(12) Patent Application Publication (10) Pub. No.: US 2005/0124701 A1 Went Et Al

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US 2005O124701A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0124701 A1 Went et al. (43) Pub. Date: Jun. 9, 2005

(54) METHOD OF TARGETING ATHERAPEUTIC (22) Filed: Jun. 14, 2004 AGENT Related U.S. Application Data (76) Inventors: Gregory T. Went, Mill Valley, CA (US); Jan WF Wasley, Guilford, CT (60) Provisional application No. 60/477,511, filed on Jun. (US); Stuart A. Lipton, Rancho Santa 11, 2003. Fe, CA (US); James W. Larrick, Woodside, CA (US); Laurence R. Publication Classification Meyerson, San Rafael, CA (US) 7 (51) Int. Cl." ...... A61K 31/13 Correspondence Address: (52) U.S. Cl...... 514/662 NoEcoHN, FERRIS, GLOWSKY (57) ABSTRACT ONE FINANCIAL CENTER Disclosed are conjugates in which an aminoadamantane BOSTON, MA 02111 (US) derivative, Such as amantadine, memantine, or rimantadine is linked to a therapeutic agent. The conjugate can then be (21) Appl. No.: 10/868,044 used to target the therapeutic agent to an injured neuron. Patent Application Publication Jun. 9, 2005 Sheet 1 of 5 US 2005/0124701 A1

Figure 1

e CH HNV a N C

Reaction Scheme O NH2 S-VA-N-OH NH-Ca-ra-(CH2)n-no O e Inert Solvent and the acid chloride of Et3N or pyridine get molecule acid O-20 C in inert Solvent Patent Application Publication Jun. 9, 2005 Sheet 2 of 5 US 2005/0124701 A1

Figure 2 O O HN-CaO ul NH-Ca1a1 N1 H t N C C HNW

Reaction Scheme

NH 2 CIOC -N-NMNHCOCFa --> HN1 8-N-N-N-NHCOCFs Et3N/net Solvent O-20 C

Water 30C

Q -8 8-MNHN BNN1)1Cl O HN1 2V H HN löN-N-N-MN2

Et3Nfnert Sovent O-2OC Using acid chloride of target acid Patent Application Publication Jun. 9, 2005 Sheet 3 of 5 US 2005/0124701 A1

Figure 3

NH-Ca-1--1N1- te H C HN-4

NH2

Reaction Scheme

NH2 fuming nitric acid NH2 OH /N-N-N-OH

–es al-e- Et3Ninet Solvent NO2 O-20 C NO2

HN-oc^1\1\\ O HN -CO N C

NO2 Et3N/net Solvent

te C HN M

NO2 Catalytic Hydrogenation or sodium dithionite

O O HN e N C HN-oc^1N1N/ e C HNN/ Patent Application Publication Jun. 9, 2005 Sheet 4 of 5 US 2005/0124701 A1

Figure 4

O H N 8, C O- 8-->O t N C HN-4

NH2

Reaction Scheme

OH Pthalic anhydride OH 1a/N1,N-OH linert Solvent cloc1a/N1\\OH O-C 30-1OOC s-e- C O

-e- w NH2 N Pyridine OC CO Inert Solvent 0-10 C N

O O inert Solvent O-C H O e C HN/

Y N X OC CO

Hydrazine Hydrate 20-80 C

O- Val1.n-1-N-1a8 O e H C

NH2 Patent Application Publication Jun. 9, 2005 Sheet 5 of 5 US 2005/0124701 A1

Figure 5

Reaction Scheme NH2 clos1N/N/N/Yo ' s1\/N/N/N OH 40. armenial-al-e-Et3N/Inert Solvent O-10 C Mesyl chloride Inert Solvent 0-20 C

US 2005/O124701 A1 Jun. 9, 2005

METHOD OF TARGETING ATHERAPEUTIC is administered not conjugated to the aminoadamantane AGENT derivative or at least 1.5 fold that of the Tmax of the therapeutic agent administered when not conjugated to the RELATED APPLICATIONS aminoadamantane derivative. 0001. This application claims priority to U.S. Ser. No. 0009. In some embodiments, the Tmax is determined by 60/477,511, filed Jun. 11, 2003. The contents of this appli determining the levels in Serum of a Subject. cation are incorporated herein by reference in their entirety. 0010. In some embodiments, levels of the conjugate are FIELD OF THE INVENTION determined by measuring the Cmax of the conjugate. In Some embodiments, the Cmax is determined by determining 0002 The invention relates generally to methods of tar the levels in the brain- or cerebrospinal fluid of a subject. geting therapeutic agents to neurons. 0011. In various embodiments, the therapeutic agent BACKGROUND OF THE INVENTION delivered as part of the conjugate reaches Cmax in brain in 0.003 Acute and chronic neurological and neuropsychi no more than about 0.25, 0.5, or 1, 2, 4, 6, 8, 16, or 24 hours atric diseases are among the leading causes of death, dis after administration of the conjugate, e.g., the conjugate ability, and economic expense in the World. One of the main reaches Cmax in the brain in no more than about 1 hour after challenges in developing treatments for these diseases is the administration of the conjugate. difficulty in getting therapeutic agents across the blood-brain 0012. In various embodiments, at the time Tmax, the barrier. ratio of the brain concentration Cmax to the corresponding 0004 Certain uncompetitive NMDAR antagonists, such concentration in serum is 1.5-fold, 1.75-fold, 2-fold, 3-fold, as memantine, readily cross the blood-brain barrier, achiev 4-fold, or more of that attained by the unconjugated thera ing nearly identical concentrations in the extra-cellulary peutic agent, e.g., in Some embodiments the ratio of the brain fluid Surrounding brain tissue and Systemic Serum. In addi concentration Cmax to the corresponding concentration in tion, these antagonists are believed to work by blocking the Serum at that time is 4-fold that attained by the unconjugated excessive activation of N-methyl-D-aspartate-type therapeutic agent or the ratio of the brain concentration glutamate receptors (NMDAR) in the brain, there by reduc Cmax to the corresponding concentration in Serum at that ing excessive Ca" influx through the receptor's associated time is 4-fold that attained by the unconjugated therapeutic ion channel. Glutamate excitotoxicity has been implicated in agent (when not conjugated to the aminoadamantane deriva neuronal injury and death due to either necrosis or apoptosis. tive). 0013) In various embodiments, the T'/3 (half life) in the SUMMARY OF THE INVENTION brain of the conjugated therapeutic agent is at least 2-fold 0005 The invention is based in part on the discovery that that of the T/3 in the brain of the unconjugated therapeutic memantine and related aminoadamantanes, which are agent, e.g., the T/3 of the conjugated therapeutic agent is at uncompetitive inhibitors of NMDAR that block the receptor least 4-fold that of the unconjugated therapeutic agent or at in excitotoxic conditions characteristic of damaged neurons, least 8-fold of the T/3 of the unconjugated therapeutic agent. can be used to Selectively target therapeutic agents to the 0014. In some embodiments, the Cmax is determined by brain, and more specifically to excitotoxic neurons. Accord determining the levels in Serum of a Subject. ingly, the invention provides conjugates in which an ami noadamantane derivative, Such as amantadine, memantine, 0015. In some embodiments, the therapeutic agent is a or rimantadine is linked to a therapeutic agent. The conju neuroprotective agent. gate can then be used to target the therapeutic agent to an 0016. In some embodiments, the therapeutic agent is for injured neuron. treating a disorder associated with excessive NMDAR activ 0006. In one aspect, the invention features a method of ity. targeting a therapeutic agent to the brain by administering to 0017. In some embodiments, the therapeutic agent is a Subject in need thereof a conjugate that includes an non-nitrosylated or is a non-NO-generating therapeutic aminoadamantane derivative linked to the therapeutic agent. agent. In Some embodiments, the method further includes identi fying a therapeutic agent in which targeting to the brain of 0018. In some embodiments, the therapeutic agent is for a Subject is desired. treating a neurological disorder (e.g., a neurological disease, condition or Syndrome). The neurological disorder is, e.g., 0007. In some embodiments, the therapeutic agent deliv Stroke, other forms of hypoxic injury, haemorrhagic brain ered in the conjugate reaches a Tmax at from between about injury, traumatic brain injury, Spinal cord injury, familial 0.1 hours to about 5 hours after administration to the subject, Alzheimer's disease (FAD), Parkinson's disease, ALS e.g., the Tmax at from about 0.25 hours to about 2 hours, or (amyotrophic lateral Sclerosis), neuroprotection in epilepsy, about 0.5 hours to about 1 hour. a metabolic disorder, hypoglycemia, encephalopathy, 0008. In some embodiments, the Tmax is determined by tumors and malignancies (brain, Spinal cord, and Systemic), determining the levels in the brain or cerebrospinal fluid of cerebellar degenerations, and ataxias, migraine, Vertigo, a Subject. In Some embodiments, the Tmax of the therapeutic tinnitus and cochlear disorders, bowel Syndromes, periph agent in the brain is at least 4-fold that of the Tmax of the eral neuropathy, metabolic bone disease and Osteoporosis, therapeutic agent administered when not conjugated to the obesity, and diabetes and pre-diabetic Syndromes, glaucoma, aminoadamantane derivative, e.g., the Tmax can be at least HIV associated dementia neuropathic pain, Huntington's 2-fold that of the Tmax obtained when the therapeutic agent disease or other dementing disease, anxiety, depression or US 2005/O124701 A1 Jun. 9, 2005 withdrawal from drug (or opiate) addiction or drug (or or equivalent to those described herein can be used in the opiate) dependency, minimal cognitive impairment (MCI), practice or testing of the invention, Suitable methods and Down's Syndrome, normal cognitive Senescence, meningi materials are described below. All publications, patent appli tis, Sepsis and Septic encephalopathy, CNS Vasculitis, cations, patents, and other references mentioned herein are Schizophrenia, alcoholic diseases, multiple Sclerosis or other incorporated by reference in their entirety. In the case of demyelinating disease, leukodystrophies and X-ADL, child conflict, the present Specification, including definitions, will birth and Surgical anesthesia. Treatment also provides neu control. In addition, the materials, methods, and examples roprotection from cerebrovascular risk factors and post are illustrative only and not intended to be limiting. ischemic neurovascular Syndromes. 0030. Other features and advantages of the invention will 0019. In some embodiments, the therapeutic agent is for be apparent from the following detailed description and treating hyperhomocysteinemia contributing to claims. atheroslcerotic and other degenerative disease processes. 0020. In some embodiments, the therapeutic agent is for BRIEF DESCRIPTION OF THE DRAWINGS treating head trauma or Spinal cord injury. 0031 FIG. 1 is an example of a synthesis for a conjugate 0021. In some embodiments, the therapeutic agent is for of an aminoadamantane derivative and a therapeutic agent. treating demyelinating disease, which can include multiple 0032 FIG. 2 is an example of a synthesis for a conjugate Sclerosis. of an aminoadamantane derivative and a therapeutic agent. 0022. In some embodiments, the therapeutic agent is a 0033 FIG. 3 is an example of a synthesis for a conjugate caspase inhibitor, a Superoxide dismutase mimetic, calcium of an aminoadamantane derivative and a therapeutic agent. chelator, MAPK antagonist, an ERK-MAPK antagonist, a p38 MAPK inhibitor, a cytochrome C chelating antibody, 0034 FIG. 4 is an example of a synthesis for a conjugate APAF-1 inhibitor, AIF (apoptosis-inducing factor caspase of an aminoadamantane derivative and a therapeutic agent. independent) inhibitor/Apoptosis inhibitor, gamma vinyl 0035 FIG. 5 is an example of a synthesis for a conjugate GABA (GVG, vigabatrin), PARP inhibitor, an NOS inhibi of an aminoadamantane derivative and a therapeutic agent. tor, a dopamine agonist, a dopamine analog, an immuno SuppreSSant, an anti-inflammatory, an anti-cancer agent, a DETAILED DESCRIPTION OF THE Statin, an anti-epilepsy agent, a cannabinoid, an anti-viral, a nootropic (cognitive enhancer), an M-2 agonist, an obesity INVENTION treatment agent, or a non-Steroidal anti-inflammatory drug 0036) The invention provides compositions and methods (NSAID). useful for acute, chronic and/or prophylactic treatment of 0023. In some embodiments, the adamantine derivative is neurologic and neurodegenerative diseases. The composi neuroprotective. Preferably, the aminoadamantane deriva tions and methods are also useful for attenuating acute or tive binds to an N-methyl-D-aspartate (NMDA) receptor chronic neuronal damage in neurological disease (“neuro expressed on an injured neuron. protection”), and prophylaxis of neurological diseases. 0037 For example, the compositions and methods are 0024 Examples of suitable aminoadamantane deriva useful for treating neurological diseases that involve exces tives include, e.g., memantine, rimantadine (1-(1-aminoet sive stimulation of the NMDA receptor, hypofunction of the hyl)adamantane), and amantadine (1-aminoadamantane) NMDA receptor, up- or down regulation of the NMDA 0.025 In some embodiments, the therapeutic agent is receptor, or abnormal Subunit Structure or function of the attached to the aminoadamantane derivative in the conjugate NMDA receptor. at the 1-(bridgehead) position or the 2-position. 0038 Neuroprotective efficiency is achieved by using the 0026. In some embodiments the therapeutic agent is aminoadamantane derivative to specifically deliver the attached to the aminoadamantane derivative via a metaboli therapeutic agent (e.g., a neuroprotective agent) to the brain cally cleavable linkage. or injured neuron. The aminoadamantane derivative in the 0027. In another aspect, the invention provides a method conjugates allows for the therapeutic agent to be delivered in of targeting a therapeutic agent to an injured neuron of a a lower systemic or topical dose than that which would be Subject by administering to a Subject in need thereof a required if the therapeutic agent were administered alone. conjugate that includes an aminoadamantane derivative The lower dose also minimizes the side effects and/or toxic linked to the therapeutic agent. In Some embodiments, the effects that may be observed when the therapeutic agent is injured neuron is in the brain of the subject. The injured administered alone and thus is more likely to interact neuron can be, e.g., in the central nervous System (CNS). undesirably with healthy neurons and other healthy tissues. 0039 The conjugates described herein thus provide a 0028. In a still further aspect, the invention provides a way to achieve effective drug concentrations at physiologi method of lowering the neurotoxicity of a therapeutic agent cally protected Sites (e.g., in the brain) and a way to reach in a Subject by administering to the Subject a conjugate that therapeutically-effective levels after Systemic administration includes an aminoadamantane derivative linked to Said of much lower levels than are currently administered to therapeutic agent. achieve a therapeutic dose of the conjugated therapeutic 0029. Unless otherwise defined, all technical and scien agent. Administration of the therapeutic agent as part of the tific terms used herein have the same meaning as commonly conjugate additionally results in results in decreased Sys understood by one of ordinary skill in the art to which this temic metabolism, degradation and toxicity, reduced Sys invention belongs. Although methods and materials similar temic adverse drug interactions, and generally reduced side US 2005/O124701 A1 Jun. 9, 2005

effects. These biological effects can also be obtained with exert unknown or multiple effects, for example, piracetam, Simplified dosage Schedules, particularly for drugs with levetiracetam, aniracetam, nefiracetam or topiramate. short systemic half-lives. 0045 Suitable nootropic agents include sedrafinil, cen 0040. Therapeutic Agents trophenoxine, deprenyl, dehydroepiandrosterone (DHEA), 0041. Therapeutic agents that are linked to the aminoada dimethylaminoethanol (DMAE), Gingko Biloba, piracetam, mantane compounds (e.g., amantadine, memantine or pyroglutamate, Vinpocetine, and Xanthinol nicotinate. rimantadine) to form the conjugates of the invention include, e.g., anticonvulsive agents, antiparkinsonian drugs, caspase 0046. Other therapeutic agents include NSAIDs such as inhibitors, Superoxide dismutase mimetics, calcium chela diclofenac, piroxicam (Feldene), and indomethacin, tors, calcium channel blockers, gamma-aminobutyric acid acetaminophen, ibuprofen, naproxen and ketoprofen, (GABA) receptor agonists, antagonists, and uptake inhibi including nitrosylated analogs thereof; COX-2 (cyclooxy tors and enhancers, p38 mitogen-activated protein kinase genase) inhibitors, including rofecoxib (VIOXXOR, or 4-4- (MAPK) antagonists, ERK-MAPKantagonists, cytochrome (methylsulfonyl)phenyl)-3-phenyl-2(5H)-furanone), cele C chelating antibodies, APAF-1 (apoptotic protease activat ing factor-1) inhibitors, AIFs (apoptosis inhibiting factors), coxib (CELEBREXCR, or 4-5-(4-methylphenyl)-3- PARP (poly (ADP-ribose) polymerase) inhibitors, anti-epi (trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide), leptic agents, immunosuppreSSants, anti-inflammatory and valdecoxib (BEXTRACE), or 4-(5-methyl-3-phenyl-4- agents, non-steroidal anti-inflammatory drugs (NSAIDs), isoxazolyl)benzenesulfonamide), and statins such as lovas anti-cancer agents, Statins, cannabinoids, anti-Virals, noot tatin, Simvastatin, pravastatin, fluvastatin, and atorvastatin; ropic (cognitive enhancer) agents, alkaloids, catecholamines and NOS inhibitors include arginine and citrulline analogs including dopamine analogues and derivatives, muscarinic Such as L-Thiocitrulline, S-alkyl-L-thiocitrullines (e.g., receptor agonists and antagonists, cholinergic receptor ago S-Methyl-L-thiocitrulline dihydrochloride), NG-Nitro-L- nists and antagonists, obesity treatment agents, and NOS arginine methyl ester (L-NAME), 7-Nitroindazole monoso (nitric oxide Synthetase) inhibitors, phenothiazines, thiox anthemes and related compounds, clozapine, haldoperidol, dium salt (7-NINA), 7-Nitroindazole and related substituted loxapine, benzodiazapene antidepressants of the norepi indazoles, NG-Monomethyl-L-arginine acetate (L-NMMA), nephrine reuptake inhibitor type; monoamine oxidase NG-N-nitro-L-arginine (L-NNA), 1-(2-Trifluoromethylphe inhibitors; antidepressants and antimanic agents, antioxi nyl) imidazole (TRIM), L-NIO (an L-ornithine analog dants and other compounds that mitigate the effects of which has an iminoethyl group instead of an amine group), reactive oxygen species (for the treatment of Alzheimer's L-NIL (an L-lysine analog which as an iminoethyl group disease, Parkinson's disease, or other neurodegenerative instead of an amine group), Diphenyleneiodonium chloride, conditions Such as ataxia telangiectasia and amyelolatero 3-Br-7-Nitroindazole, isothiourea derivatives (such as sclerosis (ALS)). S-Methyl-ITU, S-Ethyl-ITU, S-Isopropyl-ITU, and S-Ami 0042. In some embodiments, the therapeutic agent is noethyl-ITU), 2-Iminopiperidine, and DHAP. non-nitrosylated or is a non NO-generating therapeutic agent. 0047 The therapeutic agent in the conjugates of the invention can additionally include an agonist of a muscarinic 0.043 Dopamine agonists suitable for use in the conju receptor. Such agonists include Alvameline, Arecoline, gates include, e.g., the aminotetralins, treatments for damage caused by Stroke include conjugates of immunosuppressants Cevimeline, PD-151832, Milameline, CI-979A, RU35926, such as tacrolimus (FK-506); treatments for brain inflam Sabcomeline, SB 202026, SCH-217443, SDZ-210-086, SR mation include conjugates of dexamethasone; treatments for 46559A, Talsaclidine, WAL 2014-FU, Tazomeline, brain cancer include conjugates of methotrexate, Vinca alka Xanomeline, and YM 796. loids, carmustine, cisplatin, nitroSourea, hydroxyurea, and 0048. Some representative examples of therapeutic procarbazine, treatments for brain inflammation Secondary to beta amyloid plaque formation include conjugates of agents include the following (* indicates a potential site of Statins, neuroprotectant conjugates include cannibinoids conjugation via an appropriate linker): the caspase inhibitor (which increase appetite and reduce agitation in a Subject; CGP82630 (IDN-7866) from IDUN/Novartis: conjugates useful for treating viral encephalitis include acyclovir, conjugates useful for treating obesity include CCK fragments, conjugates useful for treating ALS include riluzole, and conjugates useful for treating neuroleptic maig nant Syndrome include methylprednisolone, conjugates use ful for treating Schizophrenia include dopamine antagonists, including those agents which interact with the D1 or D5 receptor Subtypes. 0044) Suitable anti-epileptic agents that can be used in the conjugates include, e.g. Sodium channel inhibitors, for example, phenytoin, carbamazepine, Oxcarbazepine; GABA receptor modulators, for example, phenobarbital, tiagabine, vigabatrin (Y-vinyl GABA, a GABA transaminase inhibitor), gabapentin, agents that reduce calcium currents, T currents, for example, ethoSuccimide and Zonisamide, and those that US 2005/O124701 A1 Jun. 9, 2005

0049 the superoxide dismutase stimulator SC 55858 0053 the apoptosis inhibitor VX-799 from Vertex: from Pharmacia

r N ~ Mn2+ CO h oc1 O* N N V HN s CO N

N N N18 n 8 l O \ /

0050 the p38 MAP kinase inhibitor from Bayer: 0054 the PARP1 inhibitor FR 247304, from Fujisawa:

F; Cl, g C YN N

N1.-- N

0051 the calcium chelator DP-b-99 from D-Pharm, Ltd.: 0.055 the NO Synthase inhibitor (Schering AG): ~~~~ OC O*

N CO: ls CO C N1 1NO 1N1 r N 2 N*;

0056 the tricyclic antidepressant MK-801 from Sigma:

0.052 the ERK-MAP kinase inhibitor CEP 1347 from Cephalon, Inc: s

0057 the anti-epileptic agent vigabatrin: US 2005/O124701 A1 Jun. 9, 2005

0.058 the anti-epileptic agent piracetam: 0065 Preferably, the aminoadamantane derivative itself has desirable therapeutic properties, e.g., the aminoadaman tane derivative demonstrates anticonvulsant, neuroprotec tive properties and/or dopaminergic effects. 0066. In some embodiments, the aminoadamantane OoN derivative quickly achieves maximal CNS concentrations within hours, and lingers for 24-72 hours in the CNS. 0067. One Suitable aminoadamantane derivative that can be present in the conjugate is memantine (1-amino-3,5- dimethyladamantane of the adamantane class). A preferred adamantine derivative has no active metabolites that possess 0059 the anti-epileptic agent levetiracetam: NMDA antagonizing properties. Other preferred aminoada mantane derivatives that can be used include those that have been approved for therapeutic use in humans, e.g., riman tadine (1-(1-aminoethyl)adamantane), and Amantadine CO M (1-aminoadamantane). N 0068 Linking Aminoadamantane Derivatives to Thera peutic Agents 0069. The therapeutic agent can be linked to the ami r N* noadamantane derivative at any Suitable position on the admantane derivative. The aminoadamantane derivative is optionally attached via a linker. 0060 the anti-epileptic agent nefiracetem: 0070 The linkage can be metabolically stable (i.e., the therapeutic agent remains attached to the aminoadamantane compound) or metabolically or physiologically labile, i.e., unstable, wherein the therapeutic agent is released from the aminoadamantane compound. 0071. A linker that is labile under certain conditions can be selected (e.g., at a certain pH)). Metabolically cleavable linkages are not equally labile or 'cleavable, particularly in terms of their rates of cleavage. The ease of metabolic cleavage has the following rank order: -COOR-CONH2-CH=N>SONH>CHN, i.e., the ester is the most readily cleaved and the alkylamine is the most Stable. Even in the case of the esters, the rate of cleavage can be controlled by further substitution on the alpha (adjacent) 0061 and the anti-epileptic agent topiramate: carbon atom. In general, a more extensive amount of Sub Stitution makes cleavage more difficult, i.e., makes for a

more Stable linkage. 0072 For example, the type of linker used in the conju gate to attach the therapeutic agent can facilitate hydrolytic release of the therapeutic agent at an intracellular Site. In other embodiments, the type of linker used in the conjugate to attach the therapeutic agent facilitates the enzymatic release of the therapeutic agent at a target Site. In Some embodiments, the linker functional group is hydrolyzed by an enzymatic activity found in brain tissue, including neu ronal, glial and other brain cell types, Such as an esterase, including an esterase having a differential expression and 0062). Other therapeutic agents include serofendic acid, activity profile in the appropriate target cell type. In addi PBAS ((5-pentafluorobenzyl)aminosalicylic acid), cannib tional embodiments, specific release of the therapeutic agent inoids, Such as CB-1 antagonists (Sanofi), and CB-2 agonists is achieved by enzymatic or chemical release of the thera peutic agent by extracellular cleavage of a cleavable linker (Mak Scientific), and anadamide. moiety via an enzymatic activity Specific for brain tissue, 0.063 Aminoadamantane Derivatives with resulting Specific uptake of the released psychotropic, neurotropic or neurological agent by the appropriate cell in 0.064 Preferably, the aminoadamantane derivative is eas ily measured in Subject's body, e.g., by measuring Serum Said tissue. levels of the aminoadamantane derivative available. The 0073. In some embodiments, each of the first and second aminoadamantane derivative is in addition preferably well functional linker groups are those which react with a tolerated in the Subject and has minimal Side effects. hydroxyl group, a primary or Secondary amino group, a US 2005/O124701 A1 Jun. 9, 2005 phosphate group or Substituted derivatives thereof, or a carboxylic acid group on the therapeutic agent or aminoada mantane derivative. oc1 No.1NCO oc1 No.1N NH 0.074. When the aminoadamantane derivative includes a primary, bridgehead amine, or the aminoadamantane com 1N N1 Nco oc1 No.1N NH pound (amantadine, memantine or rimantadine), the ami noadamantane derivative can be converted to the hydroxyl oc1Ns 1Yo os1 NCH1N NH or diamino-derivative, which may then conjugated to the therapeutic agent via a linker: oc1Ns.1No oc1 No.1N SO

NH 2 NH2 NH2 oc1\s1so oc1Not 1 No OC 1)N1)- o1 No.1 No He- O O s 'N-1N, 1-0 amantadine O* NH* 0077. Other commercially available Suitable linkers include the following:

NH2 NH2 HOC COH HOC s COH 2. -- O (CH2) memantine O* Hoc1N1 N1 Noot n = 0-5 EtOC 1N1\ ~ COH HOC 1N1S 1S-1 CO2H HOC N-1Ns 1ns 1N1 CO2H Hoc1N1 O N-1 no.1 n-1 COH2 HOC 1N1 (CH2)2)n N-1 NH'''2 NH2 NH2 NH2 n = 0-4

CIOS (CH2)5 1 1N, 1N O Her O O HOC (CH2)3 OH n = 0-4 amantadine O* NH* o1N1 O N1 No 0075. In some embodiments, the original, bridgehead "N-1-1- 'N1\o amino group is conjugated to the linker. 0.076 Cleavable linkers include those that form an ester 0078. The terminal carboxyl functionalities of the linkers (COOR), amide (CONHR), sulfonamide (NHSO), sul fonate (SOR), or ether (ROR) with the corresponding can be part of an acid chloride, ROC(O)Cl., (or reactive functionality on the aminoadamantane and on the therapeu equivalent), which form a carbamate, ROC(O)NR, when tic agent. In Some examples, the linker is an alkyl linker, in reacted with an amine, the SO reactants are Sulfonyl chlo others, the linker is a heteroalkyl linker, in others two rides, SOCl, compounds (or reactive equivalent), which adjacent atoms in the linker are joined together to form a form a Sulfonamide when reacted with an amine. Amines cycloalkyl, heterocyclyl, aryl, or heteroaryl group. Some and ethers are formed from the reaction of a compound linkers include the following, where n is 0-7: having an active leaving group: US 2005/O124701 A1 Jun. 9, 2005

-continued ROH or RNH -es 1n-1 N-1N1 CO 1N-N-1N-' O ON 1- N-1- 0079 where Y is I, Br, mesyl, tosyl, etc and X is CH, O, S, NH, NR, SO, SO. 0081. Thus, the aniracetam used for conjugation to an 0080. It may be necessary to modify a therapeutic agent aminoadamantane is represented as: So that it is reactive with a linker functional group to form a covalent bond. For example, the anti-epileptic agent aniracetam is modified Such that the methoxy group (“OMe”) is hydrolyzed to form a reactive hydroxyl group CO (OH). O

CO ON 0082) Examples of Conjugates He O OMe 0083. An illustration of various linkers used to prepare a conjugate from memantine (through the original, bridgehead aniracetam amine) and the Bayer p38 MAP kinase inhibitor (through the carboxylic acid moiety) is presented in Scheme 1.

Scheme 1

NH2 Cl

Cl --

Mermantine p38 MAK Kinase Inhibitor

Conjugate Linker Used OC 1N1 S-1 (CH2)n N1 No

Cl US 2005/O124701 A1 Jun. 9, 2005

-continued

Scheme 1

NH2 Cl

C --

Mermantine p38 MAK Kinase Inhibitor

Conjugate Linker Used

OC 1N1N1'N1a OH

OS 1N1N1 (CH2)n N1 No

OS 1N1N1 (CH2)n N-1NN

C US 2005/O124701 A1 Jun. 9, 2005

-continued

Scheme 1

Mermantine p38 MAK Kinase Inhibitor

Conjugate Linker Used

OC 1N1N1 (CH2)n N-1N

0084 Examples of syntheses for these conjugates are between 2 and 25, preferably between 2 and 5. A meman presented in FIGS. 1-5. tine-tripeptide-therapeutic agent is shown below: 0085. In Some conjugates, a therapeutic agent having a carboxylic acid functionality (COOH) is conjugated directly to the aminoadamantane amine via an amide bond, as shown below for memantine: Y

agent, NH No N1 n1 O H O Y Y

NH agent.

0088 where “agent” represents the remainder of the therapeutic agent, and each Y represents any naturally occurring amino acid Side chain. 0089 Stable linkers include carbon linkages, and can be 0.086. In Some conjugates, the linker is a peptide, linking formed by reaction of the amino functionality on the ami an amine from the aminoadamantane with a carboxylic acid noadamantane (or on the therapeutic agent) with a linker on the therapeutic agent. containing an aldehyde or ketone, to form a Schiff base, 0087. The spacer can optionally be a peptide of formula which is reduced to an aminoalkyl derivative. Synthesis of (amino acid). In Some embodiments, n is an integer metabolically stable linkages is shown in Scheme 2. US 2005/O124701 A1 Jun. 9, 2005 10

0091. In some conjugates, the linker is attached to the aminoadamantane via a metabolically stable linker and attached to the therapeutic agent via a labile linkage (e.g., an NH2 ester or carboxamide) shown for a memantine-linker-thera peutic agent below:

NH 1N1 N1 n-1N1 N n1 agent He- O

R is H, alkyl, aryl. X is CH, O, S, NH, NR

R agent O t 1N1N1\1\-1 agent, --- NH n1O N O Hydrogenation H-e-

This could undergo a similar reaction with 0092 where “agent” refers to the remainder of the thera therapeutic agents containing primary amines peutic agent which contained a carboxylic acid. A reaction Scheme for the generation of the ester is shown in Scheme 3:

0090. Ureas and thioureas are also useful linkages. Ureas 1N1\1\-1N and thioureas can be formed from a primary amine on the OHC O n1 agent aminoadamantane and a primary amine on a therapeutic O agent using the linkers depicted below:

1n-N-1-

N O

aminoadamantane1 HN N-1 nu- X n1n 1\ N ls NH-agent

O 1N-N-1- N S aminoadamantane - HN r N-1N1 X n1N1N N ul NH-agent S US 2005/O124701 A1 Jun. 9, 2005 11

0098. In some embodiments, the compositions are suit -continued able for internal use and include an effective amount of a 4n-1\-1N1)n-'n'-O agent pharmacologically active conjugate of the invention, alone O or in combination, with one or more pharmaceutically acceptable carriers. 0099. A suitable subject can be, e.g., a human, a non human primate (including a gorilla or chimpanzee, or oran gutan), a rodent (including a mouse, rat, guinea pig, or gerbil) a dog, a cat, horse, cow, pig, sheep, rabbit, or goat. catalytic hydrogenation or sodium borohydride 0100. The conjugates are administered in amounts which will be sufficient to exert their desired biological activity. A 1\-1N1-1N-1'nO 1 agent variety of preparations can be used to formulate pharma O ceutical compositions containing the conjugates, including Solid, Semi Solid, liquid and gaseous forms. Remington's Pharmaceutical Sciences, Mack Publishing Company (1995) Philadelphia, Pa., 19th ed. Tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, Solu tions Suppositories, injections, inhalants and aerosols are examples of Such formulations. The formulations can be administered in either a local or Systemic manner or in a 0093. A similar scheme can be used to produce the depot or Sustained release fashion. Administration of the carboxamide rather than the ester composition can be performed in a variety of ways. Among others, oral, buccal, rectal, parenteral, intraperitoneal, intra 0094 Method of Using the Conjugates and Pharmaceu dermal, transdermal and intratracheal means can be used. tical Compositions Containing Conjugates 0101 Where the conjugate is given by injection, it can be 0.095 The conjugates are useful for treating a neurologi formulated by dissolving, Suspending or emulsifying it in an cal condition or disorder, which can include a, e.g., neuro aqueous or nonaqueous Solvent. Vegetable or similar oils, logical disease, condition or syndrome. The neurological Synthetic aliphatic acid glycerides, esters of higher aliphatic disorder can also be, e.g., Stroke, other forms of hypoxic acids and propylene glycol are examples of nonaqueous injury, haemorrhagic brain injury, traumatic brain injury, Solvents. The conjugate is preferably formulated in aqueous spinal cord injury, mild cognitive impairment (MCI), Alzhe Solutions Such as Hank's Solution, Ringer's Solution or imer's disease, e.g., familial Alzheimer's disease (FAD), physiological Saline buffer. Parkinson's disease, ALS (amyotrophic lateral Sclerosis), epilepsy, a metabolic disorder, hypoglycemia, encephalopa 0102) Injectable compositions are preferably aqueous thy, tumors and malignancies (brain, Spinal cord, and Sys isotonic Solutions or Suspensions, and Suppositories are temic), cerebellar degenerations, and ataxias, migraine, Ver advantageously prepared from fatty emulsions or Suspen tigo, tinnitus and cochlear disorders, peripheral neuropathy, Sions. The compositions may be Sterilized and/or contain obesity, and diabetes and pre-diabetic Syndromes, glaucoma, adjuvants, Such as preserving, Stabilizing, wetting or emul HIV-associated dementia or other dementing disease, neu Sifying agents, Solution promoters, Salts for regulating the ropathic pain, Huntington's disease, anxiety, depression or oSmotic pressure and/or buffers. In addition, they may also withdrawal from drug (e.g., opiate) addiction or drug (or contain other therapeutically valuable Substances. The com opiate) dependency, Down's Syndrome, normal cognitive positions are prepared according to conventional mixing, Senescence, meningitis, Sepsis and Septic encephalopathy, granulating or coating methods, respectively, and contain CNS Vasculitis, Schizophrenia, alcoholic diseases, multiple about 0.1 to 75%, preferably about 1 to 50%, of the active Sclerosis or other demyelinating disease, leukodystrophies ingredient. and X-ADL, nociceptive pain, childbirth and Surgical anes 0.103 Liquid, particularly injectable compositions can, thesia. for example, be prepared by dissolving, dispersing, etc. The 0096. The conjugation can be also be used to provide conjugate is dissolved in or mixed with a pharmaceutically neuroprotection in Subjects with elevated cerebrovascular pure Solvent Such as, for example, water, Saline, aqueous risk factors, and/or with and post-ischemic neurovascular dextrose, glycerol, ethanol, and the like, to thereby form the Syndromes. The conjugates are additionally useful for treat injectable Solution or Suspension. Additionally, Solid forms ing hyperhomocysteinemia contributing to atheroslcerotic Suitable for dissolving in liquid prior to injection can be and other degenerative disease processes. formulated. Injectable compositions are preferably aqueous isotonic Solutions or Suspensions. The compositions may be 0097. The conjugates are typically administered to a Sterilized and/or contain adjuvants, Such as preserving, Sta patient in the form of a pharmaceutically acceptable Salt or bilizing, wetting or emulsifying agents, Solution promoters, in a pharmaceutical composition. A compound that is admin istered in a pharmaceutical composition is mixed with a Salts for regulating the osmotic preSSure and/or buffers. In Suitable carrier or excipient Such that a therapeutically addition, they may also contain other therapeutically valu effective amount is present in the composition. The term able Substances. “therapeutically effective amount” refers to an amount of the 0104. The conjugates can be administered in intravenous conjugate that is necessary to achieve a desired endpoint (both bolus and infusion), intraperitoneal, Subcutaneous or (e.g., decreasing neuronal damage). intramuscular form, all using forms well known to those of US 2005/O124701 A1 Jun. 9, 2005

ordinary skill in the pharmaceutical arts. Injectables can be using those forms of transdermal skin patches well known to prepared in conventional forms, either as liquid Solutions or those of ordinary skill in that art. To be administered in the Suspensions. form of a transdermal delivery System, the dosage admin istration will, of course, be continuous rather than intermit 0105 Parental injectable administration is generally used tent throughout the dosage regimen. Other preferred topical for Subcutaneous, intramuscular or intravenous injections and infusions. Additionally, one approach for parenteral preparations include creams, ointments, lotions, aeroSol administration employs the implantation of a slow-release or Sprays and gels, wherein the concentration of active ingre Sustained-released Systems, which assures that a constant dient would range from 0.01% to 15%, w/w or w/v. level of dosage is maintained, according to U.S. Pat. No. 0110 For Solid compositions, excipients include pharma 3,710,795, incorporated herein by reference. Where the ceutical grades of mannitol, lactose, Starch, magnesium conjugate is given orally, it can be formulated through Stearate, Sodium Saccharin, talcum, cellulose, glucose, combination with pharmaceutically acceptable carriers that Sucrose, magnesium carbonate, and the like may be used. are well known in the art. The carriers enable the compound The conjugate defined above, may be also formulated as to be formulated, for example, as a tablet, pill, Suspension, Suppositories using for example, polyalkylene glycols, for liquid or gel for oral ingestion by the patient. Oral use example, propylene glycol, as the carrier. In Some embodi formulations can be obtained in a variety of ways, including ments, Suppositories are advantageously prepared from fatty mixing the compound with a Solid excipient, optionally emulsions or Suspensions. grinding the resulting mixture, adding Suitable auxiliaries and processing the granule mixture. 0111. The conjugates of the present invention can also be administered in the form of liposome delivery Systems, Such 0106 The conjugates of the invention can also be admin as Small unilamellar vesicles, large unilamellar vesicles and istered in Such oral dosage forms as timed release and multilamellar vesicles. Liposomes can be formed from a Sustained release tablets or capsules, pills, powders, gran variety of phospholipids, containing cholesterol, Steary ules, elixirs, tinctures, Suspensions, Syrups and emulsions. lamine or phosphatidylcholines. In Some embodiments, a 0107 For instance, for oral administration in the form of film of lipid components is hydrated with an aqueous a tablet or capsule (e.g., a gelatin capsule), the active drug Solution of drug to a form lipid layer encapsulating the drug, component can be combined with an oral, non-toxic phar as described in U.S. Pat. No. 5,262,564. For example, the maceutically acceptable inert carrier Such as ethanol, glyc conjugates described herein can be provided as a complex erol, water and the like. Moreover, when desired or neces with a lipophilic compound or non-immunogenic, high Sary, Suitable binders, lubricants, disintegrating agents and molecular weight compound constructed using methods coloring agents can also be incorporated into the mixture. known in the art. An example of nucleic-acid associated Suitable binders include Starch, magnesium aluminum sili complexes is provided in U.S. Pat. No. 6,011,020. cate, Starch paste, gelatin, methylcellulose, Sodium car 0112 The conjugates of the present invention may also boxymethylcellulose and/or polyvinylpyrrolidone, natural be coupled with Soluble polymers as targetable drug carriers. SugarS Such as glucose or beta-lactose, corn Sweeteners, Such polymers can include polyvinylpyrrolidone, pyran natural and Synthetic gums Such as acacia, tragacanth or copolymer, polyhydroxypropyl-methacrylamide-phenol, Sodium alginate, polyethylene glycol, waxes and the like. polyhydroxyethylaspanamidephenol, or polyethyleneoxide Lubricants used in these dosage forms include Sodium polylysine Substituted with palmitoyl residues. Furthermore, oleate, Sodium Stearate, magnesium Stearate, Sodium ben the conjugates of the present invention may be coupled to a Zoate, Sodium acetate, Sodium chloride, Silica, talcum, class of biodegradable polymers useful in achieving con Stearic acid, its magnesium or calcium Salt and/or polyeth trolled release of a drug, for example, polylactic acid, yleneglycol and the like. Disintegrators include, without polyepsilon caprolactone, polyhydroxybutyric acid, poly limitation, Starch, methyl cellulose, agar, bentonite, Xanthan orthoesters, polyacetals, polydihydropyrans, polycy gum Starches, agar, alginic acid or its Sodium Salt, or anoacrylates and croSS-linked or amphipathic block copoly effervescent mixtures, and the like. Diluents, include, e.g., mers of hydrogels. lactose, dextrose, Sucrose, mannitol, Sorbitol, cellulose and/ or glycine. Suitable excipients include SugarS Such as lac 0113. If desired, the pharmaceutical composition to be tose, Sucrose, mannitol or Sorbitol, cellulose preparations administered may also contain minor amounts of non-toxic Such as maize Starch, wheat Starch, potato Starch, gelatin, auxiliary Substances Such as wetting or emulsifying agents, gum tragacanth, methyl cellulose, hydroxypropylmethylcel pH buffering agents, and other Substances Such as for lulose, Sodium carboxymethylcellulose and polyvinylpyr example, Sodium acetate, triethanolamine oleate, etc. rolidone (PVP). 0114. The dosage regimen utilizing the conjugates is 0108. Alternatively, the conjugates are delivered in an Selected in accordance with a variety of factors including aeroSol Spray preparation from a pressurized pack, a nebu type, Species, age, weight, SeX and medical condition of the lizer or from a dry powder inhaler. Suitable propellants that patient; the Severity of the condition to be treated; the route are used in a nebulizer include, for example, dichlorodif of administration; the renal and hepatic function of the luoro-methane, trichlorofluoromethane, dichlorotetrafluoro patient; and the particular conjugate employed. An ordi ethane and carbon dioxide. The dosage is determined by narily skilled physician or Veterinarian can readily determine providing a valve to deliver a regulated amount of the and prescribe the effective amount of the drug required to compound in the case of a pressurized aerosol. prevent, counter or arrest the progreSS of the condition. 0109 Furthermore, preferred conjugates for the present 0115 Pharmaceutical compositions typically contain a invention can be administered in intranasal form via topical therapeutically effective amount of the conjugate. The use of Suitable intranasal vehicles, or via transdermal routes, amount of the conjugate will depend on the patient being US 2005/O124701 A1 Jun. 9, 2005 treated. The patient's weight, Severity of illness, manner of taneous administration can be accomplished, for example, administration and judgment of the prescribing physician by administering to the Subject a Single capsule having a should be taken into account in deciding the proper amount. fixed ratio of each therapeutic agent or in multiple, Single The determination of a therapeutically effective amount of a capsules for each of the therapeutic agents. conjugate is well within the capabilities of one with skill in 0.122 Sequential or substantially simultaneous adminis the art. tration of each therapeutic agent can be effected by any 0116. Although a therapeutically effective amount of a appropriate route including, but not limited to, oral routes, conjugate will vary according to the patient being treated, intravenous routes, intramuscular routes, and direct absorp suitable doses will typically include between about 0.1 mg tion through mucous membrane tissues. The therapeutic and 1000 mg of the compound. Preferably, a dose contains agents can be administered by the same route or by different between about 0.1 mg and 500 mg of the compound. More routes. For example, a first therapeutic agent of the combi preferably, a dose contains between about 0.1 mg and 250 nation Selected may be administered by intravenous injec mg of the compound. tion while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all 0117. In Some cases, it may be necessary to use dosages therapeutic agents may be administered orally or all thera outside of the Stated ranges to treat a patient. Those cases peutic agents may be administered by intravenous injection. will be apparent to the prescribing physician. Where it is The Sequence in which the therapeutic agents are adminis necessary, a physician will also know how and when to tered is not narrowly critical. “Combination therapy' also interrupt, adjust or terminate treatment in conjunction with can embrace the administration of the therapeutic agents as a response of a particular patient. described above in further combination with other biologi 0118 Conjugates may be administered in a single daily cally active ingredients and non-drug therapies (e.g., Surgery dose, or the total daily dosage may be administered in or radiation treatment.) Where the combination therapy divided doses of two, three or four times daily. Tmax and further comprises a non-drug treatment, the non-drug treat Cmax for a conjugate in a Subject (and the corresponding ment may be conducted at any Suitable time So long as a therapeutic agent not conjugated to an aminoadamantane) beneficial effect from the co-action of the combination of the can be calculated using methods known in the art (see, e.g., therapeutic agents and non-drug treatment is achieved. For the USP (United States Pharmacopoeia) and U.S. Pat. No.6, example, in appropriate cases, the beneficial effect is still 555,581). Tmax and Cmax can be calculated using samples achieved when the non-drug treatment is temporally extracted from brain or cerebrospinal fluid. Values can also removed from the administration of the therapeutic agents, be calculated based on Samples taken from tissueS Such as perhaps by days or even weeks. The conjugate and the other Serum. It is expected that altered Serum values of a conjugate pharmacologically active agent may be administered to a as compared to the therapeutic agent delivered when not patient Simultaneously, Sequentially or in combination. It conjugated to the therapeutic agent will reflect delivery of will be appreciated that when using a combination of the the conjugate from tissueS outside the blood-brain barrier to invention, the compound of the invention and the other the brain. pharmacologically active agent may be in the same phar maceutically acceptable carrier and therefore administered 0119) Combinations Containing Conjugates Simultaneously. They may be in Separate pharmaceutical 0120) The conjugate can be administered with another carrierS Such as conventional oral dosage forms which are neuroprotectant, including a Second conjugate as described taken simultaneously. The term “combination” further refers herein, an anti-inflammatory agent, an immunosuppreSSant, to the case where the compounds are provided in Separate an antiviral agent conjugate of the invention in combination dosage forms and are administered Sequentially. with other conjugate of the invention. OTHER EMBODIMENTS 0121 Combination therapy” (or “co-therapy') includes 0123. While the invention has been described in conjunc the administration of a conjugate of the invention and at least tion with the detailed description thereof, the foregoing a Second agent as part of a specific treatment regimen description is intended to illustrate and not limit the Scope of intended to provide the beneficial effect from the co-action the invention, which is defined by the Scope of the appended of these therapeutic agents. The beneficial effect of the claims. Other aspects, advantages, and modifications are combination includes, but is not limited to, pharmacokinetic within the Scope of the following claims. or pharmacodynamic co-action resulting from the combina tion of therapeutic agents. Administration of these therapeu tic agents in combination typically is carried out over a What is claimed is: defined time period (usually minutes, hours, days or weeks 1. A method of targeting a therapeutic agent to the brain, depending upon the combination Selected). “Combination the method comprising therapy may, but generally is not, intended to encompass the administration of two or more of these therapeutic agents administering to a Subject in need thereof a conjugate as part of Separate monotherapy regimens that incidentally comprising an aminoadamantane derivative linked to and arbitrarily result in the combinations of the present Said therapeutic agent. invention. “Combination therapy” is intended to embrace 2. The method of claim 1, wherein said method further administration of these therapeutic agents in a Sequential includes identifying a therapeutic agent in which targeting to manner, that is, wherein each therapeutic agent is adminis the brain of a subject is desired. tered at a different time, as well as administration of these 3. The method of claim 1, wherein Said therapeutic agent therapeutic agents, or at least two of the therapeutic agents, reaches a Tmax at from between about 0.5 hours to about 8 in a Substantially Simultaneous manner. Substantially Simul hours after administering to Said Subject. US 2005/O124701 A1 Jun. 9, 2005

4. The method of claim 1, reaches a Tmax at from about Alzheimer's disease, Parkinson's disease, epilepsy, meta 1.0 hours to about 6 hours. bolic disorders, glaucoma, HIV-associated dementia, neuro 5. The method of claim 1, reaches a Tmax at from about pathic pain, Huntington's disease, anxiety, depression, and 1.5 hours to about 2.5 hours. withdrawal from drug addiction or drug dependency. 6. The method of claim 1, wherein the Tmax of said 20. The method of claim 1, wherein said therapeutic agent therapeutic agent occurs in a time that is at least 1.5 times is for treating hyperhomocysteinemia contributing to Sooner than that of the Tmax that occurs when Said thera atherOSlcerotic and other degenerative disease processes. peutic agent administered when not conjugated to Said 21. The method of claim 1, wherein Said therapeutic agent aminoadamantane derivative. is for treating head trauma or Spinal cord injury. 7. The method of claim 1, wherein the Tmax of said 22. The method of claim 1, wherein Said therapeutic agent therapeutic agent occurs in a time that is at least 2.5 times is for treating a demyelinating disease. Sooner than that of the Tmax that occurs when Said thera 23. The method of claim 22, wherein said demyelinating peutic agent administered when not conjugated to Said disease is multiple Sclerosis. aminoadamantane derivative. 24. The method of claim 2, wherein Said therapeutic agent 8. The method of claim 1, wherein the Tmax of said is for treating a disorder associated with excessive NMDAR therapeutic agent occurs in a time that is at least 4.0 times activity. Sooner than that of the Tmax that occurs when Said thera 25. The method of claim 1, wherein Said therapeutic agent peutic agent administered when not conjugated to Said is Selected from the group consisting of a caspase inhibitor, aminoadamantane derivative. a Superoxide dismutase mimetic, calcium chelator, MAPK 9. The method of claim 1, wherein Said conjugate reaches antagonist, an ERK-MAPK antagonist, a Cytochrome C Cmax in about 12 hours after administration of the product. chelating antibody, APAF-1 inhibitor, AIF inhibitor/Apop 10. The method of claim 1, wherein said conjugate tosis inhibitor, Gamma Vinyl GABA, PARP inhibitor, and an reaches Cmax in about 6 hours after administration of the NOS inhibitor. product. 26. The method of claim 1, wherein Said aminoadaman 11. The method of claim 1, wherein Said conjugate tane derivative is neuroprotective. reaches Cmax about 1 hour after administration of the 27. The method of claim 1, wherein said aminoadaman product. tane derivative binds to an N-methyl-D-aspartate (NMDA) 12. The method of claim 1, wherein Said conjugate receptor expressed on an injured neuron. reaches a Cmax in a time that is at least 1.5 times Sooner than that of the Cmax that occurs when Said therapeutic agent 28. The method of claim 1, wherein said aminoadaman administered when not conjugated to Said aminoadamantane tane derivative is memantine. derivative. 29. The method of claim 1, wherein said aminoadaman 13. The method of claim 1, wherein Said conjugate tane derivative is rimantadine (1-(1-aminoethyl)adaman reaches a Cmax in Serum in a time that is at least 2 times tane). Sooner than that of the Cmax that occurs when Said thera 30. The method of claim 1, wherein said aminoadaman peutic agent administered when not conjugated to Said tane derivative is amantadine (1-aminoadamantane) aminoadamantane derivative. 31. The method of claim 1, wherein Said therapeutic agent 14. The method of claim 1, wherein Said conjugate is attached to the aminoadamantane derivative in Said con reaches a Cmax in a time that is at least 4 times Sooner than jugate at the 1-(bridgehead) position or the 2-position. that of the Cmax that occurs when Said therapeutic agent 32. The method of claim 1, wherein Said therapeutic agent administered when not conjugated to Said aminoadamantane is attached to the aminoadamantane derivative via an derivative. unstable linkage. 15. The method of claim 1, wherein said therapeutic agent 33. A method of targeting a therapeutic agent to an injured is a neuroprotective agent. neuron of a Subject, the method comprising administering to 16. The method of claim 1, wherein Said therapeutic agent a Subject in need thereof a conjugate comprising an ami is non-nitrosylated or is a non NO-generating therapeutic noadamantane derivative linked to Said therapeutic agent. agent. 34. The method of claim 33, wherein the injured neuron 17. The method of claim 1, therapeutic agent is for is in the brain of Said Subject. treating a therapeutic agent is for treating a disorder asso 35. A method of lowering the neurotoxicity of a thera ciated with excessive NMDAR activity. peutic agent in a Subject, the method comprising adminis 18. The method of claim 1, wherein said therapeutic agent tering to Said Subject a conjugate comprising an aminoada is for treating a neurological disorder. mantane derivative linked to Said therapeutic agent. 19. The method of claim 1, wherein said neurological disorder is Selected from the group consisting of Stroke,