US 20040092583A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0092583 A1 Shanahan-Prendergast (43) Pub. Date: May 13, 2004

(54) TREATMENT FOR INHIBITING (30) Foreign Application Priority Data NEOPLASTICLESIONS Jan. 2, 2001 (IE)...... S2001/0002 (76) Inventor: Elizabeth Shanahan-Prendergast, O O O O County Kildare (IE) Publication Classification Correspondence Address: (51) Int. Cl.7 ...... A61K 31/343; A.k'S HOFFMANN & BARON, LLP 6900 JERICHO TURNPIKE (52) U.S. Cl...... 514/469; 514/475; 514/762 SYOSSET, NY 11791 (US) (57) ABSTRACT (21) Appl. No.: 10/250,535 The invention discloses the use of incensole and/or furan ogermacrens, derivatives metabolites and precursors thereof in the treatment of neoplasia, particularly resistant neoplasia (22) PCT Filed: Jan. 2, 2002 and immunodysregulatory disorders. These compounds can be administered alone or in combination with conventional chemotherapeutic, anti-rival, anti-parasite agents, radiation (86) PCT No.: PCT/IE02/00001 and/or Surgery. US 2004/0092583 A1 May 13, 2004

TREATMENT FOR INHIBITING NEOPLASTIC 0007 Chemotherapy uses poison drugs that take advan LESIONS tage of cancer cells rapid growth and consumption of large amounts of nutrients. Chemotherapy side effects include 0001. The present invention relates to a method for the nausea and temporary full or partial hair loss. Antimetabo Selective inhibition of neoplastic cells, for example for the lites, one group of these drugs, work by mimicking the treatment, inhibition or prevention of precancerous lesions, nutrients the body's cells consume. Physicians inject these tumours, cancer growth or other neoplasias in mammals. drugs into the bloodstream, where they travel throughout the This invention also relates to the use of the compounds of body, consumed by every cell. Rapidly growing cancerous the present invention including incensole and/or furanoger cells consume much more of the poisonous drugs than do macren, derivatives, metabolites, analogues, mimic mol normal cells. As a result, the drugs destroy cancerous cells ecules and to compositions containing the compounds of the faster than normal cells. Cells reproduce by duplicating their present invention including incensole and/or furanogerma genetic code, or DNA. Another group of chemotherapy cren, derivatives, metabolites, analogues, mimic molecules. drugs interferes with the duplication of DNA, so cells cannot 0002 Cancer develops from changes in the DNA, or reproduce. Chemotherapy drugs act on all the patients genetic material, of the body's cells, causing them to cells-the cancerous cells and the healthy cells. A physi develop into precancerous lesions. Such lesions exhibit a cian's challenge is to administer the drugs to kill only the Strong tendency to develop into malignant tumours, or cancer cells, not the healthy cells. Side effects Such as those cancer. Such lesions include lesions of the breast (that can immediately described prevent the long term or recurrent develop into breast cancer), lesions of the skin (that can use of these drugs. Furthermore, there are an increasing develop into malignant melanoma or basal cell carcinoma), number of effective drugs that can no longer be used due to colonic adenomatous polyps (that can develop into colon resistance by the causative agent. cancer), and other Such neoplasms. 0008 Researchers have refined these three cancer treat 0.003 Cancer may take years to develop. The process ments (Surgery, radiation therapy and chemotherapy) over typically begins with some disruption to the DNA of a cell, the past 20 years. As a result, the Survival rate among cancer the genetic code that directs the life of the cell. Many things, patents has increased dramatically. But, the Success of any Such as diet, tobacco, Sun exposure or certain chemicals can treatment for cancer depends on how much the cancer has cause Such disruptions. Some cells will enter a precancerous Spread before treatment begins. Once cancer metastasises, or phase, known as dysplasia. Some cells will also enter the Spreads into different areas of the body, treating it with State of carcinoma in situ, in which the cancer cells are Surgery, radiation therapy or chemotherapy becomes more restricted to a microScopic Site and do not pose a great threat. difficult. AS the tumour mass increases and cancerous cells Eventually, unless the body's own immune System takes proliferate, the cancer may become resistant to any type of care of the wayward cells either on its own or by being therapy medicine can provide. enhanced by Specific chemicals, a tumour will develop. It 0009 Early cancer detection is critical to successful may take as long as 30 years for a tumour to go through the treatment. If physicians destroy tumours before they have entire proceSS and become large enough to produce clinical had an opportunity to spread, a person with cancer has a Symptoms. much greater chance for Survival. 0004 Anyone can get cancer, including children, but it is 0010. The search for drugs useful for treating and pre most common in people over the age of 50. This year about venting cancer is intensive. Indeed, much of the focus of 1.22 million people in the United States will be diagnosed cancer research today is on the prevention of cancer because with cancer (not including the more than 1 million annual chemotherapy for cancer itself is often not effective and has cases of basal and Squamous-cell skin cancers.) About Severe side effects. Cancer chemoprevention is important for 563,000 people will die of cancer this year. Treatment for recovered cancer patients whom retain a risk of cancer cancer has progressed rapidly over the last 30 years. Doctors recurrence. Also, cancer chemoprevention is important for generally prescribe three main treatments for cancer: Sur individuals who, have not yet had cancer, but have heredi gery, radiation therapy, chemotherapy or a combination of tary factors that place them at risk of developing cancer. these. Choosing a course of medical treatment depends With the development of new genetic Screening technolo largely on the cancer type, Stage of progression, and loca gies, it is easier to identify patients with high-risk genetic tion. actors, whom would greatly benefit from chemopreventative 0005 Surgery is generally advisable when physicians can drugs. Therefore finding Such anti-cancer drugs that can be safely remove the cancer from the body. In situations where used for prolonged preventive use is of Vital interest. the cancerous cells have spread, Surgeons Sometimes must 0011. Unfortunately, most chemotherapeutic drugs have remove large areas of healthy tissue along with the tumour Serious Side effects that prohibit their long-term use, or use to insure that no malignancy remains. In these cases, phy in otherwise healthy individuals with precancerous lesions. Sicians remove lymph nodes from the tumour area because There side effects, which are a result of non-specific toxicity cancer can spread through nodes. However, unfortunately of the drugs, immunosuppression and other toxicities. For most cancers are discovered too late for Surgical cure. In this reason there is a need to identify new drug candidates many cases, the patient does not experience Symptoms until for therapy of patients with precancerous lesions that do not the cancer has progressed to a malignant stage. have Such Serious Side effects in humans. 0006 Radiation therapy is used to destroy cancer cells. 0012. The in vitro anti-tumour activity of several natural Ironically, radiation can cause and destroy cancer. Side products has recently been examined to identify new com effects of radiation therapy include radiation Sickness, which pounds that inhibit the cancer cells whilst having lower Side are nausea and Skin redness in the tumour area. effects, as described in U.S. Pat. No. 580,925; U.S. Pat. No. US 2004/0092583 A1 May 13, 2004

6,051,565, U.S. Pat. No. 6,080,741; U.S. Pat. No. 5,578,637; 0021. In one embodiment, the compounds of the present U.S. Pat. No. 5,578,637; U.S. Pat. No. 5,663,196, U.S. Pat. invention are Selected from the group comprising: No. 5,602,184; U.S. Pat. No. 5,817,816: and U.S. Pat. No. 56,077,840 to list but a few. A new group of drugs, utilizing monoclonal antibodies, designed to affect only cancer cells, Formula (1) leaving healthy cells intact have been tested. U.S. Pat. No. 5,064,823 discloses the anticancer activity of pentacyclic triterpenoid compounds which possess topoisomerase inhibitory activity. U.S. Pat. No. 5,876,728 is directed to a composition for treating cancer that contains at least three Formula (2) herbal extracts. These previously described compounds are unrelated to the present invention. 0013 However, despite these developments, there exists a continuing need for chemotherapeutic agents which inhibit tumour growth, especially Solid tumour growth and which have an adequate therapeutic indeX to be effective for in vivo treatment. 0.014. The correlation between the compounds of the 0022) wherein for Formula (1) present invention, incenSole and furanogermacren, deriva tives, metabolites, analogues and/or mimic molecules and 0023 Bonds between carbons 9-10, 10-1, 1-2, 2-3.3-4, neoplasia was not recognised prior to the work of the 4-5, 5-6, can be either single or double with the proviso that applicant. Accordingly the following provides information any two or more double bonds are separated by a single on each of these topics. bond. 0024 Compounds also include those containing epoxide 0.015 The present invention is directed to a composition rings formed between carbons 9-10, 10-1, 1-2, 2-3.3-4, 4-5 comprising one or more compound of the present invention with the proviso that any two or more epoxide rings are described herein, their derivatives, metabolites, analogues Separated by a Single bond. and/or mimic molecules with pharmaceutical acceptable additives, diluents, carriers, excipients and pharmaceutical 0.025 wherein for Formula (2) salts thereof. 0026 the carbocyclic ring can have optionally up to 7 endocyclic/exocyclic double bonds with the proviso that any 0016. The present invention is further directed to a phar two or more double bonds are Separated by Single bonds, maceutical formulation comprising a composition as described herein and pharmaceutically acceptable carrier 0027 Carbon atoms for Formula (1) or (2) can be singly thereof. or multiply Substituted, optionally and independently by: 0.017. The present invention is further directed to the use 0028 an oxo Substituent, H, alkyl, aryl, a heterocyclic of the pharmaceutical formulation for the manufacture of a radical, halogen, alkoxycarbonyl (C1-C5) or carboxyl, medicament for treatment of a mammal Suffering from a hydroxyl, alkoxy (C1-C5), amido, alkyl amido (C1-C5), neoplasia comprising a pharmaceutical formulation as amino, mono and dialkyl amino (C1-C5), alkyl carbamoyl described herein. (C1-C5), thiol, alkylthio (C1-C5); 0029 in addition substituents may form a spiro ring 0.018. The present invention is also directed to the use of around the carbon atom to which they are attached or they the pharmaceutical formulation for the manufacture of a can form fused or bridged rings to adjacent carbon atoms medicament for Sensitising a resistant neoplasia to Subse which may be Saturated or unsaturated; quent therapy comprising administering to a patient in need 0030) Substituents on the aryl or heterocyclic radical are thereof a therapeutically effective amount of composition Selected from the group consisting essentially of halogen, previously described. alkyl (C1-C5), hydroxyl, alkoxy (C1-C5), alkoxycarbonyl, 0019. The present invention is also directed to the use of (C1-C5), carboxyl, imido, alkyl amido (C1-C5), amino, a pharmaceutical formulation for the manufacture of a mono and dialkyl amino (C1-C5),alkyl carbamoyl (C1-C5), medicament for treatment of a mammal Suffering from an thiol, alkylthio (C1-C5) or benzenoid aryl thio, cyano, nitro, immunodysregulatory condition comprising a composition haloalkyl (C1-C5), alklsulfonyl (C1-C5), and sulfonate; as described herein to a Subject. 0031 Two of such substituents can be part of a fused ring, which can be either Saturated, or unsaturated, heterocyclic or DETAILED DESCRIPTION OF THE carbo cyclic; INVENTION 0032 and natural amino acid substituents which may be 0020. The present invention is directed to a composition attached to the compounds of formula (1) or (2) via an ester comprising one or more compound of the present invention linkage to a hydroxyl group; described herein, their derivatives, metabolites, analogues 0033 their derivatives, metabolites, analogues and/or and/or mimic molecules with pharmaceutical acceptable mimic molecules with pharmaceutical acceptable additives, additives, diluents, carriers, excipients and pharmaceutical diluents, carriers and excipients and pharmaceutically salts thereof. acceptable Salts thereof. US 2004/0092583 A1 May 13, 2004

0034). “Alkyl” as used herein means linked normal, sec 0042. In one embodiment, the composition is micronized. ondary, tertiary or cyclic carbon atoms linear, branched or In accordance with the present invention, the expression cyclic chains, Saturated or unsaturated. The number of “micronized” means that the composition has been micron carbon atoms in an alkyl group or moiety is about 1 to about ized in accordance with any proceSS for micronizing, a 20, unless otherwise Specified, e.g. C1-10 alkyl means and number of which are known in the art. The micronized alkyl moiety containing 1,2,3,4,5,6,7,8,9 or 10 carbon particles preferably include a percentage of particles, which atoms. Substituents include but are not limited to halogen, are of a diameter, which is about 10 microns, or less, alkyl (C1-C5), hydroxyl, alkoxy (C1-C5), alkoxycarbonyl, preferably, 5 microns or leSS. For example, in a preferred (C1-C5), carboxyl, amido, alkyl amido (C1-C5), amino, aspect of the invention, at least 80% of the particles in a mono and dialkylamino (C1-C5), alkyl carbamoyl (C1-C5), formulation of micronized particles have a diameter of leSS thiol, alkylthio (C1-C5) or benzenoid aryl. than 5 microns. An alternative to micronizing a compound is to Solubilize the compound and put it into liposomes of 0.035 “Aryl” as used herein refers to phenyl or naphthyl, appropriate size. The manufacture of liposomes and the or any optionally Singly or multiply Substituted benzenoid insertion of active ingredients into Such liposomes are well group (C6-C14). Substituents defined below. known in the art. 0036) “Heterocyclic” are used refers to any 4, 5 or 6 0043. In another embodiment the composition is deliv membered, optionally Substituted heterocyclic ring, Satu ered to infected cells by incorporating the compounds of the rated or unsaturated, containing 1-3 ring heteroatoms, the present invention into liposomes or carbohydrate vehicles. remaining ring atoms being carbon. In another embodiment, the composition is formulated into 0037. In one embodiment, Substituents on the aryl or liposomes or carbohydrate vehicles. heterocyclic radical may include hut are not limited to: 0044) In one embodiment, the liposomes or carbohydrate halogen, alkyl (C1-C5), hydroxyl, alkoxy (C1-C5), alkoxy vehicles are Specifically targeted to tumours by covalently carbonyl, (C1-C5), carboxyl, amido, alkyl amido (C1-C5), attaching a monoclonal antibody directed to a tumour amino, mono and dialkyl amino (C1-C5),alkyl carbamoyl asSociated antigen. (C1-C5), thiol, alkyl thio (C1-C5) or benzenoid aryl thio, cyano, nitro, haloalkyl (C1-C5), alklsulfonyl (C1-C5), and 0045. In one embodiment, the liposomes or carbohydrate Sulfonate. vehicles are targeted to HIV infected cells by putting viral antibodies on its Surface. In another embodiment, the viral 0.038. Two of such substituents can be part of a fused ring, antibodies are directed to the HIV coat protein gp160 and/or which can be either Saturated, or unsaturated, heterocyclic or gp120. carbo cyclic. 0046. In another embodiment, the present invention is 0039. In another embodiment, natural amino acid sub directed to a pharmaceutical formulation comprising a com Stituents which may be attached to the compounds of position as described herein and a pharmaceutically accept formula (1) or (2) via an ester linkage to a hydroxyl group. able carrier thereof. 0040. In another embodiment, the compounds of the 0047. In one embodiment the pharmaceutically accept present invention are Selected from the group comprising: able carrier, which in one embodiment is a cyclodextrin, incensole, incenSole acetate, incensole oxide, incensole alpha-cyclodextrin, beta-cyclodextrin, (beta-hydroxypropy oxide acetate, isoincensole, isoincensole acetate, isoincen lcyclodextrin) gamma-cyclodextrin and in another embodi Sole oxide, octyl acetate, octanol, terpinyl acetate, bornyl ment is vitamin E oil. acetate, trans-Ver-benol, Verbenone, menthadien-T7-ol, ter 0048. The compounds of the present invention can be pinen-4-ol, trans-pinocarveol, carvone, bomeol, farneSol, formulated and administered as free bases or in the form of fameSene, B-caryophyllene, humulene, B-cadinene, berga their pharmaceutically acceptable Salts for purposes of Sta motone, 3-guaiene, B-ylangene, B-bourbonene, C-copaene, bility, convenience of crystallisation, increased Solubility, terpinene, myrcene, p-cymene, C- and B-phellandrene, and the like. C-thujene, cembrane-A, isocembrane, cambranol, cembra noids, cembranoid alcohols, furanogermacrens, furanoger 0049. The present invention is further directed to the use macrene, gemacrene, elemane, cadinene, guaiane, Oplopane, of a pharmaceutical formulation for the manufacture of a eudsmane, echinodol, C.-Santalene, C.-bisabolene, furanodi medicament for treatment of a mammal Suffering from a ene, B-Santalene, B-bergamotene, B-fameSene, B-bisabolene, neoplasia comprising a pharmaceutical formulation as SKB4, their derivatives, metabolites, analogues and/or described herein. mimic molecules with pharmaceutical acceptable additives, 0050. The present invention is also directed to the use of diluents, carriers and excipients and pharmaceutically a pharmaceutical formulation for the manufacture of a acceptable Salts thereof. medicament for Sensitising a resistant neoplasia to Subse quent therapy comprising administering to a patient in need 0041. In another embodiment, the compounds of the thereof a therapeutically effective amount of composition as present invention are Selected from the group comprising at previously described. least one of incensole, incenSole acetate, incensole oxide, incensole oxide acetate, isoincenSole, isoincenSole acetate, 0051. The present invention is directed to a method of isoincensole oxide, and/or at least one of the furanosesquit inhibiting neoplastic cells by exposing those cells to a erpine furanogermacrens, their derivatives, metabolites, pharmacologically effective amount of compositions con analogues and/or mimic molecules with pharmaceutical taining those compounds of the present invention described acceptable additives, diluents, carriers and excipients and below, their derivatives, metabolites, analogues and/or pharmaceutically acceptable Salts thereof. mimic molecules with pharmaceutical acceptable additives, US 2004/0092583 A1 May 13, 2004

diluents, carriers and excipients. Such compounds are effec well as on tumour cell lines in vitro. The compounds of the tive at eliminating and inhibiting the growth of neoplasiaS present invention may be particularly useful for the treat Such as precancerous lesions, tumours and cancer growth. ment of solid tumours for which relatively few treatments One of the advantages of utilising Such compositions is that are available. Such tumours include epidermoid and myeloid they are low in toxicity, which in combination with their tumours, acute or chronic, nonSmall cell, Squamous. Specific mechanism of action diminishes resistance development. cancers which may be mentioned as Susceptible to treatment by administration of compounds in accordance with the 0.052 The present invention provides compounds, their present invention include prostate cancer, colon cancer, derivatives, metabolites, analogues and/or mimic molecules Small cell lung cancer, large cell lung cancer, lung adeno with pharmaceutical acceptable additives, diluents, carriers carcinoma, epidermoid lung cancer, melanoma (including and excipients and pharmaceutically acceptable Salts amelanotic Subtypes), renal cell carcinoma, gastric carci thereof, as well as pharmaceutical compositions comprising noma, cancers of the central nervous System (based on the the compounds of the present invention, their derivatives, likelihood that the compounds will cross the blood cell metabolites, analogues and/or mimic molecules with phar barrier) including brain tumours, neuroblastomas, gastric maceutical acceptable additives, diluents, carriers and carcinoma, breast cancer, ovarian cancer, testicular cancer, excipients and methods comprising inhibiting tumour lymphoma and leukaemia, oesophageal cancer, Stomach growth or treating cancer by administering one or more of cancer, liver cancers, prostate cancer, cerVical cancer, adre the compounds of the present invention, their derivatives, nal cancer, oral or mucosal cancer, bladder cancer, pancre metabolites, analogues and/or mimic molecules with phar atic cancer, lymphoma, Hodgkins disease, Sarcomas. maceutical acceptable additives, diluents, carriers and Hematopoeitic cell cancerS Such as B cell leukaemia/lym excipients. phomas, myelomas, T-cell leukemias/lymphomas, Small cell 0053. The present invention also provides products that leukemias/lymphomas, null cell, Sezary, monocytic, are useful for treating neoplasia with minimal toxic side myelomonocytic and Hairy cell leukemias. These lympho effects unlike the high toxicity associated with Standard mas/leukemias can be either acute or chronic. Other cancers chemotherapeutic agents. may also be Susceptible to treatment with the compounds of 0.054 The present invention is also directed to the use of the present invention. The activity can readily be measured a pharmaceutical formulation for the manufacture of a using Standardised tests known to those skilled in the art. medicament for treatment of a mammal Suffering from an 0061 AS used herein, the term “carcinomas' refers to immunodysregulatory condition comprising a composition lesions that are cancerous. Examples include malignant as described herein to a Subject. melanomas, breast cancer, and colon cancer. AS used herein, 0.055 The present invention is also directed to providing the term "neoplasm' refers to both precancerous and can a composition that regulates immune responses. cerous lesions. 0062. As used herein, the terms “inhibit” or “inhibiting.” 0056. These and other objects of the present invention mean decreasing tumour cell growth rate from the rate that will become apparent from the description of the invention would occur without treatment and/or causing tumour mass disclosed below, which descriptions are intended to limit to decrease. Inhibiting also includes causing a complete neither the Spirit or Scope of the invention but are only regression of the tumour. Thus the compounds of the present offered as illustrations of the preferred embodiments of the invention can be either cytostatic or cytotoxic to the tumour invention. cells. 0057 The present invention is directed to the treatment, 0063 AS used herein, the terms subject and patent are inhibition and/or prevention of tumours and/or cancer growth and more particularly to treating neoplasia. used interchangeably. Subjects and patients are mammals. 0064. The compounds of the present invention are useful 0.058 As used herein, the term “neoplasia” or neoplasm antineoplastic agents i.e. to inhibit tumour cell growth in coverS dysplasia, precancerous lesions, cancerous lesions, Vitro and in Vivo, in mammalian hosts, Such as humans or neoplastic cells, cancer, cancer growth, tumours, benign domestic animals, and are particularly effective against Solid tumours, malignant tumours, Solid tumours, carcinomas, etc. tumours and multidrug resistant tumours. Thus the invention 0059 AS used herein, the term “precancerous lesion” provides a method comprising inhibiting cancer cells, by includes Syndromes represented by abnormal neoplastic, contacting Said cells, in vitro and in Vivo with an effective including dysplastic, changes of tissue. Examples include amount of at least one compound of the present invention. precancerous growths in colonic, breast, renal, central ner The invention also provides a therapeutic method compris Vous, gastric, or lung tissues, or conditions Such as dysplas ing treating cancer (i.e. inhibiting tumour cell growth) by tic nevus Syndrome, a precursor to malignant melanoma of administering at least one of the compounds of the present the Skin. Examples also include, in addition to dysplastic invention to a mammal in need of Such therapy. nevus Syndromes, polyposis Syndromes, colonic polyps, 0065. The invention is directed to a method of treating precancerous lesions of the cervix (i.e., cervical dysplasia), tumours comprising administering a biologically active prostatic dysplasia, bronchial dysplasia, breast, bladder and/ amount of a composition which consists of at least one or skin and related conditions (e.g., actinic keratosis), compound of the present invention, their derivatives, whether the lesions are clinically identifiable or not metabolites, analogues and/or mimic molecules with phar 0060. The compounds of the present invention can be maceutical acceptable additives, diluents, carriers and administered to a mammal having a Susceptible cancer, i.e. excipients and pharmaceutically acceptable Salts thereof. a malignant cell population or tumour. Compounds of the 0066. The invention features a method of treating cancer present invention are effective on human tumours in Vivo as comprising administering to a patient in need thereof a US 2004/0092583 A1 May 13, 2004

cancer treatment effective amount of a composition which dysregulatory condition, Said method comprising adminis consists of at least one compound of the present invention, tering one or more to a Subject. their derivatives, metabolites, analogues and/or mimic mol 0077. The pharmaceutical formulations may also be ecules with pharmaceutical acceptable additives, diluents, administered in combination with other therapeutic treat carriers and excipients and pharmaceutically acceptable ments, Such as radiation treatment, Surgery or in combina salts thereof. tion with other anticancer, antiviral or antiparasite drugs. 0067. It was surprisingly found that when a composition The formulations of the present invention may further which consists of at least one compound of the present include as optional ingredients one or more chemotherapeu invention or their derivatives, metabolites, analogues or tic agents already known for their use in the inhibition of mimic molecules were administered, the proliferation of cancer cells for added clinical efficacy. Such combinations neoplastic cells was inhibited, which is manifested, pursuant will in Some cases provide added benefit. to one aspect of the present invention, in a broad-spectrum 0078. In one embodiment, the pharmaceutical formula anti-neoplastic activity. tion further includes at least one conventional chemothera 0068 The compounds of the present invention are indi peutic agent. vidually diverse, but collectively all act to inhibit the propa 0079. In another embodiment, the conventional chemo gation of neoplastic cells, cancers, cancer growth and/or therapeutic agent is Selected from the group comprising tumourS. flutamide and luprolide, antioestrogens, Such as tamoxifen, 0069. The invention also features a method of treating antimetabolites and cytotoxic agents, Such as daunorubicin, neoplasia comprising administering to a patient an effective flourouracil, floxuridine, interferon alpha, methotrexate, pli amount of a composition which consists of at least one camycin, mecaptopurine, thinguanine, adramycin, carmus compound of the present invention and a pharmaceutically tine, lomustine, cytarabine, cyclophosphamide, doxorubicin, acceptable carrier. estramustine, altretamine, hydroxyurea, ifosfamide, procar bazine, mutamycin, buSulfan, mitoxantrone, carboplatin, 0070 Treating neoplasia in a patient includes achieving, cispletin, Streptozocin, bleomycin, dactinomycin and idamy partially or Substantially, one or more of the following: cin, hormones Such as, medroxyprogesterone, estramustine, arresting the growth or spread of a cancer, reducing the ethinyl Oestradiol, Oestradiol, leuprolide, megestrol, oct extent of a cancer (e.g., reducing Size of a tumour or reotide, diethylstilbestrol, chlorotrianisene, etoposide, podo reducing the number of affected sites). Inhibiting the growth phyllotoxin, and goSerelin, nitrogen mustard derivatives rate of a cancer, and ameliorating or improving a clinical Such as, melphalan, chlorambucil, methlorethamine and Symptom or indicator associated with a cancer (Such as thiotepa, Steroids Such as, betamethasone, and other antine tissue or serum components). oplastic agents Such as live Mycobacterium bovis, dicarba 0071. The present invention relates to specific com Zine, asparaginase, leucoVoribin, mitotane, Vincristine, Vin pounds, defined herein, that display immuno-modulatory blastine and teXotere, cyclophosphamide, adriamycin, activity. It has been Surprisingly found the compounds of the 5-flourouracil, hexamethylmelamine, Acivicin, Aclarubicin; present invention have potent immuno-modulatory activity. Acodazole Hydrochloride; AcrCnine; Adozelesin, Aldesleu kin; Altretamine, Ambomycin; Ametantrone Acetate, Ami 0.072 The present invention also relates to compositions noglutethimide; Amsacrine; Anastrozole; Anthremycin; and methods of treatment for prevention of an immunodyS Asparaginase; ASperlin, AZacitidine, AZetepa, AZOtomycin; regulation condition. Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydro 0073. The present invention also relates to specific com chloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sul pounds, defined herein, that enhance endogenous heat shock fate; Brequinar Sodium; Bropirimine; BuSulfan; Cactinomy proteins (hsp) and precursor dendritic cell levels. cin, Calusterone; Carecemide, Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefin 0.074. In accordance with the present invention, a method gol; Chlorambucil; Cirolemycin; Cisplatin; Cladribine; Cri is provided to treat or prevent an immunodysregulatory Snatol MeSylate; Cyclophosphamide, Cytarabine; Dacarba condition comprising administering to a Subject an effective zine; Dactinomycin; Daunorubicin Hydrochloride; amount of a composition which consists of at least one of the Decitabine; DeXormaplatin, DeZaguanine, DeZaguanine compounds of the present invention, their derivatives, Mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubi metabolites, analogues and/or mimic molecules with phar cin Hydrochloride; Droloxifene; Droloxifene Citrate; Dro maceutical acceptable additives, diluents, carriers and moStanolone Propionate, DuaZomycin, Edatrexate, Eflo excipients and pharmaceutically acceptable Salts thereof. mithine Hydrochloride; Elsamitrucin; Enloplatin; 0075. The present invention also provides the use of Enpromate; Epipropidine; Epirubicin Hydrochloride, Erbu compositions which consist of one or more of the com lozole; Esorubicin Hydrochloride Estramustine; Estramus pounds of the present invention, their derivatives, metabo tine Phosphate Sodium; Etanidazole; Ethiodized Oil I 131; lites, analogues and/or mimic molecules with pharmaceuti Etoposide; Etoposide Phosphate; Etoprine; Fadrozole cal acceptable additives, diluents, carriers and excipients and Hydrochloride; Fazarabine; Fenretinide; Floxuridine, Flu pharmaceutically acceptable Salts thereof, for the manufac darabine Phosphate, Fluorouracil; Flurocitabine, Fosqui ture of a medicament for an immunodysregulatory condi done; Fostriecin Sodium; Gemcitabine; Gemcitabine Hydro tion. chloride; Gold Au 198; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a; 0.076 The present invention also provides compositions Interferon Alfa-2b; Interferon Alfa-n1; Interferon Alfa-n3; which consists of at least one compound of the present Interferon Beta-Ia; Interferon Gamma-Ib, Iproplatin; Irino invention for use in a method of treatment of an immuno tecan Hydrochloride; Lanreotide Acetate; Letrozole; Leu US 2004/0092583 A1 May 13, 2004 prolide Acetate, Liarozole Hydrochloride; Lometrexol 9-, dioxamycin; diphenyl Spiromustine, docosanol; dolas Sodium; Lomustine; Losoxantrone Hydrochloride; Maso etron, doxifluridine, droloxifene, dronabinol; duocannycin procol; Maytansine: Mechlorethamine Hydrochloride, SA, ebSelen; ecomustine, edelfosine; edrecolomab, eflo Megestrol Acetate: Melengestrol Acetate; Melphalan; mithine, elemene; emitefur; epirubicin, epristeride, estra Menoageril; Mercaptopurine; Methotrexate; Methotrexate mustine analogue; estrogen agonists, estrogen antagonists; Sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; etanidazole, etoposide phosphate; exemestane, fadrozole; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; fazarabine; fenretinide; filgrastim; finasteride, flavopiridol; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic fleZelastine, fluiasterone, fludarabine; fluorodaunorunicin Acid, Nocodazole; Nogalamycin: Ormaplatin, Oxisuran; hydrochloride; torfenimex, formeStane; fostriecin, fotemus Paclitaxel, Pegaspargase, Pelomycin; Pentamustine, Peplo tine, gadolinium teXaphyrin, gallium nitrate; galocitabine; mycin Sulfate; Perfosfamide; Pipobroman; Piposulfan; ganirelix; gelatinase inhibitors, gemcitabine; glutathione Piroxantrone Hydrochloride; Plicamycin; Plomestane; Por inhibitors, hepSulfam; heregulin; hexamethylene bisaceta fimer Sodium; Porfiromycin; Prednimustine; Procarbazine mide; hypericin; ibandronic acid; idarubicin; idoxifene, Hydrochloride; Puromycin; Puromycin Hydrochloride; idramantone, ilmofoSine, illomastat; imidazoacridones, imi Pyrazofurin; Riboprine; Rogletimide; Safrngol; Safingol quimod, immunostimulant peptides; insulin-like growth fac Hydrochloride; Semustine; SimtraZene; Sparfosate Sodium; tor-1 receptor inhibitor, interferon agonists, interferons, SparSomycin; Spirogermanium Hydrochloride, Spiromus interleukins, iobenguane; lododoxarubicin; ipomeanol, 4-; tine, Spiroplatin; Streptonigrin, Streptozocin, Strontium irinotecan; iroplact, irSogladine, isobengaZole, isohomohali Chloride Sr 89; Sulofenur; Tallisomycin; Taxane; Taxoid; condrin B; itasetron, jasplakinolide; kahalalide F, lamel Tecogalan Sodium; Tegafur, Teloxantrone Hydrochloride; larin-N triacetate, lanreotide; leinamycin; lenograstim; len Temoporfin; Teniposide; Teroxirone; Testolactone; Thiami tinan Sulfate; leptolstatin; letrozole; leukemia inhibiting prine; Thioguanine; Thiotepa, Tiazofurin, Tirapazamine; factor; leukocyte alpha interferon; leuprolide--estrogen Topotecan Hydrochloride; Toremifene Citrate; Trestolone progesterone; leuprorelin; levamisole; liarozole, linear Acetate; Triciribine Phosphate; Trimetrexate; Trimetrexate polyamine analogue, lipophilic disaccharide peptide; lipo Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil philic platinum compounds, lisSoclinamide 7; lobaplatin; Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine Sul lombricine, lometrexol; lonidamine; loSOXantrone; lovasta fate; Vincristine Sulfate; Vindesline; Vindesline Sulfate; Vine tin, loxoribine; lurtotecan; lutetium teXaphyrin, lySofylline; pidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; lytic peptides, maitansine; mannostatin A, marimastat: Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sul masoprocol; maspin; matrilysin inhibitors, matrix metallo fate; Vorozole; Zeniplatin; Zinostatin; Zorubicin Hydrochlo proteinase inhibitors menogaril; merbarone; meterelin; ride, 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; methioninase; metoclopramide; MIF inhibitor; mifepris abiraterone, aclarubicin; acylfulvene, adecypenol; adoZe tone, miltefosine, mirimoStim, mismatched double Stranded lesin; aldesleukin; ALL-TKantagonists, altretamine; amba RNA, mitoguaZone, mitolactol, mitomycin analogues, mustine; amidox, arnifostine; aminolevulinic acid; amrubi mitonafide; mitotoxin fibroblast growth factor-Saporin; cin; atrSacrine; anagrelide; anastrozole; andrographolide; mitoxantrone; mofarotene; molgramoStim; monoclonal anti angiogenesis inhibitors, antagonist D; antagonist G; DHEA, body, human chorionic gonadotrophin, monophosphoryl bromineepiandrosterone, epiandrosterone; antarelix; anti lipid A+myobacterium cell wall Sk, mopidamol, multiple dorsalizing morphogenetic protein-1, antiandrogen, proS drug resistance genie inhibitor; multiple tumor Suppressor tatic carcinoma, antiestrogen; antineoplaston; antisense oli 1-based therapy; mustard anticancer agent; my caperoxide B; gonucleotides, aphidicolin glycinate, apoptosis gene mycobacterial cell wall extract; myriaporone, N-acetyldina modulators, apoptosis regulators, apurinic acid, ara-CDP line, N-Substituted benzamides, nafarelin, nagreStip; nalox DL-PTBA, arginine deaminase, asulacrine; atameStane; atri one-pentazocine, napavin, naphterpin, nartograstim; neda mustine; axinastatin 1; axinastatin 2: axinastatin 3; aza platin, nemorubicin; neridronic acid; neutral endopeptidase; Setron; azatoxin: azatyrosine; baccatin III derivatives, nilutamide, nisamycin, nitric oxide modulators, nitroxide balanol; batimastat; BCR/ABL antagonists; benzochlorins; antioxidant, nitrullyn, O6-benzylguanine; Octreotide, oki benzoylsilauroSporine; beta lactam derivatives, beta cenone, oligonucteotides; Onapristone; ondansetron; alethine; betaclamycin B; betulinic acid; bFGF inhibitor; Ondansetron; oracin, oral cytokine inducer, ornaplatin; bicalutamide, bisantrene, bisaZiridinylspermine; bisnafide; OSaterone, Oxaliplatin, oxaunomycin; paclitaxel analogues, bistratene A, bizelesin, breflate, bropirimine; budotitane; paclitaxel derivatives, palauamine, palmitoylrhizoxin; pam buthionine Sulfoximine, calcipotriol, calphostin C; camp idronic acid, panaxytriol; panomifene, parabactin; paZellip tothecin derivatives, canarypox IL-2, capecitabine, carboxa tine, pegaspargase; peldesine, pentosan polysulfate Sodium; mide-amino-triazole; carboxyamidotriazole; CaRest M3; pentostatin; pentrozole; perflubron; perfosfamide, perillyl CARN 700; cartilage derived inhibitor; carzelesin; casein alcohol; phenazinomycin; phenylacetate; phosphatase kinase inhibitors (ICOS), castanospermine; cecropin R4, inhibitors, picibanil; pilocarpine hydrochloride, pirarubicin; cetrorelix; chlorins, chloroquinoxaline Sulfonamide, cica piritrexim; placetin A; placetin B; plasminogen activator prost, cis-porphyrin, cladribine; clomifene analogues, clot inhibitor; platinum complex, platinum compounds: plati rimazole; collismycin A, collismycin B; combretastatin A4, num-triamine complex, porfimer Sodium; porfiromycin; pro combretastatin analogue; conagenin, crambescidin 816; cri pyl bis-acridone, prostaglandin J2, proteasome inhibitors, Snatol; cryptophycin 8; cryptophycin A derivatives, curacin protein A-based immune modulator, protein kinase C inhibi A., cyclopentanthraquinones, cycloplatam, cypemycin; cyt tor, protein kinase Cinhibitors, microalgal; protein tyrosine arabine ocfosfate, cytolytic factor; cytostatin, dacliximab, phosphatase inhibitors, purine nucleoside phosphorylase decitabine; dehydrodidemnin B; deslorelin; dexifosfamide; inhibitors, purpurins, pyrazoloacridine, pyridoxylated deXraZoxane, deXVerapamil, diaziquone; didemnin B; didox; hemoglobin polyoxyethylon conjugate, raf entagonists, diethylnorspermine, dihydro-5-aZacytidine, dihydrotaxol, raltitrexed; ramosetron; ras farnesyl protein transferase US 2004/0092583 A1 May 13, 2004

inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine Vidarabine; Vidarabine Phosphate; Vidarabine Sodium demethylated; rhenium Re 186 etidronate; rhizoxin; Phosphate; Tipranavir, Viroxime; Zalcitabine; Zidovudine; ribozymes, RII retinamide, rogletimide; rohitukine; ZinviroXime and Intereron. romurtide, roquinimex, rubiginone B1, rubOXyl; Safingol; 0082 In one embodiment, the composition further Saintopin; SarCNU; Sarcophytol A, SargramoStim; Sidi 1. includes at least one anti-parasite agent. mimetics, Semustine, Senescence derived inhibitor 1; Sense oligonucleotides, Signal transduction inhibitors, Signal trans 0083. In one embodiment, the anti-parasite agents are duction modulators, Single chain antigen binding protein; Selected from the group comprising chloroquin, primacquine, sizofiran; Sobu ZOxane, Sodium borocaptate, Sodium pheny mefloquine, pyrimethamine-Sulfadoxone, atoraquone/dap lacetate, Solverol, Sornatomedin binding protein; Sonermin; Sone; halofantrine, artemisinin derivatives, atoraquone-- Sparfosic acid; Spicamycin D; Spiromustine; Splenopentin; proguanol, co-artemether, podophyllotoxin; pentamidine, ditoxanide furoate, metronidazole, tindazole, tetracycline, Spongistatin 1; Squalamine; Stem cell inhibitor, Stem-cell quinacrine, Stibogluconate, amphotericin B, quinine, doxy division inhibitors; stipiamide; stromelysin inhibitors; Sulf cline, trimethoprim-Sulfamethoxazole, metronidazole, nifur mosine, Superactive vasoactive intestinal peptide antagonist; timox, Suramin, melarSoprol, benznideZole, their metabo Suradista; Suramin; Swainsonine, Synthetic glycosaminogly lites, Salts derivatives or any other anti-parasitic agent cans, tallimustine, tamoxifen methiodide, tauromustine; taZ thereof. arotene, tecogalan Sodium, tegafur, tellurapyrylium; telom erase inhibitors, temoporfin, temozolomide; teniposide; 0084. The agents of the present invention may also be tetrachlorodecaoxide, tetraZomine; thaliblastine; thalido administered in combination with other agents for example mide; thiocoraline; thrombopoietin; thrombopoietin immunostimulating drugs or therapeutic agents. Appropriate mimetic; thymalfasin; thymopoietin receptor agonist, thy amounts in each case will vary with the particular agent, and motrinan; thyroid Stimulating hormone, tin ethyl etiopurpu will be either readily known to those skilled in the art or rin; tirapazamine, titanocene dichloride; topotecan; topsen readily determinable by routine experimentation. tin: toremifene: totipotent Stem cell factor, translation 0085. In one embodiment, the pharmaceutical formula inhibitors, tretinoin, triacetyluridine, triciribine, trimetrex tion is administered in combination with radiation treatment. ate, triptorelin; tropisetron, turosteride, tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogeni 0086. In one embodiment, the pharmaceutical formula tal Sinus-derived growth inhibitory factor; urokinase recep tion is administered in combination with Surgery. tor antagonists, vapreotide; variolin B; Vector System, eryth 0087. The invention also relates to a method of Suppress rocyte gene therapy, VelareSol, Venom, anti-Venom, ing tumour growth in a mammal by administering to the Veramine, Verdins, Verteporfin, Vinorelbine; VinXaltine: mammal an amount of a composition which consist of at Vitaxin; Vorozole, Zanoterone; Zeniplatin, Zilascorb, Zinosta least one of the compounds of the present invention, deriva tin Stimalarner, immunostimulating drugs or therapeutic tives, metabolites, analogues and/or mimic molecules, and a agents, their metabolites, Salts and derivatives thereof. Second chemotherapeutic agent effective to SuppreSS tumour growth in the mammal. The Second chemotherapeutic agent 0080. In one embodiment, the composition further is not a compound of the present invention or a derivative, includes at least one anti-Viral agent. metabolite, analogue or mimic molecule. These composi 0081. In one embodiment, the anti-viral agents are tions provide enhanced antitumour effect and may also Selected from the group comprising nucleoside analogues prevent the development of metastases. In particular, these (AZT, ddC; ddl; d4T, 3TC; BW 1592; PMEA/bis-POM compounds are useful for overcoming tumours that are drug PMEA; dOTC; DAPD); non-nucleoside reverse tran resistant. These agents may be administered Separately or as scriptase inhibitors (delavirdine; DMP 266; HBYO97; lov a cocktail. Toxicity may be reduced by administering the iride; nevirapine, emivirine; AG1549; PNU 142721, Calano compound of the present invention or a derivative, metabo lide A: DPC961), protease inhibitors (ABT-378; ritonavir, lite, analogue or mimic molecule, thereof Several hours prior nelfinavir; BW 141; KNI-272; indinavir, saquinavir; L-756, to administering the chemotherapeutic agent. The composi 423; DMP-450; BMS-232630); ALX40-4C; hydroxyurea; tions can be administered by any route. lobucavir, pentafuside; T-1249; PRO 542; FP-21399; AMD 0088. The components of any of the pharmaceutical 3100; HE-2000 and peptide T; Abacavir: Acemannan; Acy formulations disclosed herein can be administered Simulta clovir; Acyclovir Sodium; Adefovir; Alovudine; Alvircept neously (in a combination formulation), essentially simul Sudotox, Amantadine Hydrochloride; Aranotin; Arildone; taneously (e.g., administration of each compound a few Atevirdine Mesylate; Avricline; Cidofovir, Cipamfylline; minutes or a few hours apart), or can be administered Coviracil; Cytarabine Hydrochloride; Delavirdine Mesylate; Sequentially, e.g., Several days apart, or more than a week Desciclovir, Didanosine; Disoxaril; Edoxudine; Emivirine; apart. For example, a compound of the present invention, Emtricitabine; Enviradene; Enviroxime; Epivir; Famciclo (and a conventional chemotherapeutic agent) can be admin vir, Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosa istered together, or essentially simultaneously, e.g., admin rilate; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir, istration of each compound a few minutes or a few hours Ganciclovir Sodium; Idoxuridine, Indinavir; Kethoxal, apart, or can be administered Sequentially, e.g., Several days Lamivudine, Lobucavir, Lodenosine, Lopinavir, Memotine apart, or more than a week apart. All Such variations in Hydrochloride; Methisazone: Nelfinavir, Nevirapine; Pen administration of the combination therapy are encompassed ciclovir, Pirodavir; Ribavirin; Rimantadine Hydrochloride; Saquinavir Mesylate; Ritonavir; Somantadine Hydrochlo within the scope of the invention. ride; Sorivudine, Statolon; Stavudine; Tenofovir; Tilorone 0089. In one embodiment, the neoplasia is a precancerous Hydrochloride; Trifluridine; Valacyclovir Hydrochloride; lesion including Syndromes represented by abnormal neo US 2004/0092583 A1 May 13, 2004 plastic and/or dysplastic, changes of tissue comprising pre 0098. In one embodiment, a pharmaceutical formulation cancerous growths in colonic, breast, renal, central nervous, is provided to enhance endogenous hsp levels, comprising gastric, or lung tissues, or conditions Such as dysplastic administering to a patient in need thereof a therapeutically nevus Syndrome, a precursor to malignant melanoma of tho effective amount of a composition comprising at least one skin, dysplastic nevus Syndromes, polyposis Syndromes, compound of the present invention. colonic polyps, precancerous lesions of the cervix (i.e., 0099. In another embodiment, a method for enhancing cervical dysplasia), prostatic dysplasia, bronchial dysplasia, endogenous hsp levels in a living Subject is provided, breast, bladder and/or skin and related conditions (e.g., comprising administering to a patient in need thereof a actinic karatosis), whether the lesions are clinically identi therapeutically effective amount of a composition compris fiable or not. ing at least one compound of the present invention. 0090. In one embodiment, the neoplasia is prostate can cer, colon cancer, Small cell lung cancer, large cell lung 0100. In another embodiment, a method of treating the cancer, lung adenocarcinoma, epidermoid lung cancer, Symptoms of low levels of endogenous hsp levels in a living melanoma (including amelanotic Subtypes), renal cell car Subject is provided, comprising administering to a patient in cinoma, gastric carcinoma, cancers of the central nervous need thereof a therapeutically effective amount of a com System including brain tumours, neuroblastomas, gastric position comprising at least one compound of the present carcinoma, breast cancer, ovarian cancer, testicular cancer, invention. lymphoma and leukaemia, oesophageal cancer, Stomach 0101. In another embodiment, a pharmaceutical formu cancer, liver cancers, prostate cancer, cerVical cancer, adre lation is provided to enhance endogenous precursor dentritic nal cancer, oral or mucosal cancer, bladder cancer, pancre cell levels, comprising administering to a patient in need atic cancer, lymphoma, Hodgkins disease, Sarcomas. thereof a therapeutically effective amount of a composition Hematopoeitic cell cancerS Such as B cell leukaemia/lym comprising at least one compound of the present invention. phomas, myelomas, T-cell leukemias/lymphomas, Small cell 0102) Additionally, the invention provides use of the leukemias/lymphomas, null cell, Sezary, monocytic, composition to provide protection against infections in myelomonocytic and Hairy cell leukemias. immunocompromised animals and humans. These compo 0.091 In one embodiment, the neoplasia is in the form of Sitions may be used prophylactically or therapeutically to a tumour comprising an epidermoid and myeloid tumour, protect animals or patients from the consequences of infec acute or chronic, nonsmall cell, Squamous or Solid. tion by pathogens. 0092. It has been surprisingly found that the compounds 0103) Further, the invention provide use of tho compo of the present invention have potent immuno modulatory Sition in Veterinary medicine, prophylactically and therapeu effects, Accordingly, the disclosed compounds of the present tically in animal populations that are Subject to infection that invention when administered to human patients will have a compromises immune response and cause infection. broad immuno-modulatory effect, resulting in its application 0104. In another aspect of the invention, the use of a in many Syndromes, especially following treatment for or pharmaceutical formulation is provided for the manufacture infection by cancerous cells. More specifically, one aspect of of a medicament for the treatment of a mammal Suffering the present invention relates to the use of the compounds of from an immuno dysregulation condition, comprising the present invention in treatment of an immunodysregula administering to a patient in need thereof a therapeutically tion condition. effective amount of a a pharmaceutical formulation of the 0093. According to one aspect of the invention, a com present invention. position containing at least one of the compounds of the present invention enhance the production of endogenous 0105. In one embodiment, the immuno dysregulation heat shock protein (hsp) production, regardless of the immu condition is caused by a viral infection, intracellular bacte nocompetency of the individual. According to another rial infection, extracellular bacterial infection, fungal infec tion, yeast infection, extracellular parasite infection, intrac aspect of the invention, a composition containing at least one ellular parasite infection, protozoan parasite, multicellular of the compounds of the present invention enhance levels of parasite, autoimmune disease, immunosuppressive therapy, precursor dendritic cells. chemotherapy, anti-infective agent therapy, wound, burn, 0094. The advantage of administering a pharmaceutical the presence of an immunosuppressive molecule, gas formulation containing at least one compound of the present trointestinal irritation or any combination of the foregoing invention with a Suitable carrier is three fold: and is selected from (a) a DNA virus infection or an RNA virus(b) a parasite infection, a Trypanosoma, Plasmodium, 0095 1. The cancer-infected cell is presented to the Cryptosporidium, Entamoeba, Balangidium, Leishmania, immune System where its presence is detected due to Pneumocystis, Trichomoniasis or Toxoplasma infection, enhanced immunoSurveillence. wherein the TrypanoSoma, Plasmodium, Cryptosporidium, 0096 2. The compounds of the present invention Entamoeba, Balatidium, Leishmania, Pneumocystis, Tri have immuno up-regulatory properties, precursor chomoniesis or Toxoplasma infection is Selected: from but dendritic and natural killer cells are up regulated. not limited to TrypanoSoma Cruzi, TrypanoSoma brucei, Antigen capture is further enhanced by a domino TrypanoSoma gambiense, TrypanoSoma rhodesiense, Plas effect of increasing precursor dendritic cell matura modium falciparum, Plasmodium vivax, Plasmodium tion into cytotoxic T cells. malariae, Plasmodium ovale, Plasmodium berghei, Entam Oeba histolytica, Balantidium coli, Leishmania brazilienis, 0097 3. The presentation of the antigenic peptides Leishmania mexicana, Leishmania donovani, Leishmania to the cytotoxic T cells is improved. tropica, Pneumocystis carinii, Trichomoniasis vaginalis, US 2004/0092583 A1 May 13, 2004 and Toxoplasma gondii (c) a mycoplasma infection, a List of a medicament for Sensitising a resistant neoplasia to eria infection or a Mycobacterium infection; (d) a Strepto Subsequent therapy comprising administering to a patient in coccuS infection, a StaphylococcuS infection, a Vibrio infec need thereof a therapeutically effective amount of a a tion, a Salmonella infection; a Shigella infection, an pharmaceutical formulation of the present invention. enterotoxigenic, enteropathogenic, enteroinvasive or entero hemorrhagic E. coli infection, a Yersinia infection, a Campy 0112 The method of the present invention is useful in lobacter infection, a Pseudomonas infection, a Borrelia Sensitizing deSensitized cancer cells in particular: Ovarian, infection, a Legionella infection and a Haemophilus infec Sarcoma, non-Hodgkin's lymphoma, lung, breast cancer, tion; (e) pulmonary Aspergillosis, mucosal or oropharyn bladder carcinoma, colon carcinoma, pancreatic carcinoma, gealcandidlasis and juvenile paracoccidiomyosis, (f) a Can carcinoma of the ampulla of Vater, multiple myeloma, adult dida infection and a Cryptococcus infection; (g) Systemic acute lymphocytic leukemia, adult non-lymphoytic leuke lupus erythematosis, arthritis, asthma, and diabetes (h) mia and neuroblastoma. It is preferred that the cancer cells adriamycin treatment, cisplatin treatment, mitomycin C be breast cancer, multiple myeloma, Ovarian or lung. treatment, amphoteracin B treatment; (ii) a gamma-radiation 0113. It is realized that the desensitized cancer cells may is treatment; (ii) nucleoside analog treatment for viral infec be desensitized to more than one chemotherapeutic agent. If tion or for cancer; (k) Surgical and accidental wounds, Septic So, the method of the present invention will Sensitize the Shock caused by Surgery; (1) cyclosporin treatment and deSensitized cancer cells to most of the chemotherapeutic corticosteroid treatment; (m) irritable bowel treatment, agents to which they are desensitized. Crohn's disease, wasting Syndrome, cachexia, Motor Neu ron disease, Multiple Sclerosis, inflammatory bowel disease, 0114. In one embodiment, the chemotherapeutic agents to respiratory distress Syndrome, chronic diarrhoea, (n) cancer, which the cancer cells become desensitized are Selected (o) cirrhoisis; (p) gram positive multi-drug resistant bacteria from the group consisting of doxorubicin, daunomycin, or (q) any combination of (a) through (p). Vinca alkaloids, Vincristine, vinblastine, taxol, colchicine, epipodophyllotoxins Such as etopoSide, actinomycin D, 0106. In one embodiment, the DNA virus infection or the puromycin, emetine, melphalan, adozalesin, S-(R,R)6,6'- RNA virus infection is selected from a retrovirus infection, carbonylbis(imino-1H-indole-05,2-diylcarbonyl)bis8 a togavirus infection, a flavivirus infection, a rubivirus (chloromethyl) 3,6,7,8-tetrahydro-1-methyl-benzo1,2-b;4, infection, a pestivirus infection, a lipid envelope virus 3-b'dipyrrol-4I, (S)-N-2-1-(chloromethyl)-1,6-dihydro infection, a filovirus, a picornavirus infection, a rhinovirus 3-methyl-5-(phenylamino)carbonylopxybenzo 1,2-b:4, infection, a coronavirus infection, a respiratory Synoytial 3-b'dipyrrol-3(2H)-yl)carbonyl)-1H-indol-5-yl)-6- virus infection, a poliovirus infection, a parainfluenza virus (diethylamino)-2 benzofurancarboxamide, (7bR, 8aS)-7-1, infection, influenza virus infection, hantavirus, adeno-asso 6-dihydro-4-hydroxy-5-methoxy-7-(4.5, 8, 8a-tetrahydro ciated virus, measles Virus, poxvirus, filovirus, human pap 7-methyl-4-oxocyclopropacpyrrolo3.2-eindol-2(1H)- illoma virus and animal papilloma virus infection. yl)carbonylbenzo 1,2-b:4,3-b'dipyrrol-3(2H)-yl) 0107. In one embodiment, the composition enhances carbonyl-1,6-dihydro-4-hydroxy-5-methoxybenzo1,2-b:4, endogenous hsp levels. 3-b'dipyrrole-3(2H)-carboxamide. 0.115. It is realized that new chemotherapeutic agents 0108. In one embodiment, the composition enhances against cancer will be developed after this invention. The endogenous precursor dendritic cell levels. new chemotherapeutic agents to which resistance develops 0109 The invention also relates to a method for reducing and which can be treated by the method of this invention are the immunodepressive effect of a chemotherapy agent in a equivalent to those Set forth in this invention. mammal by administering to a mammal an amount of a composition which consists of at least one compound of the 0116. In one embodiment, the pharmaceutical formula present invention or a derivative, metabolite, analogue or tion has an enteric coating. In one embodiment, the enteric mimic molecule thereof effective to augment the immune coating is made of a polymer or copolymer. In one embodi System of the mammal upon treatment of the mammal with ment, the polymer or copolymer is Selected from the group the chemotherapeutic agent. The immune System may be consisting of poly(lactic-glycolic acid) polyester, cellulose augmented, for example, by increasing the total number of acetate phthalate, hydroxypropyl-methyl cellulose phthalate leukocytes, T-lymphocytes, B-lymphocytes, or immunoglo poly(butyl methacrylate), (2-dimethyl aminoethyl) meth bulins. acrylate, and methyl methacrylate. 0110. The present invention also provides a method of 0117 The pharmaceutical formulation according to the Sentisizing a neoplasia to Subsequent treatment, for example present invention can be administered to a patient in any of radiation or chemotherapy. It is known that cancer cells a wide range of routes. Thus, with regard to the types of become resistant to Some chemotherapeutic agents and are formulations in which the active compounds according to even resistant to many different chemotherapeutic agents. the present invention can be administered, as well as any This is a significant to many different chemotherapeutic additives can be included with the active compounds in the treatments. This method includes administering an effective formulations, and the possible routes of administration, it is amount of a composition which consists of at least one well known to those of skill in the art that Such formulations compound of the present invention or a derivative, metabo can be provided in a wide variety of types, and it is within lite, analogue or mimic molecule thereof to a mammal the skill of the ordinary artisans to Select a specific formu having cancer. lation and route of administration and then test Suitability for use. By way of example but not limitation, Suitable routes 0111. In another aspect of the invention, the use of a include enteric, parenteral, topical, oral, rectal, nasal or pharmaceutical formulation is provided for the manufacture vaginal routes. Parenteral routes include Subcutaneous, US 2004/0092583 A1 May 13, 2004

intramuscular, intravenous, intraperitoneal, intradermal and E oil), polyethylene glycol and ethyl oleate. A preferred Subilingual administration. Also, compositions may be carrier is cyclodextrin in water. Frequently, it is desirable to implanted into a patient or injected using a drug delivery include additives in the carrier Such as buffers and preser System. Vatives or other Substances to enhance isotonicity and 0118. The pharmaceutical formulation according to the chemical Stability. present invention may be administered locally or Systemi 0.125 The composition can also be administered topi cally. By Systemic administration means any mode or route cally. Suitable formulations for topical administration of administration that results in effective amounts of active include creams, gels, jellies, mucliages, pastes and oint ingredient appearing in the blood or at a Site remote from the ments. The compounds may be formulated for transdermal route of administration of the active ingredient. administration, for example in the form of transdermal 0119 Further, the pharmaceutical formulation according patches So as to achieve Systemic administration. to the present invention may be administered intermittently. 0.126 The composition may also be administered in the The advantage of this is that it allows the patient to Suspend form of an implant. therapy for periods without the worry of inactivity of the drug resulting from the development of resistant cells. 0127. The composition may also be administered in the form of an infusion Solution or as a nasal inhalation, aeroSol 0120) The pharmaceutical formulation according to tho or Spray. invention may be formulated for enteral, parenteral or topi cal administration. Indeed all three types of formulations 0128. In another embodiment, the composition is incor may be used Simultaneously to achieve Systemic adminis porated in a pharmaceutically acceptable carrier, diluents, vehicles and the like for Systemic administration by feeding. tration of the active ingredient. An example of Such a carrier is cyclodextrin (C-cyclodex 0121 Compounds useful in the methods of this invention trin, fB-hydroxypropylcyclodextrin or Y-cyclodextrin). may be formulated into compositions together with phar maceutically acceptable carriers for oral administration in 0129. In one embodiment, the pharmaceutical formula Solid or liquid form, or for rectal administration, although tion is administered enterally, parenterally, topically, orally, carriers for oral administration are most preferred. Sub-lingually, rectally, nasally or vaginally. 0122) Pharmaceutically acceptable carriers for oral 0.130. In one embodiment, the pharmaceutical formula administration include capsules, tablets, pills, powders, tro tion is administered to a mammal. In one embodiment, Said ches and granules. In Such Solid dosage forms, the carrier mammal is a neonate and Said administering is effected prior can comprise at least one inert diluent Such as Sucrose, to delivery of Said neonate and/or during delivery of Said lactose or Starch. Such carriers can also comprise, as is neOnate. normal practice, additional Substances other than diluents, e.g., lubricating agents Such as magnesium Stearate. In the 0131 The pharmaceutically acceptable carrier and com case of capsules, tablets, troches and pills, the carriers may pounds of this invention are formulated into unit dosage also comprise buffering agents. CarrierS Such as tablets, pills forms for administration to a patient. The dosage levels of and granules can be prepared with enteric coatings on the active ingredient (i.e. compounds of this invention) in the Surfaces of the tablets, pills or granules. Alternatively, the unit dosage may be varied So as to obtain an amount of enterically coated compound can be pressed into a tablet, active ingredient effective to achieve lesion-eliminating pill, or granule, and the tablet, pill or granules for admin activity in accordance with the desired method of adminis istration to the patient. Preferred enteric coatings include tration (i.e., oral or rectal). The Selected dosage level there those that dissolve or disintegrate at colonic pH Such as fore depends upon the nature of the active compound shellac or Eudraget S. Additional pharmaceutically accept administered, the route of administration, the desired dura able carriers include liquid dosage forms for oral adminis tion of treatment, individual needs and other factors. If tration, e.g. pharmaceutically acceptable emulsions, Solu desired, the unit dosage may be Such that the daily require tions, Suspensions, Syrups and elixirs containing inert ment for active compound is in one dose, or divided among diluents commonly used in the art, Such as water. Besides multiple doses for administration, e.g., two to four times per Such inert diluents, compositions can also include adjuvants day. Such as Wetting agents, emulsifying and Suspending agents, 0.132. With regard to dosage and duration of treatment and Sweetening, flavouring and perfuming agents. according to any aspect of the present invention, it is 0123 Pharmaceutically acceptable carriers for rectal recognized that the ability of an artisan skilled in pharma ceutical administration of drugs to determine Suitable dos administration are preferably Suppositories that may contain, ages depending on many inter-related factorS is well known, in addition to the compounds of the present invention, and skilled artisans are readily able to monitor patients to excipients Such as cocoa butter or a Suppository waX. determine whether treatment should be started, continued, 0.124 Suitable injectable solutions include intravenous, discontinued or resumed at any given time. For example, Subcutaneous and intramuscular injectable Solutions. dosages of the compounds are Suitably determined depend Examples of injectable forms include Solutions, Suspensions ing on the individual cases taking Symptoms, age and SeX of and emulsions. Typically the compound(s) is injected in the subject and the like into consideration. The amount of the asSociation with a pharmaceutical carrier Such as normal compound to be incorporated into the pharmaceutical com Saline, RingerS Solution, dextrose Solution and other aqueous position of the invention varies with dosage route, Solubility carriers known in the art. Appropriate non-aqueous carriers of the compound, administration route, administration may also be used and examples include cyclodextrin, pref Scheme and the like. An effective amount for a particular erably hydroxypropyl beta cyclodextrin, mixed oils (vitamin patient may vary depending on factorS Such as the condition US 2004/0092583 A1 May 13, 2004

being treated, the Overall health of the patient and the bodies. Accordingly, the present invention also provides a method, route and dose of administration. The clinician method comprising treating cancer (i.e. inhibiting tumour using parameters known in the art makes determination of cell growth) by administering a pharmaceutical composition the appropriate dose. Generally, the dose begins with an comprising at least one of the compounds of the present amount Somewhat less than the optimum dose and it is invention and a reagent (i.e. monoclonal or polyclonal increased by Small increments thereafter until the desired or antibody) which is capable of binding to a tumour-associ optimum is effect is achieved. Suitable dosages can be ated antigen. determined by further taking into account relevant disclo 0.137 Alternatively, the compounds of the present inven Sure in the known art. In one embodiment, the unit dose tion could be attached to or incorporated into liposomes or comprises 5-500 mg of active ingredient consisting of at carbohydrate vehicles, which are known to be useful far least one compound of the present invention. targeting anti-cancer drugs. Preferably the liposomes or 0133. The pharmaceutical formulations of this invention carbohydrate vehicles can be specifically targeted to are preferably packaged in a container (e.g. a box or bottle, tumours by covalently attaching a monoclonal antibody or both) with Suitable printed material (e.g. a package insert) directed to a tumour-associated antigen. containing indications, directions for use, etc. 0.138. The invention further provides a composition for 0134) The present invention is also directed to composi treating a cancer Selected from the group consisting of Small tions which consist of at least one compound if the present cell lung cancer, testicular cancer, lymphoma, leukaemia. invention acting as prodrug compounds analogous to the Oesophageal cancer, Stomach cancer, colon cancer, breast active compounds disclosed herein. Such compounds are cancer, central nervous System cancer, liver cancer and generally themselves inactive or low in activity, but are prostate cancer, which comprising administering to a mam converted into active compounds. Thus, for example, pro mal in need thereof an effective amount of a composition drugs. Such as the methyl ester of any acid functionality, containing as an active ingredient therein at least one of the which is not active per Se or has very low activity could be compounds of the present invention, their derivatives, hydrolysed, either uncatalytically or catalytically with an metabolites, analogues and/or mimic molecules with phar enzyme Such as an esterase to an active compound. Such maceutical acceptable additives, diluents, carriers, excipi pro-drug compounds could well be the preferred therapeutic ents and pharmaceutical Salts thereof. form of the present compounds. These analogous prodrugs 0.139. The invention provides a method for inducing can be produced from active compounds based on proce cellular differentiation, which comprises contacting a can dures and factors that are well known to one of ordinary skill cerous cell with an effective amount of at least one com in the art. Accordingly as used in the present application, pound of the present invention or a derivative, metabolite, “pro-drug analogue' means “a chemical which is relatively analogue or mimic molecule and pharmaceutically accept non-toxic and pharmacologically inert but which can be able salts thereof. transformed in Vivo to a pharmacologically active drug’. More specifically it means a derivative, metabolite or ana 0140. The invention provides pharmaceutical formula logue of the compounds of the present invention which have tions which consist of compositions comprising, at least one low or no ability as anti-neoplastic agents until converted in compound of the present invention and corresponding phar the body to a derivative, metabolite or analogue with Such maceutically acceptable derivatives, metabolites, analogues, ability or abilities. Such pro-drugs should have favourable mimic molecules and mixtures thereof are to be used as properties Such as enhanced absorption, water Solubility, anti-neoplasic and/or anti-cancer agents. lower toxicity, or better targeting to the tumour cell (such as 0.141. The invention provides pharmaceutical formula by reason of greater affinity to the tumour cell or a larger tions to be used in the preparation of medicaments having quantity of activating enzyme in the tumour cell as opposed anti-neoplastic and/or anti-cancer activity. to a normal cell So that larger concentrations of the active compound are produced in the tumour cell). Examples of 0142. The invention further provides, the use of the Such compounds are esters, Such as methyl, ethyl, phenyl, pharmaceutical formulations as anti-neoplasic and/or anti N,N-dimethylaminoethyl, acyl derivatives such as benzoyl, cancer agents. p-N,N-dimethylaminobenzoyl, N,N-dimethylaminoglycyl, 0143. In another embodiment, the use of pharmaceutical peptide derivatives Such as Y-glutamyl, glycyl, D-Val-Leu formulations for the preparation of medicaments having LyS. anti-neoplastic and/or anti-cancer activity. 0135) In one embodiment, said compounds of the present 0144. In another embodiment, pharmaceutical formula invention acts as a prodrug. tions are provided, for the preparation of medicaments 0.136 The compositions containing the active compounds having activity against neoplasm and/or cancer. or pro-drugs of the present invention can be formulated So 0145 The present invention is exemplified in terms of in as to be specifically targeted to tumours. The compounds can Vitro and in Vivo activity against various neoplastic cell be attached to the reagent that is capable of binding a lines. The test cell lines employed in the in Vitro assays are tumour-associated antigen. For example, the compounds of well recognised and accepted as models for anti-tumour the present invention could be covalently attached to a activity in animals. The term animals as used herein monoclonal antibody Such as directed to a tumour-associ includes, but is not limited to, mice, rats, domesticated ated antigen. The antigen may be located on a tumour or in animals Such as but is not limited to, cats, dogs, and other the tumour cell area. Such linkages can be made through animals but is not limited to, cattle, sheep, pigs, horses, and peptide bond formation with amino groups of an antibody. primates Such as but not limited to, monkeys, humans and Suitable reagents include polyclonal and monoclonal anti more generally mammals. US 2004/0092583 A1 May 13, 2004

0146) Without further elaboration, it is believed that one Clonogenic ASSay skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The Single Cell Suspension From Tumour Cell Lines following detailed examples describe how to test the various 0152 Human tumour cell lines were grown in RPMI compounds of this invention and/or perform the various 1640 supplemented with 10% fetal calf serum and 2 mM processes of the invention and are to be construed as merely L-glutamine. The cells were kept at 5% CO and 37 C. and illustrative, and not limitations of the preceding disclosure in passaged routinely. For treatment experiments, exponen any way whatsoever. Those skilled in the art will promptly tially growing cells were trypsinized, washed twice with recognize appropriate variations from the procedures. PBS and the percentage of viable cells was determined by 0147 The active components with anti-neoplastic activ hemocytometer count using trypan blue viable dye exclu ity were extracted from resins of plants from the plant family SO. Burseraceae, primarily Myrrh (Commiphora spp.) and Frankincense or Olibanum (Boswellia carteri). The compo Culture Methods nents were extracted from the resins using Standard extrac 0153. The clonogenic assay was performed according to tion techniques followed by chromatographic isolation. a modified two-layered Soft agar assay. The bottom layer Sample components were identified using Several methods consisted of 0.2 mls of Iscove’s Modified Dulbecco's including preparative HPLC, mass spectroscopy, NMR Medium with 20% fetal calf serum and 0.75% agar. 2.5x104 Spectroscopy, and IR and UV spectroScopy. cells in RPMI/10% FCS were added in 0.2 ml medium, but containing 0.4% agar and placed in 24-multiwell plates on 0148 Multiple components can be extracted from the top of the base layer. After 24 hours, drugs were added in resins including: incenSole, incenSole acetate, incensole additional 0.2 ml of RPMI medium. Every plate contained 6 oxide, incenSole oxide acetete, isoincensole, isoincensole vehicle controls and 6 different drug concentrations in acetate, isoincensole oxide, octyl acetate, octanol, terpinyl triplicate. 5-flourouracil was used as a positive control in acetate, bornyl acetate, trans-Ver-benol, Verbenone, mentha concentrations of 100, 300 and 1000 ug/ml. Cultures were dien-7-ol, terpinen-4-ol, trans-pinocarveol, carvone, incubated at 5% CO and 37 C. in a humidifled atmosphere borneol, farneSol, farneSene, B-caryophyllene, humulene, for 5-6 days under continuous exposure to drugs and moni B-cadinene, bergamotone, B-guaiene, B-ylangene, 3-bour tored closely for colony growth using an inverted micro bonene, C-copaene, terpinene, myrcene, p-cymene, C- and scope. Within this period, in vitro tumour growth led to the 3-phellandrene, C-thujene, cembranes, cembrane-A, iso formation of colonies with a diameter of 50 lum. At the time cembrane, cembranol, cembranoids, cembranoid alcohols, of colony formation, counts were performed with automated furanogermacrens, furanogermacrene, germacrene, image analysis system (OMNICOM FAS IV, Biosys elemane, cadinene, guaiane, Oplopane, eudsmane, echin GmbH). Vital colonies were stained with a sterile aqueous odol, C-Santalene, C.-bisabolene, furanodiene, B-Santalene, solution of 2-(4-iodophenyl)-3-(4nitrophenyl)-5-phenyltet B-bergamotene, B-farneSene, B-bisabolene, T-cadinol, razolium chloride (1 mg/ml, 100 ul/well) 24 hours prior to SKB4. evaluation. Drug effect was assessed in terms of percentage 0149. It is thought that multiple components could con of Survival obtained by comparison to the mean number of tribute to the anti-neoplasic components of the extracts. colonies in the treated wells with mean colony count of the However the most active anti-neoplasic components com untreated controls: treated controlsx100 (%T/C). prised the diterpenoids incensole, incensole acetate, incen 0154) A compound was considered active if it reduces the Sole oxide, incenSole oxide acetate, isoincensole, isoincen colony formation to 30% or less of the control group value Sole acetate, isoincensole oxide, and the furanoSesquiterpene (T/C 30%). ICso and IC7o values, representing the drug fumogermecrens in highest concentrations. concentration to inhibit colony formation by 50% (T/C50%) and 70% (T/C 30%) respectively, were determined by plot EXAMPLE 1. ting compound concentration versus T/C values. Mean ICso 0150. In vitro cytotoxic activity of extracts containing and IC7o values were calculated according to the following high concentrations of incenSole, furanogermacren and formula: incensole/furanogermacren mixture were determined in Sev eral cultured tumour cell lines by performing the MTT clonogenic assay. This assay assesses the inhibition of 3 log (C70)x colony formation of tumour Stem cells growing in Soft agar X = 1 by cytotoxic agents. Since tumour Stem cells are responsible N for the proliferate potential and aggressiveness of a tumour cell population, the clonogenic assay is highly predictive of in Vivo response. O155 Mean IC=10 0156 x=specific tumour cell line Drugs and Chemicals 0157 n=total number of cell lines studied 0151. The extracts were dissolved in DMSO/water 1:1, prepared as a 30 mg/ml solution and stored at -20° C. until 0158 If an IDs or IC value could not be determined use. Final dilutions of all drugs were prepared in culture within the examined dose range, the lowest or highest medium immediately prior to use. 5-Flourouracil was used concentration Studies was used for the calculation. An assay as a positive control and purchased from Lederle (Ham was considered valuable if the following criteria were full burg). filled: US 2004/0092583 A1 May 13, 2004 13

0159) 1. Mean number of colonies in the control 0166 The following organisms were tested: group dishes for 24-multiwells contained 20 colonies with colony diameters >50 lum. 0160 2. The positive reference 5-flourouracil (at 1. Staphylococcus aureus NCTC 10442 toxic dose of 1000 tug/ml) must affect colony Sur Staphylococcus aureus NCTC 6571 vival of 30% of controls. Enterococcus feacalis NCTC 775 0.161 Coefficient of variation in the control group <50%> 0162 The extracts were tested in several tumour cell 0.167 MIC values for incensole/furanogermacren mix lines, for their ability to affect tumour growth. The cell lines ture were 100 lug/ml. MIC values for incensole for the above tested included: HT29 colon carcinoma; SF 268 central 3 bacterial Species was 38 tug/ml causing Significant growth nervous system; GXF 251L gastric cancer, LXFE 66NL retardation. epidermoid lung carcinoma, LXFL 529L large cell lung carcinoma; H460 lung adenocarcinoma; LXFF6 529L lung 0168 Pharmaceutically acceptable refers to those prop adenocarcinoma, MCF-7 breast cancer; OVCAR3 ovarian erties and/or Substances, which are acceptable to the patient carcinoma: PG3 prostate carcinoma, DU145 prostate carci from a pharmacological/toxicological point of View includ noma; RXF944L renal call carcinoma, MEXF 514L mela ing bioavailability and patient acceptance or to the manu noma; and MEXF 426NL melanoma. facturing chemist from a physical-chemical point of view 0163 The IC50 results are for in vitro studies are pre regarding composition, formulation, Stability and isolatabil sented in Table 1 below: ity.

ICso um/ml Code Incensole? ICso um/ml Cancer Cell ICso um/ml ICso um/ml Furanogermacren 5 Cancer Cell Line Line Incensole Furanogermacren Mixture Flourouracil

Human Prostate DU145 ND ND S.OO O.O21 Carcinoma Human Prostate PC3 6.OO 7O.OO 1.2 ND Carcinoma Human Colon HT29 7OOO 7O.OO O.9 ND Carcinoma Human Melanoma MEXF 51.4L ND ND O.8 ND Human Melanoma MEXF ND ND 2O.OO ND 429NL Human Lung LXFE 66NL ND ND SO.OO ND Epidermoid Carcinoma Human Lung Large LXFL 529L. ND ND 4.OO ND Cell Carcinoma Human Lung H460 ND ND 2O.OO ND Adenocarcinoma Human Renal RXF944L ND ND 3O.OO ND Carcinoma Human Breast MACL ND ND 7.00 ND Carcinoma MCF7 Gastric Carcinoma GXF 251L, ND ND 8.OO ND Ovarian Cancer OVCL ND ND 1O.OO ND Xenograft OVCAR3 Carcinoma of the CNCL ND ND 1O.OO ND central nervous system SF288 ND = not determined

EXAMPLE 2 0169. The terms “comprise, comprised and comprising” and the terms “include, included and including” are used Antimicrobial Activity interchangeably in this Specification and are to be afforded 0164. These studies were performed to determine the the widest interpretation. minimum inhibitory concentration (MIC) of incensole/fura 0170 The invention is not limited to the embodiments nogermacren mixture. described above, but may be varied in both construction and 0.165 MIC values were determined using a macrodiluton detail within the Scope of the claims. broth procedure based on NCCLS Documents M7-A3 We claim “Methods for dilution anti-microbial susceptibility tests for 1. A composition comprising one or more compound of bacteria that grow aerobically-third edition, approved Stan the present invention, their derivatives, metabolites, ana dard (1993). The lowest test Substance concentration that logues and/or mimic molecules with pharmaceutical accept completely inhibited growth of the test organisms recorded able additives, diluents, carriers, excipients and pharmaceu ac MIC. tical Salts thereof. US 2004/0092583 A1 May 13, 2004

2. The composition as claimed in claim 1, wherein the their derivatives, metabolites, analogues and/or mimic compounds of the present invention are Selected from the molecules with pharmaceutical acceptable additives, group comprising: diluents, carriers and excipient and pharmaceutically acceptable Salts thereof. 3. The composition as claimed in claims 1 or 2, wherein Formula (1) the compounds of the present invention are Selected from the group comprising: incenSole, incenSole acetate, incensole oxide, incenSole oxide acetate, isoincensole, isoincensole acetate, isoincensole oxide, octyl acetate, octanol, terpinyl acetate, bornyl acetate, trans-Ver-benol, Verbenone, mentha dien-7-ol, terpinen-4-ol, trans-pinocarveol, carvone, Formula (2) borneol, farneSol, farneSene, B-caryophyllene, humulene, B-cadinene, bergamotone, B-guaiene, B-ylangene, 3-bour bonene, C-copaene, terpinene, myrcene, p-cyrnene, C- and 3-phellandrene, C-thujene, cembrane-A, isocembrane, cem branol, cembranoids, cembranoid alcohols, furanogermac rens, furanogermacrene, germacrene, elemane, cadinene, guaiane, Oplopane, eudsmane, echinodol, C.-Santalene, C.-bisabolene, furanodiene, B-Santalene, B-bergamotene, B-farnesene, B-bisabolene, SKB4, their derivatives, metabo wherein for formula (1) lites, analogues and/or mimic molecules with pharmaceuti cal acceptable additives, diluents, carriers and excipients and bonds between carbons 9-10, 10-1, 1-2, 2-3.3-4, 4-5, 5-6, pharmaceutically acceptable Salts thereof. can be either Single or double with the proviso that any 4. The composition as claimed in any preceding claims, two or more double bonds are Separated by a Single wherein the compounds of the present invention are Selected bond. from the group comprising at least one of incensole, incen Compounds also include those containing epoxide rings Sole acetate, incensole oxide, incensole oxide acetate, isolin formed between carbons 9-10, 10-1, 1-2, 2-3.3-4, 4-5 censole, isoincenSole acetate, isoincensole oxide, and/or at with the proviso that any two or more epoxide rings are least one of the furanoSesquiterpene fumogermacrens, their Separated by a Single bond. derivatives, metabolites, analogues and/or mimic molecules with pharmaceutical acceptable additives, diluents, carriers wherein for Formula (2) and excipients and pharmaceutically acceptable Salts the carbocyclic ring can have optionally up to 7 endocy thereof. clic/exocyclic double bonds with the proviso that any 5. A pharmaceutical formulation comprising a composi two or more double bonds are Separated by Single tion as claimed in any of claims 1 to 4 and a pharmaceuti bonds; cally acceptable carrier thereof. 6. The pharmaceutical formulation as claimed in claim 5, Carbon atoms for Formula (1) or (2) can be singly or wherein the pharmaceutical carrier is Selected from the multiply Substituted, optionally and independently by: group comprising cyclodextrin, alpha-cyclodextrin, beta an OXO Substituent, H, alkyl, aryl, a heterocyclic radical, cyclodextrin, (beta-hydroxypropylcyclodextrin) gamma-cy halogen, alkoxycarbonyl (C1-C5) or carboxyl, clodextrin and vitamin E oil. hydroxyl, alkoxy (C1-C5), amido, alkyl amido (C1 7. The use of a pharmaceutical formulation for the manu C5), amino, mono and dialkyl amino (C1-C5), alkyl facture of a medicament for treatment of a mammal Suffering carbamoyl (C1-C5), thiol, alkylthio (C1-C5); from a neoplasia comprising a pharmaceutical formulation as claimed in claims 1 to 6. in addition Substituents may form a Spiro ring around the 8. The use of a pharmaceutical formulation as claimed in carbon atom to which they are attached or they can any of the preceding claims, wherein the pharmaceutical form fused or bridged rings to adjacent carbon atoms formulation further includes at least one conventional che which may be Saturated or unsaturated; motherapeutic agent. Substituents on the aryl or heterocyclic radical are 9. The use of a pharmaceutical formulation as claimed in Selected from the group consisting essentially of halo claim 7, wherein the chemotherapeutic agent is Selected gen, alkyl (C1-C5), hydroxyl, alkoxy (C1-C5), alkoxy from the group comprising flutamide and luprolide, anti carbonyl, (C1-C5), carboxyl, amido, alkyl amido (C1 Oestrogens, Such as tamoxifen, antimetabolites and cytotoxic C5), amino, mono and dialkyl amino (C1-C5),alkyl agents, Such as daunorubicin, flourouracil, floxuridine, inter carbamoyl (C1-C5), thiol, alkyl thin (C1-C5) or ben feron alpha, methotrexate, plicamycin, mecaptopurine, Zenoid aryl thio, cyano, nitro, haloalkyl (C1-C5), alkl thioguanine, adramycin, carmustine, lomustine, cytarabine, Sulfonyl (C1-C5), and sulfonate; cyclophosphamide, doxorubicin, estramustine, altretamine, hydroxyurea, ifosfamide, procarbazine, mutamycin, buSul Two of Such Substituents can be part of a fused ring, which fan, mitoxantrone, carboplatin, cisplatin, Streptozooin, bleo can be either Saturated, or unsaturated, heterocyclic or mycin, dactinomycin and idamycin, hormones Such as, carbo cyclic; medroxyprogesterone, estramustine, ethinyl Oestradiol, and natural amino acid Substituents which may be Oestradiol, leuprolide, megestrol, Octreotide, diethylstil attached to the compounds of formula (1) or (2) via an bestrol, chlorotrianisene, etopoSide, podophyllotoxin, and ester linkage to a hydroxyl group; goSerelin, nitrogen mustard derivatives Such as, melphalan, US 2004/0092583 A1 May 13, 2004

chlorambucil, methlorethamine and thiotepa, Steroids Such Vorozole; Zeniplatin; Zinostatin; Zorubicin Hydrochloride, as, betamethaZone, and other antineoplastic agents Such as 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abirater live Mycobacterium bovis, dicarbazine, asparaginase, leu one, aclarubicin; acylfulvene, adecypenol; adoZelesin; covoribn, mitotane, Vincristine, vinblastine and texotere, aldesleukin; ALL-TK antagonists, altretamine; ambamus cyclophosphamide, adriamycin, 5-flourouracil, hexameth tine: amidox, amifostine: aminolevulinic acid; amrubicin; ylmelamine, Acivicin, Aclarubicin; Acodazole Hydrochlo atrSacrine; anagrelide; anastrozole; andrographolide, angio ride, Acronine, Adozelesin, Aldesleukin; Altretamine; genesis inhibitors, antagonist D; antagonist G; DHEA, bro Ambomycin; Ametantrone Acetate; Aminoglutethimide; mineepiandrosterone, epiandrosterone; antarelix; anti Amsacrine; Anastrozole; Anthramycin; Asparaginase; dorselizing morphogenetic protein-1, antiandrogen, ASperlin, AZacitidine, AZptepa: Azotomycin; Batimastat; prostatic carcinoma, antiestrogen; antineoplaston; antisense Benzodepa; Bicalutamide; Bisantrene Hydrochloride; oligonucleotides, aphidicolin glycinate, apoptosis gene Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Bre modulators, apoptosis regulators, apurinic acid, ara-CDP quinar Sodium; Bropirimine; BuSulfan; Cactinomycin; DL-PTBA, arginine deaminase, asulacrine, atameStane; atri Calusterone; Caracemide, Carbetimer; Carboplatin; Car mustine; axinastatin 1; axinastatin 2; axinastatin 3; aza mustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; Setron; azatoxin; azatyrosine; baccatin III derivatives, Chlorambucil; Cirolemycin; Cisplatin; Cladribino; Crisinatol balanol; batimastat; BCR/ABL antagonists; benzochlorins; MeSylate; Cyclophosphamide, Cytarabine; Dacarbazine; benzoylstauroSporine; beta lactam derivatives, beta Dactinomycin; Daunorubicin Hydrochloride; Decitabine; alethine; betaclamycin B; betulinic acid; bFGF inhibitor; DeXormaplatin, DeZaguanine, DeZaguanine MeSylate; bicalutamide, bisantrene, bisaZiridinylspermine; bisnafide; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydro bistratene A, bizelesin; breflate; bropirimine; budotitane; chloride; Droloxifene; Droloxifene Citrate; Dromostanolone buthionine Sulfoximine, calcipotriol, calphostin C; camp Propionate; Duazomycin, Edatrexate, Eflomithine Hydro tothecin derivatives, canarypox IL-2, capedtabine; carboxa chloride; Elsamitrucin; Enloplatin, Enpromate; Epipropi mide-amino-triazole: carboxyamidotriazole; CaRest M3; dine, Epirubicin Hydrochloride; Erbulozole; Esorubicin CARN 700; cartilage derived inhibitor; carzelesin; casein Hydrochloride; Estramustine; Estramustine Phosphate kinase inhibitors (ICOS), castanospermine; cecropin B; Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide; Eto cetrorelix; chlorins, chloroquinoxaline Sulfonamide, cica poside Phosphate; Etoprine; Fadrozole Hydrochloride; Faz prost, cis-porphyrin, cladribine; clomifene analogues, clot arabine; Fenretinide: Floxuridine; Fludarabine Phosphate; rimazole; collismycin A, collismycin B; combretastatin A4, Fluorouracil; Flurocitabine; Fosquidone; Fostriecin Sodium; combretastatin analogue, conagenin, crambescidin 816; cri Gemcitabine; Gemcitabine Hydrochloride; Gold Au 198; Snatol, cryptophycin 8, cryptophycin A derivatives, curacin Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmo A., cyclopentanthraquinones, cycloplatam, cypemycin; cyt fosine; Interferon Alfa-2a, Interferon Alfa-2b; Interferon arabine ocfoSfate; cytolytic factor; cytostatin, dacliximab, Alfa-n1; Interferon Alfa-n3; Interferon Beta-Ia; Interferon decitabine; dehydrodidemnin B; deslorelin; dexifosfamide; Gamma-Ib, Iproplatin; Irinotecan Hydrochloride; Lan deXrmzoxane, deXVerapamil, diaziquorie, didemnin 13; reotide Acetate; Letrozole; Leuprolide Acetate; Liarozole didox; diethylnorspermine, dihydro-5-azacytidine: dihydro Hydrochloride; Lometrexol Sodium; Lomustine; LoSox taxol, 9-, dioxamycin; diphenyl Spiromustine, docosanol; antrone Hydrochloride; Masoprocol; Maytansine; Mechlo dolasetron, doxifluridine, droloxifene, dronabinol; duocan rethamine Hydrochloride; Megestrol Acetate; Melengestrol nycin SA, ebSelen; ecorustine, edelfosine, edrocolomab, Acetate; Melphalan; Menogaril; Mercaptopurine; Methotr eflornithine, elemene; emitefur, epirubicin, epristeride; exate; Methotrexate Sodium; Metoprine; Meturedepa; Mit estramustine analogue, estrogen agonists, estrogen antago indomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; nists; etanidazole; etoposide phosphate; exemestane, fadro Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochlo Zole; faZarabine; fenretinide; fligrastim; finasteride; fla ride, Mycophenolic Acid, Nocodazole: Nogalamycin; vopiridol; fleZelastine; fluiasterone, fludarabine; Ormaplatin; OXisuran; Paclitaxel, Pegaspargase, Peliomy fluorodaunorunicin hydrochloride; forfenimex, formeStane; cin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipo fostriecin, fotemustine, gadolinium teXaphyrin, gallium broman; Piposulfan; Piroxantrone Hydrochloride; Plicamy nitrate; galocitabine; ganirelix, gelatinase inhibitors: gem cin; Plomestane; Porfimer Sodium; Porfiromycin; citabine, glutathione inhibitors, hepSulfam; heregulin; heX Prednimustine; Procarbazine Hydrochloride; Puromycin; amethylene bisacetamide, hypericin; ibandronic acid, ida Puromycin Hydrochloride; Pyrazofurin; Riboprine; rubicin; idoxifene, idramantone, ilmofoSine, illomastat; Rogletimide; Safrngol; Safingol Hydrochloride; Semustine; imidazoacridones, imiquimod; immunostimulant peptides: SimtraZene, Sparfosate Sodium; SparSomycin; Spirogerma insulin-like growth factor-1 receptor inhibitor, interferon nium Hydrochloride; Spiromustine; Spiroplatin; Streptoni agonists, interferons, interleukins, iobenguane; iododoxoru grin; Streptozocin; Strontium Chloride Sr 89; Sulofenur; bicin; ipomeanol, 4-, irinolecan; iroplact, irSogladine, Talisomycin; Taxane, Taxoid; Tecogalan Sodium, Tegafur, isobengaZole, isohomohalicondrin B; itasetron, jasplakino Teloxantrone Hydrochloride; Temoporfin; Teniposide; lide; kahalalide F, lamellarin-N triacetate; lanreotide; leina Teroxirone; Testolactone; Thiamiprine; Thioguanine; mycin; lenograstim; lentinan Sulfate, leptolstatin; letrozole; Thiotepa; Tiazofurin, Tirapazamine; Topotecan Hydrochlo leukemia inhibiting factor; leukocyte alpha interferon; leu ride; Toremifene Citrate; Trestolone Acetate; Triciribine prolide--estrogen-progesterone; leuprorelin; levamisole; Phosphate: Trimetrexate; Trimetrexate Glucuronate; Trip liarozole; linear polyamine analogue, lipophilic disaccharide torelin; Tubulozole Hydrochloride; Uracil Mustard; peptide; lipophilic platinum compounds, lisSoclinamide 7; Urodepa; Vapreotide; Verleporfin; Vinblastine Sulfate; Vin lobaplatin, lombricine, lometrexol; lonidamine; loSOX cristine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine antrone; lovastatin; loxoribine; lurtotecan; lutetlum texaphy Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorel rin; lySofylline; lytic peptides, maitansine; mannostatin A, bine Tartrate; Vinrosidine Sulfate; Vinzolidine Sulfate; marimastat; masoprocol; maspin; matrilysin inhibitors, US 2004/0092583 A1 May 13, 2004 matrix metalloproteinase inhibitors, menogaril; merbarone; variolin B; vector System, erythrocyte gene therapy; meterelin; methioninase; metoclopramide; MIF inhibitor; VelareSol, Venom, anti-Venom, Veramine, Verdins, vertepor mifepristone, miltefosine, mirimoStim; mismatched double fin; Vinorelbine, VinXaltine, Vitaxin; Vorozole; Zanoterone; Stranded RNA, mitoguaZone, mitolactol, mitomycin ana Zeniplatin, Zilascorb, Zinostatin stimalamer, immunostimu logues, mitonafide; mitotoxin fibroblast growth factor-sa lating drugs or therapeutic agents, their metabolites, Salts porin, mitoxantrone; mofarotene; molgramoStim; mono and derivatives thereof. clonal antibody, human chorionic gonadotrophin: 10. The use of a pharmaceutical formulation as claimed in monophosphoryl lipid A+myobacterium cell wall Sk, mopi claims 7 to 9, wherein the pharmaceutical formulation is damol, multiple drug resistance genie inhibitor, multiple administered in combination with radiation treatment. tumor SuppreSSor 1-based therapy; mustard anticancer 11. The use of a pharmaceutical formulation as claimed in agent, mycaperoxide B; mycobacterial cell wall extract; claims 7 to 10, wherein the pharmaceutical formulation is myriaporone, N-acetyldinaline: N-Substituted benzamides, administered in combination with Surgery. nafarelin; nagreStip; naloxone-pentazocine, napavin; naph 12. The use of a pharmaceutical formulation as claimed in terpin, nartograstim; nedaplatin; memorubicin; neridronic claims 7 to 11, wherein the neoplasia is a precancerous acid; neutral endopeptidase, nilutamide, niSamycin; nitric lesion including Syndromes represented by abnormal neo oxide modulators, nitroxide antioxidant; nitrullyn; O6-ben plastic and/or dysplastic, changes of tissue comprising pre Zylguanine; Octreotide, okicenone, oligonucleotides, cancerous growths in colonic, breast, renal, central nervous, onapristone: Ondansetron, Ondansetron; oracin, oral cytok gastric, or lung tissues, or conditions Such as dysplastic ine inducer; Ormaplatin, OSaterone; oxaliplatin, oxaunomy nevus Syndrome, a precursor to malignant melanoma of the cin, paclitaxel analogues, paclitaxel derivatives, palaua skin, dysplastic nevus Syndromes, polyposis Syndromes, mine; palmitoylrizoxin; pamidronic acid; panaxytriol; colonic polyps, precancerous lesions of the cervix (i.e., panomifene, parabactin; paZelliptine: pegaspargase; cervical dysplasia), prostatic dysplasia, bronchial dysplasia, peldesline: pentosan polysulfate Sodium; pentostatin; pentro breast, bladder and/or skin and related conditions (e.g., Zole, perflubron; perfosfamide, perillyl alcohol; phenazino actinic keratosis), whether the lesions are clinically identi mycin; phenylacetate; phosphatase inhibitors, picibanil; fiable or not. pilocarpine hydrochloride, pirarubicin; piritrexim; placetin 13. The use of a pharmaceutical formulation as claimed in A, placetin B; plasminogen activator inhibitor, platinum claims 7 to 12, wherein the neoplasia is prostate cancer, complex, platinum compounds, platinum-triamine complex; colon cancer, Small cell lung cancer, large cell lung cancer, porfimer Sodium; porfiromycin; propyl bis-acridone, proS lung adenocarcinoma, epidermoid lung cancer, melanoma taglandin J2, proteasome inhibitors, protein A-based (including amelanotic Subtypes), renal cell carcinoma, gas immune modulator, protein kinase C inhibitor, protein tric carcinoma, cancers of the central nervous System includ kinase C inhibitors, microalgal; protein tyrosine phosphatase ing brain tumours, neuroblastomas, gastric carcinoma, inhibitors, purine nucleoside phosphorylase inhibitors, pur breast cancer, ovarian cancer, testicular cancer, lymphoma purins, pyrazoloacridine, pyridoxylated hemoglobin poly and leukaemia, oesophageal cancer, Stomach cancer, liver oxyethylene conjugate, raf antagonists, raltitrexed; ramo cancers, prostate cancer, cervical cancer, adrenal cancer, oral Setron; ras farnesyl protein transferase inhibitors, ras or mucosal cancer, bladder cancer, pancreatic cancer, lym inhibitors: ras-GAP inhibitor; retelliptine demethylated; rhe phoma, Hodgkins disease, Sarcomas, Hematopoeitic cell nium Re 186 etidronate; rhizoxin; ribozymes; RII retina cancerS Such as B cell leukaemia/lymphomas, myelomas, mide, rogletimide; rohitumine; romurtide, roquinimex, T-cell leukemias/lymphomas, Small cell leukemias/lympho rubiginone B1; ruboxyl; Safingol; Saintopin: SarCNU; sar mas, null cell, Sezary, monocytic, myelomonocytic and cophytol A, SargramoStim; Sidi 1 mimetics, Semustine; Hairy cell leukemias. Senescence derived inhibitor 1; Sense oligonucleotides, Sig 14. The use of a pharmaceutical formulation as claimed in nal transduction inhibitors, Signal transduction modulators, claims 7 to 13, wherein the neoplasia is in the form of a Single chain antigen binding protein; Sizofiran; Sobu Zoxane, tumour comprising an epidermoid and myeloid tumour, Sodium borocaptate, Sodium phenylacetate, Solverol; acute or chronic, nonsmall cell, Squamous or Solid. Somatomedin binding protein; Sonermin; Sparfosic acid; 15. The use of a pharmaceutical formulation as claimed in Splicamycin D; Spiromustine: Splenopentin; Spongistatin 1; claims 7 to 14, wherein the composition is micronized. Squalamine; Stem cell inhibitor, Stem-cell division inhibi tors, stipiamide, Stromelysin inhibitors, Sulfmosine, Super 16. The use of a pharmaceutical formulation as claimed in active vasoactive intestinal peptide antagonist, Suradista; claims 7 to 15, wherein the pharmaceutical formulation has Suramin; Swainsonine, Synthetic glycosaminoglycans, talli an enteric coating. mustine; tamoxifen methiodide, tauromustine, tazaroteine; 17. The use of a pharmaceutical formulation as claimed in tecogalan Sodium, tegafur, tellurapyrylium; telomerase claim 16, wherein the enteric coating is made of a polymer inhibitors, telnoporfin, ternozolomide; teniposide, tetrachlo or copolymer. rodecaoxide, tetraZomine; thallblastine; thalidomide; thio 18. The use of a pharmaceutical formulation as claimed in coraline; thrombopoietin; thrombopoietin mimetic; thymal claim 17, wherein the polymer or copolymer is Selected from fasin; thymopoietin receptor agonist; thymotrinan; thyroid the group consisting of poly(lactic-glycolic acid) polyester, Stimulating hormone, tin ethyl otiopurpurin; tirapazamine; cellulose acetate phthalate, hydroxypropyl-methyl cellulose titanocene dichloride; topotecan; topSentin; toremifene, toti phthalate poly(butyl methacrylate), (2-dimethylaminoethyl) potent Stem cell factor; translation inhibitors, tretinoin, methacrylate, and methyl methacrylate. triacetyluridine, triciribine, trimetrexate, triptorelin: tro 19. The use of a pharmaceutical formulation as claimed in pisetron; turosteride, tyrosine kinase inhibitors, tyrphoStins, claims 7 to 18, wherein, the pharmaceutical formulation is UBC inhibitors; ubenimex; urogenital sinus-derived growth administered enterally, parenterally, topically, orally, Sub inhibitory factor; urokinase receptor antagonists; vapreotide; lingually, rectally, nasally or vaginally. US 2004/0092583 A1 May 13, 2004

20. The use of a pharmaceutical formulation as claimed in arthritis, asthma, and diabetes (h) adriamycin treatment, claims 7 to 19, wherein the composition is formulated into cisplatin treatment, mitomycin C treatment, amphoteracin B liposomes or carbohydrate vehicles. treatment; (i) a gamma-radiation treatment; (ii) nucleoside 21. The use of a pharmaceutical formulation as claimed in analog treatment for viral infection or for cancer, (k) Surgical claim 20, wherein the liposomes or carbohydrate vehicles and accidental wounds, Septic shock caused by Surgery; (1) are specifically targeted to tumours by covalently attaching cyclosporin treatment and corticosteroid treatment; (m) irri a monoclonal antibody directed to a tumour-associated table bowel treatment, Crohn's disease, wasting Syndrome, antigen. cachexia, Motor Neuron disease, Multiple Sclerosis, inflam 22. The use of a pharmaceutical formulation as claimed in matory bowel disease, respiratory distreSS Syndrome, claims 7 to 21, wherein the pharmaceutical formulation is chronic diarrhoea, (n) cancer, (o) cirrhoisis; (p) gram posi administered intermittently. tive multi-drug resistant bacteria or (q) any combination of 23. The use of a pharmaceutical formulation as claimed in (a) through (p). claims 7 to 22, wherein the pharmaceutical formulation is a 29. The use of a pharmaceutical formulation as claimed in unit dose that comprises 5-500 mg of active ingredient claim 28, wherein the DNA virus infection or the RNA virus consisting of at least one compound of the present invention. infection is Selected from a retrovirus infection, a togavirus 24. The use of a pharmaceutical formulation as claimed in infection, a flavivirus infection, a rubivirus infection, a claims 7 to 23, wherein the pharmaceutical formulation is pestivirus infection, a lipia envelope virus infection, a filovi administered to a mammal. rus, a picornavirus infection, a rhinovirus infection, a coro 25. The use of a pharmaceutical formulation as claimed in navirus infection, a respiratory Syncytial virus infection, a claim 24, wherein Said mammal is a neonate and Said poliovirus infection, a parainfluenza virus infection, influ administering is effected prior to delivery of Said neonate enza virus infection, hantavirus, adeno-associated virus, and/or during delivery of Said neonate. measles virus, poxvirus, filovirus, human papilloma virus 26. The use of a pharmaceutical formulation as claimed in and animal papilloma virus infection. claims 7 to 25, wherein Said compounds of the present 30. The use of a pharmaceutical formulation as claimed in invention acts as a prodrug. claims 27 to 29, wherein the composition further includes at 27. The use of a pharmaceutical formulation for the least one conventional chemotherapeutic agent. manufacture of a medicament for treatment of a mammal 31. The pharmaceutical formulation as claimed in claim Suffering from an immunodysregulatory condition compris 30, wherein the chemotherapeutic agent is Selected from the ing a composition as claimed in claims 1 to 6, to a Subject. group comprising flutamide and luprolide, antioestrogens, 28. The use of a pharmaceutical formulation as claimed in Such as tamoxifen, antimetabolites and cytotoxic agents, claim 27, wherein the immunodysregulation condition is Such as daunorubicin, flourouracil, floXuridine, interferon caused by a viral infection, intracellular bacterial infection, alpha, methotrexate, plicamycin, mecaptopurine, thiogua extracellular bacterial infection, fungal infection, yeast nine, adramycin, carmustine, lomustine, cytarabine, cyclo infection, extracellular parasite infection, intracellular para phosphamide, doxorubicin, estramustine, altretamine, Site infection, protozoan parasite, multicellular parasite, hydroxyurea, ifosfamide, procarbazine, mutamycin, buSul autoimmune disease, immunosuppressive therapy, chemo fan, mitoxantrone, carboplatin, cisplatin, Streptozocin, bleo therapy, anti-infective agent therapy, wound, burn, the pres mycin, dactinomycin and idamycin, hormones Such as, ence of an immunosuppressive molecule, gastrointestinal medroxyprogesterone, estramustine, ethinyl Oestradiol, irritation or any combination of the foregoing is Selected Oestradiol, leuprolide, megestrol, Octreotide, diethylstil from (a) a DNA virus infection oran RNA virus(b) a parasite bestrol, chlorotrianisene, etopoSide, podophyllotoxin, and infection, a TrypanoSoma, Plasmodium, Cryptosporidium, goSerelin, nitrogen mustard derivatives Such as, melphalan, Entamoeba, Balantidium, Leishmania, Pneumocystis, Tri chlorambucil, methlorethamine and thiotepa, Steroids Such chomoniasis or Toxoplasma Infection, wherein the Trypa as, betamethasone, and other antineoplastic agents Such as noSoma, Plasmodium, Cryptosporidium, Entamoeba, Balan live Mycobacterium bovis, dicarbazine, asparaginase, lau tidium, Leishmania, Pneumocystis, Trichomoniasis or covoribn, mitotone, Vincristine, vinblastine and texotere, Toxoplasma infection is selected from but not limited to cyclophosphamide, adriamycin, 5-flourouracil, hexameth TrypOnoSoma Cruzi, TrypOnoSoma brucei, TrypanoSOma ylmelamine, Acivicin, Aclarubicin; Acodazole Hydrochlo gambiense, Trypanosoma rhodesiense, Plasmodium falci ride, Acronine, Adozelesin; Aldesleukin; Altretamine; parum, Plasmodium vivax, Plasmodium malariae, Plasmo Ambomycin; Ametantrone Acetate; Aminoglutethimide; dium ovale, Plasmodium berghei, Entamoeba histolytica, Amsacrine; Anastrozole, Anthramycin; Asparaginase; Balantidium coli, Leishmania brazillenis, Leishmania mexi ASperlin, AZacitidine, AZetepa, AZOtomycin; Batimastat; cana, Leishmania donovani, Leishmania tropica, Pneu Benzodepa; Bicalutamide; Bisantrene Hydrochloride; mocystis carinii, Trichomoniasis vaginalis, and Toxoplasma Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Bre gondii (c) a mycoplasma infection, a Listeria infection or a quinar Sodium; Bropirimine; BuSulfan; Cactinomycin; Mycobacterium infection; (d) a Streptococcus infection, a Calusterone; Caracemide, Carbetimer; Carboplatin; Car StaphylococcuS infection, a Vibrio infection, a Salmonella mustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; infection; a Shigella infection, an enterotoxigenic, entero Chlorambucil; Cirolemycin; Cisplatin; Cladribine; Crisnatol pathogenic, enteroinvasive or enterohemorrhagic E. coli MeSylate; Cyclophosphamide, Cytarabine; Dacarbazine; infection, a Yersinia infection, a Campylobacter infection, a Dactinomycin; Daunonibicin Hydrochloride; Decitabine; Pseudomonas infection, a Borrelia infection, a Legionella DeXormaplatin, DeZaguanine, DeZaguanine MeSylate; infection and a Haemophilus infection; (e) pulmonary Diaziquone; Docetaxol; Doxorubicin; Doxorubicin Hydro Aspergillosis, mucosal or oropharyngealcandidiasis and chloride; Droloxifene; Droloxifene Citrate; Dromostanolone juvenile paracoccidiomyosis, (f) a Candida infection and a Propionate; Duazomycin; Edatrexate, Eflomithine Hydro Cryptococcus infection; (g) Systemic lupus erythematosis, chloride; Elsamitrucin; Enloplatin, Enpromate; Epipropi US 2004/0092583 A1 May 13, 2004

dine; Epirubicin Hydrochloride; Erbulozole; Esorubicin derived inhibitor; carZelesin; casein kinase inhibitors Hydrochloride; Estramustine; Estramustine Phosphate (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide; Eto chloroquinoxaline Sulfonamide, cicaprost, cis-porphyrin, poside Phosphate; Etoprine; Fadrozole Hydrochloride; Faz cladribine; clomifene analogues, clotrimazole; collismycin arabine; Fenretinide; Floxuridine: Fludirabine Phosphate; A, collismycin B; combretastatin A4, combretastatin ana Fluouracil; Flurocitabine; Fosquidone; Fostriecin Sodium; logue; conagenin, crambescidin 816; crisinatol; cryptophycin Gemcitabine; Gemcitabine Hydrochloride; Gold Au 198; 8, cryptophydin A derivatives, curacin A, cyclopentan Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmo thraquinones, cycloplatam, cypemycin; cytarabine ocfos fosine; Interferon Alfa-2a, Interferon Alfa-2b; Interferon fate; cytolytic factor; cytostatin, dacliximab, decitabine; Alfa-n1; Interferon Alfa-n3; Interferon Beta-Ia; Interferon dehydrodidemnin B; deslorelin; doxifosfamide; dexrazox Gamma-Ib, Iproplatin; Irinotecan Hydrochloride; Lan ane; deXVerapamil, diaziquone; didemnin B; didox; dieth reotide Acetate; Letrozole; Leuprolide Acetate; Liarozole ylnorspermine, dihydro-5-azacytidine, dihydrotaxol, 9; Hydrochloride; Lometrexol Sodium; Lomustine; LoSX dioxamycin; diphenyl Spiromustine, docosanol; dolasetron; antrone Hydrochloride; Masoprocol; Maytansine; Mechlo doxifluridine, droloxifene, dronabinol; duocannycin SA; rethamine Hydrochloride; Megestrol Acetate; Melengestrol ebSelen; ecomustine, edelfosine, edrecolomab, eflornithine; Acetate; Melphalan; Menogaril; Mercaptopurine; Methotr elemene; emitefur, epirubicin, epristeride; estramustine ana exate; Methotrexate Sodium; Metoprine; Meturedepa; Mit logue; estrogen agonists, estrogen antagonists; etanidazole; indomide: Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; etoposide phosphate; exemestane, fadrozole; faZarabine; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochlo fenretinide; filgrastim; frnasteride, flavopiridol; fleZelastine; ride, Mycophenolic Acid, Nocodozole; Nogalamycin; fluiasterone; fludarabine; fluorodaunorunicin hydrochloride; Ormaplatin; OXisuran; Paclitaxel, Pegaspargase, Peliomy forfenimex, formeStane; fostriecin, fotemustine, gadolinium cin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipo teXaphyrin, gallium nitrate, galocitabine; ganirelix; gelati broman; Piposulfan; Piroxantrone Hydrochloride; Plicamy nase inhibitors: gemcitabine, glutathione inhibitors, hepSul cin; Plomestane; Porfimer Sodium; Porfiromycin; fam; heregulin; hexamethylene bisacetamide; hypericin; Prednimustine; Procarbazine Hydrochloride; Puromycin; ibandronic acid, idarubicin; idruXifene, idramantone, ilmo Puromycin Hydrochloride; Pyrazofurin; Riboprine; fosine, ilomastat; imidazoacridones, imiquimod, immuno Rogletimide; Safrngol; Safingol Hydrochloride; Semustine; Stimulant peptides; insulin-like growth factor-1 receptor SimtraZene, Sparfosate Sodium; SparSomycin; Spirogerma inhibitor; interferon agonists, interferons, interleukins, nium Hydrochloride; Spiromustine; Spiroplatin; Streptoni iobenquane; iododoxorubicin; ipomeanol, 1-; irinotecan; grin, Streptozocin; Strontium Chloride Sr 89, Sulofenur; iroplact, irSOgladine, isobengaZole, isohomohalicondrin B; Talsomycin; Taxane, Taxoid; Tecogalan Sodium, Tegafur, itasetron, jasplakinolide; kahalalide F, lamellarin-N triac Teloxantrone Hydrochloride; Temoporfin; Teniposide; etate; lanreotide; leinamycin; lenograstim; lentinan Sulfate; Teroxirone; Testolactone: Thiamiprine; Thioguanine; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte Thiotepa; Tiazofurin, Tirapazamine; Topotecan Hydrochlo alpha interferon; leuprolide--estrogen-progesterone; leupro ride; Toremifene Citrate; Trestolone Acetate; Triciribine relin; levamisole; liarozole; linear polyamine analogue, lipo Phosphate; Trimetrexate; Trimetrexate Glucuronate; Trip philic disaccharide peptide; lipophilic platinum compounds, torein; Tubulozole Hydrochloride; Uracil Mustard; Uredepa, lisSoclinamide 7; lobaplatin, lombricine, lometrexol; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine lonidamine, loSOXantrone; lovastatin; loxoribine: lurtotecan; Sulfate; Vindesine; Vindesine Sulfate; Vinapidine Sulfate; lutetium texaphyrin, lySofylline, lytic peptides, maitansine; Vinglycinate Sulfate; Vinieurosine Sulfate; Vinorelbine Tar mannostatin A, marimastat; masoprocol; maspin; matrily Sin trate; Vinrosidine Sulfate; Vinzolidine Sulfate; Vorozole; inhibitors, matrix metalloproteinase inhibitors, menogaril; Zeniplatin; Zinostatin; Zorubicin Hydrochloride, 20-epi-1, merbarone; meterelin; methioninase; metoclopramide, MIF 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; acla Inhibitor, mirfepristone; miltefosine; mirimoStim; mis rubicin; acylfulvene, adecypenol; adozesin; aldesleukin; matched double Stranded RNA, mitoguaZone, mitolactol; ALL-TK antagonists, altretemine; ambamustine, amidox; mitomycin analogues, mitonafide; mitotoxin fibroblast amifostine; aminolevulinic add; amrubicin; atrSacrine; growth factor-Saporin, mitoxantrone; mofarotene; molgra anagrelide; anastraZole, andrographoilde; angiogenesis moStim; monoclonal antibody, human chorionic gonedotro inhibitors, antagonist D; antagonist G; DHEA, bromineepi phin, monophosphoryl lipid A+myobacterium cell wall sk; androsterone, epiandrosterone; antarelix; anti-dorsalizing mopidamol, multiple drug resistance genie inhibitor; mul morphogenetic protein-1, antiandrogen, prostatic carci tiple tumorsuppreSSor 1-based therapy; mustard anticancer noma, antiestrogen; antineoplaston; antisense oligonucle agent, mycaperoxide B; mycobacterial cell wall extract; otides, aphidicolin glycinate, apoptosis gene modulators, myriaporone, N-acetyldinaline, N-Substituted benzamides, apoptosis regulators; apurinic acid: ara-CDP-DL-PTSA; nafarelin; nagreStip; naloxone-pentazocine, napavin; naph arginine deaminase, asulacrine, atameStane; atrimustine; terpin, nartograstim; nedaplatin; memorubicin; neridronic axinastatin 1; axinastatin 2; axinastatin 3; aZasetron; aza acid; neutral endopeptidase, nilutamide, nisamycin; nitric toxin; azatyrosine; baccatin III derivatives, balanol, batim oxide modulators, nitroxide antioxidant, nitrullyn, O6-ben astat, BCR/ABL antagonists, benzochlorins; benzoylstauro Zylguanine; Octreotide, okicenone, oligonucleotides, Sporine: beta lactam derivatives, beta-alethine, betaclamycin onapristone; ondansetron, Ondansetron; oracin, oral cytok B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; ine inducer; Ormaplatin, OSaterone; Oxaliplatin; OXaunomy bisaZiridinylspermine, bisnafide; bistratene A, bizelesin; cin, paclitaxel analogues, paclitaxel derivatives, palaua breflate; bropirimine; budotitane; buthionine sulfoximine; mine; palmitoylrhizoxin; pamidronic acid, panaxytriol; calcipotriol, callphostin C. camptothecin derivatives, canary panomifene, parabactin; paZelliptine, pegaspargase; poX IL-2, capecitabine, carboxamide-amino-triazole; car peldesline, pentosan polysulfate Sodium; pentostatin; pentro boxyamidotriazole; CaRest M3; CARN 700; cartilage Zole, perflubron; perfosfamide; perlilyl alcohol; phenazino US 2004/0092583 A1 May 13, 2004

mycin; phenylacetate; phosphatase inhibitors, picibanil; vir, Didanosine; Disoxaril; Edoxudine; Emivirine; Emtric pilocarpine hydrochloride, pirarubicin; piritrexim; placetin itabine; Enviradene; Enviroxime; Epivir; Famciclovir; A, placetin B; plasminogen activator inhibitor, platinum Famotine Hydrochloride; Fiacitabine; Fialuridine; Fosari complex, platinum compounds, platinum-triamine complex; late; Foscarnet Sodium: Fosfonet Sodium; Ganciclovir, porfimer Sodium; porfiromycin; propyl bis-acridone; proS Ganciclovir Sodium; Idoxuridine, Indinavir; Kethoxal, taglandin J2, proteasome inhibitors, protein-based immune Lamivudine, Lobucavir, Lodenosine, Lopinavir, Memotine modulator, protein kinase C inhibitor; protein kinase C Hydrochloride; Methisazone; Nelfinavir, Nevirapine; Pen inhibitors, microalgal; protein tyrosine phosphitase inhibi ciclovir; Pirodavir; Ribavirin; Rimantadine Hydrochloride; tor, purin nucleoside phosphorylase inhibitors, purpurins, Saquinavir Mesylate; Ritonavir; Somantadine Hydrochlo pyrazoloacridine, pyridoxylated hemoglobin polyoxyethyl ride; Sorivudine; Statolon; Stavudine; Tenofovir; Tilorone ene conjugate, raf antagonists, raltitrexed; ramosetron; ras Hydrochloride; Trifluridine; Valacyclovir Hydrochloride; farnesyl protein transferase inhibitors, ras inhibitors: ras Vidarabine; Vidarabine Phosphate; Vidarabine Sodium GAP inhibitor; retelliptine demethylated; rhenium Re 186 Phosphate; Tipranavir, Viroxime; Zalcitabine; Zidovudine; etidronate, rhizoxin, ribozymes, RII retinamide, rogletim Zinviroxime and Interferon. ide, rohitukine, romurtide, roquinimex, rubiginone B1; 34. The use of a pharmaceutical formulation as claimed in ruboxyl, Safingol, Saintopin; SarCNU; Sarcophytol A, Sar claims 27 to 33, wherein the composition further includes at gramoStim; Sidi 1 mimetics, Semustine, Senescence derived least one anti-parasite agent. inhibitor 1; Sense oligonucleotides, Signal transduction 35. The use of a pharmaceutical formulation as claimed in inhibitors, Signal transduction modulators, Single chain anti claim 34, wherein the anti-parasite agents are Selected from gen binding protein; sizofiran; Sobu ZOxane, Sodium boroc the group comprising chloroquin, primaquine, mefloquine, aptate, Sodium phenylacetate, Solverol, Somatomedin bind pyrimethamine-Sulfadoxone, atoraquone/dapSone; halofan ing protein; Sonermin; Sparfosic acid, Spicamycin D; trine; artemisinin derivatives, atoraquone-proguanol, co Spiromustine, Splenopentin; Spongistatin 1; Squalamine; artemether, podophyllotoxin; pentamidine, diloxanide Stem cell inhibitor, Stem-cell division inhibitors, Stipiamide; furoate; metronidazole, tindazole, tetracycline, quinacrine, Stromelysin inhibitors, Sulfmosine, Superactive vasoactive Stibogluconate, amphotericin B, quinine, doxycline, trime intestinal peptide antagonist, Suradista; Suramin; Swainso nine, Synthetic glycosaminoglycans, tallimustine; tamoxifen thoprim-Sulfamethoxazole, metronidazole, nifurtimox, methiodide, tauromustine, tazaroteine, tecogalan Sodium; Suramin, melarSoprol, benznidazole, their metabolites, Salts tegafur, tellurapyrylium; telomerase inhibitors, temoporfin; derivatives or any other anti-parasitic agent thereof. temozolomide, teniposide, tetrachlorodecaoxide, tetraZom 36. The use of a pharmaceutical formulation as claimed in ine; thaliblastine; thalidomide; thiocoraline; thrombopoi claims 27 to 35, wherein the composition is micronized. etin; thrombopoietin mimetic; thymalfasin; thymopoietin 37. The use of a pharmaceutical formulation as claimed in receptor agonist; thymotrinan; thyroid stimulating hormone; claims 27 to 36, wherein the composition enhances endog tin ethyl etiopurpurin; tirapazamine, titanocene dichloride; enous hsp levels. topotecan; topSentin; toremifene; totipotent Stem cell factor; 38. The use of a pharmaceutical formulation as claimed in translation inhibitors, tretinoin, triacetyluridine, triciribine; claims 27 to 37, wherein the composition enhances endog trimetrexate, triptorelin: tropisetron; turosteride; tyrosine enous precursor dendritic cell levels. kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; 39. The use of a pharmaceutical formulation as claimed in urogenal Sinus-derived growth inhibitory factor; urokinase claims 27 to 38, wherein the pharmaceutical formulation has receptor antagonists, Vapreotide; variolin B; vector System, an enteric coating. erythrocyte gene therapy; VelareSol: Venom, anti-Venom, 40. The use of a pharmaceutical formulation as claimed in Veramine, Verdins, Verteporfin, Vinorelbine; VinXaltine; claim 39, wherein the enteric coating is made of a polymer Vitaxin; Vorozole; Zanoterone; Zeniplatin, Zilascorb, Zinosta or copolymer. tin Stimalamer, immunostimulating drugs or therapeutic 41. The use of a pharmaceutical formulation as claimed in agents, their metabolites, Salts and derivatives thereof. claim 40 wherein the polymer or copolymer is Selected from 32. The use of a pharmaceutical formulation as claimed in the group consisting of poly(lactic-glycolic acid) polyester, claims 27 to 31, wherein the composition further includes at cellulose acetate phthalate, hydroxypropyl-methyl cellulose least one anti-Viral agent. phthalate poly(butyl methacrylate), (2-dimethylaminoethyl) 33. The use of a pharmaceutical formulation as claimed in methacrylate, and methyl methacrylate. claim 32, wherein the anti-Viral agents are Selected from the 42. The use of a pharmaceutical formulation as claimed in group comprising nucleoside analogues (AZT, ddC, ddl; claims 27 to 41, wherein the pharmaceutical formulation is d4T, 3TC; BW 1592; PMEA/bis-POM PMEA; dOTC; administered enterally, parenterally, topically, orally, rec DAPD); non-nucleoside reverse transcriptase inhibitor tally, nasally or vaginally. (delavirdine; DMP 266; HBY097; loviride; nevirapine, emivirine; AG1549; PNU142721; Calanolide A: DPC961); 43. The use of a pharmaceutical formulation as claimed in protease inhibitors (ABT-378; ritonavir; nelfinavir; BW 141; claims 27 to 42, wherein the composition is formulated into KNI-272; indinavir; sacquinavir; L-756,423; DMP-450: liposomes or carbohydrate vehicles. BMS-2326;30); ALX40-4C; hydroxyurea; lobucavir, pen 44. The use of a pharmaceutical formulation as claimed in tafuside; T-1249; PRO 542: FP-21399; AMD 3100; claim 43, wherein the liposomes or carbohydrate vehicles HE-2000 and pepude T; Abacavir, Acemannan; Acyclovir; are targeted to HIV infected cells by putting viral antibodies Acyclovir Sodium; Adefovir; Alovudine; Alvircept Sudotox; on its Surface. Amantadine Hydrochloride; Aranotin; Arildone, AteVirdine 45. The use of a pharmaceutical formulation as claimed in Mesylate; Avridine; Cidofovir, Cipamfylline; Coviracil; claim 44, wherein the viral antibodies are directed to the Cytarabine Hydrochloride; Delavirdine Mesylate; Desciclo HIV coat protein gp160 and/or gp120. US 2004/0092583 A1 May 13, 2004 20

46. The use of a pharmaceutical formulation as claimed in Fluorouracil; Flurocitabine; Fosquidone; Fostriecin Sodium; claims 27 to 45, wherein the pharmaceutical formulation is Gemcitabine; Gemcitabine Hydrochloride; Gold Au 198; administered intermittently. Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmo 47. The use of a pharmaceutical formulation as claimed in fosine; Interferon Alfa-2a, Interferon Alfa-2b; Interferon claims 27 to 46, wherein the pharmaceutical formulation is Alfa-n1; Interferon Alfa-n3; Interferon Beta-Ia; Interferon administered to a mammal. Gamma-Ib, Iproplatin; Irinotecan Hydrochloride; Lan 48. The use of a pharmaceutical formulation as claimed in reotide Acetate; Letrozole; Leuprolide Acetate; Liarozole claim 47, wherein Said mammal is a neonate and Said Hydrochloride; Lometrexol Sodium; Lomustine; LoSox administering is effected prior to delivery of Said neonate antrone Hydrochloride; Masoprocol; Maytansine; Mechlo and/or during delivery of Said neonate. rethamine Hydrochloride; Megestrol Acetate; Melengestrol 49. The use of a pharmaceutical formulation as claimed in Acetate; Melphalan; Menogaril; Mercaptopurine; Methotr claims 27 to 48, wherein Said compounds of the present exate; Methotrexate Sodium; Metoprine; Meturedepa; Mit invention acts as a prodrug. indomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; 50. The use of a pharmaceutical formulation for the Mitomycin; Mitosper; Mitotane: Mitoxantrone Hydrochlo manufacture of a medicament for Sensitising a resistant ride, Mycophenolic Acid, Nocodazole; Nogalamycin; neoplasia to Subsequent therapy comprising administering to Ormaplatin; Oxisuran; Paclitaxel, Pegaspargase, Peliomy a patient in need thereof a therapeutically effective amount cin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipo of composition as claimed in claims 1 to 6. broman; Piposulfan; Piroxantrone Hydrochloride; Plicamy 51. The use of a pharmaceutical formulation as claimed in cin; Plomestane; Porfimer Sodium; Porfiromycin; claim 50, wherein the pharmaceutical formulation further Prednimustine; Procarbazine Hydrochloride; Puromycin; includes at least one conventional chemotherapeutic agent. Puromycin Hydrochloride: Pyrazofurin: Riboprine; 52. The use of a pharmaceutical formulation as claimed in Rogletimide; Safingol; Safingol Hydrochloride; Semustine; claim 51, wherein the chemotherapeutic agent is Selected SimtraZene, Sparfosate Sodium; SparSomycin; Spirogerma from the group comprising flutamide and luprolide, anties nium Hydrochloride; Spiromustine; Spiroplatin; Streptoni trogens, Such as tamoxifen, antimetabolites and cytotoxic grin; Streptozocin; Strontium Chloride Sr 89; Sulofenur; agents, Such as daunorubicin, flourouracil, floxuridine, inter Talisomycin; Taxane, Taxoid; Tecogalan Sodium, Tegafur, feron alpha, methotrexate, plicamycin, mecaptopurine, Teloxantrone Hydrochloride; Temoporfin; Teniposide; thioguanine, adramycin, carmustine, lomustine, cytarabine, Teroxirono, Testolactone; Thiamiprine; Thioguanine; cyclophosphamide, doxorubicin, estramustine, altretamine, Thiotepa; Tiazofurin; Tirapazamine; Topotecan Hydrochlo hydroxyurea, ifosfamide, procarbazine, mutamycin, buSul ride; Toremifene Citrate; Trestolone Acetate, Triciribine fan, mitoxantrone, carboplatin, cisplatin, Streptozocin, bleo Phosphate; Trimetrexate; Trimetrexate Glucuronate; Trip mycin, dactinomycin and idamycin, hormones Such as, torelin; Tubulozole Hydrochloride; Uracil Mustard; Ure medroxyprogesterone, estramustine, ethinyl Oestradiol, depa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincris Oestradiol, leuprolide, megestrol, Octreotide, diethylstil tine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine bestrol, chlorotrianisene, etopoSide, podophyllotoxin, and Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorel goserelin, nitrogen mustard derivatives Such as, melphalan, bine Tartrate; Vinrosidine Sulfate; Vinzolidine Sulfate; chlorambucil, methlorethamine and thiotepa, Steroids Such Vorozole; Zeniplatin; Zinostatin; Zorubicin Hydrochloride, as, betamethasone, and other antineoplastic agents Such as 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abirater live Mycobacterium bovis, dicarbazine, asparaginase, leu one, aclarubicin; acylfulvene, adecypenol; adoZelesin; covoribn, mitotane, Vincristine, vinblastine and texotere, aldesleukin; ALL-TK antagonists, altretamine; ambamus cydophosphamide, adriamycin, 5-flourouracil, hexameth tine; amidox, amifostine; aminolevulinic acid; amrubicin; ylmelamine, Acivicin, Aclarubicin; Acodazole Hydrochlo atrSacrine; anagrelide; anastrozole; andrographolide, angio ride, Acronine, AdoZolesin, Aldesloukin; Altretamine; genesis inhibitors, antagonist D; antagonist G; DHEA, bro Ambomycin; Ametantrone Acetate; Aminogluthimide; mineepiandrosterone, epiandrosterone; antarelix; anti-dor Amsacrine; Anastrozole; Anthramycin; Asparaginase; Salizing morphogenetic protein-1, antiandrogen, prostatic ASperlin, AZacitidine, AZetepa, AZOtomycin; Batimastat; carcinoma: antiestrogen; antineoplaston; antisense oligo Benzodepa; Bicalutamide; Bisantrene Hydrochloride; nucleotides, aphidicolin glycinate, apoptosis gene modula Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Bre tors, apoptosis regulators, apurinic acid, ara-CDP-DL quinar Sodium; Bropirimine; BuSulfan; Cactinomycin; PTSA, arginine deaminase, asulacrine; atameStane; Calusterone; Caracemide, Carbetimer; Carboplatin; Car atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; aza mustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; Setron; azatoxin; azatyrosine, baccatin III derivatives, bal Chlorambucil; Cirolemycin; Cisplatin; Cladribine; Crisinatol anol; batimastat, BCR/ABL antagonists; benzochlorins: MeSylate; Cyclophosphamide, Cytarabine; Dacarbazine; benzoylstaurSporine, beta lactam derivatives, beta-alethine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine; betaclamycin B; betulinic acid; bFGF inhibitor, bicaluta DeXormaplatin, DeZaguanine, DeZaguanine MeSylate; mide; bisantrene, bisaZindinylspermine; bisnafide; bis Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydro tratene A, bizelesin; breflate; bropirimine; budotitane; chloride; Droloxifene; Droloxifene Citrate; Dromostanolone buthionine Sulfoximine, calcipotriol, calphostin C; camp Propionate; Duazomyrin; Edatrexate; Eflomithine Hydro tothecin derivatives, canarypox IL-2, capecitabine, carboxa chloride; Elsamitrucin; Enloplatin, Enprorfate; Epipropi mide-amino-triazole; carboxyamidotriazole; CaRest M3; dine; Epirubicin Hydrochloride; Erbulozole; Esorubicin CARN 700; cartilage derived inhibitor; carzelesin; casein Hydrochloride; Estramustine; Estramustine Phosphate kinase inhibitors (ICOS), castanospermine: cecropin B; Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide; Eto cetrorelix; chlorins, chloroquinoxaline Sulfonamide, cica poside Phosphate; Etoprine; Fadrozole Hydrochloride; Faz prost, cis-porphyrin, cladribine; clomifene analogues, clot arabine; Fenretinide; Floxuridine; Fludarabine Phosphate; rimazole; collismycin A, collismycin B; combretastatin A4, US 2004/0092583 A1 May 13, 2004 combretastatin analogue; conagenin, crambescidin 816; cri propyl bis-acridone; prostaglandin J2, proteasome inhibi Snatol; cryptophycin 8; cryptophycin A derivatives, curacin tors, protein A-based immune modulator, protein kinase C A., cyclopentanthrequinones, cycloplatam, cypemycin; cyt inhibitor; protein kinase C inhibitors, microalgal; protein arabine ocfosfate, cytolytic factor; cytostatin, dacliximab, tyrosine phosphatase inhibitors, purino mucleoside phos decitabine; dehydrodidemnin B; deslorelin; dexifostamide; phorylast inhibitors, purpurins, pyrazoloacridine, pyridoxy deXraZoxane, deXVerapamil, diaziquone; didemnin B; didox; lated hemoglobin polyoxyethylene conjugate, raf antago diethylnorspermine, dihydro-5-aZacytidine, dihydrotaxol, nists, raltitrexed; ramosetron; ras farnesyl protein 9-: dioxamycin; diphenyl Spiromustine, docosanol; dolas transferase inhibitors: ras inhibitor,: ras-GAP inhibitor, retal liptine demethylated; rhenium Re186 etidronate; rhizoxin; etron, doxifluridine, droloxifene, dronabinol; duocannycin ribozymes, RII retinamide, rogletimide, rohitukine; SA, ebSelen; ecomustine, edelfosine; edrecolomab, eflorni romurtide, roquinimex, rubiginone B1, ruboxyl, Safingol; thine; elemene; emitefur, epirubicin, epristeride; estramus Saintopin; SarCNU; Sarcophytol A, SargramoStim, Sdi 1. tine analogue; estrogen agonists, estrogen antagonists; mimetics, Semustine, Senescence derived inhibitor 1; Sense etanidazole, etoposide phosphate; exemestane: fadrozole; oligonucleotides, Signal transduction inhibitors, Signal trans faZarbine, fenretinido, filgrastim; frnasteride; flavopiridol; duction modulators, Single chain antigen binding protein; fleZelastine, fluiasterone, fludarabine; fluorodaunorunicin sizofiran; Sobuzoxane, Sodium borocaptate, Sodium pheny hydrochloride; torfenimex, formeStane; fostriecin, fotemus lacetate, Solverol, Somatomedin binding protein; Sonermin; tine, gadolinium teXaphyrin, gallium nitrate, galocitabine: Sparfosic acid; Spicamycin D; Spiromustine; Splenopentin; ganirelix; gelatinase inhibitors, gemcitabine, glutathione Spongistatin 1; Squalamine; Stem cell inhibitor, Stem-cell inhibitors, hepSulfam; heregulin; hexamethylene bisaceta division inhibitors; stipiamide; stromelysin inhibitors; Sulf mide; hypericin; ibandronic acid; idarubicin; idoxifene, monine, Superactive vasoactive intestinal peptide antago idramantone, ilmofoSine, illomastat; imidazoacridones, imi nist, Suradista; Suramin; Swainsonine, Synthetic glycosami quimod, immunostimulant peptides; insulin-like growth fac noglycans; tallimustine; tamoxifen methiodide; tor-1 receptor inhibitor; interferon agonists, interferons, tauromustine, tazaroteine, tecogalan Sodium, tegafur, tellu interleukins, iobonguane; iododoxorubicin; ipomeanol, 4, rapyrylium, telomerase inhibitors, temoporfin, temozolo trinotecan; iroplact, irSogladine, isobengaZole, isohomohali mide; tenipoSide, tetrachlorodecaoxide, tetraZomine; thali condrin B; itasetron, jasplakinolide, kahalalide F, lamel blastine; thalidomide; thiocoraline; thrombopoietin; larin-N triacetate, lanreotide; leinamycin; lenograstim; len thrombopoietin mimetic, thymalfasin; thymopoietin recep tinan Sulfate, leptolstatin: letrozole; leukemia inhibiting tor agonist; thymotrinan; thyroid Stimulating hormone; tin factor; leukocyte alpha interferon; leuprolide--estrogen ethyl etiopurpurin; tirapazamine; titanocene dichloride; progesterone; leuprorelin; leVamisole liarozole; linear topotecan; topSentin: toremifene; totipotent stem cell factor; polyamine analogue, lipophilicadisaccharide peptide, lipo translation inhibitors, tretinoin, triacetyluridine, triciribine; philic platinum compounds, lisSoclinamide-7: lobaplatin, trimetrexate, triptorelin; tropisetron; turosteride, tyrosine lombricine: lometrexol: lonidamine; loSOXantrone; lovasta kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; tin, loxoribine; lurtotecan; lutetium teXaphyrin, lySofylline; urogenital sinus-derived growth inhibitory factor; urokinase lytic peptides, maitansine; mannostatin A, marimastat; receptor antagonists, Vapreotide; variolin B; vector System, masoprocol; maspin; matrilysin inhibitors, matrix metallo proteinase inhibitors, menogaril; merbarone; meterelin; erytrocyte gene therapy; VelareSol, Venom, anti-Venom, methioninase; metoclopramide; MIF inhibitor; mifepris Veramine, Verdins, verteporfin, Vinorelbine; VinXaltine; tone; miltefosine, mirimoStim, mismatched double Stranded Vitaxin; Vorozole; Zanoterone; Zeniplatin, Zilascorb, Zinosta RNA, mitoguaZone, mitolactol, mitomycin analogues, tin Stimalamer, immunostimulating drugs or therapeutic mitonafide, mitotoxin fibroblast growth factor-Saporin; agents, their metabolites, Salts and derivatives thereof. mitoxantrone; mofaroteine; molgramoStim; monoclonal anti 53. The use of a pharmaceutical formulation as claimed in body, human chorionic gonadotrophin, monophosplioryl claims 50 to 52, wherein the pharmaceutical formulation is lipid A+myobacterium cell wall Sk, mopidamol, multiple administered in combination with radiation treatment. drug resistance genie inhibitor, multiple tumor Suppressor 54. The use of a pharmaceutical formulation as claimed in 1-based therapy; mustard anticancer agent; my caperoxide B; claims 50 to 53, wherein the pharmaceutical formulation is mycobacterial cell wall extract; myriaporone, N-acetyldina administered in combination with Surgery. line, N-Substituted benzamides, nafarelin, nagreStip; nalox 55. The use of a pharmaceutical formulation as claimed in one-pentazocine, napavin, naphterpin, nartograstim; neda claims 50 to 54, wherein the neoplasia is a precancerous platin, nemorubicin; neridronic acid; neutral endopeptidase; lesion including Syndromes represented by abnormal neo nilutamide, nisamycin: nitric oxide modulator, nitroxide plastic and/or dysplastic, changes of tissue comprising pre antioxidant, nitrullyn, O6-benzylguanine; Octreotide, oki cancerous growths in colonic, breast, renal, central nervous, cenone, oligonucleotides, onapristone, orldarisetron; gastric, or lung tissues, or conditions Such as dysplastic Ondansetron; oracin, oral cytokine inducer; Ormaplatin; nevus Syndrome, a precursor to malignant melanoma of the OSaterone, Oxaliplatin; OXaunomycin, paclitaxel analogues, skin, dysplastic nevus Syndromes, polyposis Syndromes, paclitaxel derivatives, palauamine, palmitoylrhizoxin; pam colonic polyps, precancerous lesions of the cervix (i.e., idronic acid, panaxytriol: panomifene: parabactin; paZellip cervical dysplasia), prostatic dysplasia, bronchial dysplasia, tine, pegaepergase; peldesline; pentosan polysulfate Sodium; breast, bladder and/or skin and related conditions (e.g., pentostatin, pentrozole; perflubron; perfosfamide, perillyl actinic keratosis), whether the lesions are clinically identi alcohol; phenazinomycin; phenylacetate; phosphatase fiable or not. inhibitors, picibanil; pilocarpine hydrochloride, pirarubicin: 56. The use of a pharmaceutical formulation as claimed in piritrexim; placetin A; placetin B; plasminogen activator claims 50 to 55, wherein the neoplasia is prostate cancer, inhibitor, platinum compreX, platinum compounds, plati colon cancer, Small cell lung cancer, large cell lung cancer, num-triamine coil iplex, porfimer Sodium; portiromycin; lung adenocarcinoma, epidermoid lung cancer, melanoma US 2004/0092583 A1 May 13, 2004 22

(including amelanotic Subtypes), renal cell carcinoma, gas 62. The use of a pharmaceutical formulation as claimed in tric carcinoma, cancers of the central nervous System includ claims 50 to 61, wherein, the pharmaceutical formulation is ing brain tumours, neuroblastomas, gastric carcinoma, administered enterally, parenterally, topically, orally, Sublin breast cancer, ovarian cancer, testicular cancer, lymphoma gually, rectally, nasally or vaginally. and leukaemia, oesophageal cancer, Stomach cancer, liver 63. The use of a pharmaceutical formulation as claimed in cancers, prostate cancer, cervical cancer, adrenal cancer, oral claims 50 to 62, wherein the composition is formulated into or mucosal cancer, bladder cancer, pancreatic cancer, lym liposomes or carbohydrate vehicles. phoma, Hodgkins disease, Sarcomas, Hematopoeitic cell 64. The use of a pharmaceutical formulation as claimed in cancerS Such as B cell leukaemia/lymphomas, myelomas, claim 63, wherein the liposomes or carbohydrate vehicles T-cell leukemias/lymphomas, Small cell leukemias/lympho are specifically targeted to tumours by covalently attaching mas, null cell, Sezary, monocytic, myolomonocytic and a monoclonal antibody directed to a tumour-associated Hairy cell leukemias. antigen. 57. The use of a pharmaceutical formulation as claimed in 65. The use of a pharmaceutical formulation as claimed in claims 50 to 56, wherein the neoplasia is in the form of a claims 50 to 64, wherein the pharmaceutical formulation is tumour comprising an epidermoid and myeloid tumour, administered intermittently. acute or chronic, nonsmall cell, Squamous or Solid. 66. The use of a pharmaceutical formulation as claimed in 58. The use of a pharmaceutical formulation as claimed in claims 50 to 65, wherein the pharmaceutical formulation is claims 50 to 57, wherein the composition is micronized. a unit dose that comprises 5-500 mg of active ingredient 59. The use of a pharmaceutical formulation as claimed in consisting of at least one compound of the present invention. claims 50 to 58, wherein the pharmaceutical formulation has 67. The use of a pharmaceutical formulation as claimed in an enteric coating. claims 50 to 66, wherein the pharmaceutical formulation is 60. The use of a pharmaceutical formulation as claimed in administered to a mammal. claim 59, wherein the enteric coating is made of a polymer 68. The use of a pharmaceutical formulation as claimed in or copolymer. claim 67, wherein Said mammal is a neonate and Said 61. The use of a pharmaceutical formulation as claimed in administering is effected prior to delivery of Said neonate claim 60, wherein the polymer or copolymer is Selected from and/or during delivery of Said neonate. the group consisting of poly(lactic-glycolic acid) polyester, 69. The use of a pharmaceutical formulation as claimed in cellulose acetate phthalate, hydroxypropyl-methyl cellulose claims 50 to 68, wherein the composition acts as a prodrug. phthalate poly(butyl methacrylate), (2-dimethylaminoethyl) methacrylate, and methyl methacrylate. k k k k k