WO2010017122A2 - Methods of treating thalassemia - Google Patents
Methods of treating thalassemia Download PDFInfo
- Publication number
- WO2010017122A2 WO2010017122A2 PCT/US2009/052544 US2009052544W WO2010017122A2 WO 2010017122 A2 WO2010017122 A2 WO 2010017122A2 US 2009052544 W US2009052544 W US 2009052544W WO 2010017122 A2 WO2010017122 A2 WO 2010017122A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- group
- thalassemia
- halo
- heterocycle
- Prior art date
Links
- 0 Cc1c(*)c(*)c(C)cc1 Chemical compound Cc1c(*)c(*)c(C)cc1 0.000 description 3
- AHKMYBPVKRTURT-UHFFFAOYSA-N CC(C)(C)N/S(/c1cc(Nc2nc(Nc(cc3)ccc3-[n]3c(C)nc(CC(C)(C)NS(c4cccc(Nc5c(C)cnc(Nc6ccc(C[n]7c(C)ncc7)cc6)n5)c4)(=O)=O)c3)ncc2C)ccc1)=C\C Chemical compound CC(C)(C)N/S(/c1cc(Nc2nc(Nc(cc3)ccc3-[n]3c(C)nc(CC(C)(C)NS(c4cccc(Nc5c(C)cnc(Nc6ccc(C[n]7c(C)ncc7)cc6)n5)c4)(=O)=O)c3)ncc2C)ccc1)=C\C AHKMYBPVKRTURT-UHFFFAOYSA-N 0.000 description 1
- JOOXLOJCABQBSG-UHFFFAOYSA-N CC(C)(C)NS(c1cc(Nc2c(C)cnc(Nc(cc3)ccc3OCCN3CCCC3)n2)ccc1)(=O)=O Chemical compound CC(C)(C)NS(c1cc(Nc2c(C)cnc(Nc(cc3)ccc3OCCN3CCCC3)n2)ccc1)(=O)=O JOOXLOJCABQBSG-UHFFFAOYSA-N 0.000 description 1
- KZNGQPRTNBSQSW-UHFFFAOYSA-N Cc1c(Nc(cc2)cc3c2OCO3)nc(Nc(cc2)ccc2OCCN2CCCC2)nc1 Chemical compound Cc1c(Nc(cc2)cc3c2OCO3)nc(Nc(cc2)ccc2OCCN2CCCC2)nc1 KZNGQPRTNBSQSW-UHFFFAOYSA-N 0.000 description 1
- ZCICRUNNWRIIOK-UHFFFAOYSA-N Cc1c(Nc(cc2C(F)(F)F)ccc2Cl)nc(Nc(cc2)ccc2OC2CCNCC2)nc1 Chemical compound Cc1c(Nc(cc2C(F)(F)F)ccc2Cl)nc(Nc(cc2)ccc2OC2CCNCC2)nc1 ZCICRUNNWRIIOK-UHFFFAOYSA-N 0.000 description 1
- SKHJEMQXLBAHLW-UHFFFAOYSA-N Cc1c(Nc(cc2OC)ccc2Cl)nc(Nc(cc2)ccc2S(C2CCNCC2)(=O)=O)nc1 Chemical compound Cc1c(Nc(cc2OC)ccc2Cl)nc(Nc(cc2)ccc2S(C2CCNCC2)(=O)=O)nc1 SKHJEMQXLBAHLW-UHFFFAOYSA-N 0.000 description 1
- PQWNLMHYXLTIKE-UHFFFAOYSA-N Cc1c(Nc(cc2OC)ccc2Cl)nc(Nc(cc2C(OC)=O)ccc2N(CC2)CCN2c(cc2Nc3c(C)cnc(Nc(cc4)cc(C(OC)=O)c4OCCN4CCCC4)n3)cc3c2OCO3)nc1 Chemical compound Cc1c(Nc(cc2OC)ccc2Cl)nc(Nc(cc2C(OC)=O)ccc2N(CC2)CCN2c(cc2Nc3c(C)cnc(Nc(cc4)cc(C(OC)=O)c4OCCN4CCCC4)n3)cc3c2OCO3)nc1 PQWNLMHYXLTIKE-UHFFFAOYSA-N 0.000 description 1
- CCPRZWXORCAPHA-UHFFFAOYSA-N Cc1c(Nc(cc2OC)ccc2Cl)nc(Nc2ccc(CN3CCNCC3)cc2)nc1 Chemical compound Cc1c(Nc(cc2OC)ccc2Cl)nc(Nc2ccc(CN3CCNCC3)cc2)nc1 CCPRZWXORCAPHA-UHFFFAOYSA-N 0.000 description 1
- MZRPZVNKNDOJME-UHFFFAOYSA-N Cc1c(Nc2c3OCOc3ccc2)nc(Nc(cn2)ccc2OCCO)nc1 Chemical compound Cc1c(Nc2c3OCOc3ccc2)nc(Nc(cn2)ccc2OCCO)nc1 MZRPZVNKNDOJME-UHFFFAOYSA-N 0.000 description 1
- MLNSIDVNJLRQIG-UHFFFAOYSA-N Oc(cc1)ccc1Nc1ccnc(Nc(cc2)ccc2S(NCCN2CC(COc3cc(Nc4ccnc(Nc(cc5)ccc5S(NCCN5CCCC5)(=O)=O)n4)ccc3)CC2)(=O)=O)n1 Chemical compound Oc(cc1)ccc1Nc1ccnc(Nc(cc2)ccc2S(NCCN2CC(COc3cc(Nc4ccnc(Nc(cc5)ccc5S(NCCN5CCCC5)(=O)=O)n4)ccc3)CC2)(=O)=O)n1 MLNSIDVNJLRQIG-UHFFFAOYSA-N 0.000 description 1
- OUYKLBUUWLGYAF-UHFFFAOYSA-N Oc1cccc(Nc2ccnc(Nc(cc3)ccc3S(NCCN3CCCC3)(=O)=O)n2)c1 Chemical compound Oc1cccc(Nc2ccnc(Nc(cc3)ccc3S(NCCN3CCCC3)(=O)=O)n2)c1 OUYKLBUUWLGYAF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
Definitions
- Thalassemia and sickle cell anemia are genetic blood disorders that cause the formation of abnormal hemoglobin molecules, resulting in low red blood cell count. Hemoglobin consists of two different proteins, alpha and beta. If the body does not produce enough of either of these two proteins, red blood cells do not form properly and cannot carry sufficient oxygen.
- Beta-thalassemia one of the most common congenital anemias, arises from partial or complete lack of beta-globin synthesis.
- patients may require regular blood transfusions to sustain life.
- iron in the transfused blood cells builds up in a condition known as iron overload and becomes toxic to tissues and organs, particularly the liver and heart. As a consequence, patients are often required to undergo iron chelation therapy.
- thalassemia Common symptoms of thalassemia include an enlarged spleen or splenomegaly, caused by buildup of malformed red blood cells within the body.
- the spleen works to filter out these unhealthy cells in order to protect the body from harm, but, in a patient with thalassemia, the spleen eventually becomes enlarged and is commonly surgically removed in order to prevent a potentially fatal burst.
- spleen is removed, patients are at a much greater risk for stroke and infections. Further, removal of the spleen can cause an increase in life-threatening blood clots. After a splenectomy, patients are immunocompromised, and are typically placed on lifelong prophylactic oral antibiotics.
- Jak2 inhibitors include those compounds disclosed herein.
- Exemplary methods include treatment of thalassemia minor, thalassemia intermedia, and thalassemia major using Jak2 inhibitors.
- a method of treating, ameliorating, or delaying at least one symptom of a genetic blood disorder in a patient in need thereof comprising administering a therapeutically effective amount of a Jak2 inhibitor and/or a compound provided herein, for example, a compound represented by formula I, defined below.
- the genetic blood disorder may be thalassemia, e.g., beta- thalassemia.
- methods for delaying at least one symptom of a genetic blood disorder is provided in a patient in need thereof, wherein the symptom is an enlarged spleen.
- a method of reducing an enlarged spleen in a patient suffering from thalassemia comprising administering a therapeutically effective amount of a Jak2 inhibitor.
- a method of preventing or reducing iron overload in a patient suffering from thalassemia is also provided, comprising administering a therapeutically effective amount of a Jak2 inhibitor.
- Figure 1 depicts levels of hemolytic markers (A) bilirubin and (B) LDH (N >6 per Genotype), (C) Epo levels in mice 2-months post-BMT and (D) Epo and Hb levels in mice up to 1 year of age.
- A bilirubin and
- B LDH
- C Epo levels in mice 2-months post-BMT
- D Epo and Hb levels in mice up to 1 year of age.
- th3/+ and th3/th3 mice are indicated respectively as +/- and -/-.
- Figure 3 depicts resulting Hb and spleen analysis after animals were administered a Jak2 inhibitor or placebo. Hb levels, spleen weight, age of theanimal and days of treatment are indicated.
- Figure 4 depicts spleen size of representative animals after administration of a Jak2 inhibitor or a placebo.
- the present disclosure stems in part from the discovery that ineffective erythropoiesis (IE) in thalassemia is characterized by limited erythroid cell differentiation, and that thalassemic cells are associated with the expression of the cell cycle promoting gene Jak2.
- IE erythropoiesis
- therapeutic effect is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance. The term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and/or conditions in an animal or human.
- therapeutically-effective amount means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment.
- the therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
- certain compositions of the present invention may be administered in a sufficient amount to produce a at a reasonable benefit/risk ratio applicable to such treatment.
- a "patient,” “subject” or “host” to be treated by the subject method may mean either a human or non-human animal.
- treating is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disease.
- alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
- a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 3 O for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer, e.g. from 1 to 6 carbons.
- cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
- alkyl is also defined to include halosubstituted alkyls.
- alkyl (or “lower alkyl”) includes “substituted alkyls”, which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
- Such substituents may include, for example, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
- a carbonyl such as a carboxyl, an alkoxy
- the moieties substituted on the hydrocarbon chain may themselves be substituted, if appropriate.
- the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls may be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl- substituted alkyls, -CN, and the like.
- aralkyl is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
- alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
- alkylene refers to an organic radical formed from an unsaturated aliphatic hydrocarbon; “alkenylene” denotes an acyclic carbon chain which includes a carbon-to-carbon double bond.
- lower alkyl refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure.
- lower alkenyl and “lower alkynyl” have similar chain lengths.
- heteroatom is art-recognized and refers to an atom of any element other than carbon or hydrogen.
- Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
- aryl is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
- aryl groups having heteroatoms in the ring structure may also be referred to as "heteroaryl” or “heteroaromatics.”
- the aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like.
- aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
- ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively.
- 1,2-dimethylbenzene and ortho- dimethylbenzene are synonymous.
- heterocyclyl or “heterocyclic group” are art-recognized and refer to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be poly cycles.
- Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
- the heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
- substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,
- Carbocycle is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
- nitro is art-recognized and refers to -NO 2 ;
- halogen is art- recognized and refers to -F, -Cl, -Br or -I;
- sulfhydryl is art-recognized and refers to - SH;
- hydroxyl means -OH; and the term “sulfonyl” is art-recognized and refers to - SO2 " .
- amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:
- R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, - (CH2)m-R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
- R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and
- m is zero or an integer in the range of 1 to 8.
- only one of R50 or R51 may be a carbonyl, e.g., R50, R51 and the nitrogen together do not form an imide.
- R50 and R51 each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m- R61.
- alkylamine includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
- amide is art recognized as an amino- substituted carbonyl and includes a moiety that may be represented by the general formula: wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include imides which may be unstable.
- acylamino is art-recognized and refers to a moiety that may be represented by the general formula:
- R50 is as defined above
- R54 represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R61, where m and R61 are as defined above.
- alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
- the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2)m-R61, wherein m and R61 are defined above.
- Representative alkylthio groups include methylthio, ethyl thio, and the like.
- carbonyl is art recognized and includes such moieties as may be represented by the general formulas:
- X50 is a bond or represents an oxygen or a sulfur
- R55 and R56 represents a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R61or a pharmaceutically acceptable salt
- R56 represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R61, where m and R61 are defined above.
- X50 is an oxygen and R55 or R56 is not hydrogen
- the formula represents an "ester”.
- X50 is an oxygen
- R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid".
- X50 is an oxygen, and R56 is hydrogen
- the formula represents a "formate".
- the oxygen atom of the above formula is replaced by sulfur
- the formula represents a "thiolcarbonyl” group.
- X50 is a sulfur and R55 or R56 is not hydrogen
- the formula represents a "thiolester.”
- X50 is a sulfur and R55 is hydrogen
- the formula represents a "thiolcarboxylic acid.”
- X50 is a sulfur and R56 is hydrogen
- the formula represents a "thiolformate.”
- X50 is a bond, and R55 is not hydrogen
- the above formula represents a "ketone” group.
- X50 is a bond, and R55 is hydrogen
- the above formula represents an "aldehyde” group.
- each expression e.g. alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
- compositions of the present invention may exist in particular geometric or stereoisomeric forms.
- polymers of the present invention may also be optically active.
- the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
- Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
- a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
- the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
- substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
- the term "substituted" is also contemplated to include all permissible substituents of organic compounds.
- the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
- Illustrative substituents include, for example, those described herein above.
- the permissible substituents may be one or more and the same or different for appropriate organic compounds.
- the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
- the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67 th Ed., 1986-87, inside cover.
- the term "hydrocarbon” is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom.
- the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds that may be substituted or unsubstituted.
- compositions or vehicles refers to a pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
- a pharmaceutically- acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
- Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient.
- materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
- Methods of treating and/or ameloriating genetic blood disorders such as thalassemia or sickle cell anemia, or delaying or ameliorating at least one symptom thereof, are contemplated herein, comprising administering to a patient in need thereof an effective amount of a Jak2 inhibitor, such as a small molecule Jak2 inhibitor (e.g. a Jak2 inhibitor having a molecular weight (e.g. a free base molecular weight) of about 100 g/mol to about700 g/mol, or about 400 g/mol to about 600 g/mol.
- the Jak2 inhibitor is represented by a compound of formula I, as provided herein.
- Exemplary symptoms of thalassemia include enlarged spleen and/or anemia. Symptoms may also include excessive iron absorption, and those resulting from ineffective erythropoiesis due to excessive iron absorption, including osteoporosis, e.g. secondary osteoporosis.
- a method is provided to ameloriate or delay an enlarged spleen in a patient suffering from thalassemia, comprising administering a pharmaceutically effective amount of a Jak2 inhibitor, e.g. a compound of formula I.
- a Jak2 inhibitor e.g. a compound of formula I.
- transfusion independent beta- thalassemia intermedia patients if affected by splenomegaly, may develop a need for blood transfusion therapy and may eventually undergo a splenectomy.
- patients affected by thalassmia intermedia and splenomegaly may be treated temporarily with a Jak2 inhibitor to reduce spleen size while also using blood transfusion to prevent further anemia
- the spleen size of a patient suffering from thalassemia and receiving a Jak2 inhibitor may be reduced by 10%, 20%, 30%, 40%, or even 50% or more as compared to a patient with a similar spleen size suffering from thalassemia and not receiving a Jak2 inhibitor.
- Methods of treating, or amelioriating or delaying at least one symptom of genetic blood disorders include methods directed to e.g., the treatment of sickle cell disease, alpha-thalassemia, delta-thalassemia, and beta-thalassemia.
- Contemplated treatments herein include treatment of patients suffering from thalassemia minor, thalassemia intermedia, thalassemia major (Cooley's disease), e-beta thalassemia, and sickle beta thalassemia.
- An exemplary method for reducing the frequency of chelation therapy in a patient,e.g., suffering from thalessemia, that includes administering a disclosed compound is provided herein.
- Jak2 inhibitors for use in the provided methods are Jak2 inhibitors.
- compounds of formula I are contemplated for use in the provided methods. Such compounds may be, e.g., Jak2 inhibitors.
- the compounds of formula I include those represented by:
- A is selected from the group consisting of alkylene (e.g. C 1 -C 6 alkylene) or NR 1 .
- Q may be a monocylic or bicyclic aryl, or monocyclic or bicyclic heteroaryl, bonded to A through a ring carbon, wherein Q may be optionally substituted by 1, 2, or 3 substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, amino, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 alkoxy, NR 1 R 1 ', amido, carboxyl, alkanoyl, alkoxycarbonyl, ureido, N-alkylsulphamoyl, N-alkylcarbamoyl, carboxamide, sulphamoyl, carbamoyl, heteroaryl, heterocycle, -NR 1 -C(O
- Q may be optionally substituted phenyl, naphthyl, quinoline, benzothiophene, indole, or pyridine.
- Q is phenyl, optionally substituted by one N-tert-butyl sulfonamide.
- R 1 and R 1 ' independently, for each occurrence, can be selected from H or C 1 -C 6 alkyl, e.g. may be methyl, or ethyl.
- R 5 is H, cyano, or C 1 -C 6 alkyl, for example, methyl, ethyl, isopropyl, n-propyl, etc. In a particular embodiment, R 5 is methyl.
- B is N or CR 2 , wherein R 2 is selected from the group consisting of H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; or alkoxycarbonyl.
- Y can be selected from the group consisting of: a bond, -O-alkylene; -SO 2 -, SO 2 - NRi-alkylene-, -O-, alkylene, and -C(O)-, wherein R 1 is defined above.
- Y is an optionally substituted methylene.
- Y is -0-CH 2 - CH 2 -.
- R 3 is selected from the group consisting of H, halo, hydroxyl, and R 4 , wherein R 4 is a monocyclic heterocycle or heteroaryl bonded to Y through a ring carbon or heteroatom, and wherein R 4 is optionally substituted by 1, 2, or 3 substituents each independently selected from the group consisting of halo, hydroxyl, cyano, amino, nitro, C 1 -C 6 alkyl, carboxyl, alkanoyl, or alkoxycarbonyl.
- R 4 is selected from the group consisting of pyrrolidyl, piperazinyl, morpholinyl, or piperdinyl, tetrazole, imidazole, triazole, pyrazole, or pyridinyl.
- R 6 , R 7 , and R 8 are, independently, for each occurrence, selected from the group consisting of: H, halo, hydroxyl, cyano, amino, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amido, carboxyl, alkanoyl, alkoxycarbonyl, N-alkylsulphamoyl, N-alkylcarbamoyl, carboxamide, sulphamoyl, carbamoyl, SO 2 H, and S ⁇ 2 -(Ci-C 6 )alkyl.
- the compounds of the invention may be Jak2 inhibitors.
- An exemplary Jak2 inhibitor is compound A, which has the chemical structure:
- the dosage of the subject compounds will generally be in the range of about 0.01 ng to about 10 g per kg body weight, specifically in the range of about 1 ng to about 0.1 g per kg, and more specifically in the range of about 100 ng to about 10 mg per kg.
- An effective dose or amount, and any possible affects on the timing of administration of the formulation may need to be identified for any particular composition of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals (preferably at least 5 animals per group), or in human trials if appropriate.
- the effectiveness of any subject composition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of the administration by measuring one or more applicable indices, and comparing the post-treatment values of these indices to the values of the same indices prior to treatment.
- the precise time of administration and amount of any particular subject composition that will yield the most effective treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a subject composition, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), route of administration, and the like.
- the guidelines presented herein may be used to optimize the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage and/or timing.
- the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period. Treatment, including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring. The patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters.
- Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained.
- compositions may reduce the required dosage for any individual agent contained in the compositions because the onset and duration of effect of the different agents may be complimentary.
- compositions of the present invention may be administered by various means, depending on their intended use, as is well known in the art.
- compositions of the present invention may be formulated as tablets, capsules, granules, powders or syrups.
- formulations of the present invention may be administered parenterally as injections (intravenous, intramuscular or subcutaneous), drop infusion preparations, suppositories or administration intranasally (for example, to deliver a dosage to the brain via the nose or to deliver a dosage to the nose directly) or by inhalation (e.g. to treat a condition of the respiratory tract or to pretreat or vaccinate via the respiratory tract).
- hematopoietic fetal liver cells HFLCs
- embryonic day 14.5 E14.5
- wt lethally irradiated syngeneic wild-type adult recipients.
- Spleens from wt, th3l+ and th3lth3 mice were harvested and mechanically dissociated into single cell suspensions.
- Murine mononuclear cells were then isolated by centrifugation using Lympholyte-M density gradients (Cedarlane Laboratories Ltd, Westbury, NY) following the manufacturer's instructions. Cells were incubated on ice for 15 minutes with a cocktail containing 10 ⁇ g each of non-erythroid FITCconjugated antibodies (GR-I, MACl, CD4, CD8, CDl Ib, and CD49) (BD PharMingen).
- GR-I non-erythroid FITCconjugated antibodies
- peptide competition assay 0.05 ug of phospho-Jak2 polyclonal antibody were incubated for 2 h at room temperature with a 5-fold concentration of blocking peptide in Medium B of the Fix and Perm Kit. The peptide- antibody solution was then added to the fixed cells and they were incubated as above.
- Bilirubin and lactic acid dehydrogenase (LDH) levels in thalassemic mice [0078] Bilirubin and lactic acid dehydrogenase (LDH) levels, which are elevated if red cells hemolyze, were unchanged or only slightly increased in thalassemic compared to normal mice ( Figure IA and IB). In th3/+ mice, these observations indicated that limited hemolysis was present despite erythrocyte formation. In th3/th3 erythroid cells, the average amount of alpha- globin transcript was, on average, 3 fold less than that in wt animals.
- LDH lactic acid dehydrogenase
- the low bilirubin and LDH levels in th3/th3 mice emphasize the limited maturation of their erythroid cells, with the erythropoiesis blockade happening before the formation of fully hemoglobinized cells.
- Such immature morphology exhibited by thalassemic erythroid cells suggests that an altered cell cycle and limited cell differentiation may be responsible for the low levels of apoptosis and hemolysis seen in this disease compared to earlier predictions arising from ferrokinetic measurements.
Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2732791A CA2732791A1 (en) | 2008-08-05 | 2009-08-03 | Methods of treating thalassemia |
AU2009279825A AU2009279825A1 (en) | 2008-08-05 | 2009-08-03 | Methods of treating thalassemia |
EP09741504A EP2355827A2 (en) | 2008-08-05 | 2009-08-03 | Methods of treating thalassemia |
US13/057,133 US20110269721A1 (en) | 2008-08-05 | 2009-08-03 | Methods of treating thalassemia |
CN2009801303954A CN102112131A (en) | 2008-08-05 | 2009-08-03 | Methods of treating thalassemia |
MX2011001426A MX2011001426A (en) | 2008-08-05 | 2009-08-03 | Methods of treating thalassemia. |
JP2011522136A JP2011530517A (en) | 2008-08-05 | 2009-08-03 | How to treat thalassemia |
BRPI0917575A BRPI0917575A2 (en) | 2008-08-05 | 2009-08-03 | thalassemia treatment methods |
IL211061A IL211061A0 (en) | 2008-08-05 | 2011-02-03 | Methods of treating thalassemia |
TN2011000061A TN2011000061A1 (en) | 2009-08-03 | 2011-02-04 | Methods of treating thalassemia |
MA33672A MA32611B1 (en) | 2008-08-05 | 2011-03-04 | Operations for the treatment of thalassemia |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US8623308P | 2008-08-05 | 2008-08-05 | |
US61/086,233 | 2008-08-05 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2010017122A2 true WO2010017122A2 (en) | 2010-02-11 |
WO2010017122A3 WO2010017122A3 (en) | 2010-04-08 |
Family
ID=41581108
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2009/052544 WO2010017122A2 (en) | 2008-08-05 | 2009-08-03 | Methods of treating thalassemia |
Country Status (20)
Country | Link |
---|---|
US (1) | US20110269721A1 (en) |
EP (1) | EP2355827A2 (en) |
JP (1) | JP2011530517A (en) |
KR (1) | KR20110053347A (en) |
CN (1) | CN102112131A (en) |
AU (1) | AU2009279825A1 (en) |
BR (1) | BRPI0917575A2 (en) |
CA (1) | CA2732791A1 (en) |
CL (1) | CL2011000242A1 (en) |
CO (1) | CO6351728A2 (en) |
CR (1) | CR20110115A (en) |
DO (1) | DOP2011000044A (en) |
EC (1) | ECSP11010847A (en) |
IL (1) | IL211061A0 (en) |
MA (1) | MA32611B1 (en) |
MX (1) | MX2011001426A (en) |
NI (1) | NI201100031A (en) |
RU (1) | RU2011108563A (en) |
SV (1) | SV2011003823A (en) |
WO (1) | WO2010017122A2 (en) |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8133900B2 (en) | 2005-11-01 | 2012-03-13 | Targegen, Inc. | Use of bi-aryl meta-pyrimidine inhibitors of kinases |
US8138199B2 (en) | 2005-11-01 | 2012-03-20 | Targegen, Inc. | Use of bi-aryl meta-pyrimidine inhibitors of kinases |
WO2012071612A1 (en) * | 2010-12-03 | 2012-06-07 | Ym Biosciences Australia Pty Ltd | Treatment of jak2-mediated conditions |
US8372971B2 (en) | 2004-08-25 | 2013-02-12 | Targegen, Inc. | Heterocyclic compounds and methods of use |
US8481536B2 (en) | 2004-04-08 | 2013-07-09 | Targegen, Inc. | Benzotriazine inhibitors of kinases |
US8604042B2 (en) | 2005-11-01 | 2013-12-10 | Targegen, Inc. | Bi-aryl meta-pyrimidine inhibitors of kinases |
US8809359B2 (en) | 2012-06-29 | 2014-08-19 | Ym Biosciences Australia Pty Ltd | Phenyl amino pyrimidine bicyclic compounds and uses thereof |
US9233934B2 (en) | 2007-03-12 | 2016-01-12 | Ym Biosciences Australia Pty Ltd | Phenyl amino pyrimidine compounds and uses thereof |
KR101928225B1 (en) | 2014-06-12 | 2018-12-11 | 길리애드 사이언시즈, 인코포레이티드 | N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide hydrochloride salts |
US10202356B2 (en) | 2013-03-14 | 2019-02-12 | Tolero Pharmaceuticals, Inc. | JAK2 and ALK2 inhibitors and methods for their use |
US10391094B2 (en) | 2010-11-07 | 2019-08-27 | Impact Biomedicines, Inc. | Compositions and methods for treating myelofibrosis |
WO2019200254A1 (en) | 2018-04-13 | 2019-10-17 | Tolero Pharmaceuticals, Inc. | Pim kinase inhibitors for treatment of myeloproliferative neoplasms and fibrosis associated with cancer |
US10875864B2 (en) | 2011-07-21 | 2020-12-29 | Sumitomo Dainippon Pharma Oncology, Inc. | Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitors |
WO2021017384A1 (en) | 2019-07-30 | 2021-02-04 | 上海勋和医药科技有限公司 | Dihydro-pyrrolo-pyrimidine selective jak2 inhibitor |
EP3600318A4 (en) * | 2017-03-31 | 2021-06-09 | Epizyme, Inc. | Methods of using ehmt2 inhibitors |
US11040038B2 (en) | 2018-07-26 | 2021-06-22 | Sumitomo Dainippon Pharma Oncology, Inc. | Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same |
US20210213014A1 (en) * | 2017-10-18 | 2021-07-15 | Epizyme, Inc. | Methods of using ehmt2 inhibitors in immunotherapies |
US20210355088A1 (en) * | 2018-09-07 | 2021-11-18 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Brd4-jak2 inhibitors |
US11471456B2 (en) | 2019-02-12 | 2022-10-18 | Sumitomo Pharma Oncology, Inc. | Formulations comprising heterocyclic protein kinase inhibitors |
US11672800B2 (en) | 2017-04-21 | 2023-06-13 | Epizyme, Inc. | Combination therapies with EHMT2 inhibitors |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103664799A (en) * | 2012-09-25 | 2014-03-26 | 杨子娇 | Compounds for treating narrow chamber angle and application thereof |
WO2014139144A1 (en) | 2013-03-15 | 2014-09-18 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
MA44666A (en) * | 2016-04-15 | 2019-02-20 | Epizyme Inc | AMINE SUBSTITUTED ARYL OR HETERARYL COMPOUNDS USED AS EHMT1 AND EHMT2 INHIBITORS |
JP2021524835A (en) | 2018-04-05 | 2021-09-16 | スミトモ ダイニッポン ファーマ オンコロジー, インコーポレイテッド | AXL Kinase Inhibitors and Their Use |
CN112778282B (en) | 2021-01-06 | 2022-07-22 | 温州医科大学 | Pyrimidine micromolecule compound and application thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5191391B2 (en) * | 2005-11-01 | 2013-05-08 | ターゲジェン インコーポレーティッド | Bi-aryl meta-pyrimidine inhibitors of kinases |
-
2009
- 2009-08-03 CA CA2732791A patent/CA2732791A1/en not_active Abandoned
- 2009-08-03 BR BRPI0917575A patent/BRPI0917575A2/en not_active IP Right Cessation
- 2009-08-03 JP JP2011522136A patent/JP2011530517A/en active Pending
- 2009-08-03 MX MX2011001426A patent/MX2011001426A/en not_active Application Discontinuation
- 2009-08-03 AU AU2009279825A patent/AU2009279825A1/en not_active Abandoned
- 2009-08-03 WO PCT/US2009/052544 patent/WO2010017122A2/en active Application Filing
- 2009-08-03 RU RU2011108563/15A patent/RU2011108563A/en not_active Application Discontinuation
- 2009-08-03 US US13/057,133 patent/US20110269721A1/en not_active Abandoned
- 2009-08-03 KR KR1020117005224A patent/KR20110053347A/en not_active Application Discontinuation
- 2009-08-03 CN CN2009801303954A patent/CN102112131A/en active Pending
- 2009-08-03 EP EP09741504A patent/EP2355827A2/en not_active Withdrawn
-
2011
- 2011-02-01 SV SV2011003823A patent/SV2011003823A/en not_active Application Discontinuation
- 2011-02-02 NI NI201100031A patent/NI201100031A/en unknown
- 2011-02-03 IL IL211061A patent/IL211061A0/en unknown
- 2011-02-03 DO DO2011000044A patent/DOP2011000044A/en unknown
- 2011-02-04 CL CL2011000242A patent/CL2011000242A1/en unknown
- 2011-02-28 EC EC2011010847A patent/ECSP11010847A/en unknown
- 2011-03-02 CR CR20110115A patent/CR20110115A/en not_active Application Discontinuation
- 2011-03-04 MA MA33672A patent/MA32611B1/en unknown
- 2011-03-04 CO CO11026653A patent/CO6351728A2/en not_active Application Discontinuation
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8481536B2 (en) | 2004-04-08 | 2013-07-09 | Targegen, Inc. | Benzotriazine inhibitors of kinases |
US8372971B2 (en) | 2004-08-25 | 2013-02-12 | Targegen, Inc. | Heterocyclic compounds and methods of use |
US8133900B2 (en) | 2005-11-01 | 2012-03-13 | Targegen, Inc. | Use of bi-aryl meta-pyrimidine inhibitors of kinases |
US8138199B2 (en) | 2005-11-01 | 2012-03-20 | Targegen, Inc. | Use of bi-aryl meta-pyrimidine inhibitors of kinases |
US8604042B2 (en) | 2005-11-01 | 2013-12-10 | Targegen, Inc. | Bi-aryl meta-pyrimidine inhibitors of kinases |
US9233934B2 (en) | 2007-03-12 | 2016-01-12 | Ym Biosciences Australia Pty Ltd | Phenyl amino pyrimidine compounds and uses thereof |
US9238628B2 (en) | 2007-03-12 | 2016-01-19 | YM Biosicences Australia PTY LTD | Phenyl amino pyrimidine compounds and uses thereof |
US10391094B2 (en) | 2010-11-07 | 2019-08-27 | Impact Biomedicines, Inc. | Compositions and methods for treating myelofibrosis |
WO2012071612A1 (en) * | 2010-12-03 | 2012-06-07 | Ym Biosciences Australia Pty Ltd | Treatment of jak2-mediated conditions |
US10875864B2 (en) | 2011-07-21 | 2020-12-29 | Sumitomo Dainippon Pharma Oncology, Inc. | Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitors |
US8809359B2 (en) | 2012-06-29 | 2014-08-19 | Ym Biosciences Australia Pty Ltd | Phenyl amino pyrimidine bicyclic compounds and uses thereof |
US10202356B2 (en) | 2013-03-14 | 2019-02-12 | Tolero Pharmaceuticals, Inc. | JAK2 and ALK2 inhibitors and methods for their use |
US10752594B2 (en) | 2013-03-14 | 2020-08-25 | Sumitomo Dainippon Pharma Oncology, Inc. | JAK1 and ALK2 inhibitors and methods for their use |
KR101928225B1 (en) | 2014-06-12 | 2018-12-11 | 길리애드 사이언시즈, 인코포레이티드 | N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide hydrochloride salts |
USRE48285E1 (en) | 2014-06-12 | 2020-10-27 | Sierra Oncology, Inc. | N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide |
USRE49445E1 (en) | 2014-06-12 | 2023-03-07 | Sierra Oncology, Inc. | N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide |
EP3600318A4 (en) * | 2017-03-31 | 2021-06-09 | Epizyme, Inc. | Methods of using ehmt2 inhibitors |
US11672800B2 (en) | 2017-04-21 | 2023-06-13 | Epizyme, Inc. | Combination therapies with EHMT2 inhibitors |
US20210213014A1 (en) * | 2017-10-18 | 2021-07-15 | Epizyme, Inc. | Methods of using ehmt2 inhibitors in immunotherapies |
WO2019200254A1 (en) | 2018-04-13 | 2019-10-17 | Tolero Pharmaceuticals, Inc. | Pim kinase inhibitors for treatment of myeloproliferative neoplasms and fibrosis associated with cancer |
US11040038B2 (en) | 2018-07-26 | 2021-06-22 | Sumitomo Dainippon Pharma Oncology, Inc. | Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same |
US20210355088A1 (en) * | 2018-09-07 | 2021-11-18 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Brd4-jak2 inhibitors |
US11471456B2 (en) | 2019-02-12 | 2022-10-18 | Sumitomo Pharma Oncology, Inc. | Formulations comprising heterocyclic protein kinase inhibitors |
WO2021017384A1 (en) | 2019-07-30 | 2021-02-04 | 上海勋和医药科技有限公司 | Dihydro-pyrrolo-pyrimidine selective jak2 inhibitor |
Also Published As
Publication number | Publication date |
---|---|
CA2732791A1 (en) | 2010-02-11 |
RU2011108563A (en) | 2012-09-10 |
KR20110053347A (en) | 2011-05-20 |
WO2010017122A3 (en) | 2010-04-08 |
CR20110115A (en) | 2011-06-03 |
JP2011530517A (en) | 2011-12-22 |
NI201100031A (en) | 2011-09-26 |
SV2011003823A (en) | 2011-08-15 |
IL211061A0 (en) | 2011-04-28 |
EP2355827A2 (en) | 2011-08-17 |
BRPI0917575A2 (en) | 2019-09-24 |
ECSP11010847A (en) | 2011-07-29 |
AU2009279825A1 (en) | 2010-02-11 |
MA32611B1 (en) | 2011-09-01 |
CO6351728A2 (en) | 2011-12-20 |
DOP2011000044A (en) | 2011-04-30 |
CN102112131A (en) | 2011-06-29 |
MX2011001426A (en) | 2011-03-21 |
US20110269721A1 (en) | 2011-11-03 |
CL2011000242A1 (en) | 2011-04-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2010017122A2 (en) | Methods of treating thalassemia | |
KR100638684B1 (en) | Use of 9-deoxy-2',9-alpha-methano-3-oxa-4,5,6-trinor-3,7-1',3'-interphenylene-13,14-dihydro-prostaglandin f1 to treat peripheral vascular disease | |
AU2016222315B2 (en) | Compositions of selenoorganic compounds and methods of use thereof | |
EP2030615A2 (en) | Ribonucleotide reductase inhibitors for use in the treatment or prevention of neuroinflammatory or autoimmune diseases | |
JP2008538362A (en) | Identification of methods for treating diseases through blocking protein maturation, compounds that inhibit the function of molecular chaperones such as protein disulfide isomerase or interfere with glycosylation, pharmaceutical compositions containing them, and therapeutic agents Screening method | |
WO2019028150A1 (en) | Compositions for use in methods of treatment of hemoglobin disorders | |
KR20220029681A (en) | Methods of Treatment of Idiopathic Pulmonary Fibrosis | |
CA3113376A1 (en) | Compositions for reducing serum uric acid | |
US20210069192A1 (en) | Use of neutrophil elastase inhibitors in liver disease | |
EP0283139B1 (en) | Anticancer compounds | |
EP3091972B1 (en) | Method of treating liver disorders | |
CN116322663A (en) | AMPK activators and methods of use thereof | |
EP0292660B1 (en) | Alkylidenedithiobis (substituted) phenols for inhibiting interleukin-1 release and for alleviating interleukin-1 mediated conditions | |
WO2016129583A1 (en) | Lactate dehydrogenase inhibitor and antiepileptic drug containing same | |
AU2021240762A1 (en) | Cyclophilin inhibitors and uses thereof | |
KR20220009371A (en) | Drugs and methods for treating or preventing diabetic complications using the drugs | |
JP2013522374A (en) | Compositions and methods for the prevention and treatment of wounds | |
KR101215379B1 (en) | Pharmaceutical composition comprising decursinol derivatives | |
EP4090650A1 (en) | Novel compounds as inhibitors of pcsk9 | |
US20220257629A1 (en) | Compositions and methods for upregulation of human fetal hemoglobin | |
AU2002363318B2 (en) | Compounds and methods for treating transplant rejection | |
CA2939592A1 (en) | Compositions of selenoorganic compounds and methods of use thereof | |
JP2024509265A (en) | Compositions and methods for treating polycythemia | |
WO2019132004A1 (en) | Prophylactic agent or therapeutic agent for alzheimer's disease, screening method therefor, and composition for preventing or treating alzheimer's disease | |
KR20170005539A (en) | Pharmaceutical composition for treating renal disease including dipyridamole as active ingredient |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200980130395.4 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09741504 Country of ref document: EP Kind code of ref document: A2 |
|
ENP | Entry into the national phase |
Ref document number: 2732791 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 000116-2011 Country of ref document: PE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12011500240 Country of ref document: PH |
|
ENP | Entry into the national phase |
Ref document number: 0124911 Country of ref document: KE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 211061 Country of ref document: IL |
|
ENP | Entry into the national phase |
Ref document number: 2011522136 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2011/001426 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011020241 Country of ref document: EG |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1448/CHENP/2011 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009279825 Country of ref document: AU Ref document number: 591502 Country of ref document: NZ Ref document number: CR2011-000115 Country of ref document: CR |
|
ENP | Entry into the national phase |
Ref document number: 20117005224 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 11026653 Country of ref document: CO Ref document number: 2009741504 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: A201102592 Country of ref document: UA |
|
WWE | Wipo information: entry into national phase |
Ref document number: DZP2011000177 Country of ref document: DZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011108563 Country of ref document: RU |
|
ENP | Entry into the national phase |
Ref document number: 2009279825 Country of ref document: AU Date of ref document: 20090803 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13057133 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: PI0917575 Country of ref document: BR Kind code of ref document: A2 Effective date: 20110203 |