WO2013017974A1

WO2013017974A1 - Compositions and methods for the treatment of neuromuscular disorders and neurodegenerative diseases

Info

Publication number: WO2013017974A1
Application number: PCT/IB2012/053555
Authority: WO
Inventors: Mahesh Kandula
Original assignee: Mahesh Kandula
Priority date: 2011-07-30
Filing date: 2012-07-12
Publication date: 2013-02-07

Abstract

The disclosures herein provide compounds of formula 1 or its pharmaceutical acceptable salts, as well as polymorphs, enantiomers, stereoisomers, solvates, and hydrates thereof. These salts may be formulated as pharmaceutical compositions. The pharmaceuiicai compositions may be formulated for peroral administration, transdermal administration, transmucosal, syrups, topical, extended release, sustained release, or injection. Such compositions may be used to treatment of metabolic condition, neuromuscular disorders and neurodegenerative diseases or its associated complications.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROMUSCULAR DISOR ERS AND NEURODEGENERATIVE DISEASES

EEJORiTY

|000i| This application claims priority to United States Provisional Application No, 61 513541 , filed on 30^!ii July, 201 1. The entire disclosures of those applications are relied on and incorporated into the application by reference.

FIELD OF INVENTION

{000 1 This disclosure generally relates to compounds and compositions for the treatment of neiiromuscuiar disorders, metabolic condition and neurodegenerative diseases. More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, esters, salts, hydrates, prodrugs, or mixtures thereof.

BACKGROUND

{0003 j Intercellular communication in the central nervous system requires the precise control of the duration and the intensity of neurotransmitter action at specific molecular targets. Plasma membrane neurotransmitter transporters are responsible for the high- affinity uptake of neurotransmitters by neurons and glial cells at the level of their plasma membrane.

|000 J Parkinson's disease (PD) is a neurodegenerative disorder that is characterized, in part, by a. progressive loss of dopaminergic neurons hi the. substantia nigra, pars compacta. it affects .1.5% of the global population over 65 years of age. The lack, of dopamine causes the classical motor symptoms of hradykinesia, rigidity and resting tremors. These symptoms are improved b current dopamine replacement strategies, which include levodopa (l-DOPA, the precursor of dopamine) and dopamine receptor agonists, as well as monoamine oxidase B (MAOB) inhibitors and catechol O-methyltransf erase inhibitors. [OOOSj Current therapeutic development in. PD includes approaches such as re-formulations (for example, extended release formulation) of existing drugs that are approved for PD, repositioning of compounds that are approved for other indications (such as the antihypertensive drug isradipine, the antiepileptic toptramate or methylphenidate) and development of novel small-niolecule and gene therapy-based approaches. The therapeutic development pipelines appear to be vigorous on the surface. However, once dopaminergic compounds are removed from the development pipeline, the current, landscape is far less encouraging. Such dopaminergic therapies Include new formulations of existing drugs, which are more likely to provide incremental rather than profound improvements over existing therapies.

[00061 Many of the therapies thai are currently under development— including both dopaminergic and non-dopaminergic compounds— are focused on improvement of motor control, fluctuations and dyskinesias. Far fewer approaches address the other two key unmet clinical needs, specifically: alleviating non-motor symptoms; and disease modi.fi cation and/or neuroprotection .

{000 j eurodegenerative disorders are a heterogeneous group of diseases of the nervous system, including the brain, spinal cord, and peripheral nerves that have much different aetiology. Many are hereditary; some are secondary to toxic or metabolic processes. Free radicals are highly reactive molecules or chemical species capable of independent existence. Generation of highly Reactive Oxygen Species (ROS) is an integral feature of normal cellular function like mitochondrial respiratory chain, phagocytosis and arachidonic acid metabolism. The release of oxygen free radicals has also been reported during the recovery phases from many pathological noxious stimuli to the cerebral tissues. Some of the neurodegenerative disorders include Alzheimer's disease, Huntington's disease, Parkinson's disease and Lateral sclerosis.

{0008] 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 neuromuscular disorders and neurodegenerative diseases. SUMMARY OF INVENTION 0009] 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 conditions such as neuromuscular disorders and neurodegenerative diseases.

j^'0010| The invention herein provides compositions comprising of formula I or pharmaceutical acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula I or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of neuromuscular disorders and neurodegenerative diseases and its associated complications.

Formula i

[0011 J Accordingly, the present invention relates to the compounds and compositions of formula I, or pharmaceutically acceptable salts thereof.

Formula I

Wherein

R*. R^" each independently represents hvdroyen, hvdroxvl, methvl, ami ne, cvcohexyl methyl ether, hutoxy, propoxy, thiol, alkyl, alky! thiol, acetyl thiol, disulfide, acyl, aeyialkyl. alkenyl, alkyl thioatkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyi, aryloxyalkyl, arylthioalkyl, cycloalkyi ether, ester, heteroaryl, heterocyclyi, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl;

¾ independently represents hydrogen, alkyl, methyl, ethyl, carboxyi, amine or thiol;

R⁴ independently represents null, hydrogen, alkyl, carboxyi, amine, thiol, amine, cycohexyl methyl ether, butoxy, propoxy, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl, acyialkyi, alkenyl, alkylthioalkyl, aikyny alkoxyaryl aikoxyalkyl, aryl, aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyi, ether, ester, heteroaryl, heterocyclyi, lower alkyl, sulfone, sulfoxide, hydroxyalkyl, -NH-CO-CH₂-NH-, - H-CO-, R-COO-R¹, thiol or 2- amino-3-hydroxy-N-methylpropanamide;

R" each independently represents null, hydrogen, alkyl, methyl, ethyl, carboxyi, amine, thiol, amine, cycohexyl methyl ether, butoxy. propoxy, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl, acyialkyi, alkenyl, alkylthioalkyl, aikynyl, alkoxyaryl, aikoxyalkyl, aryl, aralky!, aryloxyalkyl arylthioalkyl cycloalkyi, ether, eater, heteroaryl, heterocyclyi, lower alkyl sulfone, sulfoxide, hydroxyalkyl, -NH-CO-CH₂~NH~, -NH-CO-, R-COO-R¹, thiol, - H2- H.2-, hydrazine, 2-amino-3-hydroxy-N-methy!propanamide_>

R° each independently represents null, hydrogen, alkyl, methyl, ethyl, carboxyi, -NH-CO- NH-, amine, cycohexyl methyl ether, butoxy, propoxy, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl, acyialkyi, alkenyl, alkylthioalkyl, aikynyl, alkoxyaryl, aikoxyalkyl, aryl, aralkyl aryloxyalkyl, arylthioalkyl, cycloalkyi, ether, ester, heteroaryl, heterocyclyi, lower alkyl, sulfone, sulfoxide, hydroxyalkyl, -NH-CO-CHa-NH-, -NH~CO-, R-COO-R¹,

thiol.

or 2-amino-3-hydroxy- -m eth l propan ami de;

R⁷, R⁹ each independently represents null, 

[0012] Also described are pharmaceutical formulations comprising at least one compound of the invention.

[0013J Also described herein are methods of simultaneously regulating neuromuscular disorders and neurodegenerati e diseases in a patient in need thereof, by administering to the patient an effective amount of a compound of the invention.

(001 ] The invention also includes pharmaceutical compositions that comprise an effective compound of the invention and a pharmaceutically acceptable carrier. The compositions are useful for treating or preventing neuromuscular disorders and neurodegenerative diseases. The compound of invention which provided as a pharmaceutically acceptable prodrug, a hydrate, a salt, such as a pharmaceutically acceptable salt, enaniiomer, stereoisomer, or mixtures thereof [0015] Described herein are compounds of Formula Ϊ:

Formula Ϊ and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enanttomers, and stereoi somer s thereof;

Wherein

R¹, R^x each independently represents hydrogen, hydroxy I, methyl, amine, cycohexyl methyl ether, butoxy, propoxy, thiol, alkyl, aikyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyi, alkylthioalkyl, alkyny!, alkoxyaryl, alkoxyaikyl, aryl, aralkyi, aryioxyalkyl, arylthioalkyl, cycloalkyi, ether, ester, heteroaryl, heterocyclyi, Iower aikyl sulfone, sulfoxide, or hydroxyalk l;

R* each independently represents hydrogen, aikyl, methyl, ethyl, carboxyl, amine or thiol;

R⁴ each independently represents null, hydrogen, alkyl, carboxyl, amine, thiol, amine, cycohexyl methyl ether, butoxy, propoxy, thiol alkyl, alkyl thiol acetyl thiol, disulfide, acyl, acylalkyl, alkenyi alkylthioalkyl , aikynyi, alkoxyaryl, alkoxyaikyl, aryl aralkyi, aryioxyalkyl, arylthioalkyl, cycloalkyi ether, ester, heteroaryl, heterocyclyi, Iower alkyl, sulfone, sulfoxide, hydroxyalkyl, -NH-CO-CH2-NH-, - H-CCk R-COO-R¹, thiol or 2- amino-3-hydroxy-N-methyJpropanamide;

R⁵ each independently represents null, hydrogen, alkyl, methyl, ethyl, carboxyl, amine, thiol, amine, cycohexyl methyl ether, butoxy, propoxy, thiol, alkyl, alky! thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyi, alkylthioalkyl, aikynyi, alkoxyaryl, alkoxyaikyl, aryl, aralkyi, aryioxyalkyl, arylthioalkyl, cycloalkyi, ether, ester, heteroaryl. heterocyclyi, lower alkyl, sulfone, sulfoxide, hydroxyalkyl, ~NH-CO~CH₂-NH-, - H-CO-, R-COO-R¹, thiol, - NH₂- M₂-, hydrazine, 2~amino~3 -hydroxy-N-methyipropanami de,

" each independently represents null, hydrogen, alkyl, methyl, ethyl, earboxyl, -NH-CO-

NH-, amine, cycofiexvl methyl ether, hutoxy, propoxv, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, aey acylaikyi, alkenyi, alkylthioalkyl, alkyny!, alkoxyaryl, alkoxyaikyl, aryl, aralkyh aryloxyalk l, arylllrioalkyl, cyeloaikyl, ether, ester, heieroaryi, heterocyeiyl, lower alkyl, suifone, sulfoxide, hydraxyalkyl, -NH-CO-CH₂-NH-, -NH-CO-, R-COO-R¹, thiol

or .2 -ami no-3 -hy droxy-N -methy !propanam ide; 7, R each independently represents null,

R R ^' each independently represents 

001< ] In other iiiustrative embodiments, compounds of the formula 1 are as set forth below:

(1 -4)

(1 -5)

(1 -6)

(1-7)

017 J Herein the application also provides a kit comprising any of the pharmaceutical compositions disclosed herein. The kit may comprise instructions for use in the treatment of neuromuscular disorders and neurodegenerative diseases or its related complications. [0018] The application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compositions herein. In some aspects, the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, parenteral administration, injection, subdermal administration, or transdermal administration.

[0019] Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the treatment of neuromuscular disorders and neurodegenerative diseases or its related complications.

[0020] The compositions described herein have several uses. The present application provides, for example, methods of treating a patient suffering from neuromuscular disorders and neurodegenerative diseases or its related complications manifested front .metabolic conditions., chronic diseases or disorders; flepatology. Hematological, Orthopedic, Cardiovascular, Renal. Skin, Neurological or Ocular complications.

DETAILED DESCRIPTION 0021] Definitions

100 21 As used herein, the following 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 commonly understood to one of ordinary skill in the art,

[0023] The term "alk l" refers to the radical of saturated aliphatic groups, including straight-chain alkyi groups, brane ed-chatn alkyl groups, cycloalkyl (alicyelie) groups, alkyl-subststuted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. I preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C 1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. ^"Likewise, preferred cycloalkyl s have from 3- 1 carbon atoms in their ring structure, and more preferably have 3, 6 or 7 carbons in the ring structure.

[0024] The term "alkyl" as used herein refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3). ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n- propyl -CB2CH2CB3), 2-propyi (i-Pr, i -propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, - CH2CH2CH2CB3 ), 2-methyW -propyl (i-Bu, i-but l, -CH2CH(CH3_.)2_;X 2-butyI (s-Bu, s- butyl, - CH(CH3)CH2CH3), 2-metbyl-2-prapyi (t-Bu, t-butyl, -C(CH.3)3), 1-pentyl (n- pentyl, - CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (- CH(CH2CH3)2), 2- methyl -2-butyl (-C(CH3)2CH2CH3)_> 3 -methyl -2 -butyl (- CH(CH3)CH(CH3)2), 3 -methyl- 1 -butyl (-CH2CH2CH(CH3)2), 2-methyl-l -butyl {- CH2CH(CH3)CH2CH3), 1 -hexyl (- CH2CH2CH2CH2CH2CH3), 2-hexyl (- CB(CH3)CH2CH2CH2 CH3), 3-hexyI (- CH(CH2CIO)(CH2CH2CH3))_s 2-methyl-2- pentyl (-C(CH3)2CH2CEJ2CH3)_> 3-.meihyl-2-peniyl (- CH(CH3)CEJ(CH3)CH2CH3), 4- methyl-2-pentyI (-CB(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2- methyl~3~pentyl (-CH(CH2CH3)CH(CEJ3)2), 2,3-dimethyl-2-butyl (- C(CH3)2CEJ(CH3)2), 3,3-dimethyl-2-buiyl (-CH(CH3)C(CH3)3, l -heptyl, 1-octy.l, and the like.

|0025| The term "aikerryl" refers to linear or braoched-chain monovalent hydrocarbon radical of two to twelve carbon atoms with ai least one site of unsaturation, i.e., a carbon- carbon, sp double bond, wherein the aikerryl radical includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. Examples include, but are not limited to, ethylenyl or vinyl (-CH=€H2), ally! (-CB2CH==€H2), and the like. The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a carbon- carbon, sp triple bond. Examples include, but are not limited to, ethynyl (-OCH), propynyl (propargy!, - CH20CH), and the like.

|0026] Moreover, the term "alkyl" (or "lower aikyi") as used throughout the specification, examples, and claims is intended to include both "unsubstitiited alkyis" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbo backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxy!, a carbonyl (such as a carboxyl, an alkoxycarboiiyl, a formyl, or an acyl). a t iocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryL, a phosphate, a phosphorate, a phospMnate, an amino, an ami do, an amidine, an iroine, a cyano, a nitro, an azido, a sulfhydryi, an alkylthio, a sulfate, a sulfonate, a sulfamoy!, a sulfonamide, a sulfonyl, a heterocyciyl, an aralky or an aromatic or heteroaromatic moiety, ft will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substitiients of a substituted alkyl may include substituted and imsubstitiited forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamide, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkyltliios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CP3, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkyl thios, aminoalkyis, carbonyl -substituted alkyls, -CF3, -CN, and the like.

[0027] The term "acyl" is art-recognized and refers to a group represented by the general formula h drocarbyl C(OK preferably alkyl C(0)~.

[0028} "Aryl" means a monocyclic or polycyclic ring assembly wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. If one or more ring atoms is not carbon (e.g., N, S). the aryl is a heteroaryi . C aryl and Cx-Y aryl are typically used where X and Y indicate the number of carbon atoms in the ring.

[0029] The term "acy'Iamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formuia hydrocarbyl C{0)NH~.

{ 003 1 The term "acylalkyl" is art-recognized and refers to an alky! group substituted with an acyl group and may be represented, for example, by the formula hydrocarbyl C(0)alkyl.

[0031] The term "acyloxy" is art-recognized and refers to a group represented by the general formuia hydrocarbyl C(Q)0-, preferably alk.ylC(0)0~

[0032] The term "alkoxy" refers to an alkyl group, preferably a. lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

[0033] The term "alkoxyalky!" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0034] The term "alkenyl", as used herein, refers to an aliphatic group containing at least, one double bond and is intended to include both "unsubstituted alken is" and "substituted alkenyls", the latter of which refers to alkenyl moieties having subsiituents replacing a hydrogen on one or more carbons of the aikenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds.

0035] Moreover, such substituents include all those contemplated for alky! groups, as discussed beiow, except where stability is prohibitive. For example, subsiituiioii of aikenyl groups by one or more alkyl, carbocyelyl, aryl, heterocyclyi, or heteroaryl groups is contemplated.

0036) The term "aikylamino", as used herein, refers to an amino group substituted with at least one alkyl group.

[0037] The term "alky!ihio", as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkyl S-.

[0038] The term "alkynyi", as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "un substituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyi moieties having substituents replacing a hydrogen on one or more carbons of the alkynyi group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed- above, except where stability is prohibitive. For example, substitution of alkynyi groups by one or more alkyl, carbocyelyl, aryl, heterocyclyi, or heteroaryl groups is contemplated.

[0039] The term "ether'^*, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O- Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocyc!e-O-heterocyc!e and aryl-O- heterocycle. Ethers include "alkoxy alkyl" groups, which may be represented b the general formula alkyl -O-alkyl.

{0040] The terms "hetaralkyi" and "heteroara!kyJ", as used herein, refers to an alkyl group substituted with a hetaryl group.

{004.1. ] The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two lieteroatoms are adjacent. {0042] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic- single ring structures, preferably 5- to 7-rnembered rings, more preferably 5- to 6- membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyciic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatie, e.g., the other cyclic rings can be cycloa!kyis, cycloaikenyls, cycioalkynyls, ary!s, heteroary!s, and/or heterocyciyls. Heteroaryl groups Include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazhie, and p rrolidi e, and the like.

[0043] The terra ".heieroatom" as used herein means an atom of any element oilier than carbon or hydrogen Preferred heteroatoms are nitrogen., oxygen, and sulfur.

[0044J The terms "heterocyclyl", "heierocycle", and "heterocyclic" refer to substituted or uns bstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include ai least one heteroatom, preferably one to four heteroatoras, more preferably one or two heteroatoms. The terms "heterocyclyi" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cyc!oalkyls, cycloaikenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyciyls. Heterocyc!yl groups include, for example, piperidtne, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

j^'0045| The term "hydroxyalkyl", as used herein, refers to an alky! group substituted with a hydroxy group.

j^'0046) The term "lower" when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyi, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably si or fewer. A "lower alkyl", for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six. or fewer. Lower alkyls include methyl and ethyl . In certain embodiments, acyl, acyloxy, alkyl , alkenyl, alkynyi, or alkoxy substituents defined herein are respectively lower acy!, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyi, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxy alky! and aralkyl (in which case, for example, the atoms within the ar l group are not counted when counting the carbon atoms in the sikyl substituent).

0047] The term "substituted^5' refers to moieties having substituents replacing hydrogen on one or more carbons of the backbone, it wiil be understood that ^'substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include al! permissible substituents of organic compounds, in a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this application, the heteroatonis such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatorns. Substituents can include any substituents described herein, for example, a halogen, a hydroxy!, a carbonyl (such as a carboxyl, an alkoxycarbony!, a fontryi, or an aeyl), a ihiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an aikoxyi, a phosphoryl, a phosphate, a phosphorate, a phosphinate, an amino, an amido, an amidine, an inline, a cyano, a nitro, an azido, a sulfhydryi, an alkylthio, a sulfate, a sulfonate, a sulfamoyi, a sulfonamide, a sulfonyi, a heterocyciyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chai n can themselves be substituted, if appropriate.

0048] Unless specifically stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

|004 ] "Substituted or unsubstituted" means thai a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety. For example, isopropyl is an example of an ethylene moiety that is substituted by -CH3. Ln general a non- hydrogen substituent may be any substituent that may be bound to an atom of the given moiety that is specified to be substituted. Examples of substituents include, but are not limited to, aldehyde, alicyciic, aliphatic, (Ci-io) alkyl, alkylene, alky!idene, amide, amino, aminoaikyl aromatic, aryl, bicycioalkyl, bicycloaryl, carbamoyl, earbocyelyl carboxyl, carbonyl group, cycloalkyl cycloalkyiene, ester, halo, heterobicycloalkyl, heterocycloalky!ene, heteroaryl, heterobicyoioaryi, heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl and oxoalkyl moieties, each of which may optionally also be substituted or unsubstituted. In one particular embodiment, examples of substituents include, but are not limited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (Ci o) alkoxy, (C4-12) aryloxy, hetero (Ci- io)aryloxy, carbonyl, oxy carbonyl, amioocarbonyl, amino, (Ci- 10) alkylamino, sulfonamido, imino, suifonyl, sulfinyl, (Ci- 10) alkyl, halo (Ci-1.0) alkyl, hydroxy (Ci-10) alkyl, carbonyl (Ci- 10) alkyl, thiocarbonyl (Ci jO) alkyl, suifonyl (Ci-10) alkyl. sulfinyl (Cijo) alkyl, (Ci jO) azaalkyl, imino (Ci-10) alkyl, (C3- 12) cycloalkyl (C1 ~ 5) alkyl hetero (C3-12) cycloalkyl (Ci-10) alkyl, aryl (Ci-10) alkyl hetero (Ci-10) aryl (C t - 5) alkyl, (C9- 12) bicycloaryl (Ci_s) alkyl, hetero (Ce-I2) bicycloaryl (Ci_5) alkyl (C3-12) cycloalkyl hetero (03-12) cycloalkyl, (C9-12) bicycioalkyl, hetero (C3-I2) bicycioalkyl (C4-I2) aryl, heiero (Ci-10) aryl, (C9~ 12) bicycloaryl and hetero (C4-12) bicycloaryl. In addition, the substituent is itself optionally substituted by a further substituent. In one particular embodiment, examples of the further substituent include, but are not limited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (Ci- 10) alkoxy, (C4-12) aryloxy, hetero (Ci-10) aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, (Ci-10) alkylamino, sulfonamido, imino, suifonyl, sulfinyl, (Ci-10) alkyl, halo (Ci- 0) alkyl, hydroxy (Ci-10) alkyl carbonyl (Ci-10) alkyl, thiocarbonyl (Ci-10) alkyl suifonyl (Ci-10) alkyl, sulfinyl (Ci- 0) alkyl, (Ci- 0) azaalkyl, imino (Ci jo) alkyl, (C3-I2) cycloalkyl (Ci- 5) alkyl, hetero (C3-.J 2) cycloalkyl (Ci-10) alkyl, aryl (O j0) alkyl, hetero (Ci-io) aryl (Ci 5) alkyl (C9-I2) bicycloaryl (C1-5) alkyl, hetero (CS-12) bicycloaryl (Ci s) alkyl, (C3-12) cycloalkyl, hetero (C3_„ 12) cycloalkyl, (C -12) bicycioalkyl, heter (C3-12) bicycioalkyl, (C4-12) aryl, hetero (Ci-10) aryl (C9-12) bicycloaryl and hetero (C4- 12) bicycloaryl. 0050] The compounds of the present invention can be present in the form of pharmaceutically acceptable salts. The compoimds 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 I 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 (hydration).

[0051 J Omega 3 fatty acids comprises of long chain fatty acids; eicosapentaenoi c acid (CAS No. 10417-94-4), docosabexaenoic acid (CAS No. 6217-54-5).

[0052] Neurotransmitters and its substituted or synthetic derivatives include L-DOPA (CAS No. 59-92-7), Carhidopa (CAS No. 28860-95-9), Benserazide (CAS No. 1491.9-77- 8), Methyidopa (CAS No. 555-30-6), alpha diflouoromethyldopa (CAS No. 69955-03-9). {00531 Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Diastereorners are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are non- superimposabie mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequeiicing rules of Cairn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized, light and designated as dextrorotatory or levorotatory (i.e., as (+) or (~)~isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof A. mixture containing equal proportions of the enantiomers is called a "racemic mixture".

[0054] As used herein, the term "metabolic condition" refers to an inborn errors of metabolism (or genetic metabolic conditions) are genetic disorders that result from a defect in one or more metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent. Metabolic condition associated diseases include: Hepatic, Neurologic, Psychiatric, Hematologic, Renal, Cardiovascular, Cancer, Musculoskeletal, Orthopedic and Gastrointestinal.

0055) The terra "polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound.

[0056] "Residue" is an art-recognized term that refers to a portion of a molecule. For instance, a residue of thioctic acid may be: dihydrolipoic acid, bisnorlipoic acid, tetranoriipoic acid, 6,8 ismethy!mercapto-octanoic acid, 4,6- ismet ylmercapto-hexanoic acid, 2,4-bismethyl.meracapto-butanoic acid, 4,6-bi$methylmercapto-.hexanok acid.

[0057] The phrases ^''parenteral administration'¹ and "administered parenteral!}'" 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, intrapericardial, i traarterial, intrathecal, intracapsular, intraorbital , intracardiac., intradennal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular., subcapsular, subarachnoid, intraspinal and mtrastemaJ injection and infusion.

[0058] A "patient," "subject," or "host" to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates,

[0059] The phrase "pharmaceutically acceptable" is art-recognized. in certain embodiments, the term includes compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0060] The phrase "pharmaceutically acceptable carrier" is art-recognized, and includes, for example, pharmaceutically 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., from 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 non-pyrogenic. Some examples of materials which may serve as pharmaceutically 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 carhoxyroeth l cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragaeanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (I I) poiyoSs, such as glycerin, sorbitol, 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) algi ic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21.) other non-toxic compatible substances employed in pharm ceutical formulatio s.

|0061] The term "polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound.

[0062] The term "prodrug" is intended to encompass compounds that, under physiological conditions, are converted into the iherapeirticaily active agents of the present invention. A common method for making a prodrug is to include selected moieties that are hydro! yzed under physiological conditions to reveal the desired raoiecuie. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

{0063^'| The term "prophylactic or therapeutic¹' treatment 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 umvanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing 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).

[0064] The term "predicting" as used herein refers to assessing the probability according to which a metabolic condition or neurodegenerative related diseases patient will suffer from abnormalities or complication and/or terminal renal failure and/or death (i.e. mortality) within a defined time window (predictive window) in the future. The mortality may be caused by the central nervous system 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. Hie predictive window may be the entire remaini ng lifespan of the subject upon analysis by the method of the present invention. Preferably, however, the predictive window is an interval of one month, six months or one, nvo, three, four, five or ten years after appearance of the cardiovascular complication (more preferably and precisely, after the sample to be analyzed by the method of the present invention has been obtained). As will be understood by those skilled in the art, such an assessment is usually not intended to be correct for 100% of the subjects to be analyzed. The term, however, requires thai the assessment, will be valid for a statistically significant portion of the subjects to be analyzed. Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g. , determination, of confidence intervals, p-vaiue determination. Student's t-tesi, Mann- Whitney test, etc. Details are found in Dowdy and Wearden, Statistics for Research, John Wiley & Sons, New Y rk 1983. Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99 %, The p-values are, preferably, 0.1 , 0.05, 0.01 , 0.005, or 0,0001 . Preferably, the probability envisaged by the present invention allows that the prediction will be correct for at least 60%, at least 70%, at least 80%, or at least 90% of the subjects of a given cohort.

{0 65| The terra "treating" is art -recognized and includes preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, di order 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 and/or condition. Treating the disease or condi tion includes a meliorating at. least one sym ptom of the particular disease or condition, even if the underlying pathophysiology is not. affected, such as treating the metabolic condition or neurodegenerative disease condition of a subject by administration of an agent even though such agent does not treat the cause of the conditio The term "treating", "treat" or "treatment" as used herein includes curative, preventative (e.g., prophylactic), adjunct and palliative treatment. [0066] Neurodegenerative related diseases or disorders includes such as Alzheimer's disease. Amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, Spinal muscular atrophy or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.

[0067] 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 benefit/risk ratio applicable to any 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 determine the effective amount of a particular composition without necessitating undue experimentation.

[0068] 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 a prophylactic or therapeutic treatment. The desired amount of the composition to he administered to a patient will depend on absorption, inaetivation, and excretion rates of the dnig as well as the delivery rate of the salts and compositions from the subject compositions, 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 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.

[0069] Additionally, the optimal concentration and/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.

0070] In certain embodiments, the dosage of the subject compositions 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 may be used,

[0071 J The term "solvate" as used herein, refers to a compound formed by solvation (e.g., a compound formed by the combination of solven molecules with molecules or ions of the solute).

[0072] When used with respect to a pharmaceutical composition or other material, the term "sustained release¹' is art-recognized. For example, a subject composition which releases a substance over time may exhibit: sustained release characteri tics, in contrast to a bolus type admini tration in which the entire amount of the substance is made biologically available at one time. For example, in particular embodiments, upon contact with body fluids including blood, spinal fluid, mucus secretions, lymph or the like, one or more of the pharmaceutically acceptable exeipients may undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic and/or biologically active 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.

[0073] The phrases "systemic administration," "administered systemicaliy," "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 systemicaliy, may be termed "local" or "topical" or "regional" administration;, 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 io metabolism and other like processes. [0074] The phrase "therapeutically effective amount" is an art-recognized terra, in certain embodiments, the temi 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 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 determine the effecti e amount of a particular composition without necessitating undue experimentation.

[0075] The present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said prodrugs.

[0076] This application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula I may be formulated for systemic or topical o oral administration. The pharmaceutical composition may be also formulated for oral administrati n, oral solution, injection., subdermal administration, or transdermal administration. The pharmaceutical composition may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, filler, binder, and lubricant.

j0077^'| In many embodiments, the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formulas 1) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formul ί or composition as part of a prophylactic or therapeutic treatment. The desired concentration of formula I 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 compositions. 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 professional judgment of the person admini tering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled i the art. [0078] Additionally, the optimal concentration and/or quantities or amounts of any particular compound of formula I may be adjusted to accommodate variations in the treatment parameters. Suc 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.

j^'0079| The concentration and/or amount of any compound of formula 1 may be readily identified by routine screening in animals, e.g., rats, by screening a. range of concentration and/or amounts of the material in question using appropriate assays. Known methods are also available to assay local tissue concentrations, diffusion rates of the salts or compositions, and local blood flow before and after administration of therapeutic formulations disclosed herein. One such method is microdialysis, as reviewed b T, E. Robinson et al. , 1 91, microdialysis in the neurosci nces, 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 such as those disclosed herein are injected adjacent to the loop, released drugs are collected in the dial y sate 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.

[0080] In certain embodiments, the dosage of the subject compounds of formula I 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 may be used,

[0081 ] Generally, in carrying out the methods detailed in this application, an effective dosage for the compounds of Formulas .1 is in the range of about 0.01 mg/kg/day to about 100 mg kg day in single or divided doses, for instance 0.01 mg kg/day to about 50 mg/kg day 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 mg kg day, 1.0 mg/kg/day, 5 mg/kg/day, 10 mg/kg day, 20 mg kg/day, 30 mg/kg day, or 40 mg/kg/day. Compounds of Formula ί may also be administered to a human patient at a dose of, for example, between 0, 1 rag and 1000 mg. between 5 rag and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000 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 10% of the compound of formula 1 required for the same therapeutic benefit.

|00S2) An effective amount of the compounds of formula 1 described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease. For example Neuromuscular and Neurodegenerative diseases include disease symptoms associated to Alzheimer's, Huntington's disease., Parkinson's disease and lateral sclerosis. 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 dem elization 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 proph lactic (prevention) administrati n as appropriate. The amount and timing of compositions administered 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 variability, the dosages given above are a guideline and the physician may titrate doses of the drug 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 well as presence of other diseases,

{0083] The compositions provided by this application may be administered to a subject in need of treatment by a varietv of conventional routes of administration, including orallv, topically, parenterally, e.g., intravenously, subcutaneous! or intramedullary. Further, the compositions may be administered intranasally, 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 controlled release dosage forms, site specific drug delivery, transdermal drug delivery, patch (active/passive) mediated drug delivery, by stereotactic injection, or in nanopartic!es. 0084] The compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitable pharmaceutical 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, powders, lozenges, syrups, injectable solutions and the 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-argi ine, 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 binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium l urvi sulfate and talc are often useful for tabletting 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 may also comprise enterically coated comprising of various excipients, as is well known in the pharmaceutical art.

{0085] For parenteral administration, solutions of the compositions may be prepared I (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 glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

0086] The formulations, for instance tablets, may contain e.g. 10 to 100, 50 to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700, 800 mg of the compounds of formula i disclosed herein, for instance, compounds of formula I or pharmaceutical acceptable salts of a compounds of Formula I.

0087] 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 administration, 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 maimer.

{00881 The dosage administered will be dependent upon the identity of the neoplastic 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.

[0089] Illustratively, dosage levels of the administered active ingredients are: intravenous, 0,1 to about 200 mg kg; intramuscular, 1 to about 500 mg/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 to about 1000 mg kg; and aerosol, 5 to about 1000 mg/kg of host bod weight.

[0090] Expressed in terms of concentration, an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasa!ly, phar ngolaryngeally, bronchially, intravaginaily, rectaliy, or ocularly in a concentratio of from about 0.01 to about. 50% w/w of the composition; preferably about 1 to about 20% w/w of the composition; and for parenteral use in a concentration of from about. 0.05 to about 50% w/v of the composition and preferably from about 5 to about 20% w/v.

[0091] The compositions of the present, invention are preferably presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, 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 cart be prepared.

[0092J Powders are prepared quite simply by comminuting the active ingredient to a suitably fine size and mixing with a similarly comminuted diluent. The diluent can be an edible carbohydrate material such as lactose or starch. Advantageously, a sweetening agent or sugar is present as well as flavoring oil.

[0 93J Capsules are produced by preparing a powder mixture as hereinbefore described and filling into formed gelatin sheaths. Advantageously, as an adjuvant, to the filling operation, a lubricant such as talc, magnesium stearate., calcium stearate and the like is added to the powder mixture before the tilling operation.

[0094} Soil gelatin capsules are prepared by machine encapsulation of slurry of active ingredients with an acceptable vegetable oil, light liquid petrolatum or other inert oil or triglyceride.

{00951 Tablets are made by preparing a powder mixture, granulating or slugging, adding a lubricant and pressing into tablets. The powder mixture is prepared by mixing an active ingredient, suitably comminuted, with diluent or base such as starch, lactose, kaolin, dicaicium phosphate and the like. The powder mixture can be granulated by wetting with a binder such as corn syrup, gelatin solution, methylcellulose solution or acacia mucilage and forci ng through a screen. As an alternative to granulating, the powder mixture can be slugged, i.e., ran through the tablet machine and the resulting imperfectly formed tablets broken into pieces (slugs). The sl gs can be lubricated to prevent sticking to the tablet- forming dies by means of the addition of stearic acid, a stearic salt, talc or mineral oil. The lubricated mixture is then compressed into tablets.

[0096J Advantageously, the tablet can be provided with a protective coating consisting of a sealing coat or enteric coat of shellac, a coating of sugar and methylcellulose and polish coating of carnauba wax.

[0097} Fluid unit dosage forms for oral administration such as in syrups, elixirs and suspensions can be prepared wherein each teaspoonful of composition contains a predetermined amount of an active ingredient for administration. The water-soluble forms can be dissolved in an aqueous vehicle together with sugar, flavoring agents and preservatives to form a syrup. An elixir is prepared by using a hydroalcoholic vebicle with suitable sweeteners together with a flavoring agent. Suspensions can be prepared of the insoluble forms with a suitable vehicle with the aid of a suspending agent such as acacia, tragacanth, methyl cellulose and the like.

{^'0098 J For parenteral administration, fluid unit dosage forms are prepared utilizing an active ingredient and a. sterile vehicle, water being preferred. The active ingredient, depending on the form and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the water- soluble active ingredient can be dissolved i water for injection and filter sterilized before filling into a suitable vial or ampule and sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except thai an active, ingredient is suspended in the vehicle instead of being dissolved and sterilization cannot be accompli shed by filtration. The active ingredient can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.

[0099] In addition to oral and parenteral administration, the rectal and vaginal routes can be utilized. An active ingredient can be administered by means of a suppository. A vehicle which has a melting point at about body temperature or one that is readily soluble can be utilized. For example, cocoa butter and various polyethylene glycols (Carbowaxes) can serve as the vehicle.

{00100} For intranasal instillation, a fluid unit dosage form is prepared utilizing an active ingredient and a suitable pharmaceutical vehicle, preferably P.P. water, a dry powder can be formulated when insufflation is the administration of choice.

[00101J For use as aerosols, the active ingredients can be packaged in a pressurized aerosol container together with a gaseous or liquified propella t, for example, dichl orodi fluoromethane, carbon dioxide, nitrogen, propane, and the like, with the usual adjuvants such as cosolvents and wetting agents, as may be necessary or desirable. [0β102| The term "unit dosage form" as used in the specification and claims refers to physically discrete units suitable as unitary dosages for human and aniinai subjects, each unit contai ning a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. The specifications for the novel unit dosage forms of this invention are dictated by and are directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitation inherent in the art of compounding such an active material for therapeutic use in humans, as disclosed in this specification., these being features of the present invention. Examples of suitable unit, dosage forms in accord with this invention are tablets, capsules, troches, suppositories, powder packets, wafers, cachets, teaspoonfuls, tafalespoonfuls, dropperfuls, ampules, vials, segregated multiples of any of the foregoing, and other forms as herein described.

{0 103} The tablets of the present invention contain one or more pharmaceutically active agents that are released therefrom upon contact of the tablet with a liquid medium, for example a dissolution medium such as gastrointestinal fluids. "Water soluble," as used herein in connection with non-polymeric materials, shall mean from sparingl soluble to very soluble, i.e., not more than 100 parts water required to dissolve 1 part of the non- polymeric, water soluble solute. See Remington, The Science and Practice of Pharmacy, pp 208-209 (2000). "Water soluble," as used herein in connection with polymeric materials, shall mean that the polymer swells in water and can be dispersed at the molecular level or dissolved in water.

[001G4J As used herein, the terra "modified release" shall apply to tablets, matrices, particles, coatings, portions thereof, or compositions that alter the release of an pharmaceutically active agent in any manner. Types of modified release include controlled, prolonged, sustained, extended, delayed, pulsatile, repeat action, and the like. Suiiable mechanisms for achieving these types of modified release include diffusion., erosion, surface area control via geometry and/or impermeable barriers, or other mechanisms known in the art.

|00 i 05| hi one embodiment of t e invention, the first pharmaceutically active agent and the hydrophilic polymer are mixed with a powder containing a phamiaceuticall -acceptable carrier, which is also defined herein as the tablet matrix. In one embodiment; the powder has an average particle size of about 50 microns to about 500 microns, such as between 50 microns and 300 microns. Particles in this size range are particularly useful for direct compression processes.

00106| In embodiment, the components of powder are blended together, for example as dry powders, and fed into the die cavity of an apparatus that applies pressure to form a tablet core. Any suitable compacting apparatus may be used, including, but not limited to, conventional unitary or rotary tablet press. In one embodiment, the tablet core may be formed by compaction using a rotary tablet press (e.g., such as those commercially available from Fette America Inc., Rockaway, N.I . or Manesty Machines LTD, Liverpool, UK). In general, a metered volume of powder is filled into a die cavity (where the powder is either gravity fed or mechanically fed from a feeder) of the rotar tabiei. press, and the cavity rotates as part of a "die table" from the filling position, to a compaction position. At the compaction position, the powder is compacted between an upper and a lower punch, then the resulting tablet core is pushed from the die cavity by the lower punch and then guided to an injection chute by a stationary "take-off bar.

1001071 In one embodi ment of the invention, the tablet core may be a directly compressed tablet core made from a powder that is substantially free of water-soluble polymeric binders and hydrated polymers. As used herein, what is meant by "substantially free" is less than 5 percent, such as less than I percent, such as less than 0. 1 percent, such as completely- free (e.g., 0 percent). This composition is advantageous for minimizing processing and material costs and providing for optimal physical and chemical stability of the tablet core. In one embodiment, the density of the tablet core is greater than about 0.9 g^'cc.

00108) The tablet core may have one of a variety of different shapes. For example, the tablet core may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometry of a space figure with some non-flat faces, such as a cone, truncated cone, cyiinder, sphere, torus, or the like. In certain embodiments, a tablet core has one or more major faces. For example, the tablet core surface typicall has opposing upper and lower faces formed by contact with the upper and lower punch faces in the compression machine. In such embodiments the tablet core surface typically further includes a "belly-band" located between the upper and lower faces, and formed by contact with the die walls in the compression machine.

00109) As discussed above, the tablet core contains one or more hydrophiiic polymers. Suitable hydrophiiic polymers include, but are not limited to, water sweliable cellulose derivatives, po!yalkylene glycols, thermoplastic polyalky!ene oxides, acrylic polymers, hydrocolloi s, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof. Examples of suitable water sweliable cellulose derivatives include, but are not limited to, sodium carboxym ethyl cell ulose, cross-linked hydroxypropylcellulose, hydroxypropyJ cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), h droxy isopropylcellul ose, hydroxybuiyl cellulose, hydroxyphenylcellulose, hydroxyethyl cellulose (HEC), hydroxypentylcellulose, hydroxypropyl ethyl cellulose, hy droxypropylbutylcel lulose, and hydroxypropy!ethyiceH ulose, and mixtures thereof. Examples of suitable poiyalkylene glycols include, but are not limited to, polyethylene glycol. Examples of suitable thermoplastic poiyalkylene oxides include, but are not limited to, polyethylene oxide). Examples of suitable acrylic polymers include, but are not limited to, potassium methacrylatedivinyibenzene copolymer, polymethylmethacrylate, high- molecular weight crosslinked acrylic acid homopo!ymers and copolymers such as those commercially available from Noveon Chemicals under the tradename CARBOPOL^m. Examples of suitable hydrocolloids include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arable, tragacanth, pectin., xanthan gum, gel lan gum, maltodextrin, gaiactomannan, pusstulan, laminarin, scieroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitiii, cyclodextrin, chitosan, and mixtures thereof. Examples of suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and lapomte; magnesium 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 glycolate and derivatives thereof, and mixtures thereof. Examples of suitabie swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyiTolidone, cross-linked agar, and cross-linked carhoxymethylcell ulose sodium, and mixtures thereof OOllOJ m one embodiment, an osmogen is incorporated into the tablet core in order to draw water into the tablet upon contact with fluids, such as gastrointestinal fluids. An osmogen as used herein is a water soluble component which preferentially draws water into the tablet core for the purposes of distributing the water throughout the core, so that the active ingredient contained in the core may be released, in one embodiment the osmogen is a salt such as but not limited to sodium chloride, potassium chloride, sodium citrate, or potassium citrate.

[001.1 ].| The carrier may contain one or more suitable excipienis for the formulation of tablets. Examples of suitable excipienis include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, glidanis, release-modifying excipients, superdisintegrants, antioxidants, and mixtures thereof.

001 121 Suitable tillers include, but are not limited to, watersoluble compressible carbohydrates such as sugars (e.g., dextrose, sucrose, maltose, and lactose), starches (e.g., com starch), sugar-alcohols (e.g., mannitol, sorbitol, maltkol, erythritol, and xylitol), starch hydrolysates (e.g., dextrins, and maltodextritxs), and water insoluble plastically deforming materials (e.g., macrocrystalline cellulose or other ceiiulosic derivatives), and mixtures thereof. Suitable adsorbents (e.g., to adsorb the liquid drug com position) include, but are not limited to, water-insoluble adsorbents such as di calcium phosphate, tri calcium phosphate, silicified microcrystai!ine cellulose (e.g., such as distributed under the PROSOLV brand (PenWest Pharmaceuticals, Patterson, N Y.)), magnesium aluminometasilieate (e.g., such as distributed under the NEUSIL-ΪΝΊ brand (Fuji Chemical Industries (USA) Inc., RobbinsviSle, N.J.), clays, silicas, bentonite, zeolites, magnesium silicates, h drotalcite, veegum, and mixtures thereof.

00113) Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxypropylrneihylcelhilose; wet binders such as water-soluble polymers, including hydroco!!oids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, tara, gum arable, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, l&minarin, scleroglucan, inulin, vvhelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, celluiosics, sucrose, and starches; and mixtures thereof. Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcelluiose, starches, microcrystalline cellulose, and mixtures thereof

{00114} 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, pH- dependent polymers, and mixtures thereof.

[001.151 Suitable insoluble edible materials for use as release-modifying excipients 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, ethyl cellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, niethacrylates, acrylic acid copolymers, copolymers thereof, and mixtures thereof. Suitable low-melting hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, 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 fatt acids and their salts, and mixtures thereof. Examples of suitabie fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, dt-, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilauryiate, glyceryl myristate, GlycoWax-932, lauroyl macrogoi-32 glycerides, stearoyl macrogoi-32 glycerides, and mixtures thereof. Examples of suitabie phospholipids include phosphatidyl choline, phosphatidyl serene, phosphotidyl enositol, phosphotidic acid, and mixtures thereof. Examples of suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, can.deli.11a wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof. Examples of super disintegrants include, but are not limited to, croscanneliose sodium, sodium starch glycolate and cross-linked povidone (crospovidone). in one embodiment the tablet core contai s up to about 5 percent by weight of such super disintegrant. 00116J ^'Examples of antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butyl hydroxytoiuene, buivlated hydroxyanisoie, edetic acid, and edetate salts, and mixtures thereof. Examples of preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof.

{^'00117} The osmotic tablets of the present invention include an osmotic coating. An osmotic coaling is one that is semipermeable thereby allows water to be drawn into the tablet core, e.g., for the purposes of releasing the active ingredient such as through a pre- made hole in the coating or through coating itself it is serai permeable membrane. The osmotic coating, thus, does not fully dissolve upon contact with water In one embodiment, the osmotic coating contains a water soluble component such as a water solible film former which aids in facilitating a further influx of water upon contact with water. In the current invention the osmotic coating is applied via spray coating. Suitable spray coating techniques include spray coating via a coating pan or fluid bed process such as Wurster coating or top spray fluid bed coating as described in the text, "The Theory and Practice of industrial Pharmacy", Lachman, Leon et. al, 3rd ed. The osmotic coating ma be applied using a solution prepared with water, organic solvents, or mixtures thereof. Suitable organic solvents include but are not iimited to acetone, isopropanol, methylene chloride, hexarse, methanol, ethanol, and mixtures thereof. In one embodiment the polymer(s) are dissolved in the coating solution. In one embodiment, the polymer(s) are dispersed, as is the case when applying water insoluble polymers via a dispersion or as is the case when using ethylcellulose dispersions.

{00118} In one embodiment in which the osmotic coating functions as a semipermeable membrane (e.g., allowing water or solvent to pass into the core, but being impermeable to dissolved pharmaceutically active agent, thereby preventing the passage of pharmaceuticall active agent therethrough) the film former is selected from water insoluble polymers, pH-dependent polymers, water soluble polymers, and combinations thereof in one embodiment, the osmotic coating includes a water insoluble polymer and a pore forming material. Examples of suitable water-insoluble polymers include ethyl cellulose, polyvinyl alcohols, polyvinyl acetate, poiycaproiactones, cellulose acetate and its derivatives, acrylates, efhacrylates, acrylic acid copolymers, and combinations thereof. In one embodiment, the water insoluble polymer is cellulose acetate. In one embodiment, the osmotic coating includes from about 10 to about 100 weight percent of a water insoluble film former.

00119| in one embodiment of the osmotic coating, the water insoluble polymer is combined with a water soluble film former in order to create pores in the resulting semipermeable membrane. Examples of suitable film formers include, but are not limited to: water soluble vinyl polymers such as po! mylaieohol (PVA); water soluble polycarhohydrates such as hydroxypropvl starch, hydroxyethyl starch, pullulan, methyl ethyl starch, carboxymethy! starch, pre-ge!atimzed starches, and film-forming modified starches; water swellable cellulose derivatives such as .hydroxypropvl cellulose (HPC), hyd.roxypropyi.ra ethyl cellulose (HP C), methyl cellulose (MC), hydroxyethylmethy icel i ulose (HEMC), hydroxybutylmethylcellulose (HBMC), hydroxy ethylethylcelluiose (HEEC), and hydroxyethylhydroxypropyimethyt cellulose (HEMPMC); water soluble copolymers such as methacrySic acid and methacf late ester copolymers, polyvinyl alcohol and polyethylene glycol copolymers, polyethylene oxide and polyvinylpyrrolidone copolymers; and mixtures thereof,

00120| in one embodiment, a pH dependent polymer is incorporated into the osmotic coating, i one embodiment, the pH dependent polymer is used at a level of from about 10 to about 50 percent by weight of the osmotic coating. Suitable film-forming pH-dependetit polymers include, but are not limited to, enteric cellulose derivatives, such as for example hydroxypropyl methyl ceil ulose phthalate, hydroxypropvl methylcellulose acetate succinate, and cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as polyvinylacetate phthalate, cellulose acetate phthalate, and acetaldehyde dimethyl cell ulose acetate; and enteric aery late derivatives such as for example polymethacrylate-based polymers such as po!yCmethacrylic acid, methyl methacrylate) .1 :2 (commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT STM), and poiy(methacrylic acid, methyl methacrylate) .1 : 1 (commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT LTM); and combinations thereof. In one embodiment, the osmotic coating has an average thickness of at least 5 microns, such as from about 10 microns to about 200 microns, e.g. from about 20 microns to about 150 microns, e.g. from about 30 to about 150 microns, in one embodiment, the osmotic coating is free of porosity (e.g., wherein the pore volume is in a pore diameter range of less than 0.01 g/cc). in one embodiment, the average pore diameter of the osmotic coating is less than about 0.2 microns (e.g., less than about 0.15 microns).

{^'00121 j In one embodiment, the osmotic coating is substantially free of anpharmaceutically active agent. In one embodiment the osmotic coating includes anpharmaceutically active agent which is different than the pharmaceutically active agent included in the immediate release eoaiins. In one embodiment, the osmotic coatina includes a plasticizer. In one embodiment the plasticizer must be of sufficient quantity to withstand the compression force of the immediate release coating. Suitable plasticizers include, but are not limited to: polyethylene glycol; propylene glycol; glycerin; sorbitol; tri ethyl citrate; tri butyl citrate; dibulyl sebecate; vegetable oils such as castor oil, grape oil, olive oil, and sesame oil; surfactants such as polysorbat.es, sodium lauryi sulfates, and dioctyl -sodium su!fosucci nates; mono acetate of glycerol; di acetate of glycerol; triacetate of glycerol, natural gums: triacetiri, acetyltribut l citrate, diethy (oxal te, diethylmalate; diethyl fumarate; diethylmalonate; dioctylphthalate; dibutyi succinate; glycerol tributyrate; hydrogenated castor oil; fatty acids such as lauric acid; glycerides such as mono-, dk and/or triglycerides, which may be substituted with the same or different fatty acids groups such as, for example, stearic, palmitic, and oleic and the like; and mixtures thereof. In one embodiment, the piasticizer is triethyl citrate.

{00122} In one embodiment at least about 50 percent of the cross-sectional area of the osmotic coati ng used in tablets of this invention is striated, such as at least about 80% of the cross-sectional area of the osmotic coating portion is striated. As used herein, "striated" means non-homogeneous with respect to appearance and with respect to the internal structure of the coating portion when viewed under any magnification and lighting conditions, at which point striations or layers can be viewed. Compressed portions of a pharmaceutical oral dosage forms do riot, display striated areas, wherein spray coated portions display striations. For example a crosssection of the osmotic coating portion is striated, and nonuniform with respect to refractive properties when observed utilizing a light microscope or a scanning electron microscope at a magnifi cation of about 50 to about 400 times. The characteristic striations are indicative of the spray-coating process consisting of multiple repetitions of the steps consisting of: (a) application via spraying of coating solution; followed by (b) warm air drying, to a tumbling bed of tablets in a revolving coating pan such that numerous layers of coating material are built up as each application of coating material dries to form a layer, i n one embodiment, the thickness of an individual striated layer is the range of about 10 microns to about 15 microns.

[001231 fa certain embodiments, the osmotic coating is semipermeable (e.g., containing a plurality of small opening) and does not require the addition of an additional opening via laser or other means. In one such embodiment, the semi-permeable membrane of the osmotic coating also allows for the release of the active ingredient in the tablet core through the membrane in a zero-order or first-order release manner.

[001241 fa ^0iie 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 1000 microns. In embodiment, the immediate release coating is typically compressed at a density of more than about 0.9 g/cc. as measured by the weight and volume of that specific layer.

{00125j In one embodiment, the immediate release coating contains a first portion and a second portion, wherei at least one of the portions contains the second pharmaceutically active agent. In one embodiment, the portions contact each other at a center axis of the tablet, in one embodiment, the first portion includes the first pharmaceutically active agent and the second portion includes the second pharmaceutically active agent.

[001261 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

|003271 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 tbe outer coating portion is included of a dried granulation including the pharmaceutically active agent.

00128) In one embodiment, a suitable flavor or aroma agent may be added to the outer coating. Examples of suitable flavor and aroma agents include, but are not limited to, essential oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, peel or pulped whole fruit containing mixtures of alcohols, esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavor of the fruit (e.g., strawberry, raspberry, and black currant): artificial and natural flavors of brews and liquors (e.g., cognac, whisky, rum, gin, sherry, port, and wine); tobacco, coffee, tea, cocoa, and mint; fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; mint; ginger; cinnamon; cac-oe/ cocoa; vanilla; liquorice; menthol; eucalyptus; aniseeds nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, and colanuts); almonds; raisins; and powder, flour, or vegetable material parts including tobacco plant pans (e.g., the genus Nicotiana in amounts not contributing significantly to a level of therapeutic nicotine), and mixtures thereof.

|00129j Formulations with different drug release mechanisms described above could be combined in a final dosage form 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, immediate 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.

00130) The immediate release dosage, unit of the dosage form, i.e., a tablet, a plurality of drug-contai ning 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 excipients. The immediate 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, particles or beads and delayed release drug-containing granules or beads). A preferred method for preparing immediate release tablets (e.g., as incorporated into a capsule) is by compressing a drugcontaining blend, e.g., blend of granules, prepared using a direct, blend, wet- granulation or dry-granulation process, immediate release tablets may also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant. However, preferred tablets described herein are manufactured using compression rather than molding. A preferred method for forming immediate release drug-containing blend is to mix drug particles directly with one or more excipients such as diluents (or fillers), binders, disintegrants, lubricants, glidants, and/or colorants. As an alternative to direct blending, a drug-containing blend may be prepared by using a wet-granulation or dry -granulation process. Beads containing the active agent may also be prepared by anyone of a number of conventional techniques, typically starting from a fluid dispersion. For example, a typical raeihod for preparing drug-containing beads involves blending the active agent with conventional pharmaceutical excipients such as microcrystalline cellulose, starch, polyvinylpyrrolidone, methytcellulose, talc, metallic stearates, and silicone dioxide. The admixture is used to coat a bead core such as a sugar sphere (e.g., "non-parcil") having a size of approximately 20 to 60 mesh.

100131 } An alternative procedure forpreparing drug beads is by blending tiie drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrro!idone, talc, magnesium stearate, and a disintegrant, extruding the blend, spheronizing the extradate, drying and optionally coating the bead to form immediate release beads.

001321 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, Md., 2000). A diffusion, system typically consists of one of two types of devices, reservoir and matrix, which are wellknown 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. The three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic matrices include, but are not limited to, methyl acrylate-metbyl methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers include, but are not limited to, methylcellulose, hydroxypropylcelluiose, hydorxypropyimethylcellulose, sodium earboxyniethykellulose, and Carbopol ^tM 934, and polyethylene oxides. Fatty compounds include, but are not limited to, various waxes such as carnatiba wax and glyceryl tristearate. Alternatively, extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form . In the latter case, the desired drug release profile can be achieved by combining, low permeability and high permeability coating materials in suitable proportion.

[001.331 An immediate release portion can be added to the extended release system by means of either applying an immediate release layer o top of the extended release core, using coating or compression processes or in a multiple unit system such as a capsule containing extended and immediate release beads.

[001.341 Extended release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation processes. These formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active phannaceuiical ingredient. The usual diluents include inert powdered substances such as different kinds of starch, powdered, cellulose, especially crystalline and mierocrystailine cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidine can also be used. Polyethylene glycol, hydrophilic polymers, ethycellulose and waxes can also serve as binders. A lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as tale, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

[001351 Extended release tablets containing wax materials are generall prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method, ^'in the congealing method, the drug is mixed with a wax material and either spray-congealed or congealed and screened and processed.

00136) Delayed release dosage formulations are created by coatin 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. Preferred coating materials include bioerodihle, gradually hydrolyzable, gradually water-soluble, and/or enzymatic-ally degradable polymers, and may be conventional "enteric" polymers. Enteric polymers, as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymaticaiiy degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon. Suitable coating materials for effecting delayed release include, but are not limited to, celluiosic polymers such as hydroxy propyl cellulose, hydoxyethyl cellulose, hydroxymethyi cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropy!roethyl cellulose phthaiate, methylcelluiose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitaie and carboxymethyiceliulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename EUDRAGITT (Rohm Pharma; [0086] Westerstadt, Germany), including EUDRAGITTM L30D-55 and LlOO-55 (soluble at pH 5,5 and above) EUDRAGITTM t. lOOD (soluble at pH 6.0 and above), EUDRAGITTM S (soluble at pH 7.0 and above, as a result of a higher degree of esterifteation), and EUDRAGITTM NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copolymers such as polyvinyl pyrrol idone, vinyl acetate, viny!acetate phthalate, vinylacetate crotonic acid copolymer, and ethyl ene-vinyi acetate copolymer; enzymatically degradable polymers such as azo polymers, pectin, chiiosan, amylase and guar gum; zein and shellac. Combinations of different coating, materials may also be used. Multi-layer coatings using different polymers may also be applied. The preferred coating weights for particular coating materials may be readily determined by those skilled in the art by evaluating individual reiease profiles for tablets, beads and granules prepared with different quantities of various coating materials. It is the combination of materials, method, and form of application that, produce the desired reiease characteristics, which one can determine only from the clinical studies.

[001.371 The coating composition may include conventional additives, such as plastieizers, pigments, colorants, stabilizing agents, glidants, etc. A. plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 t. % to 50 wt. % relative to the dry weight of the polymer. Examples of typical piasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthaiate, diethyl phthaiate, dibutyi phthaiate, dibutyi sehacate, tri ethyl citrate, trihutyl citrate, tri ethyl acetyl citrate, castor oil and acetylated monoglycerides. A. stabilizing agent is preferably used to stabilize particles in the dispersion. Typical stabilizing agents are nomonie emuisifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formatio and drying, and will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearates may also be used. Pigments such as titanium dioxide may also be used. Small quantities of an anti-foaming agent, such as a silicone (e.g., simethicone), may also be added to the coating composition.

[001.38} Alternatively, a delayed release tablet may be formulated by dispersing tire drug within a matrix of a suitable material such as a hydrophilic polymer or a fatty compound. Suitable hydrophilic polymers include, but are not. limited to, polymers or copolymers of cellulose, cellulose ester, acrylic acid, metih acrylic acid, methyl aery late, ethyl acrylate, and vinyl or enzymatically degradable polymers or copolymers as described above. These hydrophilic polymers are particularly useful for providing a delayed release matrix. Fatty compounds for use as a matrix material include, but are hot limited to, waxes (e,g. camauba wax) and glycerol tristearate. Once the active ingredient is mixed with the matrix material, the mixture can be compressed into tablets.

£00139} 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.

[001401 Each dosage form contains a therapeutically effective amount of active agent. In one embodiment of dosage forms that mi mi a twice daily dosing profile, approximately 30 wt. % to 70 wt. ¾, preferably 40 wt. % to 60 wt. ¾, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 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.

[00141| For dosage forms mimicking a three times daily dosing profile, approximately 25 wt. % to 40 wt % of the total amount of active agent in the dosage form is released in the initial pulse, and approximately 25 wt. % to 40 wt. % of the total amount of active agent in the dosage form is released in each of the second and third pulses. For dosage forms that mimic a three times daily dosing profile, release of the second pulse preferably takes place approximately 3 hours to 10 hours, and more preferably approximately 4 to 9 hours, following oral administration. Release of the third pulse occurs about 2 hours to about 8 hours following the second pulse, which is typically about 5 hours to approximately 18 hours following oral administration.

[001 21 The dosage form can be a closed capsule housing at least two drug-containing dosage units, each dosage unit containing one or more compressed tablets, or may contain, a plurality of beads, granules or particles, providing that each dosage unit has a different drug release profile The immediate release dosage unit releases drug substantially inimediately following oral administration to provide an initial dose. The delayed release dosage unit releases dmg approximately 3 hours to 14 hours following oral administration to provide a second dose. Finally, an optional second delayed release dosage unit releases dmg about 2 hours to 8 hours following the release of the second dose, which is typically 5 hours to 18 hours following oral administration.

j^'001 3} 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. In this dosage form, the immediate release dosage unit contains a plurality of beads, granules particles that, release drug substantially immediately following oral administration to provide an. initial dose. The delayed release dosage unit contains plurality of coated beads or granules, which release drug approximately 3 hours to 14 hours following oral administration to provide a second dose.

{00144} Art optional second delayed release dosage unit contains coated beads or granules that release daig about. 2 to 8 hours following administration of the Initial delayed release- dose, which is typically 5 to 18 hours following oral administration. The beads or granules in the delayed release dosage unites) are coated with a bioerodible polymeric material. This coating prevents the drug from being released until the appropriate time, i.e., approximately 3 hours to less than 14 hours following oral administration for the delayed release dosage unit and at least 5 hours to approximately 18 hours following oral administration for the optional second delayed release dosage unit. In this dosage form the components may be admixed in the tablet or may be layered to form a laminated tablet.

001451 Another dosage form is a tablet having a drag-containing immediate release dosage unit, delayed release dosage unit, and an optional second delayed release dosage unit, wherein the immediate release dosage unit comprises an outer layer that releases the drug substantially immediately following oral administration. The arrangement of the remaining delayed release dosage(s), however, depends upon whether the dosage form is designed to mimic twice daily dosing or three times daily dosing.

[001461 the dosage form mimicking twice daily dosing, the delayed release dosage unit, contains an inner core that is coated with a bioerodible polymeric material. The coating is applied such that release of the drag occurs approximately 3 hours to less than .14 hours following oral administration. In this form, the outer iayer completely surrounds the inner core. In the dosage form mimicking three times a day dosing, the (first) delayed release dose contai ns art internal layer that, releases drug approximately 3 hours to less than 14 hours following oral administration. This internal Iayer is surrounded by the outer iayer. The second delayed release dosage unit generally contains an inner core that releases the drug at least 5 hours to approximately 18 hours following oral administration. Thus, the layers of this tablet (starting from the external surface) contain an outer layer, an internal layer and an inner core. The inner core contains delayed release beads or granules. Furthermore, die internal layer contains the drug coated with a bioerodihle polymeric material . Alternatively, in this particular dosage form mimicking three times a day dosing, both the delayed release dosage unit, and second delayed release dosage units are surrounded by an inner layer. This inner layer is free of active agent. Thus, the layers of this tablet (starting from the external surface) comprise an outer layer, inner layer and an admixture of the delayed release dosage units. The first delayed release pulse occurs once the inner layer is substantially eroded thereby releasing the admixture of the delayed release dosage units. The dose corresponding to the (first) delayed release dosage unit is released immediately since the inner layer ha prevented access to this dose for the appropriate time, e.g., from approximately 3 hours to 10 hours. The second delayed release dose, however, is formulated to effectively delay release for at least 5 hours to approximately 18 hours following oral admi nistration.

{^'00147} For formulations mimicking twice dail dosing, it is preferred that the delayed release dose is released approximately 3 hours to up to 14 hours, more preferably approximately 5 hours to up to 12 hours, following oral administration. For formulations mimicking three times daily dosing, it is preferred that the (first) delayed release dose is released approximately 3 to iO hours, preferably 4 hours to 9 hours, following oral administration. For dosage forms containing a third dose, the third dose (i .e., the second delayed release dose) is released at least 5 hours to approximately 18 hours following oral administration,

|0 348| in still another embodiment, dosage form is provided which contains a coated core-type delivery system wherein the outer layer contains an immediate release dosage unit containing an active agent, such that the active agent therein is immediately released following oral administration; an intermediate layer there under which surrounds a core; and a core which contains immediate release beads or granules and delayed release beads or granules, such that the second dose is provided by the immediate release beads or granules and the third dose is provided by the delayed release beads or granules.

{^'00149} For purposes of transdermal (e.g., topical) admi istration, 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,

[00150] Methods of preparing various pharmaceutical compositions with a certain amount, of one or more compounds of formula I or other active agents are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easfcon, Pa., 19th Edition (1995).

[00151] In 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,

{00152} 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 with a carrier material to produce a single dose may vary depending upon the subject being treated, and the particular mode of administration.

[00153] 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 necessary, shaping the product. [00154J The compounds of formula 1 described herein may be administered in inhalant or aerosol formulations. The inhalant or aerosol formulations may comprise one or more agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in inhalation therapy. The final aerosol formulation may for example contain 0.005-90% w/w, for instance 0.005-50%, 0.005-5% w/w, or 0.01-1.0% w/w, of medicament relative to the total weight of the formulation .

!00155| it is desirable, but by no means .required, that the formulations herein contain no components which may provoke the degradation of stratospheric ozone. In particular it is desirable that the formulations are substantially free of chlorofluorocarbons such as CC13F, CC1.2.F2 and CF3CC13. As used to refer to ozone-damaging agents., "substantially free" means less than 1% w/w based upon the propellant system, in particular less than 0.5%, for example 0.1% or l ss.

|00156| The propellant may optionally contain an adjuvant having a higher polarity and/or a higher boiling point than the propellant. Polar adjuvants which may be used include (e.g., C2-6) aliphatic alcohols and polyols such as ethanol, isopropanol and propylene glycol . In general, only small quantities of polar adjuvants (e.g., 0.05-3.0% w/w) may be required to improve the stability of the dispersion -the use of quantities in excess of 5% w/w may tend to dissolve the medicament. The formulations described herein may contain less than 1 % w/w, e.g., about 0.1% w/w, of polar adjuvant. However, the formulations may be substantially free of polar adjuvants, such as ethanol. Suitable volatile adjuvants include saturated hydrocarbons such as propane, n-butane, isobutane, pentane and isopentane and alkyl ethers such as dimethyl ether, in general, up to 50% w/w of the propellant may comprise a volatile adjuvant, for example 1 to 30% w/w of a volatile saturated C 1 -C6 hydrocarbon.

(001.57} Optionally, the aerosol formulations may further comprise one or more surfactants. The surfactants must be physiologically acceptable upon administration by inhalation. Within this category are included surfactants such as L~a-phosphatidyIchoiine (PC), 1 ,2-άϊ palm itoylphosphatidy choline (DPPC), oleic acid, sorbitan. trioleate, sorbita mono-oleate, sorbitan monolaurate, polyoxyethyiene (20) sorbitan mono!aurate, polyoxyethyiene (20) sorbitan monooleate, natural Secithiii, oleyl polyoxyethyiene (2) ether, stearyl poly oxy eth lene (2) ether, lauryl polyoxy ethylene (4) ether, block copolymers of oxyethylene and oxypropyiene, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfu.iyi oleate, ethyl oleate, isopropyl rayristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol 400, cetyl py idinium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, corn oil, cotton seed oil, and sunflower seed oil. Appropriate surfactants include lecithin, oleic acid, and sorbitan trioleate.

[001.581 Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the disclosures herein.

[001.591 Certain pharmaceutical compositions disclosed herein suitable for parenteral administration comprise one or more subject compositions in combination with one or more pharmaceutically acceptable sterile, isotonic, aqueous, or .non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

J00160J Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions include water, ethanol, poiyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity ma be maintained, for example, b the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

00161) Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a. solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a subject composition as an active ingredient. Subject compositions may also be administered as a bolus, electuary, or paste. 001< 2| In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers and/or any of the following: ( 1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethyJceliul ose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and or acacia; (3) h mectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, aJginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium 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 Unify! sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise 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 well as high molecular weight polyethylene glycols and the like,

1001631 A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using a binder (for example, gelatin or hydroxypropy I methyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch gl col ate or cross-linked sodium carboxy methyl cellulose), surface-altering or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[001641 There has been widespread use of tablets since the latter part of the 19th century and the majority- of pharmaceutical dosage forms are marketed as tablets. Major reasons of tablet popularity as & dosage form are simplicity, low cost and the speed of production. Other reasons include stability of drug product, convenience in packaging, shipping and dispensing. To the patient or consumer, tablets offer convenience of administration, ease of accurate dosage, compactness, portability, blandness of taste, ease of administration and elegant distinctive appearance.

00165) Tablets may be plain, film or sugar coated, bisected, embossed, !ayered or sustained- release. They can be made in a variety of sizes, shapes and colors. Tablets may be swallowed, chewed or dissolved in the buccal cavity or beneath the tongue. They may be dissolved in water for local or topical application. Sterile tablets are normally used for parenteral solutions and for implantation beneath the skin.

001.661 in addition to the active or therapeutic ingredients, tablets may contain a number of inert, materials known as excipients. They may be classified according to the role they play in the final tablet. The primary composition may include one or more of a filler, binder, lubricant and glidant. Other excipients which give physical characteristics to the finished tablet are coloring agents, and flavors (especially in the case of chewable tablets). Without excipients most drugs and pharmaceutical ingredients cannot be directly- compressed into tablets. This is primarily due to the poor flow and cohesive properties of most drugs. Typically, excipients are added to a formulation to impart good flow and compression characteristics to the materi l being compressed. Such properties are imparted through pretreatment steps, such as wet granulation, slugging, spray drying spheronization or crystallization.

{00167} Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression, and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually of about 1% by weight.

{00168} Other desirable characteristics of excipients include the following: high- compressibility to allow strong tablets to be made at low compression forces; impart cohesive qualities to the powdered material; acceptable rate of disintegration; good flow properties that can improve the flow of other excipients in the formula; and cohesiveness (to prevent tablet from crumbling during processing, shipping and handling).

[00169] There are at least three commercially important processes for making compressed tablets: wet granulation, direct compression and dry granulation (slugging or roller compaction). The method of preparation and type of excipients are selected to give the tablet formulation the desired physical characteristics that allow for the rapid compression of the tablets. After compression, the tablets must have a number of additional attributes, such as appearance, hardness, disintegrating abi lity and an acceptable dissolution profile. Choice of fillers and other excipients will depend on the chemical and physical properties of the drug, behavior of the mixture during processing and the properties of the final tablets. Preform ulation studies are done to determine the chemical and physical compatibility of the active component with proposed excipients.

[001.701 The properties of the drug, its dosage forms and the economics of the operation will determine selection of the best process for tableting. Generally, both wet granulation and direct compression are used in developing a tablet.

[00171 j One form ulation comprises the following: a compound of Formula !, and binder. Examples of pharmaceutically acceptable binders include, but are not. limited to, starches; celluloses and derivatives thereof e.g., microcrystalli e cellulose, hydroxypropyl cellulose hydrox letiiyl cellulose and hydroxylpropyl ethyl cellulose, sucrose; dextrose; corn syrup; polysaccharides: and gelatin. The binder, e.g., may be present in an amount from about I % to about 40% by weight of the composition such as 1 % to 30% or 1 % to 25% or 1 % to 20%.

[ 0172J Optionally, one, two, three or more diluents can be added to the formulations disclosed herein. Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not Iimited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc. The filler and/or diluent, e.g., may be present in an amount from about 15% to about 40% by weight of the composition. In certain embodiments, diluents are microcrystalline cellulose which is manufactured by the controlled hydrolysis of alpha-cellulose, obtained as a pulp from, fibrous plant materials, with dilute mineral acid solutions. Following hydrolysis, the hydrocellulose is purified by filtration and the aqueous sluny is spray dried to form dry- , porous particles of a broad size distribution . Suitable microcrystalline cellulose will have an average particle size of from about 20 nm to about 200 tun. Microcrystalline cellulose is available from several suppliers. Suitable microcrystalline cellulose includes Avicel PH. .101 , A vice! PH 102, Avice! PH 103, Avicei PH 105 and Avicel PH 200, manufactured by FMC Corporation. The microcrystaliine cellulose may be present in a tablet formulation in an amount of from about 25% to about. 70% by weight. Another appropriate range of this material is from about 30% to about 35% by weight; yet another appropriate range of from about 30% to about 32% by weight. Another diluent is lactose. The lactose may be ground to have an average particle size of between about 50 μιη and about 500 ujn prior to formulating. The lactose may be present in the tablet formulation in an amount of from about 5% io about. 40% by weight, and can be from about 18% to about 35% by weight, for example, can be from about 20% to about .25% by weight,

[001.731 Optionally one, two, three or more disintegrants can be added to the formulations described herein. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross- linked polyvinyl pyrrolidone, cross-linked calcium carboxymethy icel i ulose and cross-linked sodium carboxymethylcelluiose; soy polysaccharides; and guar gum. The disintegrant, e.g., may be present in an amount from about 2%) to about 20%, e.g., from about 5% to about 10%, e.g., about 7% about by weight of the composition. A disintegrant is also an optional but useful component of the tablet formulation. Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration. Typical disintegrants include starch derivatives and salts of carboxymethylcelluiose. Sodium starch gl col ate is one appropriate disintegrant for this formulation, in certain embodiments, the disintegrant is present in the tablet formulation in an amount of from about 0% to about 10% by weight and can be from about 1% to about 4% by weight, for instance from about 1.5% to about 2.5% by weight,

00174) Optionally one, two, three or more lubricants can be added to the formulations disclosed herein. Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium triplicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate., magnesium oxide, polyethylene glycol, powdered cellulose and microcrystaliine cellulose. The lubricant, e.g., may be present in an amount from about 0.1% to about 5% by weight of the composition; whereas, the glida t, e.g., may be present. in an amount from about 0.1% to about 10% by weight. Lubricants are typically added to prevent the tabletii g materials from sticking to punches, minimize friction during tablet compression and ailow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than 1 % by weight. The lubricant component may be hydrophobic or hydrophilie. Examples of such lubricants include stearic acid, talc and magnesium stearate. Magnesium stearate reduces the friction betwee the die wall and tablet mix during the compression and ejection of the tablets, it. helps prevent adhesion of tablets to the punches and dies. Magnesium stearate al so aids in the flow of the powder in the hopper and into the die. it has a particle size range of 450-550 microns and a density range of 1.00-1.80 g/rn.l. It is stable and does not polymerize within the tablets tig mix. One lubricant, magnesium stearate may also be employed in the formulation, hi some aspects, the lubricant is present in the tablet formulation in an amount of from about 0.25% to about 6%; also appropriate is a level of about 0.5% to about 4% by weight; and from about 0.1% to about 2% fay weight. Other possible lubricants include- talc, polyethylene glycol, silica and hardened vegetable oils. In an optional embodiment, the lubricant is not present in the formulation, but is sprayed onto the dies or the punches rather than being added directly to the formulation,

00175| Examples of useful excipients which can optionally be added to the composition are described in the Handbook of Pharmaceutical Excipients, 3rd edition. Edited by A.RKibbe, Published by: American Pharmaceutical Association, Washington DC, ISBN: 0- 17330-96-X, or Handbook of Pharmaceutical Excipients (4th edition), Edited by Raymond C owe - Publisher: Science and Practice.

{^'00176} Liquid dosage forms for oral administration include pharmaceuticall 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, solubilizmg agents and emulstfiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butyleiie glycol, oils (in particular, cottonseed, com, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofuiyl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. [00177| Suspensions, in addition to the subject compositions, may contain suspending agents such as, for example, ethoxylated isosteary! alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystaUine cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[00178J Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable no -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 encapsulated compound(s) and compositions). 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 be appropriate.

[001 9J 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 propellents that may be required. For transdermal administration, the complexes may include lipophilic and hydrophi!ic groups to achieve the desired water solubility and transport properties.

{00180} The ointments, pastes, creams and gels may contain, in addition to subject compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, 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 poly amide powder, or mixtures of such substances. Sprays may additionally contain, customary propellants, such as chiorofluorohydrocarbons and volatiie unsubsti ruled hydrocarbons., such as butane and propane.

[001811 Methods of 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, 6,564,093, 6,312,716, 6,440,454, 6,267,983, 6,239,180, and 6,103,275. 00182| in one embodiment, a transdermal patch may comprise an outer backing foil, a matri and a protective liner wherein a) the composition or compositions are present in the matrix in a solution (which may be oversaturated), b) the matrix may contain i to 5% activated Si02, and c) the matrix may have a moisture content of less than 0.7%.

Moisture- free matrix patches which contain activated silicon dioxide in the matrix show an enhanced drug release into the skin.

|0 183| in another embodiment, a transdermal patc may comprise: a substrate sheet, comprising a composite film formed of a resin composition comprising 100 parts by weight of a polyvinyl chl.oride-polyuret.hane composite and 2-10 parts by weight of a styrerte- eth lene-hutylene-styrene 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 polyalkylene terephthalate film; and a second adhesive layer comprising a siyrene-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 by a calendar process, and then adhering a polyalkylene terephthalate film on one side of the composite film by means of an adhesi ve layer thereby forming the substrate sheet, and forming a primer layer comprising a saturated polyester resin on the outer surface of the polyalkylene terephthalate film.

|001S4| The pharmaceutical compositions herein can be packaged to produce a "reservoir type" transdermal patch with or without a rate-limiting patch membrane. The size of the patch, and or the rate limiting membrane can be chosen to deliver the transdermal flux rates desired. Such a transdermal, patch can consist of a polypropylene/polyester impervious backing member heat-sealed to a polypropylene porous/permeable membrane with a reservoir there betwee The patch can include a pharmaceutically acceptable adhesive (such as a acrylate, silicone or rubber adhesive) on the membrane layer to adhere the patch to the skin of the host, e.g., a mammal such as a human. A release liner such as a polyester release liner can also be provided to cover the adhesive layer prior to application of the patch to the skin as is conventional in the art. This patch assembly can be packaged in an aluminum foil or other suitable pouch, again as is conventional in the art.

[00185) Alternatively, the compositions herein can be formulated into "matrix-type" transdermal patch. Drug Delivery Systems Characteristics and Biomedical Application, R. L Juliano, ed., Oxford University Press, N Y. (1980); and Controlled Drug Delivery, Vol , 1 Basic Concepts, Stephen D. Brock ( 1983) describe the theory and application of methods useful for transdermal delivery systems. The drug-matrix could be formed utilizing various polymers., e.g. silicone, polyvinyl alcohol. The "drug matrix" may then be packaged into an appropriate transdermal patch.

[001.86 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 be present at a concentration which will not affect the adhesive properttes, and at the same time deliver the required clinical dose.

|00187j Transdermal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver smail-moiecule 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.

[00188) iontophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current. One example of an iomophoretic membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes. The principal mechanisms b 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 charged 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.

[00189] in 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 comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., orai and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician,

|00190J An example of such a kit 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 material that may be transparent. During the packaging process recesses ate formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. In some embodiments the strength of the sheet i such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

METHODS FOR MAKING THE COMPOUNDS OF FORMULA - 1:

{00191} Examples of synthetic pathways useful for making the compounds of

Formula I are set forth in the examples below and generalized in the schemes 1 -- 4.

Scherae-1:

001921 Step - J : Synthesis of Compound 2:

H

001 31 T a solution of compound 1 (50 mmoi) in Dichlororrsethane (10 mL), DiisopropyS ethyl amine (150 mmol) and metiioxy ethoxy methyl chloride (MEM-CI ) (1 10 mmol) were added consecutivel at 0 °C, The reaction mixture was stirred for 3.0 h, the completion of reaction mixture monitored ^'PLC and it is washed with water ( 10 Vol) and brine. The organic phase was dried {Na^SC^) and evaporated under reduced pressure to provide benzaldehyde derivative 2.

001941 Step -2: Synthesis of Compound 3:

3

[00.1.95] Soxlilet extractor was filled with 20 § of molecular sieve with benzaldehyde derivative (5 mmol) and hydrazine hydrate (75 mmol) were retluxed overnight in (.10 vol) of ethariol (16-24 h). The hot alcoholic solution was filtered, and evaporation of solvent yielded (73%) of crude mtenuediate~3. After recrystailizaiioii in solvent ethaiiol formed compound 3 to a. 99% analytically pure compound.

[00196] Step -3: Synthesis of Compound 5:

DMF [00197 j To a stirred solution of compound 3 (1 mraol) and Compound 4 (1,0 mmol) in DCM (20 vol), BDCl.HCi (1 mmol) and DMAP ( 1.2 mmpl) were added at room temperature and the reaction mixture was allowed to stir for 12 h at rt. Reaction was monitored by TLC. On. completion of the reaction, the reaction mixture was diluted with DCM (50 vol), washed with water (50 vol) followed by brine solution (20 vol) and dried over anhydrous

and evaporated under reduced pressure. The crude mixture was purified by column chromatography over 100-200 mesh silica ge! by using 40 % ethyl acetate-hexane as eluent yielded (70 %) of compound 5.

mpound 8:

KXOSDMP

{00199} To a solution of compound 5 ( 1.0 mmol) in dry DCM (10 vol) was added N, N- diisopropylethylamine (2.0 mmol) at - 1 . followed by drop wise addition of 1 - chloroethylchiorofomiate (1 ,2 mmol) for 30 mi at the same temperature and the reaction mixture was allowed to stir for 1 h at 0"C. On completion of the reaction, (monitored by TLC), the reaction mixture intermediate 6 was directly used for the next step without further isolation and purification,

{002⁽10} In another RB flask the cis-5, 8, 11, 14, 17-Eicosapentaenoi c acid 7 ( 1.2 mmol) and anhydrous K2CO3 (3.0 mmol) was taken in dry DMF (1.0 vol) stirred at room temperature for 2 h and then cooled to -10 %\ intermediate 6 was added slowly drop wise over 30 min and 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 ( 100 mL) and extracted with diethyl ether (2 x 1 L). The combined organic layers were washed with water (2 x 500 mL) followed by brine solution (100 mL), dried over anhydrous Na^SC^and evaporated under reduced pressure. The crude mixture was purified by column chromatography over 100-200 mesh silica gel by using 0 to 20% ethyl acetate in pet ether as an eluent to yield 40% of compound 8 as a viscous semi-transparent liquid. 0 201| Step -5: Synthesis of Compound 9:

00202| Compound 8 (1 .0 mm l ) dissolved in 1 ,2 Dichloroethane (10 Vol) and stirred for 2h at room temperature, then added sodium triacetoxyborohydride (1.2 mmol) at 0 °C and the reaction mixture was allowed to stir for 2h at room temperature. On completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM (500 mL), washed with saturated sodium bicarbonate {500 mL) followed by brine solution (500 mL), dried over anhydrous ajSCXj and evaporated under reduced pressure to form intermediate 9 as viscous oil to yield (76 %). 002031 Step -6: Synthesis of Compound 10;

1002041 25% TFA in DCM was added to compound 8 (1.0 mmoi) at 0 and the reaction mixture was allowed to stir for 30 min at the same temperature. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was basified with saturated Na2CO;i solution (20 vol) and extracted with DCM (20 vol), dried over anhydrous

and evaporated under reduced pressure. The crude was purified by column chromatography over neutral alumina (Merck) by using 30 % ethyl acetate-pet ether as eluent yielded 46 % of compound 9 as a pale colorless amorphous solid.

Schetne-2:

K2C03/DMF

002051 Step - ί : Synthesis of Compound 2:

[0026<>! To a two-necked 500 ml, flask were added compound 1 (50 mmol), 2,2- diniethoxypropane (200 mmol), and anhydrous toluene (20 vol). One neck of the flask was fitted with a Soxhiet extractor, the thimble of which was filled with granular anhydrous CaCl, (75g) to trap MeOH and B₂0. The other neck of the flask was sealed with a septum for sampling. Later, the system was flushed with argon for 5 min and then heated to reflux for 5 min, >-toluenesulfonic acid monohydrate (430 mg, 4.5 mol ) was added and left for refluxing for 12 h. Reaction mixture was concentrated under reduced pressure. Finally, the reaction residue was diluted with ethyl acetate ( 1 0 Vol), washed with saturated sodium bi carbonate solution followed by brine. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum to yield compound 2

{00207 -2: Synthesis of Compound 4:

[00208! Compound 2 (1 .0 mmol) and 2,4-dimethoxy benzyl aldehyde 3 ( 1.0 mmol) was taken in 1,2 Dichlororn ethane (20 vol; LR grade) and stirred for 2h at room temperature for inline formation, then sodium triacetoxy boroliydride (1 .5 mmol) was added at 0 ^<J€ and the reaction mixture was allowed to stir for 4-6 h at rt. On completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM (50 vol), washed with water (50 vol) followed by brine solutio (50 vol), dried over anhydrous Na^>SQ and evaporated under reduced pressure to get crude product as viscous oil which was purified by column chromatography over neutral alumina by using 30 % ethyl acetate-pet ether as eluent to yield 80 % of compound 4 as a transparent colorless semi-solid.

002091 Step -3: Synthesis of Compound 7:

[002101 To a solution of compound 4 ( 1.0 mrno!) in dry DCM (1.8 L) was added N, N- dnsopropylethylamine (2.0 mmol) at 4 OX, followed by drop wise addition of 1 - chloroethylchlorotbrmate ( 1.2 mmol) for 30 mm at the same temperature arid the reaction mixture was alloxved to stir for 1 h at 0°C. On completion of the reaction (monitored by TLC), the reaction mixture with intermediate 5 was directly used for the next step without further isolation and purification.

10021 1 } lit another RB flask the cis-5, 8, 11, 14, 17-Eicosapentaenoic acid 6 (1.2 mmol ) and anhydrous ₂CO (3.0 mmol) was taken in dry DMF (10 vol) stirred at room temperature for 2 h and then cooled to -10 °C, intermediate 5 was added slowly drop wise over 30 min. and then was allowed to stir at room temperature for 12 h. Reaction was monitored by TLC. On completioii of the reaction, the reaction mixture was poured into water (100 niL) and then was extracted with diethyl ether (2 x 1 L). The combined organic layers were washed with water (2 x 500 mi .) followed by brine solution (1.00 niL), dried over anhydrous Ν¾.80₄ and was evaporated under reduced pressure. The crude was purified by column chromatography over 100-200 mesh silica gel by using 0% to 20% ethyl acetate in pet ether as an eluent to yield 40% of compound 7 as a colorless liquid. 00212| 25% TFA in DCM was added to compound 6 f l .0 mmoi) at 0 "C and the reaction mixture was aliowed to stir for 30 min at the same temperature. Reactton was monitored by TLC. On completion of the reaction, the reaction mixture was basified with saturated Na;€⁽¾ solution (20 vol) and extracted with DCM (20 vol), dried over anhydrous Na₂S0₄ and evaporated under reduced pressure. The caide reaction mi ture was purified by column chromatography over neutral alumina (Merck) by using 30 % ethyl acetate-pe ether as an el ent to yield 46 % of compound 7 as a neat colorless solution.

Scheme-3:

002131 Step - J : Synthesis of Compound 2:

1 2

|00214| To a solution of compound I (50 mmol) in 1 : 1 mixture of THF/t¾0 (300 ml),

NaBCOs (150 mmol) and Bot¾0 ( 1 10 mmol) were added consecutively at 0 X. After 30 min, the solution was stirred overnight at room temperature. The turbid solution was extracted with BtjO (2x20ο mL). The aqueous layer was acidified to pH - 4-5 by careful addition of half saturated citric acid at 0 °C and then extracted with CHjCb (3x200 mL).

The combined organic phase was dried (NaaSO^ and evaporated under reduced pressure yielded the Boc-amino acid with high purity as solid, which iater was crystallized on standing. This Boc-amino acid was used for next step without purification.

|0 2 t5{ Step -2; Synthesis of Compound 3:

J00216j To a two-necked 500 mL flask was added compound 2 (50 mmol), 2,2- dimethoxypropane (200 mmol), and anhydrous toluene (20 vol). One neck of the flask was fitted with a Soxhlet extractor, the thimble of which was filled with granular anhydrous CaCi

(75g) to trap MeOH and H O. The other neck of the flask was sealed with a septum for sampling. After the system was flushed with argon for 5 min and then heated to reflux for 5 min. /.'-toluenesulfonie acid monohydrate (430 mg, 4.5 moi%) was added and left for refluxing for 12 h. Reaction mixture was concentrated under reduced pressure. The reaction residue was diluted with ethyl acetate (10 Vol), washed with saturated sodium bicarbonate solution followed by brine. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum to provide compound 3. 00217J Step -3: Synthesis of Compound 6:

100218) To a solution of compound 4 ( 1.0 mmol) in dry DCM (1.8 L) was added N, H- diisopropylethylamine (2.0 mmol) at -10°C, followed by drop wise addition of 1- chioroethylchlorotorraate (1.2 mmoi) for 30 min at the same temperature and the reaction mixture was allowed to stir for 1 h at OX. On completion of the reaction (monitored by TLC), the reaction mixture intermediate 5 was directly used for the next step without further isolation and purification.

|Ό021 ) In another RB flask the cis-5, 8, ! L 14, 17-Eicosa.pentaenoic acid ( 1 .2 mmoi) and anhydrous 2CO3 (3.0 mmol) was taken, in dry DMF (10 vol) stirred at room temperature for 2 h and then cooled to -10 X, intermediate 5 was added slowly drop wise over 30 min, and 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 (100 mL) and extracted with diethyl ether (2 x 1 L). The combined organic layers were washed with water (2 x 500 mL) followed by brine solution (100 ml.), dried over anhydrous aaSC nd evaporated under reduced pressure. The crude was purified by column chromatography over 100-200 mesh silica gel by using 0 to 20% ethy! acetate in pet ether as an eluent to yield 40% of compound 6 as a colorless solution.

-4; Synthesis of Compound 7:

j00221 | 25% IF A in DCM was added to compound 6 (1 .0 mmol) at 0 "C and the reaction mixture was aliowed to stir for 30 min at the same temperature. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was basitied with saturated solution (20 vol) and extracted with DCM (20 vol), dried over anhydrous NajSC and evaporated under reduced pressure. The crude was purified by column chromatography over neutral alumina (Merck) by usi ng 30 % ethyl acetate-pet ether as an eluent to yield 46 % of compound 7 as a semi-solid.

Schetne-4:

(00222) Step -1: Synthesis of Compound 2:

(00223) To a solution of compound 1 (50 mmol) in 1 : 1 mixture of THF/BjO (300 iuL), aHCOs (150 mmol) and Boc?<⁾ (1 10 mmol) were added consecutively ai 0 °€. After 30 min, the solution was stirred overnight at room temperature. The turbid solution was extracted with Et₂0 (2^X200 mL). The aqueous layer was acidified to pH = 4-5 by careful addition of half sat. citric acid at 0 °C and then extracted with CH₂CI₂. (3 200 mL). The combined organic phase was

and evaporated under reduced pressure to give the Boe-amino acid with high purity as hard colorless oil, which was recrystallized on standing. The Boc-amino acid was used for next step without purification.

|0 224| Step -2: Synthesis of Com pound 3;

Reflux

2

|00225| To a two-necked 500 mL flask were added compound 2 (50 rnrnol), 2,2- dimettuwy propane (200 mmo!), and anhydrous toluene (20 vol). One neck of the flask was fitted with a SoxhSei extractor, the thimble of which was filled with granular anhydrous CaCl, (75g) to trap MeOH and H O. The other neck of the flask was sealed with a septum for sampling. After the system was flushed with argon for 5 rain and then heated to reflux for 5 min, p-tolnenesuifo.nic acid monohydrate (430 mg, 4.5 mol%) was added and left for refiuxiiig for 12 h. Reaction mixture was concentrated under reduced pressure. The reaction residue was diluted with ethyl acetate (10 Vol ), washed with saturated sodium bi carbonate solution followed by brine. The organic layer dried over sodium sulfate, filtered and concentrated under vacuum to yield compound 3.

} 00226} Step -3: Synthesis of Compound 6:

00227) To a solution of cis-S, 8, 1 1, 14, 17-Eicosapentaenoic acid 4 ( 1 .0 mmo!) in dry DCM (1.8 L) was added , N-diisopropylethylamine (2,0 mmol) at -10°C, followed by drop wise addition of 1-chloroetiiyichloroformate (1.2 mmoi) for 30 min at the same temperature and the reaction mixture was allowed to stir for 1 h at 0 C. On compietion of the reaction (monitored by TLC), the reaction mixture intermediate 5 was directly used for the next step without further isolation and purification.

00228| In another RB flask the compound 3 (1.2 mmol) and anhydrous ₂CO;» (3.0 mmol) was taken in dry DMF (10 vol) stirred at room temperature for 2 h and then cooled to -10 "C intermediate 5 was added slowly drop wise over 30 min. and 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 (100 mL) and extracted with diethyl ether (2 x 1 L). The combined organic layers were washed with water (2 x 500 mL) followed by brine solution (100 mL), dried over anhydrous

and evaporated under reduced pressure. The crude was purified by column chromatography over 100-200 mesh silica gel by using 0 to 20% ethyl acetate in pet ether as an eluent to yield 40% of compound 6 as a yellow liquid.

{00229} Step -4: Synthesis of Compound 7:

{00230} 25% TFA in DC was added to compound 6 (1.0 mmol) at 0 C and the reaction mixture was allowed to stir for 30 min at the same temperature. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was basified with saturated NajCOs solution (20 vol) and extracted with DCM (20 vol), dried over anhydrous NaaS0 and evaporated under reduced pressure. The crude was purified by coiumn chromatography over neutral alumina (Merck) by using 30 % ethyl acetate-pet ether as an eluent to yield 46 % of compound 7 as a semi-solid. EXAMPLES

002311 The disclosure is further illustrated by the foil owing examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure i s intended thereby. It is to he understood that resort may be had to various other embodiments, modifications and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.

Example-1

[002321 Pharmacokinetic (PK) parameters of illustrative compounds of Formula - Ϊ (1-1) of the invention in comparison with the P parameters of the Levodopa

I00233} Male Sprague -Dawley (SD) rats weighing 250 -260 g were obtained. All surgical procedures were performed under anesthesia with ether, and an intraperitoneal injection of 0.2 irtL/kg xylazine with 0.2 mL/kg tiletamine-xolazepam was given for deeper anesthesia and immobilization. Blood sampies were collected from the caudal vein. Biood collection was terminated by decapitation. The brain was removed quickly and weighed. The brain (1 g) sample was snap-frozen on liquid nitrogen (LN.2, -^™.J96°C) and stored at -70 *C until analyzed,

[00234J Prior to oral administration, the animals were fasted overnight and kept under fasted conditions until 4 h after oral administration of a single dose of !-dopa and formula - I ( 1-1) in free amine form; they were allowed water ad libitum. The dosages oral administration was 80 mg/kg of 1-dopa and 80mg kg stoichiometric equivalent dosage of formula-ϊ was calculated of Formula- 1 (1 -1 ) compound. Blood samples were collected at 02S_f 0.5. 0.75, 1, 2, 4, 6, 8, 12, 24 and 36 h after oral administration. 1 Oral Administration

1 Parameter

I L-dopa (Levo-DOPA) Formula- 1 ( 1 -1 )

i Cinax (ug/niL) 1 0.55 ± 0.15 0.96 ± 0.20

1 AUC fcg.h/mL) 1 3.3 ± 0.8 6.1 ± 0.3

1 ti ; (h) ! 10.6 - 5.0 15.9^■± 6.8

|00235| The terra "sample" refers to a sample of a body fluid, to a sample of separated cells or to a sampk 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 herei

EQUIVALENTS

{00236} The present disclosure provides among other things compositions and methods for treating metabolic conditions or neurodegenerative disorders and their complications. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the systems and methods herein will become 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 00237| All publications and patents mentioned herein, including 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 by reference. In case of conflict, the present application, including any definitions herein, will control.

Claims

CLAIMS:

1. A pharmaceutical composition comprising a compound of Formula I,

Formula I

and a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer, and stereoi somer thereof;

Wherein

R^!, R² each independently represents hydrogen, hydroxy! methyl, amine, cycohexyl methyl ether, butoxy, propoxy, thiol, alky! alkyl thiol, acetyl thiol., disulfide, acyl, acylalkyl, alkenyl, alkylthioalk l, alkynyl, alkoxyar l, alkoxyalkyl, aiyl, aralkyi, atyloxyalkyl, arvUhioalkyl, cycloalkyl, ether, ester, heteroaryl, heterocydyi, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl;

R independently represents hydrogen, alkyl , methyl, ethyl, carboxyl, amine or thiol;

R independently represents null, hydrogen, alkyl, carboxyl, amine, thiol, amine, cycohexyl methyl ether, butoxy, propoxy, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl, alkylthioalkyl, alkynyl, alkoxyaiyl, alkoxyalkyl, ar l, aralkyi, atyloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl, heterocydyi, lower alkyl, sulfone, sulfoxide, hydroxyalkyl, - B-CO-CE₂-NB-, -NH-CO-, R-COO-R', thiol, or 2- amino-3-hydroxy- -metbylpropanamide;

R^" independently represents null, hydrogen, alkyl, methyl, ethyl, carboxyl, amine, thiol, amine, cycohexyl methyl ether, butoxy, propoxy, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl. aryl, aralkyi aryloxyalkyi, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl, heterocyciyl, lower alkyl, suifone, sulfoxide, hydroxyalky!, -NH-CO-CH₂- H-, -NH-CO-, R-COO-R thiol, NH1- H2-, hydrazine, 2-aratno-3-hydroxy-N-methyipropanamide_>

R" independently represents null, hydrogen, alkyl, methyl, ethyl, carboxyl, -NH-CO-NH-, amine, cycohexyl methyl ether, buloxy, propoxy, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acy!, acylalkyl, alkenyl, alk lthioalkyl, alkynyl, alkoxyaryl, alkoxyalky), ary1, araikyi, arvioxyalkyl, ar lt toalkyl, cycloa!kyl, ether, ester, heteroar l, heterocyciyl, lower alkyl. sulfone, sulfoxide, hydroxyaikyl, - H-CO-CH2-NH-, -NH-CO-, R-COO-R¹, thiol,

or 2-amitK>3-'hydroxy-N-methylpropan.amide;

R', R^1' each independently represents null,

or 80

2. A pharmaceutical composition comprising a molecular conjugate of claim 1 and a pharmaceutically acceptable carrier.

3. The compound of claim L wherein the compound is a molecular conjugate of carbidopa and omega-3 fatty acid.

4. The compound of claim 1 , wherein the compound is a molecular conjugate of carbidopa and thioctic acid.

5. The compound of claim 1 , wherein the compound is a molecular conjugate of Levodopa and omega-3 fatty acid.

6. The compound of claim 1 , wherein the compound is a molecular conjugate of Levodopa and thioctic acid.

7. The compound of claim 1 , wherein the compound is a molecular conjugate of benserazide and omega-3 fatty acid.

8. The compound of claim 1 , wherein the compound is a molecular conjugate of benserazide and thioctic acid.

9. The compound of claim 1 , wherein the compound is a molecular conjugate of methykiopa and omega-3 fatty acid.

10. The compound of claim 1 , wherein the compound is a molecular conjugate of methyldopa and thioctic acid,

1 1. The compound of claim 1 , wherein the compound is a molecular conjugate of alpha dtfloirromethyklopa and omega-3 fatty acid.

12. The compound of claim 1 , wherein the compound is a molecular conjugate of alpha diflouromethyidopa and thioctic acid,

13. A method for treating a disease with neuromuscular disorders or neurodegenerative diseases as the underlying etiology comprising administering to a patient in need thereof an effecti ve amount of a compound of claim 2.

1 . The method of claim 13, wherein the disease with neuromuscular disorders and neurodegenerative diseases as the underlying etiology is selected from Alzheimer's disease. Amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, or Spinal muscular atrophy.