WO2007143096A2 - Compounds for treating cancers - Google Patents

Abstract

A method of treating a patient suffering from a cancer, such as ovarian, renal, head & neck, hepatocellular, thyroid, esophageal, large bowel, pancreatic, mesothelioma, carcinoma, sarcoma and melanoma, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Definitions for the variables are provided herein.

Description

COMPOUNDS FOR TREATING CANCERS

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No. 60/810,249, filed on June 2, 2006. The entire teachings of the above application is incorporated herein by reference.

BACKGROUND OF THE INVENTION

The treatment of cancer is steadily improving in efficacy. However, the scope for further improvement is large, with successful chemotherapeutic rates for many cancers remaining low and side effects of therapy remaining unpleasant and debilitating. Slow growing cancers are especially difficult to treat with chemotherapy, since slowly dividing cells do not differ greatly from normal cells and therefore are more difficult to target. Thus, most chemotherapy drugs only affect rapidly dividing cells.

Currently commonly used cancer therapies include DNA intercalating agents such as anthracenediones (e.g., mitoxantrone) and anthracyclines (e.g., doxorubicin). Dose limiting toxicity of these compounds due to bone marrow suppression and cardiotoxicity highlight the need for the development of new anticancer drugs.

There is therefore a potential to fulfill major unmet therapeutic needs for slower growing solid tumors of humans.

SUMMARY OF THE INVENTION

The present invention is a method of treatment of cancers, such as ovarian, renal, head & neck, hepatocellular, thyroid, esophageal, large bowel, pancreatic, mesothelioma, carcinoma, sarcoma and melanoma. More specifically, the present invention is a method of treatment for certain solid tumors, in particular slow growing solid tumors by administration of imidazoacridines.

In one embodiment, the present invention is a method of treating a patient suffering from- a cancer, selected from the group consisting of of ovarian, renal, head & neck, hepatocellular, thyroid, esophageal, large bowel, pancreatic, mesothelioma, carcinoma, sarcoma and melanoma comprising administering to said patient a therapeutically effective amount of imidazoacridines represented by a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The imidazoacridines used in the present invention are described by formula (I) or a pharmaceutically acceptable salt thereof:

φ₅

R is -OH or a C1-C6 alkoxy . group;

R^a and R^b, are each independently hydrogen or an optionally substituted alkyl;

R² is -H or an C1-C6 alkyl; and n is a whole number between 2 and 5.

DETAILED DESCRIPTION OF THE INVENTION It has now been discovered that certain imidazoacridines inhibit the growth of certain types of solid tumors.

Specifically, it has been discovered that the growth of tumors in cancers, such as ovarian, renal, head & neck, hepatocellular, thyroid, esophageal, large bowel, pancreatic, mesothelioma, carcinoma, sarcoma and melanoma can be inhibited by administering to a patient suffering from such a disease a therapeutically effective amount of a compound of formula (I):

φ

The variables in formula (I) are provided above and in the following paragraphs:

R represents a hydroxy or an alkoxy group, e.g., a C1-C6 alkoxy group. Alternatively, R is an -OH or -OCH₃.

R² is -H or an C1-C6 alkyl; Preferably R² is -H or an C1-C4 alkyl.

R^a and R^b, which may be identical or different, can be hydrogen or an optionally substituted alkyl. Preferably, R^a and R^b are C1-C3 alkyl. More preferably, R^a and R^b are each ethyl. Alternatively, R^a and R^b are each methyl.

When R^a or R^b are substituted alkyls, suitable substituents on the alkyls can include a hydroxyl, an amino, a N-alkyl-amino or a N,N-dialkylamino groups, preferably containing 1-4 carbon atoms. Examples of such substituted R^a or R^b groups are hydroxyethyl, aminoethyl, N-alkylaminoethyl and N,N- dialkylaminoethyl. n is a whole number between 2 and 5. Preferably, in formula (I) n is 2 or 3.

In some preferred embodiments of a compound of formula (I), R² is a hydrogen or a C1-C6 alkyl. Preferably, R² is a hydrogen or a C1-C4 alkyl. More preferably, R² is -H.

In some preferred embodiments of a compound of formula (I), R is -OH or -OCH₃, R^a and R^b are identical and represent C1-C6 alkyl groups, preferably, methyl or ethyl; n is 2 or 3; R² represents hydrogen or a straight chain C1-C4 alkyl. Preferably, R² is -H.

Examples of compounds of formula (I) include compounds (HA) through (HG): - A -

In a most preferred embodiment, the compound of formula (I) is 5- [[(diethylamino)ethyl]amino]-8-hydroxyimidazo [4,5,1 -de]-acridine-6-one, whose structure is shown in formula (III):

The term "alkyl", as used herein, unless otherwise indicated, includes straight or branched saturated monovalent hydrocarbon radical, typically Cl-ClO, preferably Cl -C6 or C 1 -C4. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl. Suitable substituents for a substituted alkyl include those that do not substantially interfere with the pharmaceutical activity of the disclosed compound. One or more substituents can be present, which can be identical or different. Examples of suitable substituents include -OH, -SH, halogen, cyano, nitro, amino, alkylamino, dialkylamino, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 alkyl sulfanyl.

The terms "alkoxy", as used herein, means an "-O-alkyl" group, wherein alkyl, is defined above.

As used herein, an amino group may be a primary (-NH₂), secondary (-NHR_x), or tertiary (-NR_xRy), wherein R_x and R_y may be an optionally substituted alkyl as described above.

Compounds (I), (HA) through (HG) and (III) can be synthesized according to a variety of synthetic schemes disclosed in U.S. Pat. Nos. 5,231₅100 and 6,229,015, incorporated herein by reference in their entirety. One example of such a scheme is shown below:

(Scheme I) Compound (III) is known under the trade name of Symadex™ or C- 1311. Symadex™ is a member of the imidazoacridinones. Symadex™ has the chemical name: 5-[(2-(diethylamino)ethyl)amino]-8-hydroxyimidazo[4,5,l-de]-aridin-6-one 5. . dihydrochloride trihydrate).

The methods of the present invention are directed to treating cancers, such as ovarian, renal, head & neck, hepatocellular, thyroid, esophageal, large bowel, pancreatic, mesothelioma, carcinoma, sarcoma and melanoma comprising administering a therapeutically effective amount of a compound disclosed herein, in 0 particular compounds of formula (I) or a pharmaceutically acceptable salt thereof. For example, compounds of formulae (HA) through (HG) can be used. Preferably, a compound of formula (III) is used.

In another embodiment, the present invention is a method of treating a human suffering from a cancer selected from the group consisting of non-small cell 5 lung cancer and colorectal cancer, comprising administering to the human a therapeutically effective amount of a compound of formula (I), (HA) - (IIG) or (III) or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention is a method of treating a human suffering from a solid tumor, comprising administering to the human a 0 therapeutically effective amount of a compound of formula (I), (HA) - (IIG) or (III) or a pharmaceutically acceptable salt thereof.

As used herein the terms "subject" and "patient" may be used interchangeably. Typically the patient is a human, but can also be an animal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).

Treating, as used herein, refers to partially or totally inhibiting, delaying, or reducing (partially or completely) the progression of cancer including cancer metastasis; inhibiting, delaying or preventing the recurrence of cancer including cancer metastasis in, for example, a human.

As used herein the term "therapeutically effective amount" is intended to qualify the amount of the compound disclosed herein that will achieve the desired biological response. In the present invention, the desired biological response is partial or total inhibition or delay of the progression of cancer including cancer metastasis; inhibition, delay or prevention of the recurrence of cancer including cancer metastasis; in a patient, for example, a human.

In one embodiment the cancer selected from the group consisting of ovarian, renal, head & neck, hepatocellular, thyroid, esophageal, large bowel, pancreatic, mesothelioma, carcinoma, sarcoma and melanoma, non-small cell lung cancer and colorectal cancer is a solid tumor. As used herein, a "solid tumor" is used to distinguish between a localized mass of tissue and leukemia. Leukemia is a cancer that starts in blood-forming cells of the bone marrow as a result of an abnormal development of leukocytes (white blood cells) and their precursors.

Different kinds of solid tumors are named for the type of cells of which they are composed and include but are not limited to, for example, sarcomas (cancers arising from connective or supporting tissues such as bone or muscle), carcinomas (cancers arising from the body's glandular cells and epithelial cells, which line body tissues) and lymphomas (cancers of the lymphoid organs such as the lymph nodes, spleen, and thymus, which produce and store infection-fighting cells).

As used herein the term "cancer" can be primary or secondary. Primary cancer is named after their original cell type, from the oτgan where the cancer first begins to grow. Cancer cells can break away from the primary site and travel to other parts of the body in the blood or lymphatic system. The cells eventually lodge in another body organ and begin to grow there. This is called a secondary cancer. As used herein "ovarian cancer", is cancer of the ovaries or fallopian tubes, including cancers of germ cells, stromal cells, and epithelial cells. Examples of ovarian cancers include but are not limited to:

Epithelial Ovarian Tumors, which include but are not limited to, serous adenomas, mucinous adenomas, and Brenner tumors, tumors of low malignant potential (LMP tumors), borderline epithelial ovarian cancer, epithelial ovarian cancers, carcinomas and undifferentiated epithelial ovarian carcinomas; Germ Cell tumors which include but are not limited to, teratoma, dysgerminoma, endodermal sinus tumor, and choriocarcinoma; and Stromal tumors, which include but are not limited to, granulosa cell tumors, granulosa-theca tumors, and Sertoli-Leydig cell tumors.

"Renal cancer" or "kidney cancer", as used herein, includes but is not limited to, transitional cell cancer (TCC) of the renal pelvis, Wilms Tumour and renal cell cancer. Renal cell cancer is also called renal adenocarcinoma or hypernephroma. In renal cell cancer, the cancerous cells are found in the lining of the tubules (the smallest tubes inside the nephrons that help filter the blood and make urine).

There are several types of renal cell cancer including but not limited to clear cell, chromophilic, chromophobic, oncocytic, collecting duct and sarcomatoid. Renal cancer also includes cancers containing more than one of the cell types described above.

As used herein, "melanoma" is a type of skin cancer that occurs in the cells that color the skin, called melanocytes. Types of melanoma include but are not limited to: cutaneous melanoma, superficially spreading melanoma, nodular malignant melanoma, lentiginous malignant melanoma, acral lentiginous melanoma, demoplastic malignant melanomas, giant melanocyte nevus, amelanotic malignant melanoma, acral lentiginous melanoma unusual melanoma variants, including mucosal malignant melanoma, ocular malignant melanoma and metastatic malignant melanoma. "Sarcomas", as used herein, include but are not limited to, fibrosarcomas from fibrous body tissues (for example, sclerosing epithelioid sarcoma), leiomyosarcomas and rhabdomyosarcomas from muscle tissues, liposarcomas from fat, synovial sarcomas, angiosarcomas from blood vessels, MPNST - malignant peripheral nerve sheath tumours (PNSTs), GIST - gastrointestinal stromal sarcoma, osteosarcoma, myosarcoma, chondrosarcoma, bile duct sarcoma, brain sarcoma, breast sarcoma, soft tissue sarcoma, uterine sarcoma, endocardial sarcoma, stromal sarcomas from supporting tissues (endometrial stromal sarcoma), granuloytic, histiolytic, hemangioendothelial, Kupffer-cell, neurogenic, round-cell, reticulum cell, spindle cell, Kaposi's sarcoma of the skin, Ewing's sarcomas and PNETs. In certain embodiments, the sarcoma is leiomyosarcoma or liposarcoma. In one embodiment, the sarcoma is abdominal leiomyosarcoma. In another embodiment, the sarcoma is sclerosing epithelioid sarcoma (a ^"rare tumour characterised histologically by a predominant population of epithelioid cells arranged in strands and nests, embedded in a fibrotic and hyalinised stroma).

"Thyroid cancer", as used herein, includes but is not limited to, papillary and/or mixed papillary/follicular, follicular and/or Hurthle cell, lymphoma, medullary, anaplastic and combinations thereof.

The term "head and neck cancer" as used herein, encompasses tumors that occur in several areas of the head and neck region, including the nasal passages, sinuses, mouth, throat, larynx (voice box), swallowing passages, salivary glands, and skin cancers that develop on the scalp, face, or neck may also be considered head and neck cancers. These cancers include but are not limited to squamous cell carcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma, lymphoma, adenocarcinoma, esthesioneuroblastoma, tumors of the nasal cavity and paranasal sinuses, nasopharyngeal cancer, cancers of the oral cavity (including all the various parts of the mouth: the lips; the lining inside the lips and cheeks (the buccal mucosa); the bottom of the mouth; the front of the tongue; the front part of the top of the mouth (the hard palate); the gums; and the area behind the wisdom teeth (the retromolar trigone)), tumors of the oropharynx, hypopharyngeal tumors, laryngeal cancer and salivary gland cancer (including malignant salivary gland tumor).

As used herein "hepatocellular cancer" or "liver cancer" includes but is not limited to: hepatocellular carcinoma (also sometimes called hepatoma or HCC)

"carcinoma", fibrolamellar HCC, cholangiocarcinoma, angiosarcoma (also be called haemangiosarcoma) and hepatoblastoma. As used herein, "non-small cell lung cancer" includes, squamous cell carcinoma, adenocarcinoma and undifferentiated non-small cell lung cancer (undeveloped cancer cells are known as undifferentiated cells) and large cell carcinoma. ^• "Colorectal cancer" as used herein, includes any type of colon or rectal cancer, including but not limited to, adenoscarcinoma, sarcoma, melanoma, stromal, carcinoid, carcinoma and lymphoma.

As used herein, "carcinoma" refers to a cancer that arises from epithelial cells. Examples of carcinomas include esophageal carcinoma, large bowel carcinoma and colorectal carcinoma.

As used herein, where "adenocarcinoma" refers to a form of carcinoma that originates in glandular tissue.

As used herein "esophageal cancer" is a cancer that forms in tissues lining the esophagus. It includes esophageal carcinoma, and esophageal adenocarcinoma. As used herein, "pancreatic cancer" is a malignant tumour within the pancreatic gland. This term includes adenocarcinomas (exocrine tumors) as well as cystic tumors (tumors that cause a cyst or fluid filled sac in the pancreas), cancer of the acinar cells (cancers that originates with the cells at the ends of the ducts that produce the pancreatic juices), sarcomas (a cancer of the connective tissue holding together the cells of the pancreas) and rare lymphomas of pancreas.

As used herein, "mesothelioma" is a form of cancer caused by previous exposure to asbestos. In this disease, malignant cells develop in the mesothelium, a protective lining that covers most of the body's internal organs. Its most common site is the pleura (outer lining of the lungs and chest cavity), but it may also occur in the peritoneum (the lining of the abdominal cavity) or the pericardium (a sac that surrounds the heart).

In treating a patient afflicted with a condition described above, all of the disclosed compounds are administered in a form or mode which makes the compound bioavailable in therapeutically effective amounts. For example, compounds of formula (I) can be administered in a form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salts" means either an acid addition salt or a basic addition salt, whichever is possible to make with the compounds of the present invention. "Pharmaceutically acceptable acid addition salt" is any non-toxic organic or inorganic acid addition salt of the base compounds represented by formula (I), (HA) - (HG) and (III). Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tri-carboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic, p-toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, generally demonstrate higher melting points. For compounds comptising an acidic group "pharmaceutically acceptable basic addition salts" means non-toxic organic or inorganic basic addition salts of the compounds of formula (I), including formulae (HA) - (HG) and (III). Examples are alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline. The selection criteria for the appropriate salt will be known to one skilled in the art.

Compounds of the present invention can be administered by a number of routes including orally, sublingually, buccally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, topically, and the like. One skilled in the art of preparing formulations can determine the proper form and mode of administration depending upon the particular characteristics of the compound selected for the condition or disease to be treated, the stage of the disease, the condition of the patient and other relevant circumstances. For example, see Remington's Pharmaceutical Sciences, 18^th Edition, Mack Publishing Co. (1990), incorporated herein by reference. The compounds of formula (I), (HA) - (HG) and (III) may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base. The base, for example, may comprise one or more of petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.

The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials.

The compounds used in the present invention can be administered alone or in combination with one or more other pharmaceutically active agents that are effective against the cancer being treated.

As used herein, the term "combination" with reference to pharmaceutically active agents and the term "co-administering" and "co-administration" refer to administering more than one pharmaceutically active agent to a patient during one treatment cycle and not necessarily simultaneous or in a mixture.

Anti-cancer agents that can be employed in combination with the compounds of the invention include Taxol™ (also referred to as "paclitaxel", and compounds that have the basic taxane skeleton), Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;.epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl ; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate . sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin and zorubicin hydrochloride. Other anti-cancer drugs that can be employed in combination with the compounds described herein include: 20-epi-l,25 dihydroxyvitamin D3; 5- ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafϊde; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino- triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin

A4; combretastatάn analogue; conagenin; crambescidin 816; crisnatol; cryptophycin

8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5- azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; fiavopiridol; flezelastine; fluasterone; fiudarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perfiubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rdgletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; rubόxyl; safϊngol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mirnetics; semustine; senescence derived inhibitor 1 ; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. Preferred anti-cancer drugs are 5-fluorotiracil and leucovorin. Other chemotherapeutic agents that can be employed in combination with the compounds of the invention include but are not limited to alkylating agents, antimetabolites, natural products, or hormones.

The dosage range at which the disclosed compounds, for example, compounds of formula (I), including compounds of formulae (HA) - (IIG), and (III), exhibit their ability to act therapeutically can vary depending upon the severity of the condition, the patient, the formulation, other underlying disease states that the patient is suffering from, and other medications that may be concurrently administered to the patient. Generally, the compounds described herein will exhibit their therapeutic activities at dosages of between about 0.1 mg/m² free base equivalent per square meter of body surface area/single dose to about 1000 mg/m² free base equivalent per square meter of body surface area/single dose. For example, the single dosage range can be between 10-800 mg/m², 100-700 mg/m², 400-600 mg/m², 420-550 mg/m² or 440-500 mg/m² or the single dose can be 480 mg/m².

The compounds disclosed herein can be administered in the single doses described above daily, weekly, bi-weekly or monthly. In one embodiment the compounds are administered daily for two consecutive days, for three_, consecutive days, for four consecutive days, for five consecutive days. Daily dose of administration of the compounds of the present invention can be repeated, in one embodiment, for one week. In other embodiments, daily dose can be repeated for one month to six months; for six months to one year; for one year to five years; and for five years to ten years. In another embodiment the compounds are administered weekly. In another embodiment the compounds are administered weekly for three consecutive weeks followed by one weeks without any administration. In other embodiments, the length of the treatment by repeated administration is determined by a physician.

The invention is illustrated by the following examples, which are not intended to be limiting in any way. EXEMPLIFICATION

Measurability of Disease and Criteria for Analysis (RECIST)

Evaluation of Target Lesions Complete Response (CR): Disappearance of all target lesions Partial Response (PR): ^■ At least a 30% decrease in the sum of the longesi diameter (LD) of target lesions, taking as referen baseline sum LD.

Progressive Disease (PD): At least a 20% increase in the sum of the LD of t lesions, taking as reference the smallest sum LD recorded since treatment started or the appearanc one or more new lesions.

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatmen started.

Evaluation of Non-target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level.

Incomplete Response/ Stable Disease Persistence of one or more non-target lesion(s) or (SD): maintenance of tumor marker level above the nor limits.

Progressive Disease (PD) Appearance of one or more new lesions and/or unequivocal progression of existing non-target les

Evaluation of Best Overall Response

The best overall response was the best response recorded from the start of the treatment until PD/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). The subject's best response assignment depended on the achievement of both measurement and confirmation criteria. Table l : Evaluation of best overall response; RECIST criteria

Target Lesions Non-Target Lesions New Lesions Overall

Response

CR CR No CR

CR Incomplete No PR response/SD

PR Non-PD No PR

SD Non-PD No SD

PD Any Yes or No PD

Any PD Yes or No PD

Any Any Yes PD

Note:

Subjects with a global deterioration of health status requiring discontinuation of treatment without objective evidence of PD at that time were to be classified as . having "symptomatic deterioration." Every effort was to be made to document the objective progression, even after discontinuation of treatment. In some circumstances, it could be difficult to distinguish residual disease from normal tissue. When the evaluation of CR depended on this determination, it was recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the CR status.

The development of brain metastases was to be considered as a sign of PD, even if the disease was responding outside the brain. In this case, the investigator could opt to continue the study drug treatment, if the subject was responding elsewhere.

It was assumed that the requirement for irradiation was indicative of PD. If irradiation was given to any measurable lesions during the study, the subject was to be assessed as having PD from the date of irradiation. Subjects who received radiotherapy at these indicator lesions were to be withdrawn from the study. Example 1 , Phase I study to evaluate Symadex™ administered weekly as a 1 hour infusion for three consecutive weeks followed by one weeks rest (constituting 1 cycle) in patients with advanced solid tumors.

SUBJECTS

Subjects with histological proven advanced solid tumors refractory to conventional treatment or for which no suitable therapy existed, were eligible for inclusion. Subjects were to have one lesion measurable per Response Evaluation Criteria in Solid Tumours (RECIST) criteria or at least one lesion evaluable by the investigator (one measurable or evaluable lesion outside of a previous radiation field (> 20mm on CT scan, X-ray or MIR and > 10mm on spiral CT (Computerized Axial Tomography) scan); They were to be 18 years or older and to have a score of 0 to 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) scale (Karnofsky > 60% ) with an expected survival of 12 weeks or more. There were to have adequate hematological status as evidenced by a total White Blood Count

(WBC) > 3.0 x 10⁹/L (3,000/mL), neutrophils > 1.5 x 10⁹/L (1,500/ mL), platelets > 100 x 10⁹/L (100,000/ mL) and hemoglobin > 10.0g/dL (lOg/100 mL); adequate renal function as evidenced by serum creatinine within normal institutional limits, OR creatinine clearance > 60 mL/min/1.73 m² for subjects with creatinine levels above institutional normal; adequate hepatic function as evidenced by serum bilirubin < 1.5 X ULN, Alkaline phosphatase < 2.5 x ULN (< 5 x ULN, in case of liver metastases), serum AST or ALT ≤ 2.5 x ULN (< 5 x ULN, in case of liver metastases).

Prior treatment

Reasonable efforts were to be made to determine all relevant treatments received by the subject within 30 days before administration of the study drug. All relevant information was to be recorded in the subject's CRF including the name of the procedure or drug and other information required in the CRF. Concomitant treatment

Standard medications for the control of symptoms could be administered at the investigator's discretion. All concomitant medications were to be recorded in the CRF.

Treatment compliance

Treatment was administered by the investigator or his/her designee in the hospital. All drug administration data, including doses, dates and times, were recorded in the CRF. In addition, drug concentration measurements were performed during the first treatment cycle.

COMPOUNDS

C-1311 was manufactured by the Dept. of Pharmacy and Clinical Pharmacology, Slotervaart Hospital, Amsterdam (NL). Clinical trial supply management was also performed by the Slotervaart Hospital, Dept. of Pharmacy and Clinical Pharmacology, Amsterdam (NL)₅ who used World Courier for the shipments requested by NDDO Oncology. The pharmacist at the trial center was responsible for the handling of the supplies per subject. C-1311 (Symadex™) Injection, supplied in 8 mL vials containing 100 mg of lyophilized product, to be reconstituted with 5 mL water for injection (WFI) to obtain a strength of 20 mg/mL, or 20 mL vials containing SOO mg of lyophilized product were used, to be reconstituted with 8 mL WFI to obtain a strength of 100 mg/mL. The reconstitution volume for the 800 mg vials from 8 mL to 7.5 mL, in order to obtain a strength of 100 mg/mL.

The following batches were used: (100 mg vials) and (800 mg vials). Subjects received 1-hour weekly IV infusions for 3 consecutive weeks at the same dose, followed by 1 week rest. This constituted one cycle. The schedule of C- 1311 administration restarted every 28 days for an estimated 4 cycles or more, at the discretion of the investigator. Up to 4 cycles could be administered in the absence of disease progression or unacceptable toxicity. Responding subjects or subjects with Stable Disease (SD) after 4 cycles were allowed to continue C-1311 treatment until disease progression or unacceptable toxicity, at the discretion of the investigator.

During the first three doses (Cycle 1) subjects were required to remain in the hospital overnight. Thereafter, subjects were to remain under medical supervision for 1 hour following completion of the infusion.

Three subjects received a single oral dose of 480 mg/m² C-1311 on Day 1 of Cycle 1 and IV doses of 480 mg/m² on Day 8 and Day 15. Another three subjects received a single oral dose of 480 mg/m² C-1311 on Day 8 of Cycle 1 and IV doses on Day 1 and Day 15. C-131 1 was to be administered as an IV infusion in subsequent cycles.

The oral preparation consisted of the reconstituted IV dosage form of C- 1311₅ given in a glass of orange juice. Subjects were asked to have fasted 8 hours prior to study drug intake. They were allowed a light meal 2 hours after drug intake. All doses of study drug were calculated on the basis of milligrams of C-1311

(free base equivalent) per square meter of body surface area (mg/m²) as measured before each administration.

Efficacy: Tumor assessments (e.g., CT scan, spiral CT scan, MRI (magnetic resonance imaging) scan or standard X-ray) were performed within four weeks prior to C-1311 administration and at the end of every 2 cycles. The RECIST criteria were used for determination of response.

The efficacy population consisted of all subjects with measurable or _, evaluable disease at inclusion and who received at least 2 treatment cycles.

EFFICACY RESULTS:

C-131 1 , at the doses tested, showed SD observed in 6 subjects, as shown below in Tables 3 and 4. Table 3

Table 4

* Patient stable after 2 cycles, discontinued treatment due to fatigue

** Patient received one dose at 640 mg/nfi and experienced DLT, continued treatment at 480 mg/m2

** *

Patient received first dose of first cycle PO (oral administration) and rest of treatment IV

Example 2. Phase I study to evaluate Symadex™ administered as a 1-hour Daily

Infusion, for Five Consecutive Days, Every Three Weeks, in Patients with Advanced Solid Tumors. The initial clinical development strategy consists of studying two different administration schedules in patients with solid tumors. A daily x 5 dosing regimen, repeated every three weeks was used initially. However, this was subsequently amended to change the dosing regimen from daily x 5 to once every 3 weeks. A starting dose of 15 mg/m²/week was selected for the weekly x 3 protocol and 6 mg/m²/day for the daily x 5 protocol.

Based on the results of Example 1, an adequate safe starting dose of Symadex™ for administration once every three (3) weeks was determined to be 480 mg/m².

Daily x 5 Dosing Regimen Every 21 Days Study

With this regimen, five subjects were treated at doses of 6, 12 and 96 mg/m²/day respectively, without any DLT nor any grade 3 or 4 toxicity being experienced.

Once Every Three Weeks Study

The subjects were treated on a once every 3 weeks dosing regimen. The subject was treated at the established starting dose of 480 mg/m² and did not experience any toxicity. Based on the Example 1, where a subject experienced grade 4 neutropenia after receiving a single dose of 640 mg/m², it was decided for safety considerations to end the accelerated phase and not to double the dose to 960 mg/m². The next dose was therefore set to 640 mg/m² (33% dose increment) and cohorts of three subjects were entered. As no toxicity was observed at 640 mg/m² and 850 mg/m², the next cohort of patients was treated with 1100 mg/m². Toxicity was observed in >2 of 6 patients treated at this dose level. An intermediate dose level of 950 mg/m² was then tested but again toxicity was observed in > 2/6 patients. Therefore, the MTD on this schedule was determined to be 850 mg/m². EFFICACY RESULTS:

At the doses of C-1311 tested, 1 PR and 16 SD were observed, as shown below in Tables 5 (PD = Progressive Disease; PR = Partial Response; SD = Stable Disease; NE = Non-evaluable),

Table 5

patients were treated on the daily x 5 dosing regimen

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

What is claimed is:

A method of treating a patient suffering from a cancer selected from the group consisting of ovarian, renal, head & neck, hepatocellular, thyroid, esophageal, large bowel, pancreatic, mesothelioma, carcinoma, sarcoma and melanoma comprising: administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

(J)₅

wherein

R is -OH or a C1-C6 alkoxy group;

R^a and R^b, are each independently hydrogen or an optionally substituted alkyl;

R² is -H or an C1-C6 alkyl; and n is a whole number between 2 and 5.

2. The method of Claim 1 , wherein R is -OH or -OCH₃.

3. The method of Claim 1, wherein n is 2 or 3.

4. The method of Claim 1 , wherein R² is a -H or a C 1 -C4 alkyl.

5. The method of Claim 1 , wherein R^a and R are each independently a C1-C3 alkyl.

6. The method of Claim 1, wherein R^a and R^b are independently each a -H or an alkyl optionally substituted with a hydroxy, an amino, a C1-C4 N-alkyl- amino or a C1-C4 N,N-dialkylamino group.

7. The method of Claim 6, wherein R^a and R^b are independently hydroxyethyl, aminoethyl, N-alkylaminoethyl and N,N-dialkylaminoethyl.

8. The method of Claim 1 , wherein R is -OH or -OCH₃, R^a and R^b are identical and are methyl or ethyl; n is 2 or 3; and R² is a hydrogen or a C1-C4 alkyl.

9. The method of Claim 1 , wherein the cancer is ovarian cancer.

10. The method of Claim 1 wherein the cancer is renal cancer.

11. The method of Claim 1 , wherein the cancer is sarcoma.

12. The method of Claim 11 , wherein the sarcoma is spindle cell sarcoma.

13. The method of Claim 1 1 , wherein the sarcoma is liposarcoma.

14. The method of Claim 1 1 , wherein the sarcoma is leiomyosarcoma.

15. The method of Claim 11 , wherein the sarcoma is abdominal leiomyosarcoma.

16. The method of Claim 11 , wherein the sarcoma is sclerosing epithelioid sarcoma.

17. The method of Claim 1 , wherein the cancer is melanoma.

18. The method of Claim 17, wherein the melanoma is metastatic malignant melanoma.

19. The method of Claim 1, wherein the cancer is thyroid cancer.

20. The method of Claim 1, wherein the cancer is head and neck cancer.

21. The method of Claim 1 , wherein the cancer is hepatocellular cancer.

22. The method of Claim 1, wherein the cancer is an esophageal cancer.

23. The method of Claim 1, wherein the cancer is a pancreatic cancer.

24. The method of Claim 1 , wherein the cancer is carcinoma.

25. The method of Claim 24, wherein the cancer is a non-small cell lung carcinoma.

26. The method of Claim 24, wherein the carcinoma is esophageal carcinoma.

27. The method of Claim 24, wherein the carcinoma is a large bowel carcinoma.

28. The method of Claim 1 , wherein the cancer is adenocarcinoma.

29. The method of Claim 28, wherein the cancer is esophageal adenocarcinoma.

30. The method of Claim 1, wherein the cancer is mesothelioma.

31. The method of Claim 1, wherein the compound of formula (I) is selected from

32. A method of treating a patient suffering from a cancer selected from the group consisting of ovarian, renal, head & neck, hepatocellular, thyroid, esophageal, large bowel, pancreatic, mesothelioma, carcinoma, sarcoma and melanoma, comprising: administering to said patient a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt thereof:

(III).

33. The method of Claim 32, wherein the cancer is ovarian cancer.

34. The method of Claim 32 wherein the cancer is renal cancer.

35. The method of Claim 32, wherein the cancer is sarcoma.

36. The method of Claim 35, wherein the sarcoma is spindle cell sarcoma.

37 The method of Claim 35, wherein the sarcoma is liposarcoma.

38. The method of Claim 35, wherein the sarcoma is leiomyosarcoma.

39. The method of Claim 35, wherein the sarcoma is abdominal leiomyosarcoma.

40. The method of Claim 35, wherein the sarcoma is sclerosing epithelioid sarcoma.

41. The method of Claim 32, wherein the cancer is melanoma.

42. The method of Claim 41, wherein the melanoma is metastatic malignant melanoma.

43. The method of Claim 32, wherein the cancer is thyroid cancer.

44. The method of Claim 32, wherein the cancer is head and neck cancer.

45. The method of Claim 32, wherein the cancer is hepatocellullar cancer.

46. The method of Claim 32, wherein the cancer is an esophageal cancer.

47. The method of Claim 32, wherein the cancer is a pancreatic cancer.

48. The method of Claim 32, wherein the cancer is carcinoma.

49. The method of Claim 48, wherein the cancer is a non-small cell lung carcinoma.

50. The method of Claim 48, wherein the carcinoma is esophageal carcinoma.

51. The method of Claim 48, wherein the carcinoma is a large bowel carcinoma.

52. The method of Claim 32, wherein the cancer is adenocarcinoma.

53. The method of Claim 52, wherein the canceT is esophageal adenocarcinoma.

54. The method of Claim 32, wherein the cancer is mesothelioma.

55. The method of Claim 1 or 32, wherein the patient is a human.

56. The method of Claim 1 or 32, wherein the compound is administered orally, intravenously or subcutaneously.