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

Abstract

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.

1 - 98 . (canceled) 
     
     
         99 . A method of treating, managing or preventing a disease or disorder comprising administering to a patient a compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or polymorph thereof, 
         wherein at least one of Y 1 , Y 2 , Y 3 , Y 4 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , and Y 14 , is a hydrogen that is isotopically enriched with deuterium, and the others of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13  and Y 14  are non-enriched hydrogen atoms, 
         and wherein the disease or disorder is cancer, a disorder associated with angiogenesis, pain, macular degeneration or a related syndrome, a skin disease, a pulmonary disorder, an asbestos-related disorder, a parasitic disease, an immunodeficiency disorder, a CNS disorder, CNS injury, atherosclerosis or a related disorder, dysfunctional sleep or a related disorder, hemoglobinopathy or a related disorder, or a TNFα related disorder. 
       
     
     
         100 . The method of claim  1 , wherein one of Y 1 , Y 2 , Y 3 , Y 4 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13  and Y 14  is a hydrogen that is isotopically enriched with deuterium, and the others of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13  and Y 14  are non-enriched hydrogen atoms. 
     
     
         101 . The method of  claim 99 , wherein two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or all of Y 1 , Y 2 , Y 3 , Y 4 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13  and Y 14  are hydrogen atoms that are isotopically enriched with deuterium, and the others of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13  and Y 14  are non-enriched hydrogen atoms. 
     
     
         102 . The method of  claim 100 , wherein Y 1  is a hydrogen that is isotopically enriched with deuterium. 
     
     
         103 . The method of  claim 100 , wherein Y 3  is a hydrogen that is isotopically enriched with deuterium. 
     
     
         104 . The method of  claim 100 , wherein Y 6  is a hydrogen that is isotopically enriched with deuterium. 
     
     
         105 . The method of  claim 100 , wherein Y 9  is a hydrogen that is isotopically enriched with deuterium. 
     
     
         106 . The method of  claim 100 , wherein Y 10  is a hydrogen that is isotopically enriched with deuterium. 
     
     
         107 . The method of  claim 100 , wherein Y 11  is a hydrogen that is isotopically enriched with deuterium. 
     
     
         108 . The method of  claim 99 , wherein the cancer is advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant giolma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, or leiomyoma. 
     
     
         109 . The method of  claim 108 , wherein the cancer is non-Hodgkin's lymphoma. 
     
     
         110 . The method of  claim 109 , wherein the non-Hodgkin's lymphoma is diffuse large B-cell lymphoma. 
     
     
         111 . The method of  claim 99 , wherein the method comprises administering a second active agent. 
     
     
         113 . A method for preparing a compound of formula (I-A): 
       
         
           
           
               
               
           
         
         wherein Y 12 , Y 13  and Y 14  are independently H or D, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or polymorph thereof, comprising the steps of:
 (a) contacting 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione with a base and an exchangeable deuterium source; 
 (b) performing an aqueous workup on the reaction mixture from step (a) to form a compound of formula (I-A) or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; and 
 (c) optionally obtaining enantiomers using chiral separation. 
 
       
     
     
         114 . The method of  claim 113 , wherein the base is sodium C 1-14  alkoxide, potassium C 1-14  alkoxide, sodium hydride, potassium hydride, calcium hydride. sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, cesium carbonate. lithium hexamethyldisilazide (LiHMDS), lithium diisopropylamide (LDA), 2-tert-butyl-1,1,3,3-tetramethyl-guanidine (Barton's Base), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo(2.2.2)octane (DABCO), N,N-diisopropylethylamine (DIPEA or Hünig's base, pyridine, 2,6-di-tert-butyl-pyridine, 2,6-lutidine. In lithium tetramethylpiperidide (LiTMP or harpoon base, 7-methyl-1,5,7 triazabicyclo[4.4.0]dec-5-ene (MTBD), 1,2,2,6,6-pentamethylpiperidine (PMP), 2,2,6,6-tetramethylpiperidine (TMP), tributylamine, 2,4,6-tri-tert-butylpyridine, tris(trimethylsilyl)amine, n-butyllithium, sec-butyllithium, tert-butyllithium, potassium bis(trimethylsilyl)amide, sodium tert-butoxide, potassium tert-butoxide, tert-butylimino-tris(dimethylamino)phosphorane and 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine. 
     
     
         115 . The method of  claim 113 , wherein the exchangeable deuterium source is selected from the group consisting of is D 2 O, C 1-14  alkyl-OD, C 1-14  alkyl-COOD, aryl-OD, heteroaryl-OD, aryl-SO 3 D, deuterium chloride, deuterium bromide, deuterium iodide, sulfuric acid-d 2  and nitric acid-d 1 . 
     
     
         116 . A method for preparing a compound of formula I-B 
       
         
           
           
               
               
           
         
         wherein Y 12 , Y 13  and Y 14  are independently H or D, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or polymorph thereof, comprising the steps of:
 (a) contacting 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione or a salt thereof with an exchangeable deuterium source in a solvent to form a compound of formula (I-B), or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; and 
 (b) optionally obtaining enantiomers by chiral separation. 
 
       
     
     
         117 . The method of  claim 116 , wherein the exchangeable deuterium source is D 2 O, C 1-14  alkyl-OD, C 1-14  alkyl-COOD, aryl-OD, heteroaryl-OD, aryl-SO 3 D, deuterium chloride, deuterium bromide, deuterium iodide, sulfuric acid-d 2  or nitric acid-d 1 . 
     
     
         118 . The method of  claim 116 , wherein the solvent is a hydrocarbon, chlorinated hydrocarbon, alcohol, ether, ketone, ester, carbonate, amide, nitrile, sulfoxide, sulfone, nitro compound, arene, heteroarene, heterocycle, carboxylic acid, phosphoramide, carbon sulfide or water.