CA2873094A1 - Prodrugs of anti-platelet agents - Google Patents

Abstract

Disclosed is the compounds of formula (I), formula (II), formula (la), formula (IIb) or its pharmaceutical acceptable salts, polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising and effective amount of formula (I), formula (II), formula (la), formula (lIb) and may be used to treatment or management of ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular, cardiovasculard diseases and blood colts.

Description

PROD.RUGS OF ANTI-PLAT.ELET AGENTS
PRIORITY
100011 The present application claims the benefit of Indian Provisional Patent Application No. 178110-1E/2012 filed on 07-May-2012 and the International Application No .PCI1B20121053673 filed on I9-July-2012, the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference.
ffIlE,D OF TIFF: INVENTION
100021 This disclosure generally relates to compounds and compositions for the treatment of atherothrombo.sis. More particularly, this invention relates .to treating subjects with a.
pharmaceutically acceptable dose of compounds, stereoisomers, enantio.mers, crystals, esters, salts, hydrates, prodrugs, or mixtures thereof BACKGROUND OF THE INVENTION
100031 Atherothrombosis refers to the formation of thrombus superimposed on preexisting atherosclerosis. This common pathophysiologic process results in morbid or fatal clinical ischemic events affecting the cerebral, coronary, or peripheral arterial circulation. Because the platelet is a pivotal mediator in the initiation and propagation of thrombus formation, antiplatelet drugs have emerged as key agents for prevention of recurrent ischernic events.
However, there is controversy regarding choice of oral antiplatelet therapy in patients with vascular diseases (ie, ischemic stroke, coronary artery disease [CAD], and peripheral arterial disease [PAD"). While it has been established that aspirin prevents recurrent atherothromhotic events across a wide range of high-risk patients (relative risk reduction of approximately 25%), it is less clear if other antiplatelet agents, such as clopidogrel or d.ipyridamole, alone or added to aspirin, are more effective.

2 100041 This uncertainty This uncertainty is reflected in clinical practice:
neurologists prefer to use aspirin combined with dipyridamole for patients with transient ischemic attacks (TIA.$) or ischemic strokes; cardiologists use aspirin, clopidogrel, or their combination for patients with CAD; and there are few data regarding optimal antiplatelet treatment choices in patients with 'PAD, This heterogeneity in clinical practice suggests that clinicians believe that each vascular condition is different.
[000.5] Intraarterial thrombus formation could be .prevented; the major sequelae of atherosclerotic heart disease (myocardial infarction, unstable angina, and sudden cardiac death) as well as the majority of complications of percutaneous interventions could be prevented. Arterial thrombi,. in contrast to venous thrombi, are platelet rich, making antiplatelet therapy central to their prevention. Until recently, our antiplatelet arinamentarium was limited to aspirin. Today, we have a much wider selection of antiplatelet agents from which to choose, allowing us to optimize antiplatelet protection in specific clinical scenarios. Of course, the clinical benefits of platelet inhibition must be weighed against the associated risk of both surgical and nonsurgical hemorrhage.
[0006] The potential for increased hemorrhagic risk, especially in the surgical setting., In the months and years to come, it may not be unusual for a patient to require an urgent surgical procedure while being treated with two, or possibly three, different antiplatelet agents. Therefore, it is as important for the surgeon to understand the clinical benefits of antiplatelet therapy as it is for the cardiologist to appreciate the substantial risks associated with surgical bleeding.
[0007] Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a need in the art for new compositions to treatment of A th erothrom bo si s.
SUMMARY OF THE INVENTION

3 100081 The present invention provides corn pounds, compositions containing these compounds and methods for using the same to treat, prevent and/or ameliorate the effects of the conditions such as Atherothrombosis.
100091 The invention herein provides compositions comprising of formula 1 or pharmaceutical acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula I. or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents.
These, compositions may be used in the treatment of Atherothrombosis and its associated complications, "'"=-=,..õ..--""R'¨' R2 CI
N
Formula I.
100101 In certain embodiments, the present invention relates to the compounds and compositions of formula I or pharmaceutically acceptable salts thereof, CI
N
Formula Wherein,

4 PCT/1B2013/052328 RI independently represents D, methyl, NH \c sc, /FIN\
0 3S"

'31 0 01: /
NH, NH2 N 7;:s5s tõ.227,2iN
h01 NAO N
N

0/1\0AsS5 OH

-N
or R2 independently represents HC
HS

HO 'Lac-,c,....õ. /

0 , 1.372- 5 g H 14 17 20 , 44 _ ....._ 0 , `..õ....
H
-...1. OH
H HO ,.......----;.
:
N......,...õ...õ.....õ....---...õ11)( OH
HO
:sss,..N
0 0 c) H
, , el t.s, 40 co2H *I rss, alit coNH, 0-k OH A OCOCH3, 41111111) (;-2?õ.
, , ..55..4,0 T cH3 o 0 .
H3c 1111 0 cH3 CH3 6 = i 4; , OH '?=? 0, OH
NH
H

IIIth 4.,,,..
HN
/ A
' -0 , NH
H
Ni\ss-S
".

HO el a b H or , e b "a ?....
c d ;
a is independently 2,3 or 7;
each b is independently 3, 5 or C-i e is independently .1, 2 or 6;
c and d are each independently IT, D, -OH, -OD, C1-C6-alkyl, -NII2 or -COCI-13.
100111 The invention herein provides compositions comprising of =formula [f or pharmaceutical acceptable salts thereof. The invention also provides pharmaceutical compositions compising one or more compounds of formula ll Or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents.
These compositions may be used in the treatment of Atherothrombosis and its associated complications.

R
0 ....................................... N
Formula II
100121 In certain embodiments, the present invention relates to the compounds and compositions of formula II or pharmaceutically acceptable salts thereof, 7.2 1.11 R

rui Formula II
Wherein, RI independently represents .D, H. methyl, 'SOWN.0)Zz f O¨
tµj\c(ks.sS¨\(,) N sSS tzazzrjL;ssS /0/ \O

t.,7%N
N

N

H c N N
or =

R.2 independently represents .............

.),........, Hz ,..., 4 / c,s.

HCN''...---:".%-....", H
1 , , H
)27....,..N H2N
OH

, .

S-,..ss , .
o .."
--o .

..---....._, , õtziziO\
_ f 9 0 , 0 ,

5 8 11 14 17 20 f3z.z.
P

/ .
_ 0 .

--..N.
H
..- OH...
... H HO
--., .-----"-, N OH
HO
-...,s,...
cS) N

Co2H op ,, . caNH2 0.-,,.
OH 0(1; OCOCH1 0.(2i..., ., .,so Yr cH3 of ,r-N CH3 0 411 H3C %...), 4 lip 0 CH3 6 - io OH =':?-? 0 HN)NNH
H H
""Foll Rita S
0 , OH

HO
\
HN

a or 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, -01), Cr-C6-alkyl, --NR, or -COM.
[00131 In the illustrative embodiments, examples of compounds of formula I are as set forth below:
CI

Lf (1-1 ) Na-.µ

(1-2) 100141 Ineel s I
a.n embodiments, the present invention relates to the compounds and compositions of formula I active metabolite, formula la or pharmaceutically acceptable salts thereof, =õ)-1 N \

CI
formula la Wherein, RI independently represents D, Ft methyl, 0 0-µ
NH? 0 0 0 0 µ11-1 /1.\\
ITF.

/\0 xo .--, ...---o.e.
c'SSSO '111" \
/ "S%-' , , H H
/......, ...e",...........,,,,,..."....., N_....c.A.
.,,,,xiN,,,....õ.....,"..õ,--õ,,,, H .
H H
N
, H H
N õcS
¨0/17..,1\\) , 0m0 t72,0/1\As-SS OH

H H
N
or H
, R2 independently represents H, ,,,..
,...)",....,, 0 FM, i H

1 HS , OH

HO

=

\s/ 4 7 30 13 16 19 /

(172z.

N CA-1,3 `....,....
H...- OH

..., HO ...õOH
..,s 0 0 ii 1 r, NHCOCHz CO di,......., CON H2 (1111 2H tss, OH 0 40 '77 OCOCH3 I AIIIIIIH"' , , , -....55f0 CO r-%LI CH3 "

CH3 b 10 OH :7; 0 , .

OH
HN)IN NH

H nott S
H N /
0 , N H2 :v E-#
'',..
HO At \
VP N
H , , a or c d;
a is independently 2,3 or 7;
each b is independently 3, 5 or e is independently 1, 2 or 6;
c and d are each independently H, D, -OH, -OR C1-C6-a1kyl, -NH2 or -COCH3.
10015] In the illustrative embodiments, examples of compounds of fonnula Ia are as set forth below:

=
Lsõ...õ--\ 0 CI SH
(1.a-1) N OH

( 1a-2) 100161 In certain embodiments, the present invention relates to the compounds and compositiOnS of fOrMilla II active metabolite, formula Ha or pharmaceutically acceptable salts thereof, N
R2"--HS
Formula Ha W herein, R' independently represents D, H. methyl, 0 0 cz.

µ11-1 1-0¨F

'K c3,4(\

'11111' (22-cSSS'."

cN'555'L.,N

N

N

\l/No/j\o/jc OH

(3c:
or R e independently represents H2N,õ.
H3e 4.n..rxrtr HS

H
HA
4.
OH
t ' HO
S-.....,õ, =

N,./N., S-----..,, S _ µ 1) 0 .

- - -c I 1 E 4 1 7 20 0 , '3( _______________ .

8 H i4 17 20 , 0 , N CH:s '-..,..._ H
...- OH
H HO
-- .-----N."===_,._õ-------.%N.,...-.µ OH
HO
;3. -S'. . N
0 0 , H , Atli CON H2 0 (... Iiii co2H 0 (.5.5...
0-..,.
OH 4111111jz 0'?OCOCH3, 411111) (:2?õ.
. , , ,ss rzp 0 Ail s...) 1--1C `''' CH3 CH3 6 - to OH ":27 0 OH

How/
, 0 , NI-12 , H
HO, \
N
H

= =
=
= a =
or a d a is independently 2,3 or 7;
each b is independently 3, 5 or 6;
cis independently 1, 2 or 6;
c and d are each independently H, D, -OH, -OD, -INTI2 or -COCII3.
[0171 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 .Atherothrombosis or its related complications.
100181 The application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compositions herein, in some aspects, the pharmaceutical composition is formulated for systemic administration, oral administration, sustai fled release, p.arentera I administration, injection, subdernial administration, or tran s de rmal administration.
10019..1 'Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the treatment of A th erothrom b o.s s or its related complications.
100201 The compositions described herein have several uses. The present application provides, for example, methods of treating a patient suffering from Atherothrombosis or its related complications manifested from metabolic conditions, chronic diseases or disorders; Hepatology, Cancer, Neurological.Hematological, Orthopedic, Cardiovascular, Renal, Skin, Vascular or Ocular complications.

DETAILED DESCRIPTION OF THE INVENTION
Defi ni lions [00211 As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art, [0022] The compounds of the present invention can be present in the form of pharmaceutically acceptable salts. The compounds of the present invention can also be, present in the form of pharmaceutically acceptable esters (i.e., the methyl and ethyl esters of the acids of formula 1, formula II, formula la or formula ha to be used as prodruL,$).
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 IL formula la or formula ha (hydration).
100231 Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stere.oisomers." Diastereomers are stereoisomers with opposite configuration at one or more chiral. centers which are not enantiomers. :Stereoi smilers bearing one or more asymmetric centers that are non- superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, if a.
carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn, Ingold and Prolog, or by the, manner in which the molecule rotates the plane of polarized light and designated as dextrorotatorv or levorotatory (i.e., as (l-.) or ( isomers respectively). A
chiral compound can exist as either individual el-mm.43111er or as a mixture. thereof. A
mixture containing equal proportions of the enantiomers is called a "racemic mixture".
[00241 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.
10025.1 The term "polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound..
100261 The phrases "parenteral administration" and "administered parenterally"
as used.
herein refer to modes of administration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, i ntra.va scular, i ntraperi cardi al, in-tram-feria] , i ntra thec.al intracapsular, intraorbital, ntracardiac., i ntradennal, intraperitoneal, trans trachea I õ subcutaneous, sub cuti cular, infra.-articular, subcapsularõ subarachnoid, intraspinal and intra.stemal injection and infusion.
10027" 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.
100.281 The phrase "pharmaceutically acceptable" is art-recognized. in certain embodiments, the term includes compositions, polymers and other mateiials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

100291 The phrase "pharmaceutically- acceptable carrier" is an-recognized, and includes, for example, phannaceinically 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) 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) pyrog.en-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
[00301 The term "prodrug" is intended to encompass compounds that under physiological conditions, are converted into the therapeutically active agents of the present invention. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. in other embodiments, the prodrug is converted by an enzymatic activity of the host animal, 1003:1.1 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 mani fe.stati on 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 developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
10032" 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..
100331 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 path.oph.ysiology is not affected, such as treating the epilepsy, migraine, 1.1europathie pain, post herpetic neuralgia, pain.
C,reutzfeld-Jakoh disease, Alzheimer's disease, multiple sclerosis, Batten disease, multiple sclerosis, Parkinson's disease (PD) restless legs syndrome (RLS), cluster headache, depression, tibromyalgia, sexual dysfunction, amyotrophic lateral sclerosis (ALS), also known as Lou Ciehrig's disease, convulsions, partial seizures, or as an adjunctive therapy for partial, myocionic, tonic-Clonie seizures, mood-stabilizing agent, bipolar disorder, Tourette syndrome, Alzheimer's disease, autism, bipolar disorder and anxiety disorder, tri gemi n al neuralgia, attention-deficit hyperacti vity disorder, schizophrenia, neuropabic pain, seizures, bipolar disorder, mania, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotoni a, intermittent explosive disorder, borderline personality disorder, myotonia congenita and post-traumatic stress disorder of a subject by administration of an agent even though such agent does not treat the cause of the condition. The term "treating", "treat" or "treatment" as used herein includes curative, preventative (e.g., prophylactic), adjunct and palliative treatment.
100341 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 experimentanon.
100351 In certain embodiments, the pharmaceutical compositions described herein are formulated in a manner such that said compositions will be delivered to a patient in a therapeutically effective amount, as part of a prophylactic or therapeutic treatment. The desired amount of the composition to be administered to a patient will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values.
may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular sUbject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
Typically, dosing will be determined using techniques known to one skilled in the art, 100361 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.
10037" in certain embodiments, the dosage of the subject compositions provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials, For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.
100381 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, mucus secretions, lymph or the like, one or more of the pharmaceutically acceptable excipients may undergo gradual or delayed degradation (e.g.:, through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic andfor biologically active salt and/or composition, fir 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.

10039..1 The phrases "sy stemic admini stra ti on," "admini stered sy st emi cal y," "peripheral administration" and "administered peripherally are art-recognized, and include the.
administration of a subject composition, therapeutic or other material at a site remote from the disease being treated. Administration of an agent for the disease being treated, even if the agent is subsequently distributed systemically, may be 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.
10040..1 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.
[00411 The present disclosure also contemplates prodrugs of the compositi.ons disclosed herein, as well as pharmaceutically acceptable salts of said prodrugs.
[00421 This application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula. I, formula H. formula. La or formula. Ha may be formulated for systemic or topical or oral administration. The pharmaceutical composition may be also formulated for oral admini stration, oral solution, mj ecti on ubdenual administrati on, Of tran sderm a administration. The pharmaceutical composition may further comprise at least one of a.
pharmaceutically acceptable stabilizer, diluent, surfactant, tiller, binder, and lubricant.
[0043] lin many embodiments, the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formula 1, formula H, formula fa or formula Ha) to be delivered in an amount sufficient to deliver to a patient a.
therapeutically effective amount of a compound of formula 1, formula .11, formula .1:a .or formula Ha or composition as part of a prophylactic or therapeutic treatment.
The desired concentration of formula 1, formula 11, formula 1a or formula ha or its pharmaceutical acceptable salts will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. it is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional .iudgment 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.
100441 Additionally, the optimal concentration and/or quantities or amounts of any particular compound of formula. 1, formula IL formula la or formula Ifla 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.
[0045] The concentration and/or amount of any compound of formula 1, formula.
H, formula :la or formula Ha may be readily identified by routine screening in animals, e.g., rats, by screening a range of concentration and/or amounts of the material in question.
using appropriate assays. :Known methods are also available to assay local tissue concentrations, diffusion rates of .the salts or compositions, and local blood flow before and after administratiOn of therapeutic formulations disclosed herein. One Such method is microdialysis, as reviewed by Ti E. Robinson et al.., 1991, .microdialysis in the neurosciences, Techniques, volume 7, Chapter 1. The methods reviewed by Robinson may be applied, in brief, as follows. A microdialysis loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop. When compounds with formula .1, formula 11, formula. Ia or formula Ha. such as those disclosed herein are injected adjacent.
to the loop, released drugs are collected in the dialysate in proportion to their local tissue, concentrations. The progress of diffusion of the salts or compositions may be determined thereby with suitable calibration procedures using known concentrations of salts or compositions.
100461 in certain embodiments, the dosage of the subject compounds of formula 1, formula 11, formula la or formula Ha 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, 100471 Generally, in carrying out the methods detailed in this application, an effective dosage for the compounds of Formulas 1 is in the range of about 0.01 mg/kg/day to about 100 .mg/kg/day in single or divided doses, for instance 0,01 mg/kg/day to about 50 mg/kg/day in single or divided doses. The compounds of Formulas I may be administered at a dose of, for example, less than 0:2 mgiktilday, 0.5 mg/kg/day, 1.0 mg/kg/day. 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/dayõ 30 mg/kg/day, or 40 nigiloalday.
Compounds of Formula. 1, formula ll, formula or formula. Fla. may also be administered to a human patient at a dose of, for example, between. 0.1 mg and 1000 mg, between 5 mg and 80 mg, or less than 1.0, 9.0, 12,0, 20,0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000, 2000, 5000 mg per day. In certain embodiments, the compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound of formula. 1, formula II. formula la or formula ila required for the same therapeutic benefit.
f00481 An effective amount of the compounds of formula 1, formula formula la. or formula 11a described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease.
100491 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 denwelization 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 thera.peu tic (acute) andlor 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 pa.tient-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..
100501 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, :parenterally, 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 he 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 nj ecti on õ or in Ilanoparacies 100511 The compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the compositions and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.
These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipiems and the like. Thus, for purposes of oral administration, tablets containing various excipients such as L-arginine, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrates such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl 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 L
formula Il, formula la or formula Ha may also comprise enterically coated comprising of various excipients, as is well known in the pharmaceutical art.
[0052] 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 ail.
100531 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..(2,. 10, 50, 100, 300, 500, 700, 800 m2 of the compounds of formula 1, formula H, formula Ia or formula [la disclosed herein, for instance, compounds of formula 1, formula 11, formula la or formula Ha or pharmaceutical acceptable salts of a compounds of Formula 1, formula 11, formula la or formula 11a.
100541 Generally, a composition as described herein may he administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorder that prevent oral administration, or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician.
Localized administration may also be indicated, for example, when a. high dose is desired at the target tissue or organ. For buccal administration the active composition may take the form of tablets or lozenges formulated in a conventional manner, 100551 The dosage administered will be dependent upon the identity 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.
MN Illustratively, dosage levels of the administered active ingredients are:
intravenous, 0.1 to about 200 mg/kg; intramuscular, 1 to about 500 trig/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.

100571 Expressed in terms of concentration, an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasally, pharyngolaryngeally, bronchially, intmvaginallyõ rectally, or oculady in a concentration of from about 0.01 to about SW4) why' of the composition; preferably about I
to about 20% wfw of the composition; and for parenteral use in a concentration of from about 0.05 to about 50% wfv of the composition and preferably from about 5 to about 20%
wfv.
10058] 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.
10059.1 As discussed above, the tablet core contains one or more hydrophilic polymers.
Suitable hydrophilic polymers include, but are not limited to, water swellable cellulose derivatives, polyalkylerte glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloid.s, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof. Examples of suitable water swellable cellulose derivatives include, but are not limited to, sodium carb oxy m ethyl cellulose, cross-linked fly droxypmpyl.cell ulose, hydroxypropyl cellulose (1:1PC), hy droxy p ropy I methyl cellulose (EIPMC.), hydroxyi sopropy I cellulose, hydroxybutylcelluloseõ hydroxyph eny leen ulose, hydroxyethyleellulose hydroxypentylcellulose, hydroxy propyl ethyl cellulose, hydroxypropyibutylcelluloseõ and hydroxypropylethylcellulose, and mixtures thereof Examples of suitable polyalkylene glycols include, but are not limited to, polyethylene glycol. Examples of suitable thermoplastic poi yalkyiene oxides include, but are not limited to, poly(ethylene oxide). Examples of suitable acrylic polymers include, but are, not limited to, potassium met hacrylatedi vi nylbenzene copolymer, pol ymeth ylIneth a:cry I ate, high-mol ecular weight cross] inked acrylic acid homopolymers and copolymers such as those commercially available from Noveon Chemicals under the:
tradename CARBOPOLIm, Examples of suitable hydrocolloids include, but are not:

limited to, alginates, agar, guar gum, locust bean gumõ kappa carrageenan, iota carrageenan, tara, gum arabi e, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum :arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylart, chitin, eyclodextrin, 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; and mixtures thereof. Examples of suitable gelling. starches include, but are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch glycolate and derivatives thereof and mixtures thereof Examples of suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross-linked carboxvmethylcellulose sodium, and mixtures thereof (0060] The carrier may contain one or more-suitable excipients for the formulation of tablets. Example:s of suitable excipients include, but are not limited to, tillers, adsorbents, binders, di si ntegrants, lubricants, gl idants, release-modifying excipients.
superdisintegrants, antioxidants, and :mixtures thereof.
100611 Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxypropylmethylcellulose; wet hinders such as water-soluble:
polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenanõ carboxymethylcelluloseõ tara, gum arabic, tragacanth, pectin, xanthan, gellanõgelatin, maltodextrin, galactomannan, pusstulan, laminarin, seleroglucan, inulin, svhelan, rhamsanõ zooglan, methylan, chitin, cyclodextrinõ chitosan, polyvinyl pyrrolidoneõ cellulosics, sucrose, and starches; and mixtures thereof Suitable disintegrams include, but are not limited to, sodium starch glycolate, cross-linked poly vinylpyrrolidone, cross-linked carboxymethylcellulose, starches, microcrystalline cellulose, and mixtures thereof.
[0062] Suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures.
thereof Suitable glidants include, but are not limited to, colloidal silicon dioxide.
Suitable release-modifying excipients include, but are not limited to, insoluble edible materials, pH-dependent polymers, and mixtures thereof.
10063] 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, ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methactylates, acrylic acid copolymers, copolymers thereof, and mixtures thereof.
Suitable 10w-Melting hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof. Examples of suitable fats include, but are not limited to, hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids and .their salts, and mixtures thereof.
Examples of suitable fatty acid esters include, but are not limited to, sucrose .fatty acid estersõ mono-õ di-, and triglycerides, glyceryl behenate, glyceryl palmitosteara.te, glyceryl monostearate, glyceryl -tristearate, glyceryl trilaury late, glyceryl mristate, CilycoWax-932, lauroyl macrogo1-32 glycerides, steamy( .macrogol-32 glycerides, and mixtures thereof Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl 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, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof. Examples of super disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and cross-linked povidone (Crospovidone)_ In one embodiment the tablet core contains up to about percent by weight of such super disintegrant 100641 'Examples of antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, and mixtures thereof Examples of preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, mak acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof, 100651 In one embodiment, the immediate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns; e.g., from about 250 microns to about 1000 microns. In embodiment, the immediate release coating is typically compressed at a density of more than about 0.9 glee, as measured by the weight and volume of that specific layer.
100661 In one embodiment, the immediate release coating contains a first portion and a second portion, wherein at least one of the portions contains the second pharmaceutically active agent. In one embodiment, the portions contact each other at a center axis 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.
[00671 In one embodiment, the first portion contains the first pharmaceutically active agent and the second portion contains the second pharmaceutically active agent. In one embodiment, one of the portions contains a third pharmaceutically active agent. in one embodiment one of the portions contains a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet core.

100681 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.
100691 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.
100701 The immediate release dosage, unit of the dosage form, i.e., a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form, contains a therapeutically effective quantity of the active agent with conventional pharmaceutical excipients. The immediate release dosage unit may or may not be coated, and may or may not he 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-con tai g granules or beads) 100711 Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington¨The Science and Practice of :Pharmacy", 20th. Ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000). A

diffusion system typically consists of one of two types of devices, reservoir and matrix, which are wellknown and described in die art. The matrix devices are generally prepared by compressing the drug vy1tit a slowly dissolving polymer carrier into a tablet form.

100721 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.
[0073] 'Delayed release dosage formulations are created by coating, a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, but soluble in the neutral environment of small intestines. The delayed .release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. 'The drug-containing composition may be a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into.
either a tablet or capsule.
100741 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.
10075] Each dosage form contains a therapeutically effective amount of active agent. In one embodiment of dosage forms that mimic a twice daily dosing profile, approximately 30 wt. '% to 70 wt. %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt %to 3.0 -wt.
preferably 60 wt. % to 40 wt. %, of the total amount of active agent in the dosage form is released in the second pulse. For dosage forms mimicking the twice daily dosing profile, the second pulse is preferably released approximately 3 hours to less than 14 hours, and more preferably approximately 5 hours to 12 hours, following administration.
[0076] 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.
INT] For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, may be prepared.
100781 Methods of preparing various pharmaceutical compositions with a certain amount of one or more compounds of formula 1, formula H, formula la or formula ha 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).
[00791 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.

100801 Formlations useful in the methods provided herein include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
The amount of a subject composition which may be combined with a carrier material to produce a single dose may vary depending upon the subject being treated, and the particular mode of administration.
100811 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.
E0082.1 The compounds of formula I, formula II, formula la or formula Ha 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% wfw, of .medicament relative to the total weight of the formulation.
100831 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, amanita., and/or silieic acid;
(2) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic 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 also he 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.
100841 Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject compositions, the liquid dosage form.s may contain inert, diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, corn, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tettahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
100851 Suspensions, in addition to the subject compositions, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, micmcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and .tragacanth, and mixtures thereof, 100861 Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable 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 compound(s) and composition(s). FOIMUlati.OTIS which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.
[0087] 'Dosage forms for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. A
subject.
composition may he mixed under sterile conditions with a pharmaceutically acceptable:
carrier, and with any preservatives, buffers, or propellants that may be required. For transderinal administration, the complexes may include lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties.
100881 The ointments, pastes, creams and gels may contain, in addition to subject.
compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc., silicic acid, aluminum hydroxide, calcium silicates and polyamide: powder, or mixtures of such substances.
Sprays .may additionally contain customary propell ants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
[0089] Methods of delivering a composition or compositions via a .transdermal patch are:
known in the art. Exemplary patches and methods of patch delivery are described in US
Patent. -Nos. 6,974,588, 6,564,093, 6,312,716, 6,440,454, 6,267,983,

6,239,180, and 6,103,275.
10090.1 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-polyurethane composite and 2-10 parts by weight of a.
styrene-ethy ene-butyl ene-styrene copolymer, a first adhesive layer on the one side of the.
composite film, and a polyalkylene terephthalate film adhered to the one side of the composite .film by means of the first adhesive layer, a primer laver which comprises a saturated polyester resin and is formed on the surface of the polyalkylene terephthalate film; and a second adhesive layer comprising a styrene-diene-styrene block copolymer containing a pharmaceutical agent layered on the primer layer. A method for the manufacture of the above-mentioned substrate sheet comprises preparing the above resin composition molding the resin composition into a composite film by a calendar process, and then adhering a polyalkylene 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 polyalkylene terephthalate film.
100911 Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a.
suitable backing member, e.g, a polyester backing membrane. The drug should be present.
at a. concentration which will not affect the adhesive properties, and at the same time deliver the .required clinical dose.
[00921 Transdermal patches may be passive or active. .Passive .transdenmal 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..
m93.1 .1ontophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current, One example of an iontophoretic membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by which lontophoresis enhances molecular transport across the skin are (a) repelling a charged ion from an electrode of the same charge, (b) electroosrnosis, 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.
10094" In some cases, it may he desirable to administer in the form of a kit, it may comprise a container for containing the separate compositions such as a.
divided bottle tIr 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 p.arenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
10951 An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a plastic material that may be transparent 100961 Methods and compositions or the .treatment of Atherothrombosis. Among other things, herein is provided a method of treating Atherothrombosis, comprising administering to a patient in need thereof a therapeuticallv effective amount of compound of Formula N\
Forrnuia Wherein.
RI independently represents D, H. methyl.

0 0\, 0 0 tltt tlif\o"iss /1\kk As-C
N Lazz_.j..,1 0 0 Nss, s cS5S-, .... N., cssS H H
õ...,,,,,---...õ........",,, N ,;./.., ...s.tzia.õ-- N ........,..... v ¨01 H , H H H H

, ¨0/11\--)121 '22.1/1\0"0/11\ssS
OH , H H
R2 i nd epen de nil y represents H H2 N.,,,, d "....õ.1....., . e.., ,,..

H
1 HS , OH

)77...
S

=

Nkcs-S5 S

as,SS

N CH:s "...,..._ H.,- OH
H HO
-- .------N."=.,._õ-------.%N.,....-.µ
HO OH
;"5.5. N
0 0 , H , iii......, CONH2 101 CO.:.H 40 0,_ * .
0H 0,-, 0c0cH3,44, 0,2õ....
. , , ,,, r cH3 cH3 0 Ali 41 1 HC 0 i , CH3 Milli--' CH3 i.- Jo OH 77 0, , C-) HN-71[N,NH OH

Illt¨tt:
= .44/1//, 41-11---. c555-, FIN
0 , N1-12 N
\
(..3zz.
a h H or , 6 d a is independently 2,3 or 7;
each h is independently 3, 5 or 6;
e is independently 1, 2 or 6;
c and d are each independently H, D, -OHõ -OD, Ci-C.6-alkyl, -N-14,2, or -COCH3.
[00971 Methods and compositions for the treatment of Atherothrombosis. Among other things, herein is provided a method of treati ng .Atherothrombosis, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula II:
Ftp R

0 ____________________________ <I
Formula ii Wherein, independently represents D, F1, methyl, )Z2_ 555 f O¨
tµj\c(ks.sS¨\(,) N sSS tzazzrjL;ssS /0/ \O

t.,7%N
N

N

H c N N
or =

R.2 independently represents .............

.),........, Hz ,..., 4 / c,s.

HCN''...---:".%-....", H
1 , , H
)27....,..N H2N
OH

, .

S-,..ss , .
o .."
--o .

..---....._, , õtziziO\
_ f 9 0 , 0 , f3z.z.
P

/ .
_ 0 .

--..N.
H
..- OH...
... H HO
--., .-----"-, N OH
HO
-...,s,...
cS) N

Co2H op ,, . caNH2 0.-,,.
OH 0(1; OCOCH1 0.(2i..., ., .,so Yr cH3 of ,r-N CH3 0 411 H3C %...), 4 lip 0 CH3 6 - io OH =':?-? 0 HN)NNH
H H
""Foll Rita S
0 , OH

HO N
\
HN

7-a or 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, -OH, -01), --NH7 or -COCH3.
[00981 Methods and compositions for the treatment of Atherothrombosis. Among other things, herein is provided a method of treating Atherothrombosis, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula la:

C I SH
formula la Wherein, RI independently represents D, II, methyl, i-.../..0 0µ"
NH
2 \c 0 0 0 \
..----(---- to+ õi:o-------..------01, , H
0 , .

i0 A =,sµ
NH, NH2 , ' H H /
, 0 H , H H
,..!..eciNs,....,,....7.,,---,..,,......,,,,_Ni.....
N
, H H
, OH
. , H H
or H ', P,,, independently represents o Hse1.., SH
H
0 ,õ. ...,..
õ...
H
N ,....µõ... N
H
A.ctivv-OH
I HS

HO

,--.

Okd' , ,...\ .....".
s--....,, s-------s cz?z,0 , .............
, i ----------f 6 1 9 , zsgS
S . __

8 H 11 1 ") 20 0 , (k 5 7.--- H 14 17 110 P
/
\ - -0 .
, H-,..,.., -- OH
i S H
-.. Ho .....,--HO
.3.s.....

c02H c0NH2 0,c_, OH A ococH3 VIII)-- 0-tai"..
. , , , ....s.õ0 " 411 Eallo õ, cH3 LI
H3C k..1 4 4101 , OH
HN7k, NH

H ten H
1-iN
0 , NH3 , HO iithi -Z.
" a or =
a is independently 2,3 on:
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-C6-alkyl, -NH2 Or -COCI-13.
1009911 Methods and compositions for the treatment of Atherothrombosis. Among other things, herein is provided a method of treating A therot h rom bosi s, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula Ha:

R
N

Formula Wherein, RI independently represents D. H, methyl, so 4(;) 0 It NH, 0 /1\
\

0 , '1.7.1,2 N

N

OH

N = .., S = 0 N
or R .2 independently represents H 0 H 2 N.., , /
H C N
%MTV' I HS

N H N

t s -0 , ..si 5 ti¨ 11 14 17 20 , F---- 1 t 14 17 20 , ;555 \ ¨ ¨ ¨

t 10 13 16 19 :
N CH$
--,s.
F:if,.. OH

HO
,- ...-'''' N
HONNNN.....-..?......-'Nli\--.- OH
H
, C 02 H 0 csS, CONH2 0-..
OH , 11' 0'2; OCOCH3 A.
, s , s 0 .-5-r CH3 o 411 CH3 OH "?? 0 , , OH

NH
H ' H
litt = ''.?)µ11;t( A
S HN /

' H
NI, :
A
HO 0\
N
H
' b "Z
'.-k '?õ.
a b c d or ;
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, C1-C6-alkyl, -Ni-1:, or -COCH3.
Methodsfir using compounds cifirmula 1...
(001001 The invention also includes methods for treating or management of atherotfirombosis, i schemi a, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular, cardiovascular diseases and blood clots.
Methods For Makin 0 The Comlounds Of Formula ¨ ia and Formula 1:1 a :
[001011 Examples of synthetic pathways usefid for making the compounds of :Formula fa are set forth in the examples below and generalized in the scheme 1.

Scheme-I:
CN
Br -CX*-CNBr ..--"c., eN
:L:
+
s ....,,,c1......,.
reflux, 3 h, 86%;
6 h 86% 2 3 4 I
TEBA
TFRA COOM NaOH COCCI+, (a) t CSA H20 toluene 43 h 40-50% NaOH (aq), 4---0 filt ..--....
dimethy I *ulfate eut 1 '''=-= 93% ee ., 9gis5%
....... I. 1 S'..- 0' 411111"' tll ethanol , S' methanol reflux, 40 'C 12 h; (b) NaHCO3 87%
12 h. 95% 10= H or Na 6 acetone reflux 6 h, .f COOCH3 COOCH3 GOOCH:, ? enzymatic 8 ( ..------ ---\:-.
+.= HOOC/II/
-CI
'-26 'C 2 h 7 a 9 CH 212 GOOCH- ..--- -OH
K40.1 f K7C0,3 H2C 0 OC/7...0 I'll ''....r) + 1 DMF
DMF
0 'C-rt, 12 h ¨ 11 .--;"-s-i FE;;;GOOC =-=,. I

Et20 iy rt., 12h SWIM
0 0 '0 -...õ,,,----..,....---..,,..---.--.,..,--.-,,,--- -.,...---,,)=-Ø) -,--:=-;"".-, 12 1-V.:00C.4,., ,yr i Cl J
.(Th-:i 0 0 ."0 s '0 1001021 Step -1: Synthesis of Compound 2:

Br ON Br2 1110 CN
Cl 100-110C Cl 8 h, 86%

1001031Bromine(176 g, 1.1 mol) was added over a period of 3 h to 2-(2-ehlorophenvf)acetonitrile 1 (151.5 g, 1 mol) with stirring at 105-110 "C and was reacted for another 3 h. Then butyl acetate (250 nit) and sodium bisulfate (11.4 g, 0.11 mol) were added at $0 C. After 15 min stirring, the mixture was filtered, washed with water, and dried over anhydrous sodium sulfate. Removal of the solvent was done in vacuum to afford 2 (200g. 86%); p 110 C. /15 mmHg: ItiNNIR (300 MHz, CDC13): )783 (1 1-1, in), 7,38-7.45(4 H, m), 5.87 (1 H. s).
100104! Step -2: Synthesis of Compound 4:
Br / N CN
CN ', / NaHCO3, - - - - - - - - - - - - - - - - - - - - - - - - - -S methanol CI
CI
reflux, 3 h, 85%;

1001051 3 (98,7 g, 0.43 mop, 2 (70.2 g, 0.4 mot), sodium hydrogen carbonate (84 g, 1,0 mol), and methanol (300 nit) were combined and refluxed for 3 h. Then the mixture was stirred at 5 "C. for more than 30 min, filtered, washed with water and cold methanol, and dried to give 4 (98 g, 85%). 111INMR (300 MHz, CD03): 67.35-7.72 (4 H, in), 7.08 (1 H, dõ./ )5.1), 6.69(1 H, d, ) 5.1), 5,32 (1 H, s), 3.78 (1 H, d, ) 13.7), 3.65 (1 it d, 13,7), 2.8-3.0 (4 H, 1001061 Step -3: Synthesis of Compound 5:
ON TEBA COOH
40-60% NaOH (aq), methanol, reflux, 4 12 h, 96%

1001071 The mixture of 4 (60 g, 0.22 mol), triethylbenzylammonium chloride.TEBA
(1.0 g), NaOH (aq 360 g, 40-50%), and butanol (100 mf...) was relluxed for 12 h. After cooling to room temperature, the solution was neutralized with HCI (aq 35-37%) to pH 8 and then acidified with acetic acid to pH 4-5. The suspension was filtered, washed, and dried to give 5 (61 g, 95%). IIINMR (300 MHz, DMS0):6 10.3-14.3 (1 H, hr ), 7.35-7.64 (4H, in), 7.26(1 H, d, 5.1), 6.8(1 FL d, .1)5.1), 4.7 (111, s), 3.61-3.65(2 H, ddõJ.
)10.8), 2,78-2.85 (4 H, 1001081 Step -4: Synthesis of Compound 6:
TEBA
COOH NaOH COOCH3 /N dimethyi eI",õ_õ,H"'''N
S CI methanol. SCI"
40 ')C, 1211; 873/4 [001091 The mixture of acid 5 (60g. 0.198 mol), TEB A (1.2 g), methanol (250 mi.:), and NaOH (aq 20%, 60 g) was refluxed for 30 min. After cooling to about 10 "C, Me2SO4 (40g. 0,317 mot) was added dropwise. The solution was reacted at 40 'C for 12 h. After removal of methanol, butyl acetate (150 mL) was added. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate, After removal of solvent by vacuum, compound 6 was obtained as brown oil (54.7 g, 870/0. IHNMR (300 MHz, D20): 57.65 (iH, dõ/ ) 8.0), 7.5-7.6 (3 H. tn), 7.3 (1 H, d, .1) 5.2), 6.7 (1 H, dõ/ ) 4.7), 5.9(1 H., s), 4.2-4.4(2 m), 3.8 (3 H,$), 3.7-3.8(2 H, in), 3.2(2 H, s).
1001101 Step -5: Synthesis of Compound 7:
COOCH3 (a) L-CSA. H20 COOCH=
.3 tduene, 48 h I j S ci (b) NaHCO3 acetone 7 reflux, 6 h;

1001111 L-CSA.1H20 (.13.3 g, 0.053 niol) was added batchwi se into the solution of racemic 6 (32 g, 0,10 mol) and toluene (140 mi.) at room temperature. After stirring at 50 C for 1 h, the mixture was cooled to room temperature, stirred, and seeded for another 48 h, it was then filtered, washed, and dried to give a white solid (25.7 g, ee ) 99.6%), Then a mixture of the white solid (25.7 g, 0.046 mol), NaHCO,.3 (3,9 g, 0,046 mol), and acetone (100 mt.) was refluxed for 6 h, After the mixture was cooled to -5 'C, filtered, and washed with cold acetone, and evaporation of solvent gave the product 7.
[001121 Step -6: Synthesis of Compound 9:
COOCH3 GOOCH?, HOOC TiCI4, Zn HOOC N
HS 1101 ___________________________ NX-1 a -"Si 25 0C, 2 h 1001131 To a pre-stirred (30 min, 0 'C) mixture of TiC14/Zri (powder, 100 mesh) in a 4 8 molar equivalent ratio in 25 ml., ofdimethoxymethane is added the compound 8 (0.28 nunol). The resulting solution is stirred for 1-211 at 25 C. poured into water (50 miL), and extracted with Et0Ac (50mL 3). The Et0Ac extracts are washed with water and brine, dried (MgSO4), and concentrated in-vacuo. Silica gel column chromatography of the residue then -provides the pure MOM-protected compound 9,The products obtained in these processes are characterized by using spectroscopic methods.
[001.141 Step -7: Synthesis of Compound 10:
C000H3 cH2i2 COOCI*;.

N
HOOC N

MOMS-) ci DMF MOMS CI
0 C-rt, 12 h

9 10 [001151 Compound 9 ( 1 mmol) , anhydrous K7,CO3 (3,0 m mol ) was taken in dry DNIF
(10 ml) stir at room temperature for 2 h and then cooled to 0 C, methylene iodide (CH212lwas added slowly drop wise over 30 min. & then was allowed to stir at room temperature for 12 1.1.. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was poured into water (10 niL) and extracted with diethyl ether (2 x ml) The combined organic layers vere washed with water (5 mi.) followed by brine solution (5 nif,),, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get the intermediate iodo compound 1.0 was directly used for the next step without further purification.
[001161 Step -8: Synthesis of Compound 12:

..---. _._._._),..
IH2C000/ .--- NJ'''. 116 "..---Zi + I DMF
MOMS CI
0 C-it, 12 n \
/

1-1:3COOC,, Ill N Cl .----SMOM

......_ _____ ...._ .......... ......._ -' ) [001171 In a RB flask the cis-5,8,11,14,17-Eicosapentaenoic aci d 11 (1.0 mmol ) &
anhydrous K2CO3 (3.0 mmol) was taken in dry MIT (10 vol) stir at room temperature for 2 h and then cooled to -10 kt,õ intermediate 10 (1.0 mmol) was added slowly drop wise over 30 min. & then was allowed to stir at. room temperature for 12 h.
Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was poured into water (10 mi.) and extracted with diethyl ether (2 x 5 ml). The combined organic layers were washed with water (2 x 5 triL) followed by brine solution (10 ml), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude was purified by column chromatography over 100-200 mesh silica gel to get the compound 12.
1001181 Step -9: Synthesis of Compound 13:
/13CO0Cs, 14110 1 M HCI
N
Et20 12h FlaCO0C 4,õ 141111 N Cl [001191 To the compound 12 (1 mina ) in Et20 (10 mL) was added 1.0 M solution of HO in methanol (freshly made from Me011 and CH3COC1, 0.5 mL). The reaction mixture was stirred for 12 h (monitored by TLC) at room temperature before it was cooled to 0 "C and quenched with saturated aqueous NaliCO3 (10 mL). The aqueous layer was extracted with Et20 (10 mil, x 4). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel to afford the final compound 13.
(001201 Examples of synthetic pathways useful for making the compounds of Formula na are set forth in the examples below and generalized in the schemes 2.

Scheme ¨ 2:

Br Mg 0 NBS
t +
THF C>----CN Br iiii ()HF
0 C-1-1 F Chlorobenzene F IP S
1 2 3 80 Lt, 41, 4 5 ................................... s... /(-1-----"Nenzyrnabc DMF S---N--) F . ....1:':t.i.9.!:l.....,, VO-rt 8 0 CF12i2 TiC14. Zn Hoocr-1. j\1 ao K2CO3 HS F = CH=30CH,0 -CH3M MS F OMF
25 C, 2 h 0 r'C-1-t, 12 h --- OH

1 K2CO3.
a-i2C00C/701 1 ".- + DMF
MOMS F --- \ / VC-rt, 12h ¨ lir 1M FiCI
NF ------------------------Et20 rt, 12h .....' S

11 0 Olt N F

0 0.---,0sH
_ _ _ _ _ 0) 1001211 Step -1: Synthesis of Compound 3:
Br 0, Mg 1>¨CN THF
1 2 0 C-rt.

100122.1 Active magnesium (10 mmol) was added in a RB containing dry TILE
(10.m1) and added a little iodine and stirred the reaction mixture and to this was added compound 1 (in 2 ml THF)slowly and stirred to generate the Grignard reagent. The reaction mixture was cooled to 0 tt and added compound 2 (in Tilt') drop wise and stirred the reaction mixture at rt for 2h After 2h the reaction mixture was quenched with saturated solution and extracted with Et0Ac, The organic layer washed with water, brine, dried over sodium sulphate and evaporated under reduced pressure to obtain compound 3.
[001231 Step -2: Synthesis of Compound 4:

NBS
AIBN Br=
_ F Chioroberizene --3 80 C, 4h 4 [001.241 A mixture of compound 3(1 mmol) azilsobutyronitille (0.2 mm.ol) and N-bromosuccinimide(1.1 mmol..) in ehlorobenzene was stirred and heated at 80 for 4h.
After cooling to room temperature the reaction mixture was filtered to remove the solid succinimide, and then the filtrate WM washed with water and brine, dried over anhydrouos M4SO4 and filtered. The solvent of the filtrate was removed by rotary evaporation, and the crude product was purified by column chromatography on silica get to afford compound 4.
1001251 Step -3: Synthesis of Compound 6:

Br s"'-=
N
OMF
4 5 0 C¨rt 6 100.1261 To a solution of compound 5 (1.0 mmol) in dry DCM (4 ml) was added N, N-diisopropylethylamine (2.0 mmol) at -10"C, followed by drop wise addition of compound 4 (1.2 mmol in 2 ml DCM) for 30 min at the same temperature and the reaction mixture was allowed to stir for 1 h at rt. On completion of the reaction (monitored by TLC), the solvent was evaporated and the crude product was purified through column to yield compound 6.
[00.1271 Step -4: Synthesis of Compound 8:
a A
o A
TiCI4. Zn HOOCN -25 "C, 2 h [001281 To a pre-stirred (30 min, 0 'C) mixture of 1 iC14/Zn (powder, 100 mesh) in a 4 8 molar equivalent ratio in 25 mit, ofdimethoxvmethane was added the compound 7 (028 mmol). The resulting solution is stirred for 1-2 h at 25"C, poured into water (50 and extracted with Et0Ac (5)mI.: x 3). The Et0A.c extracts are washed with water and brine, dried (MgSO4), and concentrated in-vacuo Silica gel column chromatography of the residue then provides the pure MOM .protected compound 8.The products obtained in these processes are characterized by using spectroscopic methods.
[001291 Step -5: Synthesis of Compound 9:

HOOC

MOMS F DMF MOMS F
8 0 'C-rt. 12 h [001301 Compound 8 (1 mmol) , anhydrous K2CO3 (3!) minor) was taken in dry DMF

(10 ml) stir at room temperature for 2 h and then cooled to 0 'V, methylene iodide (012112)was added slowly drop wise over $0 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 (10 mL) and extracted with diethyl ether (2 x m1). The combined organic layers were washed with water (5 mL) followed by brine solution (5 mt.), dried over anhydrous Na2SO4 and evaporated under reduced pressure to get the intermediate iodo compound 9 was directly used for the next step without further purification.
1001311 Step -6: Synthesis of Compound it:

11-12COOCy DMF
MOMS' F' 0 C-rt, 12 h N F

smom 1001321 In a RB flask the cis-5,8,11,14,17-Eicosapentaenoic acid 10 (1.0 mrnol) &-anhydrous:1.<4:X)1 (30 rninol) was taken in dry :DMIF (10 vol) stir at room temperature for 2 h and then cooled to -1 0 intermediate 9 (1.0 mmol) was added slowly drop wise over 30 min, & then was allowed to stir at room temperature for 12 h. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was poured into water (it) mL) and extracted with diethyl ether (2 x 5 m1). The combined organic layers were washed with water (2 x 5 naL) followed by brine solution (10 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude was purified by column chromatography over 100-200 mesh silica gel to obtain the compound IL
1001331 Step -7: Synthesis of Compound 12:
,M HC1 N F
Et20 rt, 12h SIMON/
0 0 '0 N: F

1001341 To the compound 11(1 nyrnol ) in Et20 (10 in L) was added 1 .OM.
solution of fiC1 in methanol (freshly made from MeGif and 0-13COCI, 0.5 ml). The reaction mixture was stirred for 12 h (monitored by TLC) at room temperature before it was cooled to 0 'C and quenched with saturated aqueous Naf1CO3 (10 mi..) The aqueous layer was extracted with Et20 (10 mil, x 4). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product:

was purified by flash cOluiTill Ch romotography over silica gel to yield the final Compound .12.
[00.1.351 The term "sample" refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ. Samples of body fluids can be obtained by well known techniques and include, preferably, samples of blood, plasma, serum, or urine, more preferably, samples of blood, plasma or serum. Tissue or organ samples may be obtained from any tissue or organ by, e.g., biopsy. Separated cells may be Obtained from the body fluids or the tissues or organs by separating techniques such as centrifugation or cell sorting. Preferably, cell-, tissue- or organ samples are obtained from those cells, tissues or organs which express or produce the peptides referred to herein.
EQUIVALENTS
1001361 The present disclosure provides among other things compositions and methods for treating Atherothrombosis 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 hill scope of the claimed systems and methods should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations, INCORPORATION BY REFERENCE
(001371 All publications and patents mentioned herein, including those items listed above, are hereby incorporated by reference in their entirety es if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control,

Claims (16)

76

1.A compound of formula I:
or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer, or stereoisomer thereof;
W herein, R1 independently represents D, H. methyl, R2 independently 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, C1-C6-alkyl, -NH2 or -COCH3,

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

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

4. A compound of formula II:
or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer, or stereoisomer thereof;
Wherein, R1 independently represents D, H, methyl, R2 independently 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, C1-C6-alkyl, -NH2 or -COCH3.

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 carrier.

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, trans.mucosal, 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.

11. 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 administration or transdermal administration.

12. The pharmaceutical composition of claim 8, 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.

13. Compounds and compositions of claim 9 are formulated for the treatment or management of the underlying etiology such as atherothrombosis, ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular, cardiovascular diseases and blood clots.

14. Compounds and compositions of claim 10 are formulated for the treatment or management of the underlying etiology such as atherothrombosis, ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular, cardiovascular diseases and blood clots.

15. Compounds and compositions of claim I are formulated for the treatment or management of the underlying etiology such as atherothrombosis, ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular, cardiovascular diseases and blood clots.

16. Compounds and compositions of claim 12 are formulated for the treatment or management of the underlying etiology such as atherothrombosis, ischemia, stroke, cerebral thrombosis, arterial thrombosis, thrombotic cerebrovascular, cardiovascular diseases and blood clots.