WO2015184305A1 - TREATMENT OF CHRONIC NEUTROPHILIC LEUKEMIA (CNL) AND ATYPICAL CHRONIC MYELOID LEUKEMIA (aCML) BY INHIBITORS OF JAK1 - Google Patents
TREATMENT OF CHRONIC NEUTROPHILIC LEUKEMIA (CNL) AND ATYPICAL CHRONIC MYELOID LEUKEMIA (aCML) BY INHIBITORS OF JAK1 Download PDFInfo
- Publication number
- WO2015184305A1 WO2015184305A1 PCT/US2015/033254 US2015033254W WO2015184305A1 WO 2015184305 A1 WO2015184305 A1 WO 2015184305A1 US 2015033254 W US2015033254 W US 2015033254W WO 2015184305 A1 WO2015184305 A1 WO 2015184305A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyrimidin
- pyrrolo
- pyrazol
- acetonitrile
- trifluoromethyl
- Prior art date
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- 201000010903 chronic neutrophilic leukemia Diseases 0.000 title claims abstract description 28
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Definitions
- This invention relates to JAK selective inhibitors for use in treatment of chronic neutrophilic leukemia and atypical chronic myeloid leukemia in patients.
- Chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are hematologic neoplasms characterized by leukocytosis and hypercellular bone marrow comprised predominantly of granulocytic cells, absence of the Philadelphia chromosome (t(9;22); BCR-ABL1), and absence of platelet-derived growth factor receptor A/B (PDGFRA/B) or fibroblast growth factor receptor 1 (FGFR1) gene rearrangements.
- CNL is diagnosed based on expansion of neutrophils in both the blood and bone marrow (segmented neutrophils and band forms > 80% of white blood cells (WBC)) and is classified as a myeloproliferative neoplasm (MPN) according to World Health Organization (WHO) diagnostic criteria.
- WBC white blood cells
- the present application provides, inter alia, methods of treating a leukemia selected from chronic neutrophilic leukemia and atypical chronic myeloid leukemia in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a selective JAK1 inhibitor.
- Selective JA inhibitors include those described infra.
- the present application further provides a JAK selective inhibitor for use in treatment of a leukemia selected from chronic neutrophilic leukemia and atypical chronic myeloid leukemia in a patient in need thereof.
- the present application also provides use of a JAK selective inhibitor for manufacture of a medicament for treatment of a leukemia selected from chronic neutrophilic leukemia and atypical chronic myeloid leukemia in a patient in need thereof.
- CSF3R colony-stimulating factor 3
- SRC family-TNK2 or JAK kinases SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors.
- the specific mutation, CSF3RT618I was shown to occur exclusively in WHO-defined CNL with a mutational frequency of 83% (10 of 12 cases) (Pardanani et al, Leukemia 2013, 27: 1870). Marked clinical improvement has also been shown in one patient with CNL carrying a JAK-activating CSF3R mutation after the administration of ruxolitinib.
- the present application provides a method of treating a leukemia selected from chronic neutrophilic leukemia and atypical chronic myeloid leukemia in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a selective JAKl inhibitor.
- the leukemia is atypical chronic myeloid leukemia.
- the leukemia is chronic neutrophilic leukemia.
- the chronic neutrophilic leukemia expresses a mutation in the gene encoding the receptor for colony-stimulating factor 3 (CSF3R).
- the mutation is a CSF3R membrane proximal mutation.
- the mutation is CSF3R T618I.
- the mutation is CSF3R T615A.
- a "selective JAKl inhibitor” is an inhibitor of JAKl which is selective for JAKl over JAK2, JAK3 and TYK2.
- the compounds or salts are about 10-fold more selective for JAKl over JAK2.
- the compounds or salts are about 10-fold, about 15-fold, or about 20-fold more selective for JAKl over JAK2 as calculated by measuring ICso at 1 mM ATP (e.g., see Example A).
- the selective JAKl inhibitor is a compound of Table 1, or a pharmaceutically acceptable salt thereof.
- the compounds in Table 1 are selective JAKl inhibitors (selective over JAK2, JAK3, and TYK2).
- the ICsos obtained by the method of Assay A at 1 mM ATP are shown in Table 1.
- +++ means ⁇ 300 nM (see Example A for assay conditions)
- the selective JAKl inhibitor is ⁇ l- ⁇ l-[3-fluoro-2- (trifluoromethyl)isonicotinoyl]piperidin-4-yl ⁇ -3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- lH-pyrazol-l-yl]azetidin-3-yl ⁇ acetonitrile, or a pharmaceutically acceptable salt thereof.
- the selective JAK1 inhibitor is ⁇ l- ⁇ l-[3-fluoro-2- (trifluoromethyl)isonicotinoyl]piperidin-4-yl ⁇ -3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- lH-pyrazol-l-yl]azetidin-3-yl ⁇ acetonitrile adipic acid salt.
- the selective JAK1 inhibitor is 4- ⁇ 3-(cyanomethyl)-3-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]azetidin-l-yl ⁇ -2,5-difluoro-N-[(lS)- 2,2,2-trifluoro-l-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.
- the selective JAK1 inhibitor is selected from (R)-3-[l-(6- chloropyridin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol- l-yl]propanenitrile, (R)-3-(l-[l,3]oxazolo[5,4-b]pyridin-2-ylpyrrolidin-3-yl)-3-[4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile, (R)-4-[(4- ⁇ 3-cyano-2-[4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propyl ⁇ piperazin-l-yl)carbonyl]-3- fluorobenzonitrile,
- the compounds of Table 1 are prepared by the synthetic procedures described in US Patent Publ. No. 2010/0298334, filed May 21, 2010, US Patent Publ. No. 2011/0059951, filed August 31 , 2010, US Patent Publ. No.
- the selective JAK1 inhibitor is selected from the compounds of US Patent Publ. No. 2010/0298334, filed May 21, 2010, US Patent Publ. No. 2011/0059951, filed August 31 , 2010, US Patent Publ. No. 2011/0224190, filed March 9, 2011, US Patent Publ. No. 2012/0149681, filed November 18, 2011, US Patent Publ. No. 2012/0149682, filed November 18, 2011, US Patent Publ. 2013/0018034, filed June 19, 2012, US Patent Publ. No. 2013/0045963, filed August 17, 2012, and US Patent Publ. No. 2014/0005166, filed May 17, 2013, each of which is incorporated herein by reference in its entirety.
- the leukemia is chronic neutrophilic leukemia and the JAK1 selective inhibitor is ((2R,5S)-5- ⁇ 2-[(lR)-l-hydroxyethyl]-lH-imidazo[4,5- d]thieno[3,2-b]pyridin-l-yl ⁇ tetrahydro-2H-pyran-2-yl)acetonitrile, or a pharmaceutically acceptable salt thereof.
- the leukemia is chronic neutrophilic leukemia and the JAK1 selective inhibitor is 4-[3-(cyanomethyl)-3-(3',5'-dimethyl-lH,rH-4,4'-bipyrazol- 1 -yl)azetidin- 1 -yl]-2,5-difluoro-N-[( 1 S)-2,2,2-trifluoro- 1 -methylethyljbenzamide, or a pharmaceutically acceptable salt thereof.
- said JAK1 selective inhibitor is administered to said patient at a dosage of from 200 mg to 800 mg, or 300 mg to 600 mg per day. In some embodiments, said JAK1 selective inhibitor is administered to said patient at a dosage of from 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg per day.
- the leukemia is chronic neutrophilic leukemia and the JAK1 selective inhibitor is ⁇ l- ⁇ l-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4- yl ⁇ -3-[4-(7H-pyirolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]azetidin-3-yl ⁇ acetonitrile, or a pharmaceutically acceptable salt thereof.
- said JAK1 selective inhibitor is administered to said patient at a dosage of from 200 mg to 800 mg, or 300 mg to 600 mg per day.
- said JAK1 selective inhibitor is administered to said patient at a dosage of from 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg per day. In some embodiments, said JAK1 selective inhibitor is administered to said patient at a dosage of from 200 mg to 800 mg QD. In some embodiments, said JAK1 selective inhibitor is administered to said patient at a dosage of from 300 mg to 600 mg QD. In some embodiments, said JAK1 selective inhibitor is administered to said patient at a dosage of 300 mg QD. In some embodiments, said JAK1 selective inhibitor is administered to said patient at a dosage of 400 mg QD. In some embodiments, said JAK1 selective inhibitor is administered to said patient at a dosage of 600 mg QD.
- said JAK1 selective inhibitor is administered to said patient in a sustained release dosage form.
- sustained release dosage forms include, but are not limited those of US Prov. Appl. No. 61/913,066, filed December 6, 2013, which is incorporated herein by reference in its entirety.
- the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
- the compound has the ( ⁇ -configuration. In some embodiments, the compound has the ( ⁇ -configuration.
- Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art.
- An example method includes fractional
- Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
- optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
- resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a- methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2- phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2- diaminocyclohexane, and the like.
- Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
- an optically active resolving agent e.g., dinitrobenzoylphenylglycine
- Suitable elution solvent composition can be determined by one skilled in the art.
- Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
- Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
- Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H- imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H- pyrazole.
- Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
- Isotopes include those atoms having the same atomic number but different mass numbers.
- isotopes of hydrogen include tritium and deuterium.
- compound as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.
- All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g. hydrates and solvates) or can be isolated.
- the compounds described herein, or salts thereof are substantially isolated.
- substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
- Partial separation can include, for example, a composition enriched in the compounds described herein.
- Substantial separation can include compositions containing at least about 50%, at least about 60%>, at least about 70%>, at least about 80%>, at least about 90%), at least about 95%, at least about 97%, or at least about 99% by weight of the compounds described herein, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
- phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- ambient temperature and “room temperature” or “rt” as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.
- the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
- pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
- examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
- the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from nontoxic inorganic or organic acids.
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
- such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
- non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
- non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
- ACN acetonitrile
- the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
- the inhibitors are administered in a therapeutically effective amount.
- therapeutically effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
- the dosage of the compound, or a pharmaceutically acceptable salt thereof, administered to a patient or individual is about 1 mg to about 2 g, about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to 50 mg, or about 50 mg to about 500 mg.
- treating refers to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
- the methods described herein can further comprise administering one or more additional therapeutic agents.
- the one or more additional therapeutic agents can be administered to a patient simultaneously or sequentially.
- the selective JAKl inhibitor is administered in
- JAKl and/or JAK2 e.g., either
- the inhibitor of JAKl and/or JAK2 is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l- yljpropanenitrile.
- the inhibitor of JAKl and/or JAK2 is (3R)-3- cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile (ruxolitinib; also known as INCBO 18424).
- Ruxolitinib has an ICso of less than 10 nM at 1 mM ATP (assay A) at JAKl and JAK2.
- 3-Cyclopentyl-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl]propanenitrile and ruxolitinib can be made by the procedure described in US 7,598,257 (Example 67), filed December 12, 2006, which is incorporated herein by reference in its entirety.
- the inhibitor of JAKl and/or JAK2 is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH- pyrazol-l-yl]propanenitrile phosphoric acid salt.
- the method further comprises administering an additional therapeutic agent selected from IMiDs, an anti-IL-6 agent, an anti-TNF-a agent, a hypomethylating agent, and a biologic response modifier (BRM).
- an additional therapeutic agent selected from IMiDs, an anti-IL-6 agent, an anti-TNF-a agent, a hypomethylating agent, and a biologic response modifier (BRM).
- a BRM is a substances made from living organisms to treat disease, which may occur naturally in the body or may be made in the laboratory.
- BRMs include IL-2, interferon, various types of colony-stimulating factors (CSF, GM- CSF, G-CSF), monoclonal antibodies such as abciximab, etanercept, infliximab, rituximab, trasturzumab, and high dose ascorbate.
- the anti-TNF-a agent is infliximab, and etanercept.
- the hypomethylating agent is a DNA methyltransferase inhibitor.
- the DNA methyltransferase inhibitor is selected from 5 azacytidine and decitabine.
- IMiDs are as immunomodulatory agents.
- the IMiD is selected from thalidomide, lenalidomide, pomalidomide, CC-11006, and CC- 10015.
- the method further comprises administering an additional therapeutic agent selected from anti-thymocyte globulin, recombinant human granulocyte colony-stimulating factor (G CSF), granulocyte-monocyte CSF (GM-CSF), a
- ESA erythropoiesis-stimulating agent
- the method further comprises administering an additional JAK inhibitor to the patient.
- the additional JAK inhibitor is tofacitinib or ruxolitinib.
- One or more additional pharmaceutical agents such as, for example,
- chemotherapeutics anti-inflammatory agents, steroids, immunosuppressants, as well as ⁇ , mTor, Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors such as, for example, those described in WO 2006/056399, which is incorporated herein by reference in its entirety, or other agents can be used in combination with the compounds described herein for treatment of the leukemias described herein.
- Example chemotherapeutics include proteosome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.
- proteosome inhibitors e.g., bortezomib
- thalidomide thalidomide
- revlimid thalidomide
- DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.
- Example steroids include coriticosteroids such as dexamethasone or prednisone.
- Example Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in U.S. Pat. No. 5,521 , 184, WO 04/005281 , and U.S. Ser. No. 60/578,491 , all of which are incorporated herein by reference in their entirety.
- Example suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 03/037347, WO 03/099771 , and WO 04/046120, all of which are incorporated herein by reference in their entirety.
- Example suitable RAF inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO 05/028444, both of which are incorporated herein by reference in their entirety.
- Example suitable FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 04/080980, WO 04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 01/014402, all of which are incorporated herein by reference in their entirety.
- one or more of the compounds of the invention can be used in combination with one or more other kinase inhibitors including imatinib, particularly for treating patients resistant to imatinib or other kinase inhibitors.
- a suitable chemotherapeutical agent can be selected from antimetabolite agents, topoisomerase 1 inhibitors, platinum analogs, taxanes,
- anthracyclines and EGFR inhibitors, and combinations thereof.
- antimetabolite agents include capecitabine, gemcitabine, and fluorouracil (5-FU).
- taxanes include paclitaxel, Abraxane® (paclitaxel protein- bound particles for injectable suspension), and Taxotere® (docetaxel).
- platinum analogs include oxaliplatin, cisplatin, and carboplatin.
- topoisomerase 1 inhibitors include irinotecan and topotecan.
- anthracyclines include doxorubicin or liposomal formulations of doxorubicin.
- the chemotherapeutic is FOLFIRINOX (5-FU, lecovorin, irinotecan and oxaliplatin).
- the chemotherapeutic agent is gemcitabine and Abraxane® (paclitaxel protein-bound particles for injectable suspension).
- one or more selective JAK1 inhibitors can be used in combination with a chemotherapeutic in the treatment of cancer, such as multiple myeloma, and may improve the treatment response as compared to the response to the chemotherapeutic agent alone, without exacerbation of its toxic effects.
- additional pharmaceutical agents can include, without limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib).
- Further additional agents include Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. Additive or synergistic effects are desirable outcomes of combining selective JAK1 inhibitors with an additional agent.
- the agents can be combined with the present compounds in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
- a corticosteroid such as dexamethasone is administered to a patient in combination with at least one selective JAK1 inhibitor where the
- dexamethasone is administered intermittently as opposed to continuously.
- combinations of one or more selective JAK1 inhibitors with other therapeutic agents can be administered to a patient prior to, during, and/or after a bone marrow transplant or stem cell transplant.
- the additional therapeutic agent is fluocinolone acetonide (Retisert®), or rimexolone (AL-2178, Vexol, Alcon).
- the additional therapeutic agent is cyclosporine
- the additional therapeutic agent is a corticosteroid.
- the corticosteroid is triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone.
- the additional therapeutic agent is selected from:
- Resolvyx DYN15 (Dyanmis Therapeutics), rivoglitazone (DEOl l, Daiichi Sanko), TB4 (RegeneRx), OPH-01 (Ophtalmis Monaco), PCS 101 (Pericor Science), REV 1-31 (Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551 (Othera), PAI-2 (University of Pennsylvania and Temple University), pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednol etabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611 (Kissei Pharmaceuticals),
- dehydroepiandrosterone anakinra, efalizumab, mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267 (TorreyPines Therapeutics), actemra, gemcitabine, oxaliplatin, L-asparaginase, or thalidomide.
- the additional therapeutic agent is an anti-angiogenic agent, cholinergic agonist, TRP-1 receptor modulator, a calcium channel blocker, a mucin secretagogue, MUC 1 stimulant, a calcineurin inhibitor, a corticosteroid, a P2Y2 receptor agonist, a muscarinic receptor agonist, an mTOR inhibitor, another JAK inhibitor, Bcr-Abl kinase inhibitor, Flt-3 kinase inhibitor, RAF kinase inhibitor, and FAK kinase inhibitor such as, for example, those described in WO 2006/056399, which is incorporated herein by reference in its entirety.
- the additional therapeutic agent is a tetracycline derivative (e.g., minocycline or doxycline).
- the additional therapeutic agent binds to FKBP12.
- the additional therapeutic agent is an alkylating agent or DNA cross-linking agent; an anti-metabolite/demethylating agent (e.g., 5-flurouracil, capecitabine or azacitidine); an anti-hormone therapy (e.g., hormone receptor antagonists, SERMs, or aromotase inhibitor); a mitotic inhibitor (e.g. vincristine or paclitaxel); an topoisomerase (I or II) inhibitor (e.g. mitoxantrone and irinotecan); an apoptotic inducers (e.g. ABT-737); a nucleic acid therapy (e.g.
- an anti-metabolite/demethylating agent e.g., 5-flurouracil, capecitabine or azacitidine
- an anti-hormone therapy e.g., hormone receptor antagonists, SERMs, or aromotase inhibitor
- a mitotic inhibitor e.g. vincristine or paclitaxel
- RNAi nuclear receptor ligands
- nuclear receptor ligands e.g., agonists and/or antagonists: all-trans retinoic acid or bexarotene
- epigenetic targeting agents such as histone deacetylase inhibitors (e.g. vorinostat), hypomethylating agents (e.g. decitabine); regulators of protein stability such as Hsp90 inhibitors, ubiquitin and/or ubiquitin like conjugating or deconjugating molecules; or an EGFR inhibitor (erlotinib).
- the additional therapeutic agent(s) are demulcent eye drops
- artificial tears include, but are not limited to, compositions containing polyvinylalcohol, hydroxypropyl methylcellulose, glycerin, polyethylene glycol (e.g. PEG400), or carboxymethyl cellulose.
- Artificial tears can help in the treatment of dry eye by compensating for reduced moistening and lubricating capacity of the tear film.
- the additional therapeutic agent is a mucolytic drug, such as N-acetyl-cysteine, which can interact with the mucoproteins and, therefore, to decrease the viscosity of the tear film.
- the additional therapeutic agent includes an antibiotic, antiviral, antifungal, anesthetic, anti-inflammatory agents including steroidal and non- steroidal anti-inflammatories, and anti-allergic agents.
- suitable medicaments include aminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin, netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naphthyridine;
- rifampins sulfonamides
- polymyxin chloramphenicol; neomycin; paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines; rifampin and its derivatives ("rifampins");
- cycloserine beta-lactams; cephalosporins; amphotericins; fluconazole; flucytosine; natamycin; miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen;
- ketorolac ketorolac
- suprofen cromolyn
- lodoxamide levocabastin
- naphazoline antazoline
- pheniramine or azalide antibiotic.
- the selective JAK1 inhibitors can be administered in the form of pharmaceutical compositions.
- These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary ⁇ e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.
- Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
- Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
- formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
- Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
- compositions which contain, as the active ingredient, the selective JAK1 inhibitor in combination with one or more pharmaceutically acceptable carriers (excipients).
- the selective JAK1 inhibitor in combination with one or more pharmaceutically acceptable carriers (excipients).
- composition is suitable for topical administration.
- the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
- the excipient serves as a diluent, it can be a solid, semisolid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
- compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
- the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
- the selective JAK1 inhibitors may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.
- Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art, e.g., see International App. No. WO 2002/000196.
- excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
- the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
- the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
- the pharmaceutical composition comprises silicified microcrystallme cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof.
- SMCC silicified microcrystallme cellulose
- microcrystallme cellulose comprises about 98% microcrystallme cellulose and about 2% silicon dioxide w/w.
- the composition is a sustained release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
- the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one component selected from microcrystallme cellulose, lactose monohydrate, hydroxypropyl methylcellulose, and polyethylene oxide.
- the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystallme cellulose, lactose monohydrate, and hydroxypropyl methylcellulose.
- the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystallme cellulose, lactose monohydrate, and polyethylene oxide.
- the composition further comprises magnesium stearate or silicon dioxide.
- the microcrystallme cellulose is Avicel PHI 02TM.
- the lactose monohydrate is Fast-flo 316TM.
- the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M PremierTM) and/or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LVTM).
- the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105TM).
- a wet granulation process is used to produce the composition.
- a dry granulation process is used to produce the composition.
- compositions can be formulated in a unit dosage form, each dosage containing from about 1 to about 1,000 mg, from about 1 mg to about 100 mg, from 1 mg to about 50 mg, and from about 1 mg to 10 mg of active ingredient.
- the dosage is from about 1 mg to about 50 mg or about 1 mg to about 10 mg of active ingredient.
- each dosage contains about 10 mg of the active ingredient.
- each dosage contains about 50 mg of the active ingredient.
- each dosage contains about 25 mg of the active ingredient.
- unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
- the compositions comprise from about 1 to about 1,000 mg, from about 1 mg to about 100 mg, from 1 mg to about 50 mg, and from about 1 mg to 10 mg of active ingredient.
- the compositions comprise from about 1 mg to about 50 mg or about 1 mg to about 10 mg of active ingredient.
- this embodies compounds or compositions containing about 1 mg to about 10 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 50 mg of the active ingredient.
- the active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
- the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a selective JAKl inhibitor.
- a solid preformulation composition containing a homogeneous mixture of a selective JAKl inhibitor.
- the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the present invention.
- the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
- liquid forms in which the compounds and compositions can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
- compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
- the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
- the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
- compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
- Topical formulations can contain one or more conventional carriers.
- ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and the like.
- Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g.
- topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1 , at least about 2, or at least about 5 wt % of the compound of the invention.
- the topical formulations can be suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.
- compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
- compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
- the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
- the therapeutic dosage of a selective JAK1 inhibitor can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
- the proportion or concentration of a selective JA 1 inhibitors in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
- the compounds can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
- the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
- the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose- response curves derived from in vitro or animal model test systems.
- compositions of the invention can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
- additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
- the compound, or pharmaceutically acceptable salt thereof is administered as an ophthalmic composition.
- the methods comprise administration of the compound, or pharmaceutically acceptable salt thereof, and an ophthalmically acceptable carrier.
- the ophthalmic composition is a liquid composition, semi-solid composition, insert, film, microparticles or nanoparticles.
- the ophthalmic composition is a liquid composition. In some embodiments, the ophthalmic composition is a semi-solid composition. In some embodiments, the ophthalmic composition is a topical composition.
- the topical compositions include, but are not limited to liquid and semi-solid compositions. In some embodiments, the ophthalmic composition is a topical composition.
- the topical composition comprises aqueous solution, an aqueous suspension, an ointment or a gel.
- the ophthalmic composition is topically applied to the front of the eye, under the upper eyelid, on the lower eyelid and in the cul-de-sac.
- the ophthalmic composition is sterilized. The sterilization can be accomplished by known techniques like sterilizing filtration of the solution or by heating of the solution in the ampoule ready for use.
- the ophthalmic compositions of the invention can further contain pharmaceutical excipients suitable for the preparation of ophthalmic formulations. Examples of such excipients are preserving agents, buffering agents, chelating agents, antioxidant agents and salts for regulating the osmotic pressure.
- the term "ophthalmically acceptable carrier” refers to any material that can contain and release the compound, or pharmaceutically acceptable salt thereof, and that is compatible with the eye.
- the ophthalmically acceptable carrier is water or an aqueous solution or suspension, but also includes oils such as those used to make ointments and polymer matrices such as used in ocular inserts.
- the composition may be an aqueous suspension comprising the compound, or pharmaceutically acceptable salt thereof.
- Liquid ophthalmic compositions, including both ointments and suspensions may have a viscosity that is suited for the selected route of administration. In some embodiments, the ophthalmic composition has a viscosity in the range of from about 1,000 to about 30,000 centipoise.
- the ophthalmic compositions may further comprise one or more of surfactants, adjuvants, buffers, antioxidants, tonicity adjusters, preservatives (e.g., EDTA, BAK (benzalkonium chloride), sodium chlorite, sodium perborate, polyquaterium-1), thickeners or viscosity modifiers (e.g., carboxymethyl cellulose, hydroxymethyl cellulose, polyvinyl alcohol, polyethylene glycol, glycol 400, propylene glycol hydroxymethyl cellulose, hydroxpropyl-guar, hyaluronic acid, and hydroxypropyl cellulose) and the like.
- surfactants e.g., EDTA, BAK (benzalkonium chloride), sodium chlorite, sodium perborate, polyquaterium-1
- thickeners or viscosity modifiers e.g., carboxymethyl cellulose, hydroxymethyl cellulose, polyvinyl alcohol, polyethylene glycol, glycol 400, propylene glycol hydroxymethyl cellulose
- Additives in the formulation may include, but are not limited to, sodium chloride, sodium bicarbonate, sorbic acid, methyl paraben, propyl paraben, chlorhexidine, castor oil, and sodium perborate.
- Aqueous ophthalmic compositions (solutions or suspensions) generally do not contain physiologically or ophthalmically harmful constituents.
- purified or deionized water is used in the composition.
- the pH may be adjusted by adding any physiologically and ophthalmically acceptable pH adjusting acids, bases or buffers to within the range of about 5.0 to 8.5.
- Ophthalmically acceptable examples of acids include acetic, boric, citric, lactic, phosphoric, hydrochloric, and the like
- bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tromethamine, trishydroxymethylamino-methane, and the like.
- Salts and buffers include citrate/dextrose, sodium bicarbonate, ammonium chloride and mixtures of the aforementioned acids and bases.
- the methods involve forming or supplying a depot of the therapeutic agent in contact with the external surface of the eye.
- a depot refers to a source of therapeutic agent that is not rapidly removed by tears or other eye clearance mechanisms. This allows for continued, sustained high concentrations of therapeutic agent to be present in the fluid on the external surface of the eye by a single application.
- the ophthalmic composition is an ointment or gel.
- the ophthalmic composition is an oil-based delivery vehicle.
- the composition comprises a petroleum or lanolin base to which is added the active ingredient, usually as 0.1 to 2%, and excipients. Common bases may include, but are not limited to, mineral oil, petrolatum and combinations thereof.
- the ointment is applied as a ribbon onto the lower eyelid.
- the ophthalmic composition is an ophthalmic insert. In some embodiments, the ophthalmic composition is a ophthalmic film.
- Another aspect of the present invention relates to labeled compounds (radiolabeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating JAK in tissue samples, including human, and for identifying JAK ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes JAK assays that contain such labeled compounds.
- the present application further includes use of isotopically-labeled compounds.
- An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).
- Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 3 H (also written as T for tritium), U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 C1, 82 Br, 75 Br, 76 Br, 77 Br, 123 1, 124 I, 125 I and 131 I.
- radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro JAK labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 1 , 13 35 S or will generally be most useful. For radio-imaging applications U C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br will generally be most useful.
- a “radio-labeled " or “labeled compound” is a compound that has incorporated at least one radionuclide.
- the radionuclide is selected from the group consisting of 3 H, 14 C, 125 1 , 35 S and 82 Br.
- the compound incorporates 1, 2, or 3 deuterium atoms.
- the present application can further include synthetic methods for incorporating radio-isotopes into the compounds described herein. Synthetic methods for incorporating radio-isotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily recognize the methods applicable for the compounds described herein.
- a labeled compound of the invention can be used in a screening assay to identify/evaluate compounds.
- a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind a JAK by monitoring its concentration variation when contacting with the JAK, through tracking of the labeling.
- a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to a JAK (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the JAK directly correlates to its binding affinity.
- the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.
- kits useful for example, in the treatment or prevention of JAK-associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention.
- kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
- kits can also be included in the kit.
- reaction mixture was purged with N 2 three times, and then methylene chloride (21.3 mL), and 1.0 M triethylborane in THF (130 0.13 mmol) was added sequentially. After stirring for 10 min, 2-vinyloxirane (0.150 g, 2.14 mmol) was added and the resulting mixture was stirred overnight.
- the reaction was diluted with dichloromethane and sat. NaHCCte solution. The organic layer was separated and dried over Na 2 S0 4 , filtered and concentrated. The crude residue was purified with flash chromatography (eluting with 0-50% ethyl acetate/hexanes) to give the desired product (0.271 g, 49%).
- Step 7 ⁇ (5S)-5-[ (6-Nitrothieno[3,2-b]pyridin-7-yl)amino]-5,6-dihydro-2H-pyran-2- yljmethyl acetate
- CisHieNsOsS (M+ H) + : m/z 350.1; Found: 350.0.
- Step 8 ⁇ (5S)-5- [(6-Aminothieno [3 ',2-bj ' pyridin-7-yl) amino) ' tetrahydro-2H-pyran-2- yljmethyl acetate
- Step 10 ((2R,5S)-5- ⁇ 2-[(lR)-l-Hydroxyethyl]-lH-imidazo[4,5-d]thieno[3,2-b]pyridin-l- yl ⁇ tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate and ((2S,5S)-5- ⁇ 2-[(lR)- l-hydroxyethyl]-lH-imidazo[4,5-d]thieno[3,2-b]pyridin-l-yl ⁇ tetrahydro-2H-pyran-2- yl)methyl 4-methylbenzenesulfonate
- reaction mixture was concentrated, diluted with methanol, and purified with prep-LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give two peaks.
- prep-LCMS XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min
- Step 11 ((2R,5S)-5- ⁇ 2-[(lR)-l-Hydroxyethyl]-lH-imidazo[4,5-d]thieno[3,2-b]pyridin-l- ylj tetrahydro-2H-pyran-2-yl) acetonitrile
- Example 25 ((2R,5S)-5- ⁇ 2-[(lR)-l-Hydroxyethyl]-lH-imidazo[4,5-d]thieno[3,2-b]pyridin-l- yl ⁇ tetrahydro-2H-pyran-2-yl)acetonitrile (52 mg, 0.15 mmol) from Example 25 was crystallized from a mixture of acetonitrile (8 mL) and water (4 mL). The resulting colorless prism crystal collected was suitable for X-ray crystal structure analysis.
- reaction mixture was diluted with EtOAc (75 mL) and washed with IN HC1 (50 mL), IN NaHCOs (60 mL), 20% brine (50 mL) and water (75 mL). The aqueous layers were extracted with EtOAc (100 mL). The organic layers were combined, dried over MgS04, filtered and concentrated under reduced pressure to yield the desired product (7.59 g, 91.8%).
- Step 4 4-[3-(Cyanomethylene)azetidin-l-yl]-2,5-difluoro-N-[ (lS)-2 ,2 ,2-trifluoro-l- methylethyljbenzamide
- Step 5 4- ⁇ 3-(Cyanomethyl)-3-[ 4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH- pyrazol-l-yl]azetidin-l-yl ⁇ -2,5-difluoro-N-[(lS)-2,2,2-trifluoro-l-methy
- Step 6 4-[3-(Cyanomethyl)-3-(3 5'-dimethyl-lH 'H-4,4'-bipyrazol-l-yl)azetidin-l-yl]- 2,5-difluoro-N-[(lS)-2,2,2-trifluoro-l-methylethyl]benzamide
- the reaction mixture was diluted with EtOAc, washed with water and brine, concentrated.
- the residue was purified first with silica gel (eluting with 0-100% EtOAc/hexanes followed by 10% methanol/dichloromethane), and then by prep-LCMS (XBridge CI 8 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (30 mg, 9.7%).
- JAK1 a.a. 837-1142
- JAK2 a.a. 828-1132
- JAK3 a.a. 781-1124
- ATP phosphorylation of a biotinylated peptide.
- the phosphorylated peptide was detected by homogenous time resolved fluorescence (HTRF).
- ICsos of compounds were measured for each kinase in the 40 reactions that contain the enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA.
- ATP concentration in the reactions was 1 mM.
- Neutrophils were isolated from normal human whole blood collected in the anticoagulant heparin.
- the blood was mixed with an equal volume of sterile saline.
- Ficoll-Paque density gradient medium was underlayed at a 1 :4 ratio, and the tube spun at 3000 RPM for 30 minutes.
- the neutrophils were at the bottom of the tube with the red blood cells. This pellet was collected, and the red cells were lysed with RBC lysing buffer for 15 minutes. After the supernatant was discarded, the lysing step was repeated.
- the neutrophil pellet was resuspended in AIM-V media, and the cells were ready for the assay.
- neutrophils were incubated in a 96 well sterile tissue culture plate with the JAK compounds at the appropriate dilutions for 10 minutes in a 37 °C incubator with 5% CO2. 20 nM GCSF was added to the well for an additional 15 minutes again. The plate was centrifuged at 2000 RPM, supernatant discarded, and the cells lysed on ice for 45 minutes in cell lysing buffer that included PMSF and Protease inhibitors. Lysates can be stored at -80 °C until ready for use. Lysates were tested in a commercial pSTAT3 ELISA for inhibition of pSTAT3. The IC50 was determined by the inhibitor concentration required for 50% inhibition of pSTAT3 (see Table 2 below; "+" means the IC50 was measured and found to be less than 100 nM).
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