WO2008157211A1 - Formes cristallines de 3aalpha,4bêta,5alpha,7bêta,7aalpha)-4-(octahydro-5-éthylsulfonamido-4,7-diméthyl-1,3-dioxo-4,-7-époxy-2h-isoindol-2-yl)- - Google Patents

Formes cristallines de 3aalpha,4bêta,5alpha,7bêta,7aalpha)-4-(octahydro-5-éthylsulfonamido-4,7-diméthyl-1,3-dioxo-4,-7-époxy-2h-isoindol-2-yl)- Download PDF

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Publication number
WO2008157211A1
WO2008157211A1 PCT/US2008/066665 US2008066665W WO2008157211A1 WO 2008157211 A1 WO2008157211 A1 WO 2008157211A1 US 2008066665 W US2008066665 W US 2008066665W WO 2008157211 A1 WO2008157211 A1 WO 2008157211A1
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crystalline form
compound
ray diffraction
diffraction pattern
powder
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PCT/US2008/066665
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English (en)
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John D. Dimarco
David James Kacsur
Shawn K. Pack
Richard A. Rampulla
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Bristol-Myers Squibb Company
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Publication of WO2008157211A1 publication Critical patent/WO2008157211A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • [OuOl) Disclosed are crystalline forms of (3a ⁇ ,4 ⁇ ,5c-,7 ⁇ ,7a ⁇ )-4-(octahydro-5- ethylsulfo ⁇ amido-4,7-(iimethyl-1,3--lioxo-4,7-epoxy-2H-isoi ⁇ idol-2-yl)-2- (trifluoromethyOber ⁇ onltrile.
  • at least one pharmaceutical composition comprising at least one crystalline form of (3a ⁇ x 3 4 ⁇ J 5ct,7 ⁇ ,7a ⁇ )-4-
  • the androgen receptor (AR) is a key molecular target in the etiology and progression of prostate cancer.
  • androgens including, but not limited to, for example, testosterone (T) and dihydrotestosterone (DHT), stimulate the growth of prostate cancer by binding to the AR.
  • T testosterone
  • DHT dihydrotestosterone
  • efforts have been undertaken to develop AR agonists and/or antagonists lhat are therapeutically effective in treating prostate cancer.
  • Compound (I) has been found to be effective in treating cancer.
  • Compound (I) was found to potently bind to and act as an antagonist and/or partial antagonist of the AR.
  • Compound (I) and a process for making Compound (I) are disclosed in Example 810 of U.S Patent 7,141,578 Bl, wherein said disclosure of Example 810 is hereby incorporated herein by reference.
  • a crystalline form of Compound (I) is sought to aid in the isolation of Compound (I) from a synthesis mixture and/or the purification of Compound (I).
  • a crystalline form of the active ingredient is sought that has a balance of desired properties, such as, for example, dissolution rate, solubility, bioavailability, and/or storage stability.
  • the present invention provides crystalline forms of Compound (I) that can be useful in the isolation and/or purification of Compound (I). Also, provided is at least one crystalline form that can be used in a pharmaceutical composition suitable for the treatment of a proliferative disease such as cancer.
  • a second crystalline form of Compound (I) comprises Form SA-I.
  • a third crystalline form of Compound (I) comprises Form SA-6.
  • a fourth crystalline form of Compound (I) comprises Form SB- 1.
  • a fifth crystalline form of Compound (I) comprises Form EA-3.
  • a sixth crystalline form of Compound (I) comprises Form HAC.5-5
  • at least one pharmaceutical composition comprising Form SB-I of Compound (I); and at least one pharmaceutically acceptable carrier and/or diluent.
  • at least one method for treating at least one proliferative disease comprising administering to a patient in need thereof, a therapeutically effect amount of Compound (I), wherein Compound (I) is provided in a crystalline form.
  • FIG. 7 shows a DSC thermogram of the N-5 Form of Compound (I).
  • FIG. 8 shows a DSC thermogram of the SB-I Form of Compound (I).
  • FIG. 9 shows a TGA thermogram of the N-5 Form of Compound (I).
  • FIG. 10 shows a TGA thermogram of the SB-I Form of Compound (I).
  • polymorphs refer to crystalline forms having the same chemical structure but different spatial arrangements of the molecules and/or ions forming the crystals.
  • amorphous refers to a solid form of a molecule and/or ion that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern with sharp maxima.
  • substantially pure means the crystalline form of Compound (I) referred to contains at least about 90 wt.%, based on the weight of such crystalline form, of a Form selected from Form N-5, Form SA-I, Form SA-6, Form SB-I, EA-3, and HAC.5-5.
  • the remainder of the crystalline form of Compound (I) may comprise other Form(s) of Compound (I) and/or reaction impurities and/or processing impurities that arise, for example, when the crystalline form is prepared.
  • a crystalline form of Compound (I) may be deemed substantially pure if the crystalline form contains at least 90 wt. %, based on the weight of such crystalline form as measured by means that are at this time known and generally accepted in the art, of a Form selected from Form N-5, Form SA-I, Form SA-6, Form SB-I; EA-3, and/or HAC.5-5 and less than about 10 wt. %, based on the weight of such crystalline form, of material comprising other Form(s) of Compound (I) and/or reaction impurities and/or processing impurities.
  • reaction impurities and/or processing impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, and/or infrared spectroscopy.
  • analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, and/or infrared spectroscopy.
  • the parameter "molecules/asymmetric unit” refers to the number of molecules of Compound (I) in the asymmetric unit.
  • unit cell parameter "molecules/unit cell” refers to the number of molecules of Compound (I) in the unit cell.
  • At least one crystalline form of Compound (I) disclosed herein may be used to prepare at least one liquid formulation in which at least one crystalline form of Compound (I) is dissolved and/or suspended.
  • terapéuticaally effective amount is meant an amount that when administered either alone, or in combination with an additional therapeutic agent is effective to prevent, suppress, and/or ameliorate a disease and/or condition and/or the progression of a disease and/or condition.
  • a first crystalline form of Compound (I) comprises a neat crystalline form referred to herein as "Form N-5" or "N-5 Form".
  • the N-5 Form is characterized by unit cell parameters approximately equal to the following:
  • Density (calculated) 1.384 g/cm 3 , wherein the unit cell parameters of Form N-5 are measured at a temperature of about 25°C.
  • the N-5 Form is characterized by a simulated PXRD pattern substantially in accordance with the pattern shown in Figure 1 and/or by an observed PXRD substantially in accordance with the pattern shown in Figure 1.
  • the N-5 Form is characterized by fractional atomic coordinates substantially as listed in Table 1.
  • Table 1 Fractional Atomic Coordinates for Form N-5 Calculated at a Temperature of about 25°C Atom X Y Z Atom X Y Z
  • the N-5 Form is characterized by a DSC thermogram substantially in accordance with that shown in Figure 7.
  • the N-5 Form may be characterized by a melting point in the range of from about 159°C to about 165°C.
  • the N-5 Form is characterized by a TGA thermogram having weight loss in the range of from about 0.1 to about 0.3 wt. %, based on the weight of the sample of Form N-5, upon being heated to a temperature of about 200 0 C.
  • the N-5 Form exhibits a TGA thermogram substantially the same as shown in Figure 9.
  • the first crystalline form of Compound (I) is substantially pure.
  • the first crystalline form of Compound (I) contains at least about 90 wt.%, preferably at least about 95 wt.%, and more preferably at least about 99 wt.%, based on weight of the first crystalline form, Form N-5.
  • a substantially pure first crystalline form has substantially pure phase homogeneity with less than about 10%, preferably less than about 5%, and more preferably less than about 2% of the total peak area of the experimentally measured PXRD pattern arising from peaks that are absent from the simulated PXRD pattern. Most preferably, a substantially pure first crystalline form has substantially pure phase homogeneity with less than about 1% of the total peak area of the experimentally measured PXRD pattern arising from peaks that are absent from the simulated PXRD pattern.
  • the first crystalline form consists essentially of Form N-5.
  • the first crystalline form of this embodiment may comprise at least about 90 wt. %, preferably at least about 95 wt. %, and more preferably at least about 99 wt. %, based on weight of the first crystalline form, Form N-5.
  • a pharmaceutical composition comprises the first crystalline form; optionally at least one other component selected from, for example, excipients and carriers; and optionally at least one other active pharmaceutical ingredient having at least one molecularly different active chemical entity.
  • a pharmaceutical composition comprises the substantially pure first crystalline form; optionally at least one other component selected from, for example, excipients and carriers; and optionally at least one other active pharmaceutical ingredient having at least one molecularly different active chemical entity.
  • a therapeutically effective amount of Form N-5 may be combined with at least one pharmaceutically acceptable carrier and/or diluent to provide at least one pharmaceutical composition.
  • Still yet a further embodiment provides a method for treating a proliferative disease comprising administering to a patient in need thereof, a therapeutically effective amount of Compound (I), wherein Compound (I) is provided in the first crystalline form comprising Form N-5.
  • the patient is a human.
  • the method comprises administering the first crystalline form of Compound (I) consisting essentially of Form N-5.
  • a second crystalline form of Compound (I) comprises hydrate- hemiacetonate crystalline form referred to herein as "Form SA-I" or "SA-I Form”.
  • the SA-I Form is characterized by unit cell parameters approximately equal to the following:
  • the SA-I Form is characterized by a simulated PXRD pattern substantially in accordance with the pattern shown in Figure 2 and/or by an observed PXRD pattern substantially in accordance with the pattern shown in Figure 2.
  • the SA-I Form is characterized by fractional atomic coordinates substantially as listed in Table 2.
  • the second crystalline form of Compound (I) is substantially pure.
  • the second crystalline form of Compound (I) contains at least about 90 wt.%, preferably 95 wt.%, and more preferably at least about 99 wt.%, based on weight of the second crystalline form, Form SA-I.
  • a substantially pure second crystalline form has substantially pure phase homogeneity with less than about 10%, preferably less than about 5%, and more preferably less than about 2% of the total peak area of the experimentally measured PXRD pattern arising from peaks that are absent from the simulated PXRD pattern.
  • a substantially pure second crystalline form has substantially pure phase homogeneity with less than about 1% of the total peak area of the experimentally measured PXRD pattern arising from peaks that are absent from the simulated PXRD pattern.
  • the second crystalline form of Compound (I) consists essentially of Form SA-I.
  • the second crystalline form of this embodiment may comprise at least about 90 wt. %, preferably at least about 95 wt. %, and more preferably at least about 99 wt. %, based on the weight of the second crystalline form, Form SA-I.
  • a third crystalline form of Compound (I) comprises an acetonitrile-hydrate crystalline form referred to herein as "Form SA-6" or "SA-6 Form”.
  • the SA-6 Form is characterized by unit cell parameters approximately equal to the following:
  • the SA-6 Form is characterized by a simulated PXRD pattern substantially in accordance with the pattern shown in Figure 3 and/or by an observed PXRD pattern substantially in accordance with the pattern shown in
  • the SA-6 Form is characterized by fractional atomic coordinates substantially as listed in Table 3.
  • the third crystalline form of Compound (I) is substantially pure.
  • (I) contains at least about 90 wt.%, preferably at least about 95 wt.%, and more preferably at least about 99 wt.%, based on the weight of the third crystalline form,
  • a substantially pure third crystalline form has substantially pure phase homogeneity with less than about 10%, preferably less than about 5%, and more preferably less than about 2% of the total peak area of the experimentally measured PXRD pattern arising from peaks that are absent from the simulated PXRD pattern. Most preferably, a substantially pure third crystalline form has substantially pure phase homogeneity with less than about 1% of the total peak area of the experimentally measured PXRD pattern arising from peaks that are absent from the simulated PXRD pattern.
  • the third crystalline form consists essentially of Form SA-6.
  • the third crystalline form of this embodiment may comprise at least about 90 wt. %, preferably at least about 95 wt. %, and more preferably at least about 99 wt. %, based on the weight of the third crystalline form, Form SA-6.
  • a fourth crystalline form of Compound (I) comprises a hydrate- hemiethanolate crystalline form referred to herein as "Form SB-I" or "SB-I Form".
  • the SB- 1 Form is characterized by unit cell parameters approximately equal to the following:
  • Density (calculated) 1.413 g/cm 3 , wherein the unit cell parameters of Form SB-I are measured at a temperature of about 25°C.
  • the SB-I Form is characterized by a simulated PXRD pattern substantially in accordance with the pattern shown in Figure 4 and/or by a simulated PXRD pattern substantially in accordance with the pattern shown in Figure 4.
  • the SB-I Form is characterized by fractional atomic coordinates substantially as listed in Table 4.
  • the SB-I Form is characterized by a DSC thermogram substantially in accordance with that shown in Figure 8. [0083] In still yet a further embodiment, the SB-I Form is characterized by a TGA thermogram having weight loss in the range of from about 7.3 to about 7.6 wt. %, based on the weight of a sample of Form SB-I, upon being heated to a temperature of about 175°C.
  • the SB- 1 Form exhibits a TGA thermogram substantially the same as shown in Figure 10.
  • the fourth crystalline form of Compound (I) is substantially pure.
  • the fourth crystalline form of Compound (I) contains at least about 90 wt.%, preferably at least about 95 wt.%, and more preferably at least about 99 wt.%, based on the weight of the fourth crystalline form, Form SB-I.
  • a substantially pure fourth crystalline form has substantially pure phase homogeneity with less than about 10%, preferably less than about 5%, and more preferably less than about 2% of the total peak area of the experimentally measured PXRD pattern arising from peaks that are absent from the simulated PXRD pattern. Most preferably, a substantially pure fourth crystalline form has substantially pure phase homogeneity with less than about 1% of the total peak area of the experimentally measured PXRD pattern arising from peaks that are absent from the simulated PXRD pattern.
  • the fourth crystalline form of Compound (I) consists essentially of Form SB-I. The fourth crystalline form of this embodiment may comprise at least about 90 wt.
  • a pharmaceutical composition comprises the fourth crystalline form; optionally at least one other component selected from, for example, excipients and carriers; and optionally at least one other active pharmaceutical ingredient having at least one molecularly different active chemical entity.
  • a pharmaceutical composition comprises a substantially pure fourth crystalline form; optionally at least one other component selected from, for example, excipients and carriers; and optionally at least one other active pharmaceutical ingredient having at least one molecularly different active chemical entity.
  • a therapeutically effective amount of Form SB-I may be combined with at least one pharmaceutically acceptable carrier and/or diluent to provide at least one pharmaceutical composition.
  • Still yet a further embodiment provides a method for treating a proliferative disease comprising administering to a patient in need thereof, a therapeutically effective amount of Compound (I), wherein Compound (I) is provided in the fourth crystalline form comprising Form SB- 1.
  • the patient is a human.
  • the method comprises administering the fourth crystalline form of Compound (I) consisting essentially of Form SB-I.
  • a fifth crystalline form of Compound (I) comprises an ethyl acetate solvate crystalline form referred to herein as "Form EA-3" or "EA-3 Form".
  • the EA- 3 Form comprises one ethyl acetate molecule for each molecule of Compound (I).
  • the EA-3 Form is characterized by unit cell parameters approximately equal to the following:
  • Density (calculated) 1.385 g/cm 3 , wherein the unit cell parameters of Form EA-3 are measured at a temperature of about 25°C.
  • the EA-3 Form is characterized by a simulated PXRD pattern substantially in accordance with the pattern shown in Figure 5 and/or by a simulated PXRD pattern substantially in accordance with the pattern shown in Figure 5.
  • the fifth crystalline form of Compound (I) is substantially pure.
  • the fifth crystalline form of Compound (I) contains at least about 90 wt.%, preferably at least about 95 wt.%, and more preferably at least about 99 wt.%, based on the weight of the fifth crystalline form, Form EA-3.
  • a substantially pure fifth crystalline form has substantially pure phase homogeneity with less than about 10%, preferably less than about 5%, and more preferably less than about 2% of the total peak area of the experimentally measured PXRD pattern arising from peaks that are absent from the simulated PXRD pattern. Most preferably, a substantially pure fifth crystalline form has substantially pure phase homogeneity with less than about 1% of the total peak area of the experimentally measured PXRD pattern arising from peaks that are absent from the simulated PXRD pattern.
  • the fifth crystalline form of Compound (I) consists essentially of Form EA-3.
  • the fifth crystalline form of this embodiment may comprise at least about 90 wt. %, preferably at least about 95 wt. %, and more preferably at least about 99 wt. %, based on the weight of the fifth crystalline form, Form EA-3.
  • a sixth crystalline form of Compound (I) comprises a hemiacetic acid crystalline form referred to herein as "Form HAC.5-5" or "HAC.5-5 Form".
  • the HAC.5-5 Form is characterized by unit cell parameters approximately equal to the following:
  • the HAC.5-5 Form is characterized by a simulated PXRD pattern substantially in accordance with the pattern shown in Figure 6 and/or by a simulated PXRD pattern substantially in accordance with the pattern shown in Figure 6.
  • the sixth crystalline form of Compound (I) is substantially pure.
  • the sixth crystalline form of Compound (I) contains at least about 90 wt.%, preferably at least about 95 wt.%, and more preferably at least about 99 wt.%, based on the weight of the sixth crystalline form, Form HAC.5-5.
  • a substantially pure sixth crystalline form has substantially pure phase homogeneity with less than about 10%, preferably less than about 5%, and more preferably less than about 2% of the total peak area of the experimentally measured PXRD pattern arising from peaks that are absent from the simulated PXRD pattern.
  • a substantially pure sixth crystalline form has substantially pure phase homogeneity with less than about 1% of the total peak area of the experimentally measured PXRD pattern arising from peaks that are absent from the simulated PXRD pattern.
  • the sixth crystalline form of Compound (I) consists essentially of Form HAC.5-5.
  • the sixth crystalline form of this embodiment may comprise at least about 90 wt. %, preferably at least about 95 wt. %, and more preferably at least about 99 wt. %, based on the weight of the sixth crystalline form, Form HAC.5-5.
  • a pharmaceutical composition comprises the sixth crystalline form; optionally at least one other component selected from, for example, excipients and carriers; and optionally at least one other active pharmaceutical ingredient having at least one molecularly different active chemical entity.
  • a pharmaceutical composition comprises a substantially pure sixth crystalline form; optionally at least one other component selected from, for example, excipients and carriers; and optionally at least one other active pharmaceutical ingredient having at least one molecularly different active chemical entity.
  • a therapeutically effective amount of Form HAC.5-5 may be combined with at least one pharmaceutically acceptable carrier and/or diluent to provide at least one pharmaceutical composition.
  • Still yet a further embodiment provides a method for treating a proliferative disease comprising administering to a patient in need thereof, a therapeutically effective amount of Compound (I), wherein Compound (I) is provided in the sixth crystalline form comprising Form HAC.5-5.
  • the patient is a human.
  • the method comprises administering the sixth crystalline form of Compound (I) consisting essentially of Form HAC.5-5.
  • Compound (I) is useful for modulating the function of a nuclear hormone receptor specifically, the androgen receptor (AR).
  • Compound (I) is useful to treat AR-associated conditions.
  • Compound (I) selectively modulates the androgen receptor within the NHR family.
  • Compound (I) may be used to treat a variety of medical conditions and/or disorders associated with the androgen receptor (AR) pathway.
  • Compound (I) can modulate the function of the AR by antagonizing, and/or partially antagonizing the AR.
  • Compound (I) selectively modulates the function of the AR.
  • Medical conditions associated with the AR pathway include, but are not limited to, for example, benign prostate hyperplasia, hirsutism, acne, hyperpilosity, seborrhea, endometriosis, polycystic ovary syndrome, androgenic alopecia, adenomas and neoplasies of the prostate, benign or malignant tumor cells containing the androgen receptor, hypogonadism, osteoporosis, suppression of spermatogenesis, libido, cachexia, anorexia, androgen supplementation for age related decreased testosterone levels in men, prostate cancer, breast cancer, endometrial cancer, uterine cancer, hot flashes, and Kennedy's disease.
  • pan AR modulation is contemplated, with prostate selective AR modulation ("SARM”) being particularly preferred, such as for the treatment of early stage prostate cancers.
  • SARM prostate selective AR modulation
  • Compound (I) is used to treat prostate cancer by being employed as an antagonist or partial antagonist of the AR.
  • Compound (I) can be used to antagonize, preferably selectively antagonize, mutated ARs found, for example, in many tumor cell lines.
  • exemplary mutated ARs include, but are not limited to, those found in prostate tumor cell lines, such as, for example, LNCap (T877A mutation, Biophys. Acta, 187, 1052 (1990)); PCa2b (L701H & T877A mutations, J. Urol, 162, 2192 (1999)); and CWR22 (H874Y mutation, MoL Endo., 11, 450 (1997)).
  • a method for treating at least one proliferative disease comprises administering to a patient in need of such treatment a therapeutically effective amount of Compound (I), wherein Compound (I) is provided in a crystalline form comprising at least one form selected from Form N-5, Form SB-I, and Form HAC.5-5; optionally administering either simultaneously or sequentially at least one other anti-cancer agent, and optionally administering either simultaneously or sequentially at least one other anti-cancer treatment.
  • the method for treating at least one proliferative disease involves providing Compound (I) in a substantially pure form.
  • anti-cancer treatment includes but is not limited to, for example, radiation therapy and surgery, e.g. castration.
  • a pharmaceutical composition comprises at least one crystalline form of Compound (I) comprising Form N-5, Form SB-I, and/or Form HAC.5-5; optionally at least one component selected from, for example, excipients and carriers; and optionally at least one other anti-cancer agent.
  • the pharmaceutical composition comprises at least one substantially pure crystalline form of Compound (I), including but not limited to the crystalline forms described herein.
  • other anti-cancer agent includes any known agent useful for treating cancer, preferably prostate cancer.
  • a combination of chemotherapeutic agents and/or other treatments e.g., radiation therapy
  • the other anti-cancer agent may have the same or different mechanism of action than the primary therapeutic agent. It may be especially useful to employ cytotoxic drug combinations wherein the two or more drugs being administered act in different manners or in different phased of the cell cycle, and/or where the two or more drugs have overlapping toxicities or side effects, and/or where the drugs being combined each has a demonstrated efficacy in treating the particular disease state manifested by the patient.
  • Compound (I) may be administered in combination with other anti-cancer agents and treatments useful in the treatment of cancer or other proliferative diseases.
  • the invention herein further comprises use of Compound (I) in preparing medicaments for the treatment of cancer, and/or it comprises the packaging of the Compound (I) herein together with instructions that Compound (I) be used in combination with other anti-cancer agents and treatments for the treatment of cancer.
  • the present invention further comprises combinations of Compound (I) and one or more additional agents in kit form, e.g., where they are packaged together or placed in separate packages to be sold together as a kit, or where they are packaged to be formulated together.
  • the other anti-cancer agents may be selected from any one or more of the following: alkylating agents (including nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimine derivatives, and triazenes); anti-angiogenics (including matrix metalloproteinase inhibitors); antimetabolites (including adenosine deaminase inhibitors, folic acid antagonists, purine analogues, and pyrimidine analogues); antibiotics or antibodies (including monoclonal antibodies, CTLA-4 antibodies, anthracyclines); aromatase inhibitors; cell-cycle response modifiers; enzymes; farnesyl-protein transferase inhibitors; hormonal and antihormonal agents and steroids (including synthetic analogs, glucocorticoids, estrogens/anti-estrogens [e.g., SERMs], androgens/anti-androgens, progestins, progesterone receptor agonists, and
  • Compound (I) can be formulated or co-administered with other therapeutic agents that are selected for their particular usefulness in addressing side effects associated with the aforementioned conditions.
  • Compound (I) may be formulated with agents to prevent nausea, hypersensitivity and gastric irritation, such as antiemetics, and Hi and H 2 antihistaminics.
  • the above other therapeutic agents, when employed in combination with Compound (I) can be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
  • Compound (I) is used to treat cancer including, but not limited to, for example, carcinoma, including, for example, that of the bladder, breast, colon, kidney, liver, lung (including small cell lung cancer), esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage, such as, for example, leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B- cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, such as, for example, acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia; tumors of me
  • Compound (I) is used to treat prostate cancer.
  • Compound (I) is used to treat adenomas and neoplasies of the prostate.
  • Compound (I) may be used, for example, in combination with known therapies for treating advanced metastatic prostate cancer including, but not limited to, for example, "complete androgen ablation therapy" wherein tumor growth is inhibited by controlling the supply of androgen to the prostate tissues via chemical castration followed by the administration of at least one AR antagonist.
  • Compound (I) can be employed as an AR antagonist in complete ablation therapy, alone or in combination with other AR antagonists such as Flutamide, bicalutamide, Nilutamide, or Cyproterone acetate.
  • Compound (I) may further be employed adjuvant to surgery.
  • Compound (I) may be used, for example, either in combination with antibody therapy including, but not limited to, for example, antibody therapy against PSCA, or in concert with vaccine/immune modulating agents used to treat cancer.
  • Compound (I) can be administered by any means suitable for the condition to be treated, which can depend on the need for site-specific treatment or quantity of Compound (I) to be delivered.
  • Any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparations.
  • Exemplary oral preparations include, but are not limited to, for example, tablets; troches; lozenges; aqueous or oily suspensions; dispersible powders or granules; emulsions; hard or soft capsules; syrups; and elixirs.
  • compositions intended for oral administration can be prepared according to methods known in the art and can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents.
  • exemplary excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, and alginic acid; binding agents, such as, for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc.
  • An aqueous suspension can be prepared, for example, by admixing at least one crystalline form of Compound (I) with at least one excipient suitable for the manufacture of an aqueous suspension.
  • excipients suitable for the manufacture of an aqueous suspension include, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose or methylcellulose.
  • Oily suspensions can, for example, be prepared by suspending at least one crystalline form of Compound (I) in either a vegetable oil, such as, for example, arachis oil; olive oil; sesame oil; and coconut oil; or in mineral oil, such as, for example, liquid paraffin.
  • a vegetable oil such as, for example, arachis oil; olive oil; sesame oil; and coconut oil
  • mineral oil such as, for example, liquid paraffin.
  • Any pharmaceutical composition contemplated herein can, for example, also be delivered intravenously, subcutaneously, and/or intramuscularly via any pharmaceutically acceptable and suitable injectable form.
  • injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oleaginous suspensions.
  • a sterile injectable oil-in-water microemulsion can, for example, be prepared by 1) dissolving at least one crystalline form of Compound (I) in an oily phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining the Compound (I) containing oil phase with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.
  • an oily phase such as, for example, a mixture of soybean oil and lecithin
  • Any pharmaceutical composition contemplated herein can, for example, further be administered via any acceptable and suitable rectal preparation, including, but not limited to, for example, a suppository.
  • a suppository can be prepared by mixing at least one crystalline form of Compound (I) with at least one suitable non- irritating excipient that is liquid at rectal temperatures but solid at a temperature below rectal temperature.
  • Any pharmaceutical composition contemplated herein can, for example, be administered via any acceptable and suitable topical preparations including, but not limited to, for example, creams; ointments; jellies; solutions; suspensions, transdermal patches; and intranasal inhalers.
  • topical preparations include mouth washes and gargles.
  • compositions for nasal aerosol or inhalation administration include solutions that may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
  • An "effective amount" of Compound (I) may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a mammal of from about 0.05 to about 300 mg/kg/day, preferably less than about 200 mg/kg/day, in a single dose or in 2 to 4 divided doses.
  • the specific dose level and frequency of dosage for any particular subject may be varied and generally depends on a variety of factors, including, but not limited to, for example, the bioavailability of Compound (I) in the administered form; metabolic stability and length of action of Compound (I); species, age, body weight, general health, sex, and diet of the subject; mode and time of administration; rate of excretion; drug combination; and severity of the particular condition.
  • the patient is an animal.
  • the patient is a mammalian species including, but not limited to, for example, humans and domestic animals, such as, for example, dogs, cats, and horses.
  • Crystalline forms may be prepared by a variety of methods, including, but not limited to, for example, crystallization or recrystallization from a suitable solvent mixture; sublimation; growth from a melt; solid state transformation from another phase; crystallization from a supercritical fluid; and jet spraying.
  • Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, but are not limited to, for example, evaporation of the solvent; decreasing the temperature of the solvent mixture; crystal seeding a supersaturated solvent mixture of the compound and/or a salt from thereof; freeze drying the solvent mixture; and adding antisolvents (countersolvents) to the solvent mixture.
  • High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs.
  • the solvent(s) are typically chosen based on one or more factors including, but not limited to, for example, solubility of the compound; crystallization technique utilized; and vapor pressure of the solvent. Combinations of solvents may be employed.
  • the compound may be solubilized in a first solvent to afford a solution to which antisolvent is then added to decrease the solubility of the compound in the solution and precipitate the formation of crystals.
  • An antisolvent is a solvent in which a compound has low solubility.
  • a compound is suspended and/or stirred in a suitable solvent to afford a slurry, which may be heated to promote dissolution.
  • slurry as used herein, means a saturated solution of the compound, wherein such solution may contain an additional amount of compound to afford a heterogeneous mixture of compound and solvent at a given temperature.
  • Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control growth of a particular polymorph and/or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an average product particle as described, for example, in "Programmed Cooling of Batch Crystallizers," J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971,26, 369-377. In general, seeds of small size are needed to effectively control the growth of crystals in the batch. Seeds of small size may be generated by sieving, milling, or micronizing large crystals, or by micro- crystallizing a solution. In the milling or micronizing of crystals, care should be taken to avoid changing crystallinity from the desired crystalline form (i.e., changing to an amorphous or other polymorphic form).
  • a cooled crystallization mixture may be filtered under vacuum and the isolated solid product washed with a suitable solvent, such as, for example, cold recrystallization solvent. After being washed, the product may be dried under a nitrogen purge to afford the desired crystalline form.
  • the product may be analyzed by a suitable spectroscopic or analytical technique including, but not limited to, for example, solid state nuclear magnetic resonance; differential scanning calorimetry (DSC); and powder x-ray diffraction (PXRD) to assure the preferred crystalline form of the compound has been formed.
  • the resulting crystalline form may be produced in an amount greater than about 70 wt. % isolated yield, based on the weight of the compound originally employed in the crystallization procedure, and preferably greater than about 90 wt. % isolated yield.
  • the product may be delumped by being comilled or passed through a mesh screen.
  • Crystalline forms of Compound (I) including, but not limited to, for example, the Forms described herein, may be prepared directly from the reaction medium produced via the final process step employed in preparing Compound (I).
  • crystalline form(s) of Compound (I) could be produced by employing a solvent or a mixture of solvents in the final process step employed in preparing Compound (I).
  • crystalline forms of Compound (I) may be obtained by distillation or solvent addition techniques.
  • Suitable solvents for this purpose include, but are not limited to, for example, the aforementioned nonpolar and polar solvents, wherein polar solvents include, but are not limited to, for example, protic polar solvents, such as, for example, alcohols and aprotic polar solvents, such as, for example, ketones.
  • the presence of more than one crystalline form and/or polymorph in a sample may be determined by techniques, including, but not limited to, for example, PXRD and solid state nuclear magnetic resonance spectroscopy. For example, the presence of extra peaks when an experimentally measured PXRD pattern is compared to a simulated PXRD pattern may indicate more than one crystalline form and/or polymorph in the sample.
  • the simulated PXRD may be calculated from single crystal x-ray data. See, for example, Smith, D. K., "A FORTRAN Program for Calculating X- Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).
  • Crystalline forms of Compound (I), including, but not limited to, those described herein according to the invention may be characterized using a variety of techniques well known to person(s) of ordinary skill in the art.
  • the single x-ray diffraction technique may, under standardized operating conditions and temperatures, be used to characterize and distinguish crystalline form(s) of Compound (I).
  • Such characterization may, for example, be based on unit cell measurements of a single crystal of the desired form at a fixed analytical temperature.
  • the approximate unit cell dimensions in Angstroms (A), as well as the crystalline cell volume, space group, molecules per cell, and crystal density may be measured, for example, at a sample temperature of 25°C.
  • [00161] Another means of characterizing the crystalline structure of the subject form is by PXRD analysis, the actual diffraction profile of such form is compared to a simulated profile representing pure powder material. Preferably, the actual and simulated profiles are both run at the same analytical temperature, and the subsequent measurements characterized as a series of 2 ⁇ values (usually four or more).
  • Other means of characterizing a crystalline form include, but are not limited to, for example, solid state nuclear magnetic resonance (NMR); DSC; thermography; gross examination of the crystalline or amorphous morphology; and combinations thereof.
  • Powder X-Ray Diffraction (PXRD) Measurements - Method A About 200 mg of the sample was packed by the backloading method into a Philips PXRD-sample holder. The sample holder was transferred to a Philips MPD unit (45 KV, 40 mA, Cu Ka), and the data was subsequently collected at room temperature in the 2 to 32 2-theta range (continuous scanning mode, scanning rate
  • Powder X-Ray Diffraction Measurements Method B
  • PXRD data was obtained using a Bruker C2 GADDS.
  • the radiation was Cu Ka (40 KV, 50mA).
  • the sample-detector distance was 15 cm.
  • Powder samples were placed in sealed glass capillaries of lmm or less in diameter, and the capillary was rotated during data collection. Data were collected for 3 ⁇ 2 ⁇ 35° with a sample exposure time of at least about 2000 seconds.
  • the resulting two-dimensional diffraction arcs were integrated to create a traditional 1 -dimensional PXRD pattern with a step size of 0.02 degrees 2 ⁇ in the range of 3 to 35 degrees 2 ⁇ .
  • DSC Differential scanning calorimetry
  • TGA Thermal gravimetric analysis
  • TGA experiments were performed in a TA InstrumentsTM model Q500 or 2950.
  • the sample (about 10-30 mg) was placed in a pinpricked hermetically sealed aluminum pan on a platinum pan, both previously tared.
  • the weight of the sample was measured accurately and recorded to a thousand of a milligram by the instrument.
  • the furnace was purged with nitrogen gas at 100 mL/min. Data was collected between room temperature and about 350 0 C at a heating rate of about 10°C/min.
  • a solution was prepared by adding 1 gram of Compound (I) to 2 mL n- butyl acetate and heating to reflux. The solution was removed from the heat and slowly cooled to room temperature. White crystals precipitated from the solution. After being maintained at room temperature for 1 hour, the crystals were filtered, washed with cold diethyl ether, and dried on a sintered-glass funnel.
  • PXRD Method C
  • Example 2 Form SA-I [00174] A solution was prepared by dissolving 1 gram of Compound (I) in 2 mL of acetone at a temperature in the range of from 45 to 55°C. Next, 1.2 mL of hexanes was added dropwise and the solution became cloudy. A clear solution was obtained by the addition of 5 drops of acetone. The solution was heated and 5 drops of water were added to give a slightly cloudy solution from which white crystals were obtained. The crystals were filtered, washed with cold ether, and dried. PXRD: Method B
  • a solution was prepared by dissolving Compound (I) in acetonitrile at a temperature in the range of from 60 to 70 0 C. Crystals formed as the solution was allowed to cool slowly to room temperature.
  • PXRD Method A
  • a solution was prepared by dissolving 0.2 grams of Compound (I) in 1.3 mL of hot ethanol. While hot, water was added dropwise until the solution became slightly cloudy. Next, the solution was cooled slowly. After being allowed to sit at room temperature for 1 hour, the crystals were filtered and washed with cold diethyl ether and dried.
  • PXRD Method B
  • a solution was prepared by dissolving 0.2 grams of Compound (I) in 1.5 mL of hot ethyl acetate. The solution was filtered through filter paper. Next, hexanes was added to the warm solution until cloudiness persisted. The solution was reheated again to boiling, filtered, and allowed to cool which resulted in white crystals coming out of solution. The crystals were filtered, washed with cold hexanes, and dried.
  • a solution of Compound (I) in acetic acid was prepared at approximately 15.6 wt %.
  • the solution was heated to 60-70 0 C under reduced pressure to concentrate the solution to approximately 26.7 wt % of Compound (I) with a final KF ⁇ 0.6%.

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Abstract

L'invention concerne des formes cristallines de (3aa,4b,5a,7b,7aa)-4-(octahydro-5-éthylsulfonamido-4,7-diméthyl-l,3-dioxo-4,7-époxy-2H-isoindol-2-yl)-2-(trifluorométhyl)benzonitrile. Au moins une composition pharmaceutique comprenant au moins une forme cristalline de (3aa,4b,5a,7b,7aa)-4-(octahydro-5-éthylsulfonamido-4,7-diméthyl-1,3-dioxo-4,7-époxy-2H-isoindol-2-yl)-2-(trifluorométhyl)benzonitrile, et au moins un procédé d'utilisation d'au moins une forme cristalline de (3aa,4b,5a,7b,7aa)-4-(octahydro-5-éthylsulfonamido-4,7-diméthyl-l,3-dioxo-4,7-époxy-2H-isoindol-2-yl)-2-(trifluorométhyl)benzonitrile pour traiter un cancer et/ou d'autres maladies prolifératives sont également décrits.
PCT/US2008/066665 2007-06-15 2008-06-12 Formes cristallines de 3aalpha,4bêta,5alpha,7bêta,7aalpha)-4-(octahydro-5-éthylsulfonamido-4,7-diméthyl-1,3-dioxo-4,-7-époxy-2h-isoindol-2-yl)- WO2008157211A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7141578B2 (en) * 2000-09-19 2006-11-28 Bristol-Myers Squibb Company Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7141578B2 (en) * 2000-09-19 2006-11-28 Bristol-Myers Squibb Company Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CAIRA M R: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP001156954, ISSN: 0340-1022 *

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