihydroorotate dehydrogenase (DHODH) activity.
• the disorder is selected from chronic lymphocytic leukemia, MGUS/multiple myeloma, extranodal natural killer (NK)/T-cell lymphoma, large cell lymphoma, nasal type (EN
• Aspect 143 The method of Aspect 142, wherein the hematological cancer is chronic myeloid leukemia (CML) or acute myeloid leukemia (AML).
• Aspect 144 The method of any one of Aspect 128-Aspect 143, further comprising the step of administering a therapeutically effective amount of at least one agent known to treat a cancer.
• Aspect 145 The method of any one of Aspect 128-Aspect 143, further comprising the step of administering a therapeutically effective amount of at least one agent known to treat a cancer.
• Aspect 146 wherein the glucocorticoid is dexamethasone, prednisolone, methylprednisolone, betamethasone, triamicinolone, fludrocortisone, beclomethasone, or combinations thereof.
• Aspect 150 The method of Aspect 146, wherein the mTor inhibitor is BEZ235, everolimus, temsirolimus, rapamycin, AZD8055, or cobminations thereof.
• Aspect 151 The method of Aspect 146, wherein the mTor inhibitor is BEZ235, everolimus, temsirolimus, rapamycin, AZD8055, or cobminations thereof.
• cytotoxic agent is an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a mTor inhibitor agent or other chemotherapeutic agent.
• antineoplastic antibiotic agent is selected from one or more of the group consisting of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
• Aspect 153 is selected from one or more of the group consisting of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt, hydrate, solv
• the antimetabolite agent is selected from one or more of the group consisting of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
• the antimetabolite agent is selected from one or more of the group consisting of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable
• alkylating agent is selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
• the alkylating agent is selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a
• the method of Aspect 151 wherein the mitotic inhibitor agent is selected from one or more of the group consisting of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
• the mitotic inhibitor agent is selected from one or more of the group consisting of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
• the mTor inhibitor is everolimus, sirolimus, temsirolimus, or
• Aspect 161 The method of any one of Aspect 128-Aspect 159, wherein the at least one compound and the at least one agent are administered simultaneously.
• Aspect 162. The method of any one of Aspect 128-Aspect 159, wherein the at least one compound and the at least one agent are co-formulated.
• Aspect 163. The method of any one of Aspect 128-Aspect 159, wherein the at least one compound and the at least one agent are co-packaged.
• Aspect 164 The method of any one of Aspect 128-Aspect 133, wherein the disorder is mediated by T-cell proliferation.
• Aspect 165. The method of Aspect 164, wherein the disorder is psoriasis.
• Aspect 164 wherein the disorder is graft-versus-host disease (GVHD).
• Aspect 167 The method of Aspect 166, wherein the GVHD is associated with an organ transplant, an allograft, a xenograft, or a hematopoietic stem cell transplantation.
• Aspect 168. The method of Aspect 166 or Aspect 167, wherein the GVHD is acute GVHD.
• the method of Aspect 166 or Aspect 167, wherein the GVHD is chronic GVHD.
• Aspect 170 The method of any one of Aspect 166- Aspect 169, further comprising the step of administering a therapeutically effective amount of at least one agent known to treat GVHD.
• Aspect 171 wherein the mTor inhibitor is everolimus, sirolimus, temsirolimus, or combinations thereof.
• Aspect 175. The method of Aspect 171, wherein the other agent known to treat GVHD is tacrolimus, clofazimine, psoralen, cyclosporine, alemtuzumab, infliximab, rituximab, etanercept, antithymocyte globulin, thalidomide, mycophenolate mofetil, pentostatin, methotrexate, halofuginone, hydroxychloroquine, or combinations thereof.
• Aspect 128-Aspect 133 The method of any one of Aspect 128-Aspect 133, wherein the disorder is associated with T-cell proliferation.
• Aspect 177. The method of any one of Aspect 128-Aspect 133, wherein the disorder is an autoimmune disorder or disease.
• Aspect 179 The method of Aspect 177 or Aspect 178, further comprising the step of administering a therapeutically effective amount of at least one agent known to treat an autoimmune disorder or disease.
• Aspect 180 The method of Aspect 179, wherein the at least one agent known to treat an autoimmune disorder or disease is selected from the group consisting of: (a) disease modifying antirheumatic drugs; (b) nonsteroidal anitinflammatory drugs; (c) COX-2 selective inhibitors; (d) COX-1 inhibitors; (e) immunosuppressive drugs, including p70S6 kinase inhibitors; and inosine monophosphate dehydrogenase inhibitors; (f) steroids; (g) biological response modifiers; and (h) other agents useful for the treatment of autoimmune disorders.
• the method of Aspect 180 wherein the COX-2 selective inhibitor is selected from celecoxib, rofecoxib, etoricoxib, valdecoxib, lumiracoxib, and combinations thereof.
• the method of Aspect 180, wherein the immunosuppressive drug is selected from a calcineurin inhibitor such as cyclosporin and FK506; a p70S6 kinase inhibitor such as sirolimus and rapamycin; an inosine monophosphate dehydrogenase inhibitor such as mycophenolate; leflunomide, cyclophosphamide, azathioprine, and combinations thereof.
• the other agent useful for the treatment of autoimmune disorder is selected from hemokine receptor antagonists or modulators, cannabinoid receptor antagonists or modulators, inhibitors of matrix metalloproteinases, TNF ⁇ -converting enzymes, nitric oxide synthetases or phosphodiesterase IV, such as roflumilast or cilomilast; inhibitors of p38 MAP-kinase, the NF-kappa ⁇ , pathway or IL-1 receptor associated kinase or inhibitors of interactions involving adhesion molecules such as LFA-1, VLA-4, ICAM-1, VCAM-1, ⁇ 4 ⁇ 7 , MAdCAM-1, and ⁇ v ⁇ 3 ; and combinations thereof.
• Aspect 188 The method of any one of Aspect 128-Aspect 187, wherein the administering is administering the therapeutically effective amount of a pharmaceutical combination of any of 1-Aspect 127.
• Aspect 189. The method of any one of Aspect 128-Aspect 187, wherein the administering is administering the co-administering the at least one anti-CD38 therapeutic agent as disclosed herein and the least one DHODH inhibitor compound as disclosed herein.
• Aspect 190 The method of Aspect 189, wherein the co-administering comprises sequential administration of the at least one anti-CD38 therapeutic agent as disclosed herein and the least one DHODH inhibitor compound as disclosed herein.
• the method of Aspect 189, wherein the co-administering comprises simultaneous administration of the at least one anti-CD38 therapeutic agent as disclosed herein and the least one DHODH inhibitor compound as disclosed herein.
• the method of Aspect 189, wherein the co-administering comprises administration of the anti-CD38 therapeutic agent as disclosed herein on a first dose administration schedule and administration of the least one DHODH inhibitor compound as disclosed herein on a second dose administration schedule.
• a method for inhibiting dihydroorotate dehydrogenase activity in at least one cell comprising the step of contacting the at least one cell with either: (a) a pharmaceutical combination of any of 1-Aspect 127; or (b) at least one anti-CD38 therapeutic agent as disclosed herein and at least one DHODH inhibitor compound as disclosed herein.
• Aspect 194. The method of Aspect 193, wherein the cell is mammalian.
• Aspect 195. The method of Aspect 194, wherein the cell is human.
• Aspect 193-Aspect 195 The method of any one of Aspect 193-Aspect 195, wherein contacting is via administration to a mammal.
• Aspect 198. The method of Aspect 197, wherein the mammal has been diagnosed with a need for inhibiting dihydroorotate dehydrogenase activity prior to the administering step.
• Aspect 199. The method of Aspect 198, wherein the mammal has been diagnosed with a need for treatment of a disorder related to dihydroorotate dehydrogenase activity prior to the administering step.
• Aspect 200 The method of any one of Aspect 193-Aspect 195, wherein contacting is via administration to a mammal.
• Aspect 198. The method of Aspect 197, wherein the mammal has been diagnosed with a need for inhibiting dihydroorotate dehydrogenase activity prior to the administering step.
• Aspect 199. The method of Aspect 198, wherein the mammal has
• Aspect 204 The method of Aspect 200, exhibits inhibition of dihydroorotate dehydrogenase with an IC 50 of less than about 50 nM.
• Aspect 205 The method of any one of Aspect 193-Aspect 204, wherein the contacting is contacting the cell with a pharmaceutical combination of any of 1-Aspect 127.
• Aspect 206. The method of any one of Aspect 193-Aspect 204, wherein the contacting is co-contacting the cell with the at least one anti-CD38 therapeutic agent as disclosed herein and the least one DHODH inhibitor compound as disclosed herein.
• Aspect 207 The method of any one of Aspect 193-Aspect 204, wherein the contacting is co-contacting the cell with the at least one anti-CD38 therapeutic agent as disclosed herein and the least one DHODH inhibitor compound as disclosed herein.
• the method of Aspect 206, wherein the co-contacting comprises sequential contacting of the cell with the at least one anti-CD38 therapeutic agent as disclosed herein and the least one DHODH inhibitor compound as disclosed herein.
• Aspect 208. The method of Aspect 206, wherein the co-contacting comprises simultaneous contacting of the cell with the at least one anti-CD38 therapeutic agent as disclosed herein and the least one DHODH inhibitor compound as disclosed herein.
• EXAMPLE 1 SYNTHESIS OF EXEMPLARY DISCLOSED COMPOUNDS. [0777] Synthesis of 2-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-6-fluoroquinoline-4-carboxylic acid (Cpd3). A representative DHODH inhibitor compound was used in the studies described herein. In the figures it is designated as “Cpd3”, which is 2-(4'-ethoxy-[1,1'-biphenyl]-4-yl)-6- fluoroquinoline-4-carboxylic acid.
• Cpd3 was prepared as described in Intl. Pat. Appl. No. PCT/US19/38622, which is incorporated herein by reference.
• mice Males, 12-week old, strain NOD.Cg- Prkdcscid Il2rgtm1Wjl/SzJ. These mice were allowed to develop a fatal leukemia, at which point splenocytes containing leukemia cells were collected and cryopreserved. Subsequently, 0.3E6 of these splenocytes collected from previously MV4-11 engrafted mice were injected intravenously into 28 NSG mice (secondary engraftment).
• IACUC Institutional Laboratory Animal Care and Use Committee
• mice develop leukemia (AML) in two weeks after the injection of spleen MNC from adapted MV4-11 cells of NSG mice (Ranganathan et. al., (2012) Blood (2012) 120 (9): 1765–1773) and their lifespan was around 3 ⁇ 4 weeks.
• AML leukemia
• mice were randomly enrolled to receive: 1) vehicle, 2) 50 mg/kg Cpd 3 orally on Monday, Wednesday, and Friday (MWF), 3) 1 ⁇ g/g daratumumab via intraperitoneal injection on Tuesday and Friday (TF), or 4) Cpd 3 (MWF) and daratumumab (TF) combination therapy. Two additional mice were kept as non-engrafted controls.
• mice were considered at early/end removal criteria (ERC) and removed from the study upon: 20% weight loss (based on weight at study initiation), paralysis, inability to stand, scruffy appearance, uncontrolled shivering or unwillingness to eat or drink. Overall survival was calculated using Kapler Meyer analysis. All the experiments were conducted in accordance with the institutional guidelines for animal care and use. Each arm included 6–7 mice and treatment began a week post engraftment [0789] Study Results. Representative survival data are shown in FIG. 2A, and the median survival data are summarized in Tables 1 and 2 below.
• EXAMPLE 4 XENOGRAFT STUDIES USING MV4-11 CELLS.
• Xenograft Model Methodology Animal studies were performed at Charles River Laboratories (CRL).1E5 MOLM-13 cells were engrafted intravenously into NCG mice (males, 8-12-week old).4 days post engraftment, mice were randomly enrolled to receive: 1. Vehicle 2. 10 mg/kg Cpd 53 orally (daily) 3. 10 mg/kg Cpd 53 orally (TIWK, Monday, Wednesday, and Friday) 4. 4 mg/kg BAY2402234 orally (daily) 5. 1 ⁇ g/g Daratumumab via intraperitoneal injection (BIWK, Tuesday and Friday) 6.
• Cpd 53 (daily) and Daratumumab (BIWK) combination 8.
• Cpd 53 (TIWK) and Daratumumab (BIWK) combination 9.
• BAY2402234 (daily) and Daratumumab (BIWK) combination 10.
• Cpd 53 (daily) and Isatuximab (BIWK) combination 11.
• Body Weight qd x 5 then biwk to end ⁇ Any individual animal with a single observation of > than 30% body weight loss or three consecutive measurements of >25% body weight loss was euthanized. ⁇ Any group with a mean body weight loss of >20 % or >10% mortality ceased dosing. The group was not euthanized and recovery is allowed. Within a group with >20% weight loss, individuals hitting the individual body weight loss endpoint was euthanized. If the group treatment related body weight loss is recovered to within 10% of the original weights, dosing resumed at a lower dose or less frequent dosing schedule. Exceptions to non-treatment body weight % recovery may be allowed on a case-by-case basis. ⁇ Endpoint: Moribundity.
• FIGs. 6A-6B Representative survival data are shown in FIGs. 6A-6B, and the median survival data are summarized in Table 4 below for treatment with Cpd4 alone and in combination with either daratumumab or Isatuximab using the dosing regiment of TIWK (MWF) Cpd4 treatment.
• MPF TIWK
• mice Four days post engraftment, mice were randomly enrolled to receive vehicle, 10 mg/kg Cpd 53 (daily PO), 1 ⁇ g/g Daratumumab (IP) OR 2.5 mg/kg Isatuximab on Tuesday and Friday (TF), or Cpd4 and Daratumumab OR Isatuximab combination. Representative survival data are shown in FIGs. 7A-7B, and the median survival data are summarized in Table 5 below for treatment with Cpd4 alone and in combination with either daratumumab or Isatuximab using the dosing regiment of daily Cpd4 treatment.
• RNA will be collected one, three, and seven days after treatment with 0.5 ⁇ M of brequinar (BRQ) or Cpd 3 to measure transcriptional upregulation of CD38.
• BRQ brequinar
• flow cytometry analysis will be done to measure the protein expression level of CD38 in addition to myeloid differentiation markers, CD11b and CD14.
• the collected RNA will be submitted for sequencing to identify mutational subsets demonstrating CD38 upregulation in response to DHODH inhibition. 6.
• EXAMPLE 6 PROSPECTIVE ANALYSIS OF MECHANISM OF COMBINATION THERAPY SYNERGISM.
• ATRA all-trans retinoic acid
• Dara daratumumab
• DHODH inhibitors e.g., brequinar (BRQ) and/or Cpd 3
• BRQ brequinar
• Cpd 3 Non-Radioactive Cytotoxicity Assay
• Conjugate formation assay LDH
• LDH can be assayed as follows: 0.5E6 MV4-11 cells will be treated with vehicle, 1 ⁇ M BRQ, or Cpd3 with or without 20 ⁇ g/ml Dara.
• LDH lactate dehydrogenase
• ADCC cell-mediated antibody-dependent cell-mediated cytotoxicity

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