Crystalline diacylhydrazine and the use thereof

Abstract

The present disclosure provides crystalline polymorphic and amorphous forms of (R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide (Compound 1) or (S)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide (Compound 2). The present disclosure further provides compositions comprising crystalline polymorphic and amorphous forms of Compound 1 or Compound 2 and an excipient, methods of making crystalline polymorphic or amorphous forms of Compound 1 or Compound 2, and methods of using crystalline polymorphic or amorphous forms of Compound 1 or Compound 2 to regulate gene expression in a cell or in a subject.

1 - 19 . (canceled) 
     
     
         20 . A method of regulating gene expression of a gene of interest in a host cell, the method comprising contacting said host cell with a composition comprising crystalline (R)-3.5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide Form III Form IV, Form V, Form VI Form VII, Form VIII, or Form IX, wherein:
 Form III is characterized as having a powder x-ray diffraction pattern with peaks at 8.14, 8.52, 17.00, 18.56, and 22.19 degrees 2Θ; 
 Form IV is characterized as having a powder x-ray diffraction pattern with peaks at 6.83, 10.31, 11.30, 12.18, 12.98, 13.69, 15.11, 16.23, 17.60, 17.99, 20.70, 21.15, 21.68, 22.71, 23.79, and 24.86 degrees 2Θ; 
 Form V is characterized as having a powder x-ray diffraction pattern with peaks at 9.38, 12.22, 13.18, 14.98, 17.32, 18.40, 22.41, 23.40, 23.55, 24.63, 24.79, 25.61, 28.02, and 31.77 degrees 2Θ; 
 Form VI is characterized as having a powder x-ray diffraction pattern with peaks at 9.38, 12.23, 13.25, 17.48, 18.41, and 22.41 degrees 2Θ; 
 Form VII is characterized as having a powder x-ray diffraction pattern with peaks at 8.18, 9.71, 13.30, 16.22, 17.73, 20.98, 21.20, 22.76, 24.68, 26.72, and 29.39 degrees 2Θ; 
 Form VIII is characterized as having a powder x-ray diffraction pattern with peaks at 10.05, 10.77, 14.06, 16.76, 18.11, 18.32, 18.43, 20.89, 21.71, 21.87, 24.07, 24.90, and 28.71 degrees 2Θ; and 
 Form IX is characterized as having a powder x-ray diffraction pattern with peaks at 7.06, 15.74, and 18.71 degrees 2Θ. 
 
     
     
         21 . The method of  claim 20 , wherein the host cell comprises a polynucleotide encoding a gene switch that comprises an ecdysone receptor ligand binding domain that binds (R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide. 
     
     
         22 - 23 . (canceled) 
     
     
         24 . A method of treating a cancer, a metabolic-related disorder, kidney disease, anemia, an autoimmune disorder, an ocular disorder, a blood disorder, a neurological disorder, a lung disorder, a rheumatologic disorder, or an infectious disease in a subject, the method comprising administering to said subject a composition comprising crystalline (R)-3.5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide Form III, Form IV, Form V, Form VI, Form VII, Form VIII, or Form IX, wherein:
 Form III is characterized as having a powder x-ray diffraction pattern with peaks at 8.14, 8.52, 17.00, 18.56, and 22.19 degrees 2Θ; 
 Form IV is characterized as having a powder x-ray diffraction pattern with peaks at 6.83, 10.31, 11.30, 12.18, 12.98, 13.69, 15.11, 16.23, 17.60, 17.99, 20.70, 21.15, 21.68, 22.71, 23.79, and 24.86 degrees 2Θ; 
 Form V is characterized as having a powder x-ray diffraction pattern with peaks at 9.38, 12.22, 13.18, 14.98, 17.32, 18.40, 22.41, 23.40, 23.55, 24.63, 24.79, 25.61, 28.02, and 31.77 degrees 2Θ; 
 Form VI is characterized as having a powder x-ray diffraction pattern with peaks at 9.38, 12.23, 13.25, 17.48, 18.41, and 22.41 degrees 2Θ; 
 Form VII is characterized as having a powder x-ray diffraction pattern with peaks at 8.18, 9.71, 13.30, 16.22, 17.73, 20.98, 21.20, 22.76, 24.68, 26.72, and 29.39 degrees 2Θ; 
 Form VIII is characterized as having a powder x-ray diffraction pattern with peaks at 10.05, 10.77, 14.06, 16.76, 18.11, 18.32, 18.43, 20.89, 21.71, 21.87, 24.07, 24.90, and 28.71 degrees 2Θ; and 
 Form IX is characterized as having a powder x-ray diffraction pattern with peaks at 7.06, 15.74, and 18.71 degrees 2Θ, 
 wherein a host cell within said subject comprises a polynucleotide encoding a gene switch that comprises an ecdysone receptor ligand binding domain that binds (R)-3.5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide. 
 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 24 , wherein said subject is human. 
     
     
         27 - 31 . (canceled) 
     
     
         32 . The method of  claim 24 , wherein said host cell further comprises a polynucleotide encoding a peptide, protein or polypeptide whose expression is regulated by said gene switch. 
     
     
         33 . The method of  claim 32 , wherein said polynucleotide encodes IL-12 or a subunit thereof. 
     
     
         34 . A method of controlling insects, the method comprising contacting said insects or their habitat with an insecticidally effective amount of crystalline (R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide Form III, Form IV, Form V, Form VI, Form VII, Form VIII, or Form IX, wherein:
 Form III is characterized as having a powder x-ray diffraction pattern with peaks at 8.14, 8.52, 17.00, 18.56, and 22.19 degrees 2Θ; 
 Form IV is characterized as having a powder x-ray diffraction pattern with peaks at 6.83, 10.31, 11.30, 12.18, 12.98, 13.69, 15.11, 16.23, 17.60, 17.99, 20.70, 21.15, 21.68, 22.71, 23.79, and 24.86 degrees 2Θ; 
 Form V is characterized as having a powder x-ray diffraction pattern with peaks at 9.38, 12.22, 13.18, 14.98, 17.32, 18.40, 22.41, 23.40, 23.55, 24.63, 24.79, 25.61, 28.02, and 31.77 degrees 2Θ; 
 Form VI is characterized as having a powder x-ray diffraction pattern with peaks at 9.38, 12.23, 13.25, 17.48, 18.41, and 22.41 degrees 2Θ; 
 Form VII is characterized as having a powder x-ray diffraction pattern with peaks at 8.18, 9.71, 13.30, 16.22, 17.73, 20.98, 21.20, 22.76, 24.68, 26.72, and 29.39 degrees 2Θ; 
 Form VIII is characterized as having a powder x-ray diffraction pattern with peaks at 10.05, 10.77, 14.06, 16.76, 18.11, 18.32, 18.43, 20.89, 21.71, 21.87, 24.07, 24.90, and 28.71 degrees 2Θ; and 
 Form IX is characterized as having a powder x-ray diffraction pattern with peaks at 7.06, 15.74, and 18.71 degrees 2Θ, 
 or a composition thereof. 
 
     
     
         35 - 38 . (canceled) 
     
     
         39 . The method of  claim 20  comprising contacting said host cell with a composition comprising crystalline (R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide Form III. 
     
     
         40 . The method of  claim 20  comprising contacting said host cell with a composition comprising crystalline (R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide Form IV. 
     
     
         41 . The method of  claim 20 , wherein said host cell is an isolated host cell. 
     
     
         42 . The method of  claim 20 , wherein said host cell is in a subject. 
     
     
         43 . The method of  claim 42 , wherein the gene of interest encodes a peptide, protein, or polypeptide of therapeutic interest for the treatment of a disease, condition, or disorder in said subject. 
     
     
         44 . The method of  claim 43 , wherein said a peptide, protein, or polypeptide of therapeutic interest is IL-12. 
     
     
         45 . The method of  claim 24  comprising administering to said subject a composition comprising crystalline (R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide Form III. 
     
     
         46 . The method of  claim 24  comprising administering to said subject a composition comprising crystalline (R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide Form IV. 
     
     
         47 . The method of  claim 24  for treating cancer in a subject. 
     
     
         48 . The method of  claim 47 , wherein the cancer is myelodysplasia, breast cancer, prostate cancer, lymphoma, skin cancer, pancreatic cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, mesothelioma, osteogenic sarcoma, primary macroglobulinemia, or retinoblastoma. 
     
     
         49 . The method of  claim 48 , wherein said cancer is breast cancer, lymphoma, pancreatic cancer, colon cancer, melanoma, glioma, non-small cell lung cancer, head or neck carcinoma, lung carcinoma, cervical carcinoma, renal cell carcinoma, leukemia, Kaposi's sarcoma, Hodgkin's disease, or non-Hodgkin's lymphoma. 
     
     
         50 . The method of  claim 49 , wherein said cancer is melanoma, colon cancer, lung cancer, breast cancer, leukemia, or pancreatic cancer. 
     
     
         51 . The method of  claim 47 , wherein said composition comprising crystalline (R)-3.5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(2-ethyl-3-methoxy-benzoyl)-hydrazide Form III, Form IV, Form V, Form VI, Form VII, Form VIII, or Form IX is administered in combination with a chemotherapeutic agent.