There is provided a complex for use as a therapeutic pharmaceutical, the complex has a ligand containing at least one hydroxyalkyl phosphine donor group bound to a gold atom to form a stable gold-ligand complex. Also provided is a method of treating cancer by administering an effective amount of a complex having a ligand of at least one hydroxyalkyl phosphine group bound to a gold atom to form a stable gold-ligand complex. Also provided is a method of preventing the metastasis of cancer and arresting cell growth by administering an effective amount of a complex having a ligand of at least one hydroxyalkyl phosphine group bound to a gold atom to form a stable gold-ligand complex.

SUMMARY OF THE INVENTION

According to the present invention, there is provided a complex for use as a therapeutic pharmaceutical, the complex including a ligand containing at least one hydroxyalkyl phosphine donor group bound to a gold atom to form a stable gold-ligand complex. Also provided is a method of treating cancer by administering an effective amount of a complex having a ligand of at least one hydroxyalkyl phosphine group bound to a gold atom to form a stable gold-ligand complex. Also provided is a method of preventing the metastasis of cancer and arresting cell growth by administering an effective amount of a complex having a ligand of at least one hydroxyalkyl phosphine group bound to a gold atom to form a stable gold-ligand complex.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Generally, the present invention provides a complex for use as a therapeutic pharmaceutical. The complex includes a ligand including at least one hydroxyalkyl phosphine donor group bound to a non-radioactive gold atom to form a gold ligand complex that is stable. That is, the invention provides a ligand system containing at least one hydroxyalkyl phosphine donor group for use in forming complexes with non-radioactive gold metals wherein the complexes have high in vitro and/or in vivo stability.

The phosphorous ligands were chosen since the phosphorous atom provides a plethora of electron density that promotes formation of highly stable ligand metal bonds. This can occur even with non-radioactive gold metal in its higher oxidation states.

The hydroxyalkyl phosphine ligand is complexed with a non-radioactive gold metal, generally a gold (I) compound. These complexes contain a ratio of ligand-to-gold that is greater than or equal to 1:1 which makes the resulting chelates small and well-defined.

A complex according to the present invention can include a complex of the formula

M—[P(A—OH)₃]

wherein M is non-radioactive gold metal in a reduced oxidation state, n is 1-6, and A is an alkyl group. In a preferred embodiment of the present invention, A is —CH₂—. Additionally, A can include —C₂H₄— and iso- or normal-C₃H₆—.

The non-radioactive gold-ligand complexes can include other donor atoms or groups on the same ligand as the donor hydroxyalkyl phosphine group. These other donor groups can include N, S, O, or P atoms for coordinating the non-radioactive gold atom. In addition, the donor groups can further include amines, amides, thiols, carboxyls, and hydroxyls for coordinating the non-radioactive gold atom.

In another preferred embodiment of the present invention, the complexes can include a bidentate ligand of the formula

(HOA)₂P—X—P(AOH)₂

wherein A is —CH₂—, —C₂H₄—, or iso- or normal-C₃H₆, and X is —(CH₂)_n— where n=1-4, —CH₂CHR—, —CH₂CHRCH₂—, —CHRCH₂CH₂—, R′-aromatic where R′ is H, an alkyl group of C₁-C₄, an aromatic group, —OH, —SH, —N H₂, —COOH, activated esters, N-hydroxysuccinimides, benzyl isothiocyanate, alkyl halides, or cyclohexyldiimide. Specific examples of bidentate ligands used to complex with gold can include 1,2-bis (bis(hydroxymethyl)phosphino)benzene (HMPB, 1) and 1,2-bis(bis(hydroxymethyl)phosphino)ethane (HMPE, 2) as set forth below. The formation of non-radioactive gold complexes according to the present invention with the ligands HMPB and HMPE are shown.

In further preferred embodiments, complexes according to the present invention are contemplated which include multidentate ligands of the formula

[(HOA)₂PI]₂—P—X—P[YP(AOH)₂]₂

wherein A is —CH₂—, —C₂H₄—, or iso- or normal-C₃H₆—, and X is —(CH₂)_n-where n=1-4, —CH₂CHR—, —CH₂CHRCH₂—, —CHRCH₂CH₂—, or R′-aromatic where R′ is H, an alkyl group of C₁-C₄, an aromatic group, —OH, —SH, —NH₂, —COOH, activated esters, N-hydroxysuccinimides, benzyl isothiocyanate, alkyl halides, or cyclohexyldiimide, and Y is CH₂—, —C₂H₄— or —C₃H₆—. Along the lines of this embodiment, further embodiments can exist wherein all of the donor atoms can be phosphorous atoms. Additionally, embodiments are contemplated wherein at least one donor group is a hydroxyalkyl phosphine group.

Furthermore, complexes according to the present invention are contemplated wherein two donor atoms are hydroxyalkyl phosphine phosphorous-atoms and two donor atoms are atoms other than phosphorous-atoms. These complexes have the general formula

[(HOA)₂PY]₂K—X—K]YP(AOH)₂]₂

wherein A is —CH₂—, —(CH₂)₂—, or iso- or normal-C₃H₆—, K includes donor atoms or groups selected from the group consisting of —N—, —N(R)⁺—, —N(H)—, Ag, and —S—, Y is —CH₂—, —(CH₂)₂—, or iso- or normal —C₃H₆ X is —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH₂CHR—, —CH₂CHRCH₂—, —CHRCH₂CH₂—, or R′-aromatic wherein R′ and R can be the same or different and are selected from H, —OH, —SH, —NH₂, —COOH, activated esters, N-hydroxysuccinimides, benzyl isothiocyanate, alkyl halides, and cyclohexydiimide.

A variant of this embodiment can include a complex wherein two donor atoms are hydroxyalkyl phosphine phosphorous-atoms and two donor atoms are nitrogen-atoms (P2N2). These complexes can have the general formula

E═C—NR—[X—P(AOH)₂]₂

wherein X is —CH₂, —(CH₂)₂—, —C₃H₆—, A is —CH₂—, —(CH₂)₂—, —C₃H₆—, E is O or S. R can be the same or different and is selected from H, —OH, —SH, —NH₂, —COOH, activated esters, N-hydroxysuccinimides, benzyl isothiocyanate, alkyl halides, or cyclohexyl diimide.

N is nitrogen, and Y is —CH₂—, —(CH₂)₂—, or iso- or norman-C₃H₈.

An additional embodiment is contemplated wherein two donor atoms are hydroxyalkyl phosphine phosphorous-atoms and two donor atoms are sulfur-atoms (P2S2).

Complexes contemplated under this embodiment have the general formula

E═C—SR—[X—P)AOH)₂]₂

wherein X is —CH₂—, —(CH₂)₂, —C₃H₆—, A is —CH₂—, —(CH₂)₂—, —C₃H₆—, E is O or S. R can be the same or different and is selected from H, —OH, —SH, —NH₂, —COOH, activated esters, N-hydroxysuccinimides, benzyl isothiocyanate, alkyl halides, or cyclohexyldiimide, S is sulfur, and Y is —CH₂—, —(CH₂)₂—, or iso- or normal-C₃H₆—.

A "therapeutically effective amount" is an amount of a complex of the present invention that, when administered to a patient, ameliorates a symptom of the specific disease or condition being treated. A therapeutically effective amount of a complex of the present invention can easily be determined by one skilled in the art by administering a quantity of a complex to a patient and observing the result. In addition, those skilled in the art are familiar with identifying patients having the particular disease or condition and are readily able to identify patients who suffer from these diseases or conditions.

The complexes of the present invention can be administered to a patient alone or as part of a composition that contains other components such as excipients, diluents, and carriers, all of which are well-known in the art. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenous, by intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravescially, locally (powders, ointments or drops), or as a buccal or nasal spray.

Compositions suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluiditiy can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

These compositions can also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parbens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active complex is admixed with at least one customary inert excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium complexes; (g) wetting agents, as for example, acetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.

Solid dosage forms such as tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain pacifying agents and can also be of such composition that they release the active complex or complexes in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active complexes can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active complexes, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1.3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active complexes, can contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the complexes of the present invention with suitable nonirritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a complex of this invention include ointments, powders, sprays and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservative, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

The complexes and/or compositions of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 7000 mg per kilogram of body weight per day is sufficient. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the complex being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art.

In addition, the complexes of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

The complex of the present invention can be coadministered with an additional therapeutic agent. This therapeutic can include, but is not limited to, chemotherapeutic agents. Preferably, the complex of the present invention and the coadministered therapeutic agent work in conjunction with on another to create a more sustained effect. These two therapeutic agents can be either administered in one pharmaceutically acceptable carrier or separately.

When the non-radioactive analogue of the gold complex of THP [(Au(THP)₄)] (FIG. 4) was tested for tumor cell suppression against specific human cancer cells lines, it came as a total surprise that this compound exhibited remarkable activity in suppressing tumor growth in in vitro conditions. The data for 50% and 70% tumor growth suppression of cells derived from human colon carcinoma are summarized in Tables 1 and 2.

The data in Table 1 demonstrates that 50% tumor growth suppression occurs at ˜2 μg of the gold compound. This invention is significant in that it demonstrates high efficacy of tumor growth suppression under extremely low doses of the new antitumor agent (Au(THP)₄]Cl. The tumor growth suppression for cells derived from human gastric carcinoma have been tested. The data for 50% and 70% tumor growth suppression are summarized in Tables 2 and 4 respectively. This 50% tumor growth suppression of cells derived from human gastric carcinoma occurs at about 10 mg of [Au(THP)₄]Cl. This is the first demonstration that hydroxymethyl phosphine (HMP)-bound gold compounds display high efficacy in suppressing tumor growth of specific cells derived from human carcinoma.

Clinically, cisplatin is widely used as a chemotherapeutic agent in the treatment of human cancer. Use of cisplatin is generally associated with severe toxic side effects that include decrease in blood cell numbers, kidney dysfunction, etc. Therefore, cisplatin cannot be used in treating cancer patients for longer periods of time. Gold-containing compounds are less toxic and their non-toxic dose is generally higher than that of cisplatin. Therefore, it is practical to treat cancer patients using gold-containing chemotherapeutic agents for longer durations. In this context, the tumor growth suppression data reported for [Au(THP)₄]Cl demonstrates the potential of using this (and related) now generation of gold-containing compounds in treating cancer bearing patients.
 

Claim 1 of 3 Claims

1. A method of treating prostate, colon, or gastric cancer comprising

administering, to a subject in need thereof, an effective amount of a complex comprising a ligand comprising at least one hydroxyalkyl phosphine group, which is bound to a non-radioactive gold atom to form a stable gold-ligand complex.

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