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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems

Definitions

• This invention relates to novel indolyl pyrazinone compounds, pharmaceutical compositions containing such compounds and the use of those compounds and compositions for the prevention and/or treatment of hyper-proliferative disorders and diseases associated with angiogenesis.
• R and R are each independently selected from H, halo, CF 3 , C(O)R 9 , ' N — ' , (C ⁇ -C 6 )alkyl optionally substituted with up to two substituents selected from
• R 1 and R 2 together with the adjacent C atoms to which they are attached form a ring selected from benzo, dioxolo and imidazo, said imidazo being optionally substituted up to two times with (C C 3 )alkyl, with the proviso that R 1 and R 2 together with the adjacent C atoms to
• R 3 is selected from H, (C C 4 )alkyl, OH, NO 2 , NH 2 , NH(C r C 4 )alkyl, NHC(O)(C C 4 )alkyl and NHC(O)phenyl, said phenyl being optionally substituted with up to two substituents independently selected from (C ⁇ -C 3 )alkyl, (C C 3 )alkoxy, halo,
• R 4 is selected from H, OH, halo, CN, C(O)R 6 , S(O) 2 R 7 , OSi[(C C 4 )alkyl] 3 , tetrazolyl, thienyl, pyrrolyl, pyrimidinyl, oxazolyl, furanyl,
• NHC(O)NH(C C 3 )alkyl where said alkyl is optionally substituted . with up to two substituents independently selected from OH,
• -V-N X selected from (C 1 -C 3 )alkoxy, pyrrolidinyl, ' x — ' , and N[(C C 3 )alkyl] 2 where each alkyl is independently optionally substituted with up to two substituents independently selected from OH, F, (CrC 3 )alkoxy and phenyl, N[(C ⁇ -C 4 )alkyl] 2 where each of said alkyl groups are independently optionally substituted with up to two substituents independently selected from OH, (C C 3 )alkyl, F, (C C 3 )alkoxy, and phenyl, oxadiazolyl optionally substituted up to two times with (C C 3 )alkyl, phenyl optionally substituted with up to two substituents independently selected
• C(O)(CrC 3 )alkyl optionally substituted with up to two substituents independently selected from (C C 3 )alkoxy, OH, (C C 3 )alkoxy,
• O-pyridyl optionally substituted with up to two substituents independently selected from CF 3 , halo, and (C C 3 )alkyl;
• R 5 is selected from H, halo, CN, (C C 6 )alkoxy, and (C C 6 )alkyl;
• R 6 is selected from OH, NHR 10 , O-(C 3 -C 6 )cycloakyl, (C r C 3 )alkoxy, O-(C 2 -C 6 )alkenyl, O-(C 3 -C 6 )alkynyl,
• (CrC 6 )alkyl optionally substituted with up to two substituents independently selected from OH, (C-rC ⁇ alkoxy, F, and phenyl,
• N[(CrC 4 )alkyl] 2 where each of said alkyl groups are independently optionally substituted with up to two substituents independently selected from OH, CN, N[(C r C 4 )alkyl] 2 , (C C 3 )alkoxy, S(O) 2 -phenyl, S(O) 2 (C 1 -C 3 )alkyl, phenyl, furyl, tetrahydrofuryl, (C 3 -C 6 )cycloalkyl, and pyridyl,
• (C-rC 3 )alkyl optionally substituted with up to two substituents independently selected from N[(C-
• pyridyl optionally substituted up to two times with (CrC 3 )alkoxy
• piperidinyl optionally substituted with up to two substituents independently selected from phenyl, pyridyl, pyrrolidinyl and oxo-dihydrobenzimidazolyl;
• R 7 is selected from NH 2 , pyrrolidinyl, ' N — ' ,
• (CrC 3 )alkoxy NH-phenyl said phenyl being optionally substituted with up to two substituents independently selected from (C C 3 )alkyl, CN, (C C )alkoxy, halo and CF 3 , N[(C ⁇ -C 3 )alkyl] 2 wherein each alkyl is independently optionally substituted up to two times with (d-C )alkoxy, and phenyl optionally substituted with up to two substituents independently selected from (C C 3 )alkyl, (C C 3 )alkoxy, halo, CF 3 and CN;
• R 8 is selected from (C C 3 )alkoxy, pyridyl, piperidinyl, pyranyl and phenyl, where each ring moiety is optionally substituted with up to two substituents independently selected from (C-
• R 9 is selected from (C C 3 )alkyl, (C 1 -C 3 )alkoxy, OH, ' ⁇ v , phenyl optionally substituted with (C C 3 )alkyl, (CrC 3 )alkoxy, halo, CF 3 , and CN, N[(C ⁇ -C 4 )alkyl] 2 where each of said alkyl groups are independently optionally substituted with OH, CN, N[(C C 4 )alkyl] 2 , (C C 4 )alkoxy, S(O) 2 -phenyl, S(O) 2 (C C 3 )alkyl, phenyl, furyl, tetrahydrofuryl, (C 3 -C 6 )cycloalkyl, and pyridyl, and pyrrolidinyl optionally substituted with N[(C C 3 )alkyl] 2 ,
• R a is also selected from pyridyl, thienyl, and NHR 10 ;
• R 10 is selected from H, indolyl,
• (C C )alkyl optionally substituted with up to two substituents independently selected from OH, F, phenyl, (C C 4 )alkoxy, NHC(O)(C C 3 )alkyl,
• O-pyridyl optionally substituted with C(O)NH(C 1 -C 4 )alkyl
• R and R 12 are each selected independently from H, F and Cl with the proviso that when one of R 11 and R 12 is F or Cl, the other must be H;
• X is selected from O, S, CH 2 , and NH, and when X is NH, the H on NH is optionally replaced with pyridyl, pyrazinyl, phenyl, or (C C 4 )alkyl optionally substituted with up to two substituents independently selected from OH, (C -C 3 )alkoxy, N[(C C 3 )alkyl] 2 , C(O)-pyrrolidiny
• Ar represents a 6 membered aromatic ring containing 0, 1 or 2 N atoms. That is, one embodiment of Ar is an aromatic ring containing 6 C atoms. Those 6
• C atoms include the 2 C atoms that the Ar ring shares with the adjacent pyrazinone ring.
• This definition also includes the aromatic ring described above where 1 or 2 C atoms have been replaced with N atoms.
• the N atom(s) may be located at any position on the aromatic ring except they may not be located at the adjacent C atoms that are shared by the Ar ring and the adjacent pyrazinone ring.
• 6 membered aromatic N containing rings include pyrido, pyrimido, pyrazino, and pyridazo.
• R 1 and R 2 are each independently attached to the Ar ring at any available C atom except that when R 1 and R 2 together form a ring, each of R 1 and R 2 are attached to adjacent C atoms that are shared with the Ar ring so that the R 1 /R 2 ring is fused to the Ar ring through 2 adjacent C atoms that are shared between the R /R 2 ring and the Ar ring.
• R 4 is attached to the indolyl moiety of the core molecule at either the 5 or 6 atom of the indole moiety.
• R 5 is attached to the core molecule at the 5 or 6 atom on the indole moiety that is not occupied by the R 4 group. That is, when R 4 is attached to the 5 atom of the indoyl moiety, then R 5 is attached to the 6 atom of the indolyl moiety, and visa versa.
• the term "optionally substituted” means that, unless indicated otherwise, the moiety so modified may have from one to up to at least two of the substituents indicated. Each substituent may replace any H atom on the moiety so modified as long as the replacement is chemically possible and chemically stable. For example, a chemically unstable compound would be one where each of two substituents are bonded to a single C atom through each substituent's heteroatom.
• Another example of a chemically unstable compound would be one where an alkoxy group is bonded to the unsaturated carbon of an alkene to form an enol ether.
• each substituent is chosen independently of the other substituent and so that, accordingly, the substituents can be the same or different.
• (C C 3 )alkyl and “(C C 4 )alkyl” and “(C C 6 )alkyl” mean linear or branched saturated carbon groups having from about 1 to about 3, about 4, or about 6 C atoms, respectively. Such groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, and the like.
• (C 3 -C 6 )cycloalkyl means a saturated monocyclic alkyl group of from 3 to about 6 carbon atoms and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
• (C 2 -C 6 )alkenyl means a linear or branched carbon group having from about 2 to about 6 C atoms wherein at least two adjacent C atoms in the alkenyl group are joined by a double bond, with the proviso that when a C atom is double bonded to one adjacent C atom, it must be single bonded to any other adjacent C atom.
• the alkenyl group is attached to the rest of the molecule through a single bond.
• (C 2 -C 6 )alkynyl means means a linear or branched carbon group having from about 2 to about 6 C atoms wherein at least two adjacent C atoms in the alkynyl group are joined by a triple bond, with the proviso that when a C atom is triple bonded to one adjacent C atom, it must be single bonded to any other adjacent C atom.
• the alkynyl group is attached to the rest of the molecule through a single bond.
• (C 1 -C 3 )alkoxy means a linear or branched saturated carbon group having from about 1 to about 3, about 4, or about 6 C atoms, respectively, said carbon group being attached to an O atom.
• the O atom is the point of attachment of the alkoxy substituent to the rest of the molecule.
• Such groups include but are not limited to methoxy, ethoxy, r.-propoxy, isopropoxy, and the like.
• halo means an atom selected from Cl, Br, F and I.
• phenoxy means a phenyl ring attached to an O atom, the O atom being attached to the rest of the molecule.
• N[C C 3 )alkyl] 2 means that each of the 2 possible alkyl groups attached to the N atom are selected independently from the other so that they may be the same or they may be different.
• a phenyl ring or a heterocycle When a phenyl ring or a heterocycle is attached to the rest of the molecule, it is attached by replacing any H atom on the phenyl ring or on the heterocycle, respectively, with a bond to the rest of the molecule, as long as the replacement is chemically possible and chemically stable.
• Asymmetry i.e., where a compound's mirror image cannot be super-imposed on the compound, may be present in a compound of Formula (I) due to the inherent structure of the molecule.
• Examples of such asymmetric molecules include certain allenyl compounds.
• the compounds of this invention may also contain one or more asymmetric centers depending upon the location and nature of the various substituents selected.
• a molecule with a single asymmetric center may be a mixture of enantiomers (R,S), or may be a single (R) or (S) enantiomer.
• a molecule with more than one asymmetric center may be a mixture of diastereomers, or may be a single diastereomer.
• a compound may exhibit asymmetry due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compound. It is intended that all such configurations and conformations (including enantiomers, diastereomers, and other optical isomers) are included within the scope of the present invention.
• Separated, pure or partially purified stereo isomers of the compounds of Formula (I) are each included within the scope of the present invention.
• Preferred compounds are those with the absolute configuration or conformation which produces the more desirable biological activity.
• pharmaceutically acceptable salts of the compounds of this invention are also within the scope of this invention.
• pharmaceutically acceptable salt refers to either inorganic or organic salts of a compound of the present invention that have properties acceptable for the therapeutic use intended. For example, see S. M. Berge, et al. "Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
• Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts that are formed, for example, from inorganic or organic acids or bases by means well known in the art.
• acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate,
• Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates including dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides including benzyl and phenethyl bromides, and others.
• lower alkyl halides such as methyl, ethyl, propyl, and butyl chlor
• esters of appropriate compounds of this invention are pharmaceutically acceptable esters such as alkyl esters, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters, and the like. Additional esters such as phenyl-(CrC 5 ) alkyl may be used, although methyl ester is preferred.
• the compounds used in this invention may be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are commercially available, producible according to routine, conventional chemical methods or the synthesis of which is described herein.
• Formula (III) can then be deprotonated and quenched with an electrophile to furnish a dicarbonyl indole compound of Formula (IV).
• the Formula (IV) compound can be condensed with an aryl 1 ,2-diamine of Formula (V) to generate a compound of Formula (V).
• Reaction Schemes 2, 3, 5 through 10, 12 and 13 each describe how to make compounds with certain R 4 sub-groups where the starting material is an R 4 -sub-group compound of Formula (la) [Scheme 8, which can be applied when R 3 is H, as in Formula (la), or when R 3 is alkyl], Formula (lb) [Schemes 2, 3, 6, 7, 9,10, 12 and 13, which can be applied when R 3 is N0 2 , or is H, or alkyl].
• Formula (1c) from Reaction Scheme 1 (where R 3 is NH 2 and R 4 is as described without limitation) can be converted to a compound where R 3 is NH(C 1 -C 4 )alkyl, NHC(O)(C C 4 )alkyl, or NHC(O)phenyl according to Scheme 5.
• Scheme 2 shows how compounds of Formula (I), where R 3 is NO 2 and R 4 is CN, can be converted to compounds of Formula (I) where R 4 is C(O)R 6 by standard functional group manipulation.
• a cyanoindole (Id) can be hydrolyzed under basic conditions to an indole carboxylic acid (le). Coupling of acid (le) with an amine provides a variety of amides of general Formula (If).
• Formula (I) compounds where R 3 is NO 2 , and R 1 and R 12 are both H can be prepared by conversion of the acid (le) to the alcohol of Formula (lg) by a two step procedure employing an imidazolyl carbonyl intermediate followed by reduction as shown in Scheme 3.
• Treatment of alcohol (lg) with a halogenating agent such as SOBr 2 produces a compound of Formula (lh).
• Reaction of the halide (lh) with either an alcohol or amine furnishes the ether (Ii) or the amine (Ij), respectively.
• an optionally substituted amine e.g., an optionally substituted morpholine, NH[(C r C 3 )alkyl] 2 , Ph-NH 2 , pyrolidine, piperazine, piperidine
• Y is an optionally substituted amino group, e.g., morpolinyl, pyrolidinyl, piperizinyl, piperidinyl, NHPh, or N[(C r C 3 )alkyl] 2
• Y is an optionally substituted amino group, e.g., morpolinyl, pyrolidinyl, piperizinyl, piperidinyl, NHPh, or N[(C r C 3 )alkyl] 2
• R 1 or R 2 is an amino substituent
• R 3 is H
• Conversion of a difluoronitrobenzene of Formula (VI) to an aniline of Formula (VII) is accomplished by ammonia displacement of a fluoronitrobenzene.
• Displacement of a second fluoro group from the compound of Formula (VII) by an amine of Formula (VIII) provides a phenylenediamine intermediate of Formula (IX).
• Reduction of the nitro group in (IX), followed by intramolecular condensation with ketoester (IV) provides a compound of Formula (Ik).
• Y an optionally substituted amine, e.g., an optionally substituted amine, HN[(C r C 3 )alkyl] 2 , H 2 N[(C C 3 )alkyl], morpholine, piperarazine or pyrrolidine
• R 3 is NH 2
• R 3 is NH 2
• NHC(0)(C C 4 )alkyl HN(C r C 4 )alkyl, or NHC(0)phenyl
• Biaryl indole compounds of Formula (lllb) where R 4 is phenyl or pyridyl can be prepared as shown in Scheme 15. Performing a palladium catalyzed cross coupling between an indole boronic acid of Formula (lib) and an optionally substituted phenyl or pyridyl bromide to provide the indole of Formula (lie). Protection (lie) at the indole nitrogen provides the biaryl intermediate of Formula (1Mb).
• substituted piperazine When substituted piperazine is used in the preparation of Formula (I) compounds in which R 4 is an alkyl or acyl group substituted by piperazine, the substituted piperazine can be prepared by conversion of a compound of Formula (XIV) to a sulfonamide (XV) upon treatment with methylsulfonyl chloride.
• a ⁇ /-Boc protected piperazine (XV) can be converted to a monosubstituted piperazine of Formula (XVI) by subjecting (XV) to an acid such as TFA as shown in Scheme 17.
• the resulting Formula (XVI) can be used, for example, in the last step in Scheme 2.
• Amine derivatives of Formula (XVIII) can be prepared by conversion of a ketone of Formula (XVII) via reductive amination as shown in Scheme 18.
• This Scheme includes synthesis of the amine compounds that convert to N[(C 3 -C 6 )cycloalkyl][(CrC 3 )alkyl] and to substituted N[C C 4 )alkyl] 2 , and can be inserted into, for example, the last step of Scheme 2, the last step to make Formula (Ij) in Scheme 3, and as compound (VIII) in Scheme 4.
• Compounds of Formula (lllg) can be synthesized from anilines of Formula (XXIII) as shown in Scheme 21.
• the anilines could be converted to diazonium salts of Formula (XXIV) followed by reduction to substituted phenyl hydrazines of Formula (XXV).
• the hydrazines can be converted to phenyl hydrazones of Formula (XXVI) which can undergo an acid assisted cyclization to yield substituted indoles of Formula (lllg).
• reaction conditions for N- or O-acylation, alkylation, or sulfonylation of the intermediates and of Formula (I) compounds using acyl halides, alkyl halides and sulfonyl halides, respectively, and a suitable base are generally interchangeable, as is well known in the art.
• conditions to effect ⁇ /-acylation as described in any of the specific examples below can also be used to effect N- sulfonylation by substituting the appropriate sulfonyl halide for the acyl halide.
• Electron impact mass spectra were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 uM coating; 30 m x 0.25 mm). The ion source was maintained at 250 °C and spectra were scanned from 50-800 amu at 2 sec per scan.
• DMSO-Gfe 1.93 ppm for CD 3 CN, 3.30 ppm for CD 3 OD, 5.32 ppm for CD 2 CI 2 and 7.26 ppm for CDCI 3 for 1 H spectra, and 39.5 ppm for DMSO- ⁇ e, 1.3 ppm for CD 3 CN, 49.0 ppm for CD 3 OD, 53.8 ppm for CD 2 CI 2 and 77.0 ppm for CDCI 3 for 13 C spectra.
• step 1 In a 100 mL round-bottom flask was placed 2.0 g (8.26 mmol, 1 equiv) of fe/f-butyl 5-cyano-1H-indole-1-carboxylate (step 1) in 25 mL of T ⁇ F. The mixture was cooled to - 78 °C and 1.1 equiv (5.34 mL, 1.7 M in pentane) of t-BuLi was added dropwise. The mixture was allowed to stir for 1 h and 2.14 g (18.16 mmol, 2.2 equiv) of dimethyl oxalate in 5 mL of T ⁇ F was added quickly in one portion.
• step 2 In a 25 mL round-bottom flask was placed 114.1 mg (0.50 mmol, 1 equiv) of 5- cyano-2-[methoxy(oxo)acetyt]-1H-indole (step 2) and 132.6 mg of 1 ,2-diamino-4,5- dimethoxybenzene hydrochloride (0.55 mmol, 1.1 equiv) in 5 mL of acetic acid. The flask was equipped with a reflux condenser and heated at 130 °C for 3 h. The mixture was then allowed to cool to room temperature and diluted with 5 mL of water.
• the compound was prepared as described in WO 02/22598.
• a round bottom flask equipped with a dry ice condenser acetone/dry ice
• 2,4- difluoronitrobenzene 15 g, 94 mmol
• THF 20 mL
• Ammonia was bubbled into the solution for 10 min at -78 °C.
• the reaction was allowed to warm to room temperature and the reaction refluxed for 7 h. Stirring was continued overnight allowing the ammonia to evaporate after the condenser was removed.
• the reaction was diluted with dichloromethane and washed with water (3 x 100 mL). the organic layer was dried over MgSO 4 , filtered, and concentrated under reduced pressure to yield a solid.
• the compound was prepared as described in WO 02/22598.
• 5-fluoro-2-nitroaniline (4 g., 26.0 mmol) in 1-methyl-2-pyrrolidine (40 mL).
• (3S)-N,N-dimethyl-3-pyrrolidinamine (5.85 g., 51.2 mmol) was added to the stirring solution and the reaction was heated to 80 °C for 3 h. After cooling to room temperature, the reaction was poured over ice water. The product was diluted with dichloromethane and washed with saturated sodium bicarbonate (3 x 100 mL). The organic layer was dried with MgSO , filtered, and concentrated under reduced pressure to afford a solid.
• N 2 was bubbled through a solution of 5-indolylboronic acid (1.50 g, 9.32 mmol) in DME (55 mL) for 10 min.
• DME DME
• N 2 was then bubbled through the reaction mixture for 10 min before the mixture was heated at 60 °C for 1 h.
• the reaction temp was kept below 25 °C and the final pH is 7.5.
• the yellow precipitate which forms in the biphase aqueous layer during the quench was filtered off, washed with H 2 O (3 X 50 mL).
• the aqueous was extracted with CH 2 CI 2 (1 L), and the combined organics dried (Na 2 S0 ), filtered, and concentrated in vacuo to a yellow semi-suspension in the remaining DMF (5 mL). This was diluted with CH 2 CI 2 (10 mL) and copious amounts of hexane was added (200 mL) to give a yellow precipitate.
• Step 2 Preparation of ⁇ V-(1- ⁇ r3-amino-2-(3-oxo-3,4-dihvdroquinoxalin-2-vO-1H-indol-5- vUcarbonyl)pyrrolidin-3-yl)-/V-isopropyl-N-methylurea
• tert-butyl 3- ⁇ [tert-butyI(dimethyl)silyl]oxy ⁇ -1H- indole-1-carboxylate (0.500 g, 1.44 mol) and 100 ml of THF.
• the reaction was cooled to -78 °C before t-BuLi (1.7M in pentane, 0.93 mL, 1.6 mmol) was added slowly over 30 min.
• the solution was then allowed to stir for 2 h at -78 °C before dimethyl oxalate (0.425 g, 3.60 mmol) was added in one portion.
• the atmosphere was converted to H 2 with a balloon and the reaction allowed to stir at rt for 17 h.
• the H 2 was then removed and the mixture filtered through Celite ® under a blanket of argon.
• the solvents were then removed and the product was purified by chromatography.
• the desired product was a red oil (7.9 g, 92%).
• N 2 was bubbled through a solution of 4-bromo-6-nitroaniline (3.0 g, 14 mmol) in DME (25 mL) for 10 min before 1,1'-bis(diphenylphosphino-ferrocene) dichloropalladium (II), complex with CH 2 CI 2 (1:1) (0.60 g, 0.69 mmol), 1.0M solution of Na 2 CO 3 (35 mL, 35 mmol), and 4-fluorophenylboronic acid (2.0 g, 15mmol) were added.
• the reaction mixture was bubbled with nitrogen for an additional 10 min and then heated at 60 °C for 1 h.
• the reaction was quenched with water, extracted with EtOAc (3x).
• ⁇ /-(2-methoxyethyl)- ⁇ /-methyl-2-(3-oxo- 3,4-dihydroquinoxalin-2-yl)-1H-indole-5-sulfonamide was obtained as a red solid (0.012 g, 17%) from ⁇ /-(2-methoxyethyl)- ⁇ /-methyl-3-nitro-2-(3-oxo-3,4-dihydroquinoxalin-2-yl)-1 H- indole-5-sulfonamide (0.085 g, 0.160 mmol).
• a desired salt of a compound of this invention can be prepared in situ during the final isolation and purification of a compound by means well known in the art.
• a desired salt can be prepared by separately reacting the purified compound in its free base or free acid form with a suitable organic or inorganic acid, or _ ,
• the free base is treated with anhydrous HCl in a suitable solvent such as THF, and the salt isolated as a hydrochloride salt.
• the salts may be obtained, for example, by treatment of the free acid with anhydrous ammonia in a suitable solvent such as ether and subsequent isolation of the ammonium salt.
• Esters of the compounds identified herein can be obtained by conventional means, for example, by reaction of a carboxylic acid compound with an alcohol facilitated by an acid catalyst, or by reaction of the carboxylic acid compound and alcohol under Mitsunobu conditions. These methods are conventional and would be readily apparent to one skilled in the art.
• compositions of the compounds of this invention are provided.
• the compounds of this invention can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof in an appropriately formulated pharmaceutical composition.
• a patient for the purpose of this invention, is a mammal, including a human, in need of treatment (including prophylactic treatment) for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt or ester thereof, of the present invention.
• a pharmaceutically acceptable carrier is any carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
• a pharmaceutically effective amount of compound is that amount which produces a result or exerts an influence on the particular condition being treated.
• the compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, otically, sublingually, rectally, vaginally, and the like.
• the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
• the solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
• the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
• binders such as acacia, corn starch or gelatin
• disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn star
• Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
• Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
• Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.
• the pharmaceutical compositions of this invention may also be in the form of oil- in-water emulsions.
• the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
• Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavoring agents.
• Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
• the suspensions may also contain one or more preservatives, for example, ethyl or /.-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
• Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
• sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose.
• Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
• the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1-dioxolane-4-methanol, ethers such as poly( ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such
• Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
• Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
• Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
• suitable detergents include cationic detergents, for example di
• compositions of this invention will typically contain from about
• compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17.
• HLB hydrophile-lipophile balance
• the quantity of surfactant in such formulation ranges from about 5% to about 15% by weight.
• the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
• surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
• compositions may be in the form of sterile injectable aqueous suspensions.
• suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
• Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
• sterile fixed oils are conventionally employed as solvents or suspending media.
• any bland, fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid can be used in the preparation of injectables.
• composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
• These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• Such material are, for example, cocoa butter and polyethylene glycol.
• transdermal delivery devices Such transdermal patches may be used to .
• transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 11, 1991, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
• Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations which are known in the art.
• a mechanical delivery device It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device.
• the construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art.
• Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier.
• One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body is described in US Patent No. 5,011 ,472, issued April 30, 1991.
• compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired.
• Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al, "Compendium of Excipients for Parenteral Formulations” PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311; Strickley, R.G “Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al, "Excipients and Their Use in Injectable Products” PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.
• Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CCI 2 F 2 , F 2 CIC-CCIF 2 and CCIF 3 ); air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methyl
• clarifying agents include but are not limited to bentonite
• emulsifying agents include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate
• encapsulating agents include but are not limited to gelatin and cellulose acetate phthalate
• flavorants include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
• humectants include but are not limited to glycerol, propylene glycol and sorbitol
• levigating agents include but are not
• compositions according to the present invention can be illustrated as follows:
• Sterile IV Solution A 5 mg/mL solution of the desired compound of this invention is made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over 60 min.
• Lyophilized powder for IV administration A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lypholized powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40.
• the formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 min.
• Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection:
• Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
• Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
• Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and
• aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
• Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
• the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
• the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
• the present invention also relates to a method of using the compounds or compositions described herein for the treatment or prevention of, or in the manufacture of a medicament for treating or preventing, mammalian hyper-proliferative disorders.
• This method comprises administering to a patient (or a mammal) in need thereof, including a human, an amount of a compound, a pharmaceutically acceptable salt or ester thereof, or a composition of this invention which is effective to treat or prevent the disorder.
• Hyper-proliferative disorders include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias.
• the present invention also relates to a method for using the compounds of this invention as prophylactic or chemopreventive agents for prevention of the mammalian hyper-proliferative disorders described herein.
• This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt or ester thereof, which is effective to delay or diminish the onset of the disorder.
• breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
• hyper-proliferative disorders of the cardiovacular system include, but are not limited to, restenosis.
• cancers of the respiratory tract include, but are not limited to small- cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
• brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
• Tumors of nervous system include, but not limited to glioblastoma.
• Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
• Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
• Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
• Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
• Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
• liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
• Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
• Head-and-neck cancers include, but are not limited to laryngeal / hypopharyngeal / nasopharyngeal / oropharyngeal cancer, and lip and oral cavity cancer.
• Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
• Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
• Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
• the utility of the compounds of the present invention can be illustrated, for example, by their activity in vitro in the in vitro tumor cell proliferation assay described below.
• the link between activity in tumor cell proliferation assays in vitro and anti-tumor activity in the clinical setting has been very well established in the art.
• taxol Silvestrini et al. Stem Cells 1993, 11(6), 528-35
• taxotere taxol
• the present compounds and compositions exhibit anti-proliferative activity and are thus useful to treat the indications listed above, e.g. indications mediated by hyperproliferative disorders.
• Indications mediated by hyperproliferative disorders means diseases or conditions whose progression proceeds, at least in part, via proliferation.
• the following assay is one of the methods by which compound activity relating to treatment of the disorders identified herein can be determined.
• Measurement of anti-proliferative activity can be evaluated as follows.
• a human tumor cell line such as HCT-116, was cultured under conditions recommended by the supplier (CCL-247, American Type Culture Collection, Manassas, VA, USA).
• CCL-247 American Type Culture Collection, Manassas, VA, USA.
• Test compounds exemplified by Formula 1 above were dissolved in 100% dimethylsulfoxide at a concentration of 10 mmoles/L and diluted to the appropriated concentration such that the final dimethylsulfoxide concentration in the culture media did not exceed 0.25%.
• test compounds were added to the culture medium at the appropriate dilutions, and the cells with the test compound were allowed to remain in contact under normal cell culture conditions for 72 hours.
• the inhibitory activity was measured using a CellTiter-Glo assay kit, using the instructions provided by the manufacture (Promega, Madison, Wl, USA).
• the compounds of this invention are useful in the prevention and/or treatment of, or in the manufacture of a medicament for treating, angiogenesis dependent disorders.
• diseases are known to be associated with angiogenesis such as, for example, ocular neovascular disease, neovascular glaucoma, diabetic retinopathy, retrolental fibroplasia, hemangiomas, angiofibromas, psoriasis, age-related macula degeneration, haemangioblastoma, haemangioma, pain and inflammatory diseases such as rheumatoid or rheumatic inflammatory diseases including rheumatoid arthritis, as well as neoplastic diseases including, for example, so-called solid tumors and liquid tumors such as leukemias.
• the compounds of this inveniton are also useful to control solid tumor growth such as breast, prostate, lung, pancreatic, renal, colon, and cervical cancer, melanoma, tumor metastasis, and the like as are well known in the art.
• Tumors smaller than about 1 - 2 mm in diameter may receive oxygen and nutrients through diffusion directly into the tumor cells.
• angiogenesis is regarded as an absolute prerequisite for tumors that grow beyond that diameter.
• the principal mechanisms that play an important role in inhibition of tumor angiogenesis include inhibition of the growth of blood vessels, especially capillaries, into an avascular resting turmor, resulting in no net tumor growth due to the balance that is achieved between apoptosis and proliferation.
• Another route to treatment is through decreasing or preventing the migration of tumor cells throughout the body through the blood stream due to the inhibition of angiogenesis in relation to the tumor.
• endothelial cell growth may be inhibited to aviod the paracrine growth-stimulating effect exerted on the surrounding tissue by the endothelial cells which normally line the blood vessels.
• mice Female Ncr nude mice [Taconic Laboratories, NY] were inoculated subcutaneously with 5x106 MDA-MB-231 breast tumor cells (NCI, MD) on day 0. When tumors reached the size about 75 to 150 mm3, tumor-bearing animals were randomly divided into several groups with 10 mice per group and received the treatment with either vehicle or test compounds. All test compounds were formulated in PEG 400: Ethanol: 50mM methanesulfonic acid (40:10:50, v/v/v) vehicle, and given orally for 14 days. The dosing volumes were 0.1mL-test article/1 Og body weight or 10 mL/kg.
• tumor size was calculated at each measuring time-point based on the formula of [length (mm) x width (mm)2] / 2. Animal body weights were also recorded at the same time. All animals were observed for clinical signs daily after compound administration.
• tumors from both control animals and from animals treated with test compounds were resected and fixed in 10% buffered formalin and imbedded in paraffin.
• Tissue sections were prepared for im unohistochemistry and stained with anit-CD31 antibodies (sc-1506, Santa Cruz, CA) and developed using an ABC kit (Vector, Burlingame, CA) according to the manufacturer's instructions. The amount of CD31 staining as a percentage of the total area relative to untreated tumors was determined from images of sections using ImagePro Plus (Media Cybernetics, Silver Spring, MD) software. _
• Representative compounds of the invention were tested in the above assay and were found be active in reducing tumor size and in inhibiting angiogenisis.
• the effective dosage of the compounds of this invention can readily be determined for prevention and/or treatment of each desired indication.
• the amount of the active ingredient to be administered in the prevention and/or treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the duration of treatment (including prophylactic treatment), the age and sex of the patient treated, and the nature and extent of the condition to be prevented and/or treated.
• the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 300 mg/kg, and preferably from about 0.10 mg/kg to about 150 mg/kg body weight per day.
• a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day.
• the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
• the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
• the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
• the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
• the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
• the daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
• the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
• the desired mode of administration and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional prevention and/or treatment tests.
• the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
• the compounds of this invention can be combined with other anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
• optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednis
• anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment and/or prevention of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ.
• anti-hyper-proliferative agents suitable for use with the composition of this invention include but are not limited to other anti-cancer agents such as epothilone, irinotecan, raloxifen and topotecan.

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