US 20040072900A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0072900 A1 Artman et al. (43) Pub. Date: Apr. 15, 2004 (54) TREATING A VARIETY OF PATHOLOGICAL ation-in-part of application No. PCT/US97/15272, CONDITIONS, INCLUDING SPASTICITY filed on Aug. 29, 1997. AND CONVULSIONS, BY EFFECTING A MODULATION OF CNS ACTIVITY WITH ISOVALERAMIDE, ISOVALERIC ACID, OR A (60) Provisional application No. 60/025,050, filed on Aug. RELATED COMPOUND 30, 1996. (75) Inventors: Linda D. Artman, Salt Lake City, UT Publication Classification (US); Manuel Balandrin, Sandy, UT (US); Robert L. Smith, Lansdale, PA (51) Int. Cl." ........................ A61K 31/195; A61K 31/19 (US) (52) U.S. Cl. ........................... 514/557; 514/561; 514/562 Correspondence Address: FOLEY AND LARDNER SUTE 500 (57) ABSTRACT 3000 KSTREET NW WASHINGTON, DC 20007 (US) Preparations and extracts of Valerian, as well as iSOValera (73) Assignee: NPS PHARMACEUTICALS mide, isoValeric acid, and certain Structurally related com pounds exhibit clinically significant pharmacological prop (21) Appl. No.: 10/614,344 erties which implicate a treatment for a variety of pathological conditions, including Spasticity and convul (22) Filed: Jul. 8, 2003 Sions, which are ameliorated by effecting a modulation of Related U.S. Application Data CNS activity. The compositions in question generally are non-cytotoxic and do not elicit weakness or Sedative activity (60) Division of application No. 09/258,882, filed on Mar. at doses that are effective for the Symptomatic treatment of 1, 1999, now Pat. No. 6,589,994, which is a continu Such pathological conditions. -- o -- O or ---,O SOValericacic Amnonium isovalerate lsoyaleramide N-Ehylisovaleramide--> O ------ O O 1-to --~~ous Ethylisovalerate r OH Glycery trisovalerate Glyceryl-1,3-disowaterate ("Trisovalerin") O 1-or-ch C O --or-o- irr OH O O Glyceryl-1,2-diisovalerate Glycery-t-monoisovalerate Glycery-2-monoisowaterate Os-OH O O O r 1-r- 1-ro ISOValery salicylic acid ("SA"); N-isovalery GABA N-isovalerylglycine Salicylic acid isovalerate -- "isovaleraminophen'i. isovalery salicylamide N-(4-hydroxyphenyl)- B-Sitostery isOValerate salicylamide isovalerate ester) isovaleramide O O or Walproic acid Walpromide lsOValeryl-acetaminophen ester The Structures of ISOValeramide and Related Compounds Patent Application Publication Apr. 15, 2004 Sheet 1 of 7 US 2004/0072900 A1 --oO -- O or ---,O -->O isovaleric acid Ammonium isOValerate lsOValeramide N-Ethy isOValeramide 1-to- ------ 1-gro0 0 EthylisOValerate Glycery trisovalerate Glycery-t,3-disowaterate ("Trisovalerin") O lu. or-OH u-ji O -OH r orro lui Coh Glyceryl-1,2-diisovalerate Glycery-t-monoisOValerate Glycery-2-monosovalerate ON-OH O O O N O N O ISOValery salicylic acid ("SA"); N-lsoyalery GABA N-IsOValery glycine Salicytic acid isOValerate ON-NH2 O or u-ji O --"Isoyaleraminophen" O isovalery salicylamide N-(4-hydroxyphenyl)- 8-Sitostery isOValerate (salicylamide isOValerate ester) isOValeramide Yi'sO SctO NH2 i?O O. O r Walproic acid Walpromide lsOValeryl-acetaminophen ester The Structures of IsOValeramide and Related Compounds FIG 1 a Patent Application Publication Apr. 15, 2004 Sheet 2 of 7 US 2004/0072900 A1 1.O > -s;O 1.x:O > O 2-methyl 3-methyl 2,2-dimethy 2,3-dimethy isOValeramide isOValeramide isOValeramide isOValeramide NH2 NH2 NH2 Yx 4-methyl 2,4-dimethyl 3,4-dimethy 2,2,4-trimethyl isOValeramide isOValeramide isOValeramide isOValeramide "> -s;O Hos---O HonX Ois ----O NH2 4-hydroxy- H 6 3-hydroxy 4-hydroxy 3-methyl N-(2-acetamido) isOValeramide isOvaleramide is0Valeramide isOValeramide 1SN-2O 1stO. O 15s.O. O ro'ssNH20 0 OH 2-hydroxy 2-methyl-1-propy 1-methylethyl 2-methyl-1-propy isovaleramide sulfonamide Sulfamate Sulfamate O -on. X-ro-NH2 lsopropy Isobuty Carbamate Carbamate Structures of COmpOUnds structurally related to isovaleramide F.G. b Patent Application Publication Apr. 15, 2004 Sheet 3 of 7 US 2004/0072900 A1 s re d on r R -e CN S e C2L. cro O v C s 2 S3 800S KO)Seds US 2004/0072900 A1 (Ouluo CJO %) Xeyed JOXe Patent Application Publication Apr. 15, 2004 Sheet 5 of 7 US 2004/0072900 A1 Xaye JOX8 at 10 apnubeN Patent Application Publication Apr. 15, 2004 Sheet 6 of 7 US 2004/0072900 A1 y00£0300||000900 ºsodlosaN9/z?(6×6u) O O O CO CO r (OJuOOJO %) eSUOdse Patent Application Publication Apr. 15, 2004 Sheet 7 of 7 US 2004/0072900 A1 ?–O|Ou?u -==5.ZZTSEN e JOOS enzeS US 2004/0072900 A1 Apr. 15, 2004 TREATING AWARIETY OF PATHOLOGICAL 0008. It is another object of the present invention to CONDITIONS, INCLUDING SPASTICITY AND provide a novel prophylactic therapy for migraine and other CONVULSIONS, BY EFFECTING AMODULATION headache pathologies. OF CNSACTIVITY WITH ISOVALERAMIDE, 0009. It is another object of the present invention to ISOVALERIC ACID, OR A RELATED COMPOUND provide a novel therapy for affective mood disorderS Such as 0001. This application is a continuation-in-part of PCT bipolar disorder. application PCT/US97/15272, filed Aug. 29, 1997, which was a continuation of application Serial No. 60/025,050, 0010. It is another object of the present invention to filed Aug. 30, 1996. provide a novel neuroprotective therapy. 0011. It is another object of the present invention to BACKGROUND OF THE INVENTION provide a novel therapy to assist with Substance withdrawal therapy and the Substance cravings that often accompany 0002 The present invention provides methods of treating Such abuse. pathological conditions, Such as Spasticity and convulsions, the symptoms of which are alleviated by a modulation of 0012. In accomplishing these and other objectives, there activity in the central nervous system (CNS), without pro has been provided, according to one aspect of the present ducing undesirable excessive Sedation or muscle weakness invention, a method of using a compound Selected from the in animal Subjects, including humans. More particularly, the group consisting of isoValeramide, a pharmaceutically invention relates to the therapeutic use of isoValeramide, acceptable ester of iSOValeric acid, a pharmaceutically isovaleric acid, and related compounds in patients Suffering acceptable amide of isoValeric acid, and a compound from pathologies of this nature. Selected from the group consisting of 2-methyl isoValeram ide, 3-methylisovaleramide, 2,2-dimethylisovaleramide, 0003) A number of pathological states, diseases, and 2,3-dimethylisovaleramide, 4-methylisovaleramide, 2,4- disorders are characterized by a profound aberration in the dimethylisovaleramide, 3,4-dimethylisovaleramide, 2,2,4- normal function of the central nervous system (CNS). Such trimethylisovaleramide, 3-hydroxyisovaleramide, 4-hy conditions include Spasticity, Strokes, Spinal cord injuries, droxyisovaleramide, 4-hydroxy-3-methyl-isovaleramide, chronic neurodegenerative disorders and diseases Such as 2-hydroxyisovaleramide, N-(2-acetamido)isovaleramide, Parkinson's and Huntington's diseases, Alzheimer's disease, 2-methyl-1-propyl Sulfonamide, 1-methylethyl Sulfamate, and epilepsy. At the clinical level, these States usually only 2-methyl-1-propyl Sulfamate, isopropyl carbamate, and respond to pharmacologic intervention with compounds or isobutylcarbamate. Substances that possess significant activity at the level of the CNS. 0013 Thus, the present invention also provides a method of treatment comprising the Step of administering, to a 0004. Many agents currently employed in the treatment patient Suffering from a pathology that is ameliorated by a of pathologies Such as Spasticity and convulsions display modulation of CNS activity, a therapeutically effective troubling side-effect profiles which limit their long-term amount of a pharmaceutical formulation comprising a phar clinical utility. Among these agents, for example, are the maceutically acceptable carrier and a composition Selected benzodiazepines, which can cause impairment of cognition from the aforementioned group of agents. (impairment of memory-related performance, or “cognitive blunting”). See, for example, ANTIEPILEPTIC DRUGS, 0014. According to one embodiment of the invention, the Fourth Edition, (Levy et al, eds.), Raven Press, (1995). Two pharmaceutically acceptable amide of isoValeric acid is other clinically used agents are valproate and related thera Selected from the group consisting of isoValeramide, N-ethyl peutically useful Salts. Such as Valproic acid hemisodium Salt, isovaleramide, N-methyl isovaleramide, N,N-dimethylisov which are hepatotoxic and teratogenic, and baclofen, which aleramide, N-methyl,N-ethyl isovaleramide, N-(2-acetami produces excessive muscle weakness and Sedation. These do)isovaleramide (“N-isovaleryl glycinamide'), and N-is side-effects severely limit the therapeutic potential for both ovaleryl GABA. drugs. It is apparent, therefore that improved and better 0015 According to yet another embodiment of the inven tolerated treatments for Spasticity, convulsions, and other tion, the treated pathology is an affective mood disorder, therapeutic indications are greatly to be desired. convulsions, a central neuropathic pain Syndrome, a head ache, or a restleSSneSS Syndrome. In Still another embodi SUMMARY OF THE INVENTION ment, the pathology is spasticity that is ameliorated by a 0005 Accordingly, it is an object of the present invention centrally mediated decrease in muscle tone. In a further to provide a therapeutic approach for the treatment of embodiment, the treated pathology is a cerebral insult, various pathologies by effecting a modulation of CNS neurodegeneration, or the acquisition