BACKGROUND OF THE INVENTION Synthesis of benzodiazepin-2, 5-dione structures is known. See, e. g. : Sun. Barrow & Cooper,"Benzomalvin D, a New 1, 4-Benzodiazepine Atropisomer". Journal of Natural Products, vol. 58. no. 10 (Oct., 1995), pp. 1575-1580.

SUMMARY OF THE INVENTION The subject invention processes include: Step (a): a process for selective alkylation of benzodiazepine compounds comprising a reaction step wherein a benzodiazepin-2,5-dione having the structure: wherein-R1 is hydrogen, alkyl, aryl, or heterocyle. and each-R4 is independently hydrogen or a non- hydrogen substituent: is reacted with an atkyi bromide, R2-Br. or alkyl iodide. R2-I : (i) in dimethytformamide solvent, whereby the product of this reaction step is monoalkvlated compound having the structure: (ii) in dimethoxyethaane solvent. whereby the product of this reaction step is dialkylated compounds having the structures : Step (b) : a process for alkylation of benzodiazepindione compounds comprising a reaction step wherein a benzodiazepin-2, 5-dione having the structure of the product of Step (a) (i) is reacted with an alkyl bromide R3-Br, or an alkyl iodide. R3-I, in dimethoxyethane solvent, whereby the product of this reaction step is dialkylated compounds having the structures: The subject processes also includes processes for making libraries of such compounds.

DESCRIPTION OF THE INVENTION Glossary of Terms As used herein unless specified otherwise,"alkvl"means a hydrocarbon chain which is branche, linear or cyclic, saturated or unsaturated (but not aromatic), substituted or unsubstituted.

The term"alkvl"may be used alone or as part of another word where it may be shortened to"alk" (e. g., in alkoxy. alkylacyl). Preferred linear Alkyl have from one to about twenty carbon atoms, more preferably from one to about ten carbon atoms, more preferably still from one to about six carbon atoms, still more preferably from one to about four carbon atoms : most preferred are methyl or ethvl. Preferred cvclic and branched alkyl have from three to about twentv carbon atoms, more preferably from three to about ten carbon atoms. more preferably still from three to about seven carbon atoms, still more preferably from three to about five carbon atoms. Preferred cyclic alkyl have one hydrocarbon ring. but may have two, three, or more, fused or spirocycle hydrocarbon rings. Preferred alkvl are unsaturated with from one to about three double or triple bonds, preferably double bonds : more preferably the are mono-unsaturated with one double bond. Still more preferred alkyl are saturated. Saturated alkyl are referred to herein as"alkanyl". Alkyl unsaturated only with one or more double bonds (no triple bonds) are referred to herein as "alkenyl". Alkyl unsaturated with one or more triple bonds are referred to herein as"alkvnyl".

Preferred substituents of alkyl include halo, alkyl. aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio amino. alkylamino, arylamino. amide alkylamide arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides, sulfo, alkylsulfo, arylsulfo, sulfino, alkylsulfino, arvlsulfino. phospho, alkylphospho, arylphospho, phosphino. alkylphosphino, arylphosphino, nitro, and cyano. Substituents of cycloalkyl also include cycloalkyl, aryl and heterocyclic rings which are fused or spirocvcle with the initial cycloalkyl. Also, unsubstituted alkyl are preferred. An alkyl is bonded to another moiety at the "attaching carbon"of the alkyl As used herein,"primary alkyi"means that the attaching carbon of the alkyi has two or three hydrogens bonded to it ;''secondary alkyi"means that the attaching carbon has one hydrogen bonded to it and"tertiarv alkyl means that the attaching carbon has no hydrogens bonded to it.

Primary and secondary alkyl are preferred, primary alkyl is more preferred.

As used herein."heteroatom"means a nitrogen, oxygen, or sulfur atom.

As used herein, "alkylene" measn an alkyl which connects two other moieties, "heteroalkylene"means an alkylene having one or more heteroatoms in the connecting chain.

As used herein unless specified otherwise,"aryl"means an aromatic hydrocarbon ring (or fused rings) which is substituted or unsubstituted. The tenn"aryl"may be used alone or as part of another word (e. g., in aryloxy, arylacy). Preferred aryl have from six to about fourteen. preferably to about ten. carbon atoms in the aromatic ring (s), and a total of from about six to about twentx, preferably to about twelve, carbon atoms. Preferred aryl is phenyl or naphthyl I- most preferred is phenyl (Ph). Preferred substituents of aryl include halo. alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkvl and aryl esters and amides. sulfo, alkylsulfo, arylsulfo, sulfino. alkylsulfino, arylsulfino, phospho, alkylphospho, arylphospho, phosphino, alkylphosphino, arylphosphino, nitro, and cyano. Substituents of aryl also include cycloalkyl and heterocyclic rings which are fused with the aryl ring or rings. Also. unsubstituted aryl are preferred.

As used herein unless specified otherwise, "heterocycle" or "heterocyclic" means a saturated, unsaturated or aromatic cyclic hydrocarbon ring (or fused rings) with one or more heteroatoms in the hydrocarbon ring (s). Preferred heterocvcles have from one to about six heteroatoms in the ring (s). more preferably one or two or three heteroatoms in the ring (s).

Preferred heterocycles have from three to about fourteen, preferably to about ten. carbon plus heteroatoms in the ring (s), more preferably from three to about seven, more preferably still five or six, carbon plus heteroatoms in the rings (s) ; and a total of from three to about twenty carbon plus heteroatoms, more preferably from three to about ten, more preferably still five or six, carbon plus heteroatoms. Preferred heterocycles have one ring, but may have two, three, or more, fused rings.

More preferred heterocyclic rings include those which are one ring with 5 or 6 carbon plus heteroatoms in the ring with no more than three ring heteroatoms, no more than two of which are O and S. Still more preferred are such 5-or 6-ring atom heterocycles with one or two ring atoms being O or S and the others being C : or with one, two or three ring atoms being N and the others being C. Such preferred 5-or 6-ring atom heterocycles are preferably saturated, unsaturated with one or two double bonds, or aromatic. Such preferred 5-or 6-ring atom heterocycles are preferably a single ring ; or fused with a 3-to 6-ring atom hydrocarbon ring which is saturated, unsaturated with one double bond, or aromatic (phenyl) : or fused with another such 5-or 6-ring atom heterocyclic ring. Heterocycles are unsubstituted or substituted. Preferred heterocycle substituents are the same as for alkyl.

As used herein,"substantially free"means a product or other material has less than about 10%, preferably less than about 5%. more preferably less than about 2%. more preferably still less than about 1%, of the indicated contaminant (s).

As used herein"combinatorial librarv"of compounds means a mixture of related compounds or a group of individual compounds, e. g. in separate wells of a reaction block, made substantially simultaneously by substantially the same process using a mixture of or individual related reactants to obtain related compounds.

Processes of the Invention The subject invention processes involve the use of a solid supported reagent for the alkylation of benzodiazepin-2. 5-diones, either individually or in libraries. As a class. benzodiazepines have been shown to possess a wide range of biological activity, including antihvpertensive, angiotension II antagonist, platelet aggregation inl1ibitor gpIlb/IIla receptor antagonist, anticonvulsive. substance P inhibitor, and antimicrobial.

The selective alkylation of benzodiazepin-2 5-diones is accomplished using potassium fluoride on alumina (KF/A1203) in the presence of an alkyl bromide or iodide. In addition to the preparation of single compounds, the subject invention processes are useful for the preparation of combinatorial libraries. This approach, which sits between conventional solution phase chemistrv and resin bound techniques, shares several advantages of both fields. As with solid phase synthesis, excess support bound reagent can be used to drive reactions to completion and then be removed by filtration, avoiding cumbersome work-ups. Unlike resin based chemistry. however, the target compound is not covalently bound to the solid support, so monitoring of the reactions and analysis can be accomplished using standard methods (thin layer chromatography solution IH NMR etc.). Finally, the products are isolated by filtration and removal of the solvents, eliminating the need for the cleavage step required in solid phase preparations.

Processes of the subject invention involve preparation of benzodiazepin-2, 5-dione compounds having the structure : In structure (1), R1 is selected from hydrogen, alkyl aryl. and heterocycle. Preferred R1 is hydrogen or alkvl. the alkyl preferably being unsubstituted or substituted with: alkyl, aryl, heterocycle, alkoxy, aryloxy, alkylthio, arylthio, formyl, alkylacyl, arylacy, alkyl and aryl esters, <BR> <BR> <BR> alkvlsulfo, arylsulfo, alkylsulfino, arylsulfino alkylphospho, arylphospho, alkylphosphino, arylphosphino, nitro, cyano : more preferably with : alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, alkyl and aryl esters. Such substituents exclude any with moieties such as bromo, iodo, and the like, which would act as a competing reaction site to the intended bromo or iodo reactant site.

In structure (1). R2 is alkyl. In structure (1), R3 is hydrogen or alkyl, When R3 is alkyl, it is the same as R2 (R3=R2) or different from R2. Preferred alkyl R2 and R3 are primary or secondary alkyl. more preferably primary alkyl. Preferred alkyl R2 and R3 are each independently unsubstituted or substituted, preferably with : alkyl aryl, heterocvcle. alkoxy, aryloxy alkylthio, arylthio. formyl, alkylacyl, arylacyl, alkyl and aryl esters, alkylsulfo, arylsulfo, alkylsulfino. arylsulfino. alkylphospho. arylphospho. alkylphosphino, arylphosphino, nitro, cyano ; more preferably with : alkyi. aryl, alkoxy, aryloxy. alkylthio, arylthio. alky) and and esters. Such substituents exclude anv with moieties such as bromo. iodo. and the like. which would act as a competing reaction site to the intended bromo or iodo reactant site.

In structure (1), each R4 is independently hydrogen or a non-hydrogen substituent. Non- hydrogen R4 substituents are limited to those that will not interfere with or compete with the reaction of the subject processes. Preferred non-hydrogen R4 substituents include: halo, alkyl, aryl, heterocycle, alkoxy. aryloxy. alkvlthio, arylthio, formyl, alkylacyl. arylacyl. alkyl and aryl esters, sulfo, alkylsulfo. arylsulfo. sulfino, alkylsulfino, arylsulfino, phospho, alkylphospho, arylphospho, phosphino, alkylphosphino, arylphosphino, nitro, and cyano : more preferred non- hydrogen R4 include: halo, alkyi, alkoxy, aryloxy, alkylthio, arylthio, alkyl and aryl esters, and nitro. Preferably no more than two R4's are non-hydrogen substituents; more preferably no more than one R4 is a non-hydrogen substituent ; more preferably still all R4's are hydrogen. Non- hydrogen R4 substituents are preferably attached at the 8-or/and 9-positions of the benzodiazepine ring.

The processes of the subject invention comprise a reaction step wherein a benzodiazepin- 2,5-dione having the structure: is reacted with an alkyl bromide (R2-Br) or alkyl iodide (R2-I) in the presence of excess KF/A1203. Preferably the only material used in excess is the KF/A1203 which is easily removed by simple filtration, providing the desired product with a high degree of purity. (For subject invention processes, a typical crude 1H NMR shows little, if any. contamination with side products.) This above reaction step is carried out in a solvent which is selected depending on whether alkvlation of both nitrogens or only the 1-position nitrogen is desired.

The use of dimethylformamide (DMF) as the solvent favors alkvlation of only the 1- position nitrogen, thus producing a compound having the structure: The product of this reaction step is preferably substantially free of other alkylated benzodiazepindiones.

The use of dimethoxvethane (DME) as the solvent favors dialkylation of the two ring nitrogens or the 1-position nitrogen and the 5-position keto, thus producing a mixture of two compounds having the structures: The product of this reaction step is preferably substantially free of other alkylated benzodiazepindiones.

Another aspect of the subject invention is processes with comprise a reaction step wherein compound is reacted with an alky bromide (R3-Br) or alkyl iodide (R3-1) in the presence of excess KF/A1203 in DME solvent to produce compounds having the structures: The product of this reaction step is preferably substantially free of other alkylated benzodiazepindiones.

The above reaction steps all utilize potassium fluoride on alumina. Potassium fluoride on alumina (KF/A1203) is typically from about 10% to about 60% KF, preferably about 40% KF.

The amount of KF/A1203 present during the reaction steps is preferably at least about 2 equivalents, more preferably from about 4 equivalents to about 15 equivalents, more preferably still from about 5 equivalents to about 8 equivalents, per equivalent of reactant compound 2 or 3.

In the above reaction steps, the amount of alkyl bromide or iodide reacted with reactant compound 2 in DMF or reactant compound in DME is preferably from about 0.9 equivalent to about 1.5 equivalents, more preferably about 1.0 equivalent : and with reactant compound 2 in DME is preferably from about 1.8 equivalents to about 2.5 equivalents, more preferably about 2.0 equivalents.

The above reaction step for monoalkylation of compound 2 in DMF solvent is preferably carried out at a temperature of from about 0 °C to about 120 °C, more preferably at a temperature of from about 15 °C to about 80 °C, more preferably still at about room temperature (about 20-30 °C). The above reaction steps for dialkyation of compound 2 and monoalkylation of compound 3 in DME solvent are preferably carried out at a temperature of from about 0 °C to about 120 °C, more preferably from about 25 °C to about 100 °C, more preferably still from about 70 °C to about 85 °C. All of the above reaction steps are preferably carried out for a period of from about 1 hour to about 4 days more preferably from about 12 hours to about 3 days, more preferably still for about 2 days.

Examples The following examples provide further infonnation regarding the subject invention processes. They are simply exemplary and do not limit the scope of the subject invention.

Example 1 Monoalkylation of a Benzodiazepin-2,5-dione: 50. 0 mg (0.19 mmol) of 3-benzyl- benzodiazepin-2, 5-dione and 191 mg of KF/A1203 (40% by weight) are dissolved/suspended in 3.0 ml of DMF. 28.4 mg (22. 5 ul, 0.19 mmol) of isoamyl bromide is added, and the reaction mixture is stirred at room temperature for 48 hours. The reaction mixture is then filtered and stripped to yield the above compound.

Examples 2-6 Using the same reaction conditions and amounts of reactants (in mmols) as for Example 1. reactants having the structure of compound 2 with the following-Rl moieties are reacted with R2- Br's (except as noted in the table) to give products having the structure of compound 3 with the following-Rl and-R2 moieties: Example R1 R2 2 methyl isoamyl 3 methylthioethyl isoamyl 4 benzyl X COOEt <BR> <BR> OEt<BR> <BR> <BR> <BR> <BR> <BR> <BR> 5 benzyl 4-Cl-benzyl 6 benzyl methyl* * iodomethane is used as a reactant rather than bromomethane.

Example 7 Alkylation of a N-methyl-benzodiazepin-2, 5-dione : 25 mg (0. 09 mmol) of 1-methvl-3- benzyl-1, 4-benzodiazepin-2, 5-dione and 75 mg of KF/A1203 (40% by weight) are dissolved/suspended in 1.2 ml of DME. and 13. 5 mg (10.7 uL, 0.09 mmol) of isoamyl bromide is added. The reaction mixture is heated to 75-80 °C and stirred for 48 hours. The reaction mixture is then cooled to room temperature, filtered, and stripped to vield a product which is a mixture of the two above compounds. Chromatography with 2/1 hexane/ethyl acetate provides separation of the above N-alkylated and O-alkylated compounds.

Example 8 Monoalkylation Library and Dialkylation Library: Six reaction vials are loaded with 600 mg of KF/A1203, 0.56 mmols of a benzodiazepine 2. and 9 ml of DMF. A different alkyl bromide. R2-Br, (0. 56 mmol) is added to each vial, and the reaction mixtures are stirred for 48 hours at room temperature. The reaction mixtures are then filtered into six new vials, and then each vial is split into nine equal portions. One of each set of 9 is set aside and stripped of solvent to provide a monoalkylation library. The remaining samples are stripped of solvent (48 vials total.

6 sets of 8). 65 mg of KF/A1203 is then added to each vial. A set of 24 different alkyl bromides are then dissolved in DME to 0.063 M, and are mixed into 8 sets of 3 alkyl bromides with overall concentrations of 0. 063M. Each of the 48 vials ofmonoalkylated benzodiazepines is charged with one of the 8 alkyl bromide mixtures to generate a matrix of 48 different reaction mixtures (6x8). and then heated to 75 oC. After 48 hours the reaction mixtures are cooled, 10 mg of a polyamine scavenger resin (4.53 mmol/g. Nova Biochem) is added, and the reaction mixtures are stirred for an additional 24 hours. The reaction mixtures are then filtered into 48 new vials and stripped of solvent to yield a library ofdialkvlated compounds.

Example 9 Dialkylation Library Starting From Monoalkylated Products: Twenty-four reaction vials are loaded with 75 mg KF/A1203, 0.09 mmol of compound n and 1.2 ml of DME. Each vial is then charged with a solution that is 0.3 M in 1 of 24 different alkyl bromides. R3-Br, and the reaction mixtures are heated to 75 °C for 48 hours. The reaction mixtures are then cooled, filtered into 24 new vials, and stripped of solvents to yield the library of 24 different compound pairs.

While particular embodiments of the subject invention have been described, it will be obvious to those skilled in the art that various changes and modifications of the subject invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention.