Patent Application
20120149657
The present disclosure relates to certain 2′-fluoro arabino nucleosides. The present disclosure also relates to pharmaceutical compositions comprising the disclosed compounds. The present invention is also concerned with treating patients suffering from cancer by administering to the patients certain 2′-fluoro arabino nucleosides compounds. Compounds employed according to the present invention have exhibited good anticancer activity. The present disclosure also relates to a method for producing the disclosed compounds.
A considerable amount of research has occurred over the years related to developing treatments against cancers to inhibit and kill tumor cells. Some of this research has resulted in achieving some success in finding clinically approved treatments. Nevertheless, efforts continue at an ever-increasing rate in view of the extreme difficulty in uncovering promising anticancer treatments. For example, even when a compound is found to have cytotoxic activity, there is no predictability of it being selective against cancer cells.
Even though significant advances have occurred in the treatment of cancer, it still remains a major health concern. Cancer has been reported as the leading cause of death in the United States with one of every four Americans likely to be diagnosed with the disease.
Notwithstanding the advances in treatments for cancer and other diseases there still remains room for improved drugs that are effective for the desired treatment, while at the same time exhibiting reduced adverse side effects.
The present disclosure relates compounds represented by the formula:
Another aspect of the present disclosure relates to pharmaceutical compositions containing the above-disclosed compounds.
Also disclosed is a method of treating cancer in a mammal comprising administering to the mammal an effective treatment amount of a compound represented by the formula:
wherein X is selected from the group consisting of hydrogen, halo, alkoxy, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, amino, monoalkylamino, dialkylamino, cyano and nitro; and X1 is selected from the group consisting of hydrogen, halo, alkyl, alkenyl, alkynyl, amino, monoalkylamino, and dialkylamino; and pharmaceutically acceptable salts thereof.
Still other objects and advantages of the present disclosure will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described only the preferred embodiments, simply by way of illustration of the best mode. As will be realized, the disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the disclosure. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.
The present disclosure relates compounds represented by the formula:
The present disclosure also relates to a method of treating cancer in a mammal comprising administering to the mammal an effective treatment amount of a compound represented by the formula:
wherein X is selected from the group consisting of hydrogen, halo, alkoxy, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, amino, monoalkylamino, dialkylamino, cyano and nitro; and X1 is selected from the group consisting of hydrogen, halo, alkyl, alkenyl, alkynyl, amino, monoalkylamino, and dialkylamino; and pharmaceutically acceptable salts thereof.
The alkyl groups for R typically contain 1-4 carbon atoms and include methyl, ethyl, i-propyl, n-propyl, i-butyl and n-butyl. The alkyl group can be straight or branched chain. The preferred alkyl group for R is methyl. Examples of halo groups for R are chloro, bromo and preferably fluoro.
Suitable monoalkylamino groups for X contain 1-6 carbon atoms and include monomethylamino, monoethylamino, mono-isopropylamino, mono-n-propylamino, mono-isobutyl-amino, mono-n-butylamino and mono-n-hexylamino. The alkyl moiety can be straight or branched chain.
Suitable dialkylamino groups for Y and X contain 1-6 carbon atoms in each alkyl group. The alkyl groups can be the same or different and can be straight or branched chain. Examples of some suitable groups are dimethylamino, diethylamino, ethylmethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, methylpentylamino, ethylpropylamino and ethylhexylamino.
Suitable halogen groups for X include Cl, Br and F.
Suitable alkyl groups for X typically contain 1-6 carbon atoms and can be straight or branched chain. Some examples are methyl, ethyl, i-propyl, n-propyl, i-butyl, n-butyl, pentyl and hexyl.
Suitable haloalkyl groups typically contain 1-6 carbon atoms and can be straight or branched chain and include Cl, Br or F substituted alkyl groups including the above specifically disclosed alkyl groups.
Suitable alkoxy groups typically contain 1-6 carbon atoms and include methoxy, ethoxy, propoxy and butoxy.
Suitable alkenyl groups typically contain 2-6 carbon atoms and include ethenyl and propenyl.
Suitable haloalkenyl groups typically contain 1-6 carbon atoms and include Cl, Br or F substituted alkenyl groups including the above specifically disclosed alkenyl groups.
Suitable alkynyl groups typically contain 1-6 carbon atoms and include ethynyl and propynyl.
Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from pharmaceutically acceptable inorganic or organic acids. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, trifluoroacetic and benzenesulfonic acids. Salts derived from appropriate bases include alkali such as sodium and ammonia.
The preferred compounds according to the present disclosure are 1-(2-Deoxy-2-fluoro-4-C-methyl-β-
Compounds according to the present disclosure can be prepared as discussed below and shown in Scheme 1. The synthesis of 4′-C-hydroxymethyl-2′-fluoro-arabinofuranoside 1 and the corresponding nucleosides[1] have already been reported in the literature. Selective protection of 1 with the monomethoxytrityl (MMT) group was carried out using MMT chloride in pyridine in 30% yield.[3] The undesired isomer 2b and the unreacted 1 were recycled to increase the yield. The selectively blocked intermediate 2a was benzoylated to give 3 in 92% yield, which was then detritylated to afford the sugar intermediate 4 in 89% yield. This 4′-C-hydroxymethyl analogue 4 was converted into 4′-C-phenoxythiocarbonyloxymethyl derivative 5 in 90% yield using phenyl chlorothionoformate. Compound 5 was deoxygenated using 1,1′-azobis(cyclohexane-carbonitrile) (ACCN) and tris(trimethyl)silane to provide 4′-C-methyl analogue 6 in 84% yield.[4] Acetolysis of compound 6 using traditional methods failed to give 1-O-acetyl sugar 8, resulting in either no reaction or gradual decomposition. The methyl glycoside 6 was instead hydrolyzed using 9:1 trifluoroacetic acid/water to provide the hydroxy sugar 7 in 83% yield, which was acetylated to produce compound 8 in 91% yield. This sugar intermediate was converted cleanly into glycosyl bromide 9 using 33% HBr in acetic acid. Attempted conversion of 7 directly to 9 resulted in a complex mixture and a very low yield of 9. The bromosugar 9 was highly reactive and was used directly without purification for coupling reactions.
Conditions: (a) MMTr-Cl, pyridine, room temperature, overnight; (b) BzCl, pyridine, room temperature, overnight; (c) 80% AcOH, room temperature, overnight; (d) PhOC(═S)Cl, DMAP, MeCN, room temperature, 3 hours; (e) (TMS)3SiH, ACCN, toluene, 100° C., 5 hours; (f) TFA/H2O, 65° C., 24 hours; (g) Ac2O/pyridine, room temperature, overnight; (h) HBr/AcOH, 5° C. overnight; (i) Bases, BSA, MeCN, room temperature, 1-2 hours; (j) persilylated bases, compound 9, ClCH2CH2Cl, 100° C., 4 hours; (k) 0.5N NaOCH3, MeOH, room temperature, 2-7 hours; (l) NaH, MeCN, room temperature, 6 hours; (m) EtOH, NH3, 80° C., 16 hours; (n) NaN3, EtOH, reflux, ½ hours; (o) 10% Pd/C, H2, 1 atm, EtOH/DMAC, 18 hours; (p) NaOCH3/MeOH, room temperature, 3 hours; (q) Adenosine deaminase
Coupling of bromosugar 9 with silylated N4-benzoylcytosine in situ with BSA gave cytosine nucleosides 10/10α in 54% yield.[5,6] Separation of α, β anomers afforded pure β anomer 10 as the major product (48%) and α anomer 10α as the minor product (6%). Similarly uracil and thymine were coupled with bromo sugar 9 to obtain corresponding nucleosides 11/11α and 12/12α in 71% and 68% yields respectively with the p anomer as the predominant product. Both anomers of cytosine nucleoside 10 were deblocked using sodium methoxide to get the target compounds 13 and 13α. After purification the β anomer 13 was isolated as a hydrochloride salt in 89% yield, and the α anomer 13α was isolated as the free base in 77% yield. In the case of nucleosides 11 and 12, only the β anomers were deblocked using the same procedure to obtain compounds 14 (77%) and 15 (92%) respectively. The α anomers of compounds 11 and 12 were not further utilized and were isolated only for characterization purposes to compare with the β anomers.
A series of purine nucleoside analogues were prepared through the coupling of bromosugar 9 with 6-chloropurine and with 2,6-dichloropurine. Sodium salt coupling of 9 with 6-chloropurine gave the desired β nucleoside 16 (36%) and α anomer 16α (14%).[7] Separate treatment with ethanolic ammonia gave the target compound 17 (74%) and α anomer 17α (49%), respectively. Similarly 2,6-dichloropurine was coupled with bromo sugar 9 to obtain the corresponding nucleoside as an anomeric mixture (2:1, β:α ratio) in 64% yield. Both anomers were separated by preparative TLC to provide 18 and 18α as white foams. Separate treatment of 18 and 18α with sodium azide in aqueous ethanol at reflux produced the corresponding 2,6-diazido intermediates 19 and 19α, which were subjected to reduction with Pd/C to afford blocked diaminopurine nucleosides 20 and 20α, respectively. Deblocking of 20 and 20α with NaOMe produced the target 2-aminoadenine nucleosides 21 and 21α. Conversion of 21 to the guanine nucleoside 22 was accomplished by treatment with adenosine deaminase.[21] Though the deamination was slow, it went to completion at room temperature in 68 hours. The 2-chloroadenine nucleosides 24 (84%) and 24α (75%) were prepared by first converting the dichloropurine nucleosides 18 and 18α to their 6-methoxy intermediate 23 with sodium methoxide followed by treatment with ethanolic ammonia.[8]
The concentration of compound required to inhibit cell growth by 50% (IC50) after 72 hours of incubation was determined for each unprotected analog with eight human tumor cell lines (SNB-7 CNS, DLD-1 colon, CCRF-CEM leukemia, NCI-H23 NSCL, ZR-75-1 breast, LOX melanoma, PC-3 prostate, and CAKI-1 renal). The most active compound in this series was methyl-F-araC (13, Table 1), which was found to have significant cytotoxicity against four of the cell lines in the panel. The purine analogs demonstrated modest cytotoxicity against the solid tumor cell lines (IC50's between 5 and 80 μM), while the uracil and thymine analogs were not active against any cell line (IC50's greater than 200 μM). The α-anomers of these compounds were also screened but were not found to be cytotoxic (data not shown).
CCRF-CEM cells are a T-cell leukemia cell line that is known to be very sensitive to nucleoside analogs. Methyl-F-araC was a very potent inhibitor of this cell line with an IC50 of 0.012±0.003 μM. CCRF-CEM cell growth was also inhibited by the 2-Cl-adenine (24), 2,6-diaminopurine (21), and guanine (22) analogs with IC50's of approximately 0.5 μM. The inhibition of CCRF-CEM cell growth caused by either methyl-F-araC or the 2-Cl-adenine analog (4′-C-methyl-clofarabine, 24) was prevented by adding dCyd to the culture medium and neither compound was active in cells that lacked dCyd kinase. These results indicated that dCyd kinase was the primary enzyme responsible for the initial activation step of these two agents in CCRF-CEM cells. The cytotoxicity of the diaminopurine analog 21 was prevented by the addition of deoxycoformycin, a potent inhibitor of adenosine deaminase, which indicated that 21 was deaminated to the dGuo analog before conversion to cytotoxic nucleotides.
CCRF-CEM cells were incubated with methyl-F-araC, araC, and gemcitabine, and the amount of intracellular triphosphate (TP) of each compound was determined. There was significant metabolism of each of these compounds, and their triphosphates did not co-elute with any of the natural nucleotides (ATP, GTP, CTP, or UTP). Incubation of CCRF-CEM cells with 100 nM of each compound for two hours resulted in an intracellular concentration of methyl-F-araC-TP (16±2 pmoles/106 cells) that was similar to those of araC-TP (12±1 pmoles/106 cells) and gemcitabine-TP (17±3 pmoles/106 cells) (mean±SD, N=3). These results indicated that methyl-F-araC was a good substrate for deoxycytidine kinase. The intracellular half-life of each triphosphate was similar: methyl-F-araC-TP (7.1 hours, N=2); araC-TP (5.6 hours, N=2); gemcitabine-TP (5.0 hours, N=2).
Because of its potent in vitro activity, methyl-F-araC (13) was evaluated for in vivo activity against three solid tumor xenografts (CAKI-1 renal, NCI-H23 NSCL, and LOX melanoma). Prior to these studies the maximally tolerated dose of methyl-F-araC was determined to be 3 mg/kg given once per day for 9 consecutive days. Methyl-F-araC demonstrated excellent activity against the CAKI-1 tumors (
Xenografts were implanted sc on the flanks of female nude mice. When tumors were approximately 100-250 mg, they were treated ip with 3 or 4 mg/kg/dose of methyl-F-araC (q1d×9) and tumor size was measured twice weekly thereafter. Tumor-free survivors are the number of mice that were tumor-free at the end of the experiment/total number of mice in the treatment group.
aThe difference in the median of times poststaging for tumors of the treated (T) and control (C) groups to double in mass three times.
bThe difference in the median of times poststaging for tumors of the treated (T) and control (C) groups to double in mass two times.
cThe difference in the median of times poststaging for tumors of the treated (T) and control (C) groups to double in mass four times.
1-(4-C-Methyl-2-fluoro-β-
TLC analysis was performed on Analtech precoated (250 μm) silica gel GF plates. Melting points were determined on a Mel-Temp apparatus and are uncorrected. Purifications by flash chromatography were carried out on Merck silica gel (230-400 mesh). Evaporations were performed with a rotary evaporator, higher boiling solvents (DMF, pyridine) were removed in vacuo (<1 mm, bath to 35° C.). Products were dried in vacuo (<1 mm) at 22-25° C. over P2O5. The mass spectral data were obtained with a Varian-MAT 311A mass spectrometer in the fast atom bombardment (FAB) mode or with a Bruker BIOTOF II by electrospray ionization (ESI). 1HNMR spectra were recorded on a Nicolet NT-300 NB spectrometer operating at 300.635 MHz. Chemical shifts in CDCl3 and Me2SO-d6 are expressed in parts per million downfield from tetramethylsilane (TMS), and in D2O chemical shifts are expressed in parts per million downfield from sodium 3-(trimethylsilyl)propionate-2,2,3,3-d4 (TMSP). Chemical shifts (δ) listed for multiplets were measured from the approximate centers, and relative integrals of peak areas agreed with those expected for the assigned structures. UV absorption spectra were determined on a Perkin-Elmer lambda 9 spectrophotometer by dissolving each compound in MeOH or EtOH and diluting 10-fold with 0.1 N HCl, pH 7 buffer, or 0.1 N NaOH. Numbers in parentheses are extinction coefficients (ε×10−3). Microanalyses were performed by Atlantic Microlab, Inc. (Atlanta, Ga.) or the Spectroscopic and Analytical Department of Southern Research Institute. Analytical results indicated by element symbols were within ±0.4% of the theoretical values, and where solvents are indicated in the formula, their presence was confirmed by 1HNMR.
All cell lines were grown in RPMI 1640 medium containing 10% fetal bovine serum, sodium bicarbonate, and 2 mM L-glutamine. For in vitro evaluation of the sensitivity of these cell lines to compounds, cells were plated in 96-well microtiter plates and then were exposed continuously to various concentrations of the compounds for 72 h at 37° C. Cell viability was measured using the MTS assay [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS and an electron coupling reagent (phenazine ethosulfate; PES)]. Absorbance was read at 490 nm. The background absorbance mean was subtracted from the data followed by conversion to percent of control. The drug concentrations producing survival just above and below 50% level were used in a linear regression analysis to calculate the IC50.
CCRF-CEM cell extracts were collected by centrifugation and resuspended in ice-cold 0.5 M perchloric acid. The samples were centrifuged at 12,000×g, and the supernatant fluid was neutralized and buffered by adding 4 M KOH and 1 M potassium phosphate, pH 7.4. KClO4 was removed by centrifugation, and a portion of the supernatant fluid was injected onto a strong anion exchange HPLC (Bio Basic anion exchange column, Thermo Electron Corp., Bellefonte, Pa.). Nucleotides were eluted with a 30-min linear salt and pH gradient from 6 mM ammonium phosphate (pH 2.8) to 900 mM ammonium phosphate (pH 6). Peaks were detected as they eluted from the column by their absorbance at 254 nm.
Mice, obtained from various commercial suppliers, were housed in microisolator cages and were allowed commercial mouse food and water ad libitum. The three human tumors were obtained from the Developmental Therapeutics Program Tumor Repository (Frederick, Md.) and were maintained in in vivo passage. Only tumor lines that tested negative for selected viruses were used. For the in vivo evaluation of the sensitivity of human tumors to the compounds, female NCr-nu athymic mice were implanted subcutaneously (sc) with 30-40 mg tumor fragments. In each experiment, methyl-F-araC (13) was tested at three dosage levels. Procedures were approved by the Southern Research Institutional Animal Care and Use Committee, which conforms to the current Public Health Service Policy on Humane Care and Use of Laboratory Animals and the Guide for the Care and Use of Laboratory Animals.
Antitumor activity was assessed on the basis of delay in tumor growth (T-C). The delay in tumor growth is the difference in the median of times post staging for tumors of the treated and control groups to double in mass two, three, or four times. Drug deaths and any other animal whose tumor failed to attain the evaluation size were excluded. Tumors were measured in two dimensions (length and width) twice weekly, and the tumor weight was calculated using the formula (length×width2)/2 and assuming unit density. The mice were also weighed twice weekly.
The following non-limiting examples are presented to further illustrate the present invention.
Methyl 4-C-(p-Anisyldiphenylmethoxymethyl)-2-deoxy-2-fluoro-β-
Methyl 4-C-(p-Anisyldiphenylmethoxymethyl)-3,5-di-O-benzoyl-2-deoxy-2-fluoro-β-
Methyl 3,5-Di-O-benzoyl-2-deoxy-2-fluoro-4-C-hydroxymethyl-β-
Methyl 3,5-Di-O-benzoyl-2-deoxy-2-fluoro-4-C-phenoxythiocarbonyloxymethyl-β-
Methyl 3,5-Di-O-benzoyl-2-deoxy-2-fluoro-4-C-methyl-β-
3,5-Di-O-benzoyl-2-deoxy-2-fluoro-4-C-methyl-α,β-
1-O-Acetyl-3,5-di-O-benzoyl-2-deoxy-2-fluoro-4-C-methyl-α,β-
3,5-Di-O-benzoyl-2-deoxy-2-fluoro-4-C-methyl-α,β-
N4-Benzoyl-1-(3,5-di-O-benzoyl-2-deoxy-2-fluoro-4-C-methyl-β-
From impure fractions, the α-anomer 10α (41 mg, 6%) was recovered as a white solid by silica gel preparative TLC (Analtech GF, 10×20 cm, 500μ) with 99:1 CHCl3/MeOH as solvent: TLC 1:1 hexane/EtOAc, Rf 0.45; MS m/z 572 (m+H)+; 1H NMR (CDCl3) 8.80 (bh, 1H, NH), 7.40-8.16 (m, 17H, H-5, H-6 and aromatic H's), 6.28 (dd, 1H, H-1′, J=1 and 18 Hz), 5.90 (dd, 1H, H-3′, J=1 and 14 Hz), 5.46 (dd, 1H, H-2′, J=1 and 48 Hz), 4.44-4.50 (m, 2H, 5′-CH2), 1.64 (s, 3H, 4′-CH3).
1-(3,5-Di-O-benzoyl-2-deoxy-2-fluoro-4-C-methyl-β-
1-(3,5-Di-O-benzoyl-2-deoxy-2-fluoro-4-C-methyl-β-
1-(2-Deoxy-2-fluoro-4-C-methyl-β-
The α-anomer was prepared from 10α as described for 13 except the HCl salt formation was omitted. Pure 13α (77%) was obtained from acetone as a white solid: m.p. 222-223° C.; TLC 3:1:0.1 CHCl3/MeOH/NH4OH, Rf 0.40; HPLC 100%, tR=7.7 min, 9:1 NH4H2PO4 (0.01M, pH 5.1)/MeOH; MS m/z 260 (M+H)+; UV λmax pH 1, 278 (13.3), pH 7, 270 (9.3), pH 13, 271 (9.3); 1H NMR (DMSO-d6) 7.59 (d, 1H, H-6), 7.28 (bs, 1H, 4-NH2), 7.20 (bs, 1H, 4-NH2), 6.0 (dd, 1H, H-1′ J=4 and 18 Hz), 5.74-5.78 (m, 2H, H-5 and 3′-OH overlapped), 4.9-5.1 (m, 2H, H-2′ and 5′-OH overlapped), 4.24 (dt, 1H, H-3′, J=3 and 18 Hz), 3.30-3.40 (m, 2H, 5′-CH2), 1.24 (s, 3H, 4′-CH3). Anal. Calcd. For C10H14FN3O4: C, 46.33; H, 5.44; N, 16.21. Found: C, 46.19; H, 5.23; N, 16.09.
1-(2-Deoxy-2-fluoro-4-C-methyl-β-
1-(2-Deoxy-2-fluoro-4-C-methyl-β-
6-Chloro-9-(3,5-di-O-benzoyl-2-deoxy-2-fluoro-4-C-methyl-β-
9-(2-Deoxy-2-fluoro-4-C-methyl-β-
2,6-Dichloro-9-(3,5-di-O-benzoyl-2-deoxy-2-fluoro-4-C-methyl-β-
2,6-Diazido-9-(3,5-di-O-benzoyl-2-deoxy-2-fluoro-4-C-methyl-β-
2,6-Diamino-9-(3,5-di-O-benzoyl-2-deoxy-2-fluoro-4-C-methyl-β-
2,6-Diamino-9-(2-deoxy-2-fluoro-4-C-methyl-β-
9-(2-Deoxy-2-fluoro-4-C-methyl-β-
2-Chloro-6-methoxy-9-(2-deoxy-2-fluoro-4-C-methyl-β-
2-Chloro-9-(2-deoxy-2-fluoro-4-C-methyl-β-
In keeping with the present disclosure, the compounds of the present disclosure can be used alone or in appropriate association, and also may be used in combination with pharmaceutically acceptable carriers and other pharmaceutically active compounds such as various cancer treatment drugs and/or along with radiation. The active agent may be present in the pharmaceutical composition in any suitable quantity.
The pharmaceutically acceptable carriers described herein, for example, vehicles, adjuvants, excipients, or diluents, are well-known to those who are skilled in the art. Typically, the pharmaceutically acceptable carrier is chemically inert to the active compounds and has no detrimental side effects or toxicity under the conditions of use. The pharmaceutically acceptable carriers can include polymers and polymer matrices.
The choice of carrier will be determined in part by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, rectal, and vaginal administration are merely exemplary and are in no way limiting.
Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granule; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water, cyclodextrin, dimethyl sulfoxide and alcohols, for example, ethanol, benzyl alcohol, propylene glycol, glycerin, and the polyethylene alcohols including polyethylene glycol, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can include one or more of the following: lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acadia, emulsions, and gels containing, the addition to the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acadia, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
The compounds of the present disclosure alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, and nitrogen. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol such as poly(ethyleneglycol) 400, glycerol ketals, such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.
Oils, which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example. dimethyldialkylammonium halides, and alkylpyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl β-aminopropionates, and 2-alkylimidazoline quaternary ammonium salts, and (e) mixtures thereof.
The parenteral formulations typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
Pharmaceutically acceptable excipients are also well-known to those who are skilled in the art. The choice of excipient will be determined in part by the particular compound, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present disclosure. The following methods and excipients are merely exemplary and are in no way limiting. The pharmaceutically acceptable excipients preferably do not interfere with the action of the active ingredients and do not cause adverse side-effects. Suitable carriers and excipients include solvents such as water, alcohol, and propylene glycol, solid absorbants and diluents, surface active agents, suspending agent, tableting binders, lubricants, flavors, and coloring agents.
The formulations can be presented in unit-does or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, Eds., 238-250 (1982) and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., 622-630 (1986).
Formulations suitable for topical administration include lozenges comprising the active ingredient in a flavor, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier; as well as creams, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.
Additionally, formulations suitable for rectal administration may be presented as suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
One skilled in the art will appreciate that suitable methods of exogenously administering a compound of the present disclosure to an animal are available, and, although more than one route can be used to administer a particular compound, a particular route can provide a more immediate and more effective reaction than another route.
The present disclosure further provides a method of cancer in a mammal, especially humans. The method comprises administering an effective treatment amount of a compound as disclosed above to the mammal.
As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the inhibition of neoplasia and tumor growth and treating malignant disease including metastases.
The disclosed compounds and compositions can be administered to treat a number of cancers, including leukemias and lymphomas such as acute lymphocytic leukemia, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's Disease, non-Hodgkin's lymphomas, and multiple myeloma, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms Tumor, bone tumors, and soft-tissue sarcomas, common solid tumors of adults such as lung cancer, breast cancer, prostate cancer, urinary cancers, uterine cancers, oral cancers, pancreatic cancer, melanoma and other skin cancers, stomach cancer, ovarian cancer, brain tumors, liver cancer, laryngeal cancer, thyroid cancer, esophageal cancer, and testicular cancer.
The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal, the body weight of the animal, as well as the severity and stage of the cancer.
A suitable dose is that which will result in a concentration of the active agent in tumor tissue which is known to affect the desired response. The preferred dosage is the amount which results in maximum inhibition of cancer, without unmanageable side effects.
The total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 10 mg/kg and about 1000 mg/kg of body weight for mice, and between about 100 mg/kg and about 500 mg/kg of body weight, and more preferably between 200 mg/kg and about 400 mg/kg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.
The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.
The method disclosed comprises further administering of chemotherapeutic agent other than the derivatives of the present invention. Any suitable chemotherapeutic agent can be employed for this purpose. The chemotherapeutic agent is typically selected from the group consisting of alkylating agents, antimetabolites, natural products, anti-inflammatory agents, hormonal agents, molecular targeted drugs, anti-angiogenic drugs, and miscellaneous agents.
Examples of alkylating chemotherapeutic agents include carmustine, chlorambucil, cisplatin, lomustine, cyclophosphamide, melphalan, mechlorethamine, procarbazine, thiotepa, uracil mustard, triethylenemelamine, busulfan, pipobroman, streptozocin, ifosfamide, dacarbazine, carboplatin, and hexamethylmelamine.
Examples of chemotherapeutic agents that are antimetabolites include cytosine arabinoside fluorouracil, gemcitabine, mercaptopurine, methotrexate, thioguanine, floxuridine, fludarabine, and cladribine.
Examples of chemotherapeutic agents that are natural products include actinomycin D, bleomycin, camptothecins, daunomycin, doxorubicin, etoposide, mitomycin C, paclitaxel, taxoteredocetaxel, tenisposide, vincristine, vinblastine, vinorelbine, idarubicin, mitoxantrone, mithramycin and deoxycoformycin.
Examples of hormonal agents include antiestrogen receptor antagonists such as tamoxifen and fluvestrant, aromatase inhibitors such as anastrozole, androgen receptor antagonists such as cyproterone and flutamine, as well as gonadotropin release hormone agonists such as leuprolide. Examples of anti-inflammatory drugs include adrenocorticoids such as prednisone, and nonsteroidal anti-inflammatory drugs such as sulindac or celecoxib. Examples of molecular targeted drugs include monoclonal antibodies such as rituximab, cetuximab, trastuzumab and small molecules such as imatinib, erlotinib, ortizumib. Examples of anti-angiogenic drugs include thalidomide and bevacizimab. Examples of the aforesaid miscellaneous chemotherapeutic agents include mitotane, arsenic trioxide, tretinoin, thalidomide, levamisole, L-asparaginase and hydroxyurea.
The term “comprising” (and its grammatical variations) as used herein is used in the inclusive sense of “having” or “including” and not in the exclusive sense of “consisting only of.” The terms “a” and “the” as used herein are understood to encompass the plural as well as the singular.
The foregoing description illustrates and describes the disclosure. Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and/or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in the art to utilize the disclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments.
All publications and patent applications cited in this specification are herein incorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.
This invention was partially supported by a NIH Grant No. CA34200 from National Institute of Health and the US Government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US10/34463 | 5/12/2010 | WO | 00 | 2/29/2012 |
| Number | Date | Country | |
|---|---|---|---|
| 61177436 | May 2009 | US |
