Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/06—Peri-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

• the present invention relates to novel polymorphic forms of (2R,Z)-2-amino-2-cyclohexyl-
• CHK1 inhibition enhances the anti-cancer effect of these anti-cancer agents or radiation therapy by abrogating the S and G 2 arrest of those DNA damaged cells and thus leading to mitotic catastrophe and cell death of these cells.
• (2R,Z)-2-amino-2-cyclohexyl-N- (5-(1-methyl-1 H-pyrazol-4-yl)-1-oxo-2,6-dihydro-1 H-[1 ,2]diazepino[4,5,6-cd]indol-8-yl)acetamide is a potent CHK1 protein kinase inhibitor.
• (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1-methyl-1 H- pyrazol-4-yl)-1-oxo-2,6-dihydro-1 H[1 ,2]diazepino [4,5,6-cd]indol-8-yl)acetamide, a pharmaceutically acceptable salt or solvates thereof, or a mixture thereof, in combination with an anti-cancer agent or radiation therapy will greatly enhance the anti-cancer effect of the anti-cancer agent or radiation therapy.
• a solid compound may exist in amorphous or crystalline forms. Each of the different crystalline forms of the same compound is considered a polymorphic form of the compound. Crystalline polymorphs are different crystalline forms of the same compound. Different polymorphic forms of the same active pharmaceutical ingredient (API) may have very different physical properties, such as thermodynamic stability, solubility, hygroscopicity as well as pharmacological properties such as oral bioavailability. These properties greatly influence the properties of a drug, in such areas as shelf life, cost of production, consistent dosage and even effectiveness of the drug. Thus it is desirable to have polymorphic forms of a compound having good physical and pharmacological properties.
• API active pharmaceutical ingredient
• the present invention provides a crystalline form of (2R,Z)-2-amino-2- cyclohexyl-N-(5-(1-methyl-1 H-pyrazol-4-yl)-1-oxo-2,6-dihydro-1 H-[1,2]diazepino[4,5,6-cd]indol-8- yl)acetamide, represented by Formula 1
• the present invention provides a crystalline form of (2R,Z)-2- amino ⁇ -cyclohexyl-N ⁇ S ⁇ I-methyl-I H-pyrazol ⁇ -yO-i-oxo ⁇ .e-dihydro-I H-ti ⁇ ldiazepino ⁇ .S.e- cd]indol-8-yl)acetamide.
• the crystalline form is a substantially pure polymorph of Form I.
• the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 23.6 ⁇ 0.1 and 8.5 ⁇ 0.1.
• the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 23.6 ⁇ 0.1 , 8.5 ⁇ 0.1 and 20.7 ⁇ 0.1. In another aspect of the embodiment, the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 23.6 ⁇ 0.1 , 8.5+ 0.1 , 20.7 ⁇ 0.1 and 16.4 ⁇ 0.1.
• the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 23.6 ⁇ 0.1 , 8.5 ⁇ 0.1 , 20.7 ⁇ 0.1 , 16.4 ⁇ 0.1 and 17.0 ⁇ 0.1.
• the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) essentially the same as shown in Figure 1.
• the crystalline form has a 13 C solid state NMR peak pattern comprising peaks at chemical shifts 175.0 ⁇ 0.1 , 137.6 ⁇ 0.1 , 134.9 + 0.1 , 110.3 ⁇ 0.1 , 106.3 ⁇ 0.1 , 41.1 ⁇ 0.1 and 32.6 ⁇ 0.1 ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising at least three of the following seven peaks at chemical shifts 175.0 ⁇ 0.1 , 137.6 ⁇ 0.1 , 134.9 ⁇ 0.1 , 110.3 ⁇ 0.1 , 106.3 ⁇ 0.1, 41.1 ⁇ 0.1 and 32.6 ⁇ 0.1 ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising at least four of the following seven peaks at chemical shifts 175.0 ⁇ 0.1 , 137.6 ⁇ 0.1, 134.9 ⁇ 0.1 , 110.3 ⁇ 0.1 , 106.3 + 0.1 , 41.1 ⁇ 0.1 and 32.6 ⁇ 0.1 ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising at least five of the following seven peaks at chemical shifts 175.0 ⁇ 0.1 , 137.6 ⁇ 0.1 , 134.9 ⁇ 0.1 , 110.3 ⁇ 0.1 , 106.3 ⁇ 0.1 , 41.1 ⁇ 0.1 and 32.6 ⁇ 0.1 ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising at least six of the following seven peaks at chemical shifts 175.0 ⁇ 0.1 , 137.6 ⁇ 0.1 , 134.9 ⁇ 0.1 , 110.3 ⁇ 0.1 , 106.3 ⁇ 0.1 , 41.1 ⁇ 0.1 and 32.6 ⁇ 0.1 ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising peaks at chemical shifts 175.0 ⁇ 0.2, 137.6 ⁇ 0.2, 134.9 ⁇ 0.2, 110.3 ⁇ 0.2, 106.3 ⁇ 0.2, 41.1+ 0.2 and 32.6 ⁇ 0.2 ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising at least three of the seven peaks at chemical shifts 175.0 ⁇ 0.2, 137.6 ⁇ 0.2, 134.9 ⁇ 0.2, 110.3 ⁇ 0.2, 106.3 ⁇ 0.2, 41.1 ⁇ 0.2 and 32.6 ⁇ 0.2 ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising at least four of the seven peaks at chemical shifts 175.0 ⁇ 0.2, 137.6 ⁇ 0.2, 134.9 ⁇ 0.2, 110.3 ⁇ 0.2, 106.3 ⁇ 0.2, 41.1 ⁇ 0.2 and 32.6 ⁇ 0.2 ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising at least five of the seven peaks at chemical shifts 175.0 ⁇ 0.2, 137.6 ⁇ 0.2, 134.9 ⁇ 0.2, 110.3 ⁇ 0.2, 106.3 ⁇ 0.2, 41.1 ⁇ 0.2 and 32.6 ⁇ 0.2 ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising at least six of the seven peaks at chemical shifts 175.0 ⁇ 0.2, 137.6 ⁇ 0.2, 134.9 ⁇ 0.2, 110.3 ⁇ 0.2, 106.3 ⁇ 0.2, 41.1 ⁇ 0.2 and 32.6 ⁇ 0.2 ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising peaks at chemical shifts position essentially the same as shown in Figure 4b.
• the present invention provides a crystalline form of (2R,Z)-2- amino-2-cyclohexyl-N-(5-(1-methyl-1 H-pyrazol-4-yl)-1-oxo-2,6-dihydro-1 H-[1 ,2]diazepino[4,5,6- cd]indol-8-yl)acetamide.
• the crystalline form is a substantially pure polymorph of Form II.
• the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 25.3 ⁇ 0.1 and 16.0 ⁇ 0.1.
• the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 25.3 + 0.1 , 16.0 ⁇ 0.1 , 13.9 ⁇ 0.1 and 29.2 ⁇ 0.1.
• the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 25.3 ⁇ 0.1 , 16.0 ⁇ 0.1 , 13.9 ⁇ 0.1 , 29.2 ⁇ 0.1 and 12.2 ⁇ 0.1.
• the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 25.3 ⁇ 0.1 , 16.0 ⁇ 0.1 , 13.9 ⁇ 0.1 , 29.2+ 0.1 12.2 ⁇ 0.1 and 16.8 ⁇ 0.1.
• the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 25.3 ⁇ 0.1 , 16.0 ⁇ 0.1 , 13.9+ 0.1 , 29.2 ⁇ 0.1 12.2+ 0.1 , 16.8 ⁇ 0.1, 6.9 ⁇ 0.1 and 13.6+ 0.1.
• the crystalline form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) essentially the same as shown in Figure 2.
• the crystalline form has a 13 C solid state NMR peak pattern comprising peaks at chemical shifts 177.7 ⁇ 0.1 , 133.2 ⁇ 0.1 , 127.8 ⁇ 0.1, 103.8 + 0.1, and 22.7 ⁇ 0.1 ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising at least three of the five peaks at chemical shifts 177.7 ⁇ 0.1 , 133.2 ⁇ 0.1 , 127.8 ⁇ 0.1 , 103.8 ⁇ 0.1 , and 22.7 ⁇ 0.1 ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising at least four of the five peaks at chemical shifts 177.7 ⁇ 0.1 , 133.2 ⁇ 0.1 , 127.8 ⁇ 0.1 , 103.8 ⁇ 0.1 , and 22.7 + 0.1 ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising peaks at chemical shifts 177.7 + 0.2, 133.2 ⁇ 0.2, 127.8 ⁇ 0.2, 103.8 + 0.2, and 22.7 ⁇ 0.2ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising at least three of the five peaks at chemical shifts 177.7 ⁇ 0.2, 133.2 ⁇ 0.2, 127.8 ⁇ 0.2, 103.8 ⁇ 0.2, and 22.7 ⁇ 0.2ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising at least four of the five peaks at chemical shifts 177.7 ⁇ 0.2, 133.2 ⁇ 0.2, 127.8 ⁇ 0.2, 103.8 ⁇ 0.2, and 22.7 ⁇ 0.2ppm.
• the crystalline form has a 13 C solid state NMR peak pattern comprising peaks at chemical shifts position essentially the same as shown in Figure 5b.
• the present invention provides an amorphous form of (2R,Z)-2- amino ⁇ -cyclohexyl-N ⁇ S ⁇ I-methyl-I H-pyrazol ⁇ -yO-i-oxo ⁇ . ⁇ -dihydro-I H-fi ⁇ ldiazepino ⁇ .S. ⁇ - cd]indol-8-yl)acetamide.
• the amorphous form is substantially pure.
• the amorphous form has a 13 C solid state NMR peak pattern comprising peaks at chemical shifts 163.6 ⁇ 0.2, 138.9 ⁇ 0.2, 131.4 ⁇ 0.2, 129.9 ⁇ 0.2, and 30.8 ⁇ 0.2 ppm.
• the amorphous form has a 13 C solid state NMR peak pattern comprising at least three of the five peaks at chemical shifts 163.6 ⁇ 0.2, 138.9 ⁇ 0.2, 131.4 ⁇ 0.2, 129.9 ⁇ 0.2, and 30.8 ⁇ 0.2 ppm.
• the amorphous form has a 13 C solid state NMR peak pattern comprising at least four of the following peaks at chemical shifts 163.6 ⁇ 0.2, 138.9 ⁇ 0.2, 131.4 ⁇ 0.2, 129.9 ⁇ 0.2, and 30.8 ⁇ 0.2 ppm.
• the amorphous form has a 13 C solid state NMR peak pattern comprising peaks at chemical shifts position essentially the same as shown in Figure 6.
• the present invention provides a solid form of (2R,Z)-2-amino-2- cyclohexyl-N ⁇ i-methyl-I H-pyrazol ⁇ -yO-i-oxo ⁇ .e-dihydro-I H-ti ⁇ ldiazepino ⁇ . ⁇ . ⁇ -cdlindol- ⁇ - yl)acetamide (Compound 1 ), wherein the solid form comprises at least two forms selected from polymorphic Form I, polymorphic Form Il and an amorphous form of Compound 1.
• the solid form comprises at least 10% of polymorph Form I. More preferably, the solid form comprises at least 20% of polymorph Form I. More preferably, the solid form comprises at least 30% of polymorph Form I. Even more preferably, the solid form comprises at least 30%, at least 40%, or at least 50% of polymorph Form I. Even more preferably, the solid form comprises at least 60%, at least 70% or at least 80% of polymorph Form I. Even more preferably, the solid form comprises at least 90% of polymorph Form I. Even more preferably, the solid form comprises at least 95% of polymorph Form I.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising the polymorphic Form I, the polymorphic Form II, the amorphous form or the solid form of (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1 -methyl-1 H-pyrazol-4-yl)-1 -oxo-2,6-dihydro-1 H- [1 ,2]diazepino[4,5,6-cd]indol-8-yl)acetamide of the invention.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising the solid form of (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1 -methyl-1 H-pyrazol-4-yl)-1-oxo- 2,6-dihydro-1 H-[1 ,2]diazepino[4,5,6-cd]indol-8-yl)acetamide of the invention.
• the present invention provides a method of treating cancer in a mammal comprising administering to the mammal in need thereof the pharmaceutical composition of the invention.
• the present invention provides a method of treating cancer in a mammal comprising administering to the mammal in need thereof a therapeutically effective amount of the pharmaceutical composition of the invention, in combination with a therapeutically effective amount of an anti-cancer treatment selected from an anti-cancer agent and radiation therapy.
• the anti-cancer treatment is an anti-cancer agent.
• the anti-cancer agent is selected from the group consisting of Ara-c, VP-16, cis-platin, adriamycin, 2-chloro-2-deoxyadenosine, 9- (3-D-arabinosyl-2-fluoroadenine, carboplatin, gemcitabine, camptothecin, paclitaxel, BCNU, 5-fluorouracil, irinotecan, and doxorubicin.
• the anti-cancer treatment is radiation therapy.
• the present invention provides a method of treating a mammalian disease condition mediated by CHK1 protein kinase activity, comprising administering to a mammal in need thereof the polymorphic Form I, the polymorphic Form II, the amorphous form or the solid form of (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1-methyl-1 H-pyrazol-4-yl)-1-oxo-2,6-dihydro- 1 H-[1 ,2]diazepino[4,5,6-cd]indol-8-yl)acetamide of the invention, in combination with a anti-cancer treatment selected from anti-cancer agent, radiation therapy and the combination thereof.
• a anti-cancer treatment selected from anti-cancer agent, radiation therapy and the combination thereof.
• the anti-cancer treatment is an anti-cancer agent.
• the anticancer agent is selected from the group consisting of Ara-c, VP-16, cis-platin, adriamycin, 2- chloro-2-deoxyadenosine, 9- (3-D-arabinosyl-2-fluoroadenine, carboplatin, gemcitabine, camptothecin, paclitaxel, BCNU, 5-fluorouracil, irinotecan, and doxorubicin.
• the anti-cancer treatment is radiation therapy.
• the chemical shifts of the 13 C solid state NMR of the polymorphic Form I, Il or the amorphous form of Compound 1 may have some variance depending on the external reference used.
• the chemical shifts of the 13 C solid state NMR refer to those obtained when the upfield signal of adamantine at 29.5ppm is used as external reference.
• the term "in combination with” refers to the relative timing of the administration of a first therapeutic treatment, such as (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1-methyl-1 H-pyrazol-4-yl)-1- oxo-2,6-dihydro-1 H-[1 ,2]diazepino[4,5,6-cd]indol-8-yl)acetamide, a pharmaceutically acceptable salt or solvate thereof, or a mixture thereof, to the mammal in need, to that of a second therapeutic treatment, such as a anti-cancer agent or radiation therapy, the relative timing being those normally used in the field of medicine for combination therapy. In particular, relative timing can be sequential or simultaneous.
• a first therapeutic treatment such as (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1-methyl-1 H-pyrazol-4-yl)-1- oxo-2,6-dihydro-1 H-
• hyperproliferative disorder refers to abnormal cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition), including the abnormal growth of normal cells and the growth of abnormal cells. This includes, but is not limited to, the abnormal growth of tumor cells (tumors), both benign and malignant. Examples of such benign proliferative diseases are psoriasis, benign prostatic hypertrophy, human papilloma virus (HPV) 1 and restinosis.
• cancer includes, but is not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CN)
• CHK1 protein kinase activity refers to biological or molecular processes that are regulated, modulated, or inhibited by CHK1 protein kinase activity.
• polymorph refers to different crystalline forms of the same compound.
• Polymorph includes, but is not limited to, other solid state molecular forms including hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound.
• pharmaceutically acceptable, carrier, diluent, or vehicle refers to a material (or materials) that may be included with a particular pharmaceutical agent to form a pharmaceutical composition, and may be solid or liquid.
• solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
• liquid carriers are syrup, peanut oil, olive oil, water and the like.
• the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylceilulose, methylmethacrylate and the like.
• composition refers to a mixture of one or more of the compounds or polymorphs described herein, or physiologically/pharmaceutically acceptable salts or solvates thereof, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients.
• the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
• the term "radiation therapy” refers to medical use of radiation to control malignant cells.
• the term “substantially pure” with reference to particular polymorphic forms or an amorphous form of (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1-methyl-1 H-pyrazol-4-yl)-1-oxo-2,6- dihydro-1 H-[1 ,2]diazepino[4,5,6-cd]indol-8-yl)acetamide means the polymorphic form or the amorphous form includes less than 10%, prefereably less than 5%, prefereably less than 3%, preferably less than 1 % by weight of impurities, including other polymorphic forms of (2R,Z)-2- amino-2-cyclohexyl-N-(5-(1 -methyl-1 H-pyrazol-4-yl)-1 -oxo-2,6-dihydro-1 H-[1 ,2]diazepino
• therapeutically effective amount generally refers to an amount of a compound, a pharmaceutically acceptable salt or solvate thereof, or a mixture thereof, being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
• therapeutically effective amount refers to the amount of a particular therapeutic which will 1) enhance the therapeutic effect of another therapeutic such as an anti-cancer agent or radiation therapy, or 2) in combination with the other therapeutic, relieve to some extent one or more of the symptoms of the disorder being treated.
• symptoms of the disease being treated includes a) reducing the size of the tumor; b) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis; c) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth, and d) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the cancer.
• 2 theta value refers to the peak position based on the experimental setup of the X-ray diffraction experiment described in the present invention, including but not limited to the radiation source used and the wavelength of the radiation source, and is a common abscissa unit in diffraction patterns.
• the experimental setup requires that if a reflection is diffracted when the incoming beam forms an angle theta ( ⁇ ) with a certain lattice plane, the reflected beam is recorded at an angle 2 theta (2 ⁇ ).
• treat refers to a method of alleviating or abrogating a cancer and/or its attendant symptoms. With regard particularly to cancer, these terms simply mean that the life expectancy of an individual affected with a cancer will be increased or that one or more of the symptoms of the disease will be reduced.
• the term "essentially the same" with reference to X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account.
• the peak positions (2 ⁇ ) will show some inter- apparatus variability, typically as much as 0.1°.
• relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measures only.
• "essentially the same” with reference to solid state NMR spectra and Raman spectra is intended to also encompass the variabilities associated with these analytical techniques, which are known to those of skill in the art. For example, 13 C chemical shifts measured in solid state NMR will typically have a variability of 0.1 ppm, while Raman shifts will typically have a variability of 1 cm '1 .
• Figure 1 is a X-Ray Powder Diffraction Pattern of polymorphic Form I of (2R,Z)-2-amino- 2-cyclohexyl-N-(5-(1-methyl-1 H-pyrazol-4-yl)-1-oxo-2,6-dihydro-1 H-[1 ,2]diazepino[4,5,6-cd]indol- 8-yl)acetamide.
• Figure 2 is a X-Ray Powder Diffraction Pattern of polymorphic Form H of (2R,Z)-2-amino- 2-cyclohexyl-N-(5-(1-methyl-1 H-pyrazol-4-yl)-1-oxo-2,6-dihydro-1 H-[1 ,2]diazepino[4,5,6-cd]indol- 8-yl)acetamide.
• Figure 3a is a X-Ray Powder Diffraction Pattern of an amorphous form (the first batch) of (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1 -methyl-1 H-pyrazol-4-yl)-1 -oxo-2,6-dihydro-1 H- [1,2]diazepino[4,5,6-cd]indol-8-yl)acetamide.
• Figure 3b is a X-Ray Powder Diffraction Pattern of an amorphous form (the second batch) of (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1 -methyl-1 H-pyrazol-4-yl)-1-oxo-2,6-dihydro-1 H-
• Figure 4a is a Solid State 13 C Cross Polarization and Magic Angle Spinning (CP/MAS)
• NMR of polymorphic Form I (the first spectrum) of (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1-methyl- 1 H-pyrazol-4-yl)-1 -oxo-2,6-dihydro-1 H-[1 ,2]diazepino[4,5,6-cd]indol-8-yl)acetamide.
• Figure 4b is a Solid State 13 C Cross Polarization and Magic Angle Spinning (CP/MAS) NMR of polymorphic Form I (the second spectrum) of (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1- methyl-1 H-pyrazol-4-yl)-1 -oxo-2,6-dihydro-1 H-[1 ,2]diazepino[4,5,6-cd]indol-8-yl)acetamide.
• CP/MAS Cross Polarization and Magic Angle Spinning
• Figure 5a is a Solid State 13 C CP/MAS NMR of polymorphic Form Il (the first spectrum) of (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1 -methyl-1 H-pyrazol-4-yl)-1 -oxo-2,6-dihydro-1 H- [1 ,2]diazepino[4,5,6-cd]indol-8-yl)acetamide.
• Figure 5b is a Solid State 13 C CP/MAS NMR of polymorphic Form Il (the second spectrum) of (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1 -methyl-1 H-pyrazol-4-yl)-1-oxo-2,6-dihydro-1 H- [1 ,2]diazepino[4,5,6-cd]indol-8-yl)acetamide.
• Figure 6 is a solid State 13 C CP/MAS NMR of the amorphous form (the second batch) of (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1 -methyl-1 H-pyrazol-4-yl)-1 -oxo-2,6-dihydro-1 H- [1 ,2]diazepino[4,5,6-cd]indol-8-yl)acetamide.
• TMSCI trimethyl silyl chloride
• Trt triphenylmethyk
• 2-methyl-3,5-dinitrobenzoic acid reacts with N 1 N- dimethylformamide dimethyl acetal under heat to give compound 2.
• Solvents suitable for this reaction are DMF 1 DMA, MTBE, toluene and THF.
• THF is used.
• the reaction is carried out at around 50°C.
• the reaction mixture is concentrated under reduced pressure followed by addition of methanol. Compound 2 will then precipitate out as the product.
• Compound 2 is then treated with an acid in methanol under heat to give compound 3.
• Typical acids that can be used here are TMSCI, HCI, MSA, H 2 SO 4 and TFA.
• TMSCI is used.
• compound 3 crystallizes out from the reaction solution, thus significantly simplifies the isolation process.
• compound 3 was converted to compound 4 by a conventional hydrogenation reaction under Pd/C and H 2 .
• this conventional hydrogenation reaction condition is difficult to control on large scale due to the fact that reduction of the two nitro groups is highly exothermic.
• compound 3 is converted to compound 4 by a transfer hydrogenation reaction followed by an acid-promoted cyclization reaction. Transfer hydrogenation reaction of compound 3 provides a dose-controlled procedure and therefore reduces thermal hazard.
• Different transfer hydrogenations reagents can be used, such as HCO 2 NH 4 with Pd/C, BH 3 .NMe 3 with Pd(OH) 2 , hydrazine with FeCI 3 /C and ammonium formate with Pd/C.
• ammonium formate with Pd/C is used.
• Compound 3 can be reduced using ammonium formate with Pd/C in THF.
• the crude product is then cyclized to give compound 4 under a strong acid.
• a typical condition for this acid catalyzed cyclization is to use concentrated HCI in MeOH.
• the primary amine group of compound 4 is then BOC-protected to give compound 5.
• this reaction was carried out using triethylamine as base and the reaction was carried out in acetonitrile. In the present invention, this reaction is carried out using more benign conditions of an inorganic base such as NaOH, and a solvent such as THF.
• Compound 5 is converted to compound 6 by a Vilsmeier formylation reaction.
• US 6, 967,198 this reaction was carried out using triethylamine as base and the reaction was carried out in acetonitrile.
• this reaction is carried out using more benign conditions of an inorganic base such as NaOH, and a solvent such as
• Compound 6 is converted to compound 7 by treating compound 6 with hydrazine under acidic condition.
• Hydrazine monohydrate as well 30% hydrazine aqueous solution can be used for this reaction. More preferably, the reaction is carried out in a dilute MeOH solution with excess hydrazine, preferably more than 5 equivalents.
• a simple and effective water precipitation Pd removing procedure is developed in the present invention: 1 ) dissolve the crude product in a water immiscible solvent such as DMF, DMA, THF, DMSO DMA, preferably DMA, then add N- acetylcysteine to the resulting solution and stir for 1 hour; 2) add water to precipitate out product while the N-acetylcysteine-palladium complex remained in the aqueous solution. After the N- acetylcysteine treatment, the residual Pd level dropped below 400 ppm, which leads to the API Compound 1 with less than 20 ppm residual Pd.
• a water immiscible solvent such as DMF, DMA, THF, DMSO DMA, preferably DMA
• Compound 9 is then treated with 4M HCI in dioxane and methylene chloride to give compound 10 as hydrogen chloride salt. It was found by Ion Chromatograph analysis that the hydrogen chloride content varied from batch to batch ranging from 2.1 to 2.8 ratio of hydrogen chloride to the corresponding free base. Other acids may also be used for this reaction, for example, sulfuric acid, sulfonic acids and TFA.
• Compound 10 is then coupled with the boc protected hexyl amino acid to give compound 11.
• EDC is chosen as coupling agent. Many coupling conditions can be used such as EDC, HATU and DCC. In the present invention, EDC is used as the coupling agent, together with DMAP as catalyst.
• the required amount of DMAP should preferably be the same molar amount of hydrogen chloride presented in the starting amine salt. Large excess of DMAP in reaction mixture could cause significant racemization.
• Compound 11 is isolated by adding water into reaction mixture. Chiral HPLC analysis indicated the existence of -1 % racemized byproduct, which is removed by crystallization in the final step.
• Compound 11 is then treated with a strong acid to remove the boc group.
• Conditions such as HCI/MeOH, HCI/EtOH, TFA/CH 2 CI 2 or MSA/THF can all be used.
• the reaction mixture can be evaporated under reduced pressure to give compound 12, the HCI salt of (2R,Z)-2-amino-2-cyclohexyl-N-(5-(1-methyl-1 H- pyrazol-4-yl)-1 -oxo-2,6-dihydro-1 H-[1 ,2]diazepino[4,5,6-cd]indol-8-yl) acetamide.
• Compound 1 can be obtained directly from compound 11 by a basic aqueous work up of the de-boc reaction.
• compound 11 is mixed with MSA and refluxed in THF to remove the Boc group.
• aqueous solution of Na 2 CO 3 , K 2 CO 3 or NaHCO 3 can be added to the reaction mixture. Subsequent standard work up will give Compound 1 in good purity and yield.
• Compound 1 can also be obtained from compound 12 by mixing compound 12 with a basic aqueous solution, for example aqueous NaHCO 3 , vigorously stirring the mixture followed by extracting the mixture with an organic solvent.
• a basic aqueous solution for example aqueous NaHCO 3
• Polymorphic Form I of Compound 1 can be prepared directly from compound 11 by removing the boc group under strong acidic condition followed by a basic aqueous work up. Typical strong acidic conditions to be used here are HCI/MeOH, HCI/EtOH, MSA/THF or TFA. Preferably, compound 11 is treated with methanesulfonic acid in THF to remove the boc group. After the reaction is complete, the mixture is basified with an aqueous inorganic base solution, such as aqueous solution of NaOH, Na 2 CO 3 , NaHCO 3 , K 2 CO 3 or KHCO 3 .
• an aqueous inorganic base solution such as aqueous solution of NaOH, Na 2 CO 3 , NaHCO 3 , K 2 CO 3 or KHCO 3 .
• aqueous sodium hydroxide or saturated NaHCO 3 solution is used.
• the organic phase is separated from aqueous phase and dried with magnesium sulfate.
• the organic solution is then reduced to a smaller volume and ethanol is added.
• the resulting solution is reduced to a smaller volume followed by further addition of ethanol. This volume reduction and addition of ethanol process is repeated until Compound 1 precipitates out as polymorphic Form I.
• Polymorphic Form I of Compound 1 can also be prepared from compound 12.
• Compound 12 is dissolved in an aqueous inorganic base solution portion wise with vigorous stirring.
• Typical aqueous inorganic base solution used here are aqueous solution of NaOH, Na 2 CO 3 , NaHCO 3 , K 2 CO 3 or KHCO 3 .
• NaHCO 3 aqueous solution is used here.
• the mixture is extracted with large amount of an organic solvent such as EtOAc.
• the resulting organic solution is washed with brine and dried over Na 2 SO 4 and filtered.
• the filtrate is concentrated on vacuo to afford a yellow solid which is the amorphous form of Compound 1.
• This yellow solid is then dissolved in EtOH under heat, preferably around 75-80°C with vigorous stirring.
• the solution is cooled, preferably to room temperature of around 22°C and kept at 22°C for 12 hours. Polymorphic Form I will precipitate out.
• Compound 1 in polymorphic Form Il may be obtained from compound 12 or compound 11 following similar procedure as described in previous paragraphs except that during the final working up procedure, polymorphic Form Il forms in methanol at around 4 ° C. C.
• Amorphous form of Compound 1 can be prepared directly from compound 12 following similar procedure of preparation of polymorphic Form I. After compound 12 is dissolved in an aqueous base solution portion wise with vigorous stirring, the mixture is extracted with large amount of EtOAc. The resulting EtOAc solution is washed with brine and dried and filtered. The filtrate is concentrated on vacuo to afford a yellow solid which is the amorphous form of Compound 1.
• Amorphous form of Compound 1 can also be prepared from compound 11 following similar procedure of preparation of polymorphic Form I. Use EtOAc as the organic phase during the work up. After drying the organic phase, evaporating the solvent at around 40-70 °C affords Compound 1 in amorphous from.
• the amorphous form of Compound 1 can also be made from polymorphic Form I of
• Each solid form of Compound 1 can be characterized by one or more of the following: X- ray powder diffraction pattern (i.e., X-ray diffraction peaks at various diffraction angles (2 ⁇ )), melting point onset (and onset of dehydration for hydrated forms) as illustrated by endotherms of a Differential Scanning Calorimetry (DSC) thermogram, Raman spectral diagram pattern, aqueous solubility, light stability under International Conference on Harmonization (ICH) high intensity light conditions, and physical and chemical storage stability.
• DSC Differential Scanning Calorimetry
• Raman spectral diagram pattern Raman spectral diagram pattern
• aqueous solubility aqueous solubility
• light stability under International Conference on Harmonization (ICH) high intensity light conditions and physical and chemical storage stability.
• samples of polymorphic forms I, Il and the amorphous form, of Compound 1 were each characterized by the positions and relative intensities of peaks in their X-ray powder d
• Table 1 shows the 2 ⁇ values of polymorphic Form I and Form II.
• the amorphous form shows a continuous X-Ray power diffraction spectrum, where no 2 ⁇ value is collected.
• the X-Ray powder diffraction patterns of the second batch of the amorphous form of Compound 1 is shown in Figure 3b.
• the preparation of the second batch of the amorphous form is described in Example 4b.
• the instrument was equipped with a line focus X-ray tube.
• the tube voltage and amperage were set to 38 kV and 38 mA, respectively.
• the divergence and scattering slits were set at 1 mm, and the receiving slit was set at 0.6 mm.
• Diffracted radiation was detected by a SoI-X energy dispersive X-ray detector.
• a theta two theta continuous scan at 2.4 °2 ⁇ /min (1 sec/0.04°2 ⁇ step) from 3.0 to 40 °2 ⁇ was used. Experiments were carried out at ambient temperature. An alumina standard (NIST standard reference material 1976) was analyzed to check the instrument alignment. Data were collected and analyzed using BRUKER AXS DIFFRAC PLUS software Version 2.0. The PXRD peak was selected using the peak maximum peak height.
• Table 1 X-Ray Powder Diffraction of Polymorphic Forms I and II.
• a solid form comprises two or more polymorphs of the present invention
• the X-ray diffraction pattern will have peaks characteristic of each of the individual polymorphs of the present invention.
• a solid form that comprises two polymorphs will have a powder X-ray diffraction pattern that is a convolution of the two X-ray diffraction patterns that correspond to the substantially pure polymorphic forms.
• Solid state NMR is a powerful tool to analyze solids. Different polymorphs often show significant chemical shifts differences in solid state 13 C cross polarization and magic angle spinning (CP/MAS) NMR. Solid state 13 C CP/MAS NMR was performed on polymorphic Form I and Form II, as well as the amorphous form.
• polymorphic Form I For the polymorphic Form I, a first 13 C SSNMR spectrum was collected on a 600 MHz Bruker spectrometer and that chemical shifts were externally referenced to the methyl resonance of hexamethyl bezene at 17.36 ppm. A 500 MHz Bruker spectrometer was used for a second 13 C SSNMR spectrum of polymorphic Form I, a first and a second spectrum of polymorphic Form Il and the spectrum of the second batch of the amorphous form of Compound 1 and the chemical shifts were externally referenced to the upfield signal of adamantine at 29.5ppm. Table 2a shows the chemical shifts of the first 13 C SSNMR spectrum of polymorphic Form I and the first 13 C SSNMR spectrum of polymorphic Form II.
• Table 2b shows the chemical shift of the second spectrum of polymorphic Form I, the second spectrum of polymorphic Form Il and the spectrum of the second batch of the amorphous form of Compound 1.
• peak intensity is defined as peak heights and can vary depending on the actual setup of the CPMAS experimental parameters.
• Table 2a Solid state 13 C CP/MAS NMR Chemical Shifts for polymorphic Form I (first spectrum) and polymorphic Form Il (first spectrum) of Compound 1.
• Table 2b Solid state 13 C CP/MAS NMR Chemical Shifts for polymorphic Form I (second spectrum), polymorphic Form Il (second spectrum) and the amorphous form (second batch) of
• DSC differential scanning calorimetry
• polymorphic Form Il was heated to 26O 0 C and the resulting solid was examined by PXRD.
• the PXRD result was identical to the PXRD result of polymorphic Form I.
• polymorphic Form Il When the scanning rate for polymorphic Form Il was set at 10°C/min from 25 “C to 300 0 C, polymorphic form Il started melting at 243 "C, rapidly formed a new crystal form and then melted at 274 0 C and we believed the new crystal form was also polymorphic Form I.
• Thermal gravimetric analysis is a testing procedure in which changes in weight of a specimen are recorded as the specimen is heated in air or in a controlled atmosphere such as nitrogen.
• Thermogravimetric curves provide information regarding solvent and water content and the thermal stability of materials.
• TGA was performed on Compound 1 polymorphic Form I and Il using a TA Instruments TGA Q 500. The temperature was increased at 10°C/min from 25°C to 31O 0 C and 350°C for polymorphic Form I and Form II, respectively.
• TGA analysis of polymorphic Form I showed that the crystalline Form I lost approximately 0.26% of total weight by the time the temperature reached 265°C. The degradation of polymorphic Form I occurred rapidly just after melt.
• Polymorphic Form I and Form Il showed an approximate 1.7% and 1.3% moisture gain from 0-90% RH, respectively.
• F Stability of the different polymorphic forms.
• Polymorphs are considered enantiotropic when one form is more thermodynamically stable at one temperature and the other form is more stable at another temperature.
• the temperature at which both polymorphs are equally stable is known as the transition temperature (T t ).
• Enantiotropy study was carried out for polymorphic Form I and Form Il of Compound 1.
• a one-to-one mixture of Form I and Form Il of 10-20 mg was added 1-2 ml_ of ethanol to form a slurry. Samples of such slurry were prepared and stirred at 70°C, 60 0 C, 50 ° C, 4O 0 C, 30 ° C, room temperature (about 23 ° C) and 3.5"C respectively.
• the samples were then centrifuged.
• the supernatant was decanted and the remaining material was left to dry under vacuum at room temperature.
• the resulting materials were analyzed by PXRD. The results are summarized in the Table 5.
• the inventive polymorphic forms of Compound 1 may be useful in all aspects that Compound 1 may be useful.
• the method of using Compound 1 was described in US 6,967,198 as method to use genus of compounds which contain Compound 1. It was described in US 6,967,198 that compounds of the invention therein may be used in combination with a therapeutically effective amount of an anti-neoplastic agent or radiation therapy to treat neoplasm in a mammal. It is within contemplation of the present invention, that the polymorphic forms and the pharmaceutical compositions of Compound 1 of the current invention may be used in combination with a therapeutically effective amount of an anti-neoplastic agent or radiation therapy, as described in US 6,967,198 that could be used in combination with the compounds of the invention therein.
• reaction solution was then cooled to room temperature and concentrated in a rotorvap to remove most of the THF and the unreacted N,N-dimethylformamide dimethyl acetal until -250 g of crude material remained in the flask (water bath temperature was not allowed to exceed 30 0 C).
• Methanol 400 ml was added and the slurry was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with cold methanol (60 ml) and dried in airflow to afford 109.08 g of purple solid (84% yield).
• the purple solid 2 (92.25 g, 0.313 mol) was suspended in anhydrous MeOH (1000 mL). TMSCI (70.25 g, 0.65 mol, 2.1 eq) was added over 10 min. A clear solution was formed. The solution was heated at 60 0 C (slow reflux) for 20 hours. HPLC analysis indicated the disappearance of starting material. Reaction mixture was cooled to room temperature and white solid precipitated out (often times, the product crystallized from the reaction mixture when reaction was near completion). The reaction mixture was stirred at room temperature for 1 h. The precipitated solid was collected by filtration, washed with cold MeOH (50 mL) and dried in airflow to afford 82.71 g of white solid.
• the internal temperature was maintained at approximately 0 0 C through cooling and controlling the rate of hydrogen addition. After pressure was constant for more than 30 min, hydrogen pressure was kept at 50-60 psi and the temperature was maintained at 0 0 C for 2 hours.
• the catalyst was filtered off through an inline filter (Note: Catalyst is pyrrophoric. Do not allow the catalyst to pull dry.) The filtrate was concentrated to remove approximately 95 % of the solvent volume by vacuum distillation at an internal temperature of less than 35 0 C. Ethyl acetate (130L ) was added with stirring. 37% HCI (10kg) was then added slowly below 10°C. The resulting mixture was stirred at 10°C for 1 hour.
• EtOAc 600 ml was added to the reaction mixture followed by addition of cold aqueous NaOAc solution (3 M, 310 ml, 0.93 mol) with vigorously stirring. Temperature rose to 10 0 C after quench. Cooling bath was removed. The reaction mixture was warmed to 21 0 C over 20 minutes and stirred at this temperature for 2.5 h. Solids were completely dissolved. HPLC analysis indicated that all the intermediate was converted to product. Agitation was stopped and aqueous layer was separated. Organic layer was concentrated under reduced pressure to remove volatiles. A paste (226 g) was obtained. Water (30 ml) and EtOAc (70 ml) were added to the paste. The resulting mixture was stirred for 30 minutes.
• Reaction temperature was controlled below -5 0 C during addition. After addition was complete, the reaction mixture was stirred at 0 0 C for 1.5 hours. HPLC analysis indicated that the reaction was complete.
• Water (0.225L) was added slowly to the reaction mixture while the temperature was maintained below 20 0 C during addition.
• EtOAc (0.225L) was added to the reaction mixture at 15 0 C followed by addition of aqueous potassium carbonate (Preparation: dissolve 20.73g K 2 CO 3 in 60ml water, cool to 10 0 C for use) in one portion. The mixture was stirred for 15 minutes to dissolve solid.
• Aqueous sodium sulfite solution (Preparation: dissolve 3.78g Na 2 SO 3 in 18ml water) was then added and stirred for 10 minutes.
• N-acetylcysteine (3Og, 0.18 mol) was added into the DMA solution and the solution was stirred for 2 hours.
• Water (0.8L) was added over 10 minutes with stirring while the temperature was controlled at 30 0 C. Solid precipitated out.
• the mixture was stirred for 20 minutes to granulate solid. Additional water (2.2L) was added over 5 minutes to drive the precipitation to completion.
• the mixture was stirred for 1 hour. Solid was collected by filtration and washed sequentially with a mixture of DMA (0.2L) and water (0.4L), water (0.8L), and a mixture of acetone (0.4L) and water (0.4L).
• the compound was dried in vacuum oven at 60 0 C until the water content is reduced to less than 1.5 wt%.
• the reaction was cooled to room temperature using a water bath. 2M NaOH (255 mL) was added over 30 minutes while maintaining the temperature at 20+5 0 C. After stirring for 5 minutes, the mixture was transferred to a 2-L separatory funnel using THF for the rinse. The layers were separated. The aqueous phase was extracted with THF (60 mL). The organic fractions were combined and washed twice with saturated aqueous NaCI (2 x 60 mL). MeOH (80 mL) and MgSO 4 (42 g) were added. The mixture was stirred for 75 minutes, and then filtered through celite.
• Example 4a Preparation of the first batch of amorphous form of (2R)-2-amino-2- cyclohexyl-N-(5-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2,6-dihydro-1H-[1,2] diazepino[4,5,6- cd]indol-8-yl)acetamide amorphous form:
• Example 4b Preparation of the second batch of amorphous form of (2R)-2-amino-2- cyclohexyl- ⁇ /-(5-(1-methyl-1H-pyrazol-4-yl)-1-oxo-2,6-dihydro-1H-[1,2] diazepino[4,5,6- cd]indol-8-yl)acetamide amorphous form:
• the one dimensional 13 C spectra of form I and amorphous samples were collected using 1 H- 13 C Cross-Polarization Magic Angle Spinning (CPMAS) which was followed by Total Suppression of Spinning side bands (TOSS) in the case of form Il sample.
• the TOSS was applied to suppress the spinning side bands.
• the cross- polarization contact time was adjusted to 2.0 ms, and the decoupling field was set to approximately 75 kHz.
• 512 scans were acquired with recycle delay of 30s for form I
• 256 scans were acquired with recycle delay of 30s for form Il
• 2048 scans were acquired with recycle delay of 3s for the amorphous sample. All spectra were referenced using an external sample of adamantane with its upfield signal set to 29.5 ppm.

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