CA2873016A1 - Compositions and methods for the treatment of epilepsy - Google Patents

Abstract

Description

COMPOSITIONS AND METHODS FOR THE
TREATMENT OF EPILEPSY
PRIORITY
[00011 The present application claims the benefit. of Indian Provisional Patent Application No. 1791/CHE2012 filed on 08-May-M12, the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference, FIELD OF THE INVENTION
10002] This disclosure. generally relates to compounds and compositions for the treatment of epilepsy. Iore particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, stereoisomers, enantiomers, esters, salts, hydrates, prodrugs. OT mixtures thereof.
BACKGROUND OF THE INVENTION
1000311 'Epilepsy is defined as a chronic neurological condition characterized by recurrent, unprovoked seizures. It is one of the 1710St COM111011 serious neurological disorders in the United States and often requires long-term management Ii.:ac,11 year 150000 people in the United States are newly diagnosed as having epilepsy, with the cumulative lifetime incidence approaching 3%. The incidence is highest during the first year of life and in persons. Although most .people with epilepsy become seizure-free with .appropriate therapy, 301?.70 to 40% of patients will continue to have seizures despite the use of antiepileptic drugs either alone or in combination.
100041 Patients Avith unco.ntrolled seizures experience significant morbidity and riìortaliiy and face social stigma and discrimination as vell. In the United States, only 17% of patients .with new-onset epilep.sy are initially seen by a neurologist.
Furthermore, primary care physicians provide approxiMately 40% of the lOng-tCrtil management of epilepsy patients with or \.vithour initial consultation with a specialist.

2 [000.51 Unfortunately, a survey of general practitioners revealed that only 40% of responders felt confident in their knowledge of epilepsy and two thirds were unfamiliar with the new antiepileptic drugs. A recent survey of 71 patients with epilepsy who are treated exclusively by general practitioners showed that 45% had experienced a seizure within the past year, 68% complained of drowsiness or difficulty in concentration with their current medications, and 28% were prescribed polytherapy.
10006.1 Prior to 1993, the choice of an auticonvulsant medication .was limited to phenobarbital, prim.idone, phenytoin, carbamazepine, and valproate. Although these "traditional" anticonvulsants have the advantage of familiarity as well as proven efficacy, many patients are left with refractory seizures as well as intolerable adverse effects. Since 1993, new medications have been approved by the US Food and Drug Administration (FDA.), expanding treatment options. The newer antiepileptic drugs offer the potential advantages of .fewer drug interactions, unique mechanisms of action, and a broader spectrum of activity. With .more options, however, comes the challenge of determining what role the new antiepileptic drugs play in optimizing treatment in addition to understanding .important adverse effects and drug interactions of these increasingly prescribed medications, [0007] Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a need in. the art for new compositions to treatment of epilepsy.
SUMMARY OF THE INVENTION
[00081 The present invention provides compounds, compositions containing these compounds and methods for using the same to treat, prevent and/or ameliorate the effects of the conditi 011S such as epilepsy..

3 100091 The invention herein provides compositions comprising o.f formula I or pharmaceutical acceptable salts thereof. The invention also provides phatmaceutical compositions comprising one or more compounds of formula I. or intermediates thereof and one or more of pharmaceutically a.cceptable carriers, vehicles or diluents. These compositions may 'be used in the treatment of epilepsy and its associated complications.

s S .

\

Formula I
[001.01 In certain embodiments, the present invention relates to the compounds and compositions of formula I, or pharmaceutically acceptable salts .thereof, H3C.

\

Formula Wierein, RI independently represetiis F1, D,

4 0 0cs '772_ ......,0 NI-4,,. 0 , 0 0 A rIlln .
......._,0......1õ, .........\.: ,-- 1 H

'It..., -"0 0-- - 124, ' c555-= H
/
.c.s.5-5,,,cr........-,......,..........õNs, NH2 N i-12 .1 , hi H H
- 01 ...,L4(N `s-,....._..-=--, IN ,..-----%''',.....,...--" N 1.,...
H, C) H H
jc,...-'" 0 ....µ..,N .....õ..................,,,,, ...........-"\.................,, N
1..... - 0 \ /1\71 \sS5 ta),,N.,..,.......õ.....õ,-..õ...,.. õ."......--õ..,..õ.õ.....õ..#õ11..y $
or , o µ2"

-;SS5N... .-'`-',.,---F- \-=.
H -' R.- independently represents Acetyl (C1{3C0-.), ...õ.."..SE-t H H? es H
,.k.....,N
, HS OH
, P o bs..__---,,< , -, ' ss 0 --is ."--0 S----.60 .. , "( - - - -t!?

0 s -..., 0 s ¨ ___________________________________________ ¨
'377¨ 5 1i ) 1 1 4 ri 20 s ,ss, s5 ¨
¨ ¨ ¨ ¨

4 -7 1.0 .13 .$.6 ' N CH, -HO
H

-,--N...õ..............õ..--..1.(i.c ,. OH
-...,.
6 0 c5' -N
, NHCOCH

dit CON H2 400 .. 40 002H 401 õc.c..
0,... c.,.
OH

oc0C H3 0.5i: "7 . , .
, ..,,ss irlp I li itC-41.......õ7-N..,"\isi 41101 0 1 \
CH3 4,;,6, C1-1 OH 77 0 1-M71N 5s5õ, H N
tt \
S

0 e b "Z
a h d or C , , a is independently 2,3 or 7;
each b is independently 3, 5 or 6;
e is independently 1, 2 or 6;
c and d are each independently 11, D, -0.H., -OD, C1-C6-alkyl, -N1-12 or -COCH3.
1001 ii In the illustrative embodiments, examples of compounds of formula 1 are as set forth below:

HC S

(1-1) 1001 21 A ccordi n.glyõ the invention al so provi des pharaceutical compositions comprising one or more compounds or formula 11 or intermediates thereof and one or inore of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of epilepsy and its associated complications.
"=====. R2 oiH
Formula .111 Wherein, Rt independently represents.: :Hydrogen. D, 0 so hiti2 0 0 \ (.1 1-0¨F

\c2a, o o o o y H
/
o X A ..c.s. 5.1,, ...õ......õ.....,..õ..........",,, N ,,,ess H
......N
/1111, H H
.....µ ,,,..,,,........õ...-------,,õ,N h.01 .....,c 2 iz:
I' 4 .,, ....... , , .........õ .... - ^.. ..... ....... I ..... .õ , ,====%,......,..............., N , .1, .....
N
H õ

H
(?2,;:l.""=-,,,,õõ----.---"N--.0------",...õ...õ..--'" -..,. ¨0 , (7.2,/\. /\ /\,,s=S
0 0 , OH
- , , H H
:372...õ...N..,..,..õ..õ.õ..........---õ.õ..õ
õ...............õ..,.....,,,,,õ,N.õ..;55.!. Ao......õ..---..õ.........õ..".õ1..õ
S
or H
, R independently represents Acetyl (CC)-), ,........õSH
Q

,....,.,,, o 4,, H 0 Fi N
Ns\---9--..--------d..--OH

0 `Z.

0 , , .

-,.., ;22z, ---, S.,õ.S ,.. S...
-._õ s ..
' _ , ......... ......._ ;OS 5 t.1 11 1,1 i ? 20 0 "

4!"

0 , H

OH
IP
H HO ,----"' -..., HO
NHCOCE-i3 1110 ao , 101 CO2 H õI esS, CONK"
OH 042; OCOC H3 SI
?:
, , o sf CH3 CH3 0H 0 Hc CH3 CH3 CH3 6..19 ci-t3 QH .. 0 \\W-1 HO N;s55,,, H
HN
0 5 N}-1; 4 a c d or a is independently 2,3 or 7;
each b is independently 3, c s independently 1, 2 or 6;
c and d are each independently H. L. -OH, -OD. CI -C.(,-alkyl, -NH2 or -COCH-1 100131 In the illustrative enibodi monis, exam p 1 es of compounds of formula 1 are as set forth below:

(2-1) o 7:

(.2-2) 100141 Herein the application also provides a kit compri sitiR any a the pharmaceutical compositions disclosed herein. The kit may comprise instructions for use in the treatment of epilepsy or its related complications.
1001 51 The application also discloses a pharmaceutical composition comprising a ph armaceuti cal I y acc.eptahl c carrier an d any of the c om posi ti on s herein, In SOT11 e aspects, the pharmaceutical composition is forinulated for systemic administration, oral ad ni nistrati ori, WWI 11 ed rel ease, par en tera admini strati on, inj ecti on, s u b dean al admini stration, or transdermal admini strati on.
100161 Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the treatment of e pi I epsy or i ts related con'iplícati on s.
10017i The compositions described herein have several uses. The present application provides, for example, methods of treating a patient suffering from epilepsy of its related complications manifested from metabolic conditions, chronic diseases or disorders;
Hepatology, Cancer, Neu rol ogi cal , Umiak)] ogi cal, Orthopedi c, Cardiovascular, Renal , Skinõ Vascular or Ocular complications.

DETAILED DESCRIPTION OF THE INVENTION
Definitions loots] As used herein, the follo-wing terms and phrases shall have the meanings set forth.
below. Unless defined otherwise, all technical and scientific terms .used herein have the same Meaning as COMMOIlly understood to one of ordinary skill in the are 100191 The compounds of the .present invention can be present in the form of pharmaceutically acceptable salts. The compounds of the present invention can also be present in the form of pharmaceutically acceptable esters (i.e., the methyl and ethyl esters of the acids of formula 1 and formula 11. to be used as prodrugs). The, compounds of the present invention can also be solvated, i.e. hydrated, The solvation can be affected in the course of the .manufacturing process or can take place i.e. as a consequence of hygroscopic. properties of an initially anhydrous compound of formula I and .formula 11 (hy drati on).
100201 Compounds that have the same molecular formula but differ in the nature or sequence of bondins.), of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement (.47 their atoms in space are tallied "stereoisamers." Diastereomers are stereolsomerS with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisamers bearing one or more.
asymmetric centers that are non- superimposable mirror images of each other are terrned "enantiomers." When a. compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enaraiomers is possible. An enantiomer can be characterized by the absolute configuration of its asynimetric center or centers and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated a.s.
dextrorotatory or levorotatory (-i.e., as (-0 or -)-isomers respectively). A
chiral compound can exist as either individual outraiomer or as a .mixture thereof. A mixture containing equal proportions of -the enantiomers is called a "racemic mixture".
10041 As used herein, -the term "metabolic condition" refers to an Inborn errors of metabolism (or genetic metabolic conditions) are ,t.);en.etic disorders that result from a defect in one or more. .metabolic pathways; specilically,, the function of an enzyme is affected and is either deficient or completely absent, 100221 in some embodiments, a molecular conjugate comprises of compounds selected from the group consisting of R-lipoic acid (CAS No. 1200-22-2), salsalate (CAS
No.
552-943), acetyI cystei no (CAS N. 616-9.1-4 Ei cosapentaenoi c acid (CAS No, 94-4), Docosanexaenoic acid (CA.S No. 6217-54-5), 10023] The term "polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound.
[00241 The phrases "parenteral ad-ministration" and "administered parenterally" as used herein refer to modes of administration other -than enteral and topical administration, such as injections, and include without limitation intravenous, -intramuscular,.
intrapleural, intravascular, intrapericardialõ intraarteri al, into:the:cat intracap.sular, intraorbital, intracardiac, intradennal, intraperitoneal, transtracheal, subcutaneous, subcuticular, Ultra-articular, subeapsularõ subarachnoid, intraspinal and intrastemai injection and infusion.
100251 A "patient," "subject," or "host" -to be treated by the subject method may mean either a 'Inman or .non-human animal, such as. primates, mammals, and vertebrates.
100261 The phrase "pharmaceutically acceptable" is art-recognized. in certain embodiments, the terrn includes compositions, polymers and. other inaterials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact With the tissues of mammals, hum.an beings and animals without excessive toxicity, irritation, allergic response, or other problem or complicaijon, commensurate with a reasonable benefitirisk ratio, [00271 The phrase "pharmaceutically acceptable carrier" is art-recognized, and includes, for example, pharma.ceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, solvent or encapsulating material involved in carrying or transporting any subject composition, i'rom one organ, or portion of the body, =to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a subject. composition and not injurious to the patient. In certain embodiments, a pharmaceutically acceptable carrier is rion-pyrogenic Some examples of materials which inay serve as pharinaceutically acceptable carriers include: (I) sugars, such as lactose, glucose and sucrose, (2) starches, such as corn starch and potato starch; (3) cellulose., and its derivatives, such as sodium carboxyrnethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, ol.ive oil, corn oil and soybean oil; (1.0) glycols, such as propylene glycol; 01) polyolsõ such as glycerin, sothitol, mannitol and polyethylene glycol; (12) esters., such as ethyl oleate and ethyl laurate, (13) agar, (14) buffering, agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (2() phosphate buffer .solutions; and (20 other non-toxic co.mpatible substances employed in pharmaceutical formulations.
100281 The term -prodrug" is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active .agents of the present invention, A common method for making a prodrug is to include selected moieties that are hydrolyzed under .physiological conditions to reveal the desired molecule. In other embodiments,. the prodrug is converted by an enzy.matic activity of the host animal.

[00291 The Tenn "prophylactic t-A- .therapeutic" treatinent is art-recognized and includes.
administration to the host of one or more of the subject compositions.. .If it is administered prior to clinical -manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developiRg the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects.
thereof), 100301 The term "predicting" as used herein refers to assessing the probability related diseases patient wiII suffer from abnormalities or complication and/or terminal platelet aggregation or failure andlor death (i..e. mortality) within a defined time wind.ow (predic.five window) in the future. The mortality may be caused by the central nervous stem or complication.. The predictive window is an interval in which the subject will develop one or more of the .said complications according to the predicted probability. The.
predictive window may he the entire remaining life.span of the subject .upon analysis by the riled-10d of the present invention.
100311 The term "treating" is art -.recognized and includes preventing, a disea.se, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it;
inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder .andlor condition.
Treating the disease or condition includes ameliorating at least one symptom of the.
particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the neurological condition such as epilepsy, bipolar disorder, trigeminal neuralgia, attention-deficit hyperactivity di sorder (ADHD), schizophrenia, fie uropath i pain, seizures, bipolar disorder, mania, phantom limb syndrome,. complex regional pain syndrome, paroxysm.al extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, myotonia conaenita and post-traumatic stress disorder of a subject by administration of an agent even though such agent does not treat the cause. of the condition. The term "treating"õ "treat" or "treatment" as used herein includes curative, preventative (e.g., prophylactic), .adjunct and palliative treatment.
10032] The phrase "therapeutically effective amount" is an art-recognized term. in certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefitlrisk ratio applicable to an' medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time.
The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in. the art may empirically deterrnine the effecti v e amount of a particular composition without necessitati lig undue experi mentafion.
10033] In certain embodiments, the .pharmaceutical compositions described herein are formulated in a manner such that. said compositions will be delivered -to a patient in a therapeutically effective amount., as part of 21 prophylactic or therapeutic treatment. The desired amount of the composition to be administered to a patient will depend on absorption ina.ctivationõ and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. lt is to be noted that dosage values may also vary with the severity of the condition to be alleviated. ft is to be fitrther understood that for any particular subject., specific dosage -regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
Typically, dosing will be determined using techniques known to one skilled in the art, 10034" Additionally-, the optimal concentration arid/or quantities or amounts of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which the preparation is .put, e.g., the site treated, the type of patient, e.g.:, human or non-human, adult or child, and the nature of the disease or condition.
[0035] in certain embodiments, the dosage of the subject compositions provided herein may be detennined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials, For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.
100361 When used with respect to a pharmaceutical composition or other material, the term "sustaìried release" is art-recognized. For example, a subject composition which releases a substance over time may exhibit sustained release characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time. For example, in particular e.mbodiments, upon contact with body fluids including blood, spinal fluid, mucus secretions, lymph or the like, one or more of the pharmaceutically acceptable excipients may undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g,., an therapeutic andlor biologically a.ctive .salt and/or composition, .for a sustained or extended period (as compared to the release from a bolus). This release may result in prolonged delivery of therapeutically effective amounts of any of the therapeutic agents disclosed herein, 10037" The phrases "systemic admini stratim," "achnini stered systemically,"
"peripheral administration" and "administered peripherally" are art-recognized, and include the administration of a subject composition, therapeutic or other material at a site remote from the disease being treated. Administration of an agent for the disease being treated, even if the agent is subsequently distributed systemically, may be tenned "local" or "topical" or "regional" adm.inistration, other than directly into the central nervous system, e.g., by subcutaneous .administration, such that it enters the patient's system and, thus, is subject to Metabolism and other like processes.

100381 The phrase "therapeutically effective amount" is an art-recognized tenn. hl certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a .reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the teffil refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time.
The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a partial' ar composition without necessitating undue experimentation.
100391 The present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as ph armaccuti cally acceptable salts of said prodrugs, 'ONO] This application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of a COM pound of Fomnda I and foïiìiula 1.1. tll ay be formulated .for systemic or topical Of oral adiiiini St f ati OR . The pharmaceutical composition may be also formulated for oral administration, oral .sol uti i eeti on, sub d erm al ad mi .n.i strati on, or Iran sdein al administration, The pharmaceutical compo.sition may further comprise at lea.st one of a pharmaceutically acceptable.
stabilizer, diluent, surfactant, filler, binder, and lubricant.
[0411 In many einbodiments, the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositiallS (Formula I and :Formula II) to be.
delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a. compound of formula I and formula II or composition as part of a prophylactic or therapeutic treatment. The desired concentration of formula. I and formula II
or its.
pharmaceutical acceptable salts will depend on absorption, inactivation, .and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject conipositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the, individual need and the .prolessional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined usirig techniques known to one skilled in the art.
10042] .A.dditionally, the optimal concentration andlor quantities or amounts of any particular compound of formula I and formula 1t may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.
10043] The concentration andfor amount of any compound of formula 1 and formula 11 may be readily id.entitied by routine screening in animals, e.g., rats, by screening a range of concentration andlor amounts of the material in question using appropriate assays.
Known methods are also available to assay local ti &RIO concentrations, diffusi On rates of the salts or compositions, and local blood flow before and after administration of therapeutic formulations disclosed herein. One such method is microdiatysis, as reviewed by T. L. 11.obinson et al., 1991, microdialysis in the neuroscience.s, Techniques, volume 7. Chapter 1. The methods reviewed by :Robinson may be applied, in brief, as follows. A. Microdialysis loop is placed in situ in a. test. animal. Dialysis fluid is pumped through the loop. When compounds with formula I and formula. 11 such as those disclosed herein are injected adjacent to .the loop, released drugs are collected in the dialysate in proportion to their local tissue concentrations. The progress of diffusion of the salts or compositions may be determined .thereby with suitable, calibration procedures using known concentrations of salts or compositions.
10044] In certain embodiments, the dosage of the subject compounds of formula I and formula 11 provided herein may be determined by reference to the plasma concentrations.

of the therapeutic composition or other encapsulated materials, .For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration -time curve from time 0 to infinity ma.y be used.
100451 Generally, in carrying out the methods detailed in this application, an effective dosage for the compounds of Formulas I is in the range of about 0.01 trio/kg/day to about 100 mg/kg/day in single or .divided doses, for instance. 0.01 mg/kg/day to about 50 mAgiday in single or divided doses. The compounds of Formulas I may be administered at a dose of, for example, less than 0.2 mg/kg/day, 0.5 mglkg/day, 1.0 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 ingikWday, or 40 mg/kg/clay.
Compounds (tf -Formula. 1 and tom-luta 1-1. may also be administered to a human patient at a dose of, for example., between 0.1 m.g and 1000 mg, between 5 mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000, 2000, 5000 mg. per day.
In certain embodiments, the compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 1.0% of th.e compound of formula.
I and .formula II required for the same therapeutic benefit, (00461 An effective amount of the compounds of formula. 1- and .formula 11 described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease.
100471 An effective amount may be sufficient to prohibit, treat, alleviate., ameliorate, halt, restrain, slow or reverse the progression, or reduce the severity of a complication resulting from. nerve damage or demyelization and/or elevated reactive oxidative-nitrosative species and/or abnormalities in neurotransmitter homeostasis's, in patients who are at risk for such complications. As such, these methods include both medical.
therapeutic (acute) and/or prophylactic (prevention) administration as appropriate. The amount and timing of compositions ad.mlnistered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician. Thus, because of patient-to-patient the dosages given above are a guideline and the physician may titrate doses of the dnig to achieve the treatment that the physician considers appropriate.
for the patient.
in considering. the .degree of treatment desired, the physician must balance a variety .of factors such as age of the patient, presence of preexisting disease, as Ake as presence of other diseases.
1004Si The compositions provided by this application may be administered to a subject in need of treatment hy a variety of conventional routes of administration, including orally, topically, pare.nterally, e.g., intravenously, subcutaneously or intramedullary, Further, the compositions may be administered intrana.sally, as a rectal suppository, or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need. to use water. Furthermore, the compositions may be administered to a subject in need of treatment by cmtrolled release dosage forms, site specific drug delivery, transdertnal drug delivery, patch (activelpassi ve) mediated drug. delivery, by stereotactic injection, or in .nanoparticles.
[00491 The compositions May be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses, Suitable pha.mmceufical carriers, vehicles and diluents include inert solid diluents or fillers., sterile aqueous solutions and various. organic .solvents. The pharmaceutical compositions formed by combining the compositions and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage :forms such as tablets, powiders, lozenges, syrups., injectable solutions and Me like.
These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as L-arginine, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrates such as starch, alginic acid and certain complex silicates, together with bindimz agents such as polyvinylpyrrolidone, sucrose, gelatin and. acacia, Additionally, lubricating agents such as inagnesium stearate, sodium laurvl sulfate and talc are often useful for tahletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Appropriate Materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening: or flavoring .agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof The compounds of formula 1 and formula 11 may also comprise enterically coated comprising, of various excipien ts., as is well known in the phaimaceutical art.
10050j For parenteral a.d.ministration, solutions of the compositions ma.y be prepared in (for example) sesame or peanut oil, aqueous propylene glycol, or in .sterile aqueous solutions may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or g$1ucose.
These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In -this COnflection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
100511 The formulations, for instance tablets, may contain e.g. 10 to 100, 50 to 250, 150 to 500 mg, or 350 to 800 trig e.g.. 10, 50, 100, 300, 500, 700, 800 mg .of the compounds of formula 1 and :formula 1111 disclosed herein, for instance, compounds of formula 1 and formula 1.11 or pharmaceutical acceptable salts of a compounds of Formula i.
100521 Generally, a composition as described herein .may be administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorder that prevent oral ad:ministration. or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician.
Localized administration may also be indicated, for example, when a high dose is desired at the target tissue or organ. For buccal administration the active composition may take, the form of tablets or lozenges formulated in a. conventional .manner.
[0053] The dosage administered will be dependent upon the identity of the .neurological disease; the type. of host involved, including its age, health and weight; the kind of concurrent treatment, if any; the frequency of treatment and therapeutic.
ratio.
100541 Illustratively, dosage levels of the administered active ingredients are:
intravenous, 0.1 to about 200 mg/kgõ intramuscular, 1 to about 500 ingfkg;
orally, 5 to about 1000 mg/kg; intranasal instillation, 5 to about 1000 ingfkg; and aerosol, 5 to about.
1000 niglkg of host body weight, 100551 'Expressed in terms of concentration, an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasally, pharyngolaryngeally, intravaginally, rectally, or ocularly in a concentration.
of from about 0,01 to about 50 70 wiw of the composition; preferably about 1 to .about 20% wiw of the composition; and for parenteral use in a concentration of from about 0.05 to about 50 A wiv of the composition and preferably from about 3 to about 20%
wfv.
100561 The com.positions of the present invention are preferably presented.
for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powdersõ granulesõ suppo.sitories, sterile parenteral solutiOTIS or suspensi OnS sterile non-parenteral solutions of suspensions:, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient. For oral administration either solid or fluid unit dosage forms can be prepared..
[00571 As discussed above, the tablet core coma-it-IS one or inore hydrophilic polymers.
Suitable hydrophilic polymers include, but are not limited to, water sNvellable cellulose derivatives, polyalkylene glycols, .thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof Examples of suitable water swellable cellulose derivatives include, but are not 1 inn ted to, sodium carboxymethylcellul use, cross-linked livdrxyupylceliulose.
hydroxypropyl cellul ose hydroxypropv methylcellu I ose hydroxyisopropylcellulose, hy drox y b uty [eel lulo se, hy droxyph eny I cellulose, hydroxyethylcellulose (HEC), hydroxypentylceliulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, and mixtures thereof.
Examples of suitable polyalkylene glycols include, but are not limited to, polyethylene glycol; Examples of suitable thermoplastic polyalkylene oxides include, but are not limited to, poly(ethylene oxide). Examples of suitable acrylic polymers include, but are not limited to, potassium inethacrylatedivinylbenZene copolymer, pol y m ethyl m ethacry are, hi gh ol cent at weight crossli nked acryli c acid homopol yirièrs and copolymers such as those commercially available from Noveon Chemicals under the tradename CARBOPOLIm. Examples of suitable bydrocolloids include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa cartageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan ta1111, gClIall gum, inallodextrin, galactomannan, pusstulan, laininarin, sclerogiucan, rurir arabic, inulin, pectin, gelati n, whelan, rhomsan, zoogl an, methyl an, chitin, cyclodextrin, chi tosan, and mixtures thereof.
Examples of suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and laponite; nragnesium trisilicate; magnesium aluminum silicate; and mixtures thereof. Examples of suitable gelling starches include, but are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch glycblate and derivatives thereof, and mixtures thereof. Examples of suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked awl'', and cross-linked carboxymethylcellulose sodium, and mixtures thereof.
j00581 The carrier ma.y contain one or more suitable excipients for the formulation of tablets, Examples of suitable excipients include, but are not limited to, fillers, adsorbents, bi nders, di si ntegrants, lubricants, glidams, release-modifying excipients, superdisintegrants, antioxidants, and mixtures thereof.

[00591 Suitable binders include, but are not limited to, dry binders such as .polyvinyl pvrrolidone and hydroxypropylinethylcellulose; wet binders such as water-soluble polymers, including hydrocdloids such as acacia, alginatesõ agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrinõ galactomarman, pusstulan, laminarin, scieroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin,. cyclodextrinõ chitosan, polyvinyl pyrroli done, cellulosics, sucrose, and starches; and mixtures thereof.
Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked.
polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches, microcrystalline cellulose., and mixtures thereof.
100601 Suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof. Suitable glidants include, but are not limited to, colloidal silicon dioxide.
Suitable release-modifying excipients include., but are not limited to, insoluble edible.
materials, pll-dependent polymers, and .atixtures .thereof, 10061] Suitable insoluble edible materials for use a.,s relea.se-modifying ex.cipients include, but are not limited to, .water-insoluble polymers and low-melting hydrophobic materials, copolymers thereof., and mixtures thereof. Examples of suitable water-insoluble polymers include, but are not limited to, ethyleellulose, polyvinyl alcohols., polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic. acid copolymers, copolymers thereof, and mixtures thereof.
Suitable low-melting hydrophobic materials include, but are not limited to, fats, fatty a.cid esters, phospholipidsõ waxes, and mixtures thereof. Examples of suitable fats include, but.
are not limited to, hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids and their sal.ts, and mixtures thereof.
Examples a suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, -mono-, di-, and triglycerides, glyceryl behenate, glyceryl palmitostearate, t,tlyceryl onostearate, glyceryl .td stearate, yceryl tri aurylate, gl yceryl state, GI y co Wax-932, lauroyl macrogo1-32 glycerides, steamy( macrogo1-32 glycerides, and aux-tures thereof. Examples of suitable .phospholipids e phosphotidyt choline, phosphotidyl.
serene, .phosphotidyl enositol, phosphotidic acid,, arid mix-tures thereof.
Examples of suitable waxes .include, but are not limited to, camauba wax, spermaceti wax, beeswax, candefilla wax., Shellac wax, microcrystalline wax, and paraffin svax; fat-containing mixtures such as chocolate, and mixtures thereof. Examples of super disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycol ate and cross-linked. povidone (crospovidone). In one embodiment the tablet core contains up to .about percent by weight of such super disintegrant.
100621 Examples of antioxidants include, but are not limited to, tocopherolsõ
ascorbic acid, sodium pyrosulfiteõ butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, and mixtures thereof Examples of preservatives inclUdC, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof.
[00631 in one embodiment., the immediate release coating has an average thickness of at least 50 .microns, such as from about 50 microns to about 2500 microns; e.g.., from about 250 _microns to about 100C) microns. In embodiment, the immediate .release coating is typically compressed at a density of more than about 0,9 gicc, as measured by the weight and volume of that specific layer, 100641 In one embodiment, the immediate release coating contains a first portion and a second portionõ wherein at least one of the portions contains the second pharmaceutically active agent, in one embodiment, the portions contact each other at a center axis (Jf the tablet. In one embodiment, the first portion includes the first pharmaceutically .active agent and the second portion includes the .second pharmaceutically active agent.

[00651 in one embodiment, the first portion contains the first pharmaceutically active, agent and the second portion contains the second pharmaceutically active agent. in one embodiment, one of the portions contains a third pharmaceutically active, agent. :In one, embodiment one of the portions contains a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet. core.
1006611 in one embodiment, the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core. in another embodiment the outer coating portion is included (If a dried granulation including the pharmaceutically !active agent.
100671 Formulations with different drug release mechanisms described above could be combined in a final dosage fonn containing single or multiple units. Examples of multiple units include multilayer tablets, capsules containing tablets, beads, or granules in a solid or liquid form. Typical, i irixnedi ate release formulations include compressed tablets, gels., .films, coatings, liquids and particles that can be encapsulated, for example., in a. gelatin capsule. Many methods for preparing coatings, covering or incorporating.
drugs, are known in the art..
[00681 The immediate release dosage, unit of the dosage form, i.e.., a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form, contains a therapeutically effective quantity of the active agent with conventional pharmaceutical excipiems. The .inmiediate release dosage unit may or may not be coated, and may or may not be admixed with the delayed release dosage unit or .units (as in an encapsulated mixture of immediate release drug-containing granules, .particl es or beads and delayed release drug-containing granules or beads), 10069j Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington¨The Science and Practice of Pharmacy", 20th. Ed., Lippincott 'Williams & Wilkins, Baltimore, MA., 2000).
A.

diffusion system typically consists of one of two types of devices, reservoir afld inatfiX, which are weliknown and described in die art. The matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form, 100701 An. .immediate release portion can be added to the extended release, system by means of either applying an immediate release. layer on top of the extended release core;
using coating or ecmnpression processes or in a multiple unit system such as a capsule containing extended and immediate release beads.
[007.1.1 Delayed release dosage formulations are created by coating a solid dosage form with a film of a. polymer which is insoluble in the acid environment of the stomach., but soluble in the neutral environment of small intestines. The delayed release dosage units can be prepared., for example, by coating a. drug or a drug-containing composition with, a selected coating material. The drug-containing. composition may be a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.
10072" A pulsed release dosage form is one that mimics a multiple dosing profile without repeated dosing and .typically allows at least a twofold reduction in dosing frequency as compared to the drug presented as a conventional dosage form (e.g., as a solution or prompt drug-releasing, conventional solid dosage form). A pulsed release profile is characterized by a. time period of no release (lag time) or reduced release followed by rapid drug release, 100731 Each dosage, form contains a therapeutically effective amount, of active agent. In one embodiment of dosage forms that mimic a twice daily dosing profile, approximately 30 wt. % to 70 wt. %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in the dosage forrn is released in the initial pulse, and, correspondingly a.pproximately 70 wt % to 3.0 wt. %, preferably 60 wt.. % to 40 wt. %, of the total amount of active agent in the dosage form is released in the second pulse. For dosage forms mimicking the twice daily dosing profile, the second pulse is preferably released approximately 3 hours to less than 14 hours, and more preferably .approximately 5 hours to 12 hours, following administration.
100741 Another dosage form contains a compressed =tablet or a capsule having a drug-containing immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit. lin this dosage form, the immediate release dosage unit contains a plurality o.f beads, granules particles that release drug substantially inimediately following oral administration proyid.e an. initial dose. The delayed rel.ease dosage unit contains a plurality of coated beads or granules, which release drug approximately 3 hours to 14 hours following oral administration to provide a second dose.
100751 For.- purposes of transdermal (e.g., topical) administration, dilute sterile., aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, may be prepared.
tooN Methods c.)f preparing various pharmaceutical compositions with a certain amount of one or more compounds of formula 1 and formula 11 or other active agents are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of .inethods of preparing pharmaceutical compositions, see Remington's Pharmaceutical. Sciences, Mack Publishing Company , Easton, Pa.., 19th :Edition (1995).
[00771 lh addition, in certain eMbodiments, subject compositions Of the present application. maybe lyophilized or subjected to another appropriate drying technique such as spray drying. The subject compositions may be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time, depending in part on the release rate of the compositions and the desired dosage.

100781 Formulations useful in the methods provided herein include those suitable for oral, nasal, topical (including buccal and sublingual), .rectal, vaginal, aerosol and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of .pharmacy.
The amount of a. subject composition which may be. combined Ivith a. earlier material to produce a single dose may vary depending upon the subject being treated, and the particular mode of administration.
1.0079.1 Methods of preparing these formulations or compositions include the step of bringing into association subject compositions with the carrier and, optionally, one or more accessory ingredients. in general, the formulations are prepared by uniformly and intimately bringing into association a subject. composition with liquid carriers, or finely divided solid carriers, or both, and then, if .necessaty, shaping the product.
100801 The compounds of .formula I and fornmla 1.1 described herein may be administered in inhalant or aerosol .formulations. The inhalant or aerosol formulations may comprise one or more agentsõ such as adjuvants, diagnostic agents, itnazing agents, or the.rapeutic agents useful in inhalation the.rapy. The final ae..rosol formulation may for example contain 0.005-90% wiw, for instance 0.005-50%, 0.005-5% wiw, or 001-1.0%
w/w, of Tnedicament relative to the total weight of the formul ati 100S1] In solid dosage forms for oral administration (capsules, tablets, pills:, drag,ees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers and/or any of the f011owing: (1) tillers or extenders, such as starches, lactose, sucrose, glucose, rnannitol, and/or silt& acid t (2) binders, .such as, .for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, *ink: acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary affill10111UM compounds; (7) wetting agents, such as, .for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite, clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions .may also eomprise buffering agents. Solid compositions of a similar type. may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugars, as veil as high molecular weight polyethylene glycols and the like.
[00821 Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs... In addition to the subject compositions, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, .water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular., cottonseed, corn, peanut, sunflower, soybean, olive, castor, and .sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
[0083] Suspensions, in addition to the subject compositions, may contain suspending agents such as, for example, ethoxylated isostearyl alcoholsõ polyoxyethylene sorbitolõ
and sorbitan esters, microcrystalline cellulose, aluminum meta.hydroxide, bentonite, agar agar and tragacanth, and MiXtlifeS thereof, j00841 Formulations for rectal or vaginal administration m.ay be presented as a suppository, .which may be prepared by mixing a subject composition x.vith one or more suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the 'appropriate body cavity and.

release the icapsulated compound(s) and composition(s). Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are 'known in the art to he appropriate, 100851 Dosage forms for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. A
subject composition may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. For transdermal administration, the complexes may include lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties.
1.00861 The ointments, pastes, creams and gels may contain, in addition to subject.
compo.sitionsõ other carriers, such as animal and vegetable fats, oils,.
.waxes, paraffins, starch, .tragacanfhõ cellulose derivatives, polyethylene glycols, silicones, bentonitesõ
silicic acid, talc and zinc oxide., or mixtures thereof. Powders and sprays may contain., in addition to a subject. composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of such substances.
Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
100871 Methods a delivering a composition or compositions -via a transdermal patch are known in the art. Exemplary patches and methods of patch delivery are described in 'US
'Patent Nos. 6,974,588, 6õ564,093, 6,312,716, 6,440,454, 6,267,983, 6,239,180, and 6,103,275.
1.00881 In another embodi rrieat, a transdennal patch rriay comprise: a substrate sheet comprising a composite film formed of a resin composition comprising 100 parts by weight of a polyvinyl chloride-polyurethane composite and 2-10 parts byeight of a styrene-ethylene-butylene-stvrene copolymer, a first adhesive layer on the one side of the composite film, and a polyalkylene terephthalate film adhered to the one side of the, composite film by means of the first adhesive layer, a .primer layer which comprises a saturated polyester resin and is formed on the surface of the polyaikylene terephthalate film, and a second adhesive layer comprising a styrene-diene-styrene block copolymer containing a pharmaceutical agent layered on the primer layer. A method for the manufacture of the above-mentioned substrate sheet comprises preparing the above resin composition molding the resin composition into a. composite film hy a calendar process, and then adhering a .polyalkylene terephthalate film on cme .side of the composite film by means of an adhesive layer thereby forming the substrate sheet, and forming a primer layer comprising a. saturated polyester resin on the outer surface of the polyalkylene terephth al ate fil m 100891 Another type of patch comprises incorporating the drug directly in a.
pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a suitable backing member, e.g. a polyester backing MeMbrane. The drug should he present.
at a concentration Ishieh will not affect the adhesive properties, and at the same time deliver the required clinical dose.
10090" Transdermal patches may be passive or active. Passive transdermal drug delivery .systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver small-molecule drugs. Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transdermal patches and may be delivered using technology such as electrical assist (iontophoresis) for large-molecule drugs.
(0091.1 lontophoresis is a technique employed. for enhancing the flux of ionized substances through membranes by application of electric current. One example of an iontophoretic membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by which iontophoresis enhances molecular transport across the skin are (a) repelling, a charged ion from an electrode of the same, charge, (b) electroosmosis, the, convective movement of solvent that occurs through a changed pore in response the preferential passage of counter-ions when an electric field is applied or (c) increase skin permeability due to application of electrical current, 10092.1 It) some cases, it may be desirable to administer in the form of a kit, it may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet. Typically the kit camptises directions for the administration of the separate components. The kit fonn is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and.
parenteral), are administered at different dosage intervals., or when titration of the individual corn ponents of the combination is desired by the prescribing physician.
100931 An example of such a .k.it is a so-called blister pack. Blister packs are well known in the packaging industry and are .widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a plastic matetial that ma.y be transparent, 100941 'Methods and compositions for the treatment of epilepsy. Among other things., herein is provided a method of treating epilepsy, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula 1:

HC N S
RI
S \

\ i 0 Formula I
Wherein, R.' independently represents, Hydrogen, D, o 9 0 0 NH2 0 , \
i¨o+ ___.µ0---------0, -----C
0 , /I\
\ __ N

csss NH? P=11-i, , H
H , OH

N N
or independent1N,' represents Acetyl (CH3C0-), sH

H
H-N

K$C
)12: NNµ,õ---e.,,,,õr""OH
,./vvvc HO

0 It o s ;:sSS
\
4 '7.
i I 0.13 1 6 19 0 , Ho ,----S H
, HO N
IN.
N

. , . .

CC)2H 0 eSS' CON H2 OH 41111111F Oµ17 1.1 OCOCH3 111111 0'21 , , , , ,ss zp *V

L Oil Si cH3 HC¨N 0 1 /. 10 CHa 4.0 , CH3 OH '.1.? 0 .

FIN)(NMI
int-imisi el 0 HN
0 NH2 , Ht N ,s$ /

=
a N b , or e b t2 cl C ;
a is independently 2,3 or 7;
each b is independently 3, 5 or 6;
e is independently 1, c and d are each independently H, L. -OH, -OD, CI-C-alkyl, -NHz or -COCH3;
10095] Accordingly, Methods and compositions for the treatment of epilepsy Among Other things, herein is provided a method of treating epilepsy, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Fonnul a 11:
L......Hri,...
-: ' ""===.. R2 N"..-H

Formula 11 Wherein, independently represents, Hydrogen, a o o o ok----"C\ -0 C , o o o o H / FE H
N
H , H H
,,,t.iieiN =,,,,N.,.."0õ,,,N,,,,.. d",./.4...,,,,,,,,õ,,,, ...., , N, /11\\ /\/1\ i , , H H
tzc, N ............,..---..,,,,.... ...õ....,..",,..õ....õ.....õA õ,,,S, -A., .........---..N,,,.."....-",..,.....N...,,,,--1, or H ;
R. independently represems Acetyl (0-13C0-), .,....",SH

).....,... H,,, . 0 0 H2N4, HaC
i ( ..).N HS..=== OH
, . , HO..õ...........,................z..........õ,,,,N... ) ze. -:

, .
' o o -c) s--......-s s-,s , ......_ 0 .

.-csS5 5 8 11 14 17 20 \..
s / -0 ...
N CH-;
".....õ, ' H
.., OH
1.7:. H --OH
HO N**".,-,...õ,"-"--*N.-,õ,,õ,=,µ
cs..k NI

CO2 H lio 0 ess., el coNH2 0..... 40 (....
1110 0..(zi.-OH0(2"; OCOCH3 -s zp ..57T CH3 CH3 OH 0 H3C¨N+ 01 0 CH3 ,c, = a 01:1 OH =:27 0 HNVIIN
NH
El H
ittli S
HN d'i ,, ' Ncssk HO
O
[1 or b C d a is independently 2,3 or 7;
each b is independently 3õ 5 or 6;
e is independently 1, 2 or 6;
c and d are each independently H. D, -OH, -0D,, C1-C6-alkyl, -NH 2 or -COCH3.
Method s fir using compounds giformula I and .formula 1.11.
ioo96] The invention also includes methods for treating epilepsy and neurological disorders such as convulsions, partial seizures., or as an adjunctive therapy for partial, myocionie, tonic-clonic seizures, mood-stabilizing agent, bipolar disorder, TOUrette.
syndrome, Alzheimer's disease, autism, bipolar disorder and anxiety disorder, trigeminal neuralgia. It is also used for a variety of indications, including attention-deficit hyperactivity disorder, schizophrenia, neuropathic pain, seizures, bipolar disorder, mania, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, Myotoni a. congenita and post-traumatic stress disorder.

METHODS OF MAKING
[0971 lExampleS (4..S\inthetic path Ways useful for making coMpounds of formula 1 and formula II are set forth in example below and generalized in scheme I through scheme 2:
Scheme-I:
1) Br(C1-12)-3C00 Et Br ____ r., 6--Li ______ ), I \ ..
Et20 2) IN HU
1 5-1Oct 2 3 Br -.-K.:.1C01 S --s Ki I-a L1-1 i0.1-120 (cataJy,Vc) N.. r-- --, \
Acetone \ s Ny0 THEH, 011 \ -1'1 S NI
OH
, , rt 4.1 h 5 0 rt., 4ii 6 0 HOOCH H
--...---%..---. .) _____________________________ fp CI
S-s benzene S-s T 0 0, 4h 8 , S

\ A...........\\õ. k2CO3 \ tar CI
S OH + ______________________________ 4 0 S =-= S EWE
6 8 V c-rt, 1211 SA1 \ 0 0 S \
te S-s 100981 Step-1: Synthesis of compound 1 Br(Cf-12),3000Et n-BuLi -70 C, 2,5 h S
-c _____ Br _______ Et20 8 2)1 N HC
1 50 2 Br [00991 A mixture of n-butyllithium (44 mL, 0.11 mol, 2.5 M) and anhydrous Et20 (60 mL) was placed on an ice bath. A solution of 2-bromo-3-methylthiophene (17.7g, 0.10 mol) in anhydrous Et20 (25 mL) was added within 30 min while the temperature was kept at 5-10 A?. Stirring was continued at 10 ctµ for another 15 min. betbre the mixture was cooled to -70 ()C. A solution of ethyl 4-bromobutyrate (7.8 g, 0.040 mot') in anhydrous .Et20 (25 mlõ.-) was added at such a rate to the 2-lithio-3-methylthiophene 2 that.
the temperature was kept below -65 C.. When the addition was cmiplete the mixture as stirred at -70 'C for 2.5 h. Cold wa.ter (30 m..) and cold aqueous l N HC1(1.5 mL) were.
introduced successively while the temperature was kept below 0 C. The reaction mixture was stirred for 15 min to allow the tem.pera.ture to rise above 0 "C, and the phases were.
separated. The aqueous phase .was extracted with Et() (50 and the combined organic phases were washed with cold water (25 ntL) and brine (25 mL). After the, solution was dried over anhydrous a7SO4, the solvent vsTas evaporated in vacuo to an oll which was dissolved in 2-propanol. (100 .inL), A 2.0% aqueous El2SO4 solution (10 mt) was added, and the .mixture was stirred at room temperature for 3 h, The solvents were evaporated in vacuo to give a residue which was partitioned between CH 2C12 (200 mL) and a saturated NaHCO3 solution (50 mil4. The phases were separated, and the aqueous phase with pH 8-9.) was extracted further with CH2C12 (50 mL), The combined organic phases were washed with wat.er (50 brine (50 mL), and dried. a2SO4). The solvent was evaporated in yacuo to give an oil which was purified on a silica gel column) to provide 3 (773 yield from ethyl 4-bromobutyrate) as an oil.
[001001 Step-2: Synthesis &compound 5:

S
0 K,C,03 ' Kcayc) Br Acetone rt, 44 h 5 1001011 Compound 3 (0,02 mol) was dissolved in acetone (50 mi.:), and ethyl 3-piped dine carboxylate 4 (0.02 mol), K:1 (0,002 mot), and K2CO3 (0.02 mol) were added to give a slurry which was stirred at ambient temperature for 44 h. The reaction mixture was filtered, and the filtrate was washed with acetone, the combined filtrate was concentrated in vacuo to afford the desired ester 5 as gum.
[00.1021 Step-3: Synthesis of compound 6:
rr Li0H.H20 THF:H20(1 :1 ) OH

5 0 rt; 4h 6 0 1001031 Compound 6(.1mmol) was taken in RB and added THF, water (I :1, 4+4 ml) and Lithium hydroxide monohydrate 2 mmol at room temperature and stirred the reaction mixture at n for 4h. After completion of the reaction as indicated by TLC the mixture was acidified N.Vith. 10% aqueous citric acid and added ethyl acetate. The :layers were separated and the organic layer was dried over Na2SO4 and removed the solvent to get the product 6 1001041 Step-4: Synthesis of compound 8:
SO a2 CI
S¨

benzene S
S
7 0 C, 4h 8

6 1001051 Acid 7 (10 mmol) as taken in a RR added benzene and cooled to 0 'C and added thionyl chloride (13 mmol.) dropwise and stirred the reaction .MiXtille at same temperature for 4 h. After completion of the reaction as indicated by TLC, benzene was distilled and the crude acid chloride 8 was used for the next step.
[001061 Step-5: Synthesis of compound 9:

r. =

c-rt, 12 h \
S
- \,>
S

[001.0711n a I-U3 acid 6 (1.0 nunol) & anhydrous .K2CO3 (3.0 mmol) were suspended in dry .DMIF (10 .vol) stir at TOOM temperature for 30 min and then cooled to -10 'V, acid chloride 8 (1.0 mmol) was added slowly drop wise over then was allowed to stir at room temperature for 12 h. Reactio.n was monitored by TLC, On conviction of the reactio.n, the reaction mixture was poured into water (10 and extracted with diethyl ether (2 x.
tril). The combined organic layers were washed with water (2 x 5 -int) followed by bfine solution (10 mL), dried over anhydrous Na2SO4. and evaporated under reduced pressure. The crude: WaS purified by column chromatography over 100-200 mesh silica.
gel to get the compotmd 9.

Scherne-2:
TBAB
NH, 0 KOH KOH
V -....,...,...-NA IN DCM - N
a+ a ................ g. -------------------------i. .
Toluene -,";\,011 1 2 rt, 12 h. 800/0 0 3 Ha 4 12 h; 76%
CICOOEt, Et3N
o, 0 yL i P N
NA
Li060 cC 3 niln,.. -t..
........._,.......1."NH2 + CI o a _ ,- , IDT) H 0-4 NH4OH DCMC;143L:N 0:1) a 0 C-rt, 12 h 65% 5 6 overnight 7 K2CO3 (Hi' 0 HO H 0r \l' +
--------------------------- . 0 H
ME rjy"\-----\,--n o S,s [0.1081 Step- i : Synthesis (4.compound 3:

KOH --.) .....,,,,,,,.......õ.0H + a _________________ T
Toluene I 2 rt, 12 h, BO%

1001091 To a cold O'C. solution of compound 1 (0..122 mol) in toluene (80 ml) was added anhydrous sodium sulphate ().129 mol), and the mixture stirred at this temperature for lb. Powdered potassium hydroxide (0335 IWO was gradually added followed by dropwise ad.dition of 4-ch1orobutyryl chloride 2 (0.122 mol) with vigorous stirring After completion of the reaction, the reaction mixture is filtered through celite.
Organic extracts were dried over Na2SO4 and concentrated in mew) to give compound 3.
[00110j Step-2: Synthesis of compound 4:

KOH
=---4N¨N) DCM
KMn04 12 h, 76%
1001111 Aqueous potassium hydroxide (0.017 mot in 10 ml water), tetra-n-butyl ainmoni W11 bromide (0.0062 mol) and compound 3 (0.0063 mot) in DCM (10 ml) was stirred for 30 min at room temperature and then added potassium permanganate (0.094 mol)and continued the stirring. After completion of reaction filtered through celite bed and 'ashed with water (10 m1). The aqueous later WI was adjusted to 3 using Ha (2 ml), added sodium phosphate(0,0152 mot) and toluene (25 ml). The reaction mixture was extracted with DCM (2X25 m1). The organic layer was dried with Na2,SO4 and distilled under reduced pressure to compound 4 as oil. To this toluene (10 ml) was added and stirred at 0 'C for about 30 min. The solid was filtered and washed with toluene (5 ml) to afford the pure compound 4.
10011121 Step-3: S y nth esi s of compound 5:
CICOOEt, Et3N
THF
_ m 0 C , 30 min N
F
OH
NH, N1-1,40H
0 O C-rt,12h 0 65% 5 1001131 To a cold 0 "C solution i3f acid 4 (0,292 mol) and Et3N (0,307 mol) in anhydrous THI: (20 ml) was added ethyl chloroformate ( 0.304 mol) and the mixture stirred at 0 "C for 30 min. Ammonium hydroxide (25%, wN aqueous solution, 19 ni1,136.0 mol) was added and the reaction mixture was stirred at room .temperature .for 12b. After the addition of K2CO3 (30,0 mol), the mixture was -filtered and the volatile material ( solvent and EtiN) distilled off in vacua The solid residue was extracted with DCM (3x50 mi) and combined extracts were dried over Na2SO4 and concentrated in vacua recrystallization from acetone gave compound 5 as white solid.
1001.141 Step-4: Synthesis of compound 7:

11' H
N LO But N
= . õNI-12 + CLOC1 0 H
DCM:CH3CN (1:1) ' 6 overnight 1001151 Compound 5 (1 mmol) in 2.5 .m1 of DC and 2.5 ml of CH3C.N. is cooled to 0 T . Lithium t-butoxide (1.0M in hexanes, 1.1 Mur101) was added and the mixture was stirred at 0 'C. for 15 -min and then at room temperature for 10 min. The reaction .mixture is re cooled to 0 T and added 1-chloroeth0 chloro formate 6 (1,2 mmol) dropwise. The reaction mixture is stirred at 0 "C for 15 min and then allowed to stir at room temperature overnight. After completion of reaction, the mixture is diluted with .Dc and added water and the layers were separated. The organic layer is washed with water and brine, dried over Na2S0.4 and concentrated in. vacua Purification by silica Q:el chromatography afforded the compound 7.
1001.1.6j Step-5: Synthesis of compound 9:

K2ca$
S-s DMF
-10 '-)C

7 a .*

s [00.1..I.71 lin a. RB flask the acid 8 (1.2 mmol) & anhydrous K-,CO3 (3.0 .minol) was taken in dry DIMF (10 vol) stir at room =temperature for 30 min and then cooled to -10 'C, compound 7 (in DMF) was added slowly drop wise over 10 min. & then was allowed to stir at room temperature for 12 h. 'Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was poured into water (10 nit) and extracted with diethyl.
ether (10 ml). The combined organic layers were µ\iashed with water (2 x 5mL) followed by brine solution (10 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude was purified by column chromatography over 100-200 mesh silica gel to yield the product 9, -EXAMPLES
1001181 Blood and cerebrospinal fluid pharmacokineties in comparison of the, levetiracetam and Formula 11 (2-1) in rats The temporal pharmacokinetic interrelationship of leV tiracetam and Formula 11 (2-1) in blood and cerebrospinal fluid (CSF) was studied after acute intraperitoneal administration of levetiracetam and Formula 11 (2-I ), (20, 40 and 80 ing/kg,), using an animal model that permits concurrent blood and CSF sampling in freely moving rats. After administration, leyetira.cetain and FOrillula 1.1 rapidly appeared in. both serum (time to maximum concentration (Tmax) .mean range 0.25-0.50 h and 0.47-).89 respectively) and CST' (Tmax mean range 1.33-1.92 it and 2.14-2,83h respectively), suggesting ready penetration of the blood brain barrier. Both serum and CSF levetiracetam and Formula II
(2-1) concentrations rose essentially linearly and dose-dependently, suggesting that transport across the blood-brain barrier is not rate limiting.
Test Compounds -Elimination. half-life (t1/2) Elimination half-life (t1/2) ¨ Serum (Mean) Hours CSF (Mean) Hours e yeti racetam 1.8 - 2.8 4.4 - 4.9 Formula (2-1) 2,1 ¨3.4 4.8 ¨ 5.6 [001.I.91 The .term "sample" .refers to a sample of a body fluid, to a sample of separated cells or to a sample from a. tissue or an organ. Samples of body fluids can be obtained by well known techniques and. include, preferably, samples of blood, plasma, serum, or urine, more preferably, samples of-blood, plasma or serum. Tissue or organ samples may be obtained from any tissue or organ by, e.g, biopsy. Separated cells may be Obtained from the body :fluids or the tissues or organs by separating techniques such as centrifugation or cell sorting. Preferably, cell-, tissue- or organ samples are obtained from those cells, tissues or organs which express or produce the peptides referred to herein.
EQUIVALENTS
100120j The present disclosure provides among other =things compositions and methods for treating epilepsy and their complications. While specific embodiments of the. subject disclosure have been discussed, the above specification is illustrative and not restrictive, -N4any variations of the systems and M et h od. s herein 58' 11 b ecom e apparent to those skilled.
in the art upon review of this specification. The full scope of the claimed systems and methods should. be determined by reference to the. claims, along with their full scope of equivalents, and the specification, along with such variations, INCORPORATION BY REFERENCE
1001211 All publications and patents enti on ed herein., in C.1 tiding those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated hy reference. In case of conflict, the present application:, including, any definitions herein, will control,

Claims (17)

52

1. A compound of Formula I:
or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer, or stereoisomer thereof, wherein:
R1 represents H, D, R2 represents acetyl (CH3CO-), a is 2, 3 or 7;
each b is independently 3, 5 or 6;
e is 1, 2 or 6; and c and d are each independently H, D, -OH, -OD, C1-C6-alkyl, -NH2 or -COCH3.

2. A compound of Formula II:
or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer, or stereoisomer thereof, wherein:
R1 represents, Hydrogen, D, R2 represents acetyl (CH3CO-), a is 2, 3 or 7;
each b is independently 3, 5 or 6;

e is 1, 2 or 6; and c and d are each independently H, D, -OH, -OD, C1-C6-alkyl, -NH2 or -COCH3.

3. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 3, wherein said pharmaceutical composition is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration.

6. The pharmaceutical composition of claim 4, wherein said pharmaceutical composition is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration.

7. The compounds and compositions of claim 5, wherein said compounds and compositions are formulated for the treatment of epilepsy, bipolar disorder, trigeminal neuralgia, attention-deficit hyperactivity disorder, partial seizures, adjunctive therapy for partial, myoclonic, tonic-clonic seizures and schizophrenia, neuropathic pain, seizures, Tourette syndrome, Alzheimer's disease, autism, bipolar disorder and anxiety disorder, bipolar disorder, mania, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, myotonia congenita and post-traumatic stress disorder.

8. The compounds and compositions of claim 6, wherein said compounds and compositions are formulated for the treatment of epilepsy, bipolar disorder, trigeminal neuralgia, attention-deficit hyperactivity disorder, partial seizures, adjunctive therapy for partial, myoclonic, tonic-clonic seizures and schizophrenia, neuropathic pain, seizures, Tourette syndrome, Alzheimer's disease, autism, bipolar disorder and anxiety disorder, bipolar disorder, mania, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, myotonia congenita and post-traumatic stress disorder.

9. A compound of claim 2, having one of the following structures:

10. The pharmaceutical composition of claim 3, further comprising a molecular conjugate of compounds selected from a group consisting of (R)-1-[4,4-bis(3-methylthiophen-2-yl)but-3-enyl] piperidine-3-carboxylic acid and carboxylic acid compounds selected from a group consisting of R-Lipoic acid, eicosapentaenoic acid and docosahexaenoic acid.

11. The molecular conjugate of claim 10, wherein the carboxylic acid compound is R-Lipoic acid.

12. The molecular conjugate of claim 10, wherein the carboxylic acid compound is eicosapentaenoic acid.

13. The molecular conjugate of claim 10, wherein the carboxylic acid compound is docosahexaenoic acid.

14. The pharmaceutical composition of claim 4, further comprising a molecular conjugate of (S)-2-(2-oxopyrrolidin-1-yl)butanamide and compounds selected from a group consisting of R-Lipoic acid, eicosapentaenoic acid and docosahexaenoic acid.

15. The molecular conjugate of claim 14, wherein the carboxylic acid compound is R-Lipoic acid.

16. The molecular conjugate of claim 14, wherein the carboxylic acid compound is eicosapentaenoic acid.

17. The molecular conjugate of claim 14, wherein the carboxylic acid compound is docosahexaenoic acid.