Acyclic organonitro compounds for use in treating cancer

The present invention provides acyclic, geminal-dinitro organic compounds, methods of synthesizing the compounds, pharmaceutical compositions, therapeutic methods, and medical kits for treating various conditions using such compounds and pharmaceutical compositions. The compounds and compositions are useful in the treatment of cancer.

FIELD OF THE INVENTION

The invention provides acyclic, geminal-dinitro organic compounds, methods of synthesizing the compounds, pharmaceutical compositions, therapeutic methods, and medical kits. The compounds and pharmaceutical compositions are useful in the treatment of cancer

BACKGROUND

Cancer is a leading cause of death in the United States and many foreign countries. A recent survey by the National Cancer Institute estimates that nearly twelve million Americans have been diagnosed with cancer. Some of the most frequently encountered types of cancer include breast cancer, prostate cancer, skin cancer, colon cancer, rectal cancer, and bladder cancer. Other cancers afflicting a significant number of patients include ovarian cancer, leukemias, brain cancer, lymphomas, uterine cancer, and head and neck cancer.

Current treatment options for cancer typically involve surgery, radiation treatment, and/or chemotherapy. Surgery involves physically removing cancerous tissue. Although surgery is sometimes effective in removing tumors located at certain sites, for example, in the breast, colon, and skin, it cannot be used to treat all types of cancer, such as those located in the backbone or disseminated neoplastic conditions such as leukemia. Radiation therapy involves exposing the patient to ionizing radiation in order to damage the DNA of cancerous cells. Chemotherapy involves administering a chemotherapeutic agent that disrupts cell replication or cell metabolism. Chemotherapy is often used to treat leukemia, breast cancer, lung cancer, and testicular cancer.

Despite the efforts devoted to developing treatments for cancer, current therapeutic options are inadequate because current treatment options frequently have severe side effects and/or are not effective in treating certain types of cancers. For example, the anti-cancer agent 5-fluorouracil has been used to treat various carcinomas, sarcomas, skin cancer, and breast cancer, but this anti-cancer agent causes adverse side effects such as nausea, alopecia, diarrhea, stomatitis, leukocytic thrombocytopenia, and anorexia. The anti-cancer agent cisplatin has been used to treat testicular, ovarian, bladder, head and neck, and esophageal cancer, but this anti-cancer agent has been shown to cause nausea, vomiting, anemia, and reduced white blood cell counts.

Accordingly, the need exists for new therapeutic agents that provide improved efficacy and/or reduced side effects for treating cancer. The present invention addresses this need and provides other related advantages.

SUMMARY

The invention provides acyclic, geminal-dinitro organic compounds, methods of synthesizing the compounds, pharmaceutical compositions, therapeutic methods, and medical kits for treating various conditions using such compounds and pharmaceutical compositions. The compounds and compositions are useful in the treatment of cancer.

Accordingly, one aspect of the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description.

Another aspect of the invention provides a compound represented by Formula II:

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description.

The pharmaceutical compositions and compounds can be used to treat medical disorders. Accordingly, another aspect of the invention provides a method of treating cancer in a patient. The method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition described herein or a compound described herein.

DETAILED DESCRIPTION

The invention provides acyclic, geminal-dinitro organic compounds, methods of synthesizing the compounds, pharmaceutical compositions, therapeutic methods, and medical kits for treating various conditions using such compounds and pharmaceutical compositions. The compounds and compositions are useful in the treatment of cancer. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, and biochemistry. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming, eds., 1991-1992). Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section.

Definitions

The terms “a,” “an” and “the” as used herein mean “one or more” and include the plural unless the context is inappropriate.

The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen, such as fluorine, chlorine, bromine, or iodine. For example, —CH2F, —CHF2, —CF3, —CH2CF3, —CF2CF3, and the like.

The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C4-8cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl.

The term “aralkyl” refers to an alkyl group substituted with an aryl group.

The term “heteroaralkyl” refers to an alkyl group substituted with a heteroaryl group.

The term “aryl” refers to a carbocyclic aromatic group. Representative aryl groups include phenyl, naphthyl, anthracenyl, and the like. Unless specified otherwise, the aromatic ring may be substituted at one or more ring positions with halogen, azide, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, carboxylic acid, —C(O)alkyl, —CO2alkyl, carbonyl, carboxyl, carboxamide, or —CN. In certain embodiments, the aryl group is unsubstituted.

The term “heteroaryl” refers to aromatic groups that include at least one ring heteroatom. In certain instances, a heteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representative examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like. The term “heteroaryl” also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls. Unless specified otherwise, the heteroaromatic ring may be substituted at one or more ring positions with halogen, azide, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, carboxylic acid, —C(O)alkyl, —CO2alkyl, carbonyl, carboxyl, carboxamide, or —CN. In certain embodiments, the heteroaryl group is unsubstituted.

The terms ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms “amine” and “amino” refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:

wherein R50, R51, R52and R53each independently represent a hydrogen, an alkyl, an alkenyl, —(CH2)m—R61, or R50and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In other embodiments, R50and R51(and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or —(CH2)m—R61.

As used herein, the term “patient” refers to an organism to be treated by the methods of the present invention. Such organisms may include mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), including humans.

As used herein, the term “therapeutically effective amount” refers to the amount of a compound (e.g., a compound of the present invention) or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in a patient at a reasonable benefit/risk ratio applicable to any medical treatment. A therapeutically effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.

As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

As used herein, the term “pharmaceutical composition” refers to the combination of an active agent (e.g., a compound of the present invention) with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

As used herein, the term “pharmaceutically acceptable salt” refers to any salt (e.g., acid or base) of a compound of the present invention which is pharmaceutically acceptable and upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those of skill in the art, “salts” of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Examples of bases include, for example, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium), hydroxides, ammonia, and compounds of formula NW4+, wherein W is C1-4alkyl, and the like.

Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

As a general matter, compositions specifying a percentage of a compound are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

One aspect of the invention provides pharmaceutical compositions that comprise a pharmaceutically acceptable carrier and at least one compound described herein. For example, in certain embodiments, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R2, R3, and R6each represent independently for each occurrence hydrogen or alkyl;

the stereochemical configuration at any stereocenter in a compound represented by Formula I is R, S, or a mixture thereof.

The invention embraces pharmaceutical compositions containing particular subsets of the family of compounds embraced by Formula I. For example, in certain embodiments, R1is alkyl or cycloalkyl. In certain embodiments, R2and R3are hydrogen. In certain embodiments, R4is —X2—(C1-C6)alkylene-C(NO2)2-alkyl. In certain embodiments, X2is —O—(C1-C4)alkylene-O—. In certain other embodiments, X2is —OC(O)O—. In certain embodiments, n is 1.

One exemplary subset of compounds embraced by Formula I is the following:

In certain embodiments, the compound is represented by Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein:

R2and R3each represent independently for each occurrence hydrogen or alkyl;

n is 1, 2, 3, or 4; and

the stereochemical configuration at any stereocenter in a compound represented by Formula I-A is R, S, or a mixture thereof.

In certain embodiments, the compound is represented by Formula I-A, wherein X2is —O—(C1-C4)alkylene-O—. In certain other embodiments, X2is —O—(C1-C2)alkylene-O—. In certain embodiments, R1is methyl or ethyl. In certain embodiments, R2and R3are hydrogen. In certain embodiments, n is 1. In certain embodiments, R4is —X2—(C2-C3)alkylene-C(NO2)2-methyl. In certain other embodiments, R4is —X2—(C2-C3)alkylene-C(NO2)2-methyl, X2is —O—(C1-C2)alkylene-O—, R2and R3are hydrogen, and n is 1.

Another subset of compounds embraced by Formula I is where R1is —(C1-C4)alkylene-N(R7)C(O)-haloalkyl, and R4is —N(R6)C(O)-haloalkyl. Further, in certain embodiments, R6and R7are alkyl. In certain embodiments, n is 2, and R2and R3are hydrogen. Exemplary particular compounds embraced by this subset include, for example, the following:

In certain embodiments, the compound is represented by Formula I-B:

or a pharmaceutically acceptable salt thereof, wherein:

R2, R3, and R6each represent independently for each occurrence hydrogen or alkyl;

the stereochemical configuration at any stereocenter in a compound represented by Formula I-B is R, S, or a mixture thereof.

Another subset of compounds embraced by Formula I is where R1is —(C1-C4)alkylene-X1. In certain embodiments, X1is —OH or —OC(O)R5. In certain embodiments, R4is —OH or —OC(O)R5. In certain embodiments, R5represents independently for each occurrence hydrogen, alkyl or cycloalkyl. In certain embodiments, n is 1, and R2and R3are hydrogen. Exemplary particular compounds embraced by this subset include, for example, the following:

In certain embodiments, the compound is represented by Formula I-C:

or a pharmaceutically acceptable salt thereof, wherein:

R2, R3, and R6each represent independently for each occurrence hydrogen or alkyl;

the stereochemical configuration at any stereocenter in a compound represented by Formula I-C is R, S, or a mixture thereof.

In certain embodiments, the compound is one of the compounds in Tables 1-3.

Methods for preparing compounds described herein are illustrated in the following synthetic schemes. The following schemes are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

Scheme 1 provides an exemplary procedure for preparing compounds having two geminal-dinitro groups connected by a heteroatom-containing linker, such as the compounds shown in Table 1 above. The reaction entails the condensation of two geminal-dinitro alcohols A and B with an electrophile C (depicted as an aldehyde in Scheme 1) to produce the corresponding heteroatom-linked geminal-dinitro dimer D (depicted with oxygen atoms in Scheme 1). Each of m and n in geminal-dinitro alcohol A and x and y in geminal-dinitro alcohol B may be a positive integer greater than or equal to one, and each of n, m, x, and y may or may not be the same. Consequently, heteroatom-linked geminal-dinitro dimer D may or may not be symmetrical. U.S. Pat. Nos. 5,449,835 and 5,648,556 describe the preparation of Compounds I-1 and I-3, respectively, of Table 1. To form Compounds I-1 and I-3, 2,2-dinitropropanol is condensed with an aldehyde (formaldehyde or acetaldehyde) in the presence of an acid catalyst to give Compound I-1 or Compound I-3. Similar procedures may be used to prepare Compounds I-2 and I-4 through I-8 in Table 1 by changing the electrophile C. For example, acetone may be used as the electrophile C to produce Compounds I-7 and I-8. Derivatives of D having various heteroatom linkers may be synthesized by varying the electrophile C.

Scheme 2 provides an exemplary procedure for preparing α,ω-difunctional-geminal-dinitro alkyl compounds, such as compounds in Table 2 above. Esterification of alkyl-diol A using the desired acid anhydride B in the presence of base provides the diester (or diformate when R is hydrogen) C. Further description of exemplary procedures for esterification reactions involving diol starting materials is provided in, for example, U.S. Pat. No. 6,425,966, which is hereby incorporated by reference.

Scheme 3 provides an exemplary procedure for preparing geminal-dinitro alkyl amide compounds, such as compounds in Table 3 above. Reaction of dialkyl amine A and hydroxy-dinitroalkane B provides dinitroalkylamine C. Reaction of dinitroalkylamine C with a Lewis Acid and an acylating agent (e.g., an acid halide, such as XC(O)R′ where X is, for example, Cl or Br) provides dinitroalkylamide D. The starting dialkyl amine A and hydroxy-dinitroalkane B can be obtained from commercial sources or prepared based on procedures described in the literature. For a description of procedures to make dinitro-organic compounds, see, for example, Kornblum et al. inJ. Org. Chem. (1983) vol. 48, 332-337; Hiskey et al. inJournal of Energetic Materials(1999) vol. 17, 233-254; and Agrawal et al. inOrganic Chemistry of Explosives,Wiley & Sons, England, 2007. Further, if a particular compound contains a functional group sensitive to one or more of the synthetic transformations described herein, then conventional protecting group strategies are contemplated to be applied. For a description of protecting group strategies and procedures, see, for example, Greene, T. W.; Wuts, P. G. M.Protective Groups in Organic Synthesis,2nded.; Wiley, New York, 1991.

Scheme 4 provides an alternative exemplary procedure for preparing geminal-dinitro alkyl amide compounds. Reaction of hydroxy-dinitroalkane A with trifluoromethanesulfonic anhydride ((CF3SO2)2O; abbreviated Tf2O) provides dinitroalkyltriflate B, which upon reaction with trimethylsilylazide (TMSN3) provides dinitroalkylazide C. The azide group of C can be selectively reduced to the amine and reacted with an acylating agent (e.g., XC(O)R′ in the presence of base, where X is, for example, Cl or Br) to provide dinitroalkylamide D.

Scheme 5 provides another alternative exemplary procedure for preparing geminal-dinitro alkyl amide compounds. Reaction of hydroxy-dinitroalkane A with aryl sulfonamide B under Fukuyama-Mitsunobu conditions (using, for example, tributylphosphine (Bu3P) and diisopropyl azodicarboxylate (DIAD)) provides dinitroalkylsulfonamide C. For additional information, see, for example, Fukuyama et al. inTetrahedron Letters(1995) 36, 6373. Reaction of sulfonamide C with 2-mercaptoethanol followed by addition of an acylating agent (e.g., XC(O)R″ in the presence of base, where X is, for example, Cl or Br) provides dinitroalkylamide D.

Scheme 6 provides another alternative exemplary procedure for preparing geminal-dinitro alkyl amide compounds. Reaction of nitroalkane A with aldehyde B provides α-hydroxy-nitroalkane C, which upon dehydration provides nitroalkene D. Reaction of nitroalkene D with an amine provides α-amino-nitroalkane E that can be converted to dinitroalkane F, which is acylated to provide dinitroalkylamide G. For additional description of synthetic procedures for converting a mono-nitro alkane to a geminal dinitro-alkane, see, for example, Kornblum et al. inJ. Org. Chem. (1983) vol. 48, 332-337.

Another aspect of the invention provides a compound represented by Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

R2, R3, and R6each represent independently for each occurrence hydrogen or alkyl;

the stereochemical configuration at any stereocenter in a compound represented by Formula II is R, S, or a mixture thereof.

In certain embodiments, the compound of Formula II contains two sets of geminal dinitro groups separated by an oxygenated linker, such as where R1is (C2-C6)alkyl or cycloalkyl, and R4is —X—(C1-C6)alkylene-C(NO2)2-alkyl. In certain embodiments, X is —O—(C1-C4)alkylene-O—. In certain embodiments, R2and R3are hydrogen, and n is 1. In certain other embodiments, R1is (C3-C6)alkyl. In certain other embodiments, R1is cycloalkyl. Accordingly, in certain embodiments, the compound can be, for example, one of the following:

In certain other embodiments, the compound of Formula II has one geminal dinitro group and two alpha-haloamide groups, such as where R1is —(C1-C4)alkylene-N(R5)C(O)-haloalkyl, and R4is —N(R6)C(O)-haloalkyl. In certain embodiments, R5and R6are alkyl. In certain embodiments, n is 2, and R2and R3are hydrogen. For example, the compound may be one of the following:

Compounds described in Section II can be prepared based on the procedures described in Section I above.

III. Therapeutic Applications

The pharmaceutical compositions and compounds described herein can be used to treat cancer. Accordingly, one aspect of the invention provides a method of treating cancer in a patient. The method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition described herein or a compound described herein (such as a compound of Formula I or II) in order to treat the cancer. In certain embodiments, a combination of two or more of the compounds described herein (such as a combination of the compounds of Formula I or II) may be administered to the patient to treat the cancer.

In certain embodiments, the cancer is a solid tumor. In certain other embodiments, the cancer is squamous cell carcinoma, basal cell carcinoma, breast cancer, prostate cancer, skin cancer, small cell lung cancer, non-small cell lung cancer, colon cancer, pancreatic cancer, rectal cancer, bladder cancer, ovarian cancer, brain cancer, uterine cancer, cervical cancer, testicular cancer, head and neck cancer, a leukemia, or a lymphoma (e.g., Non-Hodgkin Lymphoma). In certain other embodiments, the cancer is a sweat gland carcinoma, sebaceous gland carcinoma, endometrial cancer, stomach cancer, thyroid cancer, kidney cancer, uterus cancer, espophagus cancer, or liver cancer. In certain other embodiments, the cancer is breast cancer, prostate cancer, skin cancer, small cell lung cancer, non-small cell lung cancer, colon cancer, pancreatic cancer, rectal cancer, bladder cancer, or ovarian cancer. In certain other embodiments, the cancer is breast cancer, prostate cancer, skin cancer, or colon cancer. In certain other embodiments, the cancer is squamous cell carcinoma.

In certain embodiments, the patient is a human.

IV. Medical Kits

Another aspect of the invention provides a medical kit. The medical kit contains (i) a pharmaceutical composition described herein or a compound described herein (such as a compound of Formula I or II), and (ii) instructions for treating a medical disorder, such as cancer.

V. Pharmaceutical Carriers, Form of Pharmaceutical Compositions, and Dosing Considerations

The pharmaceutical compositions comprise one or more of the compounds described above (as the active ingredient), formulated together with one or more pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

In certain embodiments, the pharmaceutical compositions or compounds may be administered to the patient by systemic administration. The term “systemic administration” as used herein means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

In certain embodiments, the daily dose of a compound of the invention is that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated treatment of cancer, will range from about 0.0001 to about 100 mg per kilogram of body weight per day. In certain other embodiments, the daily dose of a compound of the invention corresponds to the maximum tolerated dose.

If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.

In some embodiments, in vivo administration is effected in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and vary with the composition used for therapy, the purpose of the therapy, the target cell being treated, and the patient being treated. Single or multiple administrations are carried out with the dose level and pattern being selected by the treating physician.

Suitable dosage formulations and methods of administering the compounds are readily determined by those of skill in the art. Preferably, the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, at about 0.1 mg/kg to about 100 mg/kg, or at about 0.5 mg/kg to about 50 mg/kg. When the compounds described herein are co-administered with another agent (e.g., a sensitizing agent), the effective amount of the compound may be less than when the compound is used alone.

The description above describes multiple aspects and embodiments of the invention, including compounds, pharmaceutical compositions, therapeutic methods, and medical kits. The patent application specifically contemplates all combinations and permutations of the aspects and embodiments. For example, the invention contemplates treating breast cancer in a human patient by administering a therapeutically effective amount a pharmaceutical composition comprising compound of Formula I, particularly a compound of Formula I-A. Further, for example, the invention contemplates all combinations and permutations of the aspects and embodiments of the synthetic methods described herein, such as the methods of synthesizing the compounds of Formula I and II.

EXAMPLES

The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

Mice with SCC VII tumors were treated with a 1:1 mixture of Compound A and Compound B. Experimental procedures are results are provided below.

Part I—Experimental Procedures

The Treatment Composition was a 1:1 mixture of Compound A and Compound B in a water/DMSO carrier. The mixture of Compound A and Compound B was present at a concentration of 0.6 mg/mL. The concentration of dimethylsulfoxide (DMSO) in the Treatment Composition was 0.6%.

Compound A has the formula:

Compound A can be prepared according to the procedures described in U.S. Pat. No. 5,648,556, which is hereby incorporated by reference. Compound B has the formula:

Compound B can be prepared according to the procedures described in U.S. Pat. No. 5,449,835, which is hereby incorporated by reference.
Study Procedures:

Male C3H mice were obtained from Charles River Laboratories and maintained under specific pathogen-free conditions. Mice were housed five animals per cage and autoclaved food and water was provided ad libitum. Cages were located in rooms having a temperature of 65±2 degrees Fahrenheit, a humidity of 50%±5%, and a 12-hour day-and-night light cycle. Mice were 7-8 weeks old, with a body weight in the range of 22-25 grams, at the time inoculated with tumor cells.

Mice were inoculated subcutaneously with 5×105SCCVII tumor cells in 0.05 mL Hank's solution on the back. Ten days after tumor implantation, treatment was initiated (Day 0) by administering the Treatment Composition by intraperitoneal injection every other day (i.e., q.o.d on Days 0, 2, and 4) for 3 doses total. The length and width of the tumors were measured with calipers immediately before treatment and three times a week thereafter until the tumor volume reached at least four times (4×) the original pre-treatment volume. Tumor volume (mm3) was calculated according to the formula:
Tumor Volume=π/6×length×width
Part II—Results

Tumors in mice that received the Treatment Composition were smaller than tumors in mice that did not receive treatment. Experimental data showing tumor volume in treated and untreated (control) mice are provided inFIG. 1.

Incorporation by Reference

Equivalents