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Matched Legal Cases: ['Application No. 200880111719', 'Application No. 10057462', 'Application No. 201000642', 'Application No. 201000642', 'Application No. 378', 'Application No. 201000642', 'Application No. 60']

United States Patent 8618075
13/556404
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Non-Final Rejection in U.S. Appl. No. 13/665,184 mailed on Apr. 9, 2013.
Bellmunt et al., “Phase I-II study of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma of the urothelium,” J. Clin. Oncol, 18(18):3247-55 (2000).
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Rodriguez et al., “Phase I clinical trials of tezacitabine [(E)-2′-deoxy-2′-(fluoromethylene)cytidine] in patients with refractory solid tumors”, Clin. Cancer Res. 8:2828-34 (2002).
Thaler et al., “Comparative analysis of two consecutive phase II studies with IFN-α and IFN-α + ara-C in untreated chronic-phase CML patients,” Bone Marrow Transpl. 17(Suppl 3):S25-S28 (1996).
Watanabe et al., Nucleosides. 110. Synthesis and antiherpes virus activity of some 2′-fluoro-2′-deoxyarabinofuranosylpyrimidine nucleosides, J. Med. Chem. 22:21-24 (1979).
China Application No. 200880111719.5, filed Oct. 16, 2008; Office Action mailed Jan. 31, 2012.
Colombia Application No. 10057462, filed Oct. 16, 2008, Opposition filed Aug. 5, 2011.
Eurasia Application No. 201000642, filed Oct. 16, 2008, Office Action mailed Oct. 3, 2011.
Eurasia Application No. 201000642, filed Oct. 16, 2008, Office Action mailed Mar. 23, 2012.
Chile Application No. 378-10, filed Apr. 16, 2010, Office Action mailed Nov. 26, 2012.
Eurasia Application No. 201000642, filed Oct. 16, 2008, Office Action mailed Oct. 16, 2012.
This application is a continuation of U.S. application Ser. No. 12/252,961, filed Oct. 16, 2008, now U.S. Pat. No. 8,268,800, which claims the benefit of U.S. Provisional Application No. 60/980,397, filed Oct. 16, 2007, the entire contents of each of which is hereby incorporated by reference.
1. A kit comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof: wherein the carbon marked by an asterisk may have an (R) or an (S) configuration; and wherein R1 and R2 are fluoro.
2. The kit of claim 1, wherein the compound is represented by Compound 1 a or a pharmaceutically acceptable salt thereof:
3. The kit of claim 1, wherein the compound is represented by Compound 1 a:
4. The kit of claim 1, further comprising a second compound which is a cytidine deaminase (CDA) substrate drug selected from the group consisting of 5-azacytidine, gemcitabine, ara-C, tezacitabine, 5-fluoro-2′-deoxycytidine, and cytochlor.
5. The kit of claim 1, further comprising a second compound which is a CDA substrate drug, wherein the CDA substrate drug is not decitabine.
6. The kit of claim 1, further comprising a second compound which is a CDA substrate drug, wherein the CDA substrate drug is decitabine.
7. The kit of claim 1, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is in a unit dosage form.
8. The kit of claim 1, further comprising information.
9. A kit comprising a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof: wherein the carbon marked by an asterisk may have an (R) or an (S) configuration; and wherein R1 and R2 are fluoro; and a pharmaceutically acceptable excipient.
10. The kit of claim 9, wherein the compound is represented by Compound 1 a or a pharmaceutically acceptable salt thereof:
11. The kit of claim 9, wherein the compound is represented by Compound 1 a:
12. The kit of claim 9, further comprising a second compound which is a CDA substrate drug selected from the group consisting of 5-azacytidine, gemcitabine, ara-C, tezacitabine, 5-fluoro-2′-deoxycytidine, and cytochlor.
13. The kit of claim 9, further comprising a second compound which is a CDA substrate drug, wherein the CDA substrate drug is not decitabine.
14. The kit of claim 9, further comprising a second compound which is a CDA substrate drug, wherein the CDA substrate drug is decitabine.
15. A method for inhibiting cytidine deaminase, comprising administering to a subject in need a composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof: wherein the carbon marked by an asterisk may have an (R) or an (S) configuration; and wherein R1 and R2 are fluoro; and a pharmaceutically acceptable excipient.
16. The method of claim 15, wherein the compound is represented by Compound 1 a or a pharmaceutically acceptable salt thereof:
17. The method of claim 15, wherein the compound is represented by Compound 1 a:
18. A method for inhibiting degradation of a CDA substrate drug by cytidine deaminase, comprising administering to a subject that is undergoing treatment with the CDA substrate drug a composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof: wherein the carbon marked by an asterisk may have an (R) or an (S) configuration; and wherein R1 and R2 are fluoro; and a pharmaceutically acceptable excipient.
19. The method of claim 18, wherein the compound is represented by Compound 1 a or a pharmaceutically acceptable salt thereof:
20. The method of claim 18, wherein the compound is represented by Compound 1 a:
In some embodiments, R1 and R2 are independently selected from the group consisting of hydrogen, halo, hydroxyl, cyano, nitro, sulfhydryl, C1 to C6 straight or branched chain alkyl, C1 to C6 straight or branched chain alkenyl, C1 to C6 straight or branched chain alkynyl, C1 to C6 straight or branched chain alkoxy, and C1 to C6 straight or branched chain alkenoxy; wherein wherein each occurrence of C1 to C6 straight or branched chain alkyl, C1 to C6 straight or branched chain alkenyl, C1 to C6 straight or branched chain alkynyl, C1 to C6 straight or branched chain alkoxy, or C1 to C6 straight or branched chain alkenoxy may be independently unsubstituted or substituted with one ore more halos;
Throughout the specification and claims, the following definitions apply. As used in the specification and claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a pharmaceutical composition comprising “a compound” may encompass two or more compounds.
other chemotherapeutic agents (e.g, tamoxifen, anti-mitotic agents such as polo-like kinase inhibitors or aurora kinase inhibitors, and the like).
2′2′-DiFluoro-TetraHydroUridine (DFTHU, 1a and 1b). The DFDHU 25 (1.2 g, 4.9 mmol) is dissolved in 30 mL of MeOH and cooled to 0° C. Sodium borohydride (540 mg, 14.6 mmol) is added portion-wise to the solution and the reaction is slowly warmed to room temperature. After 4 hours of stirring at room temperature (r.t.), the MeOH is removed in vacuo and the residue is dissolved in 15 mL of H2O. The solution is neutralized with 2.0 N HCl to pH 7. The solution is then purified via prep HPLC (reverse phase C18 @5% CH3CN/H2O). The salts come out at 5.2 minutes. One peak is apparent at 7.5 minutes (12%). One epimer of the DFTHU la comes out at 9.5 minutes (350, 29%). The other epimer 1b comes out at 14.3 minutes (370 mg, 31%). The deoxygenated product 26 elutes at 17 minutes (200 mg, 17%).
2′(R)-Fluoro-2′deoxy-DiHydroUridine [(R)-FDHU, 28]. 2′-Fluoro-2′-deoxyuridine 27 (1.2 g, 4.9 mmol) is dissolved in H2O(30 mL) with a few drops of concentrated ammonium hydroxide (5 drops). Rhodium on alumina (300 mg) is added to the solution and the mixture is hydrogenated overnight at 40 psi. The next day, the mixture is filtered and the filtrate is concentrated and purified via prep HPLC (reverse phase C18 @5% CH3CN/H2O). The major product is 28, (R)-FDHU, which elutes at 9.2 minutes (780 mg, 64%). Some residual starting material 7a (5.5 minutes, 95 mg, 8%) and a minor amount of the FTHU 2a and 2b (7.2 minutes, 50 mg, 4% and 8.6 minutes, 45 mg, 4%) are isolated. 1HNMR 28 (D2O): 5.83 (dd, 1H), 5.07 (dd, 1H), 4.18 (q, 1H), 3.90-3.78 (m, 2H), 3.65 (dt, 1H), 3.52-3.35 (m, 2H), 2.64 (t, 2H).
2′(R)-Fluoro-2′-deoxy-TetraHydroUridine ((R)-FTHU, 2a and 2b). The (R)-FDHU (600 mg, 2.4 mmol) is dissolved in 20 mL of MeOH and cooled to 0° C. Sodium borohydride (355 mg, 9.6 mmol) is added portion-wise to the solution and the reaction is slowly warmed to room temperature overnight. The MeOH is removed in vacuo and the residue is dissolved in 10 mL of H2O. The solution is neutralized with 2.0 N HCl to pH 7. The solution is then purified via prep HPLC (reverse phase C18 @5% CH3CN/H2O). The desired product 2a elutes at 7.2 minutes (275 mg, 46%) followed by the other epimer 2b at 8.6 minutes (125 mg, 21%) and some residual starting material at 9.2 minutes and the fully reduced material 29 (50 mg, 9%) at 14.9 minutes. The stereochemistry at C-4 for 2a and 2b are assigned based on literature precedents on the crystal structure of cytidine deaminase in complex with a single epimer of tetrahydrouridine.
2′(S)-fluoro-2′deoxy-dihydrouridine [(S)-FDHU, 31]. Compound 30 (1.2g, 4.0 mmol) is dissolved in H2O(40 mL). Rhodium on alumina (200 mg) is added to the solution and the mixture is hydrogenated overnight at 50 psi. The next day, the mixture is filtered through a pad of celite and concentrated in vacuo. The desired product 31 is obtained in quantitative yield (>1.0 g). 1HNMR (D2O): 6.08 (dd, 1H), 5.09 (dt, 1H), 4.28 (m, 1H), 3.85-3.80 (m, 2H), 3.72 (m, 2H), 3.51 (m, 1H), 2.65 (t, J=9 Hz, 2H).
2′(S)-fluoro-2′deoxy-tetrahydrouridine [(S)-FTHU, 3a and 3b]. Compound 31 (1.12 mg, 4.55 mmol) is dissolved in 28 mL of MeOH and cooled to 0° C. Sodium borohydride (475 mg, 12.55 mmol) is added portion-wise to the solution and the reaction is allowed to continue for 1 hour and 15 minutes. The MeOH is removed in vacuo and the residue is dissolved in 15 mL of 5% CH3CN/H2O. The solution is neutralized with 2.0 N HCl to pH 7 (˜3 ml). The solution is then purified via prep HPLC (reverse phase C18 Phenomenex Luna with a 5% CH3CN/H2O (isocratic eluent and refractive index detector). The desired product 3a elutes at 9.3 minutes (163 mg, 14%) followed by the other epimer 3b at 13.4 minutes (236 mg, 21%), some residual starting material (not quantified), as well as the fully reduced product 32 (not quantified) are detected. Stereochemistry at C-4 for 3a and 3b are assigned based on literature precedents on the crystal structure of cytidine deaminase in complex with a single epimer of tetrahydrouridine.
2 L1210 i.v. and Vehicle + Compound 110 mg/kg
L1210 Intravenous (Lv.) Injection: Prior to experiment, L1210 cells are passed at least 3 times in CD2F1 female mice. The mice are injected intraperitoneally (i.p.) with L1210 ascites one prior week to sacrifice using CO2. Each mouse is placed on its back, its belly surface is cleaned with alcohol wipes and a small incision is made into its peritoneal cavity. 2 ml of ice cold 2.1% bovine serum albumin (BSA) in saline is injected into the cavity. Fluid is withdrawn from the cavity, transferred with an 18G 3 cc syringe into a clean sterile tube, and kept on ice. The fluid is diluted 1:10 in 2.1% BSA in saline and one drop of zap-o-globin is added to 2 ml of diluted ascites. Diluted ascites (dilute 1:10 again) are counted on a hematocytomer and the number of cells/ml is calculated. A stock of ascites in BSA solution is diluted to 1×104 cells/0.1 ml. Mice are injected with 0.1 ml of cell solution with a 27G needle.
7 L1210 i.v. and Compound 110 mg/kg +
* Compound 1 is dosed approximately 30 min prior to Gemcitabine
The primary endpoints used to evaluate efficacy in the A2780 model are complete and partial tumor regressions, tumor growth delay and the number of tumor free survivors at the end of the study. A complete response (CR) is defined as a decrease in tumor size to an undetectable size (<50mm3). A partial response (PR) is defined as >50% decrease in tumor mass form starting tumor size. A tumor that achieves a CR or PR during the study but starts to grow again is still considered a CR or PR. Tumor free survival (TFS) at the end of the study would be no detectable tumor (<50 mm3) at study termination (day 74). Tumor growth delay (TGD) is defined in this experiment as the median number of days for the treatment group compared to the control group to reach 750 mm3.
Cell constants and an orientation matrix for data collection correspond to a primitive trigonal cell (laue class: −3ml) with dimensions:
The data is collected at a temperature of −123±1° C. to a maximum 2θ value of 136.4°. A total of 111 oscillation images are collected. A sweep of data is done using ω scans from 20.0 to 200.0° in 5.0° steps, at χ=0.0° and φ=180.0° . A second sweep is performed from 20.0 to 200.0° in 5.0° steps, at χ=54.0° and φ=180.0°. A third sweep is performed from 20.0 to 185.0° in 5.0° steps, at χ=54.0° and φ=90.0°, and a final sweep is performed using ω scans from 20.0 to 50.0° in 5.0° steps, at χ=0.0° and φ=0.0°. The exposure rate is 12.0 [sec./°]. The crystal-to-detector distance is 127.40 mm. Readout is performed in the 0.100 mm pixel mode.
The structure is solved by direct methods (SIR92: Larson, A. C., J. Appl. Cryst., 1994, 27, 435) and expanded using Fourier techniques (DIRDIF99: Beurskens, P. T. et al., The DIRD-99 Program System. Technical Report of the Crystallography Laboratory, 1999, University of Nijmegen, The Netherlands). The non-hydrogen atoms are refined anisotropically. Some hydrogen atoms are refined isotropically and the rest are refined using the riding model. The final cycle of full-matrix least-squares refinement (least squares weights =Σw(Fo2−Fc2)2) on F2 is based on 2052 observed reflections and 181 variable parameters and converges (largest parameter shift is <0.01 times its esd) with unweighted and weighted agreement factors of:
Neutral atom scattering factors are taken from Cromer, D. T. et al., International Tables for X-ray Crystallography 1974, IV, Table 2.2 A. Anomalous dispersion effects are included in Fcalc (Ibers, J. A. et al., Acta Crystallogr. 1964, 17, 781); the values for Δf′ and Δf′ are those of Creagh, D. C. et al., International Tables for Crystallography 1992, C, Table 4.2.6.8, 219-222. The values for the mass attenuation coefficients are those of Creagh, D. C. et al. International Tables for Crystallography 1992, C, Table 4.2.4.3, 200-206. All calculations are performed using the CrystalStructure 3.8 crystallographic software package except for refinement, which is performed using SHELXL-97.
Tetrahydrouridine (THU, 5 mg) is dissolved in D2O (0.75 mL). The 1HNMR (D2O, 300 MHz, 27° C.) spectrum is shown in FIG. 10. To this same sample is added one drop of deuterated TFA followed by an immediate 1HNMR spectrum (FIG. 10). Even at this earliest time point, the peak at 5.4 ppm (˜10% conversion by integration) is indicative of the ring expansion to the TH-pyranose. Over the next several hours, spectra (D2O, 300 MHz, 27° C.) are taken as shown in FIG. 11. After 4 hours, the TH-pyranose is more prevalent indicating about 60% conversion. At 72 hours, the conversion is almost entirely complete (>80%).
Notable changes in the region from 4.0-4.5 are also indicative of THU decomposition and the TH-pyranose formation.
2. A compound of embodiment 1, wherein R1 and R2 are independently selected from the group consisting of hydrogen, halo, hydroxyl, cyano, nitro, sulfhydryl, C1 to C6 straight or branched chain alkyl, C1 to C6 straight or branched chain alkenyl, C1 to C6 straight or branched chain alkynyl, C1 to C6 straight or branched chain alkoxy, and C1 to C6 straight or branched chain alkenoxy; wherein wherein each occurrence of C1 to C6 straight or branched chain alkyl, C1 to C6 straight or branched chain alkenyl, C1 to C6 straight or branched chain alkynyl, C1 to C6 straight or branched chain alkoxy, or C1 to C6 straight or branched chain alkenoxy may be independently unsubstituted or substituted with one ore more halos;
35. The compound of embodiment 1, wherein one of R1 and R2 is —Cl to C6 straight or branched chain alkyl substituted with fluoro, and the other is —H.
59. The method of any one of embodiments 50 and 52 to 57, wherein the cancer is a hematological cancer selected from MDS and leukemia. 60. The method of embodiment 59, wherein the leukemia is AML or CML.
77. A method for treating cancer, comprising the steps of
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