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Title:
COMPOSITIONS AND METHODS FOR THE TREATMENT OF NEUROPATHIC PAIN
Document Type and Number:
WIPO Patent Application WO/2013/168019
Kind Code:
A1
Abstract:
The invention relates to the compounds of formula (I), formula (II), formula (III) and formula (IV) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), formula (II), formula (III) or formula (IV) and methods for the treatment of neuropathic pain may he formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of neuralgia, severe pain, chronic pain, chemotherapy induced pain, neuropathic pain, post herpetic neuralgia, neuralgia, motor neurone disease, diabetic neuropathy, postherpetic neuralgia, injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, cancer pain and lower back pain.

Inventors:
KANDULA MAHESH (IN)
Application Number:
PCT/IB2013/052216
Publication Date:
November 14, 2013
Filing Date:
March 20, 2013
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
KANDULA MAHESH (IN)
International Classes:
C07C229/08; A61K31/195; A61K31/27; A61K31/4406; A61P25/04; C07D211/26
Domestic Patent References:
WO2006096996A12006-09-21
WO2013008182A12013-01-17
Foreign References:
US20090118365A12009-05-07
CN1300213A2001-06-20
US20110021628A12011-01-27
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Claims:
CLAIMS:

1 . A compound of formula I:

Formula Ϊ

or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer, or stereoisomer thereof;

Wherein,

R1 , R each independently represents hydrogen, methyl, amine, carboxyl, -C¾-, D, - H, acetyl,

103

104

105

a is independently 2,3 or 7:

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

c and d are each independentiy 11 D, -OH, -OD, CrQ-alky!, -NH? or -COCf¾;

R1 independently represents ! f. D, -(' i CO, F, CI,

108

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

e and d are each independent!}' H, D, -OH, -OD, Ci-0>-alkyl, -N¾ or -COC¾.

2. A compound of formula II:

Formula ΪΪ

or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer, or stereoisomer thereof,

Wherein,

Rl , R'1 each independently represents hydrogen, methyl, amine, carhoxyl, -CHj-, D, - H, acetyl,

110

112

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

c and d are each independently H, Ό, -Oil -OD, CrCValkyi, - H2 or -COCHs;

R4 independently represents H, D, -CH3CO, F, CI,

115

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

e and d are each independently H, D, -OH, -OD, CrC<>-alkyi, - H2 or -COC¾.

3. A compound of formula HI:

Formula 111

or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer, or stereoisomer thereof; herein,

3 , R each independentl represents hydrogen, methyl, amine, carboxyl, -Cl¾~, D, - H, acetyl, 117

118

119

a is independently 2,3 or 7;

each b is independently 3, .5 or 6;

e i independently 1, 2 or 6,

c and d are each independently H, D, -OH, -OD, C C(>-alkyl, -NH2 or -COC¾;

R4 independently represents H, D, -CHjCO., F, CI, 121

122

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

c and d are each independently H, Ό, -Oil -OD, CrCValkyi, - ¾ or -COC¾.

4. A compound of formula IV

Formula IV or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer, or stereoisomer thereof;

Wherein,

R! , RJ each independently represents hydrogen, methyl, amine, carboxyl, -C¾-, D, -H, acetyl,

125

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1, 2 or 6;

c and d are each independently H, D, -OH, -OD, C V,-alkyi, - H? or -COCH¾; independently represenis H, D, -Cf¾CO, F, CI,

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

e and d are each independently H, D, -OH, -OD, Ci-0>-alkyl, - ¾ or -COC¾.

5. A Pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

6. A Pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier

7. A Pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier

8. A Pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable c rrier

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

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

1 1. The pharmaceutical composition of claim 7, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal admins strati on or transdermal administration.

12. The pharmaceutical composition of claim 8, which is formulated to treat the underlying etiology with an effective amount admi istering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration,

13. A method of treating neuropathic pain related diseases as the underlying etiology, the method comprising administering to a patient in need thereof art effective amount of claim 9.

14. A method of treating neuropathic pain related diseases as the underlying etiology, the method comprising administering to a patient in need thereof an effective amount of claim 10.

15. A method of treating neuropathic pain related diseases as the underlying etiology, the method comprising administering to a patient in need thereof an effective amount of claim 1 1.

16. A method of treating neuropathic pain reiaied diseases as the underlying etiology, the method comprising administering to a patieni in need thereof an effective amount of claim 12.

17. The method of claim 13, wherein the neuropathic pain as the underlying etiology is selected from trigeminal neuralgia, severe pain, chronic pain, chemotherapy induced pain, neuropathic pain, post herpetic neuralgia, epilepsy, neuralgia, motor neurone disease, diabetic neuropathy, postherpetic neuralgia, injury, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV related neuropathic pain, cancer pain and lower back pain.

18. The method of claim. 14, wherein, the neuropathic pain as the underlying etiology is selected from trigeminal neuralgia, severe pain, chronic pain, chemotherapy induced pain, neuropathic pain, post, herpetic neuralgia, epilepsy, neuralgia, motor neurone disease, diabetic neuropathy, postherpetic neuralgia, injury, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spina! cord injury, migraine, HIV related neuropathic pain, cancer pain and lower back pain.

1 . The method of claim 15. wherein the neuropathic pain as the underlying etiology is selected from trigeminal neuralgia, severe pain, chronic pain, chemotherapy induced pain, neuropathic pain, post herpetic neuralgia, epilepsy, neuralgia, motor neurone disease, diabetic neuropathy, postherpetic neuralgia, injury, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spina! cord injury, migraine, HIV related neuropathic pain, cancer pain and lower back pain,

20. The method of claim 16, wherein the neuropathic pain as the underlying etiology is selected from trigeminal neuralgia, severe pain, chronic pain, chemotherapy induced pain, neuropathic pain, post herpetic neuralgia, epilepsy,, neuralgia, motor neurone disease, diabetic neuropathy, postherpetic neuralgia, injury, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spina! cord injury, migraine, HIV related neuropathic pain, cancer pain and lower back pain.

A pharmaceutical composition comprising a molecular conjugate of gabapentin and R-Lipoic acid.

A pharmaceutical composition comprising a molecular conjugate of gabapentin and eicosapentaerioic acid.

A phamiace tical composition comprising a molecular conjugate of gabapentin and docosahexaerioic acid.

A pharmaceutical composition comprising a molecular conjugate of gabapentin and saisaiate.

A pharmaceutical composition comprising a molecular conjugate of gabapentin and pantothenic acid.

26. A pharmaceutical coraposition comprising a molecular conjugate of gabapentin and pyridoxamine.

27. A pharmaceutical coraposition comprising a molecular conjugate of gabapentin and iumaric acid,

28. A pharmaceutical compositioii comprising a molecular conjugate of pregabalin and R-Lipoic acid,

29. A pharmaceutical composition, comprising a molecular conjugate of pregabalin and eicosapentaenoic acid.

30. A pharmaceutical compositioii comprising a molecular conjugate of pregabalin and docosahexaeiioic acid.

31 . A pharmaceutical compositioii comprising a molecular conjugate of pregabalin and saisaiaie.

32. A pharmaceutical compositioii comprising a molecular conjugate of pregabalin and pantothenic acid.

33. A pharmaceutical compositioii comprising a molecular conjugate of pregabali and pyridoxamine.

34. A phannaceutical compositioii comprising a molecular conjugate of pregabalin and iumaric acid,

35. A phannaceutical composition comprising a molecular conjugate of phenibut and R-Lipoic acid,

36. A phannaceutical composiiioti comprising a molecular conjugate of phenibut and ei cosapen taenoi c aci d,

37. A phannaceutical composition comprising a molecular conjugate of phenibut and docosahexaeiioic acid.

A pharmaceutical composition comprising a molecular conjugate of phenibut and

39. A pharmaceutical composition comprising a molecular conjugate of phembut and pantothenic acid.

40. A pharmaceutical composition comprising a molecular conjugate of phembut and pyridoxamine.

41 . A pharmaceutical composition comprising a molecular conjugate of phembut and fumaric acid.

42. A pharmaceutical composition comprising a molecular conjugate of picami!on and R-Lipoic acid.

43. A pharmaceutical composition comprising a molecular conjugate of picami!on and eieosapentaenoic acid.

44. A pharmaceuttca! composition comprising a molecular conjugate of picami!on and docosahexaenoic acid.

45. A pharmaceutical composition comprising a molecular conjugate of picamilon and sal sal ate.

46. A pharmaceutical composition comprising a molecular conjugate of picami!on and pantothenic acid.

47. A pharmaceutical composition comprising a molecular conjugate of picamilon and pyridoxamine,

48. A pharmaceutical composition comprising a molecular conjugate of picamiion and fumaric acid.

Description:
COMPOSITIONS AND METHODS FOR THE TREATMENT OF

NEUROPATHIC PAIN

PRIORITY

[0001] The present application claims the benefit of Indian Provisional Paten Application No. 1813/CHE/2012 filed on 7- ay-20T2 and the international Application No. PCT7IB2012/053529 tiled on 10-JuSy-2012, the entire disclosure of which is relied on for ail purposes and is incorporated into this application by reference.

FIELD OF TH INVENTION

|0002| This disclosure generally relates to compounds and compositions for the treatment of neuropathic pain and oilier neurological disorders. More particularly,, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, solvates, enantiomer or stereoisomer, esters, salts, hydrates, prodrugs, or mixtures thereof.

BACKGROUND OF THE INVENTION 0003] Neuropathic pain usually responds poorly to the standard treatments described in the World Health Organization ' s analgesics ladder, such as non-steroidal antiinflammatory drugs (NSAIDs) and opioids. Antidepressants have been shown to be of benefit in diabetic neuropathy, with the best effects achieved with tricyclic antidepressants (TCAs). However, the adverse events of TCAs are frequently severe enough to lead to drug withdrawal ,

(000 1 The gamma - aminobutyric acid (GAB A) pathway forms a major inhibitory neurotransmitter system in the CNS targeted for the treatment of DPN. The anti pileptic gabapentin became the first agent for the treatment of all neuropathic pain conditions, based on evidence from large randomized trials in two types of neuropathic pain. jOOOSj Gabapentin is widely used for neuropathic pain dire to its effectiveness and relatively fewer side effects than TCA and other anticonvulsants. Gabapeniin produces analgesia via binding to the 2-o site of L-type voltage gated calcium channels and decreasing calcium influx. Gabapentin is usually well tolerated with slow titration. Moreover, it usually takes weeks of titration to reach the maximal effective close and a dosing of 3/day is often necessary. Like gabapentin, pregabaiin also acts by binding to the α2-δ subunit of calcium channels. As demonstrated in four randomized piacebo control trials, pregabaiin (300-600 mg/day) is significantly more effective in alleviating DPN than placebo. Unlike gabapentin, pregabaiin has better GI absorption and can be administered twice per day. Its linear pharmacokinetics provide a rapid (b2 weeks) onset of maximal pai n relief

|0006] Gabapentin bioavailability is dose-dependent, decreasin from an average of about 60% at a 300-mg dose to about 35% or less at doses used to treat neuropathic pain. The underlying mechanism of this dose dependence is thought to be saturation of gabapentin absorption from the intestine. Gabapentin is absorbed by a low-capacity solute transporter localized in the upper small intestine, possibly an L-type amino acid transporter. The absorption pathway for gabapentin in buroan intestine can be saturated at doses that are used to treat neuropathic pain. As a result, plasma levels of gabapentin are unpredictable and may not reach therapeutically useful levels in some patients. j 0 7| it has bee reported recently that exposure to gabapentin at high oral doses increased in a linear manner. However, this study was based on limited data from less than 10 subjects, only four of which reached the highest dose of 4800 mg/day. Several larger clinical studies have clearly demonstrated the lack of dose proportionality for oral gabapentin; eurontin Summary Basis of Approval, NDA 20-235, U.S. Food And Drug Administration)

[0008] The large interpatient differences in plasma gabapentin exposure observed clinically are likely the .result of highly variable intestinal expression of the gabapentin transporter between individuals and the narrow localization of the transporter in the small intestine. A subset of patients appears to have limited ability to absorb gabapentin, possibly due to a lower abundance of the transporter in their intestines.

|0009 ' J 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 neurological disease and conditions such as neuropaihic pain, diabetic neuropathic pain and other diseases related sub-chronic and chronic pain,

SUMMARY OF THE INVENTION

10010) 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 neurological disease and conditions such as neuropathic pain, diabetic neuropathic pain and other diseases related sub-chronic and chronic pain. 001 I] The invention herein provides compositions comprising of formula I or pharmaceuticai acceptable salts thereof The invention also provides phamiaceutical 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 neurological disease and conditions such as neuropathic pain, diabetic neuropathic pain and other diseases related sub-chronic and chronic pain.

Formula !

[001.2] in certain embodiments, the present invention relates to the compounds and compositions of formula 1, or pharmaceutically acceptable sal ts thereof.

Formula Ϊ

Wherein.

R 1 , R * each independently represents hydrogen, methyl, amine, carboxyl, -CHr, D, - H, acetyl,

a is independently 2,3 or 7:

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

c and d are each independentiy 11 D, -OH, -OD, CrQ-alky!, -NH? or -COCf¾;

R 1 independently represents H, D, -( ' i CO, F, CI,

a is independentl 2.3 or 7;

each b is independently 3, 5 or 6;

e is independently 1, 2 or 6;

c and (I are each independently H, D, -OH, -O ' D, CVCV.-alky!, -NH 2 or -COCH 3 . [0013] The invention herein provides compositions comprising of formula f! or pharmaceutical acceptable salts thereof. The invention also provides pharmaceutical composiiioiis comprising one or more compounds of formula 11 or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the ireatraent of neurological disease and conditions such as neuropathic pain, diabetic neuropathic pain and other diseases related sub-chronic and chronic pain.

Formula II

[001.4] In certain embodiments, the present invention relates to the compounds and compositions of formula Π, or pharmaceutically acceptable salts thereof.

Formula Π

Wherein,

R 1 , J each independently represents hydrogen, methyl, amine, carhoxyl, ~Ci¼r, D, - E, acetyl, 





a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently i , 2 or 6;

c and d are each independently H, D, -OH, -OD, C t -0 -alkyi - H 2 or -COCH,; independently represents H, D, -C%CO, F, CI, 



a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1, 2 or 6;

c and d are each independently H, D, -OB, -OD, Ct-Cc-alkyi, -N% or -COCH3.

|0015] The invention herein provides compositions comprising of formula 111 or pharmaceutical acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula 111 or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatrnent of neurological disease and conditions such as neuropathic pain, diabetic neuropathic pain and other diseases related sub-chronic and chronic pain.

Formula III

|ΌΘ!ό] In certain embodiments, the present invention relates to the compounds and compositions of formula III, or pharmaceutically acceptable salts thereof,

Formula ill

Wherein,

R J , R- * each independently represents hydrogen, methyl, amine, carboxyl, -&¾-, D, H, acetyl,

20

21

a is independently 2,3 or 7,

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

c and d are each independently H, D, -OH, -OD, Ct-C f -alkyi -N¾ or -COC¾; R 4 independently represents H, D, -C¾CO, F, CI,

10 13 16 1 

a is independently 2,3 or 7;

each b is independently 3, 5 o 6;

e is independently 1 , 2 or 6;

c and d are each independent!}' H, D, -OH, -OD, Ci-0 > -alkyl, - b or -COC¾.

{ ' 0017| The invention herein provides compositions comprising of formula IV or pharmaceutical acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula IV or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of .neurological disease and conditions such as neuropathic pain, diabetic neuropathic pain and other diseases related sub-chronic and chronic pain.

Formula IV

i 01 1 In certain embodiments, the present invention relates to the compounds compositions of formula IV, or pharmaceutically acceptable salts thereof.

Formula IV

Wherein, 





a is independently 2.3 or 7;

each b is independently 3, 5 or 6;

e is independently \ , 2 or 6;

c and d are each independently H, D, -OH, -OD, CrCe-alk !, -N¾ or -COC¾; 31

32

a is independently 2,3 or 7;

each b is independently 3 < 5 or 6;

e i s independently 1 , 2 or 6;

c and d are each independently H, D, -OH, -OD, CVCs-alkyi, -N % or -COC¾. |0019] in other iliusirative embodiments, examples of compounds of Formuia I are set forth below:

O- i)

[0020] in other iliusirative embodi ments, examples of compounds of Formula II are set forth below:

(3-1)

{ ' 0022) in other illustmiive embodiments, examples of compounds of Formula IV are set forth below:

(4-1)

[0023) 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 neuropathic pain, diabetic neuropathic pain and other diseases related sub-chronic and chronic pain or its related complications. 10024) The application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compositioiis herein. In some aspects, the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, parenteral administration injection, subdermal administration, or transdermal administration. f0025) Herein, the application additionally provides kits comprising the pharmaceutical compositioiis described heretn. The kits may further comprise instructions for use in the treatment neuropathic pain, diabetic neuropathic pain and other diseases reiaied sub- chronic and chronic pain or its related complications. f0026| The compositions described herein hav several uses. The present application provides, for example, methods of treating a patient suffering from neuropathic pain, diabetic neuropathic pain and other diseases related sub-chronic and chronic pain or its related complications manifested from metabolic conditions, genetic abnormalities, congenital disorders, chronic diseases or disorders,

DETAILED PESOUmON OF THE INVENTION

Definitions

|0Q27] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, ail technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art. 002S] The compounds of the present invention can be present in the form of pharmaceutically acceptable salts. The compounds of the present invention can also be present in the form of pharmaceutically acceptable esters (i .e., the methyl and ethyl esters of the acids of formula I, formula IL formul III or formula IV 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 1, formula II, formula ΪΗ or fomiula IV (hydration),

[002 J Compounds thai 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." Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more asymmetric centers that are turn- superimposable mirror images of each other are termed "enanttomers. " When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enanttomers 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-sequencing Titles of Calm, Ingoki 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 i-)-isomers respectively), A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enanttomers is called a "racemic mixture".

|0030| 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.

|003t j The term "polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound. 0032] The phrases "parenteral administration" and "administered parenteral ly" 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, inirapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra- articiiiar, subcapsular, subarachnoid, intraspinal and intra sternal injection and infusion.

[0033] 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.

[0034] The phrase "pharmaceutically acceptable" is art- recognized. in certain embodiments, the terra includes compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use i contact with the tissues of mammals, human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate wi h a reasonable benefit/ risk ratio.

[0035] 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: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxy methyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butte and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil and soybean oil; (1.0) glycols, such as propylene glycol; (1 1 ) polyols, 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) alginic 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 emp oyed in pharmaceutical formulations.

[0036) The term "prodrug" is intended to encompass compounds that, under physiological conditions, are converted into the therapeuticall active agents of the present invention. A common method for making a prodrug is to include selected moieties that are hydroi zed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal,

[0037] The term "prophylactic or therapeutic" 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 unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against deveioping the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i c . it is intended to diminish, ameliorate, or stabilize the existing unwanted condition, or side effects thereof).

[0038] The term "predicting" as used herein refers to assessing the probability related diseases patient will suffer from abnormalities or complication and/or terminal platelet, aggregation or 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. The predictive window may be the entire remaining lifespan of the subject upon analysis by the method of the present invention.

[0039] The term "treating" is art -recognized and includes preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease. disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as neuropathic pain, severe pain, chronic pain, chemotherapy induced pain, diabetic neuropathic pain, post herpetic neuralgia, restless leg syndrome, epilepsy, trigeminal neuralgia, spina! cord injury mediated pain, rheumatic pain, neuralgia of a subject by administration of an agent even though such agent does not treat the cause of the condition. The term "treatina", "treat" or "treatment" as used herein includes curative, preventative (e.g., prophylactic), adjunct and palliative treatment.

|0040] 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 ma empirically determine the effective amount of a particular composition without necessitating undue experimentation.

[0041 ] in certain embodiments, the pharmaceutical compositions described herein are formulated in a manner such that, said compositions will be delivered to a patient in therapeutically effective amount as part of a prophylactic or therapeutic treatment. The desired amount of the composition to be administered to a patient will depend on absorption, inactivaiion, 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 administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art

[0042] 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.

[0043| 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 conce tration-ti me curve from time 0 to infinit may he used.

{004 | When used with respect to a pharmaceutical composition or other material, the term "'sustained release" is art-recognized. For example, a subject composition which releases a substance over time may exhibit sustained release characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at. one time For example, in particular embodiments, upon contact with body fluids including blood, spinal fluid, rnucus secretions, lymph or the like, one or more of the pharmaceutically acceptable excipients may undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant, release of any material incorporated therein, e.g., an therapeutic 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. 10045} 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 systemtcaHy, 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 to metabolism and other like processes. 0046J 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. 0047] The present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said prodmgs

[0048) This application also discloses a phamiaceiitical composition comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula I, formula Π, formula III or formula IV may be formulated for systemic or topical or oral administration. The pharmaceutical composition may be also formulated for oral administration, 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. {0049J in many embodiments, the pharmaceutical compositions described herei wiil incorporate the disclosed compounds and compositions (Formula 1, formula II, formula 111 or formula IV) to be delivered in an amoimt sufficient to deliver to a patient a therapeutically effective amount of a compound of formula I, formula H, formula HI or formula IV or composition as part of a prophylactic or therapeutic treatment. The desired concentration of formula I, iormula II, formula HI or formula IV or its pharmaceutical acceptable salts will depend on absorption, inacttvaiion, 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 ma 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 ski lied in the art. 0050] Additionally, the optimal concentration and/or quantities or amounts of any particular compound of formula i formula H, formula III or formula IV 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.

|0051] The concentration and/or amount of any compound of formula 1, formula II, formula 111 or formula IV may he 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 assa local tissue concentrations, diffusion rate of the salts or compositions, and local blood flow before and after administration of therapeutic formulations di closed herein. One such method is mlcrodialysi , as reviewed by T. E. Robinson et ah, 199.1, microdialysis in the neuroscienees, Techniques, volume 7, Chapter 1. The methods reviewed by Robinson may be applied, in brief, as follows. A mierodialysis loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop. When compounds with formula I, formula II, formula III or formula IV such as those disclosed herein are injected adjacent to the loop, released drugs are collected in the dialysate in proportion to their local tissue concentrations. The progress of diffusion of the sal ts o compositions may he determined thereby with suitable calibration procedures using known concentrations of salts or compositions.

{00521 In certain embodiments, the dosage of the subject compounds of formula I, formula Π, formula Ϊ1Ϊ or formula IV 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.

[0053] Generally, in carrying out the methods detailed in this application, an effective dosage tor the compounds of Formulas I 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 1, formula II. formula III or formula IV may also be administered to a human patient at a dose of, for example, between 0.1 nig and 1000 mg, between 5 mg and 80 mg, or less than TO, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1.000, 2000, 5000 mg per day. In certain embodiments, the compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 1.0% of the compound of formula I, formula Π, formula 111 or formula IV required for the same therapeutic benefit. j005 j An effective amount of the compounds of formula i. formula. If formula ΪΪΙ or formula IV described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease.

|0055J 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 denwelkation and/or elevated reactive oxidative- nitrosative species and/or abnormalities in physiological homeostasis' s, in patients who are at risk for such complications. As such, these methods include both medical therapeutic (acute) and/or prophylactic- (prevention) administration as appropriate. The amount and timing of compositions 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,

|0056] The compositions provided by this application may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenteral!?, e.g., intravenously, subcutaneously 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 nanoparticies. j0057j The compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple closes. 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-arginme, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various di integrates such as starch, algi ic acid and certain complex silicates., together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium iauryl 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. I, formula Π, formula 01 or formula IV may also comprise e terically coated comprising of various excipients, as is well known in the pharmaceutical art.

[0058] For parenteral administration, solutions of the compositions may be prepared in (for example) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or 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.

J00S9] 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. 1 0, 50, 100, 300, 500, 700, 800 mg of the compounds of formula I, formula i f formula III or formula IV disclosed herein, for instance, compounds of formula 1, formula O, formula III or formula IV or pharmaceutical acceptable salts of a compounds of Formula I, formula ΪΪ, formula ΪΪΪ or formula IV.

[0060 j Generally, a composition as described herein may be administered orally, or parenteralSy (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 admi istration may also be indicated, for example, when a high dose is desired at the target tissue or organ. For buccal administration the active composition may take the form of tablets or lozenges formulated in a conventional manner. j006i| The dosage administered will be dependent upon the identit of the metabolic 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.

|0062] 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 body weight.

|0063] Expressed in terms of concentration, an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasaliy, pharyngolaryngeaily, bronchially, intravaginally, rectaliy, or ocularly in a concentration of from about 0.01 to about 50% wAv 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. j ' 0064) 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 can be prepared

[0065J As discussed above, the tablet core contains one or more hydropMlic polymers. Suitable hydrophilic polymers include, but are not limited to, water swellable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof. Examples of suitable water swellable cellulose derivatives include, but are not limited to, sodium carboxyrnethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutyieeiiulose, hydroxyphenylcellulose, hydroxy ethyl cellulose (HEC), hydroxypentylceilulose, hydroxypropylethylcellulose, hydroxypropyibutylcellulose, and hydroxypropylethylcellulose, and mixtures thereof Exampies of suitable polyalkylene glycols include, but are not limited to, polyethylene glycol. Exampies of suitable thermoplastic polyalkylene oxides include, but are not limited to, poiy (ethylene oxide). Examples of suitabie acryiic polymers include, but are not limited to, potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, high-molecular weight crossl inked acrylic acid homopolymers and copolymers such as those commercially available from Noveon Chemicals under the tradename CARBOPOL i ; t Examples of suitabie 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 Ian gum, maltodexirin, galactomannan, pusstulan, laminarin, scleroglucan, gum arable, i ilin, pectin, gelatin. whelan, rbarasan, zooglan, methylan, chitin, cyelodextrin, chitosan, and mixtures thereof. Examples of suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and laponite; magnesium trisilicate; magnesium aluminum silicate; a d 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 suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-finked agar, and cross-! inked carboxymethylcellulose sodium, and mixtures thereof..

{00661 The carrier may contain one or more suitable excipients for the formulation of tablets. Examples of suitable excipients include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, glidants, release-modifying excipients, superdisintegrants, antioxidants, and mixtures thereof.

{0067] Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxypropyimethylcellulose; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymetliylcel!uiose, tara, gum arable, tragacanth, pectin, xanthan, geHan, gelatin, maltodextrin, galactoroannars, pusstulan, laminarm, scieroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, and starches; and mixtures thereof Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches, microerystallme cellulose, and mixtures thereof.

{00681 Suitable lubricants include, but. are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, tafc, gfycerides 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. j 0069 J 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, ethyleeliulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylaies, methacrylates, 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, hydrogen ted vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof. Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceryl beheiiate, glyceryl palraitosiearate, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GiyeoWax- 932, lauroyl macrogol-32 giycerides, stearoyl macrogol-32 glycerides, and mixtures thereof Examples of suitable phospholipids include phosphotidyl 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, candelilla wax, shellac wax, microcrystallme wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereo Examples of super disintegrates include, but are not limited to, croscarraellose sodium, sodium starch, glycolate and cross- linked povidone (crospovidone) In one embodiment the tablet core contains up to about 5 percent by weight of such super disintegrant, 0070] Examples of antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, buiylhydroxytoluene. butylated hydroxyaiiisole, edetic acid, and edetale salts., and mixtures thereof. Exampies 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. 0071 ] In one embodiment, the immedi ate 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 ce, as measured by the weight and volume of that specific layer.

[0072] in one embodiment., the immediate release coating contains a first portion and a second portion, wherein at least one of the portions contai ns 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.

|0073j In one embodiment, the first portion contains the first pharmaceutically active agent and the second portion contain 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.

{0074] in one embodiment, the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core. In another embodiment the outer coating portion is included of a dried granulation including the pharmaceutically active agent.

J0075J 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 j ' 0076| The immediate release dosage, unit, of the dosage form, i.e., a tablet, a plurality of drag-containing beads, granules or particles, or an outer layer of a coated core dosage form, contains a therapeutically effective quantity of the active agent with conventional p armaceutical 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), 0077] 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 & Willdns, Baltimore, Md., 2000). A diffusion system typically consists of one of two types of devices, reservoir and matrix, which are weSiknown 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.

|007S| An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core; using coating or compression processes or in a multiple unit system such as a capsule containing extended and immediate release beads.

[0079] Delayed release dosage formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, but soluble in the neutral environment of small intestines. The delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. The drug-containing composition may be 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.

[0080] 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.

[0081] Each dosage form contains a therapeutical ly effecti ve amount of active agent, in one embodiment of dosage forms that mimic a twice daily dosing profile, approximately

30 wt. % to 70 wt. %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt, % to 3.0 wt, ¾, 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.

10082 J 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 a plurality of coated beads or granules, which release drug approximately 3 hours to 14 hours following oral administration to provide a second dose. j00S3| For purposes of transdermal (e.g., topical) admini tration, 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.

[0084) Methods of preparing various pharmaceutical compositions with a certain amount of one or more compounds of formula I, formula il, formula III or formula IV 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, Easton, Pa., 19th Edition (1995).

(0085] 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.

[0086J Formulations use ul 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 amoimt 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. fOOSTj 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. jOOSSj The compounds of formula I, formula II, formula. HI or formula IV 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.

1008 J 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, ma iitol, and/or silicic acid; (2) binders, such as, for example, earhoxyniethylceSSelose, alginates, gelatin, polyvinyl pyrroiidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, aiginic 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 lauryl 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 aiso 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.

[0090] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject compositions, t e liquid dosage forms may contain inert diluents commonly used in the art; such as, for example, water or other solvents, solubilizins assents and ernuisifsers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1.3-butylene glycol, oils (in particular. cottonseed, com, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

|0091J Suspensions, in addition to the subject compositions, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, macrocrystalline cellulose, aluminum nietahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.

|0092| Formulations for rectal or vagina! administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which is solid at room temperature, but- liquid at body temperature and, therefore, will melt in the appropriate body cavity and release the encapsulated compoundis) and composition(s). Formulations which are suitable for vagmal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate,

{ 0O93J Dosage forms for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, geis, solutions, patches, and inhalants. A subject composition may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. For transdermal administration, the complexes may include lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties. 009 | The ointments, pastes, creams and gels may contain, in addition to subject compositions, other earners, 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 poiyamide powder, or mixtures of suc , substances. Sprays may additionally contain customary propeilanis, such as chlorofluorohydrocarbons and volatile unsubstituied hydrocarbons, such as butane and propane.

10095) 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 os. 6,974,588, 6,564,093, 6,312,716, 6,440,454, 6,267,983, 6,239, 180, and 6,103,275.

1009 J In another embodiment, a transdermal patch may comprise: a substrate sheet comprising a composite film formed of a resin composition comprising 100 parts by weight of a polyvinyl chloride-polyur ethane composite and 2-10 parts by weight of a styrene-ethylene-butylene-styrene copolymer, a first adhesive layer on the one side of the composite film, and a polyalky!ene 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 polyalkyiene terephthalate film; and a second adhesive layer comprising a sty ene-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 polyalkyiene terephthalate film on one side of the composite film by means of an adhesive layer thereby forming the substrate sheet, and forming a primer layer comprising a saturated polyester resin on the outer surface of the polyalkyiene terephthalate film. 0 97] Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive and laminating the drag-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 properties, and at the same time deliver the required clinical dose.

10098] Transdermal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver small-molecule drugs. Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transdermal patches and may be delivered using technology such as electrical assist (iontophoresis) for large-molecule drugs.

{00991 iontophoresis is a technique employed for enhancing the flu of ionized substances through membranes by application of electric current. One example of an iontophoretic membrane is given, in U.S. Pat. No. 5,080,646 to Theemves. The principal mechani m by which iontophoresi enhances molecular transport across the skin are (a) repelling a charged Ion from an electrode of the same charge, (b) e!ectroosmosis, 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.

{00100} 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., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

|00101| An example of such a kit is a so-called blister pack. Blister pack 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 relati ely stiff material covered with a foil of a plastic material that may be transparent. {00102} Methods and compositions for the treatment of neuropathic pain. Among other things, herein is provided a method of treating neuropathic pain, comprising administering to a patient in need thereof a therapeutically effective amount, of compound of Formula i:

Formula ί

herein,

R l , R ' each independently represents hydrogen, methyl, amine, carboxyl, -CH H, acetyl,

independentl represents

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1, 2 or 6;

c and d are each independently H, D, -OH, -OD, CVCj-alkyi, -NH 2 or -COCHj; R independently represents H, D, -CH 3 CO > F, CI,

63

64

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

e and d are each independently H, D, -OH, -OD, CrCc-alkyi, - H 2 or -COCH 3 .

J00103J Methods and compositions for the treatment of neuropathic pain. Among other things, herein is provided a method of treating neuropathic pain, comprising administering to a patient in need thereof a therapeuti cally effective amount of compound of Formula II:

Formula I f

Wherein,

R 1 , R 3 each independently represents hydrogen, methyl, amine, carboxyl, -CH 2 ~, D, H, acetyl. 66



a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1, 2 or 6;

c and d are each independently H, D, -OH, -OD, C r Q > -alkyl, -NH 2 or -COCH 3 ;

R 4 independently represents H, D, -CH O, F, CI,

70

71

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

e and d are each independently H, D, -OH, -OD, Ci-C< > -alkyl, -NH 2 or -COCH 3 .

J00104J Methods and compositions for the treatment of neuropathic pain. Among other things, herein is provided a method of treating neuropathic pain, comprising administering to a patient in need thereof a therapeuti cally effective amount of compound of Formula III

Formula lit

Wherein,

R J , R- * each independently represents hydrogen, methyl, amine, carboxyl, ~C¾-, D, - ii acetyl, 73

74

0

a is independently 2,3 or 7;

each b i s i ndependently 3, 5 or 6;

e is independently 1, 2 or 6;

c and d are each independently Ή, D, -OB, -OD, Ct-Ce-olkyl, -NH_ or -COC¾

R independently represents } 1. D, -CH .CO. F, CI,

10 13 16 1 

a is independently 23 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

e and d are each independent!}' H, D, -OH, -OD, Ci-0 > -alkyl, -N¾ or -COC¾. j ' OOlOSj Methods and compositions for the treatment of neuropathic pain. Among other things, herein is provided a method of treating neuropathic pain, comprising administering to a patient in need thereof a therapeutical ly effective amount of compound of Formula IV:

Formula IV

Wherein,

R' , R " ' each independently represents hydrogen, methyl, amine, car oxyl, -CH2-, D, -

H, acetyl,

80

82

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6,

c and d are each independently H, D, -OH, -OD, Ci-Q-alkyl, - H 2 or -COCH 3 ; independently represents H, D, -C¾CO F, CI,

85

a is independently 2,3 or 7;

each b is independently 3, 5 or 6;

e is independently 1 , 2 or 6;

c and d are each independently H, D, -OH, -OD, CrQ-alkyl, -NH? or -COCf¾.

Methods for using compounds of formula I, formula II, formula Iff formula IV:

[00106J The invention also includes methods for treating neuropathic pain, severe pain, chronic pain, chemotherapy induced pain, diabetic neuropathic pain, post herpetic neuralgia, restless leg syndrome, epilepsy, trigeminal neuralgia, spinal cord injury mediated pain, rheumatic pain, neuralgia.

METHODS OF MAKING

M hods for making tfte compounds offormula I are set forth a examples below

£00107] Example Γ. 001081 Sy tvifiesi s of Compound-2 :

001.09| To the solution of sodium hydride (1 .0 mmol) in ( 10 vol) of tetra hydrofuran (THF), cyclo exane nitriie I ( 1 .0 mmol) in ( 10 vol) of THF was added drop wise at 0°C and kepi for stirring for 0.5 h, fert-Butyl chloroacetate ( 10 vol) was added simultaneously at room temperature & left for stirring for 2 h. Reaction completion (monitored by TLC), the reaction mixture portioned between diethyl ether (2L) and water (2 L) 5 followed by washing organic layer with brine solution (1 L), the organic layer dried over anhydrous Na 2 S04 and evaporated under reduced pressure to get product 3 which was recrystaUzed in hexane (50 vol) to yield 65 % of compound 3 as a off white solid.MF: C13H27NO2 ; Mol . Wt: 223.31

[003 10| S nthesi s of Compound-3

|001 H ] Raney i (moist weight 0.64 g, approximately lOmrnol) and dry tert-butanol ( 10 vol) were placed in a 50 mL flask, and then compound-2 (10 mmo!) was added while stirring. Flushed with nitrogen gas and followed by hydrogen gas. Reaction left for stirring vigorously at room temperature for 45 min under hydrogen atmosphere. On completion of the reaction, the mixture was filtered. The organic layer was evaporated and the residue was dissolved in ethyl acetate, and was washed with wate The organic layers were dried and evaporated, and the product was purified by flash column chromatography on silica gel to give compound-3 as pale yellow liquid (yield: 92%). M.F: Ci3t½NQ 2 : Mol. Wf. 277.34

[001.12 J Sy nthesi s of Compound-4 :

|001 :13| Compound 3 (1.0 mmol) and 2,4-dimethoxy benzyl amine (1.0 mmol) were taken in 1,2 DitJiloromethane (20 vol; LR grade) and stirred for 2h at room temperature for imine formation, then sodium triacetoxy borohydride (1.5 mmoi ) was added portion wi e at 0 °C and the reaction mixture was aiiowed 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 solution (50 vol), dried over anhydrous Na2SC> 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 elueni to yield 80 % of compound 4 as a pale yellow liquid.

[00114| Synthesis of Compound-6:

4

iOOUSJ To a solution of compound 4 ( 1.0 mmol) in dry DCM (1.8 L) was added N, N- diisopropylethylamine (2.0 mmoi) at ~10°C, followed by drop wise addition of 1- chioroemylchloroformate (1.2 mmol) for 30 mint 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 5 was directly used for the next step without further isolation and purification. In another RB flask the cis-5,8, 11,14,17- Eieosapentaenoic act d (1.2 mmol) and anhydrous 2CO3 (3.0 mmol) was taken in dry DMP (10 vol) kept for stirring at room temperature for 2 h and then cooled to -H) °C, intermediate 5 was added slowly drop wise over 30 min and then was kept at room temperature for 12 h. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was poured into water (1.00 mL) and extracted with diethyl ether (2 x 1 I.,). 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 e!uent to yield 40% of compound 6 as a yellow liquid. 00116| Synthesis of Compound-?:

001.17| 25% TFA in DCM was added to compound 6 (1.0 mmo!) at 0 °C and the reaction niixtore was allowed to stir for 30 min at the same temperaiure. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was basified with saturated Na CO.? solution (20 vol) and extracted with DCM (20 vol), dried over anhydrous NajSO,* 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 to yield 51.6 % of compound 7 as a pale yellow gummy solid. MP : C M H 4S O ft . Mol. Wt.: 543.73. Methods for making the compounds of formula II are set forth as examples below

[00! 18} Example 2:

|001.19f Synthesis of Compound-2: 1

f ' 00120| Compound I (.1 .0 mmoi) and 2,4-dimethoxy benzyl amine ( .1.0 mmol) taken in

Methanol (20 vol ; LR grade) & stirred for 12 h at room temperature for imine formation, then sodium borohynde (1 .0 mmol) was added portion wise at 0 "C and the reaction mixture was allowed to stir for 2 h at rt. On completion of the reaction (monitored by

TLC), the reaction mixture concentrated under reduced pressure and was diluted with

DCM (50 vol) . , washed with water (50 vol) followed by brine solution (50 vol), dried over anhydrous NasSC^ 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 70 % of compound 4 as a paie yellow liquid. M.F: C^H^ O, ; o!. W : 223.31

|001211 Synthesis of Compound- 3

{001.22) Concentrated sulfuric add (0.55 ml,, 10 mmol ) was added to a suspension of anhydrous magnesium sulfate (4.81 g, 40 mmol) in 40 mL of Dichloromethane The mixture was stirred for .15 mm, after which the earboxylic acid derivative 2 ( .10 mmol) is added, t rt - Butyl alcohol (50 mmol) is added last. The mixture was Stoppard tightly and stirred for 18 h at 25 0 C, or until the reaction is complete by TLC analysis. The reaction mixture was then quenched with 75 mL of saturated sodium bicarbonate solution and stirred until ail magnesium sulfate has dissolved. The solvent phase was separated, washed with brine, dried (MgS0 4 ), and concentrated to afford the crude ieri - butyl ester, which was purified by chromatography to form compound-3. M.F: Mol. W : 365.51.

[00123[ Synthesis of Compound-6:

|00124| To a solution of compound 3 ( 1.0 mmol) in dry DC (1.8 L) was added N, N- diisopropylet ylamine (2.0 mmol) at -10°C, followed by drop wise addition of 1- chioroethylchloroformate (1.2 mmol) for 30 min 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 reactio mixture intermediate 4 was directly used for the next step without further isolation and purification. In another RB flask the cis-5,8,11, 14,17- Eieosapentaefloic acid 5 (1.2 mmol) and anhydrous K2CO? (3.0 mmol) was taken in dry DMF (10 vol) stirred at room temperatur 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 nrL) 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 eiitent to yield 48 % of compound 6 as a yellow. M.F: C^NO^ M!ol. Wt.: 738, 0 1251 Synthesis of Compound-?:

{0 26| 25% TFA in DCM was added to compound 6 (1.0 mmo!) at 0 °C and the reaction mixture vvas allowed to stir for 30 rntn at the same temperature. Reaction was monitored by I LC. On completion of the reaction, the reaction mixture was basified with saturated NajCOj solution (20 vol) and extracted with DCM (20 vol), dried over anhydrous Na2$0 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 to yield 62 % of compound 7 as a pale yellow gummy solid. M.F ; C¾ f ¾ 0 6 ; MoL Wt,: 5 1.72 Methods for making the compounds of formula III are set forth as examples below00127) Example 3:

j00128| Synthesi s of Compouod-2: f 001.29} To the solution of sodium hydride (1 .0 mmol) in (10 vol) of tetra hydrofuran (THF), eyclohexane nitrite J (1.0 mmol) in. ( 10 vol) of Ti i was added drop wise at 0°C and left stirring for 0.5 h, fenf-B tyl chioroacetate (10 vol) was added simultaneously at. room temperature and left for stirring for 2 h. Reaction completion (monitored by TLC), the reaction mixture portioned between diethyl ether (2L) and water (2 L), followed by washing organic layer with brine solution (1 L), the organic layer dried over anhydrous Na2SC> and evaporated under reduced pressure to get product 3 which was recrystalized in exane (50 vol) to yield 325 g (45.7 %) of compound 3 as a off white solid. Μ.Έ: C ! B ) 7 N0 2 ; Mol . Wt; 231.29.

{00130} Synthesis of Compound-3 ;

Raney Ni (moist weight 0.64 g, approximately l Ommol) and dry tert-butanol (1.0 vol) were placed in a 50 mL flask, and then compound-2 (10 mmol) was added while stirring. Flushed with nitrogen and followed by hydrogen gas. Reaction left stirring for vigorously at room temperature for 45 rain at hydrogen atmosphere, on completion the reaction mixture was filtered. The organic layer was evaporated and residue was dissolved in ethyl acetate, and was washed with water. The organic layers were dried over sodium sulfate, filtered and evaporated, and the product was purified by flash column chromatography on silica gel to give compound-3 as pale yellow liquid (yield; 92%). M. ' F: Mol . Wt : 235.32.

{00131 J Synthesis of Compound-4:

3 00132| Compound 3 ( 1 .0 mmol) and 2,4-dimethoxy benzyl amine (1 .0 mmol) was taken in 1,2 DicMororn ethane (20 vol; L grade) and stirred for 2h at room temperature for inline formation, then sodium iriacetoxy borohydride (1.5 mmol ) was added at 0 *C 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 solution (50 vol), dried over anhydrous NajSQ* 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 SO % of compound 4 as a pale yellow liquid, MF: C23B3JNO ; Mol. Wt.; 385.5,

00133| Synthesis of Compound-6:

f00134j To a solution of compound 4 ( 1.0 mmol) in dry DCM (1.8 L) was added M, - diisopropylethylamine (2.0 mmol) at -10 n C, followed by drop wise addition of 1- chioroethylchlorofo mate ( 1.2 mmol) for 30 min 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 5 was directly used for the next step without further isolation and purification. In another RB flask the cis-5,8,11,,1 , 17- Eicosapentaenoic acid (1.2 mmol) & anhydrous 2CO3 (3.0 mmol) was taken in dry DMF (10 vol) stir at room temperature for 2 h and then cooled to -10 1> 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. .F: C«a½NG s · ol. Wt: 757.99.

|0O135J Synthesis of Compound-?:

25% TFA n DCM was added to compound 6 (1.0 mmoi) at 0 °C and the reaction mixture was allowed to stir for 30 mm at the same temperature. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was basifsed with saturated a?COn solution (20 vol) and extracted with DCM (20 vol), dried over anhydrous ajSO.* 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 to yield 51.6 % of compound 7 as a pale yellow gummy solid. M.F : Wt: 551.71.

Methods for making the compounds of formula Ware set. forth as examples below

[0 136} Example 4:

if *1 H

O O

O O O

KSC OS/DMF

O O

S Λ - A. --·- -v [00137} Synthesis of Compound-

OBn

[00138] To the solution of Benzyl 4-aminobutanoate (200.0 g, 165.2 mmol; 1.0 eq) in Ν,Ν-D methylfonaamide, dissopropvl ethylamine (2.0 mmol), nicotinoyl chloride 1 ( 1.0 mmol) was added drop wise for 0.5 h at 0 °C, The reaction mixture was brought to room temperature and left for stirring for 3 h. Ors completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate (50 vol) and washed with water (40 vol), followed by brine solution (20 Vol), the organic layer was dried over anhydrous ¾8θ 4 and evaporated under reduced pressure to get product 2 which was recrystalized in hexane (20 V) to yield (96 %) of compound 2 as a off white solid. M.F: CHH I &NJO.? ; Mol. Wt : 29S34.

[00139} Synthesis of Compound-3 :

[001 0} 10% .Palladium charcoal (lOmmoi) and dry Methanol (10 vol) were placed in a 50 m.L flask, and then compotmd-2 (10 mmol) was added while stirring. Flushed with nitrogen and followed by hydrogen gas. Reaction kept stirring for vigorously at room temperature for 2.0 h at hydrogen atmosphere, on completion of the reaction mixture was filtered over eel he and washed with methanol. The organic layer was evaporated and residue was dissolved in ethyl acetate, and was washed with water. The organic layers were dried over sodium sulfate, filtered and evaporated to give yield compound-3 (yield: 90%).M.F: CioHn iO;, ; Mol. Wt.: 208.21. |Ό01 1 Synthesis of Compound-6:

6 00142) To a solution of cis-5,8,11 , 14 ) i 7-Eicosapen.taer-oic acid 4 ( 1.0 mmol) in dry DCM (1.8 L) was added M, ' N-diisopropy1eihyJamine (2.0 mmol) at ~10°€, followed by drop wise addition of 1 -chloroethyl.chloroformate (1.2 mroo!) for 30 min at the same temperature and the reaction mixture was ailowed to stir for 1 h at 0°C. On completion of the reaction (monitored, by TLC), the reaction mixture intemiediate 5 was directly used for the next step without further isolation and purification. In another RB flask the Compound~3 (1.2 mraol) and anhydrous 2 C0 3 (3.0 rmnol) was taken in dry D F (10 vol) stir at room, temperature for 2 h and then cooled to -3.0 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 m ' L) and extracted with diethyl ether (2 x 1 L). The combined organic layers were washed with water (2 x 500 rnL) followed by brine solution (100 mL) % dried over anhydrous N¾SQ 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, M.F : C3 3 H 4 4N 2 0 7 M:ol. W : 580.71. jOOI 3j The terra "sample 1* refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ, Sampies 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 sortin Preferably, cell-, tissue- or organ samples are obtained from those cells, tissues or organs which express or produce the peptides referred to herein.

1001441 EQUIVALENTS

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. 001451 INCORPORATION BY REFERENCE

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.