CRYSTALLINE FORMS OF A DEOXYCYTIDINE KINASE INHIBITOR AND USES THEREOF
Described herein are crystalline forms of compounds that are deoxycytidine kinase (dCK) inhibitors, methods of making such crystalline forms, pharmaceutical compositions and medicaments comprising such crystalline forms, and methods of using such crystalline forms in the treatment of conditions, diseases, or disorders that would benefit from modulation of deoxycytidine kinase (dCK) activity.
This application claims the benefit of U.S. provisional application Ser. No. 63/108,803, filed Nov. 2, 2020 and 63/190,107 filed May 18, 2021, both of which are incorporated by reference in their entirety.
BACKGROUND OF THE INVENTIONDeoxycytidine kinase (dCK) is an enzyme which plays a crucial role in cellular division and which functions in the phosphorylation of several deoxyribonucleosides and their nucleoside analogs. Deoxycytidine kinase, a rate-limiting enzyme in the salvage pathway of nucleoside synthesis, is observed to be predominantly expressed in hematopoietic tissues and is upregulated in certain solid tumors. dCK deficiency is also associated with certain forms of resistance to antiviral and anticancer chemotherapeutic agents. dCK is a clinically important polypeptide target because of, for example, its role in DNA synthesis and cell division, as well as its association with drug resistance and/or drug sensitivity. Compounds and compositions that bind to and inhibit dCK activities in vivo are desirable for the treatment of diseases and disorders where dCK activity is implicated.
SUMMARY OF THE INVENTIONProvided herein, in one aspect, is a composition comprising a crystalline form of a compound of Formula I:
or a pharmaceutically acceptable salt thereof.
In some embodiments, the crystalline form is a polymorph Form I of a maleate salt of the compound of Formula I.
In some embodiments, the polymorph Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 135 to about 160° C. In some embodiments, the polymorph Form I has a melting point of about 139° C. In some embodiments, the polymorph Form I has a melting point of about 148° C. In some embodiments, the polymorph Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially as set forth in
In some embodiments, the polymorph Form I is dry, non-solvated, and/or non-hydrated.
In some embodiments, the polymorph Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 8.2±0.2° 2-θ, 12.7±0.2° 2-θ, and 16.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 16.9±0.2° 2-θ, 17.6±0.2° 2-θ, and 22.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 20.6±0.2° 2-θ, 24.9±0.2° 2-θ, and 19.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 8.2±0.2° 2-θ, 12.7±0.2° 2-θ, 16.4±0.2° 2-θ, 16.9±0.2° 2-θ, 17.6±0.2° 2-θ, 22.9±0.2° 2-θ, 20.6±0.2° 2-θ, 24.9±0.2° 2-θ, and 19.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 8.2±0.2° 2-θ, 12.7±0.2° 2-θ, 16.4±0.2° 2-θ, 16.9±0.2° 2-θ, 17.6±0.2° 2-θ, 22.9±0.2° 2-θ, 20.6±0.2° 2-θ, 24.9±0.2° 2-θ, and 19.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the polymorph Form I is characterized by an X-ray powder diffraction pattern substantially as set forth in
In some embodiments, the polymorph Form I is characterized by a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of about 1% to about 5% over a temperature range of about 25 to about 125° C. In some embodiments, the polymorph Form I is characterized by a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of less than about 4% over a temperature range of about 25 to about 125° C. In some embodiments, the polymorph Form I is characterized by a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of less than about 2% over a temperature range of about 25 to about 125° C. In some embodiments, the polymorph Form I is characterized by a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of about 4% over a temperature range of about 25 to about 125° C. In some embodiments, the polymorph Form I is characterized by a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of about 5% to about 15% over a temperature range of about 125 to about 200° C. In some embodiments, the polymorph Form I is characterized by a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of about 10.3% over a temperature range of about 125 to about 200° C. In some embodiments, the polymorph Form I is characterized by a thermogravimetric analysis (TGA) thermogram substantially as set forth in
In some embodiments, the polymorph Form I comprises less than 5% water. In some embodiments, the polymorph Form I comprises about 0.5% water. In some embodiments, the polymorph Form I comprises about 1.5% water. In some embodiments, the polymorph Form I comprises about 2.5% water.
In some embodiments, the crystalline form is a polymorph Form II of a maleate salt of the compound of Formula I.
In some embodiments, the polymorph Form II is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 150 to about 170° C. In some embodiments, the differential scanning calorimetry (DSC) thermogram further comprises an endotherm in the range of about 25 to about 60° C. In some embodiments, the polymorph Form II has a melting point in the range of about 150 to about 155° C. In some embodiments, the polymorph Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially as set forth in
In some embodiments, the polymorph Form II comprises small, acicular needle-like particles. In some embodiments, the needles range in size from about 1 μm to about 50 μm.
In some embodiments, the polymorph Form II is solvated or hydrated.
In some embodiments, the polymorph Form II is characterized by an X-ray powder diffraction pattern comprising peaks at 7.6±0.2° 2-θ, 8.7±0.2° 2-θ, and 16.0±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 12.2±0.2° 2-θ, 17.6±0.2° 2-θ, and 19.5±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 21.7±0.2° 2-θ, 10.8±0.2° 2-θ, and 13.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 7.6±0.2° 2-θ, 8.7±0.2° 2-θ, 16.0±0.2° 2-θ, 12.2±0.2° 2-θ, 17.6±0.2° 2-θ, 19.5±0.2° 2-θ, 21.7±0.2° 2-θ, 10.8±0.2° 2-θ, and 13.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 7.6±0.2° 2-θ, 8.7±0.2° 2-θ, 16.0±0.2° 2-θ, 12.2±0.2° 2-θ, 17.6±0.2° 2-θ, 19.5±0.2° 2-θ, 21.7±0.2° 2-θ, 10.8±0.2° 2-θ, and 13.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the polymorph Form II is characterized by an X-ray powder diffraction pattern substantially as set forth in
In some embodiments, the polymorph Form II is characterized by a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of about 1% to about 5% over a temperature range of about 25 to about 80° C. In some embodiments, the polymorph Form II is characterized by a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of about 2.0% to about 2.5% over a temperature range of about 25 to about 80° C. In some embodiments, the polymorph Form II is characterized by a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of about 1.8% over a temperature range of about 25 to about 80° C. In some embodiments, the polymorph Form II is characterized by a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of about 2.9% over a temperature range of about 25 to about 70° C. In some embodiments, the polymorph Form II is characterized by a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of about 0% to about 1% over a temperature range of about 70 to about 130° C. In some embodiments, the polymorph Form II is characterized by a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of about 0.5% over a temperature range of about 70 to about 130° C. In some embodiments, the polymorph Form II is characterized by a thermogravimetric analysis (TGA) thermogram comprising a loss in mass of about 0.5% over a temperature range of about 80 to about 130° C.
In some embodiments, the polymorph Form II comprises less than 5% water. In some embodiments, the polymorph Form II comprises from about 1.5% to about 2.5% water. In some embodiments, the polymorph Form II comprises about 3.78% water. In some embodiments, the polymorph Form II comprises about 2.65% water. In some embodiments, the polymorph Form II comprises about 0.8% water.
In some embodiments, greater than 90% by weight of the composition is the crystalline form of the compound of Formula I or a pharmaceutically acceptable salt thereof.
In some embodiments, the composition comprises less than about 2% impurities by weight.
Provided herein, in another aspect, is a pharmaceutical composition comprising the composition described herein and a pharmaceutically acceptable excipient.
Provided herein, in another aspect, is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the composition described herein or the pharmaceutical composition described herein.
In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is selected from lung cancer, breast cancer, colorectal cancer, prostate cancer, melanoma, stomach cancer, bladder cancer, endometrial cancer, kidney cancer, leukemia, liver cancer, lymphoma, pancreatic cancer, and thyroid cancer.
In some embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the autoimmune disease is selected from fibromyalgia, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, ulcerative colitis, and type 1 diabetes.
Provided herein, in another aspect, is a method of preparing a first crystalline form of a maleate salt of a compound of Formula I:
wherein the method comprises:
-
- (i) dissolving the compound of Formula I and an acid in a first solvent mixture at a first temperature;
- (ii) adding a second solvent at a second temperature;
- (iii) cooling the resulting solution to a third temperature;
- (iv) filtering the solution and drying the resulting solid at a fourth temperature.
In some embodiments, the acid is maleic acid. In some embodiments, the first crystalline form is polymorph Form I. In some embodiments, the first solvent mixture is EtOH/EtOAc and the first temperature is about 50 to about 60° C. In some embodiments, the second solvent is EtOAc and the second temperature is about 20 to about 25° C. In some embodiments, the third temperature is about −5 to about 5° C. In some embodiments, the fourth temperature is about 50 to 55° C.
Provided herein, in another aspect, is a method of preparing a second crystalline form of a maleate salt of a compound of Formula I:
wherein the method comprises drying a first crystalline form of a maleate salt of the compound of Formula I at a temperature of about 70° C.
In some embodiments, the second crystalline form is polymorph Form II. In some embodiments, the first crystalline form is polymorph Form I.
Provided herein, in another aspect, is a method of preparing a second crystalline form of a maleate salt of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein the method comprises slurrying a first crystalline form of a maleate salt of the compound of Formula I, or a mixture of crystalline forms of a maleate salt of the compound of Formula I, in water.
In some embodiments, the second crystalline form is polymorph Form II. In some embodiments, the first crystalline form is polymorph Form I.
Provided herein, in another aspect, is a method of treating acute disseminated encephalomyelitis (ADEM) in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula I is administered once daily. In some embodiments, the compound of Formula I is administered twice daily. In some embodiments, the administrations of the compound of Formula I are conducted twelve hours apart.
In some embodiments, the compound of Formula I is administered in a unit dosage form. In some embodiments, the unit dosage form comprises from about 0.5 to about 350 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 25 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 75 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 100 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 150 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 320 mg/kg of the compound of Formula I.
In some embodiments, the total amount of the compound of Formula I administered per day is from about 0.5 to about 350 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 50 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 100 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 150 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 320 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is from about 5 to about 350 mg.
In some embodiments, the compound of Formula I is formulated for oral administration. In some embodiments, the compound of Formula I is formulated as a tablet, a pill, a capsule, a powder, a liquid, a suspension, a solution, a suppository, or an aerosol. In some embodiments, the compound of Formula I is formulated as a solution. In some embodiments, the solution comprises from about 1 to about 50 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 5 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 15 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 20 mg/mL of the compound of Formula I.
In some embodiments, the administration of the compound of Formula I results in a decrease in interferon gamma (IFNγ) levels in the subject.
Provided herein, in another aspect, is a method of treating an autoimmune disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is administered once daily.
In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is optic neuritis. In some embodiments, the disease or disorder is acute disseminated encephalomyelitis (ADEM).
In some embodiments, the compound of Formula I is administered in a unit dosage form. In some embodiments, the unit dosage form comprises from about 0.5 to about 350 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 25 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 75 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 100 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 150 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 320 mg/kg of the compound of Formula I.
In some embodiments, the total amount of the compound of Formula I administered per day is from about 0.5 to about 350 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 50 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 100 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 150 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 320 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is from about 5 to about 350 mg.
In some embodiments, the compound of Formula I is formulated for oral administration. In some embodiments, the compound of Formula I is formulated as a tablet, a pill, a capsule, a powder, a liquid, a suspension, a solution, a suppository, or an aerosol. In some embodiments, the compound of Formula I is formulated as a solution. In some embodiments, the solution comprises from about 1 to about 50 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 5 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 15 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 20 mg/mL of the compound of Formula I.
In some embodiments, the administration of the compound of Formula I results in a decrease in interferon gamma (IFNγ) levels in the subject.
INCORPORATION BY REFERENCEAll publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
(R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethyl)thio)pyrimidine-4,6-diamine (the compound of Formula I) is a potent and selective deoxycytidine kinase (dCK) inhibitor. dCK inhibitors are useful in the treatment of various diseases, conditions, and disorders for which abnormal dCK activity plays a role, such as cancer and autoimmune diseases.
The preparation and uses of the compound of Formula I have been previously described (see, U.S. Pat. Nos. 9,598,404, 9,981,961, 9,688,673, WO 2016/130581, U.S. Pat. No. 10,570,124, and WO 2016/130562, each of which is incorporated by reference in its entirety).
As used herein, the compound of Formula I or “Compound 1” refers to (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethyl)thio)pyrimidine-4,6-diamine, which has the chemical structure shown below:
In some embodiments, the compound of Formula I is crystalline.
As used herein, “crystalline form,” “polymorph,” “Form,” and “form” may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. Compounds of the present disclosure include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. In some embodiments, the crystalline form is a single solid state form, e.g., polymorph Form I.
DefinitionsA “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative, such as those known in the art, for example, described in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).
As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including and preferably clinical results. For example, beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals.
As used herein, “delaying development of a disease” means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.
As used herein, an “effective dosage” or “effective amount” of drug, compound, or pharmaceutical composition is an amount sufficient to effect beneficial or desired results. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival. In the case of cancer or tumor, an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibiting, to some extent, tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder. An effective dosage can be administered in one or more administrations. For purposes of this invention, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
As defined herein, the term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. Inhibition may refer to reduction of a disease or symptoms of disease. Inhibition may refer to a reduction in the activity of a particular protein or nucleic acid target. The protein may be deoxycytidine kinase. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein.
The term “modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule.
The term “modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, a modulator of a target protein changes by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. A modulator of a disease decreases a symptom, cause, or characteristic of the targeted disease.
“Selective” or “selectivity” or the like of a compound refers to the compound's ability to discriminate between molecular targets. “Specific”, “specifically”, “specificity”, or the like of a compound refers to the compound's ability to cause a particular action, such as inhibition, to a particular molecular target with minimal or no action to other proteins in the cell.
“Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.
The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
As used herein, the term “administering” means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
By “co-administer” it is meant that a compound described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies, for example, an anticancer agent as described herein. The compounds described herein can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g. anticancer agents).
Co-administration includes administering one active agent (e.g. a complex described herein) within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent (e.g. anti-cancer agents). Also contemplated herein, are embodiments, where co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In some embodiments, the active and/or adjunctive agents are linked or conjugated to one another. In some embodiments, the compounds described herein are combined with treatments for cancer such as chemotherapy or radiation therapy.
The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease means that the disease is caused by (in whole or in part), a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function, or a side-effect of the compound (e.g. toxicity) is caused by (in whole or in part) the substance or substance activity or function.
“Patient,” “subject,” “patient in need thereof,” and “subject in need thereof” are herein used interchangeably and refer to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human. A “cancer-patient” is a patient suffering from, or prone to developing cancer.
Unless clearly indicated otherwise, the term “individual” as used herein refers to a mammal, including but not limited to, bovine, horse, feline, rabbit, canine, rodent, or primate (e.g., human). In some embodiments, an individual is a human. In some embodiments, an individual is a non-human primate such as chimpanzees and other apes and monkey species. In some embodiments, an individual is a farm animal such as cattle, horses, sheep, goats and swine; pets such as rabbits, dogs and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. In some embodiments, the invention find use in both human medicine and in the veterinary context.
“Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. In some embodiments, the disease as used herein refers to cancer.
“Chemotherapeutic” or “chemotherapeutic agent” is used in accordance with its plain ordinary meaning and refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.
“Cancer model organism”, as used herein, is an organism exhibiting a phenotype indicative of cancer, or the activity of cancer causing elements, within the organism. The term cancer is defined above. A wide variety of organisms may serve as cancer model organisms, and include for example, cancer cells and mammalian organisms such as rodents (e.g. mouse or rat) and primates (such as humans). Cancer cell lines are widely understood by those skilled in the art as cells exhibiting phenotypes or genotypes similar to in vivo cancers. Cancer cell lines as used herein includes cell lines from animals (e.g. mice) and from humans.
As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly indicates otherwise.
It is understood that aspect and variations of the invention described herein include “consisting” and/or “consisting essentially of” aspects and variations.
Crystalline Forms of the Compound of Formula I
The polymorphs made according to the methods of the invention may be characterized by any methodology according to the art. For example, the polymorphs made according to the methods of the invention may be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy, and/or spectroscopy (e.g., Raman, solid state nuclear magnetic resonance (ssNMR), and infrared (IR)). In some embodiments, crystallinity of a solid form is determined by X-Ray Powder Diffraction (XRPD).
XRPD: Polymorphs according to the invention may be characterized by XRPD. The relative intensities of XRPD peaks can vary, depending upon the particle size, the sample preparation technique, the sample mounting procedure and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-θ values. Therefore, the XRPD peak assignments can vary, for example by plus or minus about 0.2 degrees.
DSC: Polymorphs according to the invention can also be identified by its characteristic DSC thermograms such as shown in
TGA: The polymorphic forms of the invention may also give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior may be measured in the laboratory by thermogravimetric analysis (TGA) which may be used to distinguish some polymorphic forms from others. In one aspect, the polymorph may be characterized by thermogravimetric analysis.
The polymorph forms of the compound of Formula I are useful in the production of medicinal preparations and can be obtained by means of a crystallization process to produce crystalline and semi-crystalline forms or a solidification process to obtain the amorphous form. In some embodiments, the crystallization is carried out by either generating the desired compound (for example, the compound of Formula I) in a reaction mixture and isolating the desired polymorph from the reaction mixture, or by dissolving raw compound in a solvent, optionally with heat, followed by crystallizing/solidifying the product by cooling (including active cooling) and/or by the addition of an antisolvent for a period of time. In some embodiments, the crystallization comprises addition of a seed form of a desired polymorph. The crystallization or solidification may be followed by drying carried out under controlled conditions until the desired water content is reached in the end polymorphic form.
Polymorph Form I of the Compound of Formula I
Provided herein, in one aspect, is polymorph Form I of (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethyl)thio)pyrimidine-4,6-diamine. Some embodiments provided a composition comprising polymorph Form I of (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethyl)thio)pyrimidine-4,6-diamine. In some embodiments, polymorph Form I of (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethyl)thio)pyrimidine-4,6-diamine is characterized as having:
-
- (a) an X-ray powder diffraction pattern comprising peaks at 8.2±0.2° 2-θ, 12.7±0.2° 2-θ, and 16.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å;
- (b) an X-ray powder diffraction pattern substantially as set forth in
FIG. 2 ; - (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 135 to about 160° C.;
- (d) a differential scanning calorimetry (DSC) thermogram substantially as set forth in
FIG. 1 ; - (e) a thermogravimetric analysis (TGA) thermogram substantially as set forth in
FIG. 3 ; or - (f) combinations thereof.
In some embodiments, polymorph Form I is characterized by an X-ray powder diffraction pattern substantially as set forth in
In some embodiments, polymorph Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 8.2±0.2° 2-θ, 12.7±0.2° 2-θ, and 16.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, polymorph Form I is characterized by an X-ray powder diffraction pattern comprising peaks at 8.2±0.1° 2-θ, 12.7±0.1° 2-θ, and 16.4±0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, polymorph Form I is characterized by an X-ray powder diffraction pattern comprising peaks at about 8.2° 2-θ, about 12.7° 2-θ, and about 16.4° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.
In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 16.9±0.2° 2-θ, 17.6±0.2° 2-θ, and 22.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 16.9±0.1° 2-θ, 17.6±0.1° 2-θ, and 22.9±0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 16.9° 2-θ, about 17.6° 2-θ, and about 22.9° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.
In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 20.6±0.2° 2-θ, 24.9±0.2° 2-θ, and 19.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 20.6±0.1° 2-θ, 24.9±0.1° 2-θ, and 19.9±0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 20.6° 2-θ, about 24.9° 2-θ, and about 19.9° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.
In some embodiments, the X-ray powder diffraction pattern comprises at least one peak selected from 8.2±0.2° 2-θ, 12.7±0.2° 2-θ, 16.4±0.2° 2-θ, 16.9±0.2° 2-θ, 17.6±0.2° 2-θ, 22.9±0.2° 2-θ, 20.6±0.2° 2-θ, 24.9±0.2° 2-θ, and 19.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least two peaks selected from 8.2±0.2° 2-θ, 12.7±0.2° 2-θ, 16.4±0.2° 2-θ, 16.9±0.2° 2-θ, 17.6±0.2° 2-θ, 22.9±0.2° 2-θ, 20.6±0.2° 2-θ, 24.9±0.2° 2-θ, and 19.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least three peaks selected from 8.2±0.2° 2-θ, 12.7±0.2° 2-θ, 16.4±0.2° 2-θ, 16.9±0.2° 2-θ, 17.6±0.2° 2-θ, 22.9±0.2° 2-θ, 20.6±0.2° 2-θ, 24.9±0.2° 2-θ, and 19.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least four peaks selected from 8.2±0.2° 2-θ, 12.7±0.2° 2-θ, 16.4±0.2° 2-θ, 16.9±0.2° 2-θ, 17.6±0.2° 2-θ, 22.9±0.2° 2-θ, 20.6±0.2° 2-θ, 24.9±0.2° 2-θ, and 19.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 8.2±0.2° 2-θ, 12.7±0.2° 2-θ, 16.4±0.2° 2-0, 16.9±0.2° 2-θ, 17.6±0.2° 2-θ, 22.9±0.2° 2-θ, 20.6±0.2° 2-θ, 24.9±0.2° 2-θ, and 19.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least six peaks selected from 8.2±0.2° 2-θ, 12.7±0.2° 2-θ, 16.4±0.2° 2-θ, 16.9±0.2° 2-θ, 17.6±0.2° 2-θ, 22.9±0.2° 2-θ, 20.6±0.2° 2-θ, 24.9±0.2° 2-θ, and 19.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least seven peaks selected from 8.2±0.2° 2-θ, 12.7±0.2° 2-θ, 16.4±0.2° 2-θ, 16.9±0.2° 2-θ, 17.6±0.2° 2-θ, 22.9±0.2° 2-θ, 20.6±0.2° 2-θ, 24.9±0.2° 2-0, and 19.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least eight peaks selected from 8.2±0.2° 2-θ, 12.7±0.2° 2-θ, 16.4±0.2° 2-θ, 16.9±0.2° 2-θ, 17.6±0.2° 2-θ, 22.9±0.2° 2-θ, 20.6±0.2° 2-θ, 24.9±0.2° 2-θ, and 19.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 8.2±0.2° 2-θ, 12.7±0.2° 2-θ, 16.4±0.2° 2-θ, 16.9±0.2° 2-θ, 17.6±0.2° 2-θ, 22.9±0.2° 2-θ, 20.6±0.2° 2-θ, 24.9±0.2° 2-θ, and 19.9±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 8.2±0.1° 2-θ, 12.7±0.1° 2-θ, 16.4±0.1° 2-θ, 16.9±0.1° 2-θ, 17.6±0.1° 2-θ, 22.9±0.1° 2-θ, 20.6±0.1° 2-θ, 24.9±0.1° 2-θ, and 19.9±0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at about 8.2° 2-θ, about 12.7° 2-θ, about 16.4° 2-θ, about 16.9° 2-θ, about 17.6° 2-θ, about 22.9° 2-θ, about 20.6° 2-θ, about 24.9° 2-θ, and about 19.9° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.
In some embodiments, polymorph Form I is characterized by a differential scanning calorimetry (DSC) thermogram substantially as set forth in
In some embodiments, polymorph Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm at about 135-160° C., 135-158° C., 135-156° C., 135-154° C., 135-152° C., 135-150° C., 135-148° C., 135-146° C., 135-144° C., 135-142° C., 135-140° C., 140-160° C., 140-158° C., 140-156° C., 140-154° C., 140-152° C., 140-150° C., 140-148° C., 140-146° C., 140-144° C., 140-142° C., 142-160° C., 142-158° C., 142-156° C., 142-154° C., 142-152° C., 142-150° C., 142-148° C., 142-146° C., 142-144° C., 144-160° C., 144-158° C., 144-156° C., 144-154° C., 144-152° C., 144-150° C., 144-148° C., 144-146° C., 146-160° C., 146-158° C., 146-156° C., 146-154° C., 146-152° C., 146-150° C., 146-148° C., 148-160° C., 148-158° C., 148-156° C., 148-154° C., 148-152° C., 148-150° C., 150-160° C., 150-158° C., 150-156° C., 150-154° C., 150-152° C., 152-160° C., 152-158° C., 152-156° C., 152-154° C., 154-160° C., 154-158° C., 154-156° C., 156-160° C., 156-158° C., or 158-160° C. In some embodiments, polymorph Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm at about 135-140° C., for example at about 135° C., 136° C., 137° C., 138° C., 139° C., or 140° C. In some embodiments, the polymorph Form I has a melting point of about 139° C. In some embodiments, polymorph Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm at about 145-150° C., for example at about 145° C., 146° C., 147° C., 148° C., 149° C., or 150° C. In some embodiments, the polymorph Form I has a melting point of about 148° C.
In some embodiments, polymorph Form I is characterized by a thermogravimetric analysis (TGA) thermogram substantially as set forth in
In some embodiments, polymorph Form I is stable at room temperature. In some examples, polymorph Form I can be stored at room temperature for an extended period of time without significant chemical degradation or change in the crystalline form. In some examples, polymorph Form I can be stored at room temperature for a time period of at least about 1 day, 2 days, 3 days, or 7 days. In some examples, polymorph Form I can be stored at room temperature for a time period of more than about 7 days. In some examples, polymorph Form I can be stored at room temperature for a time period of 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, or 6-7 days. In some examples, polymorph Form I can be stored at room temperature for a time period of at least 1 day, 2 days, 3 days, or 7 days.
In some embodiments, polymorph Form I is stable at temperatures above the room temperature and/or at high relative humidity (RH). In some examples, polymorph Form I can be stored at about 40° C. and at about 75% RH for an extended period of time without significant chemical degradation or change in the crystalline form. In some examples, polymorph Form I can be stored at about 40° C. and at about 75% RH for a time period of at least about 1 day, 2 days, 3 days, or 7 days. In some examples, polymorph Form I can be stored at about 40° C. and at about 75% RH for a time period of more than about 7 days. In some examples, polymorph Form I can be stored at about 40° C. and at about 75% RH for a time period of 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, or 6-7 days. In some examples, polymorph Form I can be stored at about 40° C. and at about 75% RH for a time period of at 1 day, 2 days, 3 days, or 7 days.
In some embodiments, polymorph Form I is stable at temperatures above the room temperature and/or at high relative humidity (RH). In some examples, polymorph Form I can be stored at about 60° C. for an extended period of time without significant chemical degradation or change in the crystalline form. In some examples, polymorph Form I can be stored at about 60° C. for a time period of at least about 1 day, 2 days, 3 days, or 7 days. In some examples, polymorph Form I can be stored at about 60° C. for a time period of more than about 7 days. In some examples, polymorph Form I can be stored at about 60° C. for a time period of 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, or 6-7 days. In some examples, polymorph Form I can be stored at about 60° C. for a time period of at 1 day, 2 days, 3 days, or 7 days.
Polymorph Form II of the Compound of Formula I
Provided herein, in one aspect, is polymorph Form II of (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethyl)thio)pyrimidine-4,6-diamine. Some embodiments provided a composition comprising polymorph Form II of (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethyl)thio)pyrimidine-4,6-diamine. In some embodiments, polymorph Form II of (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethyl)thio)pyrimidine-4,6-diamine is characterized as having:
-
- (a) an X-ray powder diffraction pattern comprising peaks at 7.6±0.2° 2-θ, 8.7±0.2° 2-θ, and 16.0±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å;
- (b) an X-ray powder diffraction pattern substantially as set forth in
FIG. 5 ; - (c) a differential scanning calorimetry (DSC) thermogram comprising an endotherm in the range of about 150 to about 170° C.;
- (d) a differential scanning calorimetry (DSC) thermogram further comprising an endotherm in the range of about 25 to about 60° C.;
- (e) a differential scanning calorimetry (DSC) thermogram substantially as set forth in
FIG. 4 ; - (f) a thermogravimetric analysis (TGA) thermogram substantially as set forth in
FIG. 6 ; - or
- (g) combinations thereof.
In some embodiments, polymorph Form II is characterized by an X-ray powder diffraction pattern substantially as set forth in
In some embodiments, polymorph Form II is characterized by an X-ray powder diffraction pattern comprising peaks at 7.6±0.2° 2-θ, 8.7±0.2° 2-θ, and 16.0±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, polymorph Form II is characterized by an X-ray powder diffraction pattern comprising peaks at 7.6±0.1° 2-θ, 8.7±0.1° 2-θ, and 16.0±0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, polymorph Form II is characterized by an X-ray powder diffraction pattern comprising peaks at about 7.6° 2-θ, about 8.7° 2-θ, and about 16.0° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.
In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 12.2±0.2° 2-θ, 17.6±0.2° 2-θ, and 19.5±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 12.2±0.1° 2-θ, 17.6±0.1° 2-θ, and 19.5±0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 12.2° 2-θ, about 17.6° 2-θ, and about 19.5° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.
In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 21.7±0.2° 2-θ, 10.8±0.2° 2-θ, and 13.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 21.7±0.1° 2-θ, 10.8±0.1° 2-θ, and 13.4±0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 21.7° 2-θ, about 10.8° 2-θ, and about 13.4° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.
In some embodiments, the X-ray powder diffraction pattern comprises at least one peak selected from 7.6±0.2° 2-θ, 8.7±0.2° 2-θ, 16.0±0.2° 2-θ, 12.2±0.2° 2-θ, 17.6±0.2° 2-θ, 19.5±0.2° 2-θ, 21.7±0.2° 2-θ, 10.8±0.2° 2-θ, and 13.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least two peaks selected from 7.6±0.2° 2-θ, 8.7±0.2° 2-θ, 16.0±0.2° 2-θ, 12.2±0.2° 2-θ, 17.6±0.2° 2-θ, 19.5±0.2° 2-θ, 21.7±0.2° 2-θ, 10.8±0.2° 2-θ, and 13.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least three peaks selected from 7.6±0.2° 2-θ, 8.7±0.2° 2-θ, 16.0±0.2° 2-θ, 12.2±0.2° 2-θ, 17.6±0.2° 2-θ, 19.5±0.2° 2-θ, 21.7±0.2° 2-θ, 10.8±0.2° 2-θ, and 13.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least four peaks selected from 7.6±0.2° 2-θ, 8.7±0.2° 2-θ, 16.0±0.2° 2-θ, 12.2±0.2° 2-θ, 17.6±0.2° 2-θ, 19.5±0.2° 2-θ, 21.7±0.2° 2-θ, 10.8±0.2° 2-θ, and 13.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 7.6±0.2° 2-θ, 8.7±0.2° 2-θ, 16.0±0.2° 2-θ, 12.2±0.2° 2-θ, 17.6±0.2° 2-θ, 19.5±0.2° 2-θ, 21.7±0.2° 2-θ, 10.8±0.2° 2-θ, and 13.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least six peaks selected from 7.6±0.2° 2-θ, 8.7±0.2° 2-θ, 16.0±0.2° 2-θ, 12.2±0.2° 2-θ, 17.6±0.2° 2-θ, 19.5±0.2° 2-θ, 21.7±0.2° 2-θ, 10.8±0.2° 2-θ, and 13.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least seven peaks selected from 7.6±0.2° 2-θ, 8.7±0.2° 2-θ, 16.0±0.2° 2-θ, 12.2±0.2° 2-θ, 17.6±0.2° 2-θ, 19.5±0.2° 2-θ, 21.7±0.2° 2-θ, 10.8±0.2° 2-θ, and 13.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises at least eight peaks selected from 7.6±0.2° 2-θ, 8.7±0.2° 2-θ, 16.0±0.2° 2-θ, 12.2±0.2° 2-θ, 17.6±0.2° 2-θ, 19.5±0.2° 2-θ, 21.7±0.2° 2-θ, 10.8±0.2° 2-θ, and 13.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 7.6±0.2° 2-θ, 8.7±0.2° 2-θ, 16.0±0.2° 2-θ, 12.2±0.2° 2-θ, 17.6±0.2° 2-θ, 19.5±0.2° 2-θ, 21.7±0.2° 2-θ, 10.8±0.2° 2-θ, and 13.4±0.2° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at 7.6±0.1° 2-θ, 8.7±0.1° 2-θ, 16.0±0.1° 2-θ, 12.2±0.1° 2-θ, 17.6±0.1° 2-θ, 19.5±0.1° 2-θ, 21.7±0.1° 2-θ, 10.8±0.1° 2-θ, and 13.4±0.1° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern comprises peaks at about 7.6° 2-θ, about 8.7° 2-θ, about 16.0° 2-θ, about 12.2° 2-θ, about 17.6° 2-θ, about 19.5° 2-θ, about 21.7° 2-θ, about 10.8° 2-θ, and about 13.4° 2-θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.
In some embodiments, polymorph Form II is characterized by a differential scanning calorimetry (DSC) thermogram substantially as set forth in
In some embodiments, polymorph Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm at about 150-170° C., 150-168° C., 150-166° C., 150-164° C., 150-162° C., 150-160° C., 150-158° C., 150-156° C., 150-154° C., 150-152° C., 152-170° C., 152-168° C., 152-166° C., 152-164° C., 152-162° C., 152-160° C., 152-158° C., 152-156° C., 152-154° C., 154-170° C., 154-168° C., 154-166° C., 154-164° C., 154-162° C., 154-160° C., 154-158° C., 154-156° C., 156-170° C., 156-168° C., 156-166° C., 156-164° C., 156-162° C., 156-160° C., 156-158° C., 158-170° C., 158-168° C., 158-166° C., 158-164° C., 158-162° C., 158-160° C., 160-170° C., 160-168° C., 160-166° C., 160-164° C., 160-162° C., 162-170° C., 162-168° C., 162-166° C., 162-164° C., 164-170° C., 164-168° C., 164-166° C., 166-170° C., 166-168° C., or 168-170° C. In some embodiments, polymorph Form I is characterized by a differential scanning calorimetry (DSC) thermogram comprising an endotherm at about 150-155° C., for example at about 150° C., 151° C., 152° C., 153° C., 154° C., or 155° C. In some embodiments, the polymorph Form I has a melting point of about 150-155° C.
In some embodiments, polymorph Form II is characterized by a differential scanning calorimetry (DSC) thermogram further comprising an endotherm at about 25-60° C., 25-58° C., 25-56° C., 25-54° C., 25-52° C., 25-50° C., 25-48° C., 25-46° C., 25-44° C., 25-42° C., 25-40° C., 25-38° C., 25-36° C., 25-34° C., 25-32° C., 25-30° C., 30-60° C., 30-58° C., 30-56° C., 30-54° C., 30-52° C., 30-50° C., 30-48° C., 30-46° C., 30-44° C., 30-42° C., 30-40° C., 30-38° C., 30-36° C., 30-34° C., 30-32° C., 32-60° C., 32-58° C., 32-56° C., 32-54° C., 32-52° C., 32-50° C., 32-48° C., 32-46° C., 32-44° C., 32-42° C., 32-40° C., 32-38° C., 32-36° C., 32-34° C., 34-60° C., 34-58° C., 34-56° C., 34-54° C., 34-52° C., 34-50° C., 34-48° C., 34-46° C., 34-44° C., 34-42° C., 34-40° C., 34-38° C., 34-36° C., 36-60° C., 36-58° C., 36-56° C., 36-54° C., 36-52° C., 36-50° C., 36-48° C., 36-46° C., 36-44° C., 36-42° C., 36-40° C., 36-38° C., 38-60° C., 38-58° C., 38-56° C., 38-54° C., 38-52° C., 38-50° C., 38-48° C., 38-46° C., 38-44° C., 38-42° C., 38-40° C., 40-60° C., 40-58° C., 40-56° C., 40-54° C., 40-52° C., 40-50° C., 40-48° C., 40-46° C., 40-44° C., 40-42° C., 42-60° C., 42-58° C., 42-56° C., 42-54° C., 42-52° C., 42-50° C., 42-48° C., 42-46° C., 42-44° C., 44-60° C., 44-58° C., 44-56° C., 44-54° C., 44-52° C., 44-50° C., 44-48° C., 44-46° C., 46-60° C., 46-58° C., 46-56° C., 46-54° C., 46-52° C., 46-50° C., 46-48° C., 48-60° C., 48-58° C., 48-56° C., 48-54° C., 48-52° C., 48-50° C., 50-60° C., 50-58° C., 50-56° C., 50-54° C., 50-52° C., 52-60° C., 52-58° C., 52-56° C., 52-54° C., 54-60° C., 54-58° C., 54-56° C., 56-60° C., 56-58° C., or 58-60° C.
In some embodiments, polymorph Form II is characterized by a thermogravimetric analysis (TGA) thermogram substantially as set forth in
In some embodiments, polymorph Form II is stable at below room temperature. In some examples, polymorph Form II can be stored at about 2-8° C. for an extended period of time without significant chemical degradation or change in the crystalline form. In some examples, polymorph Form II can be stored at about 2-8° C. for a time period of at least about 1 day, 1 week, 1 month, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months. In some examples, polymorph Form II can be stored at about 2-8° C. for a time period of more than about 36 months. In some examples, polymorph Form II can be stored at about 2-8° C. for a time period of 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, 6-7 days, 1-2 weeks, 1-3 weeks, 1-4 weeks, 2-3 weeks, 2-4 weeks, 3-4 weeks, 1-3 months, 1-6 months, 1-9 months, 1-12 months, 1-15 months, 1-18 months, 1-21 months, 1-24 months, 1-27 months, 1-30 months, 1-33 months, 1-36 months, 3-6 months, 3-9 months, 3-12 months, 3-15 months, 3-18 months, 3-21 months, 3-24 months, 3-27 months, 3-30 months, 3-33 months, 3-36 months, 6-9 months, 6-12 months, 6-15 months, 6-18 months, 6-21 months, 6-24 months, 6-27 months, 6-30 months, 6-33 months, 6-36 months, 9-12 months, 9-15 months, 9-18 months, 9-21 months, 9-24 months, 9-27 months, 9-30 months, 9-33 months, 9-36 months, 12-15 months, 12-18 months, 12-21 months, 12-24 months, 12-27 months, 12-30 months, 12-33 months, 12-36 months, 15-18 months, 15-21 months, 15-24 months, 15-27 months, 15-30 months, 15-33 months, 15-36 months, 18-21 months, 18-24 months, 18-27 months, 18-30 months, 18-33 months, 18-36 months, 21-24 months, 21-27 months, 21-30 months, 21-33 months, 21-36 months, 24-27 months, 24-30 months, 24-33 months, 24-36 months, 27-30 months, 27-33 months, 27-36 months, 30-33 months, 30-36 months, or 33-36 months. In some examples, polymorph Form II can be stored at about 2-8° C. for a time period of at least 1 day, 1 week, 1 month, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.
In some embodiments, polymorph Form II is stable at room temperature and relative humidity. In some examples, polymorph Form II can be stored at about 25° C. and at about 60% RH for an extended period of time without significant chemical degradation or change in the crystalline form. In some examples, polymorph Form II can be stored at about 25° C. and at about 60% for a time period of at least about 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In some examples, polymorph Form II can be stored at about 25° C. and at about 60% RH for a time period of more than about 6 months. In some examples, polymorph Form II can be stored at about 25° C. and at about 60% RH for a time period of 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, 6-7 days, 1-2 weeks, 1-3 weeks, 1-4 weeks, 2-3 weeks, 2-4 weeks, 3-4 weeks, 1-2 months, 1-3 months, 1-4 months, 1-5 months, 1-6 months, 2-3 months, 2-4 months, 2-5 months, 2-6 months, 3-4 months, 3-5 months, 3-6 months, 4-5 months, 4-6 months, or 5-6 months. In some examples, polymorph Form II can be stored at about 25° C. and at about 60% RH for a time period of at least 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months.
In some embodiments, polymorph Form II is stable at temperatures above the room temperature and/or at high relative humidity (RH). In some examples, polymorph Form II can be stored at about 40° C. and at about 75% RH for an extended period of time without significant chemical degradation or change in the crystalline form. In some examples, polymorph Form II can be stored at about 40° C. and at about 75% RH for a time period of at least about 1 day, 2 days, 3 days, or 7 days. In some examples, polymorph Form II can be stored at about 40° C. and at about 75% RH for a time period of more than about 7 days. In some examples, polymorph Form II can be stored at about 40° C. and at about 75% RH for a time period of 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, or 6-7 days. In some examples, polymorph Form II can be stored at about 40° C. and at about 75% RH for a time period of at 1 day, 2 days, 3 days, or 7 days.
In some embodiments, polymorph Form II is stable at temperatures above the room temperature and/or at high relative humidity (RH). In some examples, polymorph Form II can be stored at about 60° C. for an extended period of time without significant chemical degradation or change in the crystalline form. In some examples, polymorph Form II can be stored at about 60° C. for a time period of at least about 1 day, 2 days, 3 days, or 7 days. In some examples, polymorph Form II can be stored at about 60° C. for a time period of more than about 7 days. In some examples, polymorph Form II can be stored at 60° C. for a time period of 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, or 6-7 days. In some examples, polymorph Form II can be stored at about 60° C. for a time period of at 1 day, 2 days, 3 days, or 7 days.
Methods of Making the Compound of Formula I and Polymorphic Forms Thereof
The compounds used in the reactions described herein are made according to organic synthesis techniques, starting from commercially available chemicals and/or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, Wis., including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, Ill.), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), Combi-blocks (San Diego, Calif.), Crescent Chemical Co. (Hauppauge, N.Y.), eMolecules (San Diego, Calif.), Fisher Scientific Co. (Pittsburgh, Pa.), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), Matrix Scientific, (Columbia, S.C.), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.), Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc. (Mount Pleasant, S.C.), Spectrum Chemicals (Gardena, Calif.), Sundia Meditech, (Shanghai, China), TCI America (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.), and WuXi (Shanghai, China).
Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modern Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.
Specific and analogous reactants are also identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C.). Chemicals that are known but not commercially available in catalogs are prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the pyrazole compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.
Isomers
Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
Labeled Compounds
In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, 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 usually found in nature. Examples of isotopes that are incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31F, 32F, 35S, 18F, and 36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., 3H and carbon-14, i. e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, solvate, hydrate or derivative thereof is prepared by any suitable method.
In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
Pharmaceutically Acceptable Salts
In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
Solvates
In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.
Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
Provided herein, in one aspect, are methods of making one or more polymorphs of the compound of Formula I:
The compound of Formula I may be prepared as previously described in U.S. Pat. Nos. 9,598,404, 9,981,961, 9,688,673, WO 2016/130581, U.S. Pat. No. 10,570,124, and WO 2016/130562. In some embodiments, the compound of Formula I is prepared according to the examples herein.
The polymorphs provided herein are not limited by the starting materials used to produce the compound of Formula I.
Provided herein, in one aspect, are methods of making polymorphs of the compound of Formula I, or a pharmaceutically acceptable salt and/or solvate thereof, either by isolation of the desired polymorph as the first solid form after synthesis of the compound of Formula I, or alternatively, by isolation of the desired polymorph as a transition from a prior solid form of the compound of Formula I. Transitions from one form to another are within the scope of this disclosure because they can be an alternative manufacturing method for obtaining the form desired for the production of the medicinal preparations.
Polymorphs of the compound of Formula I, according to the methods provided herein can be selected from polymorph Form I, polymorph Form II, and mixtures thereof.
Isolation and purification of the chemical entities and intermediates described herein can be performed, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples below. However, other equivalent separation or isolation procedures can also be used. Prior to crystallization, the compound of Formula I may be isolated in about 50% chemical purity, 55% chemical purity, 60% chemical purity, 65% chemical purity, 70% chemical purity, 75% chemical purity, 80% chemical purity, 90% chemical purity, 91% chemical purity, 92% purity, 93% chemical purity, 94% chemical purity, 95% chemical purity, 96% chemical purity, 97% chemical purity, 98% chemical purity, 99% chemical purity, about 98% chemical purity, or about 100% chemical purity.
In some embodiments, the crystalline forms disclosed herein are obtained by crystallizing the compound of Formula I with a chemical purity of less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 94%, less than about 93%, less than about 92%, less than about 91%, less than about 90%, less than about 89%, less than about 88%, less than about 87%, less than about 86%, less than about 85%, less than about 84%, less than about 83%, less than about 82%, less than about 81%, less than about 80%, less than about 78%, less than about 76%, less than about 74%, less than about 72%, or less than about 70%. In some embodiments, the crystalline forms are obtained by crystallizing the compound of Formula I with a chemical purity in the range of about 70% to about 99%, 80% to about 96%, about 85% to about 96%, about 90% to about 96%, about 80% to 98%, about 85% to about 98%, about 90% to about 98%, about 92% to about 98%, about 94% to 98%, or about 96% to about 98%.
Preparation of Polymorph Form I
In one embodiment, the desired polymorph is polymorph Form I of a maleate salt of the compound of Formula I, and the isolating step involves recrystallization of crude reaction product from a mono-solvent system. In some embodiments, the desired polymorph is polymorph Form I of a maleate salt of the compound of Formula I, and the isolating step involves recrystallization of crude product from a binary, tertiary, or greater solvent system, collectively understood as a multi-solvent system. In some embodiments, the desired polymorph is polymorph Form I of a maleate salt of the compound of Formula I, and the isolating step involves crystallization from a mono- or multi-solvent system, where the crystallization involves dissolving the compound of Formula I and maleic acid in the mono- or multi-solvent system at a temperature above ambient temperature. In some examples, the dissolving of the compound of Formula I and maleic acid in the mono- or multi-solvent system is performed at a temperature of about 40-90° C., 45-90° C., 50-90° C., 55-90° C., 60-90° C., 65-90° C., 70-90° C., 75-90° C., 40-85° C., 45-85° C., 50-85° C., 55-85° C., 60-85° C., 65-85° C., 70-85° C., 75-85° C., 80-85° C., 40-80° C., 45-80° C., 50-80° C., 55-80° C., 60-80° C., 65-80° C., 70-80° C., 75-80° C., 40-75° C., 45-75° C., 50-75° C., 55-75° C., 60-75° C., 65-75° C., 70-75° C., 40-70° C., 45-70° C., 50-70° C., 55-70° C., 60-70° C., 65-70° C., 40-65° C., 45-65° C., 50-65° C., 55-65° C., 60-65° C., 40-60° C., 45-60° C., 50-60° C., 55-60° C., 40-55° C., 45-55° C., 50-55° C., 40-50° C., or 45-50° C. In some examples, the recrystallization solvent comprises ethanol/ethyl acetate and the dissolving of the compound of Formula I and maleic acid in the solvent is performed at a temperature of about 60° C. Any suitable amount of solvent can be used for dissolving the compound of Formula I and maleic acid. In some embodiments, the amount of solvent (e.g., 1:1 ethanol/ethyl acetate) used to dissolve the compound of Formula I and maleic acid is from about 1-10 mL per gram of the compound of Formula I. For example, in some embodiments, the amount of solvent used for dissolving the compound of Formula I is 7.3 mL per gram of the compound of Formula I. In some examples, the recrystallization solvent comprises ethanol/ethyl acetate, the dissolving of the compound of Formula I and maleic acid in the solvent system is performed at a temperature of about 60° C., and the amount of solvent used for dissolving is about 7.3 mL/g of the compound of Formula I.
In some embodiments, the crystallization further involves actively cooling the heated solution containing the dissolved maleate salt of the compound of Formula I, for example to a temperature of about 0-40° C., 0-30° C., 0-20° C., 0-10° C., 10-40° C., 10-30° C., 10-20° C., 20-40° C., 20-30° C., 20-10° C., or 30° C.-40° C. In some embodiments, the crystallization further involves actively cooling the heated solution containing the dissolved maleate salt of the compound of Formula I to a temperature of about 25° C. In some embodiments, the solution containing the dissolved maleate salt of the compound of Formula I is further maintained at this lower temperature for a time period, for example for about 30 min, about 1 h, about 2 h, about 3 h, about 4 h, about 5 h, about 6 h, about 7 h, about 8 h, about 9 h, about 10 h, about 11 h, about 12 h, about 13 h, about 14 h, about 15 h, about 16 h, about 17 h, about 18 h, about 19 h, about 20 h, about 21 h, about 22 h, about 23 h, about 24 h or more.
In some embodiments, the crystallization further involves actively cooling the heated solution containing the dissolved maleate salt of the compound of Formula I, for example to a temperature of about 0-40° C., 0-30° C., 0-20° C., 0-10° C., 10-40° C., 10-30° C., 10-20° C., 20-40° C., 20-30° C., 20-10° C., or 30° C.-40° C. In some embodiments, the crystallization further involves actively cooling the heated solution containing the dissolved maleate salt of the compound of Formula I to a temperature of about 0° C. In some embodiments, the solution containing the dissolved maleate salt of the compound of Formula I is further maintained at this lower temperature for a time period, for example for about 30 min, about 1 h, about 2 h, about 3 h, about 4 h, about 5 h, about 6 h, about 7 h, about 8 h, about 9 h, about 10 h, about 11 h, about 12 h, about 13 h, about 14 h, about 15 h, about 16 h, about 17 h, about 18 h, about 19 h, about 20 h, about 21 h, about 22 h, about 23 h, about 24 h or more.
In some embodiments, the crystallization further involves filtering the solution containing the obtained crystals of the maleate salt of the compound of Formula I. In some embodiments, the crystallization optionally involves washing the obtained crystals by a solvent, for example by the recrystallization solvent one or more times. In some embodiments, the crystallization optionally involves drying the obtained crystals, for example under vacuum at a temperature of about 55° C.
In some embodiments, the chemical purity of polymorph Form I is greater than 60%, 70%, 80%, 90%, 95%, or 99%. In some embodiments, the chemical purity of polymorph Form I is greater than about 90%. In some embodiments, the chemical purity of polymorph Form I is greater than about 95%. In some embodiments, the chemical purity of polymorph Form I greater than about 99%. The chemical purity of polymorph Form I may be measured by any available analytical technique, for example by HPLC analysis.
Preparation of Polymorph Form II
In one embodiment, the desired polymorph is polymorph Form II of a maleate salt of the compound of Formula I, and the isolating step involves recrystallization of crude reaction product from a mono-solvent system. In some embodiments, the desired polymorph is polymorph Form II of a maleate salt of the compound of Formula I, and the isolating step involves recrystallization of crude product from a binary, tertiary, or greater solvent system, collectively understood as a multi-solvent system. In some embodiments, the desired polymorph is polymorph Form II of a maleate salt of the compound of Formula I, and the isolating step involves crystallization from a mono- or multi-solvent system, where the crystallization involves dissolving the maleate salt of the compound of Formula I in the mono- or multi-solvent system at a temperature above ambient temperature. In some examples, the dissolving of the maleate salt of the compound of Formula I in the mono- or multi-solvent system is performed at a temperature of about 40-90° C., 45-90° C., 50-90° C., 55-90° C., 60-90° C., 65-90° C., 70-90° C., 75-90° C., 40-85° C., 45-85° C., 50-85° C., 55-85° C., 60-85° C., 65-85° C., 70-85° C., 75-85° C., 80-85° C., 40-80° C., 45-80° C., 50-80° C., 55-80° C., 60-80° C., 65-80° C., 70-80° C., 75-80° C., 40-75° C., 45-75° C., 50-75° C., 55-75° C., 60-75° C., 65-75° C., 70-75° C., 40-70° C., 45-70° C., 50-70° C., 55-70° C., 60-70° C., 65-70° C., 40-65° C., 45-65° C., 50-65° C., 55-65° C., 60-65° C., 40-60° C., 45-60° C., 50-60° C., 55-60° C., 40-55° C., 45-55° C., 50-55° C., 40-50° C., or 45-50° C. In some examples, the recrystallization solvent comprises 1:1 DCM/methanol and the dissolving of the maleate salt of the compound of Formula I in the solvent is performed at a temperature of about 45° C. Any suitable amount of solvent can be used for dissolving the maleate salt of the compound of Formula I. In some embodiments, the amount of solvent (e.g., 1:1 DCM/methanol) used to dissolve the maleate salt of the compound is from about 1-20 mL per gram of the maleate salt of the compound of Formula I. For example, in some embodiments, the amount of solvent used for dissolving the maleate salt of the compound of Formula I is 7.4 mL per gram of the maleate salt of the compound of Formula I. In some examples, the recrystallization solvent comprises 1:1 DCM/methanol, the dissolving of the maleate salt of the compound of Formula I in the solvent system is performed at a temperature of about 45° C., and the amount of solvent used for dissolving is about 7.4 mL/g of the maleate salt of the compound of Formula I.
In some embodiments, the crystallization further involves actively cooling the heated solution containing the dissolved maleate salt of the compound of Formula I, for example to a temperature of about 0-40° C., 0-30° C., 0-20° C., 0-10° C., 10-40° C., 10-30° C., 10-20° C., 20-40° C., 20-30° C., 20-10° C., or 30° C.-40° C. In some embodiments, the crystallization further involves actively cooling the heated solution containing the dissolved maleate salt of the compound of Formula I to a temperature of about 5° C. In some embodiments, the solution containing the dissolved maleate salt of the compound of Formula I is further maintained at this lower temperature for a time period, for example for about 30 min, about 1 h, about 2 h, about 3 h, about 4 h, about 5 h, about 6 h, about 7 h, about 8 h, about 9 h, about 10 h, about 11 h, about 12 h, about 13 h, about 14 h, about 15 h, about 16 h, about 17 h, about 18 h, about 19 h, about 20 h, about 21 h, about 22 h, about 23 h, about 24 h or more.
In some embodiments, the crystallization further involves filtering the solution containing the obtained crystals of the maleate salt of the compound of Formula I. In some embodiments, the crystallization optionally involves washing the obtained crystals by a solvent, for example by the recrystallization solvent one or more times. In some embodiments, the crystallization optionally involves drying the obtained crystals, for example under vacuum at a temperature of about 70° C.
In some embodiments, the chemical purity of polymorph Form II is greater than 60%, 70%, 80%, 90%, 95%, or 99%. In some embodiments, the chemical purity of polymorph Form II is greater than about 90%. In some embodiments, the chemical purity of polymorph Form II is greater than about 95%. In some embodiments, the chemical purity of polymorph Form II greater than about 99%. The chemical purity of polymorph Form II may be measured by any available analytical technique, for example by HPLC analysis.
In some embodiments, polymorph Form II is dry. In some embodiments, polymorph Form II is non-solvated. In some embodiments, polymorph Form II is non-hydrated. In some embodiments, polymorph Form II is anhydrous. In some embodiments, polymorph Form II is solvated. In some embodiments, polymorph Form II is hydrated.
Pharmaceutical Compositions
The disclosure provides compositions, including pharmaceutical compositions, comprising one or more crystalline forms of the present invention.
In some embodiments, the ratio of desired crystalline form such as polymorph Form I to all other crystalline forms in a composition is greater than about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or more w/w. In other embodiments, the ratio of polymorph Form II to all other polymorphs is greater than about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or more w/w.
In some embodiments, the one or more polymorphs of the compound of Formula I are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds/polymorphs into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).
Provided herein are pharmaceutical compositions comprising one or more polymorphs of the compound of Formula I and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In certain embodiments, the one or more polymorphs of the compound of Formula I are administered as pharmaceutical compositions in which the one or more polymorphs are mixed with other active ingredients, as in combination therapy. Encompassed herein are all combinations of actives set forth in the combination therapies section below and throughout this disclosure. In specific embodiments, the pharmaceutical compositions include one or more polymorphs of the compound of Formula I.
A pharmaceutical composition, as used herein, refers to a mixture of one or more polymorphs of the compound of Formula I with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the polymorphs to an organism. In some embodiments, in practicing the methods of treatment or use provided herein, therapeutically effective amounts of one or more polymorphs of the compound of Formula I are administered in a pharmaceutical composition to a mammal having a disease or condition to be treated. In specific embodiments, the mammal is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject and other factors. The one or more polymorphs of the compound of Formula I described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.
In one embodiment, one or more polymorphs of the compound of Formula I are formulated in an aqueous solution. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In other embodiments, one or more polymorphs of the compound of Formula I are formulated for transmucosal administration. In specific embodiments, transmucosal formulations include penetrants that are appropriate to the barrier to be permeated. In still other embodiments wherein the one or more polymorphs described herein are formulated for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and/or excipients.
In another embodiment, the polymorphs described herein are formulated for oral administration. The polymorphs of the compound of Formula I are formulated by combining the polymorphs with, e.g., pharmaceutically acceptable carriers or excipients. In some embodiments, the polymorphs described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.
In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the polymorphs described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses.
In certain embodiments, therapeutically effective amounts of at least one of the polymorphs described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.
In other embodiments, therapeutically effective amounts of at least one of the polymorphs described herein are formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, the polymorphs described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical composition of a polymorph of the compound of Formula I is formulated in a form suitable for parenteral injection as sterile suspension, solution or emulsion in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active polymorphs in water-soluble form. In additional embodiments, suspensions of the active polymorphs are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the polymorphs to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
In still other embodiments, the one or more polymorphs of the compound of Formula I are administered topically. The one or more polymorphs described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
In yet other embodiments, the one or more polymorphs of the compound of Formula I are formulated for transdermal administration. In specific embodiments, transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. In some embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of the one or more polymorphs of the compound of Formula I is accomplished by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of the one or more polymorphs of the compound of Formula I. In specific embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, in one embodiment, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
In other embodiments, the one or more polymorphs of the compound of Formula I are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders. Pharmaceutical compositions of the polymorphs of the compound of Formula I are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In specific embodiments, the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
In still other embodiments, the one or more polymorphs of the compound of Formula I are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active polymorphs into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as suitable. Pharmaceutical compositions comprising the one or more polymorphs of the compound of Formula I are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent or excipient and at least one polymorph of the compound of Formula I described herein as an active ingredient. The active ingredient is in free-acid or free-base form, or in a pharmaceutically acceptable salt form. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
Methods for the preparation of compositions, comprising the one or more polymorphs of the compound of Formula I described herein include formulating the polymorphs with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
In some embodiments, a pharmaceutical composition comprising at least one polymorph of the compound of Formula I illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.
In certain embodiments, useful aqueous suspension contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a polymorph of the compound of Formula I. The term “solubilizing agent” generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.
Furthermore, useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
Still other useful compositions include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the polymorphs described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the polymorphs for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.
In certain embodiments, the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.
Methods of Treatment
Disclosed herein are methods of inhibiting a deoxycytidine kinase (dCK) activity comprising contacting a compound or polymorph detailed herein with the deoxycytidine kinase, either in vitro (e.g., in an enzymatic or a cell-based assay setting) or in vivo (e.g., in animal models or an individual subject in need of treatment). Compounds and polymorphs provided herein bind to a deoxycytidine kinase polypeptide and inhibit its activity. Thus in another aspect, provided are methods for inhibiting dCK activity and treating diseases and disorders where dCK activity is implicated.
In some embodiments, provided is a method for treating cancer in an individual comprising administering to the individual an effective amount of a compound or polymorph detailed herein, or a pharmaceutically acceptable salt thereof.
As used herein, the term “cancer” refers to all types of cancer, neoplasm, or malignant or benign tumors found in mammals, including leukemia, carcinomas and sarcomas. In some embodiments, cancer is a solid tumor cancer. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is a liquid tumor cancer. In some embodiments, the liquid tumor cancer is a blood cancer. In some embodiments, the cancer is refractory. Exemplary cancers include acute myeloid leukemia (“AML”), chronic myelogenous leukemia (“CML”), and cancer of the brain, breast, pancreas, colon, liver, kidney, lung, non-small cell lung, melanoma, ovary, sarcoma, and prostate. Additional examples include cervix cancers, stomach cancers, head & neck cancers, uterus cancers, mesothelioma, metastatic bone cancer, Medulloblastoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, and neoplasms of the endocrine and exocrine pancreas.
The term “leukemia” refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved: myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood: leukemic or aleukemic (subleukemic). The murine leukemia model is widely accepted as being predictive of in vivo anti-leukemic activity. It is believed that a compound that tests positive in the P388 cell assay will generally exhibit some level of anti-leukemic activity regardless of the type of leukemia being treated. Accordingly, the present invention includes a method of treating leukemia, including treating acute myeloid leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.
The term “sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Sarcomas which can be treated with a combination of antineoplastic thiol-binding mitochondrial oxidant and an anticancer agent include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.
The term “melanoma” is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas which can be treated with a combination of antineoplastic thiol-binding mitochondrial oxidant and an anticancer agent include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, and superficial spreading melanoma.
The term “carcinoma” refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Exemplary carcinomas which can be treated with a combination of antineoplastic thiol-binding mitochondrial oxidant and an anticancer agent include, for example, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypemephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum.
In some embodiments, the cancer is a liquid tumor. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia (ALL). In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is characterized by high levels of replication stress as determined by measuring gamma H2A.X expression. In some embodiments, the cancer is ovarian cancer, pancreatic cancer, lung cancer, glioblastoma, hepatocellular carcinoma, breast cancer, prostate cancer, or head and neck cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is head or neck cancer.
In some embodiments of this section, provided is a method for treating an immune disorder in an individual in need thereof comprising administering to the individual an effective amount of a compound detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the immune disorder is an autoimmune disorder or transplant rejection. In some embodiments, the autoimmune disorder is a T cell mediated autoimmune disorder. In some embodiments, the autoimmune disorder is selected from the group consisting of multiple sclerosis, lupus (including systemic lupus erythematosus), inflammatory bowel disease, rheumatoid arthritis and type 1 diabetes.
Provided herein, in another aspect, is a method of treating acute disseminated encephalomyelitis (ADEM) in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound of Formula I is administered once daily. In some embodiments, the compound of Formula I is administered twice daily. In some embodiments, the administrations of the compound of Formula I are conducted twelve hours apart.
In some embodiments, the compound of Formula I is administered in a unit dosage form. In some embodiments, the unit dosage form comprises from about 0.5 to about 350 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 25 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 50 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 75 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 100 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 125 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 150 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 175 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 200 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 225 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 250 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 275 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 300 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 320 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 325 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 350 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises from about 0.5 to about 350 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 25 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 50 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 75 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 100 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 125 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 150 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 175 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 200 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 225 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 250 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 275 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 300 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 320 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 325 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 350 mg/subject of the compound of Formula I.
In some embodiments, the total amount of the compound of Formula I administered per day is from about 0.5 to about 350 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 25 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 50 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 75 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 100 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 125 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 150 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 175 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 200 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 225 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 250 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 275 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 300 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 320 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 325 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 350 mg/kg.
In some embodiments, the total amount of the compound of Formula I administered per day is from about 0.5 to about 350 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 25 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 50 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 75 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 100 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 125 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 150 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 175 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 200 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 225 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 250 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 275 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 300 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 320 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 325 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 350 mg/subject.
In some embodiments, the total amount of the compound of Formula I administered per day is from about 5 to about 350 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 25 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 50 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 75 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 100 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 125 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 150 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 175 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 200 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 225 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 250 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 275 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 300 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 320 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 325 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 350 mg.
In some embodiments, the compound of Formula I is formulated for oral administration. In some embodiments, the compound of Formula I is formulated as a tablet, a pill, a capsule, a powder, a liquid, a suspension, a solution, a suppository, or an aerosol. In some embodiments, the compound of Formula I is formulated as a tablet. In some embodiments, the compound of Formula I is formulated as a pill. In some embodiments, the compound of Formula I is formulated as a capsule. In some embodiments, the compound of Formula I is formulated as a powder. In some embodiments, the compound of Formula I is formulated as a liquid. In some embodiments, the compound of Formula I is formulated as a suspension. In some embodiments, the compound of Formula I is formulated as a suppository. In some embodiments, the compound of Formula I is formulated as an aerosol.
In some embodiments, the compound of Formula I is formulated as a solution. In some embodiments, the solution comprises from about 1 to about 50 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 5 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 10 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 15 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 20 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 25 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 30 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 35 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 40 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 45 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 50 mg/mL of the compound of Formula I.
In some embodiments, the administration of the compound of Formula I results in a decrease in interferon gamma (IFNγ) levels in the subject.
Provided herein, in another aspect, is a method of treating an autoimmune disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is administered once daily.
In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is optic neuritis. In some embodiments, the disease or disorder is acute disseminated encephalomyelitis (ADEM).
In some embodiments, the compound of Formula I is administered in a unit dosage form. In some embodiments, the unit dosage form comprises from about 0.5 to about 350 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 25 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 50 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 75 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 100 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 125 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 150 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 175 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 200 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 225 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 250 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 275 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 300 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 320 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 325 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises about 350 mg/kg of the compound of Formula I. In some embodiments, the unit dosage form comprises from about 0.5 to about 350 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 25 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 50 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 75 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 100 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 125 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 150 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 175 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 200 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 225 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 250 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 275 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 300 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 320 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 325 mg/subject of the compound of Formula I. In some embodiments, the unit dosage form comprises about 350 mg/subject of the compound of Formula I.
In some embodiments, the total amount of the compound of Formula I administered per day is from about 0.5 to about 350 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 25 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 50 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 75 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 100 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 125 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 150 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 175 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 200 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 225 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 250 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 275 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 300 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 320 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 325 mg/kg. In some embodiments, the total amount of the compound of Formula I administered per day is about 350 mg/kg.
In some embodiments, the total amount of the compound of Formula I administered per day is from about 0.5 to about 350 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 25 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 50 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 75 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 100 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 125 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 150 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 175 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 200 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 225 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 250 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 275 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 300 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 320 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 325 mg/subject. In some embodiments, the total amount of the compound of Formula I administered per day is about 350 mg/subject.
In some embodiments, the total amount of the compound of Formula I administered per day is from about 5 to about 350 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 25 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 50 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 75 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 100 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 125 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 150 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 175 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 200 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 225 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 250 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 275 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 300 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 320 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 325 mg. In some embodiments, the total amount of the compound of Formula I administered per day is about 350 mg.
In some embodiments, the compound of Formula I is formulated for oral administration. In some embodiments, the compound of Formula I is formulated as a tablet, a pill, a capsule, a powder, a liquid, a suspension, a solution, a suppository, or an aerosol. In some embodiments, the compound of Formula I is formulated as a tablet. In some embodiments, the compound of Formula I is formulated as a pill. In some embodiments, the compound of Formula I is formulated as a capsule. In some embodiments, the compound of Formula I is formulated as a powder. In some embodiments, the compound of Formula I is formulated as a liquid. In some embodiments, the compound of Formula I is formulated as a suspension. In some embodiments, the compound of Formula I is formulated as a suppository. In some embodiments, the compound of Formula I is formulated as an aerosol.
In some embodiments, the compound of Formula I is formulated as a solution. In some embodiments, the solution comprises from about 1 to about 50 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 5 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 10 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 15 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 20 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 25 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 30 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 35 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 40 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 45 mg/mL of the compound of Formula I. In some embodiments, the solution comprises about 50 mg/mL of the compound of Formula I.
In some embodiments, the administration of the compound of Formula I results in a decrease in interferon gamma (IFNγ) levels in the subject.
Combination Therapy
In some embodiments, provided is a method for treating cancer in an individual comprising administering to the individual an effective amount of a compound or polymorph detailed herein, or a pharmaceutically acceptable salt thereof, and thymidine. In some embodiments, the compound or polymorph is co-administered with thymidine. In some embodiments, the compound or polymorph is administered before, during or after administration of thymidine. Examples of cancer treated include, but is not limited to leukemia, lymphoma, breast cancer, ovarian cancer, lung cancer, pancreatic cancer, hepatocellular carcinoma, melanoma, sarcoma, head and neck cancer, glioma, glioblastoma, and a cancer independent of tissue of origin that are characterized by genomic instability and/or activation of the DNA damage response. Inhibition of dCK by a compound or polymorph detailed herein, or a pharmaceutically acceptable salt thereof, synergizes with thymidine to induce cell cycle arrest in tumors.
In some embodiments, the compounds and polymorphs described herein are used in combination with one another, with other active drugs known to be useful in treating a disease (e.g. anti-cancer agents) or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent. In some embodiments, the compounds and polymorphs described herein are co-administered with one another or with other active drugs known to be useful in treating a disease.
“Anti-cancer agent” is used in accordance with its plain and ordinary meaning and refers to a composition (e.g. compound, drug, antagonist, inhibitor, modulator) having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. In some embodiments, an anti-cancer agent is a chemotherapeutic. In some embodiments, an anti-cancer agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for treating cancer.
Examples of anti-cancer agents include, but are not limited to, MEK (e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g. XL518, CI-1040, PD035901, selumetinib/AZD6244, GSK1120212/trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin), triazenes (decarbazine)), anti-metabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g. cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g. U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002, Syk inhibitors, mTOR inhibitors, antibodies (e.g., rituxan), gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, PD184352, 20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perilyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin stimalamer, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin (including recombinant interleukin II, or rIL.sub.2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride, agents that arrest cells in the G2-M phases and/or modulate the formation or stability of microtubules, (e.g. Taxol™ (i.e. paclitaxel), Taxotere™, compounds comprising the taxane skeleton, Erbulozole (i.e. R-55104), Dolastatin 10 (i.e. DLS-10 and NSC-376128), Mivobulin isethionate (i.e. as CI-980), Vincristine, NSC-639829, Discodermolide (i.e. as NVP-XX-A-296), ABT-751 (Abbott, i.e. E-7010), Altorhyrtins (e.g. Altorhyrtin A and Altorhyrtin C), Spongistatins (e.g. Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (i.e. LU-103793 and NSC-D-669356), Epothilones (e.g. Epothilone A, Epothilone B, Epothilone C (i.e. desoxyepothilone A or dEpoA), Epothilone D (i.e. KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (i.e. BMS-310705), 21-hydroxyepothilone D (i.e. Desoxyepothilone F and dEpoF), 26-fluoroepothilone, Auristatin PE (i.e. NSC-654663), Soblidotin (i.e. TZT-1027), LS-4559-P (Pharmacia, i.e. LS-4577), LS-4578 (Pharmacia, i.e. LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, i.e. WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, i.e. ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (i.e. LY-355703), AC-7739 (Ajinomoto, i.e. AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, i.e. AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (i.e. NSC-106969), T-138067 (Tularik, i.e. T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, i.e. DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (i.e. BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, i.e. SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, i.e. MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine (i.e. NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, i.e. T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (−)-Phenylahistin (i.e. NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, i.e. D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (i.e. SPA-110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to 111In, 90Y or 131I, etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992, CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethyl erlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, or the like.
When a polymorph of the compound of Formula I is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual subject, as well as the severity of the subject's symptoms.
In one exemplary application, a suitable amount of at least one polymorph of the compound of Formula I is administered to a mammal undergoing treatment for cancer, for example, breast cancer. Administration typically occurs in an amount of between about 0.01 mg/kg of body weight to about 100 mg/kg of body weight per day (administered in single or divided doses), such as at least about 0.1 mg/kg of body weight per day. A particular therapeutic dosage can include, e.g., from about 0.01 mg to about 1000 mg of the polymorph of the compound of Formula I, such as including, e.g., from about 1 mg to about 1000 mg. The quantity of the at least one polymorph of the compound of Formula I in a unit dose of preparation may be varied or adjusted from about 0.1 mg to 1000 mg, such as from about 1 mg to 300 mg, for example 10 mg to 200 mg, according to the particular application. The amount administered will vary depending on the particular IC50 value of the at least one polymorph of the compound of Formula I used and the judgment of the attending clinician taking into consideration factors such as health, weight, and age. In combinational applications in which the at least one polymorph of the compound of Formula I described herein is not the sole active ingredient, it may be possible to administer lesser amounts of the at least one polymorph of the compound of Formula I and still have therapeutic or prophylactic effect.
In some embodiments, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the polymorph of the compound of Formula I, e.g., an effective amount to achieve the desired purpose.
The actual dosage employed may be varied depending upon the requirements of the subject and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the at least one polymorph of the compound of Formula I. Thereafter, the dosage is increased by small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
The amount and frequency of administration of the at least one polymorph of the compound of Formula I, and if applicable other chemotherapeutic agents and/or radiation therapy, will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the subject as well as severity of the disease being treated.
The chemotherapeutic agent and/or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents (i.e., antineoplastic agent or radiation) on the subject, and in view of the observed responses of the disease to the administered therapeutic agents.
Also, in general, the at least one polymorph of the compound of Formula I need not be administered in the same pharmaceutical composition as a chemotherapeutic agent, and may, because of different physical and chemical characteristics, be administered by a different route. For example, the polymorphs/compositions may be administered orally to generate and maintain good blood levels thereof, while the chemotherapeutic agent may be administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.
The particular choice of polymorph (and where appropriate, chemotherapeutic agent and/or radiation) will depend upon the diagnosis of the attending physicians and their judgment of the condition of the subject and the appropriate treatment protocol.
The one or more polymorphs of the compound of Formula I (and where appropriate chemotherapeutic agent and/or radiation) may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the proliferative disease, the condition of the subject, and the actual choice of chemotherapeutic agent and/or radiation to be administered in conjunction (i.e., within a single treatment protocol) with the one or more polymorphs/composition.
In combinational applications and uses, the one or more polymorphs/composition and the chemotherapeutic agent and/or radiation need not be administered simultaneously or essentially simultaneously, and the initial order of administration of the one or more polymorphs/composition, and the chemotherapeutic agent and/or radiation, may not be important. Thus, the at least one polymorph of the compound of Formula I may be administered first followed by the administration of the chemotherapeutic agent and/or radiation; or the chemotherapeutic agent and/or radiation may be administered first followed by the administration of the at least one polymorph of the compound of Formula I. This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the subject. For example, the chemotherapeutic agent and/or radiation may be administered first, and then the treatment continued with the administration of the at least one polymorph of the compound of Formula I followed, where determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol is complete.
Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a polymorph of the compound of Formula I/composition for treatment according to the individual subject's needs, as the treatment proceeds.
The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the subject as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.
Routes of Administration
Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
In certain embodiments, a polymorph of the compound of Formula I is administered in a local rather than systemic manner, for example, via injection of the polymorph directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ-specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, a polymorph of the compound of Formula I is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In yet other embodiments, a polymorph of the compound of Formula I is administered topically.
Kits and Articles of Manufacture
For use in the therapeutic applications described herein, kits and articles of manufacture are also provided. In some embodiments, such kits comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic.
The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include those found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. For example, the container(s) includes one or more polymorphs described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.
For example, a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In addition, a label is used to indicate that the contents are to be used for a specific therapeutic application. In addition, the label indicates directions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack for example contains metal or plastic foil, such as a blister pack. Or, the pack or dispenser device is accompanied by instructions for administration. Or, the pack or dispenser is 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, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In some embodiments, compositions containing a polymorph of the compound of Formula I formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
EXAMPLES Example 1: Preparation of 2-(1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethylthio)pyrimidine-4,6-diamine (6)A mixture of potassium carbonate (4.52 g, 32.7 mmol), 3-hydroxy-4-methoxybenzonitrile (2.44 g, 16.4 mmol) and 4-(2-chloroethyl)morpholine (2.45 g, 16.4 mmol) was heated in a solvent mixture of DMF (40 mL) and acetone (25 mL) to 100° C. for 8 hours. After cooling to room temperature (rt), the reaction mixture was diluted with aq HCl (0.1M, 150 mL) and extracted with CH2Cl2 (3×15 mL). The combined organic layers were removed under reduced pressure and the crude residue purified over silica gel using CH2Cl2:MeOH (40:1) as the eluent. The desired product 1 was obtained in a yield of 85% as a yellow oil. HRMS calcd for C14H18N2O3 263.1390, found 263.1386.
Step 2: Synthesis of 4-methoxy-3-(2-morpholinoethoxy)benzothioamide (2)Compound 1 (2.46 g, 9.4 mmol) was dissolved in pyridine (5 mL, 61.8 mmol) and Et3N (1.44 ml, 10.3 mmol) were added, followed by aq. ammonium sulfide (20%, 12 mL, 35.2 mmol). The reaction mixture is stirred and heated to 60° C. overnight. After cooling to rt, solvents were removed under reduced pressure and mixed with EtOAc (50 mL) and sat. aq. NH4Cl (200 mL). The mixture was extracted with EtOAc (2×20 mL). The combined organic solvents were removed under reduced pressure and the residue dried to give the desired product 2 as a yellow solid in a yield of 79%. HRMS calcd for C14H20N2O3S 297.1267, found 297.1266.
Step 3: Synthesis of 1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethan-1-one (3)To a solution of compound 2 (1.40 g, 4.7 mmol) in EtOH (30 mL) was added 4-bromopentane-2,3-dione (0.84 g, 4.7 mmol). The reaction mixture was heated to 80° C. for 3 hours. After cooling to rt, the solvents were removed under reduced pressure and the residue mixed with CH2Cl2 (20 mL) and water (100 mL). The mixture was extracted with CH2Cl2 (2×10 mL) and the combined organic solvents removed under reduced pressure. The product 3 was obtained as a brown solid without further purification in a yield of 76%. HRMS calcd for C19H24N2O4S 377.1530, found 377.1526.
Step 4: Synthesis of 1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethan-1-ol (4)A solution of 3 (1.35 g, 3.6 mmol) in CH2Cl2 (40 mL) was cooled to −78° C. and DIBAL-H (1M in CH2Cl2, 14.3 mL, 14.3 mmol) was slowly added. The reaction mixture was allowed to warm to rt and stirred for 30 min. The solution was cooled to 0° C. and add sat. aq. potassium sodium tartrate (10 mL) was added and the mixture was stirred for 1 hour. The solution was extracted with CH2Cl2 (3×10 mL) and the combined organic solvents were removed under reduced pressure. The crude residue was purified over silica gel using 5-10% MeOH in CH2Cl2. The pure product 4 was obtained in a yield of 40% as a yellow oil. HRMS calcd for C19H26N2O4S 379.1686, found 379.1684.
Step 5: Synthesis of 1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethyl 2,2,2-trifluoroacetate (5)A solution of compound 4 (47 mg, 0.12 mmol) in CH2Cl2 (5 mL) was cooled to 0° C. and trifluoroacetic anhydride (70 μL, 0.5 mmol) was added dropwise. The reaction mixture was allowed to warm to rt and stirred for 1 hour. The mixture was cooled to 0° C. and ice-cooled water (20 mL) was added. The mixture was extracted with CH2Cl2 (2×5 mL) and the combined organic layers were removed under reduced pressure to give the desired compound 5 in quantitative yields.
Step 6: Synthesis of 2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethyl)thio)pyrimidine-4,6-diamine (6)To a solution of 4,6-diaminopyrimidine-2-thiol (45 mg, 0.31 mmol) in DMF (1.5 mL) was added potassium carbonate (87 mg, 0.63 mmol), followed by 5 (75 mg, 0.16 mmol). The solution was stirred and heated to 80° C. overnight. After cooling to rt, the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×5 mL). The organic layers were combined and solvents removed under reduced pressure. The crude residue was purified over silica gel using 5-10% MeOH in CH2Cl2 to give the desired final compound 6 in a yield of 25%. HRMS calcd for C23H30N6O3S2 503.1894, found 503.1876.
Example 2: Preparation of (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethyl)thio)pyrimidine-4,6-diamine (the compound of Formula I)To a stirred solution of (R)-(+)-2-Methyl-CBS-oxazaborolidine 1.0 M solution in toluene) in THF at −78° C. under Ar was added borane-tetrahydrofuran complex (1.0 M solution in THF) followed by a solution of 3 in THF. After finish adding the 3 solution with syringe pump for 6 h, the reaction mixture was stirred for another 20 min at −78° C. H2O and MeOH were added and the mixture was allowed to warm to room temperature. After concentration to remove residual solvent, the resulting residue was washed with brine and extracted with ethyl acetate. The organic layer was washed with water three times, dried over anhydrous Na2SO4 and concentrated in vacuo, and the crude residue was purified by flash column chromatography over silica gel to yield alcohol 7 as a white solid. HRMS calcd for C19H26N2O4S 379.1686, found 379.1684.
Step 2: Synthesis of (S)-1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethyl 2,2,2-trifluoroacetate (8)A solution of compound 7 (47 mg, 0.12 mmol) in CH2Cl2 (5 mL) was cooled to 0° C. and trifluoroacetic anhydride (70 μL, 0.5 mmol) was added dropwise. The reaction mixture was allowed to warm to rt and stirred for 1 hour. The mixture was cooled to 0° C. and ice-cooled water (20 mL) was added. The mixture was extracted with CH2Cl2 (2×5 mL) and the combined organic layers were removed under reduced pressure to give the desired compound 8 in quantitative yields.
Step 3: Synthesis of (R)-2-(1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethylthio)pyrimidine-4,6-diamine (9R) and (S)-2-(1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethylthio)pyrimidine-4,6-diamine (9S)To a solution of 4,6-diaminopyrimidine-2-thiol (45 mg, 0.31 mmol) in DMF (1.5 mL) was added potassium carbonate (87 mg, 0.63 mmol), followed by 8 (75 mg, 0.16 mmol). The solution was stirred and heated to 80° C. overnight. After cooling to rt, the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×5 mL). The organic layers were combined and solvents removed under reduced pressure. The crude residue was purified over silica gel using 5-10% MeOH in CH2Cl2 to afford the couple of enantiomers 9R and 9S as a white solid. Recrystallization of the enantiomers with MeOH/acetone solvent system gave 9R with 93% ee. HRMS calcd for C23H30N6O3S2 503.1894, found 503.1876.
Example 3: Preparation of Polymorph Form I of the Compound of Formula IMaleic acid (66.05 g, 1.0 equiv) was dissolved with stirring in ethanol (300 mL) at 40° C. In a separate container, (R)-2-(1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethylthio)pyrimidine-4,6-diamine (314.95 g, 1.0 equiv) was dissolved with stirring in ethanol (850 mL) and ethyl acetate (1.15 L) and stirred for 1 hour at 60° C. The maleic acid solution was slowly added and the resulting reaction mixture was stirred for 20 hours at 60° C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5.8 L), and stirred for 30 minutes at room temperature. The reaction mixture was cooled to 0° C., stirred at 0° C. for 3 hours, and filtered. The filter cake was dried at 55° C. for 64 hours to yield polymorph Form I of the compound of Formula I (317.94 g, 82.0% yield, 97.6% purity).
Example 4: Preparation of Polymorph Form II of the Compound of Formula IPolymorph Form I of the compound of Formula I (323.15 g) was dissolved with stirring in 1:1 DCM/methanol (2.4 L) at 45° C. The reaction mixture was cooled to 5° C. over the course of 1 hour and stirred at 5° C. for 16 hours. The reaction mixture was diluted with methyl tert-butyl ether (2.4 L) over 2 hours, stirred at 5° C. for 2 hours, and filtered. The filter cake was washed with methyl tert-butyl ether (700 mL) and dried at 70° C. for 47 hours to yield polymorph Form I of the compound of Formula I (295.41 g, 98.4% purity).
Example 5: X-Ray Powder Diffraction (XRPD)X-ray powder diffraction (XRPD) patterns were obtained on a Rigaku Miniflex. A CuK source (=1.54056 angstrom) operating minimally at 40 kV and 15 mA scans each sample between 3 and 45 degrees 2-θ. The step size is 0.02 degrees 2-theta and the scan speed is 2.5 degrees per minute.
The XRPD pattern obtained for polymorph Form I of the compound of Formula I is summarized in Table 1 and
The XRPD pattern obtained for polymorph Form II of the compound of Formula I is summarized in Table 2 and
Thermogravimetric analysis was carried out on a TA Instruments Q5000 thermogravimetric analyzer. Samples were heated in aluminum pans from ambient to 250° C. at 15° C./min with a nitrogen purge of 60 mL/min. The TGA thermogram obtained for polymorph Form I of the compound of Formula I is summarized in
Differential scanning calorimetry analysis was carried out on a TA Instruments Discovery thermogravimetric analyzer. Samples were heated in sealed aluminum pans from ambient to 250° C. at 10° C./min. The DSC thermogram obtained for polymorph Form I of the compound of Formula I is summarized in
High-performance liquid chromatography (HPLC) was performed using the following instrument and/or conditions.
The results of polymorph Form II in accelerated stability tests are shown in Table 3.
Adult female C57BL/6J mice were randomly allocated to experimental groups and allowed to acclimatize for one week prior to commencing the study. On Day 0 and Day 7, animals were administered an emulsion (200 μL/mouse) of MOG35-55 and complete Freund's adjuvant (CFA). MOG35-55 (300 μg/mouse) was purchased as powder and reconstituted with NaCl (0.9%) at an initial concentration of 3 mg/mL. After reconstitution, the MOG35-55 solution was mixed with an equivalent volume of CFA prepared by reconstituting Mycobacterium Tuberculosis H37Ra in Incomplete Freund's adjuvant at an initial concentration of 5 mg/mL in order to obtain a final concentration of 2.5 mg/mL. Injections were performed under gas (isoflurane) anesthesia in the two lower quadrants of the back on Day 0 (100 μL in each flank) and the two upper quadrants of the back on Day 7 (100 μL in each flank). On Day 0 (immediately post-MOG injection) and Day 2, animals were administered with pertussis toxin (PTx, 500 ng/mouse) prepared in phosphate buffered saline (PBS, 100 μL/mouse) by intraperitoneal injection.
Treatments were administered according to the administration schedule shown in Table 4.
Treatment was performed twice daily (BID) prophylactically starting on Day 1 for groups 1, 2, and 4, and therapeutically starting on day 8 for group 3. All experimental groups were n=12. The administration interval was 12 hours and the administration volume was 5 mL/kg.
Because body weight loss is known to be an important hallmark of EAE occurring in correspondence of the appearance of the first symptoms, animals were weighed daily from the day of immunization (Day 0) until the end of the experiment. The changes in body weight observed over the course of the experiment for the different experimental groups, presented as mean±SEM, are summarized in
Next, in order to assess the overall effect of the pharmacological treatment, analysis of the area under the curve (AUC) was performed. The area under the curve values of the percentage of bodyweight changes in comparison to baseline for the different experimental groups, presented as mean±SEM, are summarized in
From Day 0 until the end of the experiment, animals were scored daily for clinical signs of EAE to include paresis and paralysis affecting the tail and the limbs. The following scale was used:
-
- (0) no abnormality, the animal moves and behaves normally;
- (1) limp tail, the tail hangs limp when the mouse is held at the base of the tail;
- (2) partial hind limb paralysis, spastic paresis or paralysis affects one hind limb;
- (3) total hind limb paralysis, spastic paresis or paralysis affects both hind limbs;
- (4) front and hind limb paralysis, spastic paresis or paralysis affects one or both front limbs;
- (5) moribund.
The changes in EAE score observed over the course of the experiment for the different experimental groups, presented as mean±SEM, are summarized in
Next, in order to assess the overall effect of the pharmacological treatment, analysis of the AUC was performed. The area under the curve values of the EAE clinical scores for the different experimental groups, presented as mean±SEM, are summarized in
The overall effect of the treatment was analyzed by calculating a mean cumulative score obtained for every animal in every experimental group summing up the disease scores from the day in which the first symptom appeared until Day 25 and dividing this value by the number of days in which the animal displayed clinical scores. The cumulative disease scores for the different experimental groups, presented as mean±standard error of the mean (SEM), are summarized in
An additional parameter considered for EAE analysis is plotting and analyzing “extended data”. While the graph shown in
In a similar scenario to the one described above for
Next, in order to assess the overall effect of the pharmacological treatment, analysis of the AUC was performed on the extended disease score. The area under the curve values of the extended disease scores for the different experimental groups, presented as mean±SEM, are summarized in
Analysis of the incidence in the vehicle-treated group and in the groups treated therapeutically and prophylactically with Compound 1, considered as the percentage of symptoms free animals at any of the analyzed time points, revealed that a higher percentage of animals did not show disease symptoms in the group which received Compound 1 therapeutically in comparison to the respective vehicle-treated group at any of the analyzed time points (
At termination, spleens were removed and weighed. The spleen weights observed for the different experimental groups, presented as mean±SEM, are summarized in
Analysis of plasma cytokine levels using Luminex showed low levels of all cytokines measured (IFN-γ, IL-6, IL-10, IL-17a, and TNF-α), with most samples reporting values close to or below the functional Lower Limit Of Quantification (LLOQ) for each cytokine assay (
The IFN-γ levels observed for the different experimental groups, presented as mean±SEM, are summarized in
The Interleukin 6 (IL-6) levels observed for the different experimental groups, presented as mean±SEM, are summarized in
The Interleukin 10 (IL-10) levels observed for the different experimental groups, presented as mean±SEM, are summarized in
The Interleukin 17a (IL-17a) levels observed for the different experimental groups, presented as mean±SEM, are summarized in
The tumor necrosis factor α (TNF-α) levels observed for the different experimental groups, presented as mean±SEM, are summarized in
In the present study, all animals developed signs of EAE 7 days after disease induction by immunization with MOG35-55. The efficacy of Compound 1 was tested in the model by using a prophylactic approach (group 2, treatments started on day 1) and a therapeutic approach (group 3, treatment initiated on day 8). The prophylactic treatment with Compound 1 did not prevent or improve the clinical EAE profile when the effects were analyzed over time or when the overall effect was investigated using AUC analysis. On the contrary, the therapeutic administration of Compound 1 statistically significantly ameliorated the disease profile at earlier time points (day 13 and 14) and again at later stages (days 22-25) which are normally associated with a more neurodegenerative mechanism. Compound 1 therapeutic treatment also showed a trend towards a reduced AUC value as compared to the vehicle AUC. As expected, treatment with the positive control dexamethasone statistically significantly reduced the EAE scores (days 8-25) as well as the clinical profile compared to vehicle, as assessed by AUC. This corticosteroid was used as a positive control based on validation data for this model and on several independent studies showing the efficacy of dexamethasone treatments in EAE. Notably, the animals treated with Compound 1 in a therapeutic manner showed a significant remission of the symptoms, and ˜27% of the animals remised to zero. Whilst plasma cytokine levels did not show any significant differences between the vehicle and treatment groups, there was a general trend towards decreasing levels in the treatment groups for some cytokines such as IFN-γ, IL-17a, and TNF-α.
Example 11: Efficacy of Various Doses of Compound 1 in a Mouse Model of Myelin Oligodendrocyte Glycoprotein (MOG)-Induced Experimental Autoimmune Encephalomyelitis (EAE)60 female C57BL/6 mice were housed for an acclimation period of 1 week. 53 mice were enrolled in the study after randomization with a body weight between 18.3-22.3 g with an average body weight of 19.7 g per group on Study day minus 1.
For induction of MOG-EAE, MOG35-55 peptide was administered in phosphate buffered saline (PBS) and complete Freund's adjuvant (CFA). MOG35-55 peptide in PBS was emulsified in a 1:1 (v:v) mixture with CFA via homogenization in an Omni BeadRuptor Elite using 7 mL tubes pre-filled with 2.8 mm ceramic beads. Briefly, MOG35-55 peptide was brought up to 1 mg/mL in cold PBS, and 1.75 mL aliquoted into each homogenization tube. An equal volume (1.75 mL) CFA was then added for a total volume of 3.5 mL, on ice. Two rounds of homogenization were performed using a speed of 3.5 m/s; 3 cycles of 45 seconds with 30 seconds dwell at 4° C., followed by a third round with 2 cycles of 45 seconds and 30 seconds dwell at 4° C. In between each round, samples were placed on ice for ˜15 minutes. Tubes were spun down at 300 g for 1 minute at 4° C. Mice were anesthetized under isoflurane anesthesia. 100 μL (50 μg MOG35-55) was then injected subcutaneously into the flank of each leg (for a total of two injections and 100 μg MOG35-55). On Study Day 0 and Day 2, pertussis toxin was formulated at a concentration of 2 ng/4 in PBS, and 100 μL (200 ng) injected into each animal by intraperitoneal injection.
Treatments were administered according to the administration schedule shown in Table 5.
Treatment was performed BID starting on Day 1 for groups 2, 3, and 4, and once daily (QD) starting on day 1 for group 5. All experimental groups were n=12. The administration interval was 12 hours and the administration volume was 5 mL/kg.
Body weight measurements were taken daily for all animals except for study days 5, 6, 8, 9, 11 and 27 when the body weights were not recorded by mistake in the control group (naïve mice). The changes in body weight observed over the course of the experiment for the different experimental groups, presented as mean±SD, are summarized in
The Body condition score of all animals was monitored on study Days 0, 7, 10 and then every other day. Body condition scoring was conducted according to the scale shown in
Disease severity was scored on Day 0, 7 and every 2 days beginning on Day 10 onward for all groups. The following scale was used:
-
- (0) normal;
- (1) loss of tail tone;
- (2) loss of tail tone and hind limb weakness;
- (3) severe weakness in both limbs/single limb, paralysis;
- (4) paralysis of 2 or more limbs;
- (5) death.
The mean disease scores observed over the course of the experiment for the different experimental groups, presented as mean±SD, are summarized in
Disease incidence rate was calculated as percentage of total animals per group starting from day 0 until termination on study day 28. The percentages of disease-free mice observed over the course of the experiment for the different experimental groups are summarized in
The spleen weights of all mice and all groups were determined on study Day 28 during necropsy. The spleen weights observed for the different experimental groups, presented as mean±SEM, are summarized in
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
Claims
1-96. (canceled)
97. A method of treating an autoimmune disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula I:
- or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is administered once daily.
98. The method of claim 97, wherein the disease or disorder is multiple sclerosis.
99. The method of claim 97, wherein the disease or disorder is optic neuritis.
100. The method of claim 97, wherein the disease or disorder is acute disseminated encephalomyelitis (ADEM).
101-113. (canceled)
114. The method of claim 97, wherein the compound of Formula I is formulated for oral administration.
115. The method of claim 97, wherein the compound of Formula I is formulated as a tablet, a pill, a capsule, a powder, a liquid, a suspension, a solution, a suppository, or an aerosol.
116. The method of claim 97, wherein the compound of Formula I is formulated as a solution.
117-120. (canceled)
121. The method of claim 97, wherein the administration of the compound of Formula I results in a decrease in interferon gamma (IFNγ) levels in the subject.
122. The method of claim 121, wherein the decrease in IFNγ levels determined in a fluid sample of the subject.
123. The method of claim 122, wherein the fluid comprises plasma.
124. The method of claim 97, wherein the administration of the compound of Formula I results in a decrease in the severity of the disease or disorder, relative to a control.
125. The method of claim 124, wherein the severity of the disease or disorder is assessed by a numerical scoring system.
126. The method of claim 97, wherein the administration of the compound of Formula I results in a decrease in limb weakness in the subject, relative to a control.
127. The method of claim 97, wherein the administration of the compound of Formula I results in a decreased risk of paralysis in the subject, relative to a control subject.
128. The method of claim 97, wherein the administration of the compound of Formula I prevents or decreases a reduction in body weight in subject.
129. The method of claim 97, wherein the administration of the compound of Formula I prevents or decreases a reduction in an organ weight in subject.
130. The method of claim 129, wherein the organ comprises bone, muscle, or spleen.
131. The method of claim 97, wherein the compound of Formula I is formulated as a tablet, a pill, a capsule, or a powder.
132. The method of claim 131, wherein the tablet, pill, capsule, or powder is administered orally to the subject.
133. The method of claim 97, wherein the subject is a mammal.
Type: Application
Filed: Nov 1, 2021
Publication Date: May 5, 2022
Inventors: David LITZINGER (Poway, CA), Kenneth A. SCHULTZ (Sherman Oaks, CA)
Application Number: 17/516,420
