PROCESSES FOR THE PREPARATION OF (S)-3-(4-((4-(MORPHOLINOMETHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE AND PHARMACEUTICALLY ACCEPTABLE FORMS THEREOF

Provided are processes for the preparation of enantiomerically enriched or enantiomerically pure 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable form thereof. 167-. (canceled)68. A process to increase the enantiopurity of (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2 ,6-dione , or a salt , solvate , or solvate of salt thereof , comprising recrystallization or trituration of a first sample of (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2 ,6-dione , or a salt , solvate , or solvate of salt thereof , in a solvent or a mixture of solvents , resulting in a second sample of (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2 ,6-dione , or a salt , solvate , or solvate of salt thereof , wherein the second sample has a higher ee than the first sample.6970-. (canceled)71. The process of claim 68 , wherein the enantiopurity is increased by recrystallization.72. The process of claim 68 , wherein the enantiopurity is increased by trituration.73. The process of claim 68 , wherein the enantiopurity is increase by 10% or more.74. The process of claim 73 , wherein the enantiopurity is increase by 20% or more.75. The process of claim 68 , wherein the first sample is in the anhydrous freebase form.76. The process of claim 68 , wherein the first sample is in the freebase hydrate form.77. The process of claim 68 , wherein the first sample is in the freebase THF solvate form.78. The process of claim 68 , wherein the first sample is in the HCl salt form.79. The process of claim 68 , wherein the first sample is in the anhydrous HCl salt form.80. The process of claim 68 , wherein the ee of the first sample is from 25% to about 90%.81. The process of claim 80 , wherein the ee of the first sample is from 50% to about 80%.82. The process of claim 68 , wherein the solvent is water claim 68 , diethyl ether claim 68 , 1 claim 68 ,4-dioxane ...

SOLID FORMS OF 3-(5-AMINO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE, AND THEIR PHARMACEUTICAL COMPOSITIONS AND USES

Solid forms comprising 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, compositions comprising the solid forms, methods of making the solid forms and methods of their uses are disclosed

ASYMMETRIC SYNTHETIC PROCESSES FOR THE PREPARATION OF AMINOSULFONE COMPOUNDS

Processes for synthesizing aminosulfone compounds are provided. Aminosulfone compounds obtained using methods provided herein are useful in production or synthesis of sulfone group containing isoindoline based compounds. 2. The process of claim 1 , wherein Rand Rare substituted or unsubstituted (C-C)alkoxy claim 1 , or an isotopologue thereof.3. The process of claim 2 , wherein Ris OMe claim 2 , or an isotopologue thereof claim 2 , Ris OEt claim 2 , or an isotopologue thereof claim 2 , and Ris Me claim 2 , or an isotopologue thereof.4. The process of claim 1 , wherein the metal catalyst contains rhodium.5. The process of claim 4 , wherein the metal catalyst is Rh(cod)OTf.6. The process of claim 1 , wherein the chiral ligand or chiral metal catalyst/ligand complex is (S claim 1 ,R)-t-Bu Josiphos claim 1 , Josiphos SL-J011-2 claim 1 , (S claim 1 ,S)-Me-Duphos claim 1 , (S claim 1 ,S)-Chiraphos claim 1 , (R)-Phanephos claim 1 , (R)—Ru(OAc)(DM-segphos) claim 1 , [(R claim 1 ,R)-Me-BPE]Rh(cod)BF claim 1 , (R)—C-TunePhos claim 1 , (R)—[Rh(cod)TCFP]BF claim 1 , or a stereoisomer thereof.7. The process of claim 6 , wherein the chiral ligand is (S claim 6 ,R)-t-Bu Josiphos.8. The process of claim 1 , wherein the load of catalyst is between about 0.05 mol % and about 5 mol %.9. The process of claim 1 , wherein the molar ratio of the chiral ligand to the metal catalyst is from about 3:1 to about 1:1.10. The process of claim 1 , wherein the hydrogen pressure is between about 15 psig and about 250 psig.11. The process of claim 1 , wherein the solvent is ethyl acetate claim 1 , diethyl ether claim 1 , tetrahydrofuran claim 1 , 1 claim 1 ,4-dioxane claim 1 , acetonitrile claim 1 , dichloromethane claim 1 , chloroform claim 1 , N-methylpyrrolidinone claim 1 , dimethyl formamide claim 1 , dimethyl sulfoxide claim 1 , formic acid claim 1 , acetic acid claim 1 , methanol claim 1 , ethanol claim 1 , isopropanol claim 1 , 2 claim 1 ,2 claim 1 ,2-trifluoroethanol claim 1 , or mixtures ...

PROCESSES FOR THE PREPARATION OF (S)-3-(4-((4-(MORPHOLINOMETHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE AND PHARMACEUTICALLY ACCEPTABLE FORMS THEREOF

Provided are processes for the preparation of enantiomerically enriched or enantiomerically pure 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable form thereof. 2. The process of claim 1 , wherein step 1.1 and step 1.2 occur in one-pot.3. The process of claim 1 , wherein step 1.1 occurs in the presence of an acid.4. The process of claim 3 , wherein step 1.1 occurs in the presence of RCOOH wherein Ris hydrogen claim 3 , substituted or unsubstituted Calkyl claim 3 , substituted or unsubstituted Chaloalkyl claim 3 , or substituted or unsubstituted Caryl.5. The process of claim 4 , wherein step 1.1 occurs in the presence of formic acid claim 4 , acetic acid claim 4 , trifluoroacetic acid claim 4 , or benzoic acid.6. The process of claim 3 , wherein step 1.1 occurs in the presence of RSOH wherein le is hydrogen claim 3 , substituted or unsubstituted Calkyl claim 3 , substituted or unsubstituted Chaloalkyl claim 3 , or substituted or unsubstituted Caryl.7. The process of claim 6 , wherein step 1.1 occurs in the presence of sulfonic acid claim 6 , benzenesulfonic acid claim 6 , p-toluenesulfonic acid claim 6 , camphorsulfonic acid claim 6 , methanesulfonic acid claim 6 , or trifluoromethanesulfonic acid.8. The process of claim 7 , wherein step 1.1 occurs in the presence of benzenesulfonic acid claim 7 , p-toluenesulfonic acid claim 7 , camphorsulfonic acid claim 7 , or methanesulfonic acid.9. The process of claim 8 , wherein step 1.1 occurs in the presence of benzenesulfonic acid.10. The process of claim 1 , wherein step 1.2 occurs in the presence of a dehydrating agent.11. The process of claim 10 , wherein step 1.2 occurs in the presence of 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide (EDCI) or 2-(1H-benzotriazole-1-yl)-1 claim 10 ,1 claim 10 ,3 claim 10 ,3-tetramethyluronium tetrafluoroborate (TBTU).12. The process of claim 1 , wherein step 1.2 occurs by azeotropic distillation.13. The process of claim 1 ...

Synthesis of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl)piperidine-2,6-dione

Provided herein are processes for the preparation of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt thereof.

ISOTOPOLOGUES OF 5-AZACYTIDINE

The present disclosure provides pharmaceutical compositions comprising cytidine analogs for oral administration, wherein the compositions release the cytidine analog substantially in the stomach. Also provided are methods of treating diseases and disorders using the oral formulations provided herein. 174-. (canceled)76. The compound of claim 75 , wherein one of Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , and Yis a hydrogen isotopically enriched with deuterium claim 75 , and the others of Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , and Yare non-enriched hydrogen atoms.77. The compound of claim 75 , wherein two of Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , and Yare hydrogens isotopically enriched with deuterium claim 75 , and the others of Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , and Yare non-enriched hydrogen atoms.78. The compound of claim 75 , wherein three of Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , and Yare hydrogens isotopically enriched with deuterium claim 75 , and the others of Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , and Yare non-enriched hydrogen atoms.79. The compound of claim 75 , wherein four of Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , and Yare hydrogens isotopically enriched with deuterium claim 75 , and the others of Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , and Yare non-enriched hydrogen atoms.80. The compound of claim 75 , wherein five of Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , and Yare hydrogens isotopically enriched with deuterium claim 75 , and the others of Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , Y claim 75 , and Yare non-enriched hydrogen atoms.81. The compound of claim 75 , wherein six of Y claim 75 , ...

Isotopologues of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl)piperidine-2,6-dione and methods of preparation thereof

Provided herein are deuterated isotopologues of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or enantiomers or mixtures of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, cocrystal or polymorph thereof, and processes for making the same. Pharmaceutical compositions comprising the isotopes-enriched compounds, and methods of using such compounds are also provided.

ISOTOPOLOGUES OF 5-AZACYTIDINE

The present disclosure provides pharmaceutical compositions comprising cytidine analogs for oral administration, wherein the compositions release the cytidine analog substantially in the stomach. Also provided are methods of treating diseases and disorders using the oral formulations provided herein. 1. (canceled) This application claims priority to, and is a continuation of U.S. patent application Ser. No. 15/835,088, filed Dec. 7, 2017, which is a divisional of U.S. patent application Ser. No. 14/788,606, filed Jun. 30, 2015, entitled “Oral Formulations of Cytidine Analogs and Methods of Use Thereof”, which is a continuation of U.S. patent application Ser. No. 14/463,424, filed Aug. 19, 2014, entitled “Isotopologues of 5-Azacytidine”, which is a continuation of U.S. patent application Ser. No. 12/466,213, filed May 14, 2009, entitled “Oral Formulations of Cytidine Analogs and Methods of Use Thereof”, which claims priority to U.S. Provisional Patent Application Nos. 61/053,609, filed May 15, 2008; 61/201,145, filed Dec. 5, 2008; and 61/157,875, filed Mar. 5, 2009, the contents of each of which are incorporated by reference herein in their entireties.Provided herein are pharmaceutical formulations comprising cytidine analogs, or their salts, solvates, hydrates, precursors, and/or derivatives thereof, for oral administration in subjects. Also provided are methods for making the formulations and methods for using the formulations to treat diseases and disorders including cancer, disorders related to abnormal cell proliferation, hematologic disorders, and immune disorders, among others.Cancer is a major worldwide public health problem; in the United States alone, approximately 570,000 cancer-related deaths were expected in 2005. See, e.g., Jemal et al., 55(1):10-30 (2005). Many types of cancer have been described in the medical literature. Examples include cancer of the blood, bone, lung (e.g., non-small-cell lung cancer and small-cell lung cancer), colon, breast, ...

ISOTOPOLOGUES OF 5-AZACYTIDINE

The present disclosure provides pharmaceutical compositions comprising cytidine analogs for oral administration, wherein the compositions release the cytidine analog substantially in the stomach. Also provided are methods of treating diseases and disorders using the oral formulations provided herein. 1. (canceled) This application claims priority to, and is a divisional of U.S. patent application Ser. No. 14/788,606, filed Jun. 30, 2015, entitled “Oral Formulations of Cytidine Analogs and Methods of Use Thereof”, which is a continuation of U.S. patent application Ser. No. 14/463,424, filed Aug. 19, 2014, entitled “Isotopologues of 5-Azacytidine”, which is a continuation of U.S. patent application Ser. No. 12/466,213, filed May 14, 2009, entitled “Oral Formulations of Cytidine Analogs and Methods of Use Thereof”, which claims priority to U.S. Provisional Patent Application Nos. 61/053,609, filed May 15, 2008; 61/201,145, filed Dec. 5, 2008; and 61/157,875, filed Mar. 5, 2009, the contents of each of which are incorporated by reference herein in their entireties.Provided herein are pharmaceutical formulations comprising cytidine analogs, or their salts, solvates, hydrates, precursors, and/or derivatives thereof, for oral administration in subjects. Also provided are methods for making the formulations and methods for using the formulations to treat diseases and disorders including cancer, disorders related to abnormal cell proliferation, hematologic disorders, and immune disorders, among others.Cancer is a major worldwide public health problem; in the United States alone, approximately 570,000 cancer-related deaths were expected in 2005. See, e.g., Jemal et al., 55(1):10-30 (2005). Many types of cancer have been described in the medical literature. Examples include cancer of the blood, bone, lung (e.g., non-small-cell lung cancer and small-cell lung cancer), colon, breast, prostate, ovary, brain, and intestine. The incidence of cancer continues to climb as the general ...

Isotopologues of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl) piperidine-2-6-dione and methods of preparation thereof

Provided herein are deuterated isotopologues of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or enantiomers or mixtures of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, cocrystal or polymorph thereof, and processes for making the same. Pharmaceutical compositions comprising the isotopes-enriched compounds, and methods of using such compounds are also provided.

SYNTHESIS OF 3-(5-AMINO-2-METHYL-4-OXOQUINAZOLIN-3(4H)-YL)PIPERIDINE-2,6-DIONE

Provided herein are processes for the preparation of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt thereof. 1. A method for preparing 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2 ,6-dione , or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt , solvate , hydrate , or polymorph thereof; comprising the step of reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2 ,6-dione via transfer hydrogenation to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2 ,6-dione , or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt , solvate , hydrate , or polymorph thereof.2. The method of claim 1 , wherein the transfer hydrogenation is conducted in the presence of a hydrogen donor.3. The method of claim 2 , wherein the hydrogen donor is (i) a Calcohol claim 2 , Ccarboxylic acid claim 2 , Ccarboxylic acid salt claim 2 , Ccarboxylic acid ester claim 2 , Calkene claim 2 , Ccycloalkene claim 2 , Carene claim 2 , heteroarene claim 2 , or heterocycle claim 2 , each of which is optionally substituted with one or more substituents Q; or (ii) diazene claim 2 , hydrazine claim 2 , hydroxylamine claim 2 , or NaHPO;{'sub': 1-6', '2-6', '2-6', '3-10', '6-14', '7-15', '2', '2', '2', '2', '2', '2', '1-6', '2-6', '2-6', '3-10', '6-14', '7-15, 'sup': a', 'a', 'a', 'b', 'c', 'a', 'b', 'c', 'a', 'a', 'a', 'b', 'c', 'a', 'b', 'c', 'a', 'a', 'b', 'c', 'b', 'c', 'b', 'c', 'a', 'd', 'a', 'd', 'a', 'b', 'c', 'a', 'd', 'b', 'c', 'a', 'd', 'a', 'd', 'a', 'b', 'c', 'a', 'b', 'c', 'a', 'd', 'a', 'd', 'a', 'd', 'a', 'a', 'a', 'b', 'c', 'b', 'c', 'a', 'b', 'c', 'd', 'a', 'b', 'c', 'a, 'wherein each substituent Q is independently selected from the group consisting of (a) oxo, halo, cyano, and nitro; (b) Calkyl, Calkenyl, Calkynyl, Ccycloalkyl, Caryl, Caralkyl, heteroaryl, and heterocyclyl, ...

ISOTOPOLOGUES OF 5-AZACYTIDINE

The present disclosure provides pharmaceutical compositions comprising cytidine analogs for oral administration, wherein the compositions release the cytidine analog substantially in the stomach. Also provided are methods of treating diseases and disorders using the oral formulations provided herein. 1. (canceled) This application claims priority to, and is a continuation of U.S. patent application Ser. No. 15/835,088, filed Dec. 7, 2017, which is a divisional of U.S. patent application Ser. No. 14/788,606, filed Jun. 30, 2015, entitled “Oral Formulations of Cytidine Analogs and Methods of Use Thereof”, which is a continuation of U.S. patent application Ser. No. 14/463,424, filed Aug. 19, 2014, entitled “Isotopologues of 5-Azacytidine”, which is a continuation of U.S. patent application Ser. No. 12/466,213, filed May 14, 2009, entitled “Oral Formulations of Cytidine Analogs and Methods of Use Thereof”, which claims priority to U.S. Provisional Patent Application Nos. 61/053,609, filed May 15, 2008; 61/201,145, filed Dec. 5, 2008; and 61/157,875, filed Mar. 5, 2009, the contents of each of which are incorporated by reference herein in their entireties.Provided herein are pharmaceutical formulations comprising cytidine analogs, or their salts, solvates, hydrates, precursors, and/or derivatives thereof, for oral administration in subjects. Also provided are methods for making the formulations and methods for using the formulations to treat diseases and disorders including cancer, disorders related to abnormal cell proliferation, hematologic disorders, and immune disorders, among others.Cancer is a major worldwide public health problem; in the United States alone, approximately 570,000 cancer-related deaths were expected in 2005. See, e.g., Jemal et al., 55(1):10-30 (2005). Many types of cancer have been described in the medical literature. Examples include cancer of the blood, bone, lung (e.g., non-small-cell lung cancer and small-cell lung cancer), colon, breast, ...

SYNTHESIS OF 3-(5-AMINO-2-METHYL-4-OXOQUINAZOLIN-3(4H)-YL)PIPERIDINE-2,6-DIONE

Provided herein are processes for the preparation of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt thereof. 1. A method for preparing 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2 ,6-dione , or an enantiomer or a mixture of enantiomers thereof or a pharmaceutically acceptable salt , solvate , hydrate , or polymorph thereof comprising the step of reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2 ,6-dione via transfer hydrogenation to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2 ,6-dione , or an enantiomer or a mixture of enantiomers thereof or a pharmaceutically acceptable salt , solvate , hydrate , or polymorph thereof.2. The method of claim 1 , wherein the transfer hydrogenation is conducted in the presence of a hydrogen donor.3. The method of claim 2 , wherein the hydrogen donor is (i) a Calcohol claim 2 , Ccarboxylic acid claim 2 , Ccarboxylic acid salt claim 2 , Ccarboxylic acid ester claim 2 , Calkene claim 2 , Ccycloalkene claim 2 , Carene claim 2 , heteroarene claim 2 , or heterocycle claim 2 , each of which is optionally substituted with one or more substituents Q; or (ii) diazene (also known as diimine or diimide) claim 2 , hydrazine claim 2 , hydroxylamine claim 2 , or NaHPO;{'sub': 1-6', '2-6', '2-6', '3-10', '6-14', '7-15', '2', '2', '2', '2', '2', '2', '1-6', '2-6', '2-6', '3-10', '6-14', '7-15, 'sup': a', 'a', 'a', 'b', 'c', 'a', 'b', 'c', 'a', 'a', 'a', 'b', 'c', 'a', 'b', 'c', 'a', 'a', 'b', 'c', 'b', 'c', 'b', 'c', 'a', 'd', 'a', 'd', 'a', 'b', 'c', 'a', 'd', 'b', 'c', 'a', 'd', 'a', 'd', 'a', 'b', 'c', 'a', 'b', 'c', 'a', 'd', 'a', 'd', 'a', 'd', 'a', 'a', 'a', 'b', 'c', 'b', 'c', 'a', 'b', 'c', 'd', 'a', 'b', 'c', 'a, 'wherein each substituent Q is independently selected from the group consisting of (a) oxo, halo, cyano, and nitro; (b) Calkyl, Calkenyl, Calkynyl, Ccycloalkyl, Caryl, ...

SOLID FORMS OF 3-(5-AMINO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE, AND THEIR PHARMACEUTICAL COMPOSITIONS AND USES

Solid forms comprising 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, compositions comprising the solid forms, methods of making the solid forms and methods of their uses are disclosed 164-. (canceled)66. The method of claim 65 , wherein the solid form is a solid form of a hydrochloride salt of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2 claim 65 ,6-dione claim 65 , having an X-ray powder diffraction pattern comprising peaks at approximately 8.6 °2θ claim 65 , 13.1 °2θ claim 65 , 20.5 °2θ and 26.3 °2θ as shown in claim 65 , when analyzed using Cu Kα X-ray radiation at 1.54 Å.67. The method of claim 65 , wherein the solid form has an X-ray powder diffraction pattern comprising peaks at approximately 8.6 °2θ claim 65 , 11.3 °2θ claim 65 , 13.1 °2θ claim 65 , 15.3 °2θ claim 65 , 17.3 °2θ claim 65 , 20.5 °2θ claim 65 , 22.7 °2θ claim 65 , 23.6 °2θ claim 65 , 26.3 °2θ and 31.4 °2θ as shown in claim 65 , when analyzed using Cu Kα X-ray radiation at 1.54 Å.68. The method of claim 66 , wherein the solid form has a differential scanning calorimetry plot comprising an endothermic event with an onset temperature of approximately 276° C. claim 66 , when heated from approximately 25° C. to approximately 300° C.69. The method of claim 66 , wherein the solid form has a thermal gravimetric analysis plot comprising a mass loss of less than approximately 0.5% when heated from approximately 25° C. to approximately 150° C.70. The method of claim 66 , wherein the solid form is anhydrous.71. The method of claim 66 , wherein the solid form exhibits a mass increase of less than approximately 0.5% when subjected to an increase in relative humidity from approximately 0% to approximately 95% relative humidity.72. The method of claim 66 , wherein the solid form is substantially nonhygroscopic.73. The method of claim 66 , wherein the solid form is stable upon exposure to approximately 40° C. and approximately 75% relative humidity for approximately 4 weeks.74 ...

SOLID FORMS OF 3-(5-AMINO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE, AND THEIR PHARMACEUTICAL COMPOSITIONS AND USES

Solid forms comprising 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, compositions comprising the solid forms, methods of making the solid forms and methods of their uses are disclosed. 164-. (canceled)66. The method of claim 65 , wherein disease or disorder is leukemia or lymphoma.67. The method of claim 66 , wherein the lymphoma is Hodgkin's lymphoma.68. The method of claim 66 , wherein the lymphoma is Non-Hodgkin's lymphoma.69. The method of claim 68 , wherein the Non-Hodgkin's lymphoma is diffuse large B-cell lymphoma.70. The method of claim 68 , wherein the Non-Hodgkin's lymphoma is cutaneous T-cell lymphoma claim 68 , cutaneous B-cell lymphoma claim 68 , diffuse large B-cell lymphoma claim 68 , Waldenstrom's macrogliobineima claim 68 , mantle cell lymphoma claim 68 , or follicular lymphoma.71. The method of claim 65 , wherein the leukemia is chronic lymphocytic leukemia claim 65 , chronic myelocytic leukemia claim 65 , acute lymphoblastic leukemia claim 65 , acute myelogenous leukemia claim 65 , or acute myeloblastic leukemia.72. The method of claim 65 , wherein the disease or disorder is multiple myeloma claim 65 , smoldering myeloma claim 65 , or indolent myeloma.73. The method of claim 72 , wherein the disease or disorder is multiple myeloma.74. The method of claim 72 , wherein the disease or disorder is refractory or resistant multiple myeloma.75. The method of claim 66 , wherein the disease or disorder is myelodysplastic syndrome or myeloproliferative disease.76. The method of claim 65 , wherein the solid form has an X-ray powder diffraction pattern comprising peaks at approximately 14.6 °2θ claim 65 , 15.6 °2θ claim 65 , 16.7 °2θ claim 65 , 21.9 °2θ and 30.0 °2θ as shown in claim 65 , when analyzed using Cu Kα X-ray radiation at 1.54 Å.77. The method of claim 65 , wherein the solid form has an X-ray powder diffraction pattern comprising peaks at approximately 9.2 °2θ claim 65 , 13.4 °2θ claim 65 , 14.0 °2θ claim 65 , 14.6 °2θ claim ...

ISOTOPOLOGUES OF 5-AZACYTIDINE

The present disclosure provides pharmaceutical compositions comprising cytidine analogs for oral administration, wherein the compositions release the cytidine analog substantially in the stomach. Also provided are methods of treating diseases and disorders using the oral formulations provided herein. 1. (canceled) This application claims priority to, and is a continuation of U.S. patent application Ser. No. 16/582,779, filed Sep. 25, 2019, which is a continuation of U.S. patent application Ser. No. 16/244,014, filed Jan. 9, 2019, which is a continuation of U.S. patent application Ser. No. 15/835,088, filed Dec. 7, 2017, which is a divisional of U.S. patent application Ser. No. 14/788,606, filed Jun. 30, 2015, entitled “Oral Formulations of Cytidine Analogs and Methods of Use Thereof”, which is a continuation of U.S. patent application Ser. No. 14/463,424, filed Aug. 19, 2014, entitled “Isotopologues of 5-Azacytidine”, which is a continuation of U.S. patent application Ser. No. 12/466,213, filed May 14, 2009, entitled “Oral Formulations of Cytidine Analogs and Methods of Use Thereof”, which claims priority to U.S. Provisional Patent Application Nos. 61/053,609, filed May 15, 2008; 61/201,145, filed Dec. 5, 2008; and 61/157,875, filed Mar. 5, 2009, the contents of each of which are incorporated by reference herein in their entireties.Provided herein are pharmaceutical formulations comprising cytidine analogs, or their salts, solvates, hydrates, precursors, and/or derivatives thereof, for oral administration in subjects. Also provided are methods for making the formulations and methods for using the formulations to treat diseases and disorders including cancer, disorders related to abnormal cell proliferation, hematologic disorders, and immune disorders, among others.Cancer is a major worldwide public health problem; in the United States alone, approximately 570,000 cancer-related deaths were expected in 2005. See, e.g., Jemal et al., 55(1):10-30 (2005). Many types of ...

SOLID FORMS OF 3-(5-AMINO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE, AND THEIR PHARMACEUTICAL COMPOSITIONS AND USES

Solid forms comprising 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, compositions comprising the solid forms, methods of making the solid forms and methods of their uses are disclosed 164-. (canceled)66. The method of claim 65 , wherein the solid form has an X-ray powder diffraction pattern comprising peaks at approximately 8.6° 2θ claim 65 , 11.3° 2θ claim 65 , 13.1° 2θ claim 65 , 15.3° 2θ claim 65 , 17.3° 2θ claim 65 , 20.5° 2θ claim 65 , 22.7° 2θ claim 65 , 23.6° 2θ claim 65 , 26.3° 2θ and 31.4° 2θ as shown in claim 65 , when analyzed using Cu Kα X-ray radiation at 1.54 Å.67. The method of claim 65 , wherein the solid form has a differential scanning calorimetry plot comprising an endothermic event with an onset temperature of approximately 276° C. claim 65 , when heated from approximately 25° C. to approximately 300° C.68. The method of claim 65 , wherein the solid form has a thermal gravimetric analysis plot comprising a mass loss of less than approximately 0.5% when heated from approximately 25° C. to approximately 150° C.69. The method of claim 65 , wherein the solid form is anhydrous.70. The method of claim 65 , wherein the solid form exhibits a mass increase of less than approximately 0.5% when subjected to an increase in relative humidity from approximately 0% to approximately 95% relative humidity.71. The method of claim 65 , wherein the solid form is substantially nonhygroscopic.72. The method of claim 65 , wherein the solid form is stable upon exposure to approximately 40° C. and approximately 75% relative humidity for approximately 4 weeks.73. The method of claim 65 , wherein the molar ratio of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2 claim 65 ,6-dione to hydrochloride is from approximately 0.1 to approximately 10.74. The method of claim 65 , wherein the solid form is administered at a dose of about 1 mg to about 20 mg.75. The method of claim 65 , wherein a pharmaceutical composition comprising the solid form and ...

Solid forms of 3-(5-amino-2methyl-4-oxo-4h-quinazolin-3-yl)-piper idine-2,6-dione, and their pharmaceutical compositions and uses.

Se describen formas sólidas que comprenden 3-(5-amino-2-metil-4-ox o-4H-quinazolin-3-il)-piperidin-2,6-diona, composiciones que comprenden las formas sólidas, métodos de elaborar las formas sólidas y métodos de sus usos.

PROCESS FOR PREPARING A 2-ALKYNYL SUBSTITUTED 5-AMINO-PYRAZOLO-[4,3-e]-1,2,4-TRIAZOLO[1,5-c]PYRIMIDINE

A process for preparing 7-[2-[4-(6-fluoro -3-methyl -1,2-benzisoxazol-5-yl)-1-piperazinyl]ethyl]-2-(1-propynyl)-7H-pyrazolo-[4,3-e]-[1,2,4]-triazolo[1,5-c]pyrimidin-5-amine, intermediates useful in that process, and processes for preparing said intermediates are disclosed.

Solid forms of 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses

88001149 ABSTRACT Solid forms comprising 3-(5-amino-2-methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-dione, compositions comprising the solid forms, methods of making the solid forms and methods of their uses. Date Recue/Date Received 2021-02-19

Preparation of pharmaceutical salts of 4 ( (z) - (4-bromophenyl) (ethoxyimino) methyl )-1'-( (2,4-dimethyl-1-oxido-3-pyridinyl) carbonyl) -4'-methyl-1,4' bipiperidine as ccr5-antagonists for the treatment of aids and related hiv infections

A process for preparing a mixture of rotamers or rotamer pairs of a salt of a basic compound of formula (I) wherein said mixture comprises one or more rotamers or rotamer pairs of the salt in a higher molar percent than other corresponding rotamers or rotamer pairs of the salt, said process comprising reacting said basic compound with an acid in admixture with a solvent.

Process for preparing ccr-5 receptor antagonists utilizing 4-substituted 1-cyclopropane-sulfonyl-piperidinyl compounds

The present invention discloses a novel process to prepare 4-substituted 1-Cyclopropane-sulfonyl-Piperidinyl compounds, which are useful intermediates for the preparation of antagonists of CCR5 receptor and therefore useful for the treatment of HIV virus infected mammals. It specifically discloses a novel process to synthesize 4-[4-[(R)-[1-[cyclopropylsulfonyl)-4-piperidinyl](3-fluorophenyl)methyl]-3(S)-methyl-1-piperazinyl]-1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-methylpiperidine] compounds.

Enantio- and stereo-specific syntheses of -amino- - hydroxy amides

Processes useful for the preparation of a Compound of Formula I: Formula (I). Intermediates useful for the preparation of the compound of Formula I, and processes useful for preparing said intermediates are disclosed.

Preparation of pharmaceutical salts of 4 ( (z) - (4-bromophenyl) (ethoxyimino) methyl)-1'-( (2,4-dimethyl-1-oxido-3-pyridinyl) carbonyl) -4'-me thyl-1,4' bipiperidine as ccr5-antagonists for the treatment of aids and related hiv infections

A process for preparing a mixture of rotamers or rotamer pairs of a salt of a basic compound of formula (I) wherein said mixture comprises one or more rotamers or rotamer pairs of the salt in a higher molar percent than other corresponding rotamers or rotamer pairs of the salt, said process comprising reacting said basic compound with an acid in admixture with a solvent.</SDOA B>

Improved nitro-fatty acid oral dose regimens

The present disclosure provides methods of treating a variety of diseases, wherein the method comprises administering to a human subject an oral daily dose in an amount of at least 450 mg to 2,000 mg of compounds and compositions comprising esters and acids of nitro-containing fatty acids and esters. The present disclosure also provides pharmaceutical compositions and oral dosage units comprising acids and esters of nitro-containing fatty acids.

Enantio- and stereo-specific syntheses of beta-amino-alpha- hydroxy amides

Processes useful for the preparation of a Compound of Formula I: Formula (I). Intermediates useful for the preparation of the compound of Formula I, and processes useful for preparing said intermediates are disclosed.

Solid forms of 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses

Solid forms comprising 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)- piperidine-2,6-dione, compositions comprising the solid forms, methods of making the solid forms and methods of their uses are disclosed

Solid forms of 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses

Solid forms comprising 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)- piperidine-2,6-dione, compositions comprising the solid forms, methods of making the solid forms and methods of their uses are disclosed

processes for the preparation of (s) -3- (4 - ((4- (morpholinomethyl) benzyl) oxy) -1-oxoisoindolin-2-yl) piperidine-2,6-dione and pharmaceutically acceptable forms thereof

resumo “processos para a preparação de (s) -3- (4 - ((4- (morfolinometil) benzil) oxi) -1-oxoisoindolin-2-il) -piperidina-2,6-diona e formas farmaceuticamente aceitáveis da mesma.” são fornecidos processos para a preparação de 3-(4 -((4-(morfolinometil)benzil)oxi) -1-oxoisoindolino-2-il)piperidina-2,6-diona enantiomericamente enriquecida ou enantiomericamente pura, ou uma forma farmaceuticamente aceitável da mesma. 1 1 / 1 abstract “processes for the preparation of (s)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione and pharmaceutically acceptable forms thereof .” Processes are provided for the preparation of enantiomerically enriched or enantiomerically pure 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolino-2-yl)piperidine-2,6-dione, or an pharmaceutically acceptable thereof. 1 1 / 1

Synthesis of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl) piperidine-2,6-dione

COMPOSITION OF 3- (5-AMINO-2-METHYL-4-OXOKINAZOLIN-3 (4H) -YL) PIPE-RIDINO-2,6-DIONIS

Δίδονται εδώ μέθοδοι για την παρασκευή 3-(5-αμινο-2-μεθυλ-4-οξοκιναζολιν-3(4H)-υλ)πιπεριδινο-2,6-διόνης ή ενός εναντιομερούς ή ενός μίγματος εναντιομερών αυτής- ή ενός φαρμακευτικά αποδεκτού άλατος αυτής.

Synthesis of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl) piperidine-2,6-dione

Processes for the preparation of (s)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and pharmaceutically acceptable forms thereof

Provided are processes for the preparation of enantiomerically enriched or enantiomerically pure 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a pharmaceutically acceptable form thereof.

Solid forms of 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses

Solid forms comprising 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)- piperidine-2,6-dione, compositions comprising the solid forms, methods of making the solid forms and methods of their uses.

Synthesis of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl)piperidine-2,6-dione

Provided herein are processes for the preparation of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt thereof.

Preparation of pharmaceutical salts of 4((Z)-(4-bromophenyl)(ethoxyimino)methyl)-1'-((2,4-dimethyl-1-oxido-3-pyridinyl)(carbonyl)-4'-methyl-1-4'bipiperidine as CCR5-antagonists for the treatment of AIDS and related HIV infections.

Isotopologues of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4h)-yl) piperidine-2-6-dione and methods of preparation thereof

Provided herein are deuterated isotopologues of 3-(5-amino-2-methyl-4- oxoquinazolin-3(4 H )-yl)piperidine-2,6-dione, or enantiomers or mixtures of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, cocrystal or polymorph thereof, and processes for making the same. Pharmaceutical compositions comprising the isotopes- enriched compounds, and methods of using such compounds are also provided.

Synthesis of 4- (z)-(4-bromophenyl)(ethoxyimino)methyl]-1'- 2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl]-4'methyl-1,4'bipiperidine

In one embodiment, the present invention describes the synthesis of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1'-[(2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidine, and intermediates therefor from easily available starting materials by a simple route.

Synthesis of 4-[(z)-(4-bromophenyl)(ethoxyimino)methyl]-1'-[2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl]-4'methyl-1,4'bipiperidine

In one embodiment, the present invention describes the synthesis of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1'-[(2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidine, and intermediates therefor from easily available starting materials by a simple route.

Synthesis of 4-(Z)-(4-bromophenyl)(ethoxyimino)methylÜ-1'-2,4,dimethyl-1-oxido-3-pyridinyl)carbonylÜ-4'methyl-1,4'bipiperidine.

Sintesis de 4-((z)-(4-bromofenil)(etoxiimono)metil)-1'-((2,4-dimetil-1-oxido-3-piridinil) carbonil)-4'-metil-1,4-bipiperidina.

Un procedimiento para la preparación de un compuesto de **fórmula** comprendiendo dicho procedimiento: (a) la conversión de la oxima a un compuesto en la que G es un grupo saliente seleccionado del grupo que consiste en CN, Y, OSO2R1, OCOCY3 y benzotriazolilo, siendo R1 un grupo alquilo o arilo; Y es un halógeno; y Q es un grupo N-protector adecuado seleccionado del grupo que consiste en alilo, metoximetilo, benciloximetilo, CY3CO (en la que Y es un halógeno), benciloxicarbonilo, tritilo, pivaloiloximetilo, tetrahidropiranilo, bencilo, di(p- metoxifenil)metilo, trifenilmetilo, (p- metoxifenil)difenilmetilo, difenilfosfinilo, bencenosulfenilo, metilcarbamato, 2-trimetilsililetil carbamato, 1-metil-1-feniletil carbamato, t-butil carbamato (-t-Boc-), ciclobutil carbamato, 1-metilciclobutil carbamato, adamantil carbamato, vinil carbamato, alil carbamato, cinnamil carbamato, 8-quinolil carbamato, 4, 5- difenil-3-oxazolin-2-ona, bencil carbamato, 9-antrilmetil carbamato, difenilmetil carbamato, S-bencilcarbamato, y la fracción: (b) la reacción de dicho compuesto con un reactivo de Grignard adecuado en un disolvente adecuado, seguido de work-up, (c) la desprotección de dicho compuesto, (d) la formación de la sal del compuesto, y (e) la reacción de dicho compuesto.

Synthese von 4-(z)-(4-brom phenyl)(ethoxyimino)methyl]-1'- 2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bispiperidin

Synthese von 4-(z)-(4-brom phenyl)(ethoxyimino)methyl)-1'- 2,4-dimethyl-1- oxido-3-pyridinyl)carbonyl)-4'-methyl-1,4'- bispiperidin

Synthesis of 4- (z)-(4-bromophenyl)(ethoxyimino)methyl]-1'- 2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl]-4'methyl-1,4'bipiperidine

In one embodiment, the present invention describes the synthesis of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1'-[(2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidine, and intermediates therefor from easily available starting materials by a simple route.

Synthesis of 4-((z)-(4-bromophenyl)(ethoxyimino)methyl)-1'-(2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl)-4'methyl-1,4'bipiperidine

Solid forms of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses

Solid forms comprising 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, compositions comprising the solid forms, methods of making the solid forms and methods of their uses are disclosed.

Solid forms of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, and their pharmaceutical compositions and uses

Solid forms comprising 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, compositions comprising the solid forms, methods of making the solid forms and methods of their uses are disclosed.

Isotopologues of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl) piperidine-2-6-dione and methods of preparation thereof

Provided herein are deuterated isotopologues of 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or enantiomers or mixtures of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, cocrystal or polymorph thereof, and processes for making the same. Pharmaceutical compositions comprising the isotopes-enriched compounds, and methods of using such compounds are also provided.