US005668117A United States Patent (19) 11 Patent Number: 5,668,117 Shapiro 45 Date of Patent: Sep. 16, 1997 54 METHODS OF TREATING NEUROLOGICAL 4,673,669 6/1987 Yoshikumi et al. ...................... 514.f42 DSEASES AND ETOLOGICALLY RELATED 4,757,054 7/1988 Yoshikumi et al. ... 514742 SYMPTOMOLOGY USING CARBONYL 4,771,075 9/1988 Cavazza ............... ... 514/556 TRAPPNGAGENTS IN COMBINATION 4,801,581 1/1989 Yoshikumi et al. ...................... 514.f42 WITH PREVIOUSLY KNOWN 4,874,750 10/1989 Yoshikumi et al. ...................... 514/42 MEDICAMENTS 4,956,391 9/1990 Sapse .................. 514,810 4,957,906 9/1990 Yoshikumi et al. ...................... 514/25 tor: H . Shani 4,983,586 1/1991 Bodor....................................... 514/58 76 Inventor ES pr.) Price Ave 5,015,570 5/1991 Scangos et al. ............................ 435/6 5,037,851 8/1991 Cavazza ........... ... 514,912 5,252,489 10/1993 Macri ........................................ 436/87 21 Appl. No.: 62,201 5297,562 3/1994 Potter. ... 128/898 al 5,324,667 6/1994 Macri. ... 436/87 22 Filed: Jun. 29, 1993 5,324,668 6/1994 Macri ....................................... 436/87 Related U.S. Application Data I63 Continuation-in-part of set No. 26.617, Feb. 23, 1993, Primary Eminer ohn Kight abandoned, which is a continuation of Ser. No. 660.561, Assistant Examiner-Louise Leary Feb. 22, 1991, abandoned. Attorney, Agent, or Firm-D. J. Perrella (51) Int. Cl. ................... A01N 43/04; A01N 61/00; 57 ABSTRACT C07H1/00; C08B 37/08 52 U.S. C. ................................ 514/55; 514/54; 514/23; Therapeutic compositions comprising an effective amount 514/1: 514/811; 514/866; 514/878; 514/879; of at least one carbonyl trapping agent alone or in combi 514/903; 514/912; 436/518; 436/74; 536/1.11; nation with a therapeutically effective of a co-agent or 536/20 medicament are disclosed. The compositions are used to 58) Field of Search ................................. 514/55, 54, 23, treat a mammal suffering from a neurological disease char 514/1, 811, 866, 878, 879,903, 912; 435/6. acterized by covalent bond crosslinking between the nerve 7.9; 436/518, 74, 87; 536/1.11, 20 cells, other cellular structures and their intracellular and extracellular components, with disease induced carbonyl 56) References Cited containing aliphatic or aromatic hydrocarbons present in mammals. U.S. PATENT DOCUMENTS 4,665,069 5/1987 Rosenberg .............................. 514/817 29 Claims, No Drawings 5,668, 117 1. 2 METHODS OF TREATING NEUROLOGICAL The 16th edition of the Merck Manual (Berkow, 1992, pp. DSEASES AND ETOLOGICALLY RELATED 1497-1499) has defined symptomatic clinical treatment of SYMPTOMOLOGY USING CARBONYL Parkinson's disease to consist of: (a) oral co-administration TRAPPINGAGENTS IN COMBINATION of levodopa, the metabolic precursor of dopamine, and WITH PREVIOUSLY KNOWN carbidopa, a peripheral decarboxylase inhibitor in compo MEDCAMENTS sitions such as Sinemet CR; (b) co-agent use of amantadine HCl Symmetrel; 1-amino-adamantane, a rye ergot alkaloid RELATED PATENTAPPLICATION and neuronal transmission enhancer; (c) co-agent use of This invention is a continuation in part of U.S. patent ergot alkaloids such as bromocriptine mesylate Parlodel, application Ser. No. 08/026,617, filed on Feb. 23, 1993, now 10 which has a dopamine agonist activity for D receptors and abandoned, entitled “Method of Treating Neurological Dis antagonist activity at D receptors) and pergolide mesylate eases and Etiologically Related Symptomology Using Car Permax, a dopamine-receptor agonist active at both D and bonyl Trapping Agents,” which in turn is a continuation of D receptor subtypes (Robin, 1991); (d) selegiline HCI U.S. patent application Ser. No. 07/660,561, filed on Feb. Eldepryl, a selective inhibitor of monoamine oxidase B 22, 1991 entitled "Method of Treating Neurological Dis 15 which prolongs the action of dopamine (Rinne, 1991); (e) eases and Etiologically Related Symptomology Using Car co-agent use of anticholinergic medications such as benz bonyl Trapping Agents.” now abandoned, the entire disclo tropine mesylate Cogentin, trihexylphenidyl Artanel, pro sures of which are incorporated by reference herein. cyclidine Kemadrin, biperiden and ethopropazine Paridol; (f) co-agent use of antihistamines such as diphen BACKGROUND OF THE INVENTION hydramine Benadryland orphenadrine; (g) co-agent use of 1. Field of the Invention tricyclic antidepressants such as amitriptyline, imipramine, This invention relates to the clinical treatment of neuro nortriptyline and doxepin; and (h) co-agent use of propra degenerative diseases, including hereditary motor and sen nolol. sory neuropathies (HMSN, also known as Charcot-Marie Other well established or experimental therapeutic Tooth disease), diabetic polyneuropathy, Alzheimer's pre 25 approaches for clinical treatment of Parkinson's disease, senile and senile dementia, Down's syndrome, Parkinson's which may or may not be used in conjunction with L-dopa, disease, olivopontocerebellaratrophy, Huntington's disease, have been publicly disclosed. These include possible use of amyotrophic lateral sclerosis, age-onset neurological (a) selegiline in combination with tocopherol (Greenamyre deterioration, alcoholic polyneuropathy, tinnitus, multiple and O'Brien, 1991); (b) D-cycloserine with or without a sclerosis, and pathophysiologically symptomology. 30 cholinesterase inhibitor co-agent (Francis and coworkers, 2. Description of Prior Art 1991); (c) other dopamine receptor agonists such as (+)-4- The logic and potential value, even synergistic value, of propyl-9-hydroxynaphthoxazine (Martin and coworkers, using two or more therapeutic agents in combination has 1984), apomorphine and ciladopa (Koller and coworkers, been recognized previously (Ghose and coworkers, 1983; 1986; Goldstein and coworkers, 1990); (d) neurotransmis Goldstein and coworkers, 1990, pg. 102; Rinne, 1991). For 35 sion enhancer drugs such as lisuride, a rye ergot alkaloid example, in a study on two-drug combinations of memory (Rinne, 1989; Rinne, 1991); (e) known antioxidants such as enhancing agents Flood and coworkers (1988) noted that: ascorbic acid, alpha-tocopherol, beta-carotene (Mathews The potential for clinically desirable drug interactions has Roth, 1987), N-acetylcysteine (Smilkstein and coworkers, been emphasized for drugs in general (1) and for 1988), penicillamine or cysteamine (Harris, 1982), as memory enhancing drugs in particular (2.3). For increased levels of lipid peroxidation are apparent in par example, individual cholinergic drugs which improve kinsonian tissue (Ceballos and coworkers, 1990; Fahn, memory retention test scores (4.56) do so in two-drug 1989); (f) other peripheral decarboxylase inhibitors such as combinations at substantially lower doses than would benserazide (Madopar HBS) (Pinder and coworkers, 1978; be predicted if the two drugs acted additively (7,8,9). Pletscher, 1990); and (g) N-methyl-D-asparate (NMDA) 45 glutamate receptor antagonists such as dizocilpine In prior studies of the effect of two-drug combinations on (Clineschmidt and coworkers, 1982; Woodruff and memory processing (8,9), we determined the effect of coworkers, 1987) and millacemide (Youdim, 1988; Ferris, varying the dose of two drugs while holding the ratio 1990) or use of the possible antagonist 1-amino-3,5- constant. The ratio was based on the optimal memory dimethyl adamantane (Memantine) (Fischer and coworkers, enhancing doses of each drug administered singly. 50 1977; Schmidt and coworkers, 1990; Greenamyre and These studies showed that drugs administered in certain O'Brien, 1991); (h) tacrine (Cognex, an experimental agent combinations require 67 to 96% less drug to improve of Warner-Lambert Co.) and a hydroxy derivative thereof, retention, than when the same drugs were administered (E)-9-amino-1,2,3,4-tetrahydroacridin-1-ol (Shutske and alone. This type of drug interaction was said to yield coworkers, 1988); and (i) tiapride (Price and coworkers, Supra-additivity. 55 1978). The present disclosure describes the inventive concept of Since activation of NMDA glutamate receptors has also using the therapeutic technology of U.S. patent application been implicated in the etiologies of Huntington's disease, Ser. No. 08/026,617, filed Feb. 23, 1993, now abandoned in amyotrophic lateral sclerosis, olivopontocerebellar atrophy combination witch pharmaceutical agents previously recog and Alzheimer's disease, use of NMDA glutamate receptor nized as having, or possibly having some medicinal value antagonists such as those listed above may be of clinical for treatment of the disease entities noted above. No phar benefit for patients having these diseases (Woodruff and macological treatment of comprehensive effectiveness is coworkers, 1987; Greenamyre and O'Brien, 1991; Giuffra currently available for any of the neurological disorders and coworkers, 1992), as well as for patients suffering from discussed herein. However, a variety of pharmaceutical certain neurodegenerative effects of aging (Ferris, 1990). agents have been described which may offer at least some 65 Drugs which may enhance acetylcholine synthesis or release degree of symptomatic relief from the clinical effects of such as phosphatidylcholine, 3,4-diaminopyridine (Ferris, these diseases. 1990; Harvey and Rowan, 1990) and choline (Sitaram and 5,668,117 3 4 coworkers, 1978a), as well as the muscarinic cholinergic etam (Franklin and coworkers, 1986), pyroglutamic acid agonist arecoline (Tariot and coworkers, 1988), have