Method of preparing dendritic drugs

Abstract

Synthetic design of drug-incorporated novel dendrimer structures for quantitatively controlled drug delivery. The dendritic drugs have better control and thus a quantitative drug release can be obtained. There are no prior art dendritic drugs that control release both sequentially and quantitatively like the dendritic drugs disclosed herein. The dendritic drugs are formed by incorporating multiple same type drug units or more than two different drug types into a dendritic cascade structure to form a dendrimer drug.

1 .- 18 . (canceled) 
     
     
         19 . A dendritic drug as claimed in  claim 48  wherein said dendritic drug is prepared from a therapeutically active agent selected from the group consisting essentially of suitably functionalized analgesics, anesthetics, anti-Parkinson's agents, anti-infectives, anti-acne agents, antibiotics, anticholinergics, anticoagulants, anticonvulsants, anti-diabetic agents, anti-dyskinetics, antifibrotic agents, antifibrotics, antifungal agents, antiglaucoma 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 
     
     
         20 . A dendritic drug as claimed in  claim 49  wherein said dendritic drug is prepared from a therapeutically active agent selected from the group consisting essentially of suitably functionalized analgesics, anesthetics, anti-Parkinson's agents, anti-infectives, anti-acne agents, antibiotics, anticholinergics, anticoagulants, anticonvulsants, anti-diabetic agents, anti-dyskinetics, antifibrotic agents, antifibrotics, antifungal agents, antiglaucoma 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 
     
     
         21 . A dendritic drug as claimed in  claim 48  wherein said dendritic drug is prepared from drugs with the required functional groups within their structure, found in classes of drugs selected from the group consisting essentially of 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's agents, antisporatics, antipyretics, antiseptics/disinfectants, antithrombotics, bone resorption inhibitors, calcium regulators, keratolytics, sclerosing agents and ultraviolet screening agents. 
     
     
         22 . A dendritic drug as claimed in  claim 49  wherein aid dendritic drug is prepared from drugs with the required functional groups within their structure, found in classes of drugs selected from the group consisting essentially of 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's agents, antisporatics, antipyretics, antiseptics/disinfectants, antithrombotics, bone resorption inhibitors, calcium regulators, keratolytics, sclerosing agents and ultraviolet screening agents. 
     
     
         23 . A dendritic drug as claimed in  claim 48  wherein said dendritic drug is prepared from anti-bacterial compounds having the required functional groups within their structure selected from the group consisting of 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, and vancomycin. 
     
     
         24 . A dendritic drug as claimed in  claim 49  wherein said dendritic drug is prepared from anti-bacterial compounds having the required functional groups within their structure selected from the group consisting of 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, and vancomycin. 
     
     
         25 . The dendritic drug as claimed in  claim 48  wherein said dendritic drug is prepared from anti-fungal compounds having the required functional groups within their structure selected from the group consisting of amphotericin B, azaserine, candicidins, lucensomycin, natamycin, and nystatin. 
     
     
         26 . The dendritic drug as claimed in  claim 49  wherein said dendritic drug is prepared from anti-fungal compounds having the required functional groups within their structure selected from the group consisting of amphotericin B, azaserine, candicidins, lucensomycin, natamycin, and nystatin. 
     
     
         27 . The dendritic drug as claimed in  claim 48  wherein said dendritic drug is prepared from anti-neoplastic compounds having the required functional groups within their structure selected from the group consisting of 6-diazo-5-oxo-L-norleucine, azaserine, carzinophillin A, denopterin, edatrexate, eflomithine, melphalan, methotrexate, mycophenolic acid, podophyllinic acid 2-ethylhydrizide, pteropterin, streptonigrin, (N-((5-(((1,4-Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl) methylamino)-2-thienyl)carbonyl)-L-glutamic acid), and ubenimex. 
     
     
         28 . The dendritic drug as claimed in  claim 49  wherein said dendritic drug is prepared from anti-neoplastic compounds having the required functional groups within their structure selected from the group consisting of 6-diazo-5-oxo-L-norleucine, azaserine, carzinophillin A, denopterin, edatrexate, eflomithine, melphalan, methotrexate, mycophenolic acid, podophyllinic acid 2-ethylhydrizide, pteropterin, streptonigrin, (N-((5-(((1,4-Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl) methylamino)-2-thienyl)carbonyl)-L-glutamic acid), and ubenimex. 
     
     
         29 . The dendritic drug as claimed in  claim 48  wherein aid dendritic drug is prepared from anti-thrombics compounds having the required functional groups within their structure selected from the group consisting of argatroban, iloprost, lamifiban, taprostene, and tirofiban. 
     
     
         30 . The dendritic drug as claimed in  claim 49  wherein said dendritic drug is prepared from anti-thrombics compounds having the required functional groups within their structure selected from the group consisting of argatroban, iloprost, lamifiban, taprostene, and tirofiban. 
     
     
         31 . The dendritic drug as claimed in  claim 48  wherein said dendritic drug is prepared from immunosuppressive compounds having the required functional groups within their structure selected from the group consisting of bucillamine, mycophenolic acid, proceodazole, romurtide, and ubenimex. 
     
     
         32 . The dendritic drug as claimed in  claim 49  wherein said dendritic drug is prepared from immunosuppressive compounds having the required functional groups within their structure selected from the group consisting of bucillamine, mycophenolic acid, proceodazole, romurtide, and ubenimex. 
     
     
         33 . The dendritic drug as claimed in  claim 48  wherein the said dendritic drug is prepared from compounds having the required functional groups within their structure selected from the group consisting of 3-amino-4-hydroxybutyric acid, aceclofenac, almino-profen, 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, and tolfenamic acid. 
     
     
         34 . The dendritic drug as claimed in  claim 49  wherein said dendritic drug is prepared from compounds having the required functional groups within their structure selected from the group consisting of 3-amino-4-hydroxybutyric acid, aceclofenac, almino-profen, 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, and tolfenamic acid. 
     
     
         35 . A dendritic drug as claimed in  claim 48  that will release compounds selected from the group consisting of
 (i) biologically active compounds, and 
 (ii) drugs, 
 
       when decomposed by the biological degenerative action of a mammalian body. 
     
     
         36 . A dendritic drug as claimed in  claim 48  that will release compounds selected from the group consisting of
 (i) biologically active compounds, and 
 (ii) drugs, 
 
       when decomposed by the biological degenerative action of a mammalian body. 
     
     
         37 . A pharmaceutical composition comprising a dendritic drug of  claim 48 . 
     
     
         38 . A pharmaceutical composition comprising a dendritic drug of  claim 49 . 
     
     
         39 . A pharmaceutical composition comprising a dendritic drug of  claim 48  in combination with a pharmaceutical carrier. 
     
     
         40 . A pharmaceutical composition comprising a dendritic drug of  claim 49  in combination with a pharmaceutical carrier. 
     
     
         41 . A therapeutic method of treating a disease in an animal comprising administering to an animal an effective amount of a dendritic drug of  claim 48 . 
     
     
         42 . A therapeutic method of treating a disease in an animal comprising administering to an animal an effective amount of a dendritic drug of  claim 49 . 
     
     
         43 . A method of delivering a biologically active compound to a host comprising administering to the host a dendritic drug of  claim 48 . 
     
     
         44 . A method of delivering a biologically active compound to a host comprising administering to the host a dendritic drug of  claim 49 . 
     
     
         45 . A dendritic drug, said dendritic drug having a dendritic cascade structure wherein bioactive material is incorporated into the chemical structure of the dendritic cascade structure, said dendritic cascade structure having 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. 
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . A dendritic drug produced by 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 structure;   (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);   (XI) 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.   
     
     
         49 . A dendritic drug as claimed in  claim 48  wherein a lower generation dendritic drug is iteratively treated using steps (X) and (XI) of said method to form a higher generation dendritic drug. 
     
     
         50 . A dendritic drug wherein the dendritic drug has more than one type of drug in the structure, prepared by the method comprising:
 (I) providing at least two therapeutically active multifunctional drugs, said drugs having at least one reactive group capable of providing a linker site, said drugs having at least one functional group capable of providing a starting point for the preparation of a dendritic structure;   (II) chemically protecting any reactive group in the drugs that are 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);   (XI) 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.