Patent Publication Number: US-2017368185-A9

Title: Method of preparing dendritic drugs

Description:
This application is a divisional application of U.S. Ser. No. 11/653,548, filed Jan. 16, 2007, currently pending, which is a U.S. patent application filed from U.S. Provisional patent application Ser. No. 60/761,439, filed Jan. 24, 2006 from which priority is claimed. 
    
    
     BACKGROUND OF THE INVENTION 
     This invention deals with a synthetic design of drug incorporated novel dendrimers for quantitatively controlled drug delivery. 
     Dendrimers are well known in the art and there are multiple patents, treatises, and textbooks on their preparation and use. 
     Dendrimers have unique cascade structures with multiple functional termini. The multifunctional surface of dendrimers makes them easy to chemically conjugate with other molecules, such as drugs, for targeted delivery and controlled release of the drugs. Up to now, little attention has been paid to utilizing the cascade feature of dendrimer structures for controlled-release of drugs. This invention takes advantage of this distinct feature to develop an ideal drug delivery system since each layer of the structure can be tailored with a certain amount of drug entities that are well defined by the dendrimer structure. 
     Under proper physiological conditions, the dendritic drug can be degraded naturally or digested by enzymes to release the drugs sequentially and quantitatively layer by layer. The drugs on the surface, or exterior of the dendrimer, are released first, and then the interior drug units begin to be liberated when all of the periphery drug units have left. The drug units at the core of the dendrimer will be released last. Thus, a well-controlled quantitative delivery of the drug can be approached through this dendritic design. 
     At the current time, there are two known methods for utilizing dendrimers in drug delivery, dendrimer drug conjugation and dendrimer drug encapsulation. In the conjugation method, a drug is attached to the surface of the carrier molecule, i.e. the dendrimer, and the encapsulation method utilizes the dendritic voids to accommodate the drug molecules for improving the drug properties such as solubility and toxicity in therapeutic treatment. 
     However, both methods have limitations in drug controlled release and targeted delivery. For example, in the dendrimer, the conjugated drugs are only located on the surface of the dendrimer and they all can be easily released at the same time. Therefore, the drug-controlled release will be obviously limited in this system. The encapsulation of drugs with dendrimers is rather unstable for in vivo applications since the drugs are just physically entrapped inside the dendritic voids and the leakage of the drug can be a big issue during the delivery. 
     Examples of U.S. Patents and publications that deal with dendrimer drug encapsulation, dendrimer drug conjugation and alternative drug delivery systems are: U.S. Pat. No. 6,756,037 to Greenwald et al.; U.S. Pat. No. 6,838,528 to Zhao; U.S. Pat. No. 6,942,877 to Vogt, et al.; U.S. Pat. No. 6,913,761) to Carr, et al.; U.S. Pat. No. 6,681,068 to Ng, et al.; U.S. Pat. No. 6,576,222 to Platzek, et al.; U.S. Pat. No. 5,945,100 to Fick; U.S. Pat. No. 6,864,350 to Harris; U.S. Pat. No. 6,790,437 to Malik, et al.; U.S. Pat. No. 6,706,892 to Ezrin, et al.; U.S. Pat. No. 6,623,729 to Park et al.; U.S. Pat. No. 6,475,495 to Maignan; U.S. Pat. No. 6,458,347 to Sugawara, et al.; U.S. Pat. No. 6,432,423 to Maignan; U.S. Pat. No. 6,296,842 to Jaworowicz, et al.; U.S. Pat. No. 6,623,764 to Sokoll, et al.; U.S. Pat. No. 6,623,730 to Williams, et al.; U.S. Pat. No. 6,600,010 to Mao, et al.; U.S. Pat. No. 6,280,745 to Flore, et al.; U.S. Pat. No. 5,965,119 to Greenwald, et al.; U.S. Pat. No. 6,861,066 to Van de Casteele; U.S. Patent publication 2005/0169′882 A1 to Lowe, et al.; U.S. Patent publication 2005/0147688 A1 to Van de Casteele; U.S. Patent publication 2005/0147681 At to Zhao; U.S. Patent publication 2005/0119450 A1 to Wang, et al.; U.S. patent publication 2005/0112088 A1 to Zhao, et al.; U.S. Patent publication 2005/0042753 A1 to Yang, et al.; U.S. Patent publication 2005/0037075 A1 to Farokhzad, et al.; U.S. Patent publication 2005/0036973 A1 to Sato, et al.; U.S. publication 2005/0025820 A1 to Kester, et al.; U.S. Patent publication 2005/0019923 A1 to Uchegbu, et al.; U.S. Patent publication 2004/0247680 A1 to Farokhzad, et al.; U.S. Patent publication 2004/0228831 A1 to Belinka, et al.; U.S. Patent publication 2004/0161403 A1 to Zhao, et al.; U.S. Patent publication 2004/0151689 to Majoros, et al.; U.S. Patent publication 2004/0142475 A1 to Barman, et al.; U.S. Patent publication 2004/0028745 A1 to Bouhadir, et al.; U.S. Patent publication 2003/0232968 A1 to Li, et al.; U.S. Patent 2003/0232929 A1 to Huang, et al.; U.S. Patent publication 2003/0219785 A1 to Hallahan, et al.; U.S. Patent publication 2003/0190364 A1 to Panitch, et al.; U.S. Patent publication 2003/0181619 A1 to Matyjaszewski, et al.; U.S. Patent publication 2003/0175209 A1 to Mueller, et al.; U.S. Patent publication 2003/0170311 A1 to Van de Casteele; U.S. Patent publication 2003/0147812 A1 to Ueberle U.S. Patent publication 2003/0133972 A1 to Danthi, et al.; U.S. Patent publication 2003/0129223 A1 to Wanchow, et al.; U.S. Patent publication 2003/0083286 A1 to Teng, et al.; U.S. Patent publication 2003/0082103 A1 to Wartchow, et al.; U.S. Patent Publication 2003/0077295 A1 to Malik, et al.; U.S. Patent publication 2003/0073852 A1 to Ng, et al.; U.S. Patent publication 2003/0068379 A1 to Li, et al.; U.S. Patent publication 2003/0064984 A1 to Ng, et al.; U.S. Patent publication 2003/0064050 A1 to Malik, et al. U.S. Patent publication 2003/0059461 A1 to Backer, et al.; U.S. Patent publication 2003/0050426 A1 to Shastri; U.S. Patent publication 2002/0192843 A1 to Kaganove, et al.; U.S. Patent publication 2002/0165179 A1 to Baker; U.S. Patent publication 2002/0164648 A1 to Goins, et al.; U.S. Patent publication 2002/0156047 A1 to Zhao; U.S. Patent publication 2002/0151004 A1 to Craig; U.S. Patent publication 2002/0123609 A1 to Frechet, et al.; U.S. Patent publication 2002/0071843 A1 to Li, et al.; U.S. Patent publication 2002/0045263 A1 to Leong, et al.; U.S. Patent publication 2002/0022012 A1 to Cooper, et al.; U.S. Patent publication 2002/0000681 A1 to Gupta, et al.; U.S. Patent publication 2001/0011109 A1 to Balogh, et al., and U.S. Patent publication 2001/0007666 A1 to Hoffman, et al. 
     Linear polymeric drugs have been discovered for drug delivery applications. For example in U.S. Pat. No. 6,613,807, that issued on Sep. 2, 2003 and U.S. Pat. No. 6,468,519 that issued on Oct. 22, 2002, both to Uhrich, there is disclosed therapeutic polyanhydride compounds for drug delivery. Uhrich also discloses linear drugs in U.S. Pat. No. 6,689,350, that are based on therapeutic polyesters and polyanmides. 
     The linear drugs dissociate into free drug units under certain critical conditions, leading to the sudden release of the drug. Thus, the control of the drug delivery for linear drugs is not well controlled and the drug release is not quantitative. 
     The dendritic drugs of this invention have better control and thus a quantitative drug release can be obtained. There is no prior art relating to drugs that control release both sequentially and quantitatively like the dendritic drugs of this invention. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is the preparation of the building block  200  starting with reacting drug  100  and bifunctional linkers. 
         FIG. 2  is the reaction of the drug  100  using the bifunctional linker (i) to give the core (G 0 )  300 . 
         FIG. 3  shows using drug  100  and bifunctional linkers (i) and (ii) to form the core (G 0 )  400 . 
         FIG. 4  is building block  200  and core  300  or  400  reacted together to form generation 1,  500 . 
         FIG. 5  is the preparation of Generation 2 (G2)  600  by using the building block  200  and the Generation 1 molecule  500 . 
         FIG. 6  is the preparation of a Generation 3 (G3) molecule  700  using building block  200  and the Generation 2 molecule  600 . 
         FIG. 7  is the reaction of the drug  1000  to give the building block  1100 . 
         FIG. 8  is the preparation of the core group G 0    1200  using the drug  1000  and a bifunctional linker (i). 
         FIG. 9  is the reaction of the drug  1000  and the use of bifunctional linkers (i) and (ii) to form the core  1300 . 
         FIG. 10  illustrates the preparation of the first generation molecule  1400  using the building block  1100  and the G 0  core  1200  or  1300 . 
         FIG. 11  shows in schematic form, the preparation of Generation 2,  1500 . 
         FIG. 12  shows the preparation of Generation 3  1600  dendritic drugs. 
         FIG. 13  is the reaction of a bifunctional drug  2000  with a trifunctional linker  2100  to give compound  2200 . 
         FIG. 14  shows compound  2200  reacted with a bifunctional linker  2300  to give the building block  2400 . 
         FIG. 15  shows compound  2200  reacted with a bifunctional linker  2500  to give the core molecule (G 1 )  2600 . 
         FIG. 16  shows the reaction of building block  2400  and G 0    2600  to prepare Generation 1 dendritic drug (G 1 )  2700 . 
         FIG. 17  shows the preparation of the second generation dendritic drug wherein building block  2400  is reacted with G 1  to provide Generation 2 (G 2 ) dendritic drug  2800 . 
         FIG. 18  shows the preparation of the third generation dendritic drug wherein building block  2400  is reacted with G 2    2800  to give Generation 3 (G 3 ) dendritic drug  2900   
         FIG. 19  shows the reaction of a bifunctional drug  2000  with a trifunctional linker  2100  to give the compound  2200  and the reaction of compound  2200  with the bifunctional linker  2300  to give the building block  2400 . 
         FIG. 20  shows the reaction of the drug  2000  with the bifunctional linker  3100  to give a new core molecule G 0 ,  3200 . 
         FIG. 21  shows the building block  2400  reacted with the new core  3200  to give the first generation dendritic drug (G 1 )  3300 . 
         FIG. 22  shows the building block  2400  reacted with G 1    3300  to give the second generation molecule (G 2 )  3400 . 
         FIG. 23  shows the building block  2400  reacted with G2  3400  to give the third generation dendritic drug (G 3 )  3500 . 
         FIG. 24A  shows the structure of a first generation dendritic drug made from L-DOPA (HO-G 1 -NH 2 ). 
         FIG. 24B  shows the structure of a second generation dendritic drug. 
         FIG. 24C  shows the structure of a third generation dendritic drug. 
         FIG. 25A  is the chemical formula for L-Dopa. 
         FIG. 25  B is HO-DOPA-NH 2 —COOMe. 
         FIG. 25  C is HO-DOPA-NH-Boc-COOMe. 
         FIG. 25  D is Benzyl-DOPA-NH-Boc-COOMe. 
         FIG. 25  E is Benzyl-DOPA-NHBoc-COOH. 
         FIG. 25  F is Benzyl-DOPA-NHBoc-COOCH 2 CH 2 OH. 
         FIG. 25  G is Benzyl-DOPA-NHBoc-linker. 
         FIG. 25  H is BnO-G 0 -NHBoc. 
         FIG. 25  I is —HO-G 0 -NHBoc. 
         FIG. 25  J is BO-G 1 -NHBoc. 
         FIG. 25  K is HO-G 1 -NHBoc. 
         FIG. 25  L is BnO-G 2 -NHBoc. 
         FIG. 25  M is HO-G 2 -NHBoc. 
         FIG. 25  N is HO-G 2 -NH 2 . 
         FIG. 25  O is BnO-G 3 -NHBoc. 
         FIG. 25  P is HO-G 3 -NHBoc. 
         FIG. 25  Q is HO-G 3 -NH 2 . 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The instant invention deals with the synthetic design of drug-incorporated novel dendrimer structures for quantitative controlled drug delivery. 
     With more specificity, this invention deals, in one embodiment, with a method of preparing a dendritic drug, the method comprising providing a therapeutically active multifunctional drug, wherein the drug has at least one reactive group capable of providing a linker site. The drug also has at least one functional group capable of providing a starting point for the preparation of a dendritic structure. 
     Any reactive group in the drug that is not capable of providing a linker site or providing a starting point for the preparation of a dendritic molecule is chemically protected. Also, before any synthetic modification, any reactive groups capable of providing a linker site and any functional group capable of providing a starting point for the preparation of a dendritic molecule are first chemically protected. 
     The method then provides the deprotection of the protected group formed when the original linker sites of the starting drug molecule are chemically protected, and then reacting the deprotected groups with a first linker group selected from the group consisting of biologically compatible compounds, biologically inactive compounds, biologically active compounds, biologically compatible and bioactive compounds, biologically compatible and biologically inactive compounds. 
     The product from the above reaction (just Supra) is reacted with a second linker group selected from the group consisting of biologically compatible compounds, biologically inactive compounds, biologically active compounds, combinations of biologically compatible and bioactive compounds, and combinations of biologically compatible and biologically inactive compounds. The product of the reaction serves as the building block for the preparation of the dendritic drug. 
     Next, two units of building block molecules formed during the reactions of the first linker and second groups are coupled together with a linker molecule or two linker molecules, to yield a core molecule for the preparation of the dendritic drug. 
     Thereafter, a predetermined amount of active sites in the core formed in the coupling reaction above are generated by deprotecting the protected linker sites of the core for the preparation of a dendritic molecule. So, the core to be used for building up the dendritic drug is still chemically protected with any groups in the drug precursor that is not capable of providing a linker site or providing a starting point for the preparation of a dendritic molecule. Then the synthesis of the first generation dendritic drug, can be done by reacting the active linker sites of the core molecule with the certain amount of building block molecules (based on number of the active sites), then deprotecting the rest of the protected groups in the formed structure to give a first generation dendritic drug. 
     What follows is the formal used in the claims so that the method can be more easily followed. 
     Thus, the invention deals with a method of preparing a dendritic drug, the method comprising (I) providing a therapeutically active multifunctional drug, said drug having at least one reactive group capable of providing a linker site, said drug having at least one functional group capable of providing a starting point for the preparation of a dendritic molecule; (II) chemically protecting any reactive group in the drug that is not capable of providing a linker site or providing a starting point for the preparation of a dendritic molecule; (III) chemically protecting any reactive groups capable of providing a linker site; (IV) chemically protecting any functional group capable of providing a starting point for the preparation of a dendritic molecule; (V) deprotecting any group formed in (III); (VI) reacting any group formed in (V) with a first linker group selected from the group consisting of: (i) biologically compatible compounds, (ii) biologically inactive compounds, (iii) biologically active compounds, (iv) biologically compatible and bioactive compounds, (v) biologically compatible and biologically inactive compounds; (VII) reacting the first linker from (VI) with a second linker group selected from the group consisting of (i) biologically compatible compounds, (ii) biologically inactive compounds, (iii) biologically active compounds, (iv) biologically compatible and bioactive compounds, (v) biologically compatible and biologically inactive compounds; (VIII) coupling two units formed in (VI) through the first linker groups; (IX) deprotecting the groups formed in (IV) to yield a core molecule for the dendritic drug; (X) reacting a predetermined amount of the molecules formed in (VI) with each one equivalent of the molecule formed in (VIII), and deprotecting the protected groups formed in (IV); deprotecting any group in the molecule that is not capable of providing a linker site or providing a starting point for the preparation of a dendritic molecule to give a first generation dendritic drug. 
     Another embodiment of this invention is treating the first generation dendritic drug iteratively using steps (X) and (XI) to form higher generation dendritic drugs. 
     Still further, an additional embodiment of this invention is to provide a process for preparing and dendritic drugs wherein more than one type of drug is incorporated into the dendritic molecule. 
     An additional embodiment of this invention is a dendritic drug prepared by the processes set forth above. 
     Yet another embodiment of this invention is a dendritic drug that will release biologically active compounds when decomposed by the biological degenerative action of a mammalian body. 
     Still another embodiment of this invention is a pharmaceutical composition comprising the dendritic drug and a pharmaceutical carrier. 
     Another embodiment of this invention is a therapeutic method of treating a disease in an animal comprising administering to an animal an effective amount of a dendritic drug as disclosed herein. 
     Going to another embodiment of this invention there is a method of delivering a biologically active compound to a host comprising administering to the host, a dendritic drug as disclosed herein. 
     A final embodiment is a dendritic drug wherein the dendritic drug has a dendritic cascade structure wherein bioactive material in incorporated into the chemical structure of the dendritic cascade structure. The dendritic cascade structure has biocompatible linking groups that are capable of degenerating under the influence of enzymes or degenerating under the influence of the bioactivity of a host body to provide controlled release of the bioactive material. 
     The method of this invention uses biocompatible linkers with biodegradable bonding such that drug molecules can be incorporated into a dendritic structure to form a dendritic drug that consists of a known amount of drug molecules. Each layer of the cascade structure of the dendrimer will contain a known amount of drug units, with the largest amount at the periphery and the least amount at the core of the dendrimer. 
     It is believed by the inventors herein that these unique dendritic drugs by having better control over release of the drug, reduces the toxic effect from drug accumulation. 
     The use of biologically active compounds in this invention includes therapeutic agents that provide a therapeutically desirable effect when administered to an animal. Therapeutic agents that can be incorporated into the drugs of this invention are those that are suitably functionalized analgesics, anesthetics, anti-Parkinson&#39;s agents, anti-infectives, anti-acne agents, antibiotics, anticholinergics, anticoagulants, anticonvulsants, anti-diabetic agents, anti-dyskinetics, antifibrotic agents, antifibrotics, antifungal agents, amntiglaucoma agents, anti-inflammatory agents, antineoplastics, antiosteoporotics, antipagetics, antiporatics, antipyretics, antiseptics/disinfectants, antithrombotics, bone resorption inhibitors, calcium regulators, cardioprotective agents, cardiovascular agents, central nervous system stimulants, cholinesterase inhibitors, contraceptives, deodorants, dopamine receptor agonists, erectile dysfunction agents, fertility agents, gastrointestinal agents, gout agents, hormones, hypnotics, immunomodulators, immunosuppressives, keratolytics, migraine agents, motion sickness agents muscle relaxants, nucleoside analogs, obesity agents, ophthalmic agents. Osteoporosis agents, parasympatholytics, parasympathomimetics, prostaglandins, psychotherapeutic agents, respiratory agents, sclerosing agents, sedatives, skin and mucous membrane agents, smoking cessation agents, sympatholytics, synthetic antibacterial agents, ultraviolet screening agents, urinary tract agents, vaginal agents, and vasodilators (see Physicians&#39; Desk Reference, 55 ed., 2001, Medical Economics Company, Inc., Montvale, N.J., pages 201 to 202). 
     Suitable examples of drugs with the required functional groups within their structure can be found in almost all classes of drugs including, but not limited to, analgesics, anesthetics, anti-acne agents, antibiotics, synthetic antibacterial agents, anticholinergics, anticoagulants, anti-dyskinetics, antifibrotics, antifungal agents, antiglaucoma agents, anti-inflammatory agents, antineoplastics, antiosteoporotics, antipagetics, anti-Parkinson&#39;s agents, antisporatics, antipyretics, antiseptics/disinfectants, antithrombotics, bone resorption inhibitors, calcium regulators, keratolytics, sclerosing agents and ultraviolet screening agents. 
     Lists of therapeutic agents can be found, for example, in the Physicians&#39; Desk Reference, referred-to Supra. USPN Dictionary of USAN and International Drug Names, 2000. The United States Pharmacopoeia Convention, Inc., Rockville, Md.; and the Merck Index, 12 ed., 1996, Merck &amp; Co., Inc., Whitehouse Station, N.J. One skilled in the art can readily select therapeutic agents that possess the necessary functional groups for use in this invention. 
     Examples of anti-bacterial compounds suitable for use in the present invention include, but are not limited to, 4-sulfanilamidosalicylic acid, acediasulfone, amfenac, amoxicillin, ampicillin, apalcillin, apicycline, asosicillin, axtreonam, bambermycins, biapenem, carbenicillin, carumonam cefadroxil, cefamandole, cefatrizine, cefbuperazone, cefclidin, cefdinir, cefditoren, cefepime, cefetament, cefixime, cefinenoxime, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefoetan, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefprozil, cefroxadine, ceftazidime, cefteram, ceftibuten, ceftriaxone, cefuzonam, cephalexin, cephaloglycin, cephalosporin C, cephradine, ciprofloxacin, clinafloxacin, cyclacillin, enoxacin, epicillin, flomoxef, grepafloxacin, hetacillin, imipenem, lomefloxacin, lymecycline, meropenem, moxalactam, mupirocin, nadifloxacin, norfloxacin, panipenem, pazufloxacin, penicillin N, pipemidic acid, quinacillin, ritipenem, salazosulfadimidine, sparfloxacin, succisulfone, sulfachrysoidine, sulfaloxic acid, teicoplanin, temafloxacin, temocillin, ticarcillin, tigemonam, tosulfoxacin, trovafloxacin, vancomycin, and the like. 
     Examples of anti-fungal compounds suitable for use in the present invention include, but are not limited to, amphotericin B, azaserine, candicidins, lucensomycin, natamycin, nystatin, and the like. 
     Examples of anti-neoplastic compounds suitable for use in the instant invention include, but are not limited to, 6-diazo-S-oxo-L-norleucine, azaserine, carzinophillin A, denopterin, edatrexate, eflomithine, melphalan, methotrexate, mycophenolic acid, podophyllinic acid 2-ethylhydrizide, pteropterin, streptonigrin, Tomudex® (N-((5-(((1,4-Dihydro-2-methyl-4-oxo*-quinazolinyl)methyl)methylamino)-2-thienyl)carbonyl)-L-glutamic acid), ubenimex, and the like. 
     Examples of anti-thrombics useful in the instant invention include, but are not limited to, argatroban, iloprost, lamifiban, taprostene, tirofiban and the like. 
     Examples of immunosuppressive compounds suitable for use in the present invention include, but are not limited to, bucillamine, mycophenolic acid, proceodazole, romurtide, ubenimex and the like. 
     Examples of NSAID compounds suitable for use in the instant invention include, but are not limited to 3-amino-4-hydroxbutyric acid, aceclofenac, alminoprofen, bromfenac, bumadizon, carprofen, diclofenac, diflunisal, enfenamic acid, etodolac, fendosal, flufenamic acid, gentisic acid, meclofenamic acid, mefenamic acid, mesalamine, niflumic acid, olsalazine oxaceprol, S-adenosylmethionine, salicylic acid, salsalate, sulfasalizine, tolfenamic acid, and the like. 
     The dendritic drugs prepared by the method of the instant invention can be used neat, or can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient or an animal such as a dog or horse. This can be done in a variety of forms, such as, for example, orally, rectally, or parenterally, by intravenous, intramuscular, intraperitoneal, intraspinal, intracranial, topical, ocular, and subcutaneous routes. 
     Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient&#39;s diet. For oral therapeutic administration, the active compound may be combined with one or more excipients or adjuvants used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations preferably contain at least 0.1% by weight of the dendritic drug. The percentage of the compositions and preparations may be varied and may conveniently be between about 0.1% to about 100% by weight of the composition as long as an effective dosage level is maintained. 
     The tablets, troches, pills, capsules, and the like may also contain the following. Binders, such as gum tragacanth, acacia, corn starch or gelatin, excipients such as dicalcium phosphate, a disintegrating agent such as corn starch, potato starch, alginic acid and the like, a lubricant such as magnesium stearate, and a sweetening agent such as sucrose, fructose, lactose, or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. 
     When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coating or to otherwise modify the physical form of the solid unit dosage form, as long as the effectiveness of the drug is not compromised. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, a dye, and flavoring, such as cherry or orange flavor. Any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained release preparations and devices. 
     Solutions of the dendritic drug can be prepared in a suitable solvent such as an alcohol, or mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof, and in certain oils, with care being taken to avoid hydrolysis of the dendritic drug. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms. 
     Suitable injection or infusion forms can include sterile solutions or dispersions or sterile powders comprising the dendritic drug that are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, ethanol, a polyol, for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like, vegetable oils, nontoxic glycerol esters and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. 
     Sterile injectable solutions are prepared by incorporating the dendritic drug in the required amount in the appropriate solvent with various of the other ingredients enumerated Supra, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, that yield a powder of the active ingredient plus any additional desired ingredients present in the previously sterile filtered solutions. 
     For topical administration, the inventive dendritic drugs can be applied in pure form. However, it will generally be desirable to administer them as compositions or formulations, in combination with a dermatologically acceptable carrier, that may be a solid or a liquid. 
     Useful solid carriers include finely divided solids such as talc clay, micro-crystalline cellulose, silica, alumina and the like. Useful liquid carriers include alcohols or glycols or alcohol/glycol blends, in which the present compound can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid composition can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. 
     Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user. 
     Examples of useful dermatological compositions that can be used to deliver the dendritic drugs of this invention to the skin are known in the art, for example, Jacquet et al in U.S. Pat. No. 4,608,392; Geria in U.S. Pat. No. 4,992,478. Smith et al in U.S. Pat. No. 4,559,157 and Wortzman, in U.S. Pat. No. 4,820,508. 
     Useful dosages of the drugs can be determined by comparing their in vitro activity, and in vivo activity of the therapeutic agent in animal modes. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known in the art, for example, (see U.S. Pat. No. 4,938,949). Additionally, useful dosages can be determined by measuring the rate of hydrolysis for a given drug under various physiological conditions. The amount of the drug required for use in treatment will vary not only with the particular polymer selected, but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. 
     The desired dose may conveniently be presented in a single dose or sub-divided doses administered at appropriate intervals. 
     The dendritic drugs of the instant invention are also useful for administering a combination of therapeutic agents to an animal. Such a combination therapy can be carried out in the following ways: 1) a second therapeutic agent can be dispersed within the polymer matrix of the dendritic structure of the dendritic drug of this invention which can be released upon degradation of the drug; 2) a second therapeutic agent can be appended to the dendritic drug, that is, not in the backbone of the polymer with bonds that hydrolyze to release the second therapeutic agent under physiological conditions; 3) the dendritic drug of this invention can incorporate two therapeutic agents into the dendritic structure, that is, a dendritic drug that is prepared using two different types of drugs and, 4) two dendritic drugs of this invention each with a different therapeutic agent can be administered together or within a short time of each other. 
     As will abundantly clear to one skilled in the art, suitable protecting groups can be used during the reactions illustrated herein. For example, functional groups present in the biologically active compound or the linker precursors can be protected during subsequent reactions and then the protecting groups can subsequently be removed (deprotected) to provide the eventual dendritic drugs of this invention. Some suitable protecting groups and methods for their incorporation and removal are well known in the art (see for example, Green. T. W., Wutz, P. G. M., “Protecting Groups in Organic Synthesis”, second edition, 1991, New York. John Wiley &amp; Sons, Inc. 
     For purposes of this invention, what is meant by “therapeutically active multifunctional drug” is any therapeutically active material that has at least one reactive functional group attached to it to provide a linker site and at least one functional group capable of providing a starting point for the preparation of a dendritic molecule of this invention. Preferred for this invention are drugs having one or two functional groups capable of providing a starting point for the preparation of the dendritic molecule. Further preferred are multifunctional drugs that have bi-functionality or tri-functionality, but the invention is not limited to those functionalities. What is meant by “chemically protecting any reactive group in the drug that is not capable of providing a linker site or providing a starting point for the preparation of a dendritic molecule” is that those groups in the therapeutically active material that are susceptible to reaction and that are part of the generic make up of the drug per se, are protected before the preparation of the dendritic drug has begun. This is to avoid undesired reactions. It is also an attempt to retain the necessary groups of the drug that make it effective as a drug. 
     Then, those groups that will be used to provide the linker sites are chemically protected, and then, those groups capable of providing a starting point for the preparation of a dendritic molecule are chemically protected. 
     The beginning of the actual construction of the dendritic drug begins with deprotecting those groups that have been chemically protected and are capable of providing a linker. Once these sites are deprotected, they can be reacted with the biologically compatible first linker groups that will eventually form the drug. For example, the linker molecule should be bi-functional for trifunctional drugs, and trifunctional for bi-functional drugs. This concept can be better understood by referring to the synthetic schemes set for a  FIG. 3 . 
     The first linker groups are then reacted with a second linker group that is also biologically compatible with the mammalian body, and then the two linker groups are reacted together. At this point in the method, the groups that are chemically protected and deprotected to form a core molecule for the dendritic drug. This part of the method provides a building block molecule that will be repeatedly used in the later steps toward the final synthesis of the dendritic drug. 
     The coupled units are then reacted with the groups formed from the first linker group in a ratio such that the building block molecules formed in the previous steps are reacted through their available functional groups with each one equivalent of the core molecule in a stoichiometrical amount. 
     Finally, deprotection is carried out until the functional groups on the original drug are available to carry out the original drug function. 
     What is meant herein by “bioactive material is incorporated into the chemical structure of the dendritic cascade structure” is that the bioactive materials actually form pan of the structure of the dendritic cascade as opposed to being chemically reacted to the exterior surface of the dendrimer molecule (i.e. conjugated dendrimers), or being physically held in the voids of the dendrimer structure. 
     The reaction schematics are described infra to illustrate the invention methods. 
     Turning now to  FIG. 1 , there is shown the preparation of the building block starting with bifunctional linkers. Thus, there is shown the drug  100 , having functional groups Z, Z 1 , and Z 2  wherein Each of Z 1  and Z 2  are selected from the group consisting of —OH, —SH, and —NH 2  and Z is —COOH. The biofunctional linkers are shown as (i) and (ii) and (i) is selected from a group consisting of —OH, —SH, and —NH 2 , while (ii) is —COOH. These reactions result in ester, thioester and amide linkages to form the building block  200  shown in  FIG. 1 . The various constituents are summarized in Table I, infra. 
     
       
         
           
               
               
               
             
               
                 TABLE I 
               
             
            
               
                   
               
               
                 Functional Group On Drug 
                 Functional Group On Biofunctional Linkers 
                 Resulting Linkage 
               
            
           
           
               
               
               
               
               
            
               
                 Z 1  or Z 2   
                 Z 
                 i 
                 ii 
                 in Dendritic Drug 
               
               
                   
               
               
                 —OH 
                 —COOH 
                 —OH 
                 —COOH 
                 Ester 
               
               
                 —SH 
                 —COOH 
                 —SH 
                 —COOH 
                 Thioester 
               
               
                 —NH 2   
                 —COOH 
                 —NH 2   
                 —COOH 
                 Amtde 
               
               
                   
               
            
           
         
       
     
     X in  FIG. 1  is selected from the group consisting of —O—, —S—, and —NH— and L is —R′—X—CO—(CH 2 ) m — wherein m has a value of from 2 to 20, R′ is —(CHR—CH 2 ) p —, wherein R is hydrogen or an alkyl group, and p has a value of from 1 to 10. 
     Turning to  FIG. 2 , there is shown the reaction of the drug  100  using the bifunctional linker (i) to give the core (G 0 )  300  and in the formulae X is —O—, —S—, or —NH—; L 1  is —(CH 2 ) q — wherein q has a value of from 2 to 20. 
     In the alternative, using drug  100  and bifunctional linkers (i) and (ii), the core (G 0 )  400  can be formed as shown in  FIG. 3 , wherein X is —O—, —S—, or —NH—; L 1  is R′X—CO—(CH 2 ) t —CO—X—R′, wherein r has a value of from 2 to 20, R′ is —(CHR—CH 2 ) 8 —. R is hydrogen or an alkyl group and s has a value of from 1 to 10. 
     Thereafter, building block  200  and core  300  or  400  are reacted together to form generation 1 ( 500 ) as shown in  FIG. 4 . Thereafter, there is shown in  FIG. 5 , the preparation of Generation 2 (G2)  600  by using the building block  200  and the Generation 1 molecule  500 . 
     The preparation of a Generation 3 (G3) molecule  700  is shown in  FIG. 6  using building block  200  and the Generation 2 molecule  600 . 
     Similarly, even higher generation dendritic drugs can be synthesized. This synthetic scheme is not limited to the use of drugs with three functionalities. Extra functional groups of the drug can be protected and finally deprotected to restore it to its intrinsic form using proper methods. 
     In a second scheme, there is shown in  FIG. 7 , the reaction of the drug  1000  and building block  1100 , wherein Z 1  and Z 2  each are —COOH, Z is selected from the group consisting of —OH, —SH, and —NH 2 , the bifunctional linker (i) is —COOH and (ii) is selected from a group consisting of —OH, —SH, —NH; X is —O—, —S—, or —NH—; L is —(CH 2 ) t —CO—X—R′—, wherein t has a value of from 2 to 20, R′ is —(CHR—CH 2 ) u —R is either hydrogen or an alkyl group, and u has a value of from 1 to 10. The various constituents are summarized on Table II. 
     
       
         
           
               
               
               
             
               
                 TABLE II 
               
             
            
               
                   
               
               
                 Functional Group On Drug 
                 Functional Group On Biofunctional Linkers 
                 Resulting Linkage 
               
            
           
           
               
               
               
               
               
            
               
                 Z 1  or Z 2   
                 Z 
                 i 
                 ii 
                 in Dendritic Drug 
               
               
                   
               
               
                 —COOH 
                 —OH 
                 —COOH 
                 —OH 
                 Ester 
               
               
                 —COOH 
                 —SH 
                 —COOH 
                 —SH 
                 Thioester 
               
               
                 —COOH 
                 —NH 2   
                 —COOH 
                 —NH 2   
                 Amide 
               
               
                   
               
            
           
         
       
     
     In  FIG. 8 , there is shown the preparation of the core group G 0    1200  using the drug  1000  and a bifunctional linker (i), wherein X is —O—, —S— or —NH— and L 1  is —(CH 2 ) v —, wherein v has a value of from 2 to 20, and in  FIG. 9 , there is shown the reaction scheme of the drug  1000  and the use of bifunctional linkers (i) and (ii) to form the core  1300 , wherein (i) is set forth just Supra, and (ii) is selected from the group consisting of —OH, —SH, and —NH 2 , and wherein X is —O—, —S— or —NH—; L 1  is —(CH 2 ) w , —CO—X—R′—X—O—(CH 2 ) w —, wherein w has a value of from 2 to 20, R′ is —(CHR—CH 2 )z—, R is hydrogen or an alkyl group, and z has a value of from 1 to 10. 
       FIG. 10  illustrates the preparation of the first generation molecule  1400  using the building block  1100  and the G 0  core  1200  or  1300 .  FIG. 11  shows in schematic form, the preparation of Generation 2  1500  and  FIG. 12  shows the preparation of Generation 3  1600  dendritic drugs. The various constituents are summarized on Table III. 
     
       
         
           
               
               
               
             
               
                 TABLE III 
               
             
            
               
                   
               
               
                 Functional Group On Drug 
                 Functional Group On Biofunctional Linkers 
                 Resulting Linkage 
               
            
           
           
               
               
               
               
               
               
            
               
                 Z 1    
                 Z 2   
                 Y 
                 Y 1   
                 Y 2   
                 in Dendritic Drug 
               
               
                   
               
               
                 —OH 
                 —COOH 
                 —OH 
                 —OH 
                 —COOH 
                 Ester 
               
               
                 —SH 
                 —COOH 
                 —SH 
                 —SH 
                 —COOH 
                 Thioester 
               
               
                 —NH 2   
                 —COOH 
                 —NH 2   
                 —NH 2   
                 —COOH 
                 Amide 
               
               
                   
               
            
           
         
       
     
     This invention, as mentioned Supra, deals with methods using a bifunctional drug as a precursor, and the following schematics illustrate such methods. 
     Turning now to  FIG. 13 , there is shown the reaction of a bifunctional drug  2000  wherein Z 1  is selected from —OH, —SH—, and —NH 2 — and Z 2  is —COOH, and a trifunctional linker group  2100  wherein Y and Y 1  are —OH, —SH, and —NH 2  to give the compound  2200 . The compound  2200  is then reacted with a bifunctional linker group  2300  to give the building block  2400  as shown in  FIG. 14 , wherein X and X 1  are selected from —O—, —S— or —NH—, and L is —(CH 2 ) a — wherein a has a value of from 2 to 20. Compound  2200  is then reacted with compound  2500  to give the core group (G 0 )  2600  as shown in  FIG. 15 . Wherein Y 2  is —COOH, X 1  is —O—, —S—, or —NH—, and L 1  is —(CH 2 ) b  wherein b has a value of from 2 to 20. Building block  2400  and G 0  and then reacted to give the first generation G 1    2700  as shown in  FIG. 16 . 
     The second and third generations are shown in  FIGS. 17 and 18 , respectively, wherein building block  2400  is reacted with G 1    2700  to provide G 2    2800 , and the building block  2400  is reacted with compound G 2    2800  to give G 3 , compound  2900 . The various constituents are summarized in Table III. 
     
       
         
           
               
               
               
             
               
                 TABLE IV 
               
             
            
               
                   
               
               
                 Functional Group On Drug 
                 Functional Group On Biofunctional Linkers 
                 Resulting Linkage 
               
            
           
           
               
               
               
               
               
               
            
               
                 Z 1    
                 Z 2   
                 Y 
                 Y 1   
                 Y 3   
                 in Dendritic Drug 
               
               
                   
               
               
                 —OH 
                 —COOH 
                 —OH 
                 —OH 
                 —OH 
                 Ester 
               
               
                 —SH 
                 —COOH 
                 —SH 
                 —SH 
                 H 
                 Thioester 
               
               
                 —NH 2   
                 —COOH 
                 —NH 2   
                 —NH 2   
                 —NH 2   
                 Amide 
               
               
                   
               
            
           
         
       
     
     Turning now to  FIG. 19 , there is shown the reaction of a bifunctional drug  2000  with a trifunctional linker  2100  to give the compound  2200  and the reaction of compound  2200  with the bifunctional linker  2300  to give the building block  2400 , wherein X and X 1  are selected from —O—, _S_, or —NH—, and L is —(CH 2 ) c —, wherein c has a value of from 2 to 20. Further,  FIG. 20  shows the reaction of the drug  2000  with the bifunctional linker  3100  to give a new core molecule G 0 ,  3200 . 
     The building block  2400  is reacted with the new core  3200  to give the first generation dendritic drug  3300  shown in  FIG. 21  and the building block  2400  is reacted with the first generation molecule  3300  to give the second generation molecule  3400  as shown in  FIG. 22 , while the building block  2400  is reacted with the second generation compound  3400  to give the third generation  3500  as is shown in  FIG. 23 . The various constituents are summarized in Table IV. 
     Preparation of a First Generation Dendritic Drug 
     Example 1 
     This example deals with a novel preparation method to form multiple drug units into a cascade structure to form a first generation dendritic drug as shown in  FIG. 24 . 
     Example 1a 
     Formation of HO-DOPA-NH 2 —COOMe (FIG.  25 B) 
     The reaction sequence beings with commercially available L-DOPA ( FIG. 25A ) which was converted to the hydrochloride. 
     Methanol, 20 ml was cooled to 0° C. and then thionyl chloride (0.89 ml, 12.2 mmol) was slowly added. After 30 minutes. L-Dopa (2.00 g, 10.1 mmol) was slowly added. The mixture was allowed to return to room temperature and was stirred for another 18 hours at room temperature. The mixture was concentrated in vacuo to give a light yellow powder. The solid did not need further purification and was utilized to continue the next reaction. 
     Example 1b 
     Formation of HO-DOPA-NH-Boc-COOMe (FIG.  25 C) 
     The yellow powder of example 1a (1.000 g, 4.74 mmol) was dissolved in tetrahydrofuran (10 ml) and a solution of 1M NaHCO 3  (10.0 ml, 10.0 mmol) was added. The resulting solution was cooled at 0*C, and di-tertbutyl-dicarbonate (1.093 g, 5.0 mmol) was added slowly. The solution was stirred at 0° C. for 1 hour, and then warmed to room temperature and it was stirred for another one hour at room temperature. The organic solvent was removed by vacuum and the aqueous layer was extracted using ethyl acetate (3×10 ml). All organic fractions were combined. The organic layer was washed respectively with water (2×20 ml), 5% HCl (2×20 ml), water (20 ml), brine (20 ml), and dried over MgSO 4  and the solvent was removed using vacuum. Further purification was performed using flash chromatography with the eluent; 1:1 ethyl acetate hexane. The pure product was retrieved as a white solid (1.315 g.). 
     Example 1c 
     Formation of Benzyl-DOPA-NH-Boc-COOMe (FIG.  25 D) 
     The white powder of example 1b 1.31 g., 4.17 mmol) was dissolved in acetone (15 ml). Potassium carbonate (2.881 g, 20.85 mmol) and sodium iodide (125 tug, 0.83 mmol) were added to the solution. Benzyl bromide (BnBr) (2.25 ml, 18.76 mmol) was added and then the mixture was refluxed at 50° C. for 18 hours. The solvent was removed in vacuo and the sediment was dissolved in dichloromethane (DCM) (30 ml) and then filtered. The organic phase was washed with water (2×30 ml), 5% HCl (2×30 ml), water (30 ml), brine (30 ml), respectively, and then was dried over MgSO 4 . The liquid was concentrated to result in a brown oil. Purification was done by flash chromatography with the eluent: 1:3 ethyl acetate:hexane, which gave a white powder (1.800 g.) of the product. 
     Example 1d 
     Formation of Benzyl-DOPA-NHBoc-COOH (FIG.  25 E) 
     The white powder of example 1c (1.000 gm, 2.04 mmol) was dissolved in a solution (10 ml) of 1:1 tetrahydrofuran to methanol, and 1M NaOH solution 5 ml) was added to the above solution. The mixture was stirred at room temperature for 6 hours. The mixture was poured into pH=3 KHSO 4  aqueous solution (30 ml) and then extracted three times with ethyl acetate (10 ml, 10 ml, 10 ml). The combined organic phase was washed with water (30 ml), and brine (30 mol), and dried over MgSO 4 . The liquid was concentrated and afforded a white solid (868 mg) as the product. 
     Example 1e 
     Formation of Benzyl-DOPA-NHBoc-COOCHCH 2 OH (FIG.  25 F) 
     The white powder of Example 1d (200 mg, 0.42 mmol) was dissolved in dichloromethane (DCM) (10 ml), and ethylene glycol (0.11 ml, 1.89 mmol), and 4-(dimethylamino) pyridinium p-toluenesulfonate (DPTS) (81.9 ng, 0.42 mmol), and 1,3-dicyclohexylcarbodiimide (DCC) (1M in dichloromethane) (0.5 ml, 0.5 mmol) was added in a dropwise manner. The solution was stirred at room temperature for 18 hours. The by-product precipitate (dicyclohexyl urea) was filtered and the organic layer was washed with water (2×10 ml), 5% HCl (2×10 ml), water (2×10 ml), saturated NaHCO 3  (2×10 ml), water (1×10 ml), brine (1×10 ml), respectively, and then dried over MgSO 4 . After the solvent was removed in vacuo, flash chromatography was used with the eluents: 1:2 and then 1:1.5 ethyl acetate to hexane mixed solvents, that afforded a colorless oily solid as the product (180 mg.). 
     Example 1f 
     Formation of Benzyl-DOPA-NHBoc-linker (FIG.  25 G) 
     The colorless solid of example 1e (3.910 g., 7.5 mmol) was stirred in pyridine (20 ml). A solution of succinic anhydride (1.125 mg, 11.25 mmol) in pyridine (20 ml) was added to the previous solution. The mixed solution was stirred at room temperature for 18 hours. The solvent was removed in vacuo. The sediment was dissolved in DCM (30 ml) and washed with 5% HCl (20 ml), water (2×30 ml), brine (30 ml), and then dried over MgSO 4 . After the organic solvent was removed in vacuo, flash chromatography was applied for purification with the eluents: first 1:2, and then 1:1 ethyl acetate to hexane mixed solvents, that generated a white solid product (3.120 g.). 
     Example 1g 
     Formation of B no -GO-NHBoc (FIG.  25 H) 
     The white solid product of example 1f (1.163 g., 2.43 mmol) was stirred with ethylene glycol (50 mg, 0.81 mmol), 4-(dimethylamino) pyridinium p-toluenesulfonate (473 mg, 2.43 mmol) and 1,3-dicyclohexylcarbodiimide (1M in dichloromethane) (2.43 ml, 2.43 mmol) in dichloromethane (10 ml) at room temperature for 18 hours. The precipitate (dicyclohexyl urea by-product) was filtered out. The organic layer was washed with water (2×10 ml), 5% HCl (2×10 ml), water (2×10 ml), saturated NaHCO 3  (2×10 ml), water (2×10 ml), and brine (10 mil), respectively, and then dried over MgSO 4 . After the solvent was removed in vacuo, flash chromatography was used to purify the product with the eluent: 1:2 ethyl acetate to hexane mixed solutions, which afforded a colorless solid (836 mg.). 
     Example 1h 
     Formation of —HO-GO-NHBoc (FIG.  25 I) 
     To a solution of the colorless solid of example 1 g (836 tug, 0.85 mmol) in tetrahydrofuran (10 ml), 5% palladiumn on charcoal (100 mg) was added and the mixture was hydrogenated using H 2  under a pressure of 54) bars for 4 hours. The mixture was then filtered and the filtrate was concentrated by removing the solvent in vacuo to give a white powder. Flash chromatography was performed with the eluent: 1:1 ethyl acetate to hexane mixed solvents, which afforded a white solid (392 mg) as the product. 
     Example 1i 
     Formation of BnO-G 1 -NHBoc (FIG.  25 J) 
     The white solid product of example 1h (246 mg, 0.4 mmol) was stirred with the compound from example 1f (1.184 g, 1.9 mmol), 4-(dimethylamino)Pyridinium p-toluenesulfonate (120 mg., 0.4 mmol), and 1,3-dicyclohexylcarbodiimide (1M solution in dichloromethane) (1.9 ml, 1.9 mmol) in dichloromethane (10 ml) at room temperature for 18 hours. The mixture was filtered and the organic layer was washed with 5% HCl (2×15 ml), water (2×15 ml), saturated NaHCO 3  (2×5 ml), water (2×15 ml), and brine (15 ml), respectively, and then dried over MgSO 4 . After the solvent was removed in vacuo-flash chromatography was applied to purify the product with the eluents: 1:2 and then 1:1 ethyl acetate to hexane mixed solvents, which gave a white solid (400 mg). 
     Example 1j 
     Formation of HO-G1-NHBoc (FIG.  25 K) 
     The white solid (505 rag 0.17 mmol) was dissolved in tetrahydrofuran (10 ml), 5% palladium on charcoal (100 mg) was added. The suspension was charged with hydrogen (50) bars and agitated for 6 hr. The mixture was then filtered, and the filtrate was evaporated in vacuo. Purification by a column chromatography, eluent: 1:1 and then 2:1 ethyl acetate to hexane mixed solvent, afforded product as a white solid (354 mg.) 
     Example 1k 
     Formation of Example HOOG1-NH2 (FIG.  24 A) 
     The white solid (180 mg) was stirred in 2 ml of 4M HCl in dioxane at room temperature for 5 minutes. The solvent and the remaining HCl was removed in vacuo and the white sediment was washed with DCM (2×1 ml). After drying, the product was afforded as a colorless powder (139 mg). 
     Similarly. HO-G2-NH 2  and HO-G3-NH 2  can be accessed as shown in  FIGS. 24B and 25C , respectively. 
     a=SOCl 2 , McOH, rm, 18 h;
 
b=Boc 2 O, THF, 1M Na 2 CO 3 , 0° C., 2 h, 90%
 
c=BnBr, K 2 CO 3 , acetone, reflux, 18 h, 79%
 
d=MeOH-THF, 1M NaOH, 6 h, rm, 93%
 
e=4.5 equiv. ethylene glycol, DCC, DPTS, DCM, rm, 6 h, 86%
 
f=succinic anhydride, pyridine, rm, 18 h, 68%
 
g=0.5 eq. ethylene glycol, DCC, DPTS, DCM, rm, 16 h, 78%
 
h=THF, 5% Pd/C, 50 bars H 2 , 4 h, 94%
 
i=DCC, DPTS. DCM, rm, 18 h, 76% G 1 , 72% G 2 , 68% G 3  
 
j=THF, 5% P/C, 50 bars H 2 , 6 h, 92% G 1 , 90% G 2 /G 3 ,
 
k=4N HCI/Dioxane, rm, 3 minutes, 87% G 1 , 86% G 2 , 82% G 3 .
 
     Example 2 
     Synthesis of ACP Dendrimer 
     Using aspirin as the starting drug, an ACP dendrimer drug was prepared by the schematic representation described infra. Abbreviations and acronyms are defined throughout this specification. 
     Step 1 Construction of Building Block and G0 (Core): 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     The synthesis of Generations G 1 , G 2 , and G 3 , follow. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Example 4 
     Preparation of Multiple Drug Dendrimer 
     The following is the preparation of a multiple drug dendrimer provided in a schematic form. Abbreviations and acronyms are defined elsewhere in this specification. 
     I. Drugs Protection 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     II. Pre-Core and Pre-Linker Preparations 
     
       
         
         
             
             
         
       
     
     III. First Drug Coupling 
     
       
         
         
             
             
         
       
     
     IV. Second Drug Coupling 
     
       
         
         
             
             
         
       
     
     V. Third Drug Coupling 
     
       
         
         
             
             
         
       
     
     VI. Fourth Drug Coupling