AU2005289317A1 - Dibenzodiazepinone analogues, processes for their production and their use as pharmaceuticals - Google Patents

Description

WO 2006/034574 PCT/CA2005/001467 DIBENZODIAZEPINONE ANALOGUES, PROCESSES FOR THEIR PRODUCTION AND THEIR USE AS PHARMACEUTICALS FIELD OF THE INVENTION This invention relates to dibenzodiazepinone analogues having improved properties, which are chemical derivatives of Compound 1. The invention further relates to their pharmaceutically acceptable salts, solvates and prodrugs, and to methods for obtaining the compounds. One method of obtaining the derivatives involves post o10 biosynthesis chemical modification of Compound 1. The present invention further relates to the use of dibenzodiazepinone analogues, and their pharmaceutically acceptable salts, solvates and prodrugs as pharmaceuticals, in particular to their use as inhibitors of cancer cell growth, mammalian lipoxygenase, andfor treating acute and chronic inflammation, and to pharmaceutical compositions comprising a dibenzodiazepinone analogue, or a pharmaceutically acceptable salt, solvate or prodrug thereof. BACKGROUND OF THE INVENTION The euactinomycetes are a subset of a large and complex group of Gram 20 positive bacteria known as actinomycetes. Over the past few decades these organisms, which are abundant in soil, have generated significant commercial and scientific interest as a result of the large number of therapeutically useful compounds, particularly antibiotics, produced as secondary metabolites. The intensive search for strains able to produce new antibiotics has led to the identification of hundreds of new species. i Many of the euactinomycetes, particularly Streptomyces and the closely related Saccharopolyspora genera, have been extensively studied. Both of these genera produce a notable diversity of biologically active metabolites. Because of the commercial significance of these compounds, much is known about the genetics and 30 physiology of these organisms. Another representative genus of euactinomycetes, Micromonospora, has also generated commercial interest. For example, U.S. Patent No. 5,541,181 (Ohkuma et al.) discloses a dibenzodiazepinone compound, specifically 5-farnesyl-4,7,9-trihydroxy-dibenzodiazepin-11-one (named "BU-4664L"), produced by 1 WO 2006/034574 PCT/CA2005/001467 a known euactinomycetes strain, Micromonospora sp. M990-6 (ATCC 55378). ECO 4601 (Compound 1) and Micromonospora sp. strains 046-ECO11 and [S01]046 are disclosed in CA 2,466,340. Its use for the treatment of cancer is disclosed in PCT/CA2005/000751. 0 N OH H1 HO ECO-4601 (Compound 1) Synthetic dibenzodiazepinone analogs were disclosed in the published Canadian patent application 2,248,820 as having anti-histamine properties. Although many biologically active compounds have been identified from bacteria, 10 there remains the need to obtain novel compounds with enhanced properties. Thus, there exists a considerable need to obtain pharmaceutically active compounds in a cost-effective manner and with high yield. The present invention solves these problems by providing new therapeutic compounds and methods to generate these novel compounds by post-biosynthetic chemical modifications. SUMMARY OF THE INVENTION In one aspect of the invention, the dibenzodiazepinone analogue is represented by a compound of Formula 1 as defined below, or a hydrogenated or hydroalkoxylated farnesyl derivative, or a pharmaceutically acceptable salt, solvate or prodrug of a 20 compound of Formula 1. In another embodiment, the dibenzodiazepinone analogue is represented by any one of Compounds 2 to 27 as defined below, or a pharmaceutically acceptable salt, solvate or prodrug, or salt of a prodrug of any one of Compounds 2 to 25. In a further embodiment, the dibenzodiazepinone analogue is represented by any one of Compounds 2 to 5, 7, 13, 14, 15, 18, 21, and 22 as defined below, ora pharmaceutically acceptable solvate or prodrug of any one of Compounds 2 to 5, 7, 13, 14, 15, 18, 21, and 22. In yet another aspect of the invention, the dibenzodiazepinone analogue is represented by any one of Compounds 23 to 25 as defined below, or a 2 WO 2006/034574 PCT/CA2005/001467 pharmaceutically acceptable solvate or prodrug of any one of Compounds 23 to 25. The invention further encompasses a dibenzodiazepinone analogue obtained by a method comprising the steps of: (a) providing an isolated form of ECO-4601, (b) chemically modifying Compound 1. In another embodiment, the dibenzodiazepinone analogue is a compound of Formula I, or a hydrogenated or hydroalkoxylated farnesyl derivative, or a pharmaceutically acceptable salt, solvate or prodrug thereof. In another embodiment the chemical modification step (b) is one or more steps selected from N alkylation, O-triacetylation, aryl bromination, and farnesyl hydrogenation or hydroalkoxylation. In another embodiment the dibenzodiazepinone analogue is selected 10 from Compounds 2 to 27. In another embodiment the dibenzodiazepinone analogue is selected from Compounds 2 to 5, 7, 13, 14, 15, 18, 21, and 22. In another embodiment the dibenzodiazepinone analogue is selected from Compounds 23 to 25. The invention further encompasses a method for making a dibenzodiazepinone compound, comprising chemically modifying the farnesyl dibenzodiazepinone Compound 1, and optionally isolating and purifying the dibenzodiazepinone compound produced. In one embodiment, the chemical modification step comprises at least one step selected from N-alkylations, O-acylations, aryl bromination and modifications of the double bonds of the farnesyl side chain including, hydrogenation, and hydroalkoxylation. In a subclass of this embodiment, the farnesyl side chain 20 modification reaction is partial (one or two double bonds modified) or complete (all three double bonds modified). The invention further encompasses the use of a compound of Formula I or a hydrogenated or hydroalkoxylated farnesyl derivative, or a pharmaceutically acceptable salt, solvate or prodrug thereof as an antitumor agent for the treatment of a pre cancerous or cancerous condition in a mammal. In one embodiment, the compound is selected from Compounds 2 to 27. In another embodiment, the compound is selected from Compounds 2 to 5, 7, 13, 14, 15, 18, 21, and 22. In another embodiment the compound is selected from Compounds 23 to 25. The invention further encompasses the use of a compound of Formula 1 or a 30 hydrogenated or hydroalkoxylated farnesyl derivative, or a pharmaceutically acceptable salt or prodrug thereof as an antineoplastic agent for the treatment of a proliferative disorder in a mammal. In one embodiment, the compound is selected from 3 WO 2006/034574 PCT/CA2005/001467 Compounds 2 to 27. In another embodiment, the compound is selected from Compounds 2 to 5, 7, 13, 14, 15, 18, 21, and 22. In another embodiment the compound is selected from Compounds 23 to 25. The invention further encompasses the use of a compound of Formula I or a hydrogenated or hydroalkoxylated farnesyl derivative, or a pharmaceutically acceptable salt or prodrug thereof in the preparation of a medicament for the treatment of a pre cancerous or cancerous condition in a mammal. In one embodiment, the compound is selected from Compounds 2 to 27. In another embodiment, the compound is selected from Compounds 2 to 5, 7, 13, 14, 15, 18, 21, and 22. In another embodiment the o10 compound is selected from Compounds 23 to 25. The invention further encompasses a commercial package comprising a compound of Formula I or a hydrogenated or hydroalkoxylated farnesyl derivative, or a pharmaceutically acceptable salt or prodrug thereof, together with instructions for use in the treatment of a neoplasm or a pre-cancerous or cancerous condition. In one embodiment, the compound is selected from Compounds 2 to 27. In another embodiment, the compound is selected from Compounds 2 to 5, 7, 13, 14, 15, 18, 21, and 22. In another embodiment the compound is selected from Compounds 23 to 25. In one embodiment, the cancer cell, neoplastic, pre-cancerous or cancerous condition, in the above-mentioned uses, is selected from leukemia, melanoma, breast 20 cancer, lung cancer, pancreatic cancer, ovarian cancer, renal cancer, colon or colorectal cancer, prostate cancer, and CNS cancer. In another embodiment, the cancer cell, and pre-cancerous or cancerous condition, in the above-mentioned methods and uses, is selected from leukemia, breast cancer, prostate cancer, and CNS cancer. BRIEF DESCRIPTION OF THE FIGURES Figure 1: shows inhibition of tumor growth resulting from bolus administration of 10 to 30 mg/kg of Compound 1 to C6 glioblastoma-bearing mice one day after tumor cell inoculation. 30 Figure 2: shows inhibition of tumor growth resulting from bolus administration of 20-30 mg/kg of Compound 1 to glioblastoma-bearing mice ten days after tumor cell inoculation. 4 WO 2006/034574 PCT/CA2005/001467 Figure 3: shows micrographs of tumor sections from mice bearing glioblastoma tumors and treated with saline or Compound 1. The cell density of tumor treated with Compound 1 appears decreased and nuclei from tumor cells are larger and pycnotic suggesting a cytotoxic effect. Figure 4: inhibition of tumor growth resulting from bolus administration of 20 to 75 mg/kg of Compound 2 to C6 glioblastoma-bearing mice from day 11 to day 20 of treatment. Figure 5: shows the mean (±SD) plasma concentrations of Compound 1 in Swiss mice following 30 mg/kg intravenous (iv), intraperitoneal (ip), subcutaneous (sc) and oral (po) 10 bolus administrations. Figure 6: shows the mean (±SD) plasma concentrations of Compounds 1 and 2 in CD-1 mice following 30 mg/kg intravenous (iv) and intraperitoneal (ip) bolus administrations. Figure 7: shows the mean concentration of Compound 1 in various tissues, 30 minutes after 30mg/kg intravenous (iv), intraperitoneal (ip) and subcutaneous (sc) bolus administrations. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel dibenzodiazepinone analogues having improved properties, herein referred as the compounds of Formula I and hydrogenated 20 or hydroalkoxylated farnesyl derivatives, and Compounds 2 to 27. The invention further relates to pharmaceutically acceptable salts, solvates and prodrugs of dibenzodiazepinone compounds. The invention further relates to processes of obtaining the analogs by chemical modification of Compound 1. Compound 1 is isolated from strains of actinomycetes, Micromonospora sp. 046-ECO 11 (also as 046(ECO11)) or [S011046, as described in PCT/CAO4/000069. The invention also relates to a method for producing novel dibenzodiazepinone analogs, by chemical modification of the farnesyl dibenzodiazepinone obtained from fermentation and isolation. In a subclass of this embodiment, the compound produced is a compound of Formula I or a hydrogenated or hydroalkoxylated farnesyl derivative 30 thereof, or a compound selected from Compounds 23 to 27. 5 WO 2006/034574 PCT/CA2005/001467 The present invention also relates to pharmaceutical compositions comprising a compound selected from the compounds of Formula I, and Compounds 2 to 27, and their pharmaceutically acceptable salts, solvates and derivatives. The compounds are useful as pharmaceuticals, in particular for use as inhibitors of neoplastic cell growth. The following detailed description discloses how to make and use the dibenzodiazepinone analogs and compositions containing these compounds to inhibit tumor growth. Accordingly, certain aspects of the present invention relate to pharmaceutical compositions comprising the dibenzodiazepinone compounds of the present invention o10 together with a pharmaceutically acceptable carrier, and methods of using the pharmaceutical compositions to treat pre-cancererous or cancerous conditions. 1. Definitions All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For convenience, the meaning of certain terms and phrases used in the specification, examples, and appended claims, are provided below. As used herein, the term "farnesyl dibenzodiazepinone" refers to Compound 1, namely 10-farnesyl-4,6,8-trihydroxy-5,10 O-dihydrodibenzo[b,e][1,4]diazepin-11-one, also 20 referred to as ECO-4601. As used herein, the terms "compound(s) of the invention", "dibenzodiazepinone analogue(s)", "dibenzodiazepinone compound(s)", and equivalent expressions refer to a class of dibenzodiazepinone compounds containing a farnesyl moiety or being derived from a farnesyl moiety, and pharmaceutically acceptable salts, solvates and prodrugs thereof. The term includes a compound of Formula I, a compound selected from Compounds 2 to 27, or the exemplified compounds of the present invention, Compounds 2 to 5, 7, 13, 14, 15, 18, and 21 to 25, or a pharmaceutically acceptable salt, solvate or prodrug of any of the above compounds. As used herein, the term "dibenzodiazepinone analogues" includes compounds of this class that can be used as 30 intermediates in chemical syntheses and variants containing different isotopes than the most abundant isotope of an atom (e.g, D replacing H, 13C replacing 12C, etc). The 6 WO 2006/034574 PCT/CA2005/001467 compounds of the invention are also sometimes referred as "active ingredients". As used herein, the term "chemical modification" refers to one or more steps of modifying a dibenzodiazepinone compound,referred to as "starting material", by chemical synthesis. Preferred compound used as starting materials in a chemical modification process is Compound 1. Examples of chemical modification steps include N-alkylations, O-acylations, aromatic bromination, and modifications of the double bonds of the farnesyl side chain including, hydrogenation and hydroalkoxylation. Farnesyl side chain modification reaction can be partial (one or two double bonds modified) or complete (three double bonds modified). Chemical modification steps are o10 also defined in the Schemes of Section IIIB, and exemplified in Examples 4 to 8. The term "ester" refers to a dibenzodiazepinone analogue obtained by the replacement of a hydrogen atom from an alcohol by a C(O)R" replacement group by an O-acylation reaction as defined in Scheme 1(b) below, wherein C(O)R" can also be a C coupled amino acid. The term ester also encompasses ester equivalents including, without limitation, carbonate, carbamate, and the like. More particularly, the term "ester" encompasses esters of the alcohols in positions 4, 6, and 8 (see Exampes 3-8 for atom numbering). The term "N-alkylated derivative" refers to a dibenzodiazepinone analogue obtained by the replacement of a hydrogen atom of a nitrogen atom by an R 20 replacement group by an N-alkylation reaction as defined in Scheme 2(a) below. More particularly, the term "N-alkylated derivative" encompasses substituted derivatives at the nitrogen in position 5 (see Exampes 3-8 for atom numbering). As used herein, the term "hydrogenated or hydroalkoxylated farnesyl derivative" refers to a compound having a modified farnesyl side chain at one to three positions by either saturation (addition of two hydrogen atoms) or by addition of a molecule of alcohol (H and OC1- 6 alkyl) produced respectively by the procedures generally defined in Schemes 3(a) and (b) of Section IIIB, and more specifically in Examples 4 and 7. SAs used herein, abbreviations have their common meaning. Unless otherwise noted, the abbreviations "Ac", "Me", "Et", "Pr", "i-Pr", "Bu", "Bz", "Bn" and "Ph", 30 respectively refer to acetyl, methyl, ethyl, propyl (n- or iso-propyl), iso-propyl, butyl (n-, iso-, sec- or tert-butyl), benzoyl, benzyl and phenyl. Abbreviations in the specification correspond to units of measure, techniques, properties or compounds as follows: "RT" 7 WO 2006/034574 PCT/CA2005/001467 and "Rt" mean retention time, "min" means minutes, "h" means hour(s), "pL" means microliter(s), "mL" means milliliter(s), "mM" means millimolar, "M" means molar, "mmole" means millimole(s), "eq" means molar equivalent(s). "High Pressure Liquid Chromatography" or "High Performance Liquid Chromatography" are abbreviated HPLC. The term "alkyl" refers to linear, branched or cyclic, saturated hydrocarbon groups. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, pentyl, hexyl, heptyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, and the like. Alkyl groups may optionally be substituted with substituents selected from 10 acyl, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, oxo, guanidino and formyl. The term "Cl-nalkyl", wherein n is an integer from 2 to 12, refers to an alkyl group having from 1 to the indicated "n" number of carbons. The C 1 -nalkyl can be cyclic or a straight or branched chain. The term "linear C 1 -nalkyl", wherein n is an integer from 2 to 10, refers to an alkyl group having from 1 to the indicated "n" number of carbons and being liear, i.e. not cyclic or branched in the vicinity of the attached atom (herein the nitrogen). The Cj_ nalkyl can optionally be substituted with groups such as amino, cyano, halo, hydroxyl, 20 nitro, thio, and alkoxy. The term "alkenyl" refers to linear, branched or cyclic unsaturated hydrocarbon groups containing, from one to six carbon-carbon double bonds. Examples of alkenyl groups include, without limitation, vinyl, 1-propene-2-yl, 1-butene-4-yl, 2-butene-4-yl, 1 pentene-5-yl and the like. Alkenyl groups may optionally be substituted with substituents selected from acyl, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, formyl, oxo and guanidino. The double bond portion(s) of the unsaturated hydrocarbon chain may be either in the cis or trans configuration. 30 The term "C2-nalkenyl", wherein n is an integer from 3 to 12, refers to an alkenyl group having from 2 to the indicated "n" number of carbons. The C 2 -nalkenyl can be cyclic or a straight or branched chain. 8 WO 2006/034574 PCT/CA2005/001467 The term "alkynyl" refers to linear, branched or cyclic unsaturated hydrocarbon groups containing at least one carbon-carbon triple bond. Examples of alkynyl groups include, without limitation, ethynyl, 1-propyne-3-yl, 1-butyne-4-yl, 2-butyne-4-yl, 1 pentyne-5-yl and the like. Alkynyl groups may optionally be substituted with substituents selected from acyl, amino, acylamino, acyloxy, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl, formyl, oxo and guanidine. The term "C 2 -nalkynyl", wherein n is an integer from 3 to 12, refers to an alkynyl 10 group having from 2 to the indicated "n" number of carbons. The C 2 -nalkynyl can be cyclic or a straight or branched chain. The term "cycloalkyl" or "cycloalkyl ring" refers to an alkyl group, as defined above, further comprising a saturated or partially unsaturated carbocyclic ring in a single or fused carbocyclic ring system having from three to fifteen ring members. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonanyl, norbornyl, and the like. Cycloalkyl groups may optionally be substituted with substituents selected from acyl, amino, acylamino, acyloxy, carboalkoxy, carboxy, 20 carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl and formyl. The term "C 3 -ncycloalkyl", wherein n is an integer from 4 to 15, refers to a cycloalkyl ring or ring system or having from 3 to the indicated "n" number of carbons. The term "heterocycloalkyl", "heterocyclic" or "heterocycloalkyl ring" refers to a cycloalkyl group, as defined above, further comprising one to four hetero atoms (e.g. N, O, S, P) or hetero groups (e.g. NH, NRx, PO 2 , SO, SO2) in a single or fused heterocyclic ring system having from three to fifteen ring members (e.g. tetrahydrofuranyl has five ring members, including one oxygen atom). Examples of a heterocycloalkyl, heterocyclic or heterocycloalkyl ring include, without limitation, pyrrolidino, 30 tetrahydrofuranyl, tetrahydrodithienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 9 WO 2006/034574 PCT/CA2005/001467 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3,1,0]hexanyl, 3 azabicyclo[4,1,0]heptanyl, 3H-indolyl, and quinolizinyl. The foregoing heterocycloalkyl groups, as derived from the compounds listed above, may be C-attached or N-attached where such is possible. Heterocycloalkyl, heterocyclic or heterocycloalkyl ring may optionally be substituted with substituents selected from acyl, amino, acylamino, acyloxy, oxo, thiocarbonyl, imino, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, 10 alkoxy, aryloxy, sulfinyl, sulfonyl and formyl. The term "C 3 -nheterocycloalkyl", wherein n is an integer from 4 to 15, refers to an heterocycloalkyl group having from 3 to the indicated "n" number of atoms in the cycle and at least one hetero group as defined above. The terms "halo" or "halogen" refers to bromine, chlorine, fluorine or iodine substituents. The term "aryl" or "aryl ring" refers to common aromatic groups having "4n+2" Tr(pi) electrons, wherein n is an integer from 1 to 3, in a conjugated monocyclic or polycyclic system and having from five to fourteen ring atoms. Aryl may be directly attached, or connected via a C1- 3 alkyl group (also referred to as aralkyl). Examples of 20 aryl include, without limitation, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, and the like. Aryl groups may optionally be substituted with one or more substituent group selected from acyl, amino, acylamino, acyloxy, azido, alkythio, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl and formyl. The term "C 5 -naryl", wherein n is an integer from 5 to 14, refers to an aryl group having from 5 to the indicated "n" number of atoms, including carbon, nitrogen, oxygen and sulfur. The Cs 5 -naryl can be mono or polycyclic. The term "heteroaryl" or "heteroaryl ring" refers to an aryl ring, as defined above, 30 further containing one to four heteroatoms selected from oxygen, nitrogen, sulphur or phosphorus. Examples of heteroaryl include, without limitation, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isooxazolyl, thiazolyl, oxazolyl, 10 WO 2006/034574 PCT/CA2005/001467 isothiazolyl, pyrrollyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl groups. Heteroaryl may optionally be substituted with one or more substituent group selected from acyl, amino, acylamino, acyloxy, azido, alkythio, carboalkoxy, carboxy, carboxyamido, cyano, halo, hydroxyl, nitro, thio, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, aryloxy, sulfinyl, sulfonyl and formyl. Heteroaryl may be directly attached, or connected via a C 1

-

3 alkyl group (also referred to as o10 heteroaralkyl). The foregoing heteroaryl groups, as derived from the compounds listed above, may be C-attached or N-attached where such is possible. The term "C 5 -nheteroaryl", wherein n is an integer from 5 to 14, refers to an heteroaryl group having from 5 to the indicated "n" number of atoms, including carbon, nitrogen, oxygen and sulphur atoms. The C 5 -nheteroaryl can be mono or polycyclic. The term "amino acid" refers to an organic acid containing an amino group. The term includes both naturally occurring and synthetic amino acids; therefore, the amino group can be but is not required to be, attached to the carbon next to the acid. A C coupled amino acid substituent is attached to the heteroatom (nitrogen or oxygen) of the parent molecule via its carboxylic acid function. C-coupled amino acid forms an 20 ester with the parent molecule when the heteroatom is oxygen, and an amide when the heteroatom is nitrogen. Examples of amino acids include, without limitation, alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, asparagine, glutamine, tyrosine, histidine, lysine, arginine, aspartic acid, glutamic acid, desmosine, ornithine, 2-aminobutyric acid, cyclohexylalanine, dimethylglycine, phenylglycine, norvaline, norleucine, hydroxylysine, allo-hydroxylysine, hydroxyproline, isodesmosine, allo-isoleucine, ethylglycine, beta alanine, aminoadipic acid, aminobutyric acid, ethyl asparagine, and N-methyl amino acids. Amino acids can be pure L or D isomers or mixtures of L and D isomers. The compounds of the present invention can possess one or more asymmetric 30 carbon atoms and can exist as optical isomers forming mixtures of racemic or non racemic compounds. The compounds of the present invention are useful as single isomers or as a mixture of stereochemical isomeric forms. Diastereoisomers, i.e., nonsuperimposable stereochemical isomers, can be separated by conventional means 11 WO 2006/034574 PCT/CA2005/001467 such as chromatography, distillation, crystallization or sublimation. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, including chiral chromatography (e.g. HPLC), immunoassay techniques, or the use of covalently (e.g. Mosher's esters) or non-covalently (e.g. chiral salts) bound chiral reagents to respectively form a diastereomeric ester or salt, which can be further separated by conventional methods, such as chromatography, distillation, crystallization or sublimation. The chiral ester or salt is then cleaved or exchanged by conventional means, to recover the desired isomer(s). The invention encompasses isolated or purified compounds., An "isolated" or 10 "purified" compound refers to a compound which represents at least 10%, 20%, 50%, 80% or 90% of the mixture by weight, provided that the mixture comprising the compound of the invention has demonstrable (i.e. statistically significant) biological activity including cytostatic, cytotoxic, enzyme inhibitory or receptor binding action when tested in conventional biological assays known to a person skilled in the art. The term "pharmaceutically acceptable salt" refers to nontoxic salts synthesized from a compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media 20 like ether, ethyl acetate, methanol, ethanol, isopropanol, or acetonitrile are preferred. Another method for the preparation of salts is by the use of ion exchange resins. The term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts, either of the parent compound or of a prodrug or solvate thereof. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Exemplary acids used in acid addition salts include, without limitation, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, sulfonic, phosphoric, formic, acetic, citric, tartaric, succinic, oxalic, malic, glutamic, propionic, glycolic, gluconic, maleic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, 30 cyclohexylaminosulfonic, stearic, algenic, P-hydroxybutyric, malonic, galactaric, galacturonic acid and the like. Suitable pharmaceutically acceptable base addition salts include, without limitation, metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts, such as those made from 12 WO 2006/034574 PCT/CA2005/001467 N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, lysine, procaine and the like. Additional examples of pharmaceutically acceptable salts are listed in Berge et al (1977), Journal of Pharmaceutical Sciences, vol 66, no 1, pp 1-19, the content of which is incorporated herein by reference in its entirety. The term "solvate" refers to a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated o10 in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include hydrates, ethanolates, methanolates, hemiethanolates, and the like. The term "pharmaceutically acceptable prodrug" means any pharmaceutically acceptable ester, salt of an ester or any other derivative of a compound of this invention, which upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or a biologically active metabolite or residue thereof. Particularly favored salts or prodrugs are those with improved properties, such as solubility, efficacy, or bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an 20 orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. As used herein, a prodrug is a drug having one or more functional groups covalently bound to a carrier wherein metabolic or chemical release of the drug occurs in vivo when the drug is administered to a mammalian subject. Pharmaceutically acceptable prodrugs of the compounds of this invention include derivatives of hydroxyl groups such as, without limitation, acyloxymethyl, acyloxyethyl and acylthioethyl ethers, esters, amino acid esters, phosphate esters, sulfonate and sulfate esters, and their metal salts, and the like. 30 11. Compounds of the invention 13 WO 2006/034574 PCT/CA2005/001467 In one aspect, the invention relates to novel dibenzodiazepinone analogues, referred to herein as the compounds of the invention, and to pharmaceutically acceptable salts, solvates and prodrugs thereof. The compounds of the invention, Compounds 2 to 5, 7, 13, 14, 15, 18, and 21 to 25, may be characterized by any one of their physicochemical and spectral properties, such as mass and NMR spectra, detailed in Example 4 through Example 8. In another aspect, compounds of the invention are characterized by Formula I: 0 P N Hoo N HO / R- OH Ho Formula I wherein, 10 R 1 is a linear C0 1 -0oalkyl; or a farnesyl derivative thereof, wherein said farnesyl derivative has one, two or three hydrogenated or hydroalkoxylated double bonds; or a pharmaceutically acceptable salt or prodrug thereof. In one embodiment, R 1 is a linear C 1 -10alkyl, and all other groups are as previously disclosed. In a subclass of this embodiment, the alkyl group is optionally substituted with a substituent selected from halo, fluoro, amino and carboxy, or pharmaceutically acceptable salt thereof. In another embodiment, R, is methyl. In another embodiment, R 1 is ethyl. In another embodiment, R 1 is n-propyl. In another 20 embodiment, R 1 is n-butyl. In another embodiment, R 1 is n-pentyl. In another embodiment, R 1 is n-hexyl..In another embodiment, R 1 is methyl, and the farnesyl is fully hydrogenated (i.e. saturated). In another embodiment, R 1 is methyl, and one double bond of the farnesyl is hydrogenated. In another embodiment, R 1 is methyl, and two double bonds of the farnesyl are hydrogenated. In another embodiment, R 1 is a linear C 1

..

1 oalkyl, and one double bond of the farnesyl is hydrogenated. In another embodiment, R 1 is a linear C 1 1 0alkyl, and two double bonds of the farnesyl are hydrogenated. In another embodiment, R 1 is a linear C 1

-

1 0 alkyl, and the farnesyl is fully hydrogenated (i.e. saturated). In another embodiment, R 1 is a linear C 1 -10alkyl, and one 14 WO 2006/034574 PCT/CA2005/001467 double bond of the farnesyl is hydromethoxylated. In another embodiment, R 1 is a linear Cl0 1 0 alkyl, and two double bonds of the farnesyl are hydromethoxylated. In another embodiment, R 1 is methyl, and one double bond of the farnesyl is hydroalkoxylated. In another embodiment, R 1 is methyl, and two double bonds of the farnesyl are hydroalkoxylated. In another embodiment, R ' is ethyl, and one double bond of the farnesyl is hydroalkoxylated. In another embodiment, R, is ethyl, and two ,double bonds of the farnesyl are hydroalkoxylated. The invention encompasses all esters or N-alkylated derivatives, and pharmaceutically acceptable salts, solvates and prodrugs of the foregoing compounds. 10 The following are exemplary compounds of the invention, such named compounds are not intended to limit the scope of the invention in any way: A. N-Alkylated products: O 0 N N N < OH N /\O-H OH Me OH e HO ' HO Compound 2; Compound 3; 0 ON ON OH N N OH OH OH HO HO Compound 4; Compound 5; 0 0 ........ ON N OH OH N N OH OH HO HO 20 Compound 6; Compound 7; 15 WO 2006/034574 PCT/CA2005/001467 O 0O - N N' / OH / OH NN OH OH HO HO Compound 8; Compound 9; 0 N ON /- O OH NoHo O OH CF2 - F 2 C HO OH CF, HO CF 3 Compound 10; Compound 11; 0 0 ON N / OH OH NN OH OH CD 3

F

3 C HO HO Compound 12; Compound 13 10 B. Hydrogenated derivatives of N-alkylated products: 0 0 N ON / OH N /\ OH N N OH CH, OH CH 3 HO HO Compound 14; Compound 15; 0 N OH N OH

CH

3 HO Compound 16; 20 C. Hydroalkoxylated derivatives of N-alkylated products: 16 WO 2006/034574 PCT/CA2005/001467 O 0HO OCH, OCH 3 / OH OH N. N OH CH, OH OH HO HO Compound 17; Compound 18; O 0 NOCH OCH 3

OCH,

3 N OH N N OH C 3 OH HO HO Compound 19; Compound 20; 100 ON OC 3 N0C 3 CM OCH OCWz OCHN / -OH NOH N N OH OH HO HO Br Compound 21; Compound 22; 10 D. Other selections: 1 00 ON ON / H OHO OH 1 OH HO HO Br Compound 23; Compound 24; 0 N ON N \ OAc NO OAc H OH Me AcO HO Br 20 Compound 25; Compound 26; and 17 0 N OH Me HO Br 20 Compound 27; 17 WO 2006/034574 PCT/CA2005/001467 or a pharmaceutically acceptable salt, solvate of prodrug of any one of Compounds 2 to 27. The invention further provides esters and N-alkylated derivatives of any of the foregoing compounds. Certain embodiments expressly exclude one or more of the compounds of Formula I. Prodrugs of the compounds of the invention include compounds wherein one or more of the 4, 6 and 8-hydroxy groups, or any other hydroxyl group on the molecule is bounded to any group that, when administered to a mammalian subject, is cleaved to 10 form the free hydroxyl group. Examples of prodrugs include, but are not limited to, acetate, formate, hemisuccinate, benzoate, dimethylaminoacetate and phosphoryloxycarbonyl derivatives of hydroxy functional groups; dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters or carboxyalkyl esters of hydroxy functional groups. Carbamate and carbonate derivatives of the hydroxy groups are also included. Derivatizations of hydroxyl groups also encompassed, are (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group contains an alkyl group optionally substituted with groups including, but not limited to, ether, amino and carboxylic acid functionalities, or where the acyl group is an amino acid ester. Also included are phosphate and phosphonate esters, sulfate esters, sulfonate esters, which are in 20 alkylated (such as bis-pivaloyloxymethyl (POM) phosphate trimester or -P(O)O 2 Et 2 ) or in the salt form (such as sodium phosphate ester (-P(O)O- 2 Na 2 )). For further examples of prodrugs used in anticancer therapy and their metabolism, see Rooseboom et al (2004), Phamacol. Rev., vol 56, 53-102, incorporated herein by reference. When the prodrug contains an acidic or basic moiety, the prodrug may also be prepared as its pharmaceutically acceptable salt. The compounds of this invention may be formulated into pharmaceutical compositions comprised of a compound of the invention, in combination with a pharmaceutically acceptable carrier, as discussed in Section IV below. 30 Ill1. Methods of Producing Dibenzodiazepinone Analoques 18 WO 2006/034574 PCT/CA2005/001467 A. Fermentation The terms "farnesyl dibenzodiazepinone-producing microorganism" and "producer of farnesyl dibenzodiazepinone," as used herein, refer to a microorganism that carries genetic information necessary to produce a farnesyl dibenzodiazepinone compound, whether or not the organism naturally produces the compound. The terms apply equally to organisms in which the genetic information to produce the farnesyl dibenzodiazepinone compound is found in the organism as it exists in its natural environment, and to organisms in which the genetic information is introduced by recombinant techniques. 10 Compound is produced by isolation of the fermentation broth of Micromonospora strains 046-ECO11 and [S01]046 as described in USSN 10/762,107, incorporated herein by reference in its entirety. It is to be understood that the production of Compound 1 is not limited to the use of the particular strains 046-ECO 11 and [S01]046. Rather, other ECO-4601 producing organisms may be used, such as mutants or variants of 046-ECO 11 and [S01]046 that can be derived from this organism by known means such as X-ray irradiation, ultraviolet irradiation, treatment with nitrogen mustard, phage exposure, antibiotic resistance selection and the like; or through the use of recombinant genetic engineering techniques. For examples, see Manual of Industrial Microbiology and biotechnology, Demain and Solomon, American Society for 20 Microbiology, Washington D.C., 1986; Hesketh et al. (1997), J. Antibiotics, vol 50, no 6, 532-535; and Hosoya et al. (1998), AntimicrobialAgents and Chemotherapy, vol 42, no 8, 2041-2047), the content of which are incorporated herein by reference in their entirety. The farnesyl dibenzodiazepinone compound may be biosynthesized by various microorganisms. Microorganisms that may synthesize the farnesyl dibenzodiazepinone compound include but are not limited to bacteria of the order Actinomycetales, also referred to as actinomycetes. Non-limiting examples of members belonging to the genera of Actinomycetes include Nocardia, Geodermatophilus, Actinoplanes, Micromonospora, Nocardioides, Saccharothrix, Amycolatopsis, Kutzneria, Saccharomonospora, Saccharopolyspora, Kitasatospora, Streptomyces, Microbispora, 30 Streptosporangium, and Actinomadura. The taxonomy of actinomycetes is complex and reference is made to Goodfellow, Suprageneric Classification of Actinomycetes (1989); Bergey's Manual of Systematic Bacteriology, Vol. 4 (Williams and Wilkins, Baltimore, pp. 2322-2339); and to Embley and Stackebrandt, "The molecular phylogeny 19 WO 2006/034574 PCT/CA2005/001467 and systematics of the actinomycetes," Annu. Rev. Microbiol. (1994) 48:257-289, for genera that may synthesize the compounds of the invention. The content of which refrences is incorporated by reference in their entirety. Farnesyl dibenzodiazepinone-producing microorganisms are cultivated in culture medium containing known nutritional sources for actinomycetes. Such media having assimilable sources of carbon, nitrogen, plus optional inorganic salts and other known growth factors, at a pH of about 6 to about 9. Suitable media include, without limitation, the growth media provided in Table 1. Microorganisms are cultivated at incubation temperatures of about 18 0C to about 40 oC for about 3 to about 40 days. 10 Table 1 Examples of Fermentation Media for Compound 1 Production Component QB MA KH RM JA FA XX CL pH* 7.2 7.5 7 6.85 7.3 7.0 7.0 7.0 Glucose 12 10 10 10 Sucrose 100 Cane molasses 15 Corn starch 30 Soluble starch 10 25 Potato dextrin 20 40 20 20 Corn steep solid 5 Corn steep liquor 5 15 Dried yeast 2 Yeast extract 5 8.34 Malt extract 35 PharmamediaTM 10 15 Glycerol 30 20 NZ-Amine A 5 10 Soybean powder 15 Fish meal 10 Bacto-peptone 2.5 5 MgSO 4 .7H 2 0 1 CaCO 3 4 1 2 2 3 2 NaCl 5

(NH

4

)

2

SO

4 2 2

K

2

SO

4 0.25 MgCl 2 .6H 2 0 10 Na 2

HPO

4 3 Casamino acid 0.1 Proflo oilTM (mL/L) 4 0.05 Silicon defoamer oil (mL/L) 0.3 20 WO 2006/034574 PCT/CA2005/001467 Table 1 Examples of Fermentation Media for Compound 1 Production Component QB MA KH RM JA FA XX CL MOPS 21 Trace element solution *2 mi/L 2 Unless otherwise indicated all the ingredients are in g/L. *1 The pH is to adjusted as marked prior to the addition of CaCO 3 . *2 Trace elements solution contains: ZnCI 2 40 mg; Fe Cl3 6H 2 0 (200 mg); CuCI 2 .2H 2 0 (10 mg); MnCI 2 .4H 2 0; Na 2

B

4 07.10H 2 0 (10mg); (NH 4

)

6

MO

7 0 24 .4H 2 0 (10 mg) per litre. The culture media inoculated with a farnesy dibenzodiazepinone-producing microorganism may be aerated by incubating the inoculated culture media with agitation, for example, shaking on a rotary shaker, a shaking water bath, or in a fermentor. Aeration may also be achieved by the injection of air, oxygen or an 10 appropriate gaseous mixture to the inoculated culture media during incubation. Following cultivation, the farnesyl dibenzodiazepinone compound can be extracted and isolated from the cultivated culture media by techniques known to a person skilled in the art and/or disclosed herein, including for example centrifugation, chromatography, adsorption, filtration. For example, the cultivated culture media can be optionally acidified and mixed with a suitable organic solvent such as methanol, ethanol, n butanol, ethyl acetate, n-butyl acetate or 4-methyl-2-pentanone. The organic layer can be separated from the mycelial cake for example, by centrifugation and decantation or filtration. The mycelial cake is further optionally extracted with an organic solvent, and the organic extracts combined. The organic layer is further optionally treated, for 20 example by: aqueous washings, precipitation, filtration and the like, followed the removal of the solvent, for example, by evaporation to dryness under vacuum. The resulting residue can optionally be reconstituted with for example water, ethyl ether, ethanol, ethyl acetate, methanol or a mixture thereof, and re-extracted in a two-phase system with a suitable organic solvent such as hexane, carbon tetrachloride, methylene chloride or a mixture thereof. After removal of the solvent, the compound can be further purified by the use of standard techniques such as normal and reverse-phase liquid chromatography, crystallization, sublimation, adsorption, mass exclusion chromatography, and the like. 30 21 WO 2006/034574 PCT/CA2005/001467 B. Chemical Modifications: The farnesyl dibenzodiazepinone Compound 1 is biosynthesized by microorganisms and isolated as described herein, and in Canadian patent 2,466,340 (and PCT/CAO4/000069). Compound 1 is subjected to random and/or directed chemical modifications to form compounds that are derivatives or structural analogues. Such derivatives or structural analogues having similar functional activities are within the scope of the present invention. The farnesyl dibenzodiazepinone may be modified by one or more chemical modification steps, using methods known in the art and described herein. Examples of chemical modifications procedures are also provided in 10 Examples 4 to 8. Dibenzodiazepinone analogues that are derivatives of Compound 1, for example those identified herein as the compounds of Formula I and their derivatives, and Compounds 2 to 27, are generated by standard organic chemistry approaches. General principles of organic chemistry required for making and manipulating the compounds described herein, including functional moieties, reactivity and common protocols are described, for example, in "Advanced Organic Chemistry," 4 th Edition by Jerry March (1992), Wiley-lnterscience, USA, incorporated herein by reference in its entirety. In addition, it will be appreciated by one of ordinary skill in the art that the synthetic methods described herein may use a variety of protecting groups, whether or 20 not they are explicitly described. A "protecting broup" as used herein means a moiety used to block one or more functional moieties such as reactive groups including oxygen, sulfur or nitrogen, so that a reaction can be carried out selectively at another reactive site in a polyfunctional compound. General principles for the use of protective groups, their applicability to specific functional groups and their uses are described for example in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3 rd Edition, John Wiley & Sons, New York (1999), incorporated herein by reference in its entirety. Alcohols and phenols are protected, if necessary with, for example: silyl ethers (TMS: trimethylsilyl, TIPS: triisopropylsilyl), acetals (MOM: methyloxymethyl, BOM: 30 benzyloxymethyl), esters (acetate, benzoyl) and ethers (Bn: benzyl). Alcohols are deprotected by conditions such as: TBAF (tetrabutylammonium fluoride) for silyl ethers, aqueous acid catalysis for acetals and esters, saponification for esters, and hydrogenolysis for Bn and BOM. Amine is protected, if necessary, using standard 22 WO 2006/034574 PCT/CA2005/001467 amino acid protecting groups, for example, carbamates (such as t-butyl (BOC) and benzyl (CBZ)), fluorene derivatives (such as FMOC: N-(9-fluorenylmethoxycarbonyl)-), etc. Amine is deprotected by conditions such as: acid hydrolysis for BOC, hydrogenolysis for CBZ, or base treatment for FMOC. All protection and deprotection conditions are demonstrated in the Greene et al reference above. Those skilled in the art will readily appreciate that many synthetic chemical processes may be used to produce derivatives of Compound 1. The following schemes are exemplary of the routine chemical modifications that may be used to produce compounds of the invention. Any chemical synthetic process known to a person skilled 10 in the art providing the structures described herein may be used and are therefore comprised in the present invention. Scheme 1: Alcohol(s) modifications (O-acylations) 0:s O H 0j- 0 (a) \ 0 I IO wherein, R" is an acetate. In Scheme 1, phenolic alcohols are converted to esters when reacted with activated carboxylic acids (R"C(O)X) such as an acid halide, anhydride, N hydroxysuccinimide ester, or a carboxylic acid activated by a coupling agent (e.g.: EDC (1-(3-dimethylaminopropyl)-3-dT'fsopropylethylcarbodiimide hydrochloride); or HATU (O 20 (7-azabenzotriazol-1 -yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate)) with a base (e.g., pyridine or N,N-diisopropylethylamine (DIPEA)) and optional acatalysts such HOBt (1-hydroxybenzotriazole hydrate) and/or DMAP (4-(dimethylamino)pyridine). The same reactions may be accomplished on alcohols formed by farnesyl modification reactions (Scheme 3). Scheme 1 is used to obtain, for example, Compounds 25 from Compound 1; and to produce esters of the Compounds of the invention. 23 WO 2006/034574 PCT/CA2005/001467 Scheme 2: Amine modifications (N-alkylations) S NH (a) S N R I I I I wherein, R is selected an optionally substituted linear C 1 -o10alkyl. In Scheme 2, amine group in position 5 (for position, see Example 3) is alkylated. In Scheme 2(a), an amine is alkylated using an RX alkylating agent such as dialkyl sulfates and alkyl halides, preferably in the presence of a base (e.g., sodium bicarbonate, pyridine and the like). Scheme 2 is used to prepare, for example, Compounds 2 to 13 from Compound 1, and Compound 14 from Compound 23; and to produce any of the Compounds of io Formula I comprising an N-alkyl group. Scheme 3: Double bond(s) modifications H H H H Rz (b) H H wherein Rz is OC 1

-

6 alkyl. In Scheme 3, double bond is modified by: (a) hydrogenation; and (b) hydroalkoxylation. In (a) hydrogenation is carried out using a hydrogen source (e.g. hydrogen, formic acid) and a catalyst (such as rhodium, platinum, or palladium). In (b), electrophilic addition to the double bond is achieved by the formation of a carbocation from addition of a proton in acidic conditions (e.g., p-toluene sulfonic acid, alkyl 20 sulfate/NaHCO 3 /MeOH, and the like), and trapping of the carbocation with an alcohol

(C

1

-

6 alkyl alcohol, hydroalkoxylation). Scheme 3 is used to obtain, for example: in (a) Compound 23 from Compound 1, and Compounds 14 to 16 from Compound 2; in (b) Compounds 17 to 19 from Compound 2, Compounds 20 to 22 from Compound 3. Schemes 3 (a) and (b) are also 24 WO 2006/034574 PCT/CA2005/001467 used to produce any hydrogenated and hydroalkoxylated farnesyl derivative of the Compounds of Formula I. Scheme 4: Aromatic substitutions wherein, X is Br. In Scheme 4, the aryl group is modified by aromatic substitutions (bromination). brominating agents include bromine, N-haloamides (e.g, N-bromosuccinimide (NBS), tetraalkylammonium polyhalides). 10 Scheme 4 is used to prepare Compound 24 from Compound 1, Compound 26 from Compound 2 and Compound 27 from Compound 14. Prodrugs are prepared by routine chemical modifications such as described in Jerry March, supra, including esterification (Scheme 1) and alkylation reactions, i.e., use of activated acids or mixed anhydrides (acyl halides, use of coupling reagents, etc), and by the use of alkylating agents (R-X, wherein X is a leaving group, such as diazo, and R is the desired group). Phosphate prodrugs are prepared by phosphorylation, for example, with dialkyl phosphites using procedure such as described in Silverberg et al. (1996), Tet. Lett., Vol. 37, 711-774, U.S. patent 5,561,122 (Pettit et al) and in Hwang 20 and Cole (2004), Org. Lett., vol 6, no 10, 1555-1556 ((POM) 2 phosphate triester from

(POM)

2 phosphoryl chloride), the content of which is incorporated herein by reference in their entirety. IV. Pharmaceutical compositions comprising the compounds of the invention The invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with a pharmaceutically acceptable carrier. The pharmaceutical composition comprising a dibenzodiazepinone analogue is useful for treating diseases and disorders associated with uncontrolled cellular growth and proliferation, such as a 25 WO 2006/034574 PCT/CA2005/001467 neoplastic condition. The pharmaceutical composition is also useful in treating other diseases and disorders, including inflammation, autoimmune diseases, infections, neurodegenerative diseases and stress. The pharmaceutical composition comprising a dibenzodiazepinone analogue may be packaged into a convenient commercial package providing the necessary materials, such as the pharmaceutical composition and written instructions for its use in treating a neoplastic condition, in a suitable container. The compounds of the present invention, or pharmaceutically acceptable salts, solvates or prodrugs thereof, can be formulated for oral, sublingual, intranasal, intraocular, rectal, transdermal, mucosal, topical or parenteral administration for the o10 therapeutic or prophylactic treatment of neoplastic and proliferative diseases and disorders. Parenteral modes of administration include without limitation, intradermal, subcutaneous (s.c., s.q., sub-Q, Hypo), intramuscular (i.m.), intravenous (i.v.), intraperitoneal (i.p.), intra-arterial, intramedulary, intracardiac, intra-articular (joint), intrasynovial (joint fluid area), intracerebral or intracranial, intraspinal, intracisternal, and intrathecal (spinal fluids). Any known device useful for parenteral injection or infusion of drug formulations can be used to effect such administration. For oral and/or parental administration, compounds of the present invention can be mixed with conventional pharmaceutical carriers and excipients and used in the form of solutions, emulsions, tablets, capsules, soft gels, elixirs, suspensions, syrups, wafers and the like. The 20 compositions comprising a compound of the present invention will contain from about 0.1% to about 99.9%, about 1% to about 98%, about 5% to about 95%, about 10% to about 80% or about 15% to about 60% by weight of the active compound. The pharmaceutical preparations disclosed herein are prepared in accordance with standard procedures and are administered at dosages that are selected to reduce, prevent, or eliminate cancer. (See, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA; and Goodman and Gilman, Pharmaceutical Basis of Therapeutics, Pergamon Press, New York, NY, the contents of which are incorporated herein by reference, for a general description of the methods for administering various agents for human therapy). 30 As used herein, the term "unit dosage" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of dibenzodiazepinone analogue calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutically acceptable 26 WO 2006/034574 PCT/CA2005/001467 carriers. In one embodiment, the unit dosage contains from 10 to 3000 mg of active ingredient. In another embodiment, the unit dosage contains 20 to 1000 mg of active ingredient. The compositions of the present invention can be delivered using controlled (e.g., capsules) or sustained release delivery systems (e.g., bioerodable matrices). Exemplary delayed release delivery systems for drug delivery that are suitable for administration of the compositions of the invention are described in U.S. Patent Nos 4,452,775 (issued to Kent), 5,039,660 (issued to Leonard), and 3,854,480 (issued to Zaffaroni), incorporated herein by reference in their entirety. The pharmaceutically-acceptable compositions of the present invention comprise o10 one or more compounds of the present invention in association with one or more non toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants and/or excipients, collectively referred to herein as "carrier" materials, and if desired other active ingredients. Pharmaceutically acceptable carriers include, for example, solvents, vehicles or medium such as saline, buffered saline, dextrose, water, glycerol, ethanol, propylene glycol, polysorbate 80 (Tween-80

TM

), poly(ethylene) glycol 300 and 400 (PEG 300 and 400), PEGylated castor oil (E.g. Cremophor EL), poloxamer 407 and 188, hydrophobic carriers, and combinations thereof. Hydrophobic carriers include, for example, fat emulsions, lipids, PEGylated phopholids, polymer matrices, biocompatible polymers, lipospheres, vesicles, particles, and liposomes. The term specifically 20 excludes cell culture medium. Excipients or additives included in a formulation have different purposes depending, for example on the nature of the drug, and the mode of administration. Examples of generally used excipients include, without limitation: stabilizing agents, solubilizing agents and surfactants, buffers, antioxidants and preservatives, tonicity agents, bulking agents, lubricating agents, emulsifiers, suspending or viscosity agents, inert diluents, fillers, disintegrating agents, binding agents, wetting agents, lubricating agents, antibacterials, chelating agents, sweetners, perfuming agents, flavouring agents, coloring agents, administration aids, and combinations thereof. The compositions may contain common carriers and excipients, such as 30 cornstarch or gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid. The compositions may contain crosarmellose sodium, microcrystalline cellulose, sodium starch glycolate and alginic acid. 27 WO 2006/034574 PCT/CA2005/001467 Formulations for parenteral administration can be in the form of aqueous or non aqueous isotonic sterile injection solutions, suspensions or fat emulsions, comprising a compound of this invention, or a pharmaceutically acceptable salt or prodrug thereof. The parenteral form used for injection must be fluid to the extent that easy syringability exists. These solutions or suspensions can be prepared from sterile concentrated liquids, powders or granules. The compounds can be dissolved in a carrier such as a solvent or vehicle, for example, polyethylene glycol, propylene glycol, ethanol, corn oil, benzyl alcohol, glycofurol, N,N-dimethylacetamide, N-methylpyrrolidone, glycerine, saline, dextrose, water, glycerol, hydrophobic carriers, and combinations thereof. 10 Excipients used in parenteral preparations also include, without limitation, stabilizing agents (e.g. carbohydrates, amino acids and polysorbates), solubilizing agents (e.g. cetrimide, sodium docusate, glyceryl monooleate, polyvinylpyrolidone (PVP) and polyethylene glycol (PEG)) and surfactants (e.g. polysorbates, tocopherol PEG succinate, poloxamer and CremophorTM), buffers (e.g. acetates, citrates, phosphates, tartrates, lactates, succinates, amino acids and the like), antioxidants and preservatives (e.g. BHA, BHT, gentisic acids, vitamin E, ascorbic acid and sulfur containing agents such as sulfites, bisulfites, metabisulfites, thioglycerols, thioglycolates and the like), tonicity agents (for adjusting physiological compatibility), suspending or viscosity agents, antibacterials (e.g. thimersol, benzethonium chloride, benzalkonium 20 chloride, phenol, cresol and chlorobutanol), chelating agents, and administration aids (e.g. local anesthetics, anti-inflammatory agents, anti-clotting agents, vaso-constrictors for prolongation and agents that increase tissue permeability), and combinations thereof. Parenteral formulations using hydrophobic carriers include, for example, fat emulsions and formulations containing lipids, lipospheres, vesicles, particles and liposomes. Fat emulsions include in addition to the above-mentioned excipients, a lipid and an aqueous phase, and additives such as emulsifiers (e.g. phospholipids, poloxamers, polysorbates, and polyoxyethylene castor oil), and osmotic agents (e.g. sodium chloride, glycerol, sorbitol, xylitol and glucose). Liposomes include natural or 30 derived phospholipids and optionally stabilizing agents such as cholesterol. In another embodiment, the parenteral unit dosage form of the compound can be a ready-to-use solution of the compound in a suitable carrier in sterile, hermetically sealed ampoules or in sterile pre-loaded syringes. The suitable carrier optionally 28 WO 2006/034574 PCT/CA2005/001467 comprises any of the above-mentioned excipients. Alternatively, the unit dosage of the compound of the present invention can be in a concentrated liquid, powder or granular form for ex tempore reconstitution in the appropriate pharmaceutically acceptable carrier at the time of delivery. In addition the above-mentioned excipients, powder forms optionally include bulking agents (e.g. mannitol, glycine, lactose, sucrose, trehalose, dextran, hydroxyethyl starch, ficoll and gelatin), and cryo or lyoprotectants. For example, in intravenous (IV) use, a sterile formulation of the compound of formula I and optionally one or more additives, including solubilizers or surfactants, can o10 be dissolved or suspended in any of the commonly used intravenous fluids and administered by infusion. Intravenous fluids include, without limitation, physiological saline, phosphate buffered saline, 5% glucose or Ringer's T M solution. In another example, in intramuscular preparations, a sterile formulation of the compound of the present invention or suitable soluble salts or prodrugs forming the compound, can be dissolved and administered in a pharmaceutical diluent such as Water-for-Injection (WFI), physiological saline or 5% glucose. A suitable insoluble form of the compound may be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, e.g. an ester of a long chain fatty acid such as ethyl oleate. 20 For oral use, solid formulations such as tablets and capsules are particularly useful. Sustained released or enterically coated preparations may also be devised. For pediatric and geriatric applications, suspension, syrups and chewable tablets are especially suitable. For oral administration, the pharmaceutical compositions are in the form of, for example, tablets, capsules, suspensions or liquid syrups or elixirs, wafers and the like. For general oral administration, excipient or additives include, but are not limited to inert diluents, fillers, disintegrating agents, binding agents, wetting agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. The oral pharmaceutical composition is preferably made in the form of a unit 30 dosage containing a therapeutically-effective amount of the active ingredient. Examples of such dosage units are tablets and capsules. For therapeutic purposes, the tablets and capsules which can contain, in addition to the active ingredient, 29 WO 2006/034574 PCT/CA2005/001467 conventional carriers such as: inert diluents (e.g., sodium and calcium carbonate, sodium and calcium phosphate, and lactose), binding agents (e.g., acacia gum, starch, gelatin, sucrose, polyvinylpyrrolidone (Providone), sorbitol, or tragacanth methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and ethylcellulose), fillers (e.g., calcium phosphate, glycine, lactose, maize-starch, sorbitol, or sucrose), lubricants or lubricating agents (e.g., magnesium stearate or other metallic stearates, stearic acid, polyethylene glycol, waxes, oils, silica and colloical silica, silicon fluid or talc), disintegrants or disintegrating agents (e.g., potato starch, corn starch and alginic acid), flavouring, coloring agents, or acceptable wetting agents. Carriers may io also include coating excipients such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Oral liquid preparations, generally in the form of aqueous or oily solutions, suspensions, emulsions, syrups or elixirs, may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous agents, preservatives, coloring agents and flavoring agents. Examples of additives for liquid preparations include acacia, almond oil, ethyl alcohol, fractionated coconut oil, gelatin, glucose syrup, glycerin, hydrogenated edible fats, lecithin, methyl cellulose, methyl or propyl para hydroxybenzoate, propylene glycol, sorbitol, or sorbic acid. For both liquid and solid oral preparations, flavoring agents such as peppermint, 20 oil of wintergreen, cherry, grape, fruit flavoring or the like can also be used. It may also be desirable to add a coloring agent to make the dosage form more aesthetic in appearance or to help identify the product. For topical use the compounds of present invention can also be prepared in suitable forms to be applied to the skin, or mucus membranes of the nose and throat, and can take the form of creams, ointments, liquid sprays or inhalants, lozenges, or throat paints. Such topical formulations further can. include chemical compounds such as dimethylsulfoxide (DMSO) to facilitate surface penetration of the active ingredient. For application to the eyes or ears, the compounds of the present invention can be presented in liquid or semi-liquid form formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints or powders. For 30 rectal administration the compounds of the present invention can be administered in the form of suppositories admixed with conventional carriers such as cocoa butter, wax or other glyceride. 30 WO 2006/034574 PCT/CA2005/001467 V. Medical Use in the Treatment of Neoplasms In one aspect, the invention relates to a method for inhibiting growth and/or proliferation of cancer cells in a mammal. In another aspect, the invention provides a method for treating neoplasms in a mammal. Mammals include ungulates (e.g. sheeps, goats, cows, horses, pigs), and non-ungulates, including rodents, felines, canines and primates (i.e. human and non-human primates). In a preferred embodiment, the mammal is a human. The dibenzodiazepinone analogues of the present invention may bind to or interact with other cancer-associated proteins and polypeptides, including, without 10 limitation, polypeptides encoded by oncogenes, polypeptides that induce angiogenesis, proteins involved in metastasizing and/or invasive processes, and proteases that regulate apoptosis and the cell cycle. Regardless of the mechanism of action, the dibenzodiazepinone analogues of the invention have been demonstrated to exhibit anti cancer activity both in vitro and in vivo. Based on these discoveries, applicants have developed methods for treating neoplasms. As used herein, the terms "neoplasm", "neoplastic disorder", "neoplasia" "cancer," "tumor" and "proliferative disorder" refer to cells having the capacity for autonomous growth, i.e., an abnormal state of condition characterized by rapidly proliferating cell growth which generally forms a distinct mass that show partial or total 20 lack of structural organization and functional coordination with normal tissue. The terms are meant to encompass hematopoietic neoplasms (e.g. lymphomas or leukemias) as well as solid neoplasms (e.g. sarcomas or carcinomas), including all types of pre-cancerous and cancerous growths, or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. Hematopoietic neoplasms are malignant tumors affecting hematopoietic structures (structures pertaining to the formation of blood cells) and components of the immune system, including leukemias (related to leukocytes (white blood cells) and their precursors in the blood and bone marrow) arising from myeloid, lymphoid or erythroid lineages, and lymphomas (relates to 30 lymphocytes). Solid neoplasms include sarcomas, which are malignant neoplasms that originate from connective tissues such as muscle, cartilage, blood vessels, fibrous tissue, fat or bone. Solid neoplasms also include carcinomas, which are malignant neoplasms arising from epithelial structures (including external epithelia (e.g., skin and 31 WO 2006/034574 PCT/CA2005/001467 linings of the gastrointestinal tract, lungs, and cervix), and internal epithelia that line various glands (e.g., breast, pancreas, thyroid). Examples of neoplasms that are particularly susceptible to treatment by the methods of the invention include leukemia, and hepatocellular cancers, sarcoma, vascular endothelial cancers, breast carcers, central nervous system cancers (e.g. astrocytoma, gliosarcoma, neuroblastoma, oligodendroglioma and glioblastoma), prostate cancers, lung and bronchus cancers, larynx cancers, esophagus cancers, colon cancers, colorectal cancers, gastro-intestinal cancers, melanomas, ovarian and endometrial cancer, renal and bladder cancer, liver cancer, endocrine cancer (e.g. thyroid), and pancreatic cancer. 10 The dibenzodiazepinone analogue is brought into contact with or introduced into a cancerous cell or tissue. In general, the methods of the invention for delivering the compositions of the invention in vivo utilize art-recognized protocols for delivering therapeutic agents with the only substantial procedural modification being the substitution of the dibenzodiazepinone analogue of the present invention for the therapeutic agent in the art-recognized protocols. The route by which the dibenzodiazepinone analogue is administered, as well as the formulation, carrier or vehicle will depend on the location as well as the type of the neoplasm. A wide variety of administration routes can be employed. The dibenzodiazepinone analogue may be administered by intravenous or intraperitoneal infusion or injection. For example, for a 20 solid neoplasm that is accessible, the compound of the invention may be administered by injection directly into the neoplasm. For a hematopoietic neoplasm the compound may be administered intravenously or intravascularly. For neoplasms that are not easily accessible within the body, such as metastases or brain tumors, the compound may be administered in a manner such that it can be transported systemically through the body of the mammal and thereby reach the neoplasm and distant metastases for example intrathecally, intravenously or intramuscularly or orally. Alternatively, the compound can be administered directly to the tumor. The compound can also be administered subcutaneously, intraperitoneally, topically (for example for melanoma), rectally (for example colorectal neoplasm) vaginally (for example for cervical or vaginal 30 neoplasm), nasally or by inhalation spray (for example for lung neoplasm). The dibenzodiazepinone analogue is administered in an amount that is sufficient to inhibit the growth or proliferation of a neoplastic cell, or to treat a neoplastic disorder. The term "inhibition" refers to suppression, killing, stasis, or destruction of cancer cells. 32 WO 2006/034574 PCT/CA2005/001467 The inhibition of mammalian cancer cell growth according to this method can be monitored in several ways. Cancer cells grown in vitro can be treated with the compound and monitored for growth or death relative to the same cells cultured in the absence of the compound. A cessation of growth or a slowing of the growth rate (i.e., the doubling rate), e.g., by 50% or more at 100 micromolar, is indicative of cancer cell inhibition (see Anticancer Drug Development Guide: preclinical screening, clinical trials and approval; B.A. Teicher and P.A. Andrews, ed., 2004, Humana Press, Totowa, NJ). Alternatively, cancer cell inhibition can be monitored by administering the compound to an animal model of the cancer of interest. Examples of experimental non-human o10 animal cancer models are known in the art and described below and in the examples herein. A cessation of tumor growth (i.e., no further increase in size) or a reduction in tumor size (i.e., tumor volume by least a 58%) in animals treated with the compound relative to tumors in control animals not treated with the compound is indicative of significant tumor growth inhibition (see Anticancer Drug Development Guide: preclinical screening, clinical trials and approval; B.A. Teicher and P.A. Andrews, ed., 2004, Humana Press, Totowa, NJ). The term "treatment" refers to the application or administration of a dibenzodiazepinone analogue to a mammal, or application or administration of a dibenzodiazepinone analogue to an isolated tissue or cell line from a mammal, who has 20 a neoplastic disorder, a symptom of a neoplastic disorder or a predisposition toward a neoplastic disorder, with the purpose to cure, heal, alleviate, relieve, alter, ameliorate, improve, or control the disorder, the symptoms of disorder, or the predisposition toward disorder. The term "treating" is defined as administering, to a mammal, an amount of a dibenzodiazepinone analogue sufficient to result in the prevention, reduction or elimination of neoplastic cells in a mammal ("therapeutically effective amount"). The therapeutically effective amount and timing of dosage will be determined on an individual basis and may be based, at least in part, on consideration of the age, body weight, sex, diet and general health of the recipient subject, on the nature and severity of the disease condition, and on previous treatments and other diseases present. 30 Other factors also include the route and frequency of administration, the activity of the administered compound, the metabolic stability, length of action and excretion of the compound, drug combination, the tolerance of the recipient subject to the compound and the type of neoplasm or proliferative disorder. In one embodiment, a 33 WO 2006/034574 PCT/CA2005/001467 therapeutically effective amount of the compound is in the range of about 0.01 to about 750 mg/kg of body weight of the mammal. In another embodiment, the therapeutically effective amount is in the range of about 0.01 to about 300 mg/kg body weight per day. In yet another embodiment, the therapeutically effective amount is in the range of 10 to about 50 mg/kg body weight per day. The therapeutically effective doses of the above embodiments may also be expressed in milligrams per square meter (mg/m 2 ) in the case of a human patient. Conversion factors for different mammalian species may be found in:Freireich et al, Quantitative comparison of toxicity of anticancer agents in mouse, rat, dog, monkey and man,. Cancer Chemrnoth. Report, 1966, 50(4): 219-244, o10 incorporated herein by reference in its entirety. When special requirements may be needed (e.g. for children patients), the therapeutically effective doses described above may be outside the ranges stated herein. Such higher or lower doses are within the scope of the present invention. To monitor the efficacy of tumor treatment in a human, tumor size and/or tumor morphology is measured before and after initiation of the treatment, and treatment is considered effective if either the tumor size ceases further growth, or if the tumor is reduced in size, e.g., by at least 10% or more (e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 100%, that is, the absence of the tumor). Prolongation of survival, time-to-disease progression, partial response and objective response rate are surrogate 20 measures of clinical activity of the investigational agent. Tumor shrinkage is considered to be one treatment-specific response. This system is limited by the requirement that patients have visceral masses that are amenable to accurate measurement. Methods of determining the size of a tumor in vivo vary with the type of tumor, and include, for example, various imaging techniques well known to those in the medical imaging or oncology fields (MRI, CAT, PET, etc.), as well as histological techniques and flow cytometry. For certain types of cancer, evaluation of serum tumor markers are also used to evaluate response (eg prostate-specific antigen (PSA) for prostate cancer, and carcino-embryonic antigen (CEA), for colon cancer). Other methods of monitoring cancer growth include cell counts (e.g. in leukemias) in blood or relief in bone pain (e.g. 30 prostate cancer). The dibenzodiazepinone compound may be administered once daily, or the compound may be administered as two, three, four, or more sub-doses at appropriate intervals throughout the day. In that case, the dibenzodiazepinone compound 34 WO 2006/034574 PCT/CA2005/001467 contained in each sub-dose must be correspondingly smaller in order to achieve the total daily dosage. The dosage unit can also be compounded for delivery over several days, e.g., using a conventional sustained release formulation which provides sustained release of the dibenzodiazepinone compound over a several day period. Sustained release formulations are well known in the art. In this embodiment, the dosage unit contains a corresponding multiple of the daily dose. The effective dose can be administered either as a single administration event (e.g., a bolus injection) or as a slow injection or infusion, e.g. over 30 minutes to about 24 hours. The compound may be administered as a treatment, for up to 30 days. Moreover, treatment of a subject with a o10 therapeutically effective amount of a composition can include a single treatment or a series of treatments (e.g., a four-week treatment repeated 3 times, with a 2 months interval between each treatment). Estimates of effective dosages, toxicities and in vivo half-lives for the dibenzodiazepinone compounds encompassed by the invention can be made using conventional methodologies or on the basis of in vivo testing using an appropriate animal model. The dibenzodiazepinone compound may be administered in conjunction with or in addition to known other anticancer treatments such as radiotherapy, or other known anticancer.compounds or chemotherapeutic agents. Such agents include, but are not limited to, 5-flurouracil, mitomycin C, methotrexate, hydroxyurea, cyclophosphamide, 20 dacarbazine, mitoxantrone, anthracyclines (Epirubicin and Doxurubicin), etopside, pregnasome, platinum compounds such as carboplatin and cisplatin, taxanes such as Paclitaxel T M and DocetaxelTM; hormone therapies such as tamoxifen and anti estrogens; antibodies to receptors, such as herceptin and Iressa; aromatase inhibitors, progestational agents and LHRH analogues; biological response modifiers such as IL2 and interferons; multidrug reversing agents such as the cyclosporin analogue PSC 833. Toxicity and therapeutic efficacy of dibenzodiazepinone compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. Therapeutic efficacy is determined in animal models as described above and 30 in the examples herein. Toxicity studies are done to determine the lethal dose for 10% of tested animals (LD10). Animals are treated at the maximum tolerated dose (MTD): the highest dose not producing mortality or greater than 20% body weight loss. The effective dose (ED) is related to the MTD in a given tumor model to determine the 35 WO 2006/034574 PCT/CA2005/001467 therapeutic index of the compound. A therapeutic index (MTD/ED) close to 1.0 has been found to be acceptable for some chemotherapeutic drugs, a preferred therapeutic index for classical chemotherapeutic drugs is 1.25 or higher. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of compositions of the invention will generally be within a range of circulating concentrations that include the MTD. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially 10 from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range of the compound. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by HPLC. Animal models to determine antitumor efficacy of a compound are generally carried out in mice. Either murine tumor cells are inoculated subcutaneously into the hind flank of mice from the same species (syngeneic models) or human tumor cells are inoculated subcutaneously into the hind flank of severe combined immune deficient (SCID) mice or other immune deficient mice (nude mice) (xenograft models). Advances in mouse genetics have generated a number of mouse models for the 20 study of various human diseases including cancer. The MMHCC (Mouse models of Human Cancer Consortium) web page (emice.nci.nih.gov), sponsored by the National Cancer Institute, provides disease-site-specific compendium of known cancer models, and has links to the searchable Cancer Models Database (cancermodels.nci.nih.gov), as well as the NCI-MMHCC mouse repository. Mouse repositories can also be found at: The Jackson Laboratory, Charles River Laboratories, Taconic, Harlan, Mutant Mouse Regional Resource Centers (MMRRC) National Network and at the European Mouse Mutant Archive. Such models may be used for in vivo testing of dibenzodiazepinone compounds, as well as for determining a therapeutically effective dose. 30 In addition to the compounds of the invention, pharmaceutically acceptable salts, solvates or prodrugs of said compounds may also be employed in compositions to treat or prevent the above-identified disorders. 36 WO 2006/034574 PCT/CA2005/001467 EXAMPLES Unless otherwise noted, all reagents were purchased from Sigma Chemical Co. (St. Louis, MO), Aldrich. All NMR spectra were collected in deuterated solvent on a Varian 500TM Spectrometer (1H NMR at 500 MHz, 13C NMR at 125 MHz). UV and mass spectra were collected by Waters 2690TM HPLC using a photodiode array detector (PDA, 210 400nm) coupled to a Waters MicromassTM ZQTM mass detector. Unless otherwise indicated, all numbers expressing quantities of ingredients, 10 properties such as molecular weight, reaction conditions, molar equivalents (eq), percentage of binding and/or inhibition, G1 50 , IC50 and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of significant figures and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set in the examples, 20 Tables and Figures are reported as precisely as possible. Any numerical values may inherently contain certain errors resulting from variations in experiments, testing measurements, statistical analyses and such. In the following section, examples describe in detail the chemical synthesis of representative compounds of the present invention. The procedures are illustrations, and the invention should not be construed as being limited by chemical reactions and conditions they express. No attempt has been made to optimize the yields obtained in these reactions, and it would be obvious to one skilled in the art that variations in reaction times, temperature, solvent and/or reagents could increase the yields. In addition, the materials, methods, and examples, including in vitro and in vivo 30 efficacy, bioavailability, toxicity and pharmacological properties are illustrative only and not intended to be limiting. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, 37 WO 2006/034574 PCT/CA2005/001467 suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. EXAMPLE 1: PRODUCTION OF COMPOUND 1 BY FERMENTATION Examplary fermentation procedures: a) Fermentation procedure Micromonospora sp. (deposit accession number IDAC 070303-01) was 10 maintained on agar plates of ISP2 agar (Difco Laboratories, Detroit, MI). An inoculum for the production phase was prepared by transferring the surface growth of the Micromonospora sp. from the agar plates to 125-mL flasks containing 25 mL of sterile medium comprised of glucose 10 Og, potato dextrin type IV (Sigma) 20 g, yeast extract 5 g, N Z Amine-A 5 g, 1 g CaCO 3 made up to one liter with tap water (pH 7.0). The culture was incubated at about 280C for approximately 70-72 hours on a rotary shaker set at 250 rpm. Following incubation, 10 mL of culture was transferred to a 2L baffled flask containing 600 mL of sterile production medium containing 20 g/L potato dextrin type IV (sigma), 30 g/L glycerol, 2.5 g/L Bacto-peptone, 8.34 g/L yeast extract, 3 g/L CaCO 3 , pH 7.0. Fermentation broth was prepared by incubating the production culture 20 at 280C in a rotary shaker set at 250 rpm for 5 days. b) Alternate procedure: The fermentation was accomplished as a 1 x 10OL batch in a 14.5 L fermentor (BioFlo 1 10 T M Fermentor, New Brunswick Scientific, Edison, NJ, USA) using an improved procedure described in CA patent application 2,466,340, filed January 21, 2004. Micromonospora sp. (deposit accession number IDAC 070303-01) was maintained on agar plates of ISP2 agar (Difco Laboratories, Detroit, MI). An inoculum for the production phase was prepared by transferring the surface growth of the Micromonospora sp. from the agar plates to 2-L flasks containing 500 mL of sterile 30 medium comprised of 10 g glucose, 20 g potato dextrin, 5 g yeast extract, 5 g NZ Amine A, and 1 g CaCO 3 made up to one liter with tap water (pH 7.0). The culture was 38 WO 2006/034574 PCT/CA2005/001467 incubated at about 28 0 C for approximately 70 hours on a rotary shaker set at 250 rpm. Following incubation, 300 mL of culture was transferred to a 14.5 L fermentor containing 10 L of sterile production medium. Each liter of production medium was composed of 20 g potato dextrin, 30 g glycerol, 2.5 g Bacto-peptone, 8.34 g yeast extract, 0.3 mL Silicone defoamer oil (Chem Service), 0.05 ml Proflo oilTM (Traders protein) and 3 g CaCO3 made to one liter with distilled water and adjusted to pH 7.0. The culture was incubated at 28 OC, with dissolved oxygen (dO 2 ) controlled at 25% in a cascade loop with agitation varied between 320-600 RPM and aeration set at a fixed rate of 0.5 v/v/m. 10 In addition to the above medium, other preferred media for the production of Compound 1 by fermentation are provided in Table 1 (QB, MA, KH, RM, JA, FA, CL). Any one of Micromonospora sp. 046-ECO 11 or [S01]046 may be used in these exemplified methods. EXAMPLE 2: ISOLATION OF COMPOUND 1 Examplary isolation procedures: a) Isolation procedure 1: 500 mL ethyl acetate was added to 500 mL of fermentation broth prepared as described in Example 1 above. The mixture was agitated for 30 minutes on an orbital 20 shaker at 200 rpm to create an emulsion. The phases were separated by centrifugation and decantation. Between 4 and 5 g of anhydrous MgSO 4 was added to the organic phase, which was then filtered and the solvents removed in vacuo. An ethyl acetate extract from 2 L fermentation was mixed with HP-20 resin (100 mL; Mitsubishi Casei Corp., Tokyo, Japan) in water (300 mL). Ethyl acetate was removed in vacuo, the resin was filtered on a BOchner funnel and the filtrate was discarded. The adsorbed HP-20 resin was then washed successively with 2 x 125 mL of 50% acetonitrile in water, 2x125 mL of 75% acetonitrile in water and 2 x 125 mL of acetonitrile. Fractions containing Compound 1 were evaporated to dryness and 100 mg was 30 digested in the 5 mL of the upper phase of a mixture prepared from chloroform, cyclohexane, methanol, and water in the ratios, by volume, of 5:2:10:5. The sample 39 WO 2006/034574 PCT/CA2005/001467 was subjected to centrifugal partition chromatography using a High Speed Countercurrent Chromatography (HSCC) system (Kromaton Technologies, Angers, France) fitted with a 200 mL cartridge and prepacked with the upper phase of this two phase system. The HSCC was run with the lower phase mobile and Compound 1 was eluted at approximately one-half column volume. Fractions were collected and Compound 1 was detected by TLC of aliquots of the fractions on commercial Kieselgel 60F 254 plates. Compound could be visualized by inspection of dried plates under UV light or by spraying the plates with a spray containing vanillin (0.75%) and concentrated sulfuric acid (1.5%, v/v) in ethanol and subsequently heating, the plate. Fractions io contained substantially pure Compound 1, although highly colored. A buff-colored sample could be obtained by chromatography on HPLC as follows. 6 mg of sample was dissolved in acetonitrile and injected onto a preparative HPLC column (Xterra T M ODS (10pm), 19x150mm, Waters Co., Milford, MA), with a 9 mL/min flow rate and UV peak detection at 300 nm. The column was eluted with acetonitrile/buffer (5 mM of NH 4

HCO

3 ) according to the following gradient shown in Table 2. Table 2 Preparative HPLC gradient Time (min) Water (%) Acetonitrile (%) 0 50 50 10 0 100 20 0 100 25 50 50 30 50 50 Fractions containing Compound 1 were combined, concentrated and lyophilized 20 to give a yield of 3.8 mg compound. b) Isolation procedure 2: Compound 1 was also isolated using the following alternative protocol. At the end of the incubation period, the fermentation broth from the baffled flasks of Example 1 was centrifuged and the supernatant decanted from the pellet containing the bacterial mycelia. 100 mL of 100% MeOH was added to the mycelial pellet and the sample was stirred for 10 minutes and centrifuged for 15 minutes. The methanolic supernatant was 40 WO 2006/034574 PCT/CA2005/001467 decanted and saved. 100 mL of acetone was then added to the mycelial pellet and stirred for 10 minutes then centrifuged for 15 minutes. The acetonic supernatant was decanted and combined with the methanolic supernatant. Finally, 100 mL of 20% MeOH/H 2 0 was added to the mycelial pellet, stirred for 10 minutes and centrifuged for 15 minutes. The supernatant was combined with the acetonic and methanolic supernatants. The combined supernatant was added to 400 ml of HP-20 resin in 1000 mL of water and the organics were removed in vacuo. The resulting slurry was filtered on a Buchner funnel and the filtrate was discarded. HP-20 resin was washed successively 10 with 2x500mL of 50% MeOH/H 2 0, 2x500mL of 75% MeOH/H 2 0 and 2x500mL of MeOH. The individual washes were collected separately and analyzed by TLC as described above. Those fractions containing Compound 1 were evaporated to near dryness and lyophilized. The lyophilizate was dissolved in methanol and injected onto a preparative HPLC column (Xterra T M ODS (10tm), 19x150mm, Waters Co., Milford, MA) with a flow rate of 9 mL/min and peak detection at 300 nm. The column was eluted with acetonitrile/buffer (5 mM of NH 4

HCO

3 ) according to gradient shown in Table 3. Table 3 Preparative HPLC gradient Time (min) Buffer (%) Acetonitrile (%) 0 95 5 15 45 55 20 5 95 30 5 95 35 95 5 20 Fractions containing Compound 1 were combined, concentrated and lyophilized to yield about 33.7 mg of compound. c) Isolation procedure 3: 10 liters of the whole broth from Example 1 was extracted twice with equal volumes of ethyl acetate and the two extracts were combined and concentrated to dryness. The dried extract was weighed, and for every gram of dry extract, 100 mL of 41 WO 2006/034574 PCT/CA2005/001467 MeOH-H 2 0 (2:1 v/v) and 100 mL of hexane was added. The mixture was swirled gently but well to achieve dissolution. The two layers were separated and the aqueous layer is washed with 100 mL of hexane. The two hexane layers were combined and the combined hexane solution was washed with 100 mL methanol:water (2:1, v/v). The two methanol:water layers were combined and treated with 200 mL of EtOAc and 400 mL of water. The layers were separated and the aqueous layer extracted twice further with 200 mL portions of EtOAc. The EtOAc layers are combined and concentrated. The residue obtained (220 mg) was suitable for final purification, either by HSCC or by HPLC as described above. This extraction process achieved a ten-fold purification 10 when compared with the extraction protocol used in (a) or (b). EXAMPLE 3: ELUCIDATION OF THE STRUCTURE OF COMPOUND 1 1"2" 3"' 0 1 1a 12' 2 9a 9 3 4a 8OH 4 5 N 5a

C

28

H

34

N

2 0 4 -- Mol. Wt.: 462.25 OH H 6 7 HO The calculated molecular weight of the major isotope (462.25) and formula

(C

28

H

34

N

2 0 4 ) of Compound 1 was confirmed by mass spectral analysis: negative ionization gave an (M-H)- molecular ion of 461.2 and positive ionization gave an (M+H) molecular ion of 463.3. UVmax was determined to be 230nm with a shoulder at 290 nm. Proton and carbon NMR spectral analysis is shown in Table 4. NMR data were 20 collected dissolved in MeOH-d4 including proton, carbon and multidimensional pulse sequences gDQCOSY, gHSQC, gHMBC, and NOESY. A number of cross peaks in the 2D spectra of Compound 1 are key in the structural determination. For example, the farnesyl chain is placed on the amide nitrogen by a strong cross peak between the proton signal of the terminal methylene of that chain at 4.52 ppm and the amide carbonyl carbon at 170 ppm in the gHMBC experiment. This conclusion is confirmed by a cross peak in the NOESY spectrum between the same methylene signals at 4.52 ppm and the aromatic proton signal at 6.25 ppm from one of the two protons of the tetra 42 WO 2006/034574 PCT/CA2005/001467 substituted benzenoid ring. Assignment of proton and carbon signals are shown in Table 4. Table 4 H and 13C NMR (SH, ppm) Data of Compound 1 in MeOH-D 4 Assignment 1H 13C Group 1 7.15 122.3 CH 2 6.74 121.0 CH 3 6.83 116.9 CH 4 - 146.0 C-OH 4a - 142.0 C 5a - 126.0 C 6 - 148.2 C-OH 7 6.20 100.0 CH 8 - 153.0 C-OH 9 6.25 101.0 CH 9a - 135.0 C 11 - 170.0 C(0) 11a - 125.0 C 1' 4.52 48.7 CH 2 2' 5.35 121.1 CH 3' - 138.5 C 4' 2.03 39.5 CH 2 5' 2.08 26.7 CH 2 6' 5.09 124.1 CH 7' - 135.0 C 8' 1.95 39.6 CH 2 9' 2.02 26.3 CH 2 10' 5.06 124.4 CH 11' - 130.9 C 12' 1.64 24.8 CH 3 1" 1.72 15.5 CH 3 2" 1.59 14.9 CH 3 3" 1.55 16.5 CH 3 Based on the mass, UV and NMR spectroscopy data, the structure of the compound was determined to be the structure of Compound 1 shown above. EXAMPLE 4: DIALKYLSULFATE REACTIONS a) Synthesis and structural elucidation of Compounds 2 and 18 43 WO 2006/034574 PCT/CA2005/001467 1" 2" 3" 0 11a 31 1 11l 10 12' 2 9a 9 3 a 8 OH 4 5 N 5a 0 29

H

36

N

2 0 4 I - Mol. Wt.: 476.27 OH CH 3 6 7 HO Compound 2, namely 10-farnesyl-4,6,8-trihydroxy-5-methyl-5,10-dihydro dibenzo[b,e][1,4]diazepin-11-one, and 1" 2" 3" 0 1 11 10 2'1 11a N ' 12' 2 9a 9 H 3 CO 4 a 8 OH C 30

H

40

N

2 0 5 4 5 N Sa Mol. Wt.: 508.29 OH CH 3 6 7 HO Compound 18, namely 10-(7-methoxy-3,7,11-trimethyldodeca-2,10-dienyl)-4,6,8 trihydroxy-5-methyl-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one, were prepared and identified as follows: Preparation: Compound 1 (500.0 mg) was dissolved in methanol (MeOH, 20 mL) and stirred o10 with dimethyl sulfate (0.5 mL) and NaHCO 3 (250 mg) at room temperature for 48 hrs. The reaction mixture was diluted to 200 mL by adding water and extracted with ethyl acetate (EtOAc, 300 mL x 3). The organic layer was separated and dried under vacuum, re-dissolved in MeOH and filtered through a 0.45 pm 13 mm Acrodisc T M GHP syringe filter. The filtrate was subjected for isolation on a Waters HPLC coupled to a photodiode array detector. Compound 18 (12.1 mg) and Compound 2 (308.5 mg) were isolated by the multiple injections on Nova-Pack T M HR C18 6pm 25 x 200 mm column (20 mL/min, H 2 0/CH 3 CN gradient 80:20-30:70, 0-8 min; 30:70-0:100, 8-18 min), eluting at 14.5 and 16.8 min, respectively. Structural elucidation of Compounds 2 and 18: 20 The calculated molecular weight for the major isotope (476.27) and formula

(C

29

H

36

N

2 0 4 ) of Compound 2 was confirmed by mass spectral analysis: negative ionization gave an (M-H) molecular ion of 475.6 and positive ionization gave an (M+Na) molecular ion of 499.4. Proton and carbon NMR spectral analysis is shown in Table 5. Signals were easily assigned based on Compound 1 structure knowledge. The 44 WO 2006/034574 PCT/CA2005/001467 calculated molecular weight for the major isotope (508.29) and formula (C 30

H

40

N

2 0 5 ) of Compound 18 was confirmed by mass spectral analysis: negative ionization gave an (M-H)- molecular ion of 507.3 and positive ionization gave an (M+H) + molecular ion of 509.3. The characteristic N-methyl (signal 5), methoxy (signal 7'-OMe) and the methylene group (6'), from the addition of methanol on the farnesyl chain were easily assigned as shown in Table 5. Table 5 NMR (8, ppm) Data of Compounds 2 and 18 in MeOH-D 4 Compound 2 Compound 18 Assignment 1 13c 1 Group 1 7.21 122.1 7.21 CH 2 7.14 127.3 7.14 CH 3 7.02 118.4 7.02 CH 4 - 152.6 - C-OH 4a - 139.3 - C 5-N-Me 2.92 41.1 2.93 N-CH 3 5a - 125.4 - C 6 - 154.8 - C-OH 7 6.22 99.6 6.20 CH 8 - 156.8 - C-OH 9 6.34 101.4 6.34 CH 9a - 142.0 - C 11 - 168.2 - C(0) 11a - 133.5 - C 1' 4.83, 4.58 47.7 4.89, 4.57 CH 2 2' 5.44 119.8 5.42 CH 3' - 139.3 - C 4' 2.07 b 39.5 2.06 CH 2 5' 2.12 b 26.2 1.42 CH 2 6' 5.10 123.8 1.42 CH (CH 2 )a 7' - 135.1 - C 7' OMe N/A N/A 3.13 OCH 3 8' 1.95 b 39.8 1.42 CH 2 9' 2.04 b ' 26.8 1.93 CH 2 10' 5.07 124.3 5.12 CH 11' - 130.8 - C 12' 1.65 24.9 1.68 CH 3 1" 1.78 15.8 1.77 CH 3 2" 1.60 15.1 1.10 CH 3 3" 1.55 16.6 1.60 CH 3 N/A: not applicable, group not present in the molecule a. CH in Compound 2, CH 2 in Compound 18 b. Signals for 4', 5', 8' and 9' are very close; assignment was based on Compound 1 10 45 WO 2006/034574 PCT/CA2005/001467 b) Synthesis and structural elucidation of Compounds 3, 21, and 22 1" 2" 3" 0 1\ 1 11 10 2' 4' 5' 6 7, 8' 9 10 1 12' 113 NV1 2 2'9a 9 3 4a8 OH 4 a 5N 8 H C 30

H

38

N

2 0 4 5 a- Mol. Wt.: 490.28 OH 6 7 HO Compound 3: 10-farnesyl-4,6,8-trihydroxy-5-ethyl-5, 1O-dihydro dibenzo[b,e][1,4]diazepin-11-one; S2" 3" 0 S 11 10 1 ' 7' 11 1 2' lia N 3 ' 4 ' 6' 8' 10' 2 9a 9 HaCO 3 4a 8 oH 0 3 1

H

42

N

2 0 5 4 N 5a Mol. Wt.: 522.31 OH 6 7 HO Compound 21: 10-(11-methoxy-3,7,11-trimethyl-2,6-dodecadienyl)-4,6,8-trihydroxy-5 ethyl-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one; 1" 2" 3" 0 1' ,7' ,1' S 1 1 10 2 ' 4' 5' 6 ' 8' 9' 10' 12' 9a 9 H 3 CO H 3 CO 3 a 8 OH 0 3 2

H

4 6

N

2 0 5 4 5 N 5a Mol. Wt.: 554.34 OH 6 7 HO Compound 22:10-(7,11-dimethoxy-3,7,11-trimethyl-2-dodecenyl)-4,6,8-trihydroxy-5 10 ethyl-5,10-dihydro-dibenzo[b,e][1,4]diazepin- 1 -one; Preparation: Compound 1 (85.3 mg) was stirred for 72 hrs at room temperature in a mixture of diethyl sulfate (2.0 mL) and NaHCO 3 (99.9 mg) in MeOH (2 mL). The resulting mixture was filtered through a 0.45 pm 13 mm Acrodisc TM GHP syringe filter. The solution was purified by preparative HPLC (multiple injections on a NovaPack T M HR C-18 25x200 mm column (20 mL/min, H 2 0/CH 3 CN gradient 80:20-30:70, 0-8 min; 30:70-0:100, 8-18 min) to give four major peaks: Compound 3 (20.0 mg with some impurities, RT: 16.6 min), Compound 21 (17.54 mg, RT:.14.3 min) and Compound 22 (7.82 mg, RT: 12.6 min) were obtained. Fractions containing non-ethylated analogs of Compounds 21 and 46 WO 2006/034574 PCT/CA2005/001467 22 were also isolated respectively in 5.65 mg (RT: 11.6 min) and 2.20 mg (RT: 10.3 min) quantities. The fraction containing Compound 3 was further purified by HPLC using the same column (20 mL/min, H 2 0/CH 3 CN gradient 80:20-30:70, 0-8 min; 30:70 0:100, 8-18 min, curve 7), to give substantially pure Compound 3 (13.85 mg, RT: 17.9 min). Structural elucidation of Compounds 3, 21 and 22: The calculated molecular weight of the major isotope (490.28) and formula

(C

30

H

38

N

2 0 4 ) of Compound 3 was confirmed by mass spectral analysis: negative ionization gave an (M-H)- molecular ion of 489.3 and positive ionization gave an (M+H) o10 molecular ion of 491.3. Proton NMR signals were easily assigned based on Compounds 1 and 2 structures knowledge. The characteristic N-ethyl group (5-N-Et) was easily assigned as shown in Table 6. The calculated molecular weight of the major isotope (522.31) and formula

(C

31

H

42

N

2 0 5 ) of Compound 21 was confirmed by mass spectral analysis: negative ionization gave an (M-H)- molecular ion of 521.3 and positive ionization gave an (M+H) molecular ion of 523.5, and a fragment having an (M+H-HOCH 3 ) molecular ion of 491.3. The characteristic N-ethyl group (5-N-Et), and the methoxy (1 1'-OMe) and methylene (10') groups from the addition of methanol on the farnesyl chain were easily assigned as shown in Table 6. 20 The calculated molecular weight of the major isotope (554.34) and formula

(C

32

H

46

N

2 0 6 ) of Compound 22 was confirmed by mass spectral analysis: negative ionization gave an (M-H) molecular ion of 553.4 and positive ionization gave an (M+H) + molecular ion of 555.4, and fragments having respectively (M+H-HOCH 3 ) and (M+H

HOCH

3

-HOCH

3

)

+ molecular ion of 523.5 and 491.3. The characteristic N-ethyl group (5 N-Et), and methoxy (7'-OMe and 11'-OMe) groups from the addition of two molecules of methanol on the farnesyl chain were easily assigned as shown in Table 6. The methylene groups (5', 6', 8', 9' and 10') were all found to have similar chemical shifts, which is consistent with the saturated alkyl group. Table 6 1 H NMR (SH, ppm) Data of Compounds 3, 21 and 22 in MeOH-D 4 Assignment 3 21 22 Group 1 7.20 7.20 7.20 CH 2 7.13 7.14 7.14 CH 47 WO 2006/034574 PCT/CA2005/001467 Table 6 1 H NMR (SH, ppm) Data of Compounds 3, 21 and 22 in MeOH-D 4 Assignment 3 21 22 Group 3 7.02 7.03 7.03 CH 5-N-Et (C1) 3.23, 3.15 3.23, 3.15 3.24, 3.16 CH 2 5-N-Et (C2) 1.07 1.09 1.09 CH 3 7 6.22 6.22 6.22 CH 9 6.34 6.34 6.34 CH 1' 4.58, 4.56 4.82, 4.56 4.91,4.54 CH 2 2' 5.41 5.41 5.38 CH 4' 2.06 2.07 2.05 CH 2 5' 2.11 2.13 ** CH 2 6' 5.10 5.11 ** CH (CH 2 ) a 7'-OMe N/A N/A 3.17 OCH 3 8' 1.95 1.95 ** CH 2 9' 2.04 1.38 ** CH 2 10' 5.07 1.38 ** CH (CH 2 ) b 11'-OMe N/A 3.13 3.12 OCH 3 12' 1.65 1.08 1.14 CH 3 1" 1.77 1.78 1.78 CH 3 2" 1.60 1.10. 1.10 CH 3 3" 1.55 1.08 1.14 CH 3 N/A: not applicable, group not present in the molecule ** signal 1.22-1.49 ppm, 10 protons a. CH in Compounds 3 and 21, OH 2 in Compound 22 b. CH in Compound 3, CH 2 in Compounds 21 and 22 c) Synthesis and structural elucidation of Compound 4 1" 2" 3" 0 1 1 1 1 1 2 ' Ila __N 6' ' 8' ' 10 12 2 9a 9 3 a 8 OH C 31

H

40

N

2 0 4 4 5 N 5a Mol. Wt.: 504.30 OH 6 7 HO Compound 4, namely 10-farnesyl-4,6,8-trihydroxy-5-n-propyl-5,10-dihydro dibenzo[b,e][1,4]diazepin-11-one, was prepared and identified as follows: o10 Preparation: Compound 1 (46.7 mg) was stirred for 72 hrs at room temperature in a mixture of dipropyl sulfate (0.5 mL) and NaHCO 3 (46.3 mg) in MeOH (3 mL). The resulting mixture was filtered through a 0.45 pm 13 mm AcrodiscTM GHP syringe filter. The solution was 48 WO 2006/034574 PCT/CA2005/001467 purified by preparative HPLC (multiple injections on a NovaPack T M HR C-18 25x200 mm column: 20 mL/min, H 2 0/CH 3 CN gradient 80:20-30:70, 0-8 min; 30:70-0:100, 8-18 min) to give substantially pure Compound 4 (18.0 mg, RT: 17.3 min). Structural elucidation of Compound 4: The calculated molecular weight of the major isotope (504.30) and formula (031H 40

N

2 0 4 ) of Compound 4 was confirmed by mass spectral analysis: negative ionization gave an (M-H) molecular ion of 503.4 and positive ionization gave an (M+H) + molecular ion of 505.5. Proton NMR signals were easily assigned based on Compounds 1 and 2 structures knowledge. The characteristic N-Propyl group (5-N-Pr o10 (C1 to C3)) was easily assigned as shown in Table 7 below. d) Synthesis and elucidation of Compound 13 0" 2 " 3 " 1 11 10 1 21 2 Ila N" ~ ~ '6 ' 'g 2 2 S9a 9 4a 8 OH 4 5 N 5a C 2 9

H

33

D

3

N

2 0 4 OH -D3 7 Mol. Wt.: 479.29 OH CD 3 6 7 HO Compound 13: 10-Farnesyl-4,6,8-trihydroxy-5-(trideuteriomethyl)-5,10-dihydro dibenzo[b,e][1,4]diazepin-11-one, was prepared and identified according to the following procedure: Preparation: Compound 1 (121.3 mg) was dissolved in MeOH (3.0 mL), dimethyl sulfate-d 6 20 (150 pL, CDN isotopes Inc.) and NaHCO 3 (58.1 mg) were added, and the reaction was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was subjected to Waters HPLC purification (multiple injections on Nova PackTM HR C 18 25 x 200 mm column: 20 mL/min, H 2 0/CH 3 CN gradient 70:30-20:80, 0-4 min; 20:80 0:100, 4-9 min, 100% CH 3 CN, 9-12 min) to give Compound 13 (82.7 mg, RT 9.4 min). Structural elucidation: The calculated molecular weight of the major isotope (479.29) and formula

(C

29

H

33

D

3

N

2 0 4 ) of Compound 13 was confirmed by mass spectral analysis: negative ionization gave an (M-H)- molecular ion of 478.5, and positive ionization gave an 49 WO 2006/034574 PCT/CA2005/001467 (M+H) molecular ion of 480.6. The structure was further confirmed by proton NMR spectrum as shown in Table 7 below. Table 7 1 H NMR (SH, ppm) Data of Compounds 4 and 13 in MeOH-D 4 Assign Compound 4 Compound 13 Group 1 7.19 7.21 CH 2 7.12 7.14 CH 3 7.01 7.02 CH 5-N-Pr (C1) 3.04, 3.15 - CH 2 a 5-N-Pr (C2) 1.50 N/A CH 2 5-N-Pr (C3) 0.91 N/A CH 3 7 6.22 6.22 CH 9 6.34 6.34 CH 1' 4.54, 4.88 4.83, 4.59 CH 2 2' 5.40 5.44 CH 4' 2.07 2.07 CH 2 5' 2.12 2.12 CH 2 6' 5.09 5.10 CH 8' 1.96 1.95 CH 2 9' 2.03 2.03 CH 2 10' 5.07 5.07 CH 12' 1.65 1.65 CH 3 1" 1.78 1,77 CH 3 2" 1.60 1.60 CH 3 3" 1.55 1.55 CH 3 N/A: not applicable, group not present in the molecule a. CH 2 in Compound 4, CD 3 in Compound 13. EXAMPLE 5: ALKYL HALIDE REACTIONS a) Synthesis and structural elucidation of Compound 5 0 1 11 10 2> 3, ' 6>-T 8' 9 12' 11a N 2 9a 9 3 a 8 OH 32H42N204 4 5 N 5a Mol. Wt.: 518.31 OH 6 7 HO Compound 5, namely 10-farnesyl-4,6,8-trihydroxy-5-n-butyl-5,10-dihydro o10 dibenzo[b,e][1,4]diazepin-11-one, was prepared and identified as follows: 50 WO 2006/034574 PCT/CA2005/001467 Preparation: Compound 1 (43.5 mg) was stirred in 1-bromobutane (2.0 mL) with pyridine (50 pL) at 80 OC overnight. The reaction mixture was diluted with MeOH (1.0 mL), filtered and subjected for Waters HPLC as described above (in Example 4(c)) to give a semi purified Compound 5 (RT: 18.1 min). The semi-purified compound was further purified using the same conditions (except with curve 7) to give substantially pure Compound 5 (10.5 mg, RT: 17.9 min). Structure elucidation: The calculated molecular weight of the major isotope (518.31) and formula 10 (C 32

H

42

N

2 0 4 ) of Compound 5 was confirmed by mass spectral analysis: negative ionization gave an (M-H)- molecular ion of 517.4 and positive ionization gave an (M+H) molecular ion of 519.5. The characteristic N-n-butyl group (5-N-alkyl (C1-C4)) was easily assigned as shown in Table 8 below. b) Synthesis and structural elucidation of Compound 7 0 1 11 10 '12' 2 2 9a 9 3 a / OH C 34

H

46

N

2 0 4 4 5 5N Sa Mol. Wt.: 546.35 OH 6 7 HO Compound 7, namely 10-farnesyl-4,6,8-trihydroxy-5-n-hexyl-5,10-dihydro dibenzo[b,e][1,4]diazepin-11-one, was prepared and identified as follows: Preparation: 20 Compound 1 (39.2 mg) was stirred in 1-bromohexane (2.0 mL) with pyridine (50 pL) at 80 oC overnight. The reaction mixture was diluted with MeOH (1.0 mL), filtered and subjected for Waters HPLC (multiple injections on a NovaPack T M HR C-18 25x200 mm column: 20 mL/min, H 2 0/CH 3 CN gradient 80:20-30:70, 0-8 min; 30:70-0:100, 8-18 min; isocratic CH 3 CN 18-24 minutes) to give substantially pure Compound 7 (14.0 mg, RT: 20.1 min). Structural elucidation: 51 WO 2006/034574 PCT/CA2005/001467 The calculated molecular weight (546.35) and formula (C 34

H

4 6

N

2 0 4 ) of Compound 7 was confirmed by mass spectral analysis: negative ionization gave an (M H) molecular ion of 545.6 and positive ionization gave an (M+H) + molecular ion of 547.6. Proton NMR signals were easily assigned based on Compounds 1 and 2 structures knowledge. The characteristic N-n-hexyl group (5-N-alkyl (C1-C6)) was easily assigned as shown in Table 8 below. c) Synthesis of Compounds 2 to 4, 6, and 8 to 12 Compounds 2 to 4, 6, and 8 to 12 are produced by the procedure described in a) 10 and b), by substituting the alkylating agent used in these procedures respectively by the following alkylating agents: iodomethane, bromoethane, 1-bromopropane, 1 bromopentane, 1-bromoheptane, 1-chlorooctane, trifuoromethyl iodide, heptafluoro-1 iodopropane, and 2-iodo-1,1,1-trifluoroethane. Table 8 1 H NMR (SH, ppm) Data of Compounds 5 and 7 in MeOH-D 4 Assignment 5 7 Group 1 7.20 7.20 CH 2 7.13 7.12 CH 3 7.02 7.02 CH 5-N-alkyl (C1) 3.18, 3.09 3.18, 3.08 CH 2 ,(C2) 1.46 1.48 CH 2 (C3) 1.35 1.30 CH 2 (C4) 0.89 1.30 b (C5) N/A 1.30 CH 2 (C6) N/A 0.89 CH 3 7 6.22 6.23 CH 9 6.34 6.33 CH 1' 4.89, 4.54 4.92, 4.52 CH 2 2' 5.40 5.39 CH 4

'

a 2.06 2.06 OH 2 5' a 2.12 2.11 CH 2 6' 5.09 5.09 CH 8 ' a 1.96 1.96 CH 2 9 ' a 2.04 2.04 CH 2 10' 5.07 5.07 CH 12' 1.65 1.64 CH 3 1" 1.78 1.78 CH 3 2" 1.60 1.60 CH 3 52 WO 2006/034574 PCT/CA2005/001467 Table 8, 1 H NMR (SH, ppm) Data of Compounds 5 and 7 in MeOH-D 4 Assignment 5 7 Group 3" 1.55 1.56 CH 3 N/A: not applicable, group not present in the molecule a. Signals at 4', 5', 8' and 9' are very close; assignment was based on Compound 1. b. CH 3 in Compound 5, OH 2 in Compound 7. EXAMPLE 6: O-ACYLATION Synthesis and structural elucidation of Compound 25 (O-acetylation): 1" 2" 3" 0 1 111 10 N 212 a 1 0 2' 4' 5' 6' T 8"' 1 12' 9a 9 3 a / 8 OAc 4 5 N 5a C0 34

H

40

N

2 0 7 S 6 7 Exact Mass: 588.28 OAc H 6 7 AcO Compound 25:4,6,8-triacetoxy-10-farnesyl-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11 10 one, was prepared and identified according to the following procedure: Preparation: Compound 1 (120.5 mg) was stirred overnight with acetic anhydride (720 pL, 29 eq, Aldrich) in presence of 6 drops of pyridine (Aldrich). The reaction mixtures submitted to HPLC separation. Purification by multiple injection on a Waters T M RCM Nova-Pak HR T M C18, 6pm, 60A 25 x 200 mm column (20 mL/min H 2 0/CH 3 CN 80:30 70:75, 0-8 min; 30:70-0:100, 8-18 min, 100% CH 3 CN, 18-20 min) gave Compound 25 (91.2 mg) with a retention time of 18.5 min. The 4,8-diacetoxy (11.4 mg), 4,6-diacetoxy (9.2 mg), and 6,8-diacetoxy (11.4 mg) compounds were also isolated at retention times of 16.2, 17.6, and 18.0 respectively. 20 Structural elucidation: The calculated molecular weight of the major isotope (588.28) and formula

(C

34

H

40

N

2 0 7 ) of Compound 25 were confirmed by mass spectral (MS) analysis. MS of Compound 25 gave a (M-H)- molecular ion of 587.6 by negative ionization and a (M+Na) molecular ion of 611.5 by positive ionization. Proton NMR spectral analysis for Compound 25 is shown in Table 9. Signals were easily assigned based on comparison 53 WO 2006/034574 PCT/CA2005/001467 with the spectra of Compound 1. Table 9 1 H NMR (SH, ppm) Data of Compound 25 in CDCI3 Assignment 25 Group 1 7.75 CH 2 7.10 CH 3 7.16 CH 4-OAc 2.41 CH 3 5 6.15 NH 6-OAc 2.40 CH 3 7 6.96 CH 8-OAc 2.27 CH 3 9 6.84 CH 1' 4.58 CH 2 2' 5.42 CH 4' a 2.06 CH 2 5' a 2.09 CH 2 6' 5.10 CH 8 ' a 1.98 CH 2 9' a 2.06 CH 2 10' 5.10 CH 12' 1.68 CH 3 1" 1.72 CH 3 2" 1.61 CH 3 3" 1.60 CH 3 N/A: Not applicable, group not present in the molecule. a. Signals of 4', 5', 8' and 9' are very close; assignment was based on Compound 1. EXAMPLE 7: FARNESYL SIDE CHAIN MODIFICATIONS a) Synthesis and structural elucidation of Compound 14 1"2" 3" 0 1' 11 1 010 2' ' 5' 6' 7 8' 9' 10' 11' 12' 2 9a 9 3 /a 8 OH C 2 9

H

4 2

N

2 0 4 4 5 N Sa Mol. Wt.: 482.31 OH CH 3 6 7 HO Compound 14, namely 10-(3,7,11-trimethyldodecyl)-4,6,8-trihydroxy-5-methyl-5,10 10 dihydro-dibenzo[b,e][1,4]diazepin-11 -one, was prepared and identified as follows: Preparation: 54 WO 2006/034574 PCT/CA2005/001467 A solution of Compound 2 (23.7 mg) in MeOH (2.0 mL) was stirred under hydrogen gas overnight in presence of platinum oxide (PtO 2 , 10 mg, catalyst) as a catalyst. The reaction mixture was filtered and concentrated in vacuo to give 21.6 mg of Compound 14. Structural elucidation: The calculated molecular weight (482.31) and formula (C 29

H

42

N

2 0 4 ) of Compound 14 was confirmed by mass spectral analysis: negative ionization gave an (M-H)- molecular ion of 481.3 and positive ionization gave an (M+H) molecular ion of 483.3. The farnesyl olefinic protons on the NMR spectra were replaced by aliphatic 10 proton signals in the region of around 0.76-1.86 ppm, integrating for 17 protons, 3CH, 7CH 2 . The characteristic N-methyl group (5-N-Me) was easily assigned as shown in Table 10 below. b) Synthesis and structural elucidation of Compound 15 1" 2" 3" 0 11a 1 3 4' 5, 6' 7 8' 9 " 1 0 ' 11, 12' Il1a O N2 2 2I 9a 9 1 8 c H 3 4a OH C 29

H

40

N

2 0 4 4 5 N 5a Mol. Wt.: 480.30 OH CH 3 6 7 HO Compound 15, namely 10-(3,7,11-trimethyl-2-dodecenyl)-4,6,8-trihydroxy-5-methyl 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-one, was prepared and identified as follows: Preparation: A solution of Compound 2 (308.5 mg) in MeOH (220 mL) was stirred under 20 hydrogen gas overnight in presence of platinum oxide (PtO 2 , 10 mg) as catalyst. The reaction mixture was filtered and purified by HPLC according to the procedure described in Example 4(c) to give pure Compound 15 (82.3 mg, RT: 17.0 min). Structural elucidation: The calculated molecular weight (480.30) and formula (C 29

H

40

N

2 0 4 ) of Compound 15 was confirmed by mass spectral analysis: negative ionization gave an (M-H) molecular ion of 479.3 and positive ionization gave an (M+H) + molecular ion of 481.6. The NMR spectrum analysis was based on the structural elucidation of 55 WO 2006/034574 PCT/CA2005/001467 Compounds 2 and 14, and the results presented in Table 10. The farnesyl olefinic protons of positions 6'-7' and 10'-11' on the NMR spectra were replaced by aliphatic proton signals and, together with the aliphatic protons of positions 5', 8' and 9', are observed in the region of about 1.07 to 1.51 ppm, integrating for 12 protons, 2CH, 5CH 2 . The farnesyl olefinic proton at position 2'(CH) was shown on the NMR to have a chemical shift of 5.41 ppm. The methylene group at positions 4' was shown at 2.03 ppm. The characteristic 5-N-methyl group was also easily assigned to a chemical shift of 2.93 ppm. o10 c) Synthesis and structural elucidation of Compound 23 1"2" 3" 0 1 10 2' , 6' 7 ' 1 12' N 2 9a 9 3 4a9a 8 OH 4 5 N 5a c 28

H

40

N

2 0 4 OH H 6 7 Mol. Wt.: 468.30 HO Compound 23: 10-(3,7,11-trimethyldodecyl)-4,6,8-trihydroxy-5,10-dihydro dibenzo[b,e][1,4]diazepin-11-one, was prepared and identified according to the following procedure: Preparation: A solution of Compound 1 (51.1 mg in 3.0 mL MeOH) was stirred under hydrogen gas overnight in presence of platinum oxide (PtO 2 ,10 mg, 0.4 eq) as a catalyst. The reaction mixture was filtered and purified by direct preparative HPLC using a Phenomenex Synergi T M MAX RP 21.2 x 200 mm column (20 mL/min, H 2 0/CH 3 CN 20 gradient 30:70-30:70, 0-2 min; 30:70-0:100, 2-20 min). Fractions having a retention time of 12.8 min were combined to give 45.2 mg of Compound 23. Structural elucidation: Calculated molecular weight of the major isotope (468.30) and formula

(C

2 8

H

40

N

2 0 4 ) were confirmed by mass spectral analysis. Compound 23 mass spectra gave a (M-H) molecular ion of 467.4 by negative ionization and a (M+H) + molecular ion of 469.4 by positive ionization. Proton NMR spectral analysis of Compound 23 is shown in Table 10 below. Signals were easily assigned based on Compound 1 structure 56 WO 2006/034574 PCT/CA2005/001467 knowledge. As expected, aliphatic proton signals at positions 2'-11' all have very close chemical shifts ranging from about 1 to 1.75 ppm (integrating for 17 protons), methyl protons at positions 12' and 1"-3" are all very close as well (shifts 0.8-0.95 ppm, integrating for 12 protons). These signals are also complex from the fact that 2 diastereomers of positions 3' and 7' are present in the mixture, and in different proportions. Labile protons were not observed since NMR was done in deuterated methanol. Table 10 1 H NMR (SaH, ppm) Data of Compounds 14, 15 and 23 in CD 3 OD Assignment 14 15 23 Group 1 7.18 7.21 7.15 CH 2 7.12 7.14 6.76 CH 3 7.01 7.02 6.84 CH 5-N-Me 2.96, 2.95 b 2.93 N/A CH 3 7 6.23 6.21 6.24 CH 9 6.33, 6.35 b, 6.34 6.26 CH 1' 4.42,.3.86 4.56, 4.87 4.16, 3.99 CH 2 2'-11' a -0.76-1.86 C ~ 1.00-1.75 C 12' and 1"-3" a - 0.87-1.00 d - 0.8-0.95 d N/A: not applicable, group not present in the molecule a. Signals are very close. 10 b. Mixture of isomers. c. Compounds 14 and 23: 3CH, 7CH 2 (17H); Compound 15: 2'(CH) at 5.41 ppm, 4'(CH 2 ) at 2.03 ppm, 5'-11' (12H) at 1.07-1.51 ppm. d. Compounds 14 and 23: 4CH 3 (12H); Compound 15: 1" (CH 3 ) at 1.75 ppm, 2", 3" and 12' (9H) at 0.88-0.80 ppm. EXAMPLE 8: AROMATIC SUBSTITUTION REACTION a) Synthesis and structural elucidation of Compound 24 by bromination 0 1 11a1O 10 2' 4' 12' 2 9a 9 3 4 4a N Sa OH

C

28

H

33 BrN 2 04 45 - 7 Mol. Wt.: 540.16 (M) OH H 6 Mol. Wt.: 542.16 (M+2) HO Br 20 Compound 24: 1 0-(farnesyl)-7-bromo-4,6,8-trihydroxy-5,10-dihydro dibenzo[b,e][1,4]diazepin-11-one, was prepared and identified according to the 57 WO 2006/034574 PCT/CA2005/001467 following procedure: Preparation: Compound 1 (116.0 mg) and N-bromosuccinimide (NBS, 45.5 mg) were dissolved in tetrahydrofuran (THF, 3.0 mL) and stirred at room temperature for 4 days. The reaction mixture was filtered and subjected to Waters HPLC purification (Nova Pack T M HR C-18 25 x 200 mm column: 20 mL/min, H 2 0/CH 3 CN gradient 80:20-30:70, 0-8 min; 30:70-0:100, 8-18 min) to give Compound 24 (13.6 min) together with some impurities. The semi-purified sample was further purified by HPLC (Symmetry T M C-18 25 x 100 mm column: 20 mL/min, H 2 0/CH 3 CN gradient 70:30-30:70, 0-15 min), to give 10 pure Compound 24 (9.5 mg, RT 13.0 min). Structural elucidation: The calculated molecular weight of the major isotopes (540.16 and 542.16) and formula (C 28

H

33 BrN 2 0 4 ) of Compound 24 was confirmed by mass spectral analysis: negative ionization gave (M-H)- molecular ions of 539.2 and 541.1, and positive ionization gave (M+H) molecular ions of 541.3 and 543.2. The presence of the two molecular ions in each mass spectrum confirmed the presence of a bromine group in the molecule. The structure was further confirmed by the absence of the aromatic (position 7) signal in the proton NMR spectrum as shown in Table 11 below. Table 11 1 H NMR (SH, ppm) Data of Compound 24 in CD 3 0D Assignment Compound 24 Group 1 7.18 CH 2 6.79 CH 3 6.87 CH 9 6.49 CH 1' 4.56 CH 2 2' 5.34 CH 4' 2.06 CH 2 5' 2.09 CH 2 6' 5.10 CH 8' 1.96 CH 2 9' 2.04 CH 2 10' 5.08 CH 12' 1.66 CH 3 1" 1.74 CH 3 2" 1.60 CH 3 3" 1.57 CH 3 58 WO 2006/034574 PCT/CA2005/001467 b) Synthesis of Compound 26 Compound 2 and N-bromosuccinimide are dissolved in tetrahydrofuran and stirred at room temperature for 4 days (conditions as described in (a)). The reaction mixture is filtered and subjected to HPLC purification to provide pure Compound 26. c) Synthesis of Compound 27 Compound 14 and N-bromosuccinimide are dissolved in tetrahydrofuran and stirred at room temperature for 4 days (conditions as described in (a)). The reaction o10 mixture is filtered and subjected to HPLC purification to provide pure Compound 27. EXAMPLE 9. IN VITRO PROFILING OF THE COMPOUNDS OF THE INVENTION (a) In vitro anticancer activity of the compounds of Formula I against four cell lines: In vitro cytotoxic activities of exemplified Compounds are shown in Table 12, along with hemolytic activity of each compound. Compounds were tested in four cell lines: HT-29 (colorectal carcinoma), SF268 (CNS), MDA-MB-231 (mammary gland adenocarcinoma) and PC-3 (prostate adenocarcinoma). Procedures used for each series of tests are described below. Table 12 In vitro Cytotoxic Activities Compound HT-29 SF-268 PC-3 MDA-MB-231 Average No: (G1 50 pM) (GI 50 pM) (G1 5 0 pM) (G1 5 0 pM) (G1 0 pM) 1 a/b 11.2 / 9.33 1.96/1.55 1.95 / 3.76 1.79 / 3.18 4.23/4.45 2 b 0.65 0.12 0.45 0.24 0.36 3 b 2.04 0.76 1.15 2.16 1.53 4 b 2.57 0.89 1.25 2.27 1.74 5 b 2.50 0.56 1.14 1.39 1.40 7 b 2.44 0.53 1.33 1.92 1.55 13 b 0.69 0.16 0.82 0.51 0.54 14 b 0.29 0.07 0.23 0.24 0.21 15 b 0.69 0.23 0.65 0.37 0.49 18 b 1.43 0.33 1.80 1.02 1.14 21 b 1.89 1.73 1.08 2.19 1.72 22 b 1.83 0.91 1.39 2.40 1.63 23 a 4.26 0.72 0.90 0.59 1.62 24 b 2.02 2.04 1.19 2.02 1.82 25a 9.33 1.95 1.20 2.79 3.82 a. Results obtained by method (a) below 20 b. Results obtained by method (b) below c. Average G1 50 values in pM. 59 WO 2006/034574 PCT/CA2005/001467 All compounds described in Table 12 were shown to have better anticancer activity than Compound 1. These compounds include Compounds 2 to 5, 7, 13, 14, 15, 18, and 21 to 25. Compounds Compounds 2 to 5, 7, 13, 14, 15, 18, 21, and 22 are N linear alkyl derivatives of Compound 1, encompassed by Formula I, and their hydrogenated and hydromethoxylated farnesyl derivatives. The hydrogenated farnesyl derivative Compound 23, brominated aryl derivative Compound 24, and triacetylated Compound 25 were also found to be generally more active than Compound 1. 10 Method (a): Cytotoxic activities were determined in vitro for Compounds 1, 23 and 25 to determine the concentration of each compound needed to obtain a 50% inhibition of cell proliferation (Gs1 50 ). The Gs1 50 value emphasizes the correction for the cell count at time zero and, using the seven absorbance measurements [time zero, (Tz), control growth, (C), and test growth in the presence of drug at the five concentration levels (Ti)], G1 50 is calculated as [(Ti-Tz)/(C-Tz)] x 100 = -50, which is the drug concentration resulting in a 50% reduction in the net DNA content intreated relative to control cells during the drug incubation. Compounds were dissolved at 10 mM in DMSO. Dilution in vehicle to 20 concentrations of 30, 10, 3, 1 and 0.3 pM were prepared immediately before assays. Depending on the cell line's growth characteristics, 4000-10000 cells were plated in two 96-wells pates (day 0) and incubated for 16 hours. The following day, propidium iodide ws added to one of the two plates and fluorescence measured (Tz). Test compounds were added to the second plate, as well as vehicle control, and cells further incubated for 96 hours. Each compound was tested at each concentration and in triplicates. The equivalent cell number was determined after adding propidium iodide by measuring the signal by fluorescence (C for control). Gs1 50 results were calculated using the formula above and are shown in Table 12. 30 Method (b): In vitro cytotoxic activities (GI 50 ) of Compounds 1,2 to 5, 7, 13, 14, 15, 18, 21, 22, and 24 were determined using propidium iodide (PI) as being the concentration of drug resulting in 50% growth inhibition, and by using the following method. 60 WO 2006/034574 PCT/CA2005/001467 Two 96-well plates were seeded in duplicate with each cell line at the appropriate inoculation density (HT29: 3,000; SF268: 3,000; PC-3: 3,000; and MDA-MB-231: 7,500 cells) and according to the technical data sheet of each cell line (rows A-G, 75 pL of media per well). Row H was filled wih medium only (150 pL, negative control-medium). The plates were incubated at appropriate temperature and CO2 concentration for 24 hrs. Test Compounds were prepared as 15X stock solutions in appropriate medium and corresponding to 450, 45, 0.45, 0.045, and 0.0045 pM (prepared the day of the experiment). An aliquot of each was diluted 7.5-fold in appropriate test medium to give 10 a set of six 2X concentration solutions (60, 6, 0.6, 0.06, 0.006, and 0.0006 pM). A 75 pL aliquot of each concentration was added to each corresponding well (rows A to F) of the second plate. Row G was filled with 75 pL of medium/0.6% DMSO (negative control-cells). The second plate was incubated at appropriate temperature and CO2 concentration for 96 hrs. First Plate: PI (30 pL, 50 pg/mL) was added to each well of the first plate without removing the culture medium. The plate was centrifuged (Sorvall Legend-RT, swinging bucket) at 3500 rpm/10 min. Fluorescence intensity (Thermo, Varioskan, Aex: 530 nm; Aem: 620 nm) was measured to give the first measurement, dead cells (DC at To; before freezing). Two round of Freeze (-80 0 C)/Thaw (37oC) were done. Fluorescence intensity 20 was determined to give the second measure, total cells (TC at To; after freeze/thaw) Second plate was processed as the first one, except there were three rounds of freeze/thaw instead of two. First measurement gave the treated dead cells value (TDC), and the second measurement gave the treated total cells value (TTC). Both values were collected for each treated well and control (CTC and CDC). Each value (DC, TC, TDC, TTC, CTC and CDC) was corrected by removing the background value (medium only) to give the value (FUDc(T=0), FUTc(T=o), FUTDc, FUTTC, FUcTc and FUcDc) used in the calculation of the T/C (%) (Treated/Control) for each concentration. T/C (%) for each concentration is calculated using the following formula: (FUTTc - FUTDC) - (FUTC(T=0) - FUDc(T=0)) X 100 T/C (%)= (FUCTC - FUCDC) - (FUTC(T=0) - FUD(T=0)) 30 The G1 50 value emphasizes the correction for the cell count at time zero for cell survival. The T/C values are transposed in a graph to determine G1 50 values, the concentration at with the.T/C is 50%. 61 WO 2006/034574 PCT/CA2005/001467 (b) Anticancer activity profiling of Compound 2 against 36 cell lines (IC 50 ): Culture conditions and activity evaluations of Compound 2 against 36 cancer cell lines were done as described in Method(a) of Example 9(a), except that results were expressed as the concentration of drug which inhibits 50% of the cell growth (IC 50 , calculated using the formula: [Ti/C] x 100 = -50). The low micromolar to nanomolar levels of IC 50 values shown in Table 13 demonstrated a pharmacologically relevant cytotoxic activity of Compound 2 against a variety of 36 tumor types including melanomas, pancreatic, lung, colon, gastric, bladder, renal, CNS, head and neck, 10 prostate, uterus, ovarian and breast carcinomas. Table 13 In vitro profiles of Compound 2 (IC 50 ) # Type Cell line Origin Histology in nude mice IC 5 0 (pM) 1 Bladder T24 ATCC Transitional cell ca 0.127 2 Bladder 1218L Xenograft Urothelial adeno ca 0.166 3 Colon HCT116 NCI Adeno ca, pd 0.156 4 Colon HT29 NCI Adeno ca, pd 0.223 5 CNS 498NL Xenograft Glioblastoma 0.176 6 CNS SF268 NCI Nd 0.010 7 Gastric 251L Xenograft Adeno ca, pd 0.105 8 Head & Neck 536L Xenograft Hypopharynx ca 0.181 9 Lung 1121L Xenograft Large cell ca 0.125 10 Lung 289L Xenograft Adeno ca 1.553 11 Lung 526L Xenograft Adeno ca 0.104 12 Lung 629L Xenograft Adeno ca 0.164 13 Lung 529L Xenograft Large cell ca, 0.127 14 Lung H460 NCI Large cell ca 0.366 15 Mammary 401NL Xenograft Pap adeno ca, wd 0.194 16 Mammary MCF7 NCI Mamma ca 0.276 17 Melanoma 276L Xenograft Mm, amelanotic 1.948 18 Melanoma 394NL Xenograft mm, amelanotic,pd 0.020 19 Melanoma 462NL Xenograft Mm, amelanotic 0.978 20 Melanoma 514L Xenograft Mm, melanotic 0.110 21 Melanoma 520L Xenograft Mm, melanotic 0.085 22 Ovarian 1619L Xenograft Adeno ca, md 0.579 23 Ovarian 899L Xenograft Pap serous ca, md 0.238 24 Ovarian OVCAR3 NCI Adeno ca, md 0.139 25 Pancreas 1657L Xenograft Adeno ca, md 1.777. 26 Pancreas PANC1 ATCC nd 0.125 27 Prostate 22RV1 ATCC Adeno ca, md 0.142 28 Prostate DU145 NCI Adeno ca, md 0.158 29 Prostate LNCAP DSMZ Adeno ca, md 0.485 62 WO 2006/034574 PCT/CA2005/001467 Table 13 In vitro profiles of Compound 2 (IC50) # Type Cell line Origin Histology in nude mice IC 5 0 (pM) 30 Prostate PC3M NCI Adeno ca, pd 0.114 31 Pleuramesot. 1752L Xenograft pleuromesothelioma 1.503 32 Renal 1781L Xenograft renal ca 0.172 33 Renal 393NL Xenograft Hypernephroma, wd 0.527 34 Renal 486L Xenograft Hypernephroma, pd 1.144 35 Renal 944L Xenograft Hypernephroma 0.230 36 Uterus 1138L Xenograft Carcinosarcoma, wd 0.139 Mean of all cell lines: 0.407 ca=carcimoma; pd=poorly differentiated; pap=papillary; md=moderately differentiated; wd=well differentiated; mm=malignant melanoma; nd=not determined EXAMPLE 10: IN VIVO EFFICACY OF COMPOUNDS 1 AND 2 In vivo efficacy of Compounds I ahd 2 in a glioma model: The aim of this study was to test whether Compounds 1 and 2 prevent or delay tumor growth in C6 glioblastoma cell-bearing mice, and to determine an effective dosage regimen. Animals: A total of 60 six-week-old female mice (Mus musculus nude mice), ranging between 18 to 25 g in weight, were observed for 7 days before treatment. Animal 10 experiments were performed according to ethical guidelines of animal experimentation (Charte du comit6 d'6thique du CNRS, juillet 2003) and the English guidelines for the welfare of animals in experimental neoplasia (WORKMAN, P., TWENTYMAN, P., BALKWILL, F., et al. (1998). United Kingdom Coordinating Committee on Cancer Research (UKCCCR) Guidelines for the welfare of animals in experimental neoplasia (Second Edition, July 1997; British Journal of Cancer, 77:1-10). Any dead or apparently sick mice were promptly removed and replaced with healthy mice. Sick mice were euthanized upon removal from the cage. Animals were maintained in rooms under controlled conditions of temperature (23±20C), humidity (45±5%), photoperiodicity (12 hrs light / 12 hrs dark) and air exchange. Animals were housed in polycarbonate cages 20 (5/single cage) that were equipped to provide food and water. Animal bedding consisted of sterile wood shavings that were replaced every other day. Food was provided ad libitum, being placed in the metal lid on the top of the cage. Autoclaved tap water was provided ad libitum. Water bottles were equipped with rubber stoppers and sipper tubes. Water bottles were cleaned, sterilized and replaced once a week. Two different 63 WO 2006/034574 PCT/CA2005/001467 numbers engraved on two earrings identified the animals. Each cage was labeled with a specific code. Tumor Cell Line: The C6 cell line was cloned from a rat glial tumor induced by N nitrosomethyurea (NMU) according to Premont et al. (Premont J, Benda P, Jard S., [3H] norepinephrine binding by rat glial cells in culture. Lack of correlation between binding and adenylate cyclase activation. Biochim Biophys Acta. 1975 Feb 13;381(2):368-76.) after series of alternate culture and animal passages. Cells were grown as adherent monolayers at 37 0 C in a humidified atmosphere (5% CO 2 , 95% air). The culture medium was DMEM supplemented with 2 mM L-glutamine and 10% fetal bovine o10 serum. For experimental use, tumor cells were detached from the culture flask by a 10 min treatment with trypsin-versen. The cells were counted in a hemocytometer and their viability assessed by 0.25% trypan blue exclusion. Preparation of the Test Article: For the test article, the following procedure was followed for reconstitution (performed immediately preceding injection). The vehicle consisted of a mixture of benzyl alcohol (1.5%), ethanol (8.5%), propylene glycol (27%), PEG 400 (27%), dimethylacetamnide (6%) and water (30%). The vehicle solution was first vortexed in order to obtain a homogeneous liquid. 0.6 mL of the vortexed vehicle solution was added to each vial containing the test article (Compound 1). Vials were mixed thoroughly by vortexing for 1 minute and inverted and shaken vigorously. Vials 20 were mixed again prior to injection into each animal. Animal Inoculation with tumor cells: Experiment started at day 0 (Do). On Do, mice received a superficial intramuscular injection of C6 tumor cells (5 x 105 cells) in 0.1 mL of DMEM complete medium into the upper right posterior leg. Treatment regimen and Results: First series of experiments: In a first series of experiments, treatment started 24 hrs following inoculation of C6 cells. On the day of the treatment, each mouse was slowly injected with 100 pL of test or control articles by the i.p. route. For all groups, treatment was performed until the tumor volume of the saline-treated mice (group 1) reached approximately 3 cm 3 (around 30 day 16). Mice of group 1 were treated daily with a saline isosmotic solution for 16 days. Mice of group 2 were treated daily with the vehicle solution for 16 days. Mice of group 3 were treated daily with 10 mg/kg of Compound 1 for 16 days. Mice of group 4 were 64 WO 2006/034574 PCT/CA2005/001467 treated every two days with 30 mg/kg of Compound 1 and received 8 treatments. Mice of group 5 were treated every three days with 30 mg/kg of Compound 1 and received 6 treatments. Measurement of tumor volume started as soon as tumors became palpable (>100 mm 3 ; day 11 post-inoculation) and was evaluated every second day until the end of the treatment using callipers. As shown in Table 14 and Figure 1, the mean value of the tumor volume of all Compound 1 treated groups (6 mice/group) was significantly reduced as demonstrated by the one-way analysis of variance (Anova) test followed by the non-parametric Dunnett's multiple comparison test comparing treated groups to the saline group. An asterisk in the P value column of Table 14 indicates a statistically 10 significant value, while "ns" signifies not significant. Table 14 Compound 1 in vivo antitumor efficacy against C6 glioblastoma Treatment Treatment Tumor volume (mm 3 ) % Inhibition P value regimen (mean ± SEM) Saline Q1 x 16 3,004.1 ± 249.64 - Vehicle solution Q1 x 16 2,162.0 + 350.0 28.0% >0.05 ns Compound 1 (10 mg/kg) Q1 x 16 1,220.4 ± 283.46 59.4% <0.01 * Compound 1 (30 mg/kg) Q2 x 8 1,236.9 + 233.99 58.8% <0.01 * Compound 1 (30 mg/kg) Q3 x 6 1,184.1 ± 221.45 60.6% <0.01 * Second series experiments: In a second series of experiments, treatment started at day 10 following inoculation of C6 cells when tumors became palpable (around 100 to 200 mm 3 ). Treatment was repeated daily for 5 consecutive days. On the day of the treatment, each mouse was slowly injected with 100 pL of Compound 1 by i.p. route. Mice of group 1 were treated daily with saline isosmotic solution. Mice of group 2 were treated daily with the vehicle solution. Mice of group 3 were treated daily with 20 mg/kg of Compound 1. Mice of group 4 were treated daily with 30 mg/kg of Compound 1. Mice 20 were treated until the tumor volume of the saline-treated control mice (group 1) reached around 4 cm 3 . Tumor volume was measured every second day until the end of the treatment using callipers. As shown in Table 15 and Figure 2, the mean value of the tumor volume of all Compound 1 treated groups (6 mice/group) was significantly reduced as demonstrated by the one-way analysis of variance (Anova) test followed by the non-parametric Dunnett's multiple comparison test comparing treated groups to the saline group. An asterisk in the P value column of Table 15 indicates a statistically 65 WO 2006/034574 PCT/CA2005/001467 significant value, while "ns" signifies not significant. Histological analysis of tumor sections showed pronounced morphological changes between tumors from Compound 1-treated mice and those from mice in the control groups. In tumors from mice treated with Compound 1 (20 - 30 mg/kg), cell density was decreased and the nuclei of remaining tumor cells appeared larger and pycnotic while no such changes were observed for tumors from vehicle-treated mice (Figure 3). Table 15 Compound 1 in vivo antitumor efficacy against C6 glioblastoma Treatment Tumor volume (mm') TTreatmentTreatment Tumor volume (mm 3 ) % Inhibition P value regimen (mean ± SEM) Saline Q1 x 5 4,363.1 ± 614.31 - Vehicle solution Q1 x 5 3,205.0 ± 632.37 26.5% >0.05 ns Compound 1 (20 mg/kg) Q1 x 5 1,721.5 ± 374.79 60.5% <0.01 * Compound 1 (30 mg/kg) Q1 x 5 1,131.6 ± 525.21 74.1% <0.01 * In vivo antitumor efficacy of Compound 2: 10 Antitumor efficacy of Compound 2 against rat glioblastoma tumor (C6) xenografts in female swiss nude mice was accomplished as described above. The results and dosage regimen are summarized in Figure 4. Significant efficacy was shown following intravenous administration, at a dosage regimen of 75 mg/kg (qd5/2/qd5). EXAMPLE 11: Pharmacokinetic profiles Compounds 1 and 2 were separately dissolved in ethanol (5%), Polysorbate 80 (15%), PEG 400 (5%) and dextrose (5%) at a final concentration of 6 mg/ml (for all parenteral administration routes). For oral administration, Compound 1 was solubilized in Cremophor® EL/ Ethanol (50%:50%) at a final concentration of 6 mg/ml. Prior to 20 dosing, animals (female Crl: CD1 mice; 6 weeks of age, 22-24g) were weighed, randomly selected and assigned to the different treatment groups. Compound 1 was administered by the intravenous (iv), subcutaneous (sc), intraperitoneal (ip), or oral (po) route to the assigned animals. Compound 2 was administered by the intravenous (iv), or intraperitoneal (ip) route to the assigned animals. The dosing volume of Compounds 1 and 2 was 5 mL per kg body weight. Animals were anesthetized with 5% isoflurane 66 WO 2006/034574 PCT/CA2005/001467 prior to bleeding. Blood was collected into microtainer tubes containing the anticoagulant K 2 EDTA by cardiac puncture from each of 4 animals per bleeding timepoint (2 min, 5 min, 15 min, 30 min, lh, 2h, 4h and 8h). Following collection, the samples were centrifuged and the plasma obtained from each sample was recovered and stored frozen (at approximately -80oC) pending analysis. At the 5 min and 30 min time points, the following organs were harvested from each animal: brain, lungs, skeletal muscle, fat tissue, kidneys, spleen, thymus and liver. Tissues were frozen (at approximately -80oC) pending analysis. Samples were analysed by LC/MS/MS. Standard curve ranged from 25 to 2000 ng/mL with limit of quantitation (LOQ) < 25 10 ng/mL and limit of detection (LOD) of 10 ng/mL. Plasma values of Compounds 1 and 2 falling below the limit of quantitation (LOQ) were set to zero. Mean concentration values and standard deviation (SD) were calculated at each timepoints of the pharmacokinetic study (n=4 animals/timepoint). The following pharmacokinetic parameters were calculated: area under the plasma concentration versus time curve from time zero to the last measurable concentration time point (AUCo-t), area under the plasma concentration versus time curve extrapolated to infinity (AUCinf), maximum observed plasma concentration (Cmax), time of maximum plasma concentration (tmax), apparent first-order terminal elimination rate constant (kei), apparent first-order terminal elimination half-life will be calculated as 20 0.693/kel (t/ 1 12 ). The systemic clearance (CL) of Compound 1 after intravenous administration was calculated using Dose/AUCinf. Pharmacokinetic parameters were calculated using Kinetica m 4.1.1 (InnaPhase Corporation, Philadelphia, PA). Results: Mean plasma concentrations of Compound 1 following intravenous (iv), intraperitoneal (ip), subcutaneous (sc), and oral (po) administrations at 30 mg/kg are presented in Figure 5. Mean plasma concentrations of Compound 2 following iv and ip administrations at 30 mg/kg, compared with Compound 1 via the same routes of administration, are presented in Figure 6. When administered iv, Compound 2 had an AUC of 92.08 pM*h and an observed Cmax of 105 pg/mL, compared to an AUC of 40.4 30 pM*h and an observed Cmax of 130 pg/mL for Compound 1. When administered ip, Compound 2 had an AUC of 58.75 pM*h and an observed Cmax of 5.8 pg/mL, compared to an AUC of 9.5 pM-h and an observed Cmax of 2.25 pg/mL for Compound 1. 67 WO 2006/034574 PCT/CA2005/001467 Mean (±+ SD) plasma concentrations of Compound 1 following I.V. administration of a 30 mg/kg dose declined rapidly in a biexponential manner resulting in very short half lives (tl/ 2 c and P of 4.6 min and 2.56 h, respectively). The pharmacokinetics of Compound 1 following intraperitoneal and subcutaneous administrations, and Compound 2 following intraperitoneal and intravenous administration, showed a PK profile suggestive of slow release. With these routes of administration, the compound plasma concentration was sustained and maintained at therapeutically relevant levels for over 8 hours. Compound 2 showed a half life (t 1

/

2 ) of more than 40 hours following both IP and IV administrations. Oral administration of Compound 1 resulted in o10 moderate but sustained drug levels. These data indicated that Compound 1 was orally bioavailable at a 5-8% level. Mean tissue concentrations of Compound 1, 30 min after intravenous (iv), intraperitoneal (ip) or subcutaneous (sc) administrations at 30 mg/kg are presented in Figure 7. The 30 min time point was chosen since plasma concentrations were similar with all three routes of administration. Compound 1 is well distributed following iv and ip dosing. Surprisingly, although ip and sc administrations resulted in a similar PK profile, tissue levels were significantly lower following sc dosing. This could be explained by the absence of peak levels following sc administration compared with iv and ip administrations. 20 Acute toxicity studies in CD-1 nu/nu mice for Compound 2, using the same formulation, gave an MTD > 50 mg/kg (ip, NOAEL: 30 mg/kg) and > 100 mg/kg (iv, NOAEL: 75 mg/kg), with weight losses of about 7% for several days post-injection. Compound 1 had an MTD of 150 mg/kg when administered iv. Acute toxicity studies with Compound 46 gave an MTD of 30 mg/kg (ip). All patents, patent applications, and published references cited herein are hereby incorporated by reference in their entirety. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details 30 may be made therein without departing from the scope of the invention encompassed by the appended claims. 68

Claims (46)

1. A compound of Formula I: 0 / N N HO / Ri OH HO Formula I wherein, R 1 is a linear CI-0alkyl; or a farnesyl derivative thereof, wherein said farnesyl derivative has one, two or three hydrogenated or hydroalkoxylated double bonds; 10 or a pharmaceutically acceptable salt or prodrug thereof.

2. The compound of claim 1, wherein R 1 is a linear C 1 .- 10alkyl, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

3. The compound of claim 1, wherein said compound is a mono-hydrogenated farnesyl derivative, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

4. The compound of claim 1, wherein said compound is a di-hydrogenated farnesyl derivative, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 20

5. The compound of claim 1, wherein said compound is a fully hydrogenated farnesyl derivative, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

6. The compound of claim 1, wherein R 1 is a linear C 1 .10alkyl and the farnesyl is fully hydrogenated, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

7. The compound of claim 1, wherein R 1 is a linear C1-6alkyl, or a pharmaceutically acceptable salt, solvate or prodrug thereof. WO 2006/034574 PCT/CA2005/001467

8. The compound of claim 1, wherein R 1 is a linear C 1 - 6 alkyl and the farnesyl is fully hydrogenated, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

9. The compound of claim 1, wherein R 1 is methyl, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

10. The compound of claim 1, wherein R 1 is ethyl, or a pharmaceutically acceptable salt, solvate or prodrug thereof. 10

11. The compound of claim 1, wherein R 1 is n-propyl, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

12. The compound of claim 1, wherein R 1 is n-butyl, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

13. The compound of claim 1, wherein R 1 is n-hexyl, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

14. The compound of claim 1, wherein said compound is selected from Compounds 20 2 to 22, or a pharmaceutically acceptable solvate or prodrug thereof: 0N 0 OH OH NN OH Me OH HO HO Compound 2; Compound 3; 0 N ON /NOH N N OH OH IHO HCompound 4; Compound 5; Compound 4; Compound 5; WO 2006/034574 PCT/CA2005/001467 0 0 NW - N /N- OH N- O -H ON ON OH OH HO HO Compound 6; Compound 7; 0 0 N ON OH OH OH OH HO HO Compound 8; Compound 9; 0 N N OH N N OH CF2 F 2 C HO OH CFI HO CFa Compound 10; Compound 11 0 0 ON ON N -OH - NOH NN OH OH CD, 10 FC HO HO Compound 12; Compound 13; 0 0 N N / OH N OH NN I I OH CH, OH CH 3 HO HO Compound 14; Compound 15; 0 0 NO -~ N-~ NOCH, N OH NOH I I OH CH, OH CH, HO HO Compound 16; Compound 17; WO 2006/034574 PCT/CA2005/001467 O 0O OCH, OCH, OCH, N N OH OH OHJ OH CH, OH CH, HO HO Compound 18; Compound 19; OCH3 OCH, N- N OH OH HO HO Compound 20; Compound 21; and 0 NH OCH, OCH, / OH N OH HO Compound 22. 10

15. The compound of claim 14, wherein said compound is selected from Compounds 2 to 5, 7, 13, 14, 15, 18, 21, and 22, or a pharmaceutically acceptable solvate or prodrug thereof.

16. The compound of claim 15, wherein ,said compound is selected from Compounds 2 to 5 and 7, or a pharmaceutically acceptable solvate or prodrug thereof.

17. The compound of claim 14, wherein said compound is selected from Compounds 2 to 13, or a pharmaceutically acceptable solvate or prodrug thereof. 20

18. The compound of claim 14, wherein said compound is selected from Compounds 14 to 22, or a pharmaceutically acceptable solvate or prodrug thereof.

19. A compound selected from Compounds 23 to 27, or a pharmaceutically acceptable solvate or prodrug thereof: WO 2006/034574 PCT/CA2005/001467 ON ON OH NOH OH OH HO HO Br Compound 23; Compound 24; ON ON , OAc N OH N I N OAc 1 OH Me AcO HO Br Compound 25; Compound 26; and 0 ON OH N OH Me HO Br Compound 27. 10

20. The compound of claim 19, wherein said compound is Compound 23, or a pharmaceutically acceptable solvate or prodrug thereof.

21. The compound of claim 19, wherein said compound is selected from Compounds 24, 26 or 27, or a pharmaceutically acceptable solvate or prodrug thereof.

22. The compound of claim 19, wherein said compound is Compound 25, or a pharmaceutically acceptable solvate or prodrug thereof.

23. A process for producing a compound of any one of claims 1 to 18, said process 20 comprising chemically modifying Compound 1: 0 ON OH HI HO wherein said chemical modification comprises an N-alkylation chemical step. WO 2006/034574 PCT/CA2005/001467

24. The process of claim 23, wherein said process further comprises one step selected from farnesyl hydrogenation and farnesyl hydroalkoxylation, wherein said farnesyl hydrogenation or farnesyl hydroalkoxylation step is partial or total.

25. Theprocess of claim 23, wherein said N-alkylation chemical step comprises reacting Compound 1, as described in claim 23, with an alkylating agent selected from a dialkyl sulfate and an alkyl halide.

26. A process for producing a compound of any one of claims 18 to 22, said process 10 comprising chemically modifying Compound 1: 0 ON N, OH OH H HO wherein said chemical modification comprises one step selected from the group consisting of: O-acylations, aromatic halogenation, and farnesyl hydrogenation, wherein said farnesyl hydrogenation step is total.

27. The process of claim 26, wherein said chemical modification comprises a farnesyl hydrogenation step.

28. A pharmaceutical composition comprising a therapeutically effective amount of a 20 compound of claim 1 and a pharmaceutically acceptable carrier.

29. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 2 to 14 and a pharmaceutically acceptable carrier.

30. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 15 to 18 and a pharmaceutically acceptable carrier.

31. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 19 and a pharmaceutically acceptable carrier. 30 WO 2006/034574 PCT/CA2005/001467

32. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 20 to 22 and a pharmaceutically acceptable carrier.

33. Use of a compound of any one of claim 1, to inhibit the growth of a neoplastic cell.

34. Use of a compound of any one of claims 2 to 13, to inhibit the growth of a neoplastic cell. 10

35. Use of a compound of any one of claims 14 to 18, to inhibit the growth of a neoplastic cell.

36. Use of a compound of any one of claims 19 to 22, to inhibit the growth of a neoplastic cell.

37. Use of a compound of any one of claim 1, to inhibit the growth of a neoplastic cell.

38. Use of a compound of any one of claims 2 to 13, in the preparation of a 20 medicament for the treatment of a neoplastic condition.

39. Use of a compound of any one of claims 14 to 18, in the preparation of a medicament for the treatment of a neoplastic condition.

40. Use of a compound of any one of claims 19 to 22, in the preparation of a medicament for the treatment of a neoplastic condition.

41. Use of any one of claims 37 to 40, wherein said neoplastic condition is selected from leukemia, melanoma, breast cancer, lung cancer, pancreatic cancer, ovarian 30 cancer, renal cancer, colon or colorectal cancer, prostate cancer, and CNS cancer.

42. A commercial package comprising a compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, and a written matter describing instructions for the use of the compound for treating a neoplastic condition. WO 2006/034574 PCT/CA2005/001467

43. A commercial package comprising a compound of any one of claims 2 to 13, or a pharmaceutically acceptable salt or prodrug thereof, and a written matter describing instructions for the use of the compound for treating a neoplastic condition.

44. A commercial package comprising a compound of any one of claims 14 to 18, or a pharmaceutically acceptable salt or prodrug thereof, and a written matter describing instructions for the use of the compound for treating a neoplastic condition. 10

45. A commercial package comprising a compound of claim 19, or a pharmaceutically acceptable salt or prodrug thereof, and a written matter describing instructions for the use of the compound for treating a neoplastic condition.

46. A commercial package comprising a compound of any one of claims 19 to 22, or a pharmaceutically acceptable salt or prodrug thereof, and a written matter describing instructions for the use of the compound for treating a neoplastic condition.