Convalent conjugates of biologically-active compounds with amino acids and amino acid derivatives for targeting to physiologically-protected sites

Abstract

This invention herein describes a method of facilitating the entry of drugs into cells and tissues at physiologically protected sites at pharmacokinetically useful levels and also a method of targeting drugs to physiologically protected sites in vivo. Also provided are drug conjugates with an amino acid or derivative thereof for facilitating such targeted drug delivery. The conjugates and methods of this invention provide an advance over other drug targeting methods known in the prior art, because the invention provides drug concentrations in such physiologically protected sites that can reach therapeutically-effective levels after administration of systemic levels much lower than are currently administered to achieve a therapeutic dose. This technology is appropriate for use with psychotropic, neurotropic, neurological, antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drugs, agents and conjugates, for rapid and efficient introduction of such agents across, e.g., the blood-brain barrier. Further, the invention provides means for retention and prolonged enzymatic release of such drugs, agents and conjugates comprising the conjugates of the invention, in the brain and central nervous system and other physiologically-protected sites.

1 . A method for treating a pathological condition or disease state in cells, tissues or organs in a human or animal, the method comprising the step of administering to the animal a pharmaceutical composition comprising a psychotropic, neurotropic or neurological drug, or an antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drug, an amino acid or amino acid derivative specifically transported into a physiologically-protected site, two linker functional groups and a spacer, wherein the spacer has a first end and a second end and wherein the amino acid or amino acid derivative is attached to the first end of the spacer through a first linker functional group and the drug is attached to the second end of the spacer through a second linker functional group, in an acceptable carrier or formulation and in an amount sufficient to alleviate the pathological condition or disease state in the animal.  
   
   
       2 . A method of  claim 1 , wherein the pathological condition or disease state is present in a physiologically restricted or protected site in the human or animal.  
   
   
       3 . A method of  claim 1 , wherein the pharmaceutical composition comprises L-dopa, hydroxytryptamine, amantadine, benztropine, bromocryptine, diphenhydramine, levadopa, pergolid, trihexphenidyl, ethosuximide, valproic acid, carbamazepine, 10-hydroxycarbamazepine, 11-hydroxycarbamazepine, primidone, gabapentin, lamotrigine, felbamate, paramethadione, trimethadione, phenothiazine, thioxantheme, clozapine, haldoperidol, loxapine, a benzodiazapene antidepressants of the norepinephrine reuptake inhibitor type, a monoamine oxidase inhibitor, carotene, glutathione, N-acetylcysteine, methotrexate, azidothymidine, dideoxyinosine, dideoxycytosine, acyclovir, or gancyclovir.  
   
   
       4 . A method for treating a pathological condition or disease state in cells, tissues or organs in a human or animal, the method comprising administering to the animal a pharmaceutical composition comprising a psychotropic, neurotropic or neurological drug, or an antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drug, having a first functional linker group, and an amino acid or amino acid derivative specifically transported into a physiologically-protected site, having a second functional linker group, wherein the drug is covalently linked to the amino acid or amino acid derivative by a chemical bond between the first and second functional linker groups, in an acceptable carrier or formulation and in an amount sufficient to alleviate the pathological condition or disease state in the animal.  
   
   
       5 . A method of  claim 4 , wherein the pathological condition or disease state is present in a physiologically restricted or protected site in the human or animal.  
   
   
       6 . A method of  claim 4 , wherein the pharmaceutical composition comprises L-dopa, hydroxytryptamine, amantadine, benztropine, bromocryptine, diphenhydramine, levadopa, pergolid, trihexphenidyl, ethosuximide, valproic acid, carbamazepine, 10-hydroxycarbamazepine, 11-hydroxycarbamazepine, primidone, gabapentin, lamotrigine, felbamate, paramethadione, trimethadione, phenothiazine, thioxantheme, clozapine, haldoperidol, loxapine, a benzodiazapene antidepressants of the norepinephrine reuptake inhibitor type, a monoamine oxidase inhibitor, carotene, glutathione, N-acetylcysteine, methotrexate, azidothymidine, dideoxyinosine, dideoxycytosine, acyclovir, or gancyclovir.  
   
   
       7 . The method of claims  1  or  3 , wherein the disease state is a neurological disease.  
   
   
       8 . The method according to  claim 7  wherein the neurological disease is Alzheimer's disease, Parkinson's disease, epilepsy, seizure disorder, migraine or Lennox-Gastaut syndrome.  
   
   
       9 . The method of claims  1  or  3 , wherein the disease state is a neuropathy.  
   
   
       10 . The method of  claim 9  wherein the neuropathy is trigeminal neuralgia, diabetic neuropathy or shingles.  
   
   
       11 . The method of claims  1  or  3 , wherein the disease state is a psychological disorder.  
   
   
       12 . The method of  claim 11  wherein the psychological disorder is bipolar disorder, explosive aggression, depression or agitation associated with elderly dementia.  
   
   
       13 . The method of claims  1  or  3 , wherein the disease state is a microbial infection.  
   
   
       14 . The method of  claim 13 , wherein the disease is AIDS, encephalitis, meningitis, or syphilis.  
   
   
       15 . The method of claims  1 ,  2 ,  3 ,  4 , or  5 , wherein the disease state is a malignant or benign tumor or proliferative disease.  
   
   
       16 . The method of  claim 15 , wherein the disease is neuroblastoma, glioblastoma or astrocytoma.  
   
   
       17 . The method of claims  1  or  3 , wherein the disease state is present in testes.  
   
   
       18 . The method of claims  1  or  3 , wherein the disease state is present in spleen.  
   
   
       19 . The method of claims  1  or  3 , wherein the disease state is present in an eye.  
   
   
       20 . The method of claims  1  or  3 , wherein the disease state is present in brain, central nervous system or other neurological tissue.