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

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(12) Patent Application Publication (10) Pub. No.: US 2005/0124701 A1 Went Et Al 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 ' s 1\/N/N/NOH 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.
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