MXPA99001176A - PURINE INHIBITORS OF CYCLIN DEPENDENT KINASE 2 AND I&kgr;B-&agr; - Google Patents

Abstract

A 2,6,9-trisubstituted purine composition that is useful for inhibiting cell proliferative disorders and as an antifungal agent.

Description

INHIBITORS PURINE OF KINASE 2 AND I? B - a DEPENDENTS OF CYCLIN BACKGROUND OF THE INVENTION (1) Field of the Invention This invention relates to 2, 6, 9-trisubstituted purines that have been discovered as selective inhibitors of cell cycle kinases and, as such, the compounds are inhibitors of cell proliferation. Purines 2, 6, 9-trisubstituted are useful in, for example - treatment of autoimmune diseases, for example, rheumatic arthritis, lupus, type I diabetes, multiple sclerosis, etc., in the treatment of cancer, cardiovascular disease, as is restenosis, host against graft disease, gout, polycystic kidney disease and other proliferative diseases whose pathogenesis involves the abnormal proliferation of cells.

This invention also relates to 2, 6, 9-trisubstituted purines that have been discovered as potent and specific inhibitors of I? B-a kinase that prevents signal-induced NF-KB activation and cytokine synthesis in vitro and in vivo. It is expected that said inhibitors inhibit the synthesis of cytokines and adhesion proteins whose synthesis is transcriptionally regulated by NF-KB. Proinflammatory cytokines such as IL-1, IL-6, TNF and adhesion proteins (eg, ICAM, VCAM and selections) belong to this class of molecules and have been implicated in the 1 pathogenesis of inflammatory diseases. Thus a potent inhibitor of the I? B-a kinase is useful in the clinical management of diseases where NF-KB activation is required for the induction of the disease. (2) Description of the Prior Art In past years, advances in molecular and cellular biology have contributed to our understanding of the mechanisms of cell proliferation and of specific events that occur during the progress of cells through mitosis. For example, "Progress in Cell Cycle Research", Volume 1, Eds. L. Meijer, S. Guidet and H.I.L. Tung; Plenum Press, New York, 1995. These studies have shown that progress through the cell cycle is controlled by a family of serine / threonine kinases called cyclin-dependent kinases. These enzymes contain (a) a catalytic protein called cylin-dependent kinase (CDK) that uses ATP as a substrate and (b) a regulatory protein called ciclin. Different combinations of ciclin - CDK control events such as growth, DNA reproduction and cell division. A key member of the CDK family of enzymes is CDK2. The activity of CDK2 has been shown to be essential for the progress of the mammalian cell cycle at the Gl / S limit. The microinjection of antibodies directed against CDK2 blocks the progress of human diploid fibroblasts in the S phase of the cell cycle. The expression of a dominant negative CDK2 mutant in human osteosarcoma cells has a similar effect. Together, these studies indicate that inhibition of the cellular activity of CDK2 will prevent the progress of cells through the mitotic cycle and induce an arrest to growth before the S phase. Consistent with this view, in vivo studies with olomoucine (2) - (hydroxyethylamino) -6-benzylamino-9-methylpurine), have been shown to be a specific inhibitor of CDK2 with an IC 50 of approximately 2.1 μg / ml, J. Vesely, et al., Eur. J. Biochem 224, 771- 786 (1994), L. Meijer "Chemical Inhibitors of Ciclin-Dependent Kinases" pages 351-356 in "Progress in Cell Cycle Research Volume 1, Eds. L. Meijer, S. Guidet and HYL Tung; Plenum Press, New York, 1995. In vivo studies using mammalian cells in culture have shown that olomoucine inhibits cell proliferation at a concentration of approximately 50 μg / ml.

In this invention, we have developed several compounds whose biological activity is considerably more potent than olomoucine. In vivo studies using mammalian cells indicate that some of the presented compounds inhibit cell proliferation at concentrations that are significantly better than olomoucine.

Recently, an I? B-a kinase activity has been described in the cytoplasm of simulated human umbilical vein endothelial cells (Bennett et al., (1996) J. Biol. Chem. 271, 19680- 19688). Some of the compounds of this invention have been identified as potent and specific inhibitors of the I? B-a kinase that prevent signal-induced NF-KB activation and cytokine synthesis in vitro and in vivo. The activation of the heterodimeric transcription factor NF-KB is a complex process. In unstimulated cells, the NF-KB heterodimer (p50 / p65) is located in the cytosol where it is complexed with an inhibitory subunit I? B - a, I? B - a, binds to NF - KB thus hiding its nuclear localization signal and preventing the translocation of the nucleus. After a stimulation of the cells with a variety of signals (for example, lipopolysaccharide) I? B-a is phosphorylated, uniquitinata and rapidly degraded, by the proteasome. The degradation of I? B - a allows the translocation of NF - KB to the nucleus where it activates the transcription of a number of inflammatory response genes.

These observations suggest that the I? B-a kinase is an attractive target for the identification of inhibitors that may be useful in the treatment of inflammatory diseases wherein NF-KB activation is required for the induction of the disease.

SUMMARY OF THE INVENTION It is an object of this invention to provide purified 2, 6, 9-trisubstituted purine compounds that inhibit cylin-dependent kinase 2.

Another objective of this invention is to provide 2, 6, 9 -substituted purine compounds that are useful for inhibiting cell proliferation.

This invention also constitutes a pharmaceutical composition, comprising a 2, 6, 9-trisubstituted purine compound and a pharmaceutically acceptable carrier.

This invention further comprises a method for inhibiting cell proliferation, comprising administering to a mammal in need thereof an effective amount of 2, 6, 9-trisubstituted purine compound.

In one example, this invention is a 2, 6, 9-trisubstituted purine composition of matter having the following formula: O) wherein X is NH, O, thio or half sulfone; Ri is halogen or RX where X is an amino, oxo, thio or half sulfone. X is preferably amino.

Ri 'is a lower alkyl, substituted minor alkyl, substituted cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, aralkyl, heteroaralkyl, heteroalkyl, alkenyl alkyl, alkyl alkynyl, cycloalkyl alkyl, or alkyl cycloheteroalkyl, each having from 1 to 20 carbon atoms wherein the substitutions include optional substitution with from 1 to 3 substitutes chosen independently of the group consisting of halo, CF3, aryl, heteroaryl, heterocyclyl, R22, SR22, S (O) R21, SO2R21, SO2NR20R23, SO NR20COR21, SO2NR20CONR20R23 'SO2NR20CO2R21, NR20R23, NR20COR21, NR20CO2R21, NR20CONR20R23, N (R20) C (NR20) NHR23, NR20SO2R21, OR20, OCONR20R23, OCONR20SO2R21, OCONR20R23, CN, CO2R20, CONR20R23, CONR20SO2R21 and COR20; R 2 is hydrogen, lower alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, aralkyl, heteroaralkyl, heteroalkyl, alkyl alkenyl, alkyl alkynyl, cycloalkyl alkyl or cycloheteroalkyl alkyl, each having one to 20 carbon atoms wherein the substitution includes the optional substitution with from 1 to 3 substitutes chosen independently of the group consisting of halo, aryl, heteroaryl, heterocyclyl, R22, SR22, S (O) R21, SO2R21, SO2NR20R23 , SO2NR20COR21, SO2NR20CONR20R23 'SO2NR20CO2R21, NR20R23, NR20COR21, NR20CO2R21, NR20CONR20R23, N (R20) C (NR20) NHR23, NR?? SO2R, OR, OCONR, 2¿0? Rt, 23, OCONR 20? CS / O2R, 21, OCONR, 20? Rt_23, CN, CO2R, 20, CONR20R23, CONR20SO2R21 and COR20; R3 is halogen, hydroxyl, thio, alkylthio, lower alkyl, -NR R5 or a component having the formula: where m = 1 - 3, n = 1 - 3, and o = 1 - 3; Y = carbonyl, - NR4R5, hydroxyl, thiol, alkoxy, alkylthiol; As an alternative, when R3 is NR4R5, Rt and R5 are each independently linked to hydrogen, lower alkyl having from 1 to 6 carbon atoms, or aralkyl which is monosubstituted or disubstituted with hydroxy, halo, alkoxy, trifluoromethyl, cyano, alkoxycarbonyl or mixtures thereof. Some examples of useful substitutes for R3 are: wherein Re is H, lower alkyl having from 1 to 6 carbon atoms or aralkyl which is monosubstituted, monosubstituted or disubstituted with hydroxy, halo, alkoxy, trifluoromethyl, cyano, carbonyl alkoxy and mixtures thereof.

R4 and R5 are each independently selected from the group including minor alkyl, substituted minor alkyl, amino, amido, carboxyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, aryl, substituted aryl, aryloxy, hetaryl, substituted hetaryl, aralkyl, heteroaralkyl, alkenyl alkyl, alkyl alkynyl, cycloalkyl alkyl, cycloheteroalkyl alkyl, wherein each has from 1 to 20 carbon atoms wherein the substitution includes the optional substitution with from 1 to 3 substitutes chosen independently of the group consisting of halo, aryl, heteroaryl, heterocyclyl, R22, SR22, S (O) R21, SO2R21, SO2NR20R23, SO2NR20COR21, SO2NR20CONR20R23, SO2NR20CO2R21, NR20R23, NR20COR21, NR.20UC / O2R21, NR20CONR20R23, N (R20) C ( NR20) NHR23, NR20SO2R21, OR20, OCONR20R23, OCONR20SO2R21, OCONR20R23, CN, CO2R20, CONR20R23, CONR20SO2R21 and COR20; provided that when Y is carbonyl, Y and Rt 'can be together a single oxygen atom, R "and R5" together can be a single oxygen atom and where R3 is 2 -hydroxyethylamino and R2 is methyl, R-X does not is amino, 3-methyl-2-butenylamino, benzylamino om-hydroxybenzylamino, when R3 is not 2-hydroxyethylamino, when R2 is isopropyl, Ri'-X is not benzylamino, m-hydroxybenzylamino or 3-netylbutylamino, when R3 is 2 - hydroxyethylamino and R2 is 2-hydroxyethyl, Ri'-X is not benzylamino and when R3 is chosen di group consisting of 2-methyl-2-hydroxypropylamino and 2-dimethylaminoethylamino and R2 is methyl, then Ri'-X is not benzylamino.

In the above composition, R20 is a member selected from the group consisting of H, Ci. 8 alkyl, aryl and heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with 1 to 3 substitutes chosen independently of halo, alkyl, mono - or dialkylamino, alkyl or aryl or heteroaryl amide, CN, alkyl O-Ci-Ce, CF3; R21 is a member selected from the group consisting of Ci. 8 alkyl, aryl, and heteroaryl, said alkyl, aryl, and heteroaryl being optionally substituted with 1 to 2 substitutes chosen independently from the halo group, CF3, CN, OR20, SR20 , N (R20) 2, S (O) R ", SO2R ..22, SO2N (R?) 2, NR? CO2R, MTCON (R 2/0 ??) 2, COR, CO2R, CON (R?) 2, , 20 NR? SO2R 22, O? Rr > 2/0?; R is an elected member of the group consisting of Ci alkyl. s, aryl and heteroaryl, said alkyl, aryl and heteroaryl are optionally substituted with 1 to 3 substitutes independently chosen from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-Ci-C6 alkyl, CF3, aryl and heteroaryl; Y R23 is R21 or H.

In another example, this invention is a method for inhibiting mammalian cell proliferation comprising the administration of a therapeutically effective amount of the composition of claim 1 to a mammal. The method is useful for treating cell proliferation disorders such as rheumatic arthritis, lupus, type I diabetes, multiple sclerosis, cancer, restenosis, host graft disease and gout.

In yet another example, this invention is a pharmaceutical composition of matter comprising the above composition in a mixture with one or more pharmaceutical excipients.

In yet another example, this invention is a composition useful for treating fungal infections in humans, animals and plants.

DESCRIPTION OF THE FIGURE Figure 1 is an impression of the actual neointimal area of a rat carotid artery treated with a saline vehicle and treated with compound 3 prepared according to Example 2 wherein the unshaded bar represents the untreated section of the carotid artery and the shaded bar represents the treated section of the carotid artery. DESCRIPTION OF THE EXEMPLARY PRESENT The present invention relates to a 2, 6, 9-trisubstituted compound having the following formulas: (I) where: Ri is halogen or Ri '- X where X is an amino, oxo, thio or half sulfone. X is preferably amino.

Ri 'is a lower alkyl, substituted minor alkyl, substituted cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, aralkyl, heteroaralkyl, heteroalkyl, alkenyl alkyl, alkyl alkynyl, cycloalkyl alkyl, or alkyl cycloheteroalkyl, each having from 1 to 20 carbon atoms wherein the substitutions include optional substitution with from 1 to 3 substitutes chosen independently of the group consisting of halo, CF3, aryl, heteroaryl, heterocyclyl, R22, SR22, S (O) R21, SO2R21, SO2NR20R23, SO2NR20COR21, SO2NR20CONR20R23 'SO2NR20CO2R21, NR20R23, NR20COR21, NR20CO2R21, NR20CONR 0R23, N (R20) C (NR20) NHR23, NR20SO2R21, OR20, OCONR20R23, OCONR20SO2R21, OCONR20R23, CN, CO2R20, CONR20R23, CONR20SO2R21 and COR20?;.

R 2 is hydrogen, lower alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, aralkyl, heteroaralkyl, heteroalkyl, alkyl alkenyl, alkyl alkynyl, cycloalkyl alkyl or cycloheteroalkyl alkyl, each having one to 20 carbon atoms wherein the substitution includes the optional substitution with from 1 to 3 substitutes chosen independently from the group consisting of halo, aryl, heteroaryl, heterocyclyl, R22, SR22, S (O) R21, SO2R21, SO2NR20R23 , SO2NR20COR21, SO2NR20CONR20R23 'SO2NR20CO2R21, NR20R23, NR20COR21, NR20CO2R21, NR20CONR20R23, N (R20) C (NR20) NHR23, NR20SO2R21, OR20, OCONR20R23, OCONR20SO2R21, OCONR20R23, CN, CO2R20, CONR20R23, CONR20SO2R21 and COR20; R? is halogen, hydroxyl, thio, alkylthio, lower alkyl, -N + Rs or a component having the formula: where m = 1 - 3, n = l - 3, and o = 1 - 3; Y = carbonyl, - NR R5, hydroxyl, thiol, alkoxy, alkylthiol; R4 and R5 are each independently selected from the group including minor alkyl, substituted minor alkyl, amino, amido, carboxyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, aryl, substituted aryl, aryloxy, hetaryl, substituted hetaryl, aralkyl, heteroaralkyl, alkenyl alkyl, alkyl alkynyl, cycloalkyl alkyl, cycloheteroalkyl alkyl, wherein each has from 1 to 20 carbon atoms wherein the substitution includes the optional substitution with from 1 to 3 substitutes chosen independently of the group consisting of halo, aryl, heteroaryl, heterocyclyl, R22, SR22, S (O) R21, SO2R21, SO2NR20R23, SO2NR20COR21, SO2NR20CONR20R23 'SO2NR20CO2R21, NR20R23, NR20COR21, NR20CO2R21, NR20CONR20R23, N (R20) C (NR20) NHR23, NR 0SO2R21, OR20, OCONR20R23, OCONR20SO2R21, OCONR20R23, CN, C02R20, CONR20R23, CONR20SO2R21 and COR20; provided that when Y is carbonyl, Y et 'can be together a single oxygen atom, t "and R5" together can be a single oxygen atom and where R3 is 2 -hydroxyethylamino and R2 is methyl, Ri' - X not is amino, 3-methyl-2-butenylamino, benzylamino om-hydroxybenzylamino, when R3 is not 2-hydroxyethylamino, when R2 is isopropyl, Ri'-X is not benzylamino, m-hydroxybenzylamino or 3-netylbutylamino, when R3 is 2 - hydroxyethylamino and R2 is 2-hydroxyethyl, Ri'-X is not benzylamino and when R3 is chosen di group consisting of 2-methyl-2-hydroxypropylamino and 2-dimethylaminoethylamino and R2 is methyl, then Ri'-X is not benzylamino.

In the above composition, R20 is a member selected from the group consisting of H, Ci. 8 alkyl, aryl and heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with 1 to 3 substitutes chosen independently of halo, alkyl, mono - or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-Ci-C6 alkyl, CF3; R21 is a member selected from the group consisting of aikyl Ci. 8, aryl, and heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with 1 to 2 substitutes chosen independently from the halo group, CF3, CN, OR20, SR20 , N (R20) 2, S (O) R22, SO2R22, SO2N (R20) 2, NR20CO2R22, NR20CON (R20) 2, COR20, CO2R20, CON (R20) 2, NR20SO2R22, OR20; R is a member selected from the group consisting of Ci. 8 alkyl, aryl and heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with 1 to 3 substitutes independently chosen from halo, alkyl, mono- or dialkylamino, alkyl or aryl or amide heteroaryl, CN, O-Ci-C6 alkyl, CF3, aryl and heteroaryl; Y R23 is R21 or H.

There are some limitations to the scope of Ri, Ri ', R2 and R3. When R3 is 2-hydroxyethylamino and R2 is methyl, Ri'-X can not be Ri'NH, 3-methyl-2-butenylamino, benzylamino or m-hydroxybenzyl-amino. When R3 is 2-hydroxyethylamino and R2 is isopropyl, Ri'-X can not be benzylamino, m-hydroxybenzylamino or 3-methylbutylamino.

When R3 is 2-hydroxyethylamino and R2 is 2-hydroxyethyl, Ri'-X can not be benzylamino.

When R3 is 2-methyl-2-hydroxypropylamino or 2-dimethylaminoethylamino and R2 is methyl, Ri '- X can not be benzylamino.

The following are definitions for certain terms used herein.

"Halo" or "halogen" alone or in combination means all halogens, i.e. chlorine (Cl), fluorine (F), bromine (Br), iodine (I).

"Hydroxy" refers to the group - OH.

Thiol "or" mercapto "refer to the group - SH.

"Alkyl" - together or in combination means a radical derived from alkane containing from 1 to 20, preferably from 1 to 15, carbon atoms (unless specifically defined). It is a straight or branched chain alkyl, alkyl or branched cycloalkyl. Preferably, straight or branched alkyl groups containing from 1 to 15, more preferably from 1 to 8, still more preferably 1-6, still more preferred 1-4 and more preferably 1-2, carbon atoms, as is methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like. Preferably, the cycloalkyl groups are monocyclic, bicyclic or tricyclic chain systems of 3-8, more preferably 3-6, chain members per chain, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl and the like. Alkyl also includes a straight chain or branched chain alkyl group that contains or is interrupted by a cycloalkyl moiety. The straight or branched chain alkyl group is attached to any available site to produce a stable compound. Examples of the foregoing include, but are not limited to, 4 - (isopropyl) -cyclohexylethyl or 2-methyl-cyclopropylpentyl. A substituted alkyl is a straight chain alkyl, branched alkyl or cycloalkyl group previously defined, independently substituted with 1 to 3 halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkyl sulfonyl, acyloxy, aryloxy, heteroaryloxy, amino groups or substitutes. optionally mono- or disubstituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl, aminosulfonyl optionally N-mono- or N, N-disubstituted with alkyl, aryl or heteroaryl, alkylsulfonylamino groups, Arsulfonylamino, heteroarylsulphonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino or the like.

"Alkenyl" - alone or in combination means a straight, branched or cyclic hydrocarbon containing from 2 to 20, preferably 2-17, more preferably 2 - 10., more preferably 2-8, more preferably 2-4 carbon atoms and at least one, preferably 1-3, more preferably 1-2, more preferably one, carbon-carbon double bond. In the case of a cycloalkyl group, the conjugation of more than one carbon-carbon double bond is not such as to confer aromaticity to the chain. The carbon-carbon double bonds can be either contained within a cycloalkyl portion, with the exception of cyclopropyl, or. within a straight chain or branched portion. Examples of the alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, cyclohexenyl, cyclohexenylalkyl and the like. A substituted alkenyl is straight chain alkenyl, branched alkenyl or cycloalkenyl group previously defined, independently substituted with from 1 to 3 halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino groups or substituents or substitutes. optionally mono-or disubstituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl, heteroaryl or heterocyclyl, aminosulfonyl groups optionally N-mono or N, N-disubstituted with alkyl, aryl or heteroaryl, alkylsulfonylamino, aryisulphonylamino, heteroarylsulphonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl or the like adjoining groups at any available point to produce a stable compound.

"Alkynyl" - alone or in combination means a straight or branched hydrocarbon containing from 2 to 20, preferably 2-17, more preferably 2-10, still more preferably 2-8, more preferably 2-4 carbon atoms which it contains at least one, preferably one, triple carbon to carbon bond. Examples of the alkynyl groups include ethynyl, propynyl, butynyl, and the like. A "substituted alkynyl" refers to the straight chain alkynyl or branched alkenyl defined previously, independently substituted with from 1 to 3 halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono or substituents or substituents or disubstituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl or heteroaryl, or heterocyclyl, aminosulfonyl groups optionally N-mono- or N, N-disubstituted with alkyl, aryl or heteroaryl, alkylsulfonylamino, aryisulfonylamino groups , heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino or the like attached at any available site to produce a stable compound.

"Alkenyl alkenyl" refers to a group -R-CR '= CR' "R '", wherein R is minor alkyl or substituted minor alkyl, R', R '", R'" may independently be hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, hetaryl or substituted hetaryl as defined below.

"Alkynyl alkynyl" refers to groups - RC = CR 'wherein R is minor alkyl or substituted minor alkyl, R' is hydrogen, minor alkyl, substituted minor alkyl, acyl, aryl, substituted aryl, hetaryl or substituted hetaryl as defined ahead.

"Alkoxy" denotes the group -OR, wherein R is lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, aralkyl or substituted aralkyl as defined at the moment.

"Alkylothio" denotes the group - SR, - S (O) n =? - 2 - R, wherein R is lower alkyl, substituted minor alkyl, aryl, substituted aryl, aralkyl or substituted aralkyl as defined herein.

"Acyl" denotes the groups C (O) R, wherein it is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, and the like as defined herein.

"Aryloxy" denotes the groups - OAr, where Ar is an aryl, substituted aryl, heteroaryl or substituted heteroaryl group as defined herein.

"Amino" denotes the group NRR1, wherein R and R 'may independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, or substituted hetaryl as defined herein or acyl.

"Amido" denotes the group - C (O) NRR ', wherein R and R' may independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl as defined herein.

"Carboxyl" denotes the group -C (O) OR, wherein R is hydrogen, lower alkyl, substituted minor alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl as defined herein.

"Aryl" - alone or in combination means phenyl or naphil optionally fused carbocyclicly with a cycloalkyl preferably 5-7, more preferably 5-6 chain members and / or optionally substituted with from 1 to 3 halo or hydroxy groups or substitutes , alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or disubstituted with alkyl, aryl groups, heteroaryl or heterocyclic, aminosulfonyl optionally N-mono- or N, N-disubstituted with alkyl, aryl or heteroaryl, alkylsulfonylamino, aryisulphonylamino, heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino or the like. "Substituted aryl" refers to aryl optionally substituted with one or more functional groups, for example, halogen, minor alkyl, minor alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, heteroaryl, substituted hetaryl , nitro, cyano, thiol, sulfamido and the like.

"Heterocycle" refers to a saturated, unsaturated or aromatic carbocyclic group having a single ring (eg, morpholino, pyridyl or furyl) or multiple fused rings (eg, napyridyryl, quinoxalyl, indolizinyl or benzo { B] thienyl) and having at least one hetero atom, such as N, O, or S, within the ring, which may or may not be substituted with, for example, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino , amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

"Heteroaryl" - alone or in combination means a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having from 8 to 10 atoms, containing one or more, preferably from 1 to 4, more preferably 1-3, even more preferably 1-2, heteroatoms independently chosen from the group O, S and N, and optionally substituted with from 1 to 3 halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfophenyl, groups or substituents, acyloxy, aryloxy, heteroaryloxy, amino optionally mono- or disubstituted with alkyl, aryl or heteroaryl groups, amidino, urea optionally substituted with alkyl, aryl or heteroaryl groups, or heterocyclic, aminosulfonyl optionally N-mono'N, N-disubstituted with alkyl groups , aryl or heteroaryl, alkylsulfonylamino, aryisulfonylamino, heteroarylsulphonylamino, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino or the like, heteroaryl also it is intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary chain nitrogen. A carbon or nitrogen atom is the binding point of the heteroaryl chain structure as it is a stable aromatic chain. Examples of the heteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl and the like. A substituted heteroaryl contains a substitute attached to a nitrogen or available carbon to produce a stable compound, "heterocyclyl" - alone or in combination means a non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring they are replaced by heteroatoms of O, S or N, and are optionally fused to benzo or heteroaryl of 5-6 chain members and / or optionally substituted as in the case of cycloalkyl. Heterocyclyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary chain nitrogen. The coupling point is a carbon or nitrogen atom. Examples of heterocyclyl groups are tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, dihydroindolyl and the like. A substituted heterocyclyl contains a substitute nitrogen coupled to a carbon or nitrogen available to produce a stable compound. "Substituted heteroaryl" refers to an optionally mono or polysubstituted heterocycle with one or more functional groups, eg, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, heterocycle substituted, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like. "aralkyl" - alone or in combination means a radical wherein an aryl group as defined above is coupled to an alkyl radical as defined above. Examples of such radicals include benzyl, phenylpropyl, nañylmethyl, 4-fluorobenzyl and the like.

"Heteroalkyl" refers to the group -R-Het wherein Het is a heterocycle group and R is a lower alkyl group. Heteroalkyl groups can be optionally substituted or substituted with, for example, halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, aryl, aryloxy, heterocycle, substituted heterocycle, heteroaryl, substituted hetaryl, nitro, cyano , thiol, sulfamido and the like.

"Heteroarylalkyl" refers to the group -R-HetAr wherein HetAr is a heteroaryl group and R lower alkyl or substituted lower alkyl. The heteroarylalkyl groups may be optionally substituted or substituted with, for example, halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, heteroaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

"Cycloalkyl" refers to a cyclic or polycyclic divalent alkyl group containing from 3 to 15 carbon atoms.

"Substituted cycloalkyl" refers to a cycloalkyl group comprising one or more substitutes with, for example, halogen, lower alkyl, substituted minor alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamino and the like.

"Cycloheteroalkyl" refers to a cycloalkyl group in which one or more of the ring carbon atoms is replaced with a heteroatom (eg, N, O, S or P).

"Substituted cycloheteroalkyl" refers to a cycloheteroalkyl group as defined herein that contains one or more substitutes such as halogen, minor alkyl, substituted minor alkyl, minor alkoxy, alkylthiol, acetylene, amino, amido, carboxyl, hydroxyl, aryl , aryloxy, heterocycle, substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

"Alkyl cycloalkyl" denotes the group -R-cycloalkyl wherein cycloalkyl is a cycloalkyl group and R is a lower alkyl or substituted lower alkyl. Cycloalkyl groups can be optionally substituted or substituted with, for example, halogen, lower alkyl, substituted lower alkyl, lower alkoxy, alkylthiol, acetylene, amino, amiso, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, heteroaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

"Alkyl cycloheteroalkyl" denotes the group -R-cycloheteroalkyl wherein R is a lower alkyl or a substituted lower alkyl. The cycloheteroalkyl groups can be optionally substituted or substituted with, for example, halogen, lower alkyl, substituted lower alkyl, lower alkoxy, alkylthiol, acetylene, amino, amiso, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, heteroaryl, substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

"Pharmaceutically acceptable salt" - a salt prepared by conventional means, and are well known to those skilled in the art. "Pharmaceutically acceptable salts" include the basic salts of inorganic and organic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid , tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. When the compounds of the Formula I-DI include an organic function such as a carboxy group, then the pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, cations of quaternary ammonia and the like. For further examples of "pharmaceutically acceptable salts", see Berge et al., J. Pharm.

Sci., 66, 1 (1977).

If the final 2, 6, 9-trisubstituted purine compound of this invention contains a basic group, then the acid addition salt of the composition can be prepared. The acid addition salts of the compounds of this invention are prepared in a standard manner in an appropriate solvent from the parent compound and an excess of acid, such as, but not limited to, hydrochloric, hydrobromic, sulfuric, phosphoric, acetic. , maleic, succinic or methanesulfonic. The hydrochloric salt form is especially useful.

If the final 2, 6, 9-trisubstituted purine compound contains an acidic group, then the cationic salts of the composition can be prepared. Typically the acidic master compound is treated with an excess of alkaline agent, such as, but not limited to, hydroxide, carbonate or alkoxide, containing the appropriate cation as is, but not limited to, Na +, K +, Ca + 2 and NIL. Certain of the compounds form inner salts or zwitterions that are also acceptable.

The compounds of this invention are useful in the inhibition of cell proliferation in even human mammals. The 2, 6, 9-trisubstituted purines are useful in, for example, the treatment of autoimmune diseases, for example, rheumatic arthritis, lupus, type I diabetes, multiple sclerosis, etc., in the treatment of cancer, cardiovascular disease such as restenosis, host disease against graft, gout, polycystic kidney disease and other proliferative diseases whose pathogenesis involves abnormal cell proliferation.

The method of treatment comprises the parenteral and oral administration of an effective amount of the compound chosen from this invention, preferably dispersed in a pharmaceutical carrier. Therapeutically useful amounts of the composition of this invention will generally vary from about 0.01 to about 100 mg / kg, but will be readily determined by one skilled in the art depending on the route of administration, and the age and condition of the patient. . Therapeutically useful amounts of the composition of this invention can be administered from one to ten times a day or more for acute or chronic disease. Unacceptable toxicological effects are not expected when the compounds of the invention are administered in accordance with the present invention.

The compounds of this invention are also useful as anti-inflammatory and anti-fungal agents. As such, the compositions of this invention are useful for the treatment of anti-inflammatory and fungal infections in humans, animals and fungal infections in plants.

Pharmaceutical compositions that include the compounds of this invention, and / or derivatives thereof, can be formulated as lyophilized solutions or powders for parenteral administration. The powders can be reconstituted as solutions by the addition of a compatible diluent or other pharmaceutically acceptable carrier before use. If used in liquid form the compositions of this invention are preferably incorporated in a regulated, isotonic and aqueous solution. Examples of the appropriate diluents are isotonic saline solution, standard 5% dextrose in water and sodium acetate solution or regulated ammonia. Said liquid formulations are suitable for parenteral administration, but may also be used for oral administration.

It may be desirable to add excipients such as polyvinyl pyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride, sodium citrate or any other excipient known to those of skill in the art pharmaceutical compositions including compounds of this invention. As an alternative, the pharmaceutical compounds can be encapsulated, tabletted or prepared in an emulsion or syrup for oral administration. The pharmaceutically acceptable solid or liquid carriers can be added to improve or stabilize the composition, or to facilitate the preparation of the composition. Liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, glycerin, saline, alcohols, and water. Solid carriers include, but are not limited to, starch, lactose, calcium sulfate, dihidate, teffa alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as, but not limited to, glyceryl monostearate or glyceryl distearate, alone or with wax. The amount of solid carrier varies but, preferably, it will be between about 20 mg to about 1 gram per unit dose.

The pharmaceutical doses are made using conventional techniques such as, but not limited to, melting, mixing, granulating and compressing, when necessary, to form tablets; or casting, mixing and filling for forms of hard gelatin capsules. When a liquid carrier is used, the preparation will take the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Said a liquid formulation can be administered directly or filled into a soft gelatin capsule.

The following examples serve to illustrate this invention. The examples are not intended in any way to limit the scope of this invention, but are offered to show how to make and use the compounds of this invention. In the Examples, all temperatures are in degrees centigrade. RT indicates room temperature.

EXAMPLE 1 The compounds of this invention are prepared by conventional methods of organic chemistry. The reaction sequence indicated in the synthesis scheme below is a general method useful for the synthesis of the compounds of this invention. 2,6-Dichloropurine is dissolved in butanol and the appropriate Ri amine is added. After heating for several hours, the reaction mixture is cooled, and compound 1 is obtained. To compound 1, sodium hydride is added followed by R2, and compound 2 is isolated. To compound 2, R3 is added in solution with N-methylpyrrolidone. The mixture is heated for an appropriate period followed by purification leading to the desired compound.

The following compound was prepared according to the above method. Preparation of purine 2-chloro-6 - (4-methoxybenzylamino) (1). 2,6-Dichloropurine (4.06 g, 21.5 mmol) was suspended in n-butanol (150 mL) and 4-methoxybenzylamino was added (3.4 mL, 26 mmol). The solution became clear and then it became cloudy a few minutes later. The solution was heated at 120 ° C for 2 hours and then the n-butanol was evaporated followed by suspension of the residue in a mixture of water and diethyl ether. A solution of 2N NaOH (1.3 ml, 26 mmol) was added and the solution stirred for 10 minutes before filtration. The filtered precipitate was washed with water and a small portion of ether and then vacuum sealed. The residual liquor was left overnight and more crystals were collected the next day and washed with diethyl ether. Production = 71%.

Preparation of 2-chloro-6- (4-methoxybenzylamino) -9-isopropulpurine (2) Purine 2-chloro-6 - (4-methoxybenzylamino was suspended in dry DMF (5 ml) and treated with sodium hydride, 60% dispersion (82 mg, 2.06 mmol) .The solution was stirred for 30 minutes during the which became a clear yellow / green solution, 2-iodopropane (0.280 ml, 1.7 eq) was added for 5 minutes and the resulting solution was stirred for 2 days, water was added and the solution was extracted with ethyl acetate. organic was evaporated to give the product purine isopropyl (Production = 508 mg, 89%).

Preparation of 2-diethanolamino-6- (4-methoxybenzylamino) -9-isopropylpurine (3). The purine (1.65 g, 4.98 mmol) was dissolved in DMSO (12 ml) and diethanolamine (4 ml) and then heated at 140 ° C for 2-3 days and then at 160 ° C for 1 day. The solution was then washed with water (3 x 50 ml), before being evaporated to give a brown oil. The residue is chromatographed to give the product (Production = 730 mg, 37%) as a pale yellow oil. Production 37%. 1H-NMR (5CDC13): 7.29 (br s HI), 7.25 (d, 2H), 6.94 (br s HI), 6.83 (d, 2H), . 43 (brs. < 2H), 4.63 brs. 2H), 4.53 (mHH), 3.86 (tH 4H), 3.76 m, 7H), 1.47 (d 6H).

Table 1 identifies compounds of this invention that were prepared according to the synthesis method set forth in this Example. TABLE 1 Compounds Prepared by the Method of Example 1 EXAMPLE 2 This example describes a method for preparing compounds of this invention according to the following general synthesis scheme: Preparation of . { 2-chloropurin-6-yl} [(4-chlorophenyl) methyl] amine: To a suspension of 15 g (0.0794 mol) of 2,6-dichloropurine in 250 ml of absolute ethanol was added 12.7 ml (0.0873 mol) of triethylamine and 10.62 ml (0.0873 mol) of 4-chlorobenzylamine. The mixture is refluxed at 80 ° C for 16 hours (formation of creamy white precipitate is observed). The reaction mixture was cooled and the precipitated product was removed by filtration. The precipitate is washed with ethanol (3x 50 ml) and dried under high vacuum for 24 hours (yield = 15.7 g, 67.4%). The product was characterized by 1H-NMR.

Preparation of . { 2-Chloro-9- (methylethyl) purin-6-yl} [(4-chlorophenyl) methyl] amine: To a solution of 6 g (0.020 mol) of 2-chloro-6 - (4-chlorophenyl) methylaminopurine in 41 ml of DMF ani 5.64 (0.041 mol) of potassium carbonate was added. ani and 3.41 ml (0.035 mol) of 2-iodopropane and stirred at room temperature for 16 hours, 500 ml of water was added to the mixture and stirred for 1 hour. The precipitate was filtered, washed with water (3 x 50 ml) and dried in a vacuum oven at 50 ° C for 16 hours. The product was obtained as an almost white solid (6.5 g, 97%) and characterized by 1 H-NMR.

Preparation of . { 2 - [(2-aminoethyl) amino] -9- (methylethyl) purin-6-yl} [(4-chlorophenyl) methyl] amine: To a solution of 3.36 g (0.01 mol) of. { 2-Chloro-9- (methylethyl) purin-6-yl} [(4-chlorophenyl) methyl] amine in 13 ml of 1-methyl-2-pyrrolidone ani. 4.68 ml (0.70 mol) of 2-aminoethylamine was added and the mixture was heated at 140 ° C for 24 hours. The compound was subjected to silica gel variable gradient chromatography with dichloromethane / methanol mixtures and 3.95 g of product containing 1-methyl-2-pyrrolidinone was produced. The mixture was dissolved in dichloromethane and extracted with water (5 x 20 ml). The organic layer is dried over sodium sulfate ani. and evaporated to an almost white solid (2.94 g, 81.7%). The product was characterized by 1 H-NMR and the purity was verified by RP-HPLC (YMC C-18 column, 50 x 4.4 mm, S-5 120 A ° 0.1% TFA-water / 0.1% TFA-acetonitrile).

The Table, below, identifies the compounds of this invention that were prepared according to the method of general synthesis established in this Example. In Table 2, MS = Mass spectrum and MH + = main molecular ion mass plus a hydrogen atom.

TABLE 2 COMPOUNDS PREPARED BY THE EXAMPLE METHOD EXAMPLE 3 This example describes a method for preparing compounds of this invention. The synthesis method presented in this example is only slightly modified from that presented in Example 1.

The following compound was prepared according to the above method.

Preparation of 2,6-dichloro-9-isopropylpurine (4). To a solution of 0.67 g of 2,6-dichloropurine in 5 ml of dry DMF at room temperature was added 0.16 g (1.1 e.q.) of 50% sodium hydride / oil powder. after evolution of hydrogen ceased, a large excess of isopropyl iodide (2 ml) was added to the anionic solution. This reaction solution was stirred for 3 days at room temperature. The reaction was quenched with 30 mL of water and extracted with ethyl acetate (3 x 50 mL). The organic extracts were combined and washed with 3 x 50 ml of water followed by 20 ml of pitch. The ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated. The compound was subjected to flash chromatography with variable gradient on silica gel with hexane / ethyl acetate mixtures and 0.37 g of the desired N-9 product (45%) and 0.08 g of the N-7 isomer (10%) was produced.

Preparation of 2-chloro-6-anilino-9-isopropylpurine (5). 2,6-dichloro-9-isopropylpurine (0.019 g, 0.081 mol) was dissolved in butanol (0.5 ml) and aniline (0.044 ml, 0.244 mmol) was added. The reaction mixture was heated at 120 ° C for 10 hours, cooled and diluted with EtOAc and washed three times with water. The mixture was dried over MgSO4 and concentrated to an almost white solid.

Preparation of 2-diethanolamino-6- (4-phenylamino) -9-isopropylpurine (6) A solution of 67 mg of 2,6-dichloro-N-9-isopropylpurine and 100 mg of 4-phenylaniline in 1 ml of n-octanol was heated at 80 ° C for 24 hours. The n-octanol was removed under vacuum and then replaced with 1 ml of 40% diethanolamine in DMSO. The solution was heated at 130 ° C for 48 hours. The reaction was cooled to room temperature and then diluted with 10 mL of water and subsequently extracted with ethyl acetate 83 x 30 mL). The organic extracts were combined and washed with 3 x 20 ml of water followed by 10 ml of pitch. The ethyl acetate solution was dried over anhydrous magnesium sulfate and filtered and the solvent was evaporated. The 65 mg of crude product was crystallized from THF-ether solution to yield 28 mg of pure product (23%).

Table 3 below identifies compounds of this invention that were prepared according to the general synthesis method set forth in this Example.

TABLE 3 Compounds prepared by the Method of Example 3 EXAMPLE 4 This example describes a method for preparing compounds of this invention. The synthesis method presented in this Example is only slightly modified from that presented in Example 1.

The following compound was prepared according to the above method.

Preparation of 2,6-dichloro-9-isopropylpurine (4).

The 2,6-dichloropurine (5.00 g, 26.46 mmol) was suspended in 55 ml of dry DMF at room temperature and treated with sodium hydride, 60% dispersion (1.27 g, 31.75 mmol) added in portions. After stirring for 1 hour, 2-iodopropane (4.5 ml, 44.98 mmol) was added and the reaction was stirred for 2 days. The reaction was poured into diethyl ether and washed once with saturated sodium bicarbonate solution and once with water. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrate was chromatographed on silica gel eluting with 10% acetone in dichloromethane solution to give the N-9 alkylation product as a white solid. Production = 47%.

Preparation of 2-chloro-6- (4-methylmercapto) anilino-9-isopropylpurine (5A). 2,6-9-isopropylpurine (0.15 g, 0.649 mmol) was dissolved in n-butanol (4 ml) and 4 - (methylmercapto) aniline (0.089 ml, 0.714 mmol) and triethylamine (0.20 ml, 1.43 mmol) were added. The reaction mixture was heated at 80 ° C overnight. The cooled reaction was diluted with ethyl acetate and washed 1 x 1M HCl, 1 x saturated sodium bicarbonate and 1 x pitch before being dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 2% methanol in dichloromethane to give the desired product as a white solid. Production = 83%.

Preparation of 2-diethanolamine-6- (4-methylmercapto) anilino-9-isopropylpurine (6A). The purine (0.18 g, 539 mmol) was dissolved in N-methyl pyrrolidinone (3 ml) and diethanolamine (1 ml) and then heated at 120 ° C overnight, the cooled reaction was poured into diethyl ether and washed three times. times with water before drying over anhydrous sodium sulfate and concentrating in vacuo. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the desired product as an almost white solid. Production = 82%. 1H-NMR (d, CDC13): 8.08 (s, ÍH), 7.58 (d, 2H), 7. 47 (s, ÍH), 7.18 (d, 2H), 4.95 (br s, < 2H), 4.52 (m, ÍH), 3.94 (m, 4H), 3.83 (m, 4H), 2. 43 (s, 3H), 1.47 (d, 6H).

Preparation of 4- (2-thienyl) benzonitrile. Some Ri 'groups must be synthesized before reacting them with 2,6-dichloro-9-isopropylpurine. These groups can be synthesized through various coupling methods and other synthetic methods known to those skilled in the art of organic synthesis. 4-bromobenzonitrile (0.20 g) was added to a pressure tube., 1.10 mmol), tetrakis (triphenylphosphine) palladium (0) (0.127 g, 0.1 eq) and 2-thiofeneboronic acid (0.211 g, 1.65 mmol). The reaction is rinsed in vacuo and rinsed with dry nitrogen three times. After rinsing, dimethyl ethylene glycol ether (5.5 ml) and an aqueous solution of sodium carbonate (2.53 ml, IM) are added to the tube. The tube was then sealed and heated at 80 ° C overnight. The cold reaction was diluted with diethyl ether and washed twice with water before being dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10% ethyl acetate in hexane to the desired product as a white solid. Production = 84%.

Preparation of 4- (2-thienyl) benzylamine The 4- (2-thienyl) benzonitrile (0.086 g, 0.464 mmol) was dissolved in dry tetrahydrofuran (1.6 ml) before adding in drops lithium aluminum hydride (0.46 ml, 0.464 mmol). ), 1 M in THF). The reaction was allowed to stand at room temperature overnight. TLC (5% methanol in dichloromethane) still showed remaining initial material. 1 eq of LAH was added. After an additional hour, the reaction was quenched by the method of Fieser and Fieser using water (17.46 μl), aqueous sodium hydroxide solution (17.46 μl, 15% soln.) And water (52.37 μl) was added sequentially to the reaction. The reaction was then diluted with diethyl ether and water and extracted twice with diethyl ether before being dried over sodium sulfate and concentrated in vacuo. The residue was carried out in crude without any other purification. Production = 89%.

Table 4 below identifies the compounds of this invention that were prepared according to the general synthesis method set forth in this Example.

TABLE 4 Compounds prepared by the Method of Example 4.

EXAMPLE 5 This example describes a method for preparing compounds of this invention. The synthesis method presented in this Example is only slightly modified from that presented in Example 1.

The following compound was prepared according to the above method.

Preparation of 2-amino-6-chloro-9-methylpurine (7). The 2-amino-6-chloropurine (1.08 g, 6.4 mmol) was suspended in dry DMF (75 ml) and treated with sodium hydride, 60% dispersion (0.28 g, 7 mmol). The suspension was stirred for 15 minutes before adding iodomethane (0.44 ml, 7.06 mmol) and the resulting yellow solution was stirred for 1 minute and 45 minutes. The solid was filtered and the filtrate was evaporated before the addition of water for 10 minutes. The resulting solid was filtered and dried overnight to give the product as a mixture of N-7 and N-9 alkylation products. The residual liquor was left overnight and more crystals were collected the next day and dried. Production = 77%.

Preparation of 6-chloro-2 - (2-methoxyacetylamino) -9-methylpurine (8). the above isomer mixture was dissolved in dichloromethane and pyridine (2 eq) followed by treatment with methoxyacetyl chloride (4 eq). The reaction was stirred at room temperature until complete. The reaction was evaporated and filtered through a plug of silica gel eluting with 2% methanol in dichloromethane followed by purification over a comatotron using silica gel and eluting with 2% methanol in dichloromethane to isolate the desired product, yield = 31% Table 4 below identifies compounds of this invention that were prepared according to the synthesis method set forth in this Example.

TABLE 5 Compounds Prepared by the Method of Example 5 EXAMPLE 6 This example describes a method for preparing compounds of this invention. The synthesis method presented in this Example is only slightly modified from that presented in Example 1.

The following compound was prepared according to the above method.

Preparation of 2-chloro-6- (4-phenylbenzylamino) purine (9). The 2,6-dichloropurine (5.0 g, 26.45 mmol) was suspended in n-butanol 850 ml) and 4-phenylbenzylamino (6.61 g, 29.1 mmol) and triethylamine (4.1 ml, 29.1 mmol) were added. The solution was heated to 120 ° C overnight and then cooled. The filtrate was filtered using excess n-butanol and the precipitate was washed with 100 ml of HCl and 200 ml of water. The solid was dried under vacuum overnight at 70 ° C to give the desired product as a pale yellow solid. Production = 99%.

Preparation of 2-diethanolamino-6- (4-phenylbenzylamino) purine (10). The 2-chloro-6- (4-phenylbenzylamino) purine (2.0 g, 5.96 mmol) was added together with diethanolamine (11.4 ml, 119.2 mmol) and N-methylpyrrolidoneone (10 ml) and heated at 120 ° C for one night. The cooled reaction was poured into dichloromethane and washed twice with water. The organic layer was dried with anhydrous sodium sulfate and concentrated in vacuo to give the desired product as a pale green solid which was further dried in a 70 ° C vacuum oven for 2 days.

Preparation of 2-diethanolamino-6 - (4-phenylbenzylamino) -9-methylpurine (11) The 2-diethanolamino-6- (4-phenylbenzylamino) purine (0.050 g, 0.124 mmol) was dissolved in dry MF and treated with sodium hydride, 60% dispersion (5.5 mg, 0.136 mmol) for 1 hour. iodomethane (0.009 mL, 0.148 mmol) was added and the resulting solution was stirred at room temperature overnight. The reaction was poured into ethyl ether and washed twice with saturated sodium bicarbonate solution before drying over anhydrous sodium sulfate and concentrating in vacuo. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane for the product as a white solid. Production = 63%. * - NMR (d, CDC13): 7.55 (m, 4H), 7.41 (m, 4H), 7.35 (m, 4H), 6.41 (br s, < 1H), . 10 (br s, <2H), 4.72 (br s, 2H), 3.86 (m, 4H), 3.74 (m, 4H), 3.59 (s, 3H).

Table 6 identifies the compounds of this invention that were prepared according to the synthesis method set forth in this Example.

TABLE 5 Compounds Prepared by the Method of Example 6 EXAMPLE 7 The composition of this invention was evaluated in the following tests: CDK2 assays: The compositions of this invention were tested for their CDK2 inhibitory activity. The assay system (total volume 50 μl) contained 50 mm Tris-Cl, pH 7.4, 10 mm MgCl 2, 5 mm DTT, 1 μg histone Hl, 30 μm ATP (1 μCi gamma32P with ATP tag), μg of BSA and 1 ng of purified CDK2, after incubation at 30 ° C for 30 minutes, the reaction was determined by adding 10 μl of 10% TCA samples stained on nitrocellulose filters. These filters were extensively washed in 10% TCA and assayed by radioactivity. The vacuums did not contain enzymes. To ensure the potency of several compounds of this invention, the compounds were added to the above assay at concentrations ranging from 100 to 0.02 μg / ml. After incubation for 30 minutes, the test tubes were processed as before. In all trials, various concentrations of allomoucin were added and used as a standard positive control. The IC50 (enzyme) listed in Table 6 is defined as the concentration required to inhibit the activity of DCK2 by 50%.

EXAMPLE 8 Rat aortic smooth muscle cells were seeded in early passage (Repository of CV Therapeutic Cells) in 48-well dishes (Falcon, ml / well) in a density of 20,000 / ml of DME containing 5% of hot inactivated bovine serum, the cells were incubated in a tissue culture incubator standard for 48 hours. The medium was aspirated and the wells were replenished with 0.2 ml of fresh medium. The compounds of this invention were added in concentrations ranging from 100 to 0.37 μg / ml. After incubation for 48 hours, the medium was aspirated and the cultures were treated with 0.2 ml of 0.25 μl saline of methosulphate phenozine solution containing MTS (Cell Tilter 96® non-radioactive cell proliferation assay kit, catalog number 5430 , Promega, 2800 Woods Hollow Road, Madison, Wisconsin 53711-5399). The IC5o cells listed in Table 7 are defined as the concentration required to inhibit cell proliferation by 50%. Olomoucine was added in various concentrations and was used as a standard positive control.

TABLE 6 Bioactivity of Selective Representatives of this Invention The inhibition of the cell proliferation properties of the compounds of this invention is demonstrated by their ability to inhibit cell proliferation in the range of about 0.5 μg / ml to 100 μg / ml, preferably less than 0.5 μg / ml. Similar assays were carried out using the following cell lines; P388 - mouse lymphoid neoplasm; L1210 - mouse lymphocytic leukemia; human colon adenocarcinoma Caco2; human breast adenocarcinoma MCF7; rat neonatal aortic smooth muscle cells PupVSMC; Carcinoma of human ovaries Ovcar; human pancreatic adenocarcinoma Panel; and endothelial cells of human Umbiiexal cord HUVEC. The inhibitory activity of various compositions of this invention against one or more cell lines are reported in Table 6 A, below. TABLE 6A IC50 (μg / ml) for Inhibition of Cell Proliferation EXAMPLE 7 A compound of this invention was evaluated by effectiveness using the Murine Leukemia Model. The Murine Leukemia model is a standard model used in the evaluation of antitumor agents. CDFl ip mice were injected with L1210 cells (1 x 103 cells / mouse). Twenty-four hours later, these mice were treated with several doses (ip) of compound 3 of Example 1 in saline. The dosage regimen used in this study is shown in Table 7, below. The mice were dosed with compound 3 daily or on alternating days. Control mice received saline. After 7 days, the dosage was discontinued and the survivors were monitored.

TABLE 7 The results indicate that the rats given the compound 3 survived longer than the control rats.

EXAMPLE 9 This example measured the effect of an acute local supply of compound 3 of Example 1 on the reduction of neointimal formation after balloon angioplasty in the rat carotid artery model. In this example, the left common carotid arteries of adult male rats (n = 10 per experimental groups) were surgically injured using a Fogarty arterial embocto- tomy catheter. Immediately after the injury, the common carotid artery was bisected with a vascular clamp, thus establishing an untreated and a treated segment. A drug delivery catheter was then inserted into the distal half of the common carotid. After delivery of the drug, the catheter was removed and the excess drug was washed by removing the vascular clamp and blood flow was restored after closing the artery. The animals were allowed to recover for 14 days before recovering the common carotid artery. The collected tissue was sectioned and the neointima area was digitized and measured with a computer planimetry system. For each animal, 15 measurements were averaged for the untreated segment and for the treaty. It was administered. { 2 - [(2-aminoethyl) amino] -9- (methylethyl) purine-6-yl} [(4-chlorophenyl) methyl] amine in a dose of 5 mg / ml reducing the neointimal area by about 90% compared to the 6% reduction of saline alone.

The results of this Example are found in Figure 1. According to Figure 1, administration of compound 3 of the Example to a damaged carotid artery reduced the neointima area by about 88% compared to the 6% reduction produced by the vehicle saline alone.

EXAMPLE 10 Assays I? B-a: The compositions of this invention were tested for their kinase I? B - inhibitory activity. The human umbilical vein endothelial cell line (HUVEC) used in these studies was purchased from Clonetics (San Diego, California) and maintained on endothelial cell growth medium supplemented with 2% fetal bovine serum, 10 ng / ml recombinant epidermal growth factor, 1 μg / ml hydrocortisone, 50 μg / ml gentamicin, 50 ng / ml amphotericin B and 12 μg / ml bovine brain extract at 37 ° C in a tissue culture incubator. All growth medium and supplements were purchased from Clonetics (San Diego California). E. Coli lipopolysaccharide (LPS) serotype 0111: B4 was purchased from Sigma (San Luis, Missouri). All other chemicals are reactive in grade.

Preparation of cellular Lisato: The monolayers (75 cm 2) were treated with LPS (100 ng / ml) for 5 minutes after which the cell medium was rapidly removed and the monolayer was washed three times with ice cold PBS. The cell layer was scraped in 10 ml of PBS and the cells were encapsulated by centrifugation (3000 rmp, 5 minutes, 4 ° C). The cell lysate was prepared by incubating the cell pills in 0.2 ml regulator lysis (20 mm HEPES, pH 7.3, 50 mm NaCl, 10 mm MgCl 2, 1 mm EDTA, 1 mm EGTA, 1 mm sodium orthovanadate, 10 mm ß - glycerophosphate, 1 mm phenylmethylsulfonyl fluoride, 1 mm dithiothreitol, 0.5% Nonidet P - 40 for 15 minutes at 37 ° C for frequent vortices Cell debris was removed from the sample by microcentrifugation (10,000 xg, 15 minutes, 4 ° C ) and the supernatant was "preclarified" by the addition of 100 ml of a suspension of Sepharose 4B in regulator lysis and mixed gently for 1 hour at 4 ° C. Sepharose 4B pills were removed by centrifugation and the supernatant was aliquoted and stored at 80 ° C.

Solid phase I? B - a kinase assay 1 μg of GST I? B - a, corresponding to full length of I? B - a of human origin, (Santa Cruz Biotechnology), was incubated with 20 μl of a 50% glutathione S sepharose 4B (Pharmacia) in reaction buffer (20 mm HEPES, pH 7.3, 10 mm MgCl 2, 15 mm β-glycerophosphate, 0.5 mm sodium orthovanadate, 0.5 mm EGTA) for 30 minutes at room temperature. The I? B GST pill complex was then washed three times with 0.5 ml of reaction buffer by resuspension and microcentrifugation. 10 μg of HUVEC cellular lysate protein in 100 μl of reaction buffer were then added to the I? B GST pill complex and the mixture was incubated with gentle shaking at 4 ° C for 1 hour. The pill complex was then washed three times with a reaction regulator containing 0.1 mm NaCl and once with a reaction regulator alone. Finally the pill complex was again suspended in 20 μl of reaction regulator containing 5μCi [y-32P] ATP (> 5000 ci / mmol, New England Nuclear Corp., Boston, Massachusetts) and incubated at room temperature for 15 minutes. The reaction was terminated by the addition of 10 μl SDS sample buffer - PAGE and boiled for 3 minutes before separation of SDS-PAGE (ReadyGel gradient 10-20%, BioRad). After electrophoresis the gel was fixed (50% methanol 10% acetic acid) for 15 minutes, washed three times for 5 minutes each time with distilled H2O and treated with 5% glycerol for 15 minutes before being dried and exposed to a film for autoradiography (X_OMAT XAR - 5 Kodak).

Gel Kinase Assay I? B-a isozymes were assayed per activity using a modification of previously published methods (11, 19, 20). Briefly duplicated samples of the I? B glutathione sepharose 4B pill complex were prepared as described above and separated by electrophoresis through 12% SDS-PAGE gel that had been polymerized in the presence of 15 μg / ml GST - I was going. After electrophoresis the gel was gently washed twice for 30 minutes each time with 50 mm Tris-HCl pH 8.0, 5 mm β-mercaptoethanol; 20% isopropanol to remove the SDS. The proteins were then denatured within the gel by incubation for 45 minutes in 100 ml 50 mm Tris-HCl pH 8.0; 5 mm β-mercaptoethanol; 0.04% Tween 40.

The gel was then cut in half to separate duplicate samples, one half was incubated in 10 ml reaction buffer alone and the other in 10 ml reaction buffer containing 10 μg / ml 2-diethanolamino-6 ( 4 - phenyl anilino) - 9 - isopropyl purine (compound 6 of Example 2) for 1 hour at room temperature to which 10 μCi [y- 32 P] ATP was added and the incubation continued for another hour at room temperature. The gels were then subjected to multiple 15 minute washes of 100 ml each 15% trichloroacetic acid containing 1% sodium pyrophosphate until 1 ml of the wash solution closed the previous radioactivity. The gels were then dried and exposed to file for autoradiography.

Preparation of Affinity Matrix Sepharose 6B Activated with Epoxy 2-diethanolamino-6- (4-phenybenzylamino) -9-isopropyl purine Sepharose 6B activated dry and frozen epoxy (Pharmacia, Piscataway, New Jersey) was chosen for the coupling reaction due to its ability to form an ether bond between a ligand containing hydroxyl and the epoxide group in sepharose. The gel was increased according to the manufacturer's instructions (100 mg), of compound 6 of Example 2 were dissolved in 1 ml of coupling solution (1.2: 1 v / v dimethylformamide: 0.1N NaOH) and mixed with 0.5 ml of gel increased in pH 10-11 for 72 hours at room temperature with gentle agitation. Excess reactive groups were blocked with IM ethanolamine for 4 hours at 50 ° C and the gel slurry was poured into a 1 ml syringe column. The resin was activated with three alternate cycles of volumes of twenty columns each of pH 4.0 (0.1 m acetate, 0.5 m NaCl) and regulator (20 mm HEPES, pH 7.3, 10 mm MgCl2, 15 mm ß - glycerophosphate, 0.5 mm orthovanadate sodium, 0.5 mm EGTA). The column was stored at 4 ° C in reaction buffer with 5% sodium azide content and regenerated before each use with alternating cycles of high and low pH as described above.

The HUVEC cell lysate (500 μg protein in 1 ml reaction buffer) was passed over the CVT-1545 sepharose matrix sequentially five times and the flow through was saved (unbound material). The matrix was then washed three times with 1 ml of reaction buffer (wash 1-3) and then three times each with reaction buffer containing 0.5 m NaCl (eluted 1-3) - The aliquots (20 μl of 1 ml) each sample were assayed for their ability to phosphoralize in IKBGST sepharose pill complex and analyzed by SDS-PAGE as described above.

Enriched affinity I? B-a kinase assay Eluted 0.5 M crude NaCl from the affinity matrix was used as the enzyme source for the development of a I? B-a kinase filter assay. each reaction contained enriched affinity I? B-a kinase (1 μg protein), 10 ng GST of kinase I? B - a and 0.5 μCui [y-32P] ATP (> 500 Ci / mmol, New England Nuclear Corp. , Boston, Massachusetts) in 20 μl of reaction regulator. The reaction was incubated for 15 minutes at room temperature and terminated by the addition of 2 μl 0.5 M EDTA. The reaction mixtures were plotted on phosphocellulose discs (Gibco BRL Life Technologies, Gaithersburg, Mariland) and the filters were washed three times with 0.15 M phosphoric acid with gentle agitation for 15 minutes (up to 10 filters were washed with 300 ml of 0.15M phosphoric acid). after a third wash, the filters were dried, added to the scintillation fluid and tested by liquid scintillation spectrometry.

Electrophoretic Mobility Change Assay: The nuclear extracts were prepared using a high saline regulator extraction procedure. 10 pmol of double stranded NF-KN consensus oligonucleotide (5 'AGTTGAGGGGACTTTCCCAGGC-3')) Promega) had a 5 'end tag with 5μCi [y-32P] ATP (> 500 Ci / mmol, New England Nuclear Corp, Boston , Massachusetts) by incubation with T4 polynucleotide kinase for 1 hour at 37 ° C. The unincorporated nucleotides were removed by passing the reaction mixture over 1 ml of spin column G-5 Sephadex. The binding assays were carried out at room temperature for 1 hour and consisted of 10 μg of nuclear extraction protein, 1 μg of salmon sperm DNA and 5 x 104 cpm of consensus 32 P labeled oligonucleotide in the presence and absence of fifty so many of unlabeled oligonucleotide. The DNA-protein complexes were resolved by electrophoresis at 8% non-denaturing polyacrylamide gel, the gels were dried on filter paper and visualized by autoradiography.

TABLE 8 Enzyme Activity of Elected Representatives of this Invention MRC - 5 Human fibroblasts PupVSMC Rat neonatal aortic smooth muscle cells

Claims (3)

1. CLAIMS: 1. A 2, 6, 9-trisubstituted purine composition of matter having the following formula: (i) where Ri is halogen or Ri '- X where X = NH, O, S, S (O2). Ri 'is minor alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted hetaryl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, alkenyl alkyl, alkenyl alkyl, alkynyl alkyl , cycloalkyl alkyl, or cycloheteroalkyl alkyl, each having from one to 20 carbon atoms wherein the substitutions include optional substitution with from 1 to 3 substitutes chosen independently of the group consisting of halo, aryl, CF3, heteroaryl, heterocyclyl , R22, SR20, S (O) R21, SO2R21, SO2NR20R21, SO2NR20COR21, SO2NR20CONR20R23, SO2NR20CO2R21, NR20R23, NR20COR21, NR20CO2R21, NR20CONR20R23, N (R20) C (NR20) NHR23, NR20SO2R21, OR20, OCONR 0R23, OCONR20SO2R21, OCONR20R23, CN, CO2R20, CONR20R23, CONR20SO2R21 and COR20; R2 is a hydrogen or hydrocarbon selected from the group substituted minor alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted hetaryl, aralkyl, heteraralkyl, heteraralkyl, alkyl alkenyl, alkyl alkynyl, cycloalkyl alkyl, or cycloheteroalkyl alkyl, each having from one to 20 carbon atoms wherein the substitutions include optional substitution with from 1 to 3 substituted independently of the group consisting of halo, aryl, heteroaryl, heterocyclyl, R22, SR20, S (O) R21, SO2R21, SO2NR20R21, SO2NR20COR21, SO2NR20CONR20R23, SO2NR20CO2R21, NR20R23, NR20COR21, NR20CO2R21, NR20CONR20R23, N (R20) C (NR20) NHR23, NR20SO2R21, OR20, OCONR20R23, OCONR20SO2R21, OCONR20R23, CN, CO2R20, CONR20R23, CONR20SO2R21 and COR20; R3 is halogen, hydroxyl, thio, alkoxy, alkylthio, lower alkyl, -NR R5 or a component having the formula: wherein m = 1 - 3, n = 1-3, or = 1.3, y = carbonyl, - NR R5, hydroxyl, thiol, alkoxy, alkylthiol; R t and R 5 are each independently hydrogen or a hydrocarbon selected from the group including minor alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, aryl, substituted aryl, hetaryl, substituted hetaryl, aralkyl , heteroaralkyl, alkenyl alkyl, alkynyl alkyl, cycloalkyl alkyl, cycloheteroalkyl alkyl, wherein each has from 1 to 20 carbon atoms wherein the substitution includes the optional substitution with from 1 to 3 substitutes chosen independently of the group consisting of halo, aryl, heteroaryl, heterocyclyl, R22, SR22, S (O) R21, SO2R21, SO2NR20R23, SO2NR20COR21, SO2NR20CONR20R23 'SO2NR20CO2R21, NR20R23, NR20COR21, NR20CO2R21, NR20CONR20R23, N (R20) C (NR20) NHR23, NR20SO2R21, OR20, OCONR20R23, OCONR20SO2R21, OCONR20R23, CN, CO2R20, CONR20R23, CONR20SO2R21 and COR20; provided that when Y is carbonyl, Y and R_. ' they can be together a single oxygen atom, Rt "and R5" together can be a single oxygen atom and where R3 is 2 -hydroxyethylamino and R2 is methyl, Ri '- X is not amino, 3-methyl-2-butenylamino , benzylamino om-hydroxybenzylamino, when R3 is not 2-hydroxyethylamino, when R2 is isopropyl, Ri'-X is not benzylamino, m-hydroxybenzylamino or 3-netylbutylamino, when R3 is 2-hydroxyethylamino and R2 is 2-hydroxyethyl, Ri ' - X is not benzylamino and when R3 is chosen di group consisting of 2-methyl-2-hydroxypropylamino and 2-dimethylaminoethylamino and R2 is methyl, then Ri '- X is not benzylamino. R20 is a member selected from the group consisting of H, Ci alkyl. 15, alkenyl Cz-15, alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, alkynyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substitutes chosen independently of halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-Ci-Cß alkyl, CF3, aryl and heteroaryl; R21 is a member selected from the group consisting of Ci alkyl. 15, C2-15 alkenyl, C2 alkynyl. 15, heterocyclyl, aryl, and heteroaryl, said alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl are optionally substituted with 1 to 3 substitutes chosen independently from the group of halo, heterocyclyl, aryl, heteroaryl, CF3, CN, OR20, SR20, N (R20) 2, S (O) R22, SO2R22, SO2N (R20) 2, SO2NR20COR22, SO2NR20CO2R22, SO2NR20CON (R20) 2, N (R20) 2NR20COR22, NR20CO2R22, NR20CON (R20) 2, NR20C (NR20) NHR23, COR20, CO2R20, CON (R20) 2, CONR20SO2R22, NR20SO2R22, SO2NR20CO2R22, OR20, OCONR20SO2R22, OC (O) R20, C (O) OCH2OC (O) R20 and OCON (R20) 2 and each optional heteroaryl, aryl and heterocyclyl substituent is optionally substituted with halo, alkyl, CF3, amino, mono- or dialkylamino , alkyl or aryl or heteroaryl amide, NCOR22, NR20SO2R22, COR20, CO2R20, CON (R20) 2, NR20CON (R20) 2, OC (O) R20, OC (O) N (R20) 2, SR20, S (O) R22, SO2R22, SO2N (R20) 2, CN or OR20; R22 is a member selected from the group consisting of Ci alkyl. 15, alqueml C2-15, C2-15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, alkynyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substitutes independently chosen from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-Ci-Cß alkyl, CF 3, aryl and heteroaryl; and R23 is R21 or H.

   2. A 2, 6, 9-trisubstituted purine composition of Claim 1 wherein: Ri 'is minor alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted hetaryl, aralkyl , substituted aralkyl, heteroaralkyl, alkenyl alkyl, alkenyl alkyl, alkyl alkynyl, cycloalkyl alkyl or cycloheteroalkyl alkyl, each having from one to 20 carbon atoms wherein the substitution includes the optional substitution with from 1 to 3 substitutes chosen independently of the group consisting of halo, CF3, aryl, heteroaryl, heterocyclyl, R22, SR22, S (O) R21, S02R21, SO2NR20R23, NR20R23, NR20COR21, NR20CO2R21, NR? CONR, 2/0? Rt »23, - NvttR > 20? CS / O-v2 tR > 21, OTR > 2"0, CN, CO2R 20, CONR, 20? RR> 23? And COR, 20?;. R 2 is a hydrogen or hydrocarbon selected from the group substituted minor alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, aralkyl, heteroaralkyl, heteroalkyl, alkenyl, alkenyl, alkynyl, alkyl cycloalkyl, or cycloheteroalkyl alkyl, each having from one to 20 carbon atoms wherein the substitutions include optional substitution with from 1 to 3 substituted independently of the group consisting of halo, aryl, heteroaryl, heterocyclyl, R22, SR20, S (O) R21, SO2R21, SO2NR20R23, NR20R23, NR20COR21, NR20CO2R21, NR20CONR20R23, NR20SO2R21, OR20, CN, CO2R20, CONR20R23, and COR20; Rt and R5 are each independently hydrogen or a hydrocarbon selected from the group including minor alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, aryl, substituted aryl, hetaryl, substituted hetaryl, aralkyl , heteroaralkyl, alkenyl alkyl, alkynyl alkyl, cycloalkyl alkyl, cycloheteroalkyl alkyl, wherein each has from 1 to 20 carbon atoms wherein the substitution includes the optional substitution with from 1 to 3 substitutes chosen independently from the group consisting of halo, aryl, heteroaryl, heterocyclyl, R22, SR20, S (O) R21, SO2R21, SO2NR20R23, NR20R23, NR20COR21, NR20CO2R21, NR20CONR20R23, NR20SO2R21, OR20, CN, CO2R20, CONR20R23, and COR20; R20 is a member selected from the group consisting of H, Ci. 8 alkyl, C2.8 alkenyl, C2 heterocyclyl. 15, aryl and heteroaryl, said alkyl, alkenyl, heterocyclic, aryl and heteroaryl are optionally substituted with 1 to 3 substitutes chosen independently from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, alkyl O- Ci - Ce, CF3, aryl and heteroaryl; R21 is a member selected from the group consisting of Ci. 8 alkyl, C2.8 alkeml, heterocyclyl, aryl, and heteroaryl, said alkyl, alkenyl, aryl, heterocyclyl and heteroaryl being optionally substituted with 1 to 3 substitutes chosen independently of the halo group, heterocyclyl, aryl, heteroaryl, CF3, CN, OR20, SR20, N (R20) 2, S (O) R22, SO2R22, SO2N (R20) 2, SO2NR20COR22, SO2NR20CO2R22, SO2NR20CON (R20) 2, N (R20) 2NR20COR22, NR20CO2R22, NR 0CON (R20) 2, NR20C (NR20) NHR23, COR20, CO2R20, CON (R20) 2, CONR20SO2R22, NR20SO2R22, SO2NR20CO2R22, OR20, OCONR20SO2R22, OC (O) R20, C (O) OCH2OC (O) R20 and OCON (R20) 2 and each optional heteroaryl, aryl and heterocyclyl substitute is optionally substituted with halo, alkyl, CF3, amino, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, NCOR22, NR20SO2R22, COR20, CO2R20, CON (R20) 2, NR20CON (R20) 2, OC (O) R20, OC (O) N (R20) 2, SR20, S (O) R22, SO2R22, SO2N (R20) 2, CN or OR20; R22 is a member selected from the group consisting of Ci alkyl. 8, C2 alkenyl. 8, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 3 substitutes independently chosen from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, alkyl O- Ci-C6, CF3, aryl and heteroaryl;

   3. A 2, 6, 9-trisubstituted purine composition of Claim 1 wherein: Ri 'is minor alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted hetaryl, aralkyl , substituted aralkyl, heteroaralkyl, alkenyl alkyl, alkenyl alkyl, alkyl alkynyl, cycloalkyl alkyl or cycloheteroalkyl alkyl, each having from one to 20 carbon atoms wherein the substitution includes the optional substitution with from 1 to 3 substitutes chosen independently of the group consisting of halo, CF3, aryl, heteroaryl, heterocyclyl, R22, SR22, S (O) R21, SO2R21, SO2NR20R23, NR20R23, NR20COR21, NR20CO R21, NR20SO2R21, OR20, CN, CO2R20, CONR20R23 and COR20; R2 is a hydrogen or hydrocarbon selected from the group substituted minor alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, aryl substituted, each having from one to 10 carbon atoms wherein the substitutions include optional substitution with from 1 to 3 substituted independently selected from the group consisting of halo, aryl, heteroaryl, heterocyclyl, R22, SR20, S (O) R21, SO2R21, SO2NR20R23, NR20R23, NR20COR21, NR20CO2R21, NR20SO2R21, OR20, CN, CO2R20, CONR20R23, and COR20; R_t and R5 are each independently hydrogen or a hydrocarbon selected from the group including minor alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, aryl, substituted aryl, hetaryl, substituted hetaryl, aralkyl , heteroaralkyl, alkenyl alkyl, alkynyl alkyl, cycloalkyl alkyl, cycloheteroalkyl alkyl, wherein each has from 1 to 20 carbon atoms wherein the substitution includes the optional substitution with from 1 to 3 substitutes chosen independently from the group consisting of halo, aryl, heteroaryl, heterocyclyl, R22, SR20, S (O) R21, SO2R21, SO2NR 0R23, NR20R23, NR20COR21, NR20CO2R21, NR20SO2R21, OR20, CN, CO2R20, CONR 0R23, and COR20; R20 is a member selected from the group consisting of H, Ci alkyl. 8, aryl and heteroaryl, said alkyl, aryl and heteroaryl are optionally substituted with 1 to 3 substitutes chosen independently from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-Ci-Cß alkyl, CF3; R21 is a member selected from the group consisting of Ci. 8 alkyl, aryl, and heteroaryl, said alkyl, alkenyl, aryl, heterocyclyl and heteroaryl being optionally substituted with 1 to 2 substitutes chosen independently of the halo group, CF3, CN , OR20, SR20, N (R20) 2, S (O) R22, SO2R22, SO2N (R20) 2, NR20CO2R22, NR20CON (R20) 2, COR20, CO2R20, CON (R20) 2, NR20SO2R22, OR20; and R22 is a member selected from the group consisting of Ci. 8 alkyl, aryl and heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with 1 to 3 substitutes independently chosen from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-Ci-Cß alkyl, CF 3, aryl and heteroaryl;

   4. A 2, 6, 9-trisubstituted purine composition of Claim 1 wherein: Ri 'is minor alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted hetaryl, aralkyl , substituted aralkyl, heteroaralkyl, heteroalkyl, alkenyl alkyl, alkenyl alkyl, alkyl alkynyl, cycloalkyl alkyl or cycloheteroalkyl alkyl, each having from one to 20 carbon atoms wherein the substitution includes optional substitution with from 1 to 2 substitutes chosen in OO 0 (\ 01 0 \ mdependent form of the group consisting of halo, CF3, aryl, R, SR, S (O) R, SO2R, SO2NR20R23, NR20R23, NR20COR21, NR20CO2R21, NR20SO R21, OR20, CN, CO2R20, and CONR20R23 R2 is a hydrogen or hydrocarbon selected from the group substituted minor alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, aryl substi Each of them has from one to 10 carbon atoms wherein the substitutions include the optional substitution with from 1 to 2 substitutes chosen independently from the group consisting of halo, aryl, heteroaryl, heterocyclyl, R22, SR20, S (O ) R21, SO2R21, SO2NR20R23, NR20R23, NR20COR21, NR20CO2R21, NR20SO2R21, OR20, CN, CO2R20, CONR20R23, and COR20; 4 and R5 are each independently hydrogen or a hydrocarbon selected from the group including minor alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, aryl, substituted aryl, hetaryl, substituted hetaryl, aralkyl , heteroaralkyl, alkenyl alkyl, alkynyl alkyl, cycloalkyl alkyl, cycloheteroalkyl alkyl, wherein each has from 1 to 20 carbon atoms wherein the substitution includes the optional substitution with from 1 to 2 substitutes chosen independently of the group consisting of halo, aryl, R22, SR20, S (O) R21, SO2R21, SO2NR20R23, NR20R23, NR20COR21, NR20CO2R21, NR20SO2R21, OR20, CN, CO2R20, and CONR20R23; R20 is a member selected from the group consisting of H, Ci alkyl. 8, aryl and heteroaryl, said alkyl, aryl and heteroaryl are optionally substituted with 1 to 3 substitutes chosen independently from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-Ci-Cß alkyl, CF3; R21 is a member selected from the group consisting of Ci. 8 alkyl, aryl, and heteroaryl, said alkyl, aryl, and heteroaryl being optionally substituted with 1 to 2 substitutes chosen independently from the halo group, CF3, CN, OR20, SR20, N (R20) 2, S (O) R, 22, SO2R, 2 ^ 2, SO2N (R> 2"0?) X 2, NR? CO2R ^, NR ^ CON (R ^?) 2, COR2U, CO2R, CON (R2?) 2, NR20SO2R22, OR20; and R22 is a member selected from the group consisting of Ci.g alkyl, aryl and heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with 1 to 3 substitutes independently chosen from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-Ci-Cß alkyl, CF 3, aryl and heteroaryl.

   5. The 2, 6, 9-trisubstituted purine composition of Claim 1 wherein X NH.

   6. The 2, 6, 9-trisubstituted purine composition of Claim 1 wherein R3 is a component having the formula: where m = 1 - 3, n = 1 - 3, or = 1.3, y = carbonyl, - NR R5, hydroxyl, thiol, alkoxy, alkylthiol provided that when Y is carbonyl, Y and R'4 together can be a single oxygen atom, Rt "and R5" can be together a single oxygen atom, Rt '"and R5'" can be together a single oxygen atom; and Rt and R5 are each independently hydrogen or a hydrocarbon selected from the group including minor alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, aryl, substituted aryl, hetaryl, substituted hetaryl, aralkyl, heteroaralkyl, alkenyl alkyl, alkynyl alkyl, cycloalkyl alkyl, cycloheteroalkyl alkyl, wherein each has from 1 to 20 carbon atoms wherein the substitution includes the optional substitution with from 1 to 2 substitutes chosen independently of the group consisting of of halo, aryl, R22, SR20, S (O) R21, SO2R21, SO2NR20R23, NR20R23, NR 0COR21, NR20CO2R21, NR20SO2R21, OR20, CN, CO2R20, and CONR20R23.

   7. The 2, 6, 9-trisubstituted purine composition of Claim 3 wherein Ri 'is selected from the group consisting of aralkyl and heteroarylalkyl.

   8. The 2, 6, 9-trisubstituted purine composition of Claim 7 wherein R is selected from the group consisting of aralkyl, unsubstituted pyridylalkyl and substituted pyridylalkyl and wherein R 2 is selected from the group consisting of lower alkyl, substituted lower alkyl and alkyl cycloalkyl.

   9. A 2, 6, 9-trisubstituted purine composition of Claim 8 wherein: Ri 'is an aryl, substituted aryl, heterocycle, heteroaryl, substituted hetaryl, aralkyl, substituted aralkyl, heteroaralkyl, each having from one to 20 carbon atoms wherein the substitution includes the optional substitution with from 1 to 2 substitutes chosen independently of the group consisting of halo, CF3, aryl, R22, SR20, S (O) R21, SO2NR20R23, NR20R23, NR20COR21, NR20CO2R21, NR20SO2R21, OR20 , CN, CO2R20, and CONR20R23; R 2 is a hydrogen or hydrocarbon selected from the group substituted minor alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, each having from one to 10 carbon atoms wherein the substitutions include the optional substitution with from 1 to 2 substitutes chosen independently of the group consisting of halo, R22, SR20, S (O) R21, SO2R21, NR20R23, OR20, and CN; R 4 and R are each independently hydrogen or a hydrocarbon selected from the group including minor alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aralkyl, heteroaralkyl, cycloalkyl alkyl, cycloheteroalkyl alkyl, wherein each has from 1 to 20 carbon atoms wherein the substitution includes the optional substitution with from 1 to 2 substitutes chosen independently from the group consisting of halo, aryl, R22, SR20, NR20R23, NR20COR21, NR20CO2R21, NR20SO2R21, OR20, CN, CO2R20, and CONR20R23; R20 is a member selected from the group consisting of H, Ci. 8 alkyl, said alkyl is optionally substituted with 1 to 2 substitutes chosen independently of halo, alkyl, mono- or dialkylamino, alkyl or CN, alkyl O-Ci- Cß, CF3; R21 is a member selected from the group consisting of Ci. 8 alkyl, said alkyl being optionally substituted with 1 to 2 substitutes chosen independently from the halo group, CF3, CN, OR20, SR20, N (R20) 2; and R22 is a member selected from the group consisting of Ci. 3 alkyl, aryl and heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with 1 to 3 substitutes independently chosen from halo, alkyl, mono- or dialkylamino, alkyl or aryl, CN, alkyl O-Ci-C6, CF3.

   10. The 2, 6, 9-trisubstituted purine composition of Claim 3 wherein Ri 'is selected from the group consisting of aryl, heterocycle, heteroaryl, substituted heteroaryl and substituted aryl.

   11. The 2, 6, 9-trisubstituted purine composition of Claim 3 wherein Ri 'is selected from the group consisting of aryl, unsubstituted pyridyl, substituted pyridyl, and substituted aryl, and R 2 is selected from the group consisting of lower alkyl, substituted lower alkyl and cycloalkyl alkyl.

   12. The 2, 6, 9-trisubstituted purine composition of Claim 2 wherein R3 is NR-1R5 wherein R_t and R5 are each selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkoxy, amino, amido, carboxyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, aryl, substituted aryl, aryloxy, hetaryl, substituted hetaryl, aralkyl, heteroaralkyl, alkyl alkenyl, alkyl alkynyl, cycloalkyl alkyl, cycloheteroalkyl alkyl or cyano.

   13. A 2, 6, 9-trisubstituted purine composition of Claim 12 wherein: Ri 'is an aryl, aryl substituted, each having from 6 carbon atoms wherein the substitution includes the optional substitution with from 1 to 2 substitutes chosen in independently of the group consisting of halo, CF3, aryl, R22, NR20R23, NR20COR21, OR20, CN; R2 is a hydrogen or hydrocarbon selected from the substituted lower alkyl, cycloalkyl, substituted cycloalkyl group, each having from one to 6 carbon atoms wherein the substitutions include the optional substitution with from 1 substituted independently of the group consisting of halo , R, NR R, OR; Rt and R5 are each independently hydrogen or a hydrocarbon selected from the group including minor alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloalkyl alkyl, cycloheteroalkyl alkyl, wherein each has from 1 to 12 carbon atoms wherein the substitution includes the optional substitution with from 1 to 2 substitutes chosen independently of the group consisting of halo, R22, SR20, OR20, NR20R23, CN, CO2R20, and CONR20R23; R20 is a member selected from the group consisting of H, Ci-8 alkyl; R21 is a member selected from the group consisting of Ci .3 alkyl, said alkyl being optionally substituted with 1 to 2 substitutes chosen independently from the halo group, CF3, CN, OR20, SR20, N (R20) 2; and R22 is a member selected from the group consisting of Ci. 3 alkyl, aryl and heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with 1 to 3 substitutes independently chosen from halo, alkyl, mono- or dialkylamino, alkyl or aryl, CN, alkyl O-Ci-C6, CF3. 14, A 2, 6, 9-trisubstituted purine composition of Claim 12 wherein: Ri 'is an aryl, substituted aryl, each having 6 carbon atoms wherein the substitution includes optional substitution with from 1 to 2 substitutes chosen independently of the group consisting of halo, CF3, R22, OR20, CN; R2 is isopropyl; R4 and R5 are each independently hydrogen or a hydrocarbon selected from the group including minor alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl alkyl, wherein each has from 1 to 12 carbon atoms where the substitution includes the optional substitution with from 1 2 substitute chosen independently from the group consisting of R22, OR20, NR20R23; R20 is a member selected from the group consisting of H, alkyl Ci.
2. 2, R21 is a member selected from the group consisting of alkyl d -3; R22 is a member selected from the group consisting of Ci alkyl. 3, said alkyl, aryl are optionally substituted with 1 substitute independently chosen from halo, alkyl, mono- or dialkylamino, CN, CF3; and R23 is R21 or H.

   15. A 2, 6, 9-trisubstituted purine composition of Claim 12 wherein: Ri 'is an aralkyl, substituted aralkyl, each tends from 6 to 8 carbon atoms wherein the substitution includes the optional substitution with from 1 to 2 substitutes chosen independently from the group consisting of halo, CF3, aryl, R22, NR20R23, NR20COR21, OR20, CN; R2 is a hydrogen or hydrocarbon selected from the group consisting of lower alkyl, cycloalkyl, substituted cycloalkyl each having from one to 6 carbon atoms wherein the substitution includes the optional substitution with 1 substitute chosen independently of the group consisting of halo, R22, NR20R23, OR20; R_t and Rs are each independently hydrogen or a hydrocarbon selected from the group including minor alkyl, substituted minor alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroaryl, substituted cycloheteroalkyl, cycloalkyl alkyl, cycloheteroalkyl alkyl, wherein each has from 1 to 12 carbon atoms wherein the substitution includes the optional substitution with from 1 to 2 substitutes chosen independently of the group consisting of halo, R22, SR20, OR20, NR20R23, CN, CO2R20 and CONR20R2 R20 is a member selected from the group consisting of of H, alkyl Ci. s, R21 is a member selected from the group consisting of Ci. 3 alkyl, said alkyl being optionally substituted with from 1 to 2 substitutes chosen independently of the halo group, CF, CN, OR20, SR20, N (R20) 2; and R22 is a member selected from the group consisting of Ci. 3 alkyl, aryl, heteroaryl, said alkyl, aryl and heteroaryl are optionally substituted with from 1 to 3 substitutes independently chosen from halo, alkyl, mono- or dialkylamino, alkyl, aryl , CN, alkyl O - d - C6, CF3.

   16. A 2, 6, 9-trisubstituted purine composition of Claim 12 wherein: Ri 'is -CH2-feml wherein the phenyl ring is optionally substituted with from 1 to 2 substitutes chosen independently from the group consisting of halo, CF3 , R22, OR20, CN; R2 isopropyl; R and R5 are each independently hydrogen or a hydrocarbon selected from the group including lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl alkyl, wherein each has from 1 to 12 carbon atoms where the substitution includes the optional substitution with from 1 substitute chosen independently from the group consisting of R22, OR20, NR20R23; R20 is a member selected from the group consisting of H, C1-2alkyl; R21 is a member selected from the group consisting of Ci. 3 alkyl; R22 is a member selected from the group consisting of Ci alkyl. 3, aryl, said alkyl, aryl are optionally substituted with from 1 substitute independently chosen from halo, alkyl, mono- or dialkylamino, CN, CF3; and R23 is R21 or H.

   17. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein Ri 'is selected from the group consisting of aralkyl, pyridylalkyl, and substituted pyridylalkyl, z is selected from the group consisting of lower alkyl, substituted minor alkyl, cycloalkyl, and substituted cycloalkyl, R 4 is a substituted lower alkyl substitute having from 2 to 6 carbon atoms and R 5 is selected from the group consisting of hydrogen, lower alkyl, substituted minor alkyl, aryl, substituted aryl, cycloalkyl, aryl cycloalkyl, heterocycle , substituted heterocycle, heteroaryl, substituted heteroaryl, heteroalkyl, and substituted cycloalkyl.

   18. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein Ri 'is selected from the group consisting of aryl, substituted aryl, pyridyl and substituted pyridyl, R 2 is selected from the group consisting of lower alkyl, substituted minor alkyl, cycloalkyl alkyl, and substituted cycloalkyl, Rt is a substituted lower alkyl having from 2 to 6 carbon atoms and R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, cycloalkyl, aryl cycloalkyl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, heteroalkyl, and substituted cycloalkyl.

   19. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein Ri 'is selected from the group consisting of aralkyl, pyridylalkyl and substituted pyridylalkyl, R 2 is selected from the group consisting of lower alkyl, substituted minor alkyl and cycloalkyl alkyl, and Rt and R5 are each a substituted lower alkyl having from 2 to 6 carbon atoms.

   20. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein Ri 'is CH2-Aril or substituted CH2-aryl, R2 is lower alkyl or substituted lower alkyl and Rt and Rs are each CH2 CH2OH, - CHR'CH2OH or - CH2 CHR'OH wherein R 'is hydrogen or alkyl having from 1 to 6 carbon atoms.

   21. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein Ri 'is CH2-Aril or substituted CH2-aryl, R2 is minor alkyl and R4 = H, and R5 is -CH2CH2NH2, CHR'CH2NH2, - CH2CHR' NH2 wherein R 'is hydrogen or alkyl having from 1 to 6 carbon atoms.

   22. The 2, 6, 9-trisubstituted purine composition of Claim 21 wherein R2 is isopropyl.

   23. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein Ri 'is CH2-aryl or -CH2-aryl substituted, R2 is lower alkyl, and = - CH2CH2OH, Rs is CH2CH2NH2, CHR'CH2NH2, - CH2CHR' NH2 wherein R 'is hydrogen or alkyl having from 1 to 6 carbon atoms.

   24. The 2, 6, 9-trisubstituted purine composition of Claim 23 wherein R2 is isopropyl.

   25. The 2, 6, 9-trisubstituted purine composition of Claim 20 wherein R 2 is isopropyl.

   26. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein R is selected from the group consisting of aryl, substituted aryl, pyridyl, and substituted pyridyl, R 2 is selected from the group consisting of lower alkyl, substituted minor alkyl, and cycloalkyl alkyl, and R5 are each a substituted lower alkyl having from 2 to 6 carbon atoms.

   27. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein Ri 'is aryl or substituted aryl, R 2 is lower alkyl or substituted minor alkyl and R t and R s are each CH 2 CH 2 OH, - HR'CH 2 OH, - CH 2 CHR'OH wherein R 'is hydrogen or alkyl having from 1 to 6 carbon atoms.

   28. The 2, 6, 9-trisubstituted purine composition of Claim 27 wherein R is isopropyl.

   29. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein Ri 'is benzyl substituted with a halogen, alkoxy, phenyl, pyridyl or nitro group, R 2 is isopropyl, and R t and R 5 are each - CH 2 CH 2 OH.

   30. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein Ri 'is benzyl substituted with a halogen, phenyl, pyridyl or nitro group, R 2 is isopropyl,

   11. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein Ri 'is benzyl substituted with a halogen, alkoxy, Ci. 3 alkyl, CF 3, phenyl, pyridyl or nitro group, R 2 is isopropyl, t = H and R 5 = CH2CHR'NH2 wherein R 'is hydrogen or alkyl having from 1 to 6 carbon atoms.

   32. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein Ri 'is benzyl substituted with a halogen, alkoxy, Ci. 3 alkyl, CF 3, phenyl, pyridyl or nitro group, R 2 is isopropyl, R t = H and R 5 = CH2CR'R'NH2 wherein R 'is hydrogen or alkyl having from 1 to 6 carbon atoms.

   33. The 2, 6, 9-trisubstituted purine composition of Claim 1 chosen from the group consisting of 2. { (2-hydroxyethyl) [9 - (methylethyl) -6 - ( { [4 - (trifluoromethyl) phenyl] methyl} amino) purin-2-yl] amino} etan - l - ol,. { ((2S) oxolan-2-yl) methyl] (6 -. {[[(4-fluorophenyl) methyl] amino]} - 9 - (methylethyl) purin-2-yl) amine, [((2R) oxolan - 2 - il) methyl] (6 - { [(4-fluorophenyl) methyl] amino.}. - 9 - (methylethyl) purine-2-yl) amine, (2-aminoethyl) (6 -. { [(4-fluorophenyl) methyl] amino} - 9 - (methylethyl) purin-2-yl) amine, (2-aminoethyl) (6 -. {[[(3,5-dichlorophenyl) methyl] amino]} - 9 - (methylethyl) purin-2-yl ) amine, (2-aminoethyl) [6 - ( { [4-chloro-3 - (trifluoromethyl) phenyl] methyl.}. amino-9 - (methylethyl) purin-2-yl] amine, [- [( 6 - { [(4-chlorophenyl) methyl] amino.}. - 9 - (methylethyl) purin-2-yl] amino] -3-methylbutanamide, (2-amino-2-methylpropyl) (6 -. { . [(4-chlorophenyl) methyl] amino.}. 9 - (methylethyl) purin-2-yl] amine, 3- (2 - [bis (2-hydroxyethyl) amino] -6 - { [4-chlorophenyl ) methyl] amino.}. purin) -yl) butane-2-one, 2 - [(6 -. {[[(4-chlorophenyl) methyl] amino} - 9 - (methylethyl) purin-2-yl ] amino] -3-methylbutan-1-ol, 4 - [(. {2 - [(2-aminoethyl) amino] -9] - (methylethyl) purin-6-yl} amino) methyl] benzenesulfonamia, 2 - [(2-hydroxyethyl) (6 - { [(4-methoxyphenyl) methyl] amino.}. 9 - (methylethyl) purin-2-yl) amino] ethan-1-ol , 2 - ((2-hydroxyethyl). {9-methylethyl) -6 - [(4-phenylphenyl) amino] purin-2-yl} amino) etan - l - ol,. { 2 - [(2-amino-2-propyl) amino] 9 - (methylethyl) purin-6-yl} [(4-chlorophenyl) methyl] amine,. { 2 - [(2-aminoethyl) amino] -9- (methylethyl) purin-6-yl} [(4-chlorophenyl) methylamine,. { 2 - [(2-aminopropyl) amino] -9- (methylethyl) purin-6-yl} [(4-chlorophenyl) methyl] amine and 2 - [(2-aminoethyl) (6 -. {[[(4-chlorophenyl) methyl] amino]} 9- (methylethyl) purin-2-yl) amino] ethane - LOL.

   34. A composition comprising mixtures that include two or more compounds of Claim 33.

   35. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein Ri 'is phenyl substituted with a halogen, alkoxy, phenyl, pyridyl or nitro group, R 2 is isopropyl and R? and Rs are each - CH2CH2OH.

   36. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein Ri 'is biphenylmethyl, R 2 is isopropyl and t and Rs are each - CH 2 CH 2 OH.

   37. The 2, 6, 9-trisubstituted purine composition of Claim 12 wherein Ri 'is selected from the group consisting of 3-thiomethoxyphenyl, 4-thiomethoxyphenyl 4-bromo phenyl, 4-phenylbenzyl, 4-methoxybenzyl, 4-biphenyl, 3 - methoxybenzyl, 4- (2-thienyl) benzyl, 4- (4-methyl) phenylbenzyl, 4- (4-trifluoromethyl) phenylbenzyl, 4- (4-nitrile) phenylbenzyl, 4- (2-pyridinyl) benzyl, piperonyl, 3 - methoxybenzyl, 4-chlorobenzyl, and 4-nitrobenzyl, R2 is isopropyl and R and R5 are both CH2CH2OH.

   38. The 2, 6, 9-trisubstituted purine composition of Claim 36 wherein R is selected from the group of compounds consisting of 4-methoxybenzyl, 4-phenylbenzyl, 4-methoxybenzyl, 4-biphenyl, 3-methoxybenzyl, 4 - ( 2-thienyl) benzyl, 4- (4-methyl) phenylbenzyl, 4- (4-trifluoromethyl) phenylbenzyl, 4- (4-nitrile) phenylbenzyl, 4- (2-pyridinyl) benzyl, piperonyl, 3-thiomethoxyphenyl, 4 - thiomethoxyphenyl and 4-bromophenyl.

   39. A cationic salt of the composition of Claim 1.

   40. An acid addition salt of the composition of Claim 1.

   41. The method of Claim 40 wherein the therapeutically effective amount ranges from about 0.001 to about 100 mg / kg of the animal's weight.

   43. The method of Claim 40 wherein the composition to be administered to a mammal suffering from a cell proliferation disorder selected from the group consisting of rheumatic arthritis, lupus, type I diabetes, multiple sclerosis, cancer, restenosis, graft host disease. and drop.

   44. The method of Claim 42 wherein the cell proliferation disorder is restenosis.

   45. The method of Claim 42 wherein the disorder of cell proliferation is cancer.

   46. The method of Claim 42 wherein the disorder of cell proliferation is polycystic kidney disease.

   47. The method of Claim 42 wherein the mammal is a human.

   48. A pharmaceutical composition comprising the composition of Claim 1 and one or more pharmaceutical excipients.

   49. An antifungal agent useful for treating fungal infections in humans, and animals comprising the composition of Claim 1. EXTRACT OF THE INVENTION A 2, 6, 9-trisubstituted purine composition that is useful for inhibiting cell proliferation disorders and as an antifungal agent.