CA2872978A1 - Compositions and methods for suppression of carbonic anhydrase activity - Google Patents

Abstract

Provided are the compounds of formula (I) 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), and methods for treating or preventing or modulating carbonic anhydrase activity in a disease may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral admimstration, syrup, or injection. Such compositions may be used to treatment of glaucoma, epileptic seizures, Idiopathic intracranial hypertension (pseudotumor cerebri), altitude sickness, cystinuria, periodic paralysis and dural ectasia, congestive heart failure, drug induced edema, diuretic, intermittent claudication resulting from obstructed arteries in the limbs, and vascular dementia.

Description

COMPOSITIONS AND METHODS FOR SUPPRESSION OF CARBONIC ANHYDRASE ACTIVITY
PRIORITY
10001] The present application claims the benefit of Indian Provisional -Patent Application No. '1810101E12012 filed on 08-May-2012, the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference.
FIELD OF THE 1...NVENTION
tow2.1 This disclosure generally relates to compounds and compositions for the suppression of carbonic anhydrase activity. More particularly,. this iriventí
on relates to treating subjects with a pharmaceutically acceptable dose of compounds, stereoisomers, enantiomers, crystals, esters, salts, hydrates, prodrugs, or mixtures thereof BACKGROUND OF THE INVENTION
['WW1 Carbonic anhydrases (CAs, also known as carbonate dehydratases EC
4.2.1.1) are ubiquitous metalloenzy.mes present in prokaryotes and eukaryotes that are encoded by four evolutionarily unrelated gene families. CAs catalyse a simple physiological rea.etiori.
the conversion of CO2 to the bicarbonate ion and protons. The active site of most CAs contains a zinc ion (2n2+), which is essential for catalysis. The CA reaction is involved in many physiological and pathological processes, including respiration and transport of CO, and bicarbonate between metabolizing .tissues and lungs; pli and CO, homeostasis;
electrolyte secretion in various tissues and organs; biosynthetic reactions (such as gluconeogenesis, lipogenesis and ureagenesis); bone resorption; calcification, and tumorigenieity, j0004-1 Many of the CA isozymes involved in these processes are important therapeutic targets with the potential to be .inhibited to treat a range of disorders .including oedema;
glaucoma.; obesity, cancer, epilepsy and osteoporosis. Two main classes of CA
inhibitors

2 (C.Als) are known: the Metal-complexing anions and the unsubstituted .,sulphonamide.s and their bioisosteres. CAls include the classical inhibitors aeetazolamide, methazolatnide, ethoxzolamide , sulthiame and dichlorophenamide 10005] The reduced compounds (thiots) are less bulky and show excellent CA
inhibitory activity (in the low nanomolar range.) compared with the corresponding sterically hindered di sul phi des, N.vhich have di fficul ty entering the limi ted space of the enzy me.
active site and also NVith low bioavailability as well as poor pharmacdkinetics with very COMMOD side effects such as numbness in toes, taste, ataxia,. paraesthesia of face and limbs and blurred visim.
f00061 I\4anaging 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 or delay of the onset of carbonic anhydrase enzyme actvity and its associated complications progression.
SUMINIA.RY OF T.H.E. :INVENTION
[0007" The present invention provides compounds, compositions containing.
these compounds and methods for using. the same to treat, prevent andfor ameliorate the effects of the conditions such as complications or diseases manifested from carbonic anhydrase enzyme activity..
100081 The invention herein provides compositions comprising of .formula 1 or pharmaceutical acceptable salts thereof. The in.vention also provides pharmaceutical compositions comprising one or more compounds of .formul a l or intermediates thereof and one or more of phannaceutically acceptable carriers, vehicles or diluents.
These.
compositions may be used in the suppression of carbonic anhydrase activity and its associated complications.

3 S
H N Nsr N¨N

Formula 1 j00091 In certain embodiments, the present invention relates to the compounds and compositions of t7ormula or pharmaceutically acceptable salts thereof, N-N

Formula I
Wherein, Ri each independently represents D, o 0 0 et, 111/C\0/ \s,cr -1\

4 PCT/1B2013/050899 H \:s -=-.. ,..... '1.1.L.," LI
csS5 0 õrµ

H H
N "It.a ¨0.--A*0 H , H H
N

H H
.;22;INN's=...,,,,NN,.o,,.-N-..,%.õ.-- s' ¨
{2Z, 0 0 sSS
OH

H H i or H
, R2 each independently represents "....., SH

..,---0 N/ s H3C .,,,,,.
4,, 0 ...../...N'e 1 ,HS H2N
, .
..7,N.,,,NNs,..õ...7.CH 3 OH
HO
OH

l'N'...../..
H
H
0 0 N õsS
\esS:\ HO
OH HS \\........õ,.......... ....... \

H
OH
: =

0 .2..
0 e S -...,,, S
, i' 0 t ..i.sS5 , :SS'S
-i 9 0 , H. OH 0 1:-1, HO ...o S s .1 0 0 0 c., 100 CO2 H
OH A to rss. ococH3 coNH2 0.,..
o=??...
. , r CH 3 C1-E3 OH 0 14. 10 01 CH;
11,5C ¨N........._õ7-N.N.,...",s5' 0 0 OH
o tiVI\ NH
Ea 0 Matt s HN if 0 , NH2 , ' a d 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, -OH., -OD, C1-C6-a1kyl, -NH 2 or -COCH3;
R3 independently represents H, D, methyl, F. CI, ethyl or acetyl.
100101 In the illustrative embodiments, examples of compounds of formula I are as set forth below:

NH

- 1 ) N/ y ,,s%

(1-2) HN
s,s '0 (1-3) 100111 'Herd n the application also provides a kit comprising any of the pharmaceutical compositions disclosed herein. The kit may comprise instructions for use in the suppression of carbonic anhydrase activity or -its related complications.
100121 The application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable earlier and any of the compositions herein. in some aspects, the pharmaceutical composition is formulated .for systemic .administrationõ
oral administration, .sustained rel ease, parenteral admi in strati on, inj ecti on, sub derm admini strati on, or transdermal ad mi ni strati on.
100131 Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the suppression of carbonic anhydrase activity or its related complications.
1001.41 The compositions described herein have several uses. The present application provides, for example, methods of treating a patient suffering from carbonic anhydrase modulation activity or its related complications manifested from ne-urodegeneration, neurological dysilinction, metabolic conditions or disorders, metabolic syndrome, chronic diseases or disorders; Hyperinsulinemia. Insulin resistance, Glucose intolerance, .Hepatology, Cancer, Respiratory, Hematological, Orthopedic, Cardiovascular, Renal, Skin, N e pivot ogi cal , or Ocular complications.

.DETAILED DESCRIPTION OF THE INVENTION
=Lefiiiì ti ons 100151 As used herein, the following terms and phrases shall have the meanings set. forth below. -Unless defined otherwise, all technical and scientific terms used hefeill have the same meaning as comnionly understood to one of ordinary skill in the art.
100161 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 to be used as prodrugq 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 propeAies of an initially anhydrous compound .of formula 1 (hydration).
10017-] 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 "stereoisome.rs." Dia.stereomers are stereoisomers with opposite configuration at. one or more chiral centers which are .not enantiomers. .Stereoisomers bearing one or more asymmetric centers that are non- 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 enamiomer can ic thara.cterized by the absolute configuration of its a.symmetric center or centers and.
is described by the R.- and S-sequencing rules of Cahn, lngold and Prelog, or by the manner in which the molecule,' rotates the plane of polarized light and designated as dextrorotatoly or levorotatory (i.e., as (3-) or (-)isomers respectively). A
chiral compound can exist as either individual enantiomer or as a mixture .ihereof A IlliXtUte containing equal -proportions, of the enantiomers i called a "ra.cetnic mixture".

100181 .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 inore metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent.
[001.91 In some embodi men ts, a T11.01 ecu ar conjugate compri se& of COM pou 11 d S Se ected from the group consisting of R-lipoic acid (CAS No. 120(3-22-2), salsalate (CAS No.
552-94-3), acetylcysteine WAS No. 616-91-1), Eicosapentaenoic acid (CAS No. 1.
04 .17-94-4), :Docosahexaenoic acid (CAS No. 6217-54-5).
10020] The term ".polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound., 10021" 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, intravascular, intrapericardial, imraarterial, intrathecal, intraeapsular, intraorbital, intracardiac, intradennal, intraperitoneal, transtracheal, subcutaneous, subcuticular, Ultra-articular, subea.psular, subarachnoid, intraspinal and intrastemal injection .and infusion..
10022] .A "patient," "subject," or "host" to be treated by the subject method may mean either a human or non-human animal, .such as prim.ates, mammals, and vertebrates, (00251 The phrase "pharmaceutically acceptable" is art-recognized. 1.ri certain embodiments, the term includes compositions, polymers and other niaterials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, huinan beings and animals without excessive.
toxicity. rri tati on, allergic re spon se:, or other problem or complication:, commensurate with a reasonable benefit/risk ratio.

100241 The phrase "pharmaceutically acceptable carrier" is art-recot.mi zed, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid tiller, diluent solvent or encapsulating .material .involved in carrying or transporting any subject compo.siti on, 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 compatibile .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, sorbit.ol, 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 employed in pharmaceutical .formulations.
[00251 The term "prodrug" is intended to encompass compound.s that under physiological conditions, are converted into the therapeutically active agents of the present invention. A common method for rnaking a prodrug is to include selected Moieties that are hydrolyzed under physiological conditions to reveal the desired molecule, .In other embodinients, the prodrug is converted by an enzymatic activity of the host animal.
1002611 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- 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 cnchtioii or side effects thereof).
100271 The term "predicting" as used herein refers to assessing the probability related di sea ses pati e.nt will suffe.c from ab norm ali ties or conipli cati on an dlor term i nal plate" et aggregation or failure andfor death (i.e. mortality) within a. defined tiine 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 invendon.
100281 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 andlor condition, 'Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected., such as treating the glaucoma, epileptic seizures., Idiopathic intracranial hypertension (pseud.otumor cerebri), altitude sickness, cystinuria.õ periodic paralysis and (Jura! ectasia, conge.stive heart failure, drug induce,d edema, intermittent claudication resulting froni.
obstructed arteries in the limbs, and vascular dementia., improves blood flow through peripheral blood vessels and therefore helps with blood circulation in the arms and legs (e.g. intermittent claudication), and the brain (hence its use in vascular dementia), Peyronie's disease and .neuropathie injuries, prevent strokes and can be used in managing.
sickle cell disease, .to treat nausea and headaches in. the mountains (altitude sickness), and has been shown to reduce mortality in acute alcoholic and non-alcoholic steatohepatifis arid alcoholic liver disease, reduc.int.t, the extent of fibrotic lesions .induced by radiation therapy for breast cancer. IV treatment of cytokine release syndrome., type 1 diabetes and type 2 diabetes, asthma.õ bronchodilation., neuroprotective properties, vasodilation, Alzheimer's disease, dementia, stroke, and treatment of endatiletriosis. It is also used in the treatment of venous disease 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.
100291 The phrase 'therapeutically effective .amount" is an art-recognized term. in certain embodiments, the term refers to an amotmt 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 detemine the effective amount of a particular composition without .necessitating undue experi inentati on.
100301 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 cif 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 Iva as the delivery rate of the salts and com.positions 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 far any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the persolì.
admi.nistering or supervising the administration of the compositions..
Typically, dosing will be determined -using techniques known to one skilled in the. art.

100311 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.
[0032] 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.
concentratio.n (Cmax) and .the area under .the plasma concentration-time curve from time 0 to infinity may he used, [00331 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 )xhich 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 inay undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic andlor biologically active salt andfor composition, for a sustained or extended period (as compared to the release from a bolus). This release may result in prolOn ged delivery of therapeutically effective amounts of any of the therapeutic a.gents disclosed herein.
100341 The phrases "systemic administration," "administered systemically,"
'peripheral administration" and "administered peripherally" are art-recognized, and include, the administration of a subject composition, therapeutic or other material at a site remote from. the disease being treated. Administration of an agent for the disease being treated, even if .the agent is subsequently distributed systemically, may be .termed "local or "topical" or 'regional' administration, other than directly into the central nervous system, e.g., by subcutaneous a_dministration, such that it enters the patient's system and, thus, is subject to metabolism and other like processes 10035] The phrase "therapeutically effective amount" is an art-recognized term. In certain embodiments, the term refers to an amount of a salt or co.mposition 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 compositi on wi th out necessitating undue experimentation.
100361 The present disclosure also contemplates prodrugs of the compositions disclosed herein, as well as phamiaceutically acceptable salts of -said prodrugs.
[0037] This application al so discloses a. pharmaceutical composition compri sing a pharmaceutically acceptable carrier and the composition of a compound of Formula I
may be formulated for .63,,stemic or topical or oral administration. The pharmaceutical composition m.ay be also formulated for oral ad.ministrationõ oral solution, injection, subderin al administration, or trans& rm al ad mi ni strati on. The pharmaceuti cal composition may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, tiller, binder, and lubricant.
100381 In many em.bodiments, the pharmaceuticai compositions described herein incorporate the disclosed compounds and compositions (Formula l) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a. compound of formula 1 or composition as part of a prophylactic or therapeutic treatment. The desired concentration of .formula 1 or its pharmaceutical acceptable salts will depend on ab.sorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. 1.t 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 thatt for any particular subject, specific dosage regillIEMS should be adjusted over time according .to the individual need and the professional ju4unent of .the person administering or supervising the administration of the compositions_ Typically, dosing will be determined using techniques knowe to one skilled in the: art, NO391 Additionally, the optimal concentration andfor quantities or amounts of any particular compound of formula I may be adjusted to accommodate variations in the treatment para.meters. 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 o.r non-huma.n, adult or child, and the nature of the disease or condition.
10040" The concentration andlor .amount of any compound of formula I may be .readily identified by routine screening in animals, e.g., rats, by screening a range of concentration andlor amounts of the material in question using appropriate assays.
Known methods are also available to assay local tissue concentrations, diffusion rates of the salts or com.positions, and local blood flow before and after administration of therapeutic formulations disclosed .herein. One such method is micro:dialysis, as reVieWed by T. E. Robinson et al., 1991, mierodialysis in the neuroscienees, Techniques, volume 7, Chapter I. 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 fomiula such as those disclosed herein .are injected adjacent to the loop, released drugs are collected in the di alysate 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.
10041] in certain embodiments., .the dosage of the subiect compounds of formula provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum pla.sma concentration (Cmax) and the area under the plasma concentration-tim.e curve from time 0 to infinity rnay be used.
100421 Generally, in carrying- out the methods detailed in this applicationõ
an effective dosage for the compounds of Formulas'', 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 nigilerglday in single or divided doses. The compounds of Fonnullas I May be administered at a dose of, .for example, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0 ing/k1gday,. 5 mg/kg/day,. 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day.
Compounds of Formula I may also be administered to a human patient at a dose of, fOr example, between 0,1 mg and 1000 mg, between 5 ma and 80 mg, or less than LO, 9.0, 12,0, 20.0õ
50,0, 75,0, 100, 300,, 400, 500, 800, 1000, 2000, 5000 mg per day. In certain embodiments, the compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 1 of the compound of formula 1 required for the same therapeutic 'benefit.
1.0043.1 An effective amount of the compounds of formula I described herein refers to the amount of one of said salts ar corn posi lions which is capable of inhi biting or preventing a di sea s e..
100441 An effective at/1mA 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 dam.age or demyelization andlor elevated reactive oxidative-nitrosative species andlor abnormalities in physiological homeosta.sis's, in patients who are at risk for such complications. As such., these methods include both medical therapeutic (acute) andlor prophylactic (prevention) administration as appropriate. The.
amount and timing of compositions administered willõ 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 di sease.s.
[00451 The compositions provided by this application .may be administered to a subject in need of treatment by a variety of conventional routes of administration, induding 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 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 nanoparticles.
10046" The compositions may be administered alone or in combination with phamaceutically 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 ìrî
a. variety of dosage forms such as tablets, powders, lozermes, 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 ,I...-arginine, sodium citrate, calciwn 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 polvvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as inagnesium stearate, sodium lauryl sulfate and talc. are often useful for tabletting purposes. Solid compositions of a similar type !nay also be employed a.s .fillers in soft and hard filled gelatin capsules. Appropriate materials for this include lactose or milk sugar and .high molecular weight polyethyle.ne 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 compound.s of formula. 1 may also cornprise emetically coated comprising of various excipients, as is well known in the.
pharmaceutical art.
10047] For parenteral administration, SOILitiOnS 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 adnìinistratìoi't. n this connection, the sterile aqueous.
media employed are all readily available by standard techniques known to those skilled .in the art.
10048.1 The formulations, for instance tablets, may contain e.g.. 10 to 100, 50 to 250, 150 to 5(X) ir.P/, or 350 to 800 nn, es. 10, 50, 100, 300, 500, 700, 800 mg of the compounds of formula I disclosed herein, for instance, compounds of .formula. II or pharmaceutical acceptable salts of a compound.s of Formula 1.
1.0049.1 Generally, a composition as described herein may be administered orally, or parenterally (e.g., intravenous, intram.uscular, subcutaneous or inttam ed ul ary) 'Topical adniinistration may also be indicated, for example., where the patient is suffering fromgastrointestinal 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.

100501 The dosage administered ì1l 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.
1005.1.1 Illustratively, dosage levels of' the administered active ingredients are:
intravenous, 0.1 to about 200 ing/kg; intramuscular, 1 to about 500 mg/kg;
orally, 5 to about 1.000 mg/kg; intranasal instillation; 5 to about 1000 mg/kg; and il.CFOS01, 5 to about.
1000 m'lg. of host body weight.
10052] 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, pharyngol aryngeally,, bronchi ally:, intravagi nal ly; rectally, or ocularly in a concentratioi'i.
of from about 0.01 to about 50% siew 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.
[00531 The compositions of the present invention are preferably presented for administration to humans and animals in unit dosage fonns, such as tablets, capsules, pills, powders, granules, s-uppositories, 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.
100541 As discussed above, the tablet core contains one or more hydrophilic polymers, Suitable hydrophilic pol.ym.ers include, but are not limited to, water swellable cellulose derivatives, polyalkyiene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, gelling.; starches, givellims cross-linked polymers, and mixtures;
thereof. Examples of suitable -water swell a.ble cellulose derivatives include, but are not Finn ted to, sodium carboxy methylcell ulose, cross-linked hydro.xypropyl cellulose, hydroxypropyl ceiiut ose WPC), h:ydroxypropylm ethyl cellul ose (IIPMC), hydrctxyisopropyieeitul ose, hydrox.ybutylcellul ose, hy droxyphenyl cellulose, hydroxyethy 1 cell those (HEC), hydroxypen ty cel tdose, hydroxypropy ethy 1 cell tiloseõ
hy droxy prop ylbutylc el 1 ul o se, and hydroxypropyl et hy 1 cel 1 ul ose, and mixtures thereof Examples of suitable polyalkylene glycols include, but are not limited to, polyethylene glycol. Examples of suitable thermoplastic polyallcylene oxides include, but are not limited to, poly(ethylene oxide). :Examples of suitable acrylic polymers include, but are not limited toõ potassium meth acryl atedi vinylbenzene copol ymer, pol meth eth ac ry ate, h igh-mol eat! ar weight cross] inked acrylic acid homopolymers and copolymers such as those commerciallly available from Noveon Chemicals under the tradename CARTIOPOLIm. Examples of suitable hydrocollolds include, but are not limited to, alginates, agar, guar gum, locust bean pill, kappa carrageenan, iota carrageenan, tara, gum arabi c, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, sclerogiucan, gum arabic, inulin, pectin, gelatin, whelan, rhainsan, zooglan, methylanõ chitin, cyclodextrin, chitosan, and mixtures thereof.
Examples of suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and laponite, magnesium trisilicateõ 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 pyrrolidon e, cross-linked agar, and cross-linked carboxymethyleellulose sodium, and .mixtures thereof, 10055] The carrier may contain me or more suitable excipients for the formulation of tablets. Examples of suitable excipients include, but are not limited to, fillers. adsorbents, binders, di si ntegrants, lubricants, gl d ants, release-modifying ex cipi en tsõ
superdisintegrants, antioxidants, and mixtures thereof.
100561 Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrol i done and hy d roxyp ropy! m eth yl cellul ose ; wet hi riders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum:, locust bean, earrageenan, carboxymethylcellulose, tara, gum arable, traQacanth, pectin, xantlaan, gellan, gelatin, maltodextrin, galactomannan; pusstdlan, laminarin, selerogluean, inulin, when, rh a msan, zoogl an, in ethyl an, chitin, eye] od ex trin, chi tos a nõ
polyvinyl pyrroli done, cellulois, sucrose, and starches; and mixtures thereof..
Suitable disintegrants include, but are not limited to, .sodi um starch glycolate, cross-1inked polyvinylpyrrolidonc, cross-linked carboxymethylcellulose, starches, microcrystalline cellulose, and mixtures thereof.
[00571 Suitable lubricants include, but are not limited to, long chain tatty 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 iiiixture.s thereof, 10058] Suitable insoluble edibl.e 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, aerylatesõ
meth.acrylates, acrylic a.cid 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 Ex.amples 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 esters, mono-, di.-, and triglycerides, glyceryl belienate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl uilaurylate, glyceryl myristate.
G1ycoWax-:932, lauroyi acrogol-32 glycerides, stearoyl macrogo1-32 glyce.rides, and mixtures thereof. Examples cif suitable phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositolõ phosphotidic acid, and mixtures thereof.
Examples of suitable waxes include, but are not limited to, camauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, micmcrystalline wax, and paraffin wax; fat-containing.

mixtures such as chocolates, 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 e.mbodiment the tablet core contains up to about S percent by weight of such super disintegrant.
(00591 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, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures =thereof.
(00601 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 a more than about 0.9 Wee, as measured by the weight and volume of that specificlayer.
1.0061.1 In one embodiment, the immediate release coating contains a first portion and a second portion, ti=vh erei n at least one of the portions contains the second pharmaceutically active agent. In one embodinuint, 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.
1.00621 in one embodim.ent, the first portion contains the first pharm.aceutically active agent and the second portion contains the second phartn.aceutically 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 ph armaceuti call y active agent as that contained in the tablet core.
10063] 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 embodi.ment the outer coating portion is included of a dried granulation including the pharmaceutically active agent.
10064] Formuladons 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., Mills, coatings, liquids and particles that can be.
encapsulated, for example, in a. gelatin capsule. Many methods for preparing coatings, covering or incorporatiag drugs, are known in -the art..
[00651 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. .ag,ent with conventional pharmaceutical excipients. The .immediate release dosage unit may or may not be coated, and may or may not be admixed with the delayed release dosage unit or units (as in an.
encapsulated .mixture of immediate release drug-containing granules, particles or beads and delayed release drug-containing granules or beads), 100661 .Emended 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, id.. MOO), A
diffusion .system typically consists of one of two types of devices, reservoir and matrix, which are -wellknown and described in die art. The matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.
[00671 An immediate release portion can be added to the extended release system by means of either ap-plying 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.

100681 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 dnig 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 fbritn or a plurality of drug-containing beads, particles or granules, for incorporation into either a. tablet or capsule.
loo691 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 .ptilsed release profile is characterized by a time period of no release (1.a.g time) or reduced release followed by rapid drug release.
100701 Each dosage form contains a therapeutically effective amount of active=
agent, in one e.mbodiment of dosage forms that mimic a twice daily dosing profile, approximately M.. 4 to 70 wt. %õ preferably 40 wt. % to 60 \vt. Vo, of the total amount of active auent.
in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt. to 3.0 wt. %, preferably 60 .svt. to 40 wt. 'X), of the total amount of active agent in the dosage fonn is relea.sed 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 admini stration.
100711 Another dosage form contains a compressed .ta.blet or a capsule having a drug-containing iffinlediate 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 follosving 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 .141 hours following oral administration to provide a second dose.
10072] For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous;
or partially aqueous solutions (usually in about. 0..1% to 5% conce.ntration), otherwise similar to the above parenteral solutions, may be prepared.
10073] Methods of preparing vanous pharmaceutical compositions with a certain amount of one or more compounds of formula 1 or other active agents are known, or .wit.1 be apparent in light of this disclosure, to .those stilled in this art, For examples of methods of preparing pharmaceutical compositions, see Remi.ngton's Pharmaceutical Sciences, Mack. Publishing Company, Easton, Pa., 19th Editi on (1995).
100741 En 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 10075i Formulations useful in the methods provided herein include those suitable for oral, .nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol .and/or parenteral administration. The fomulations 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 prod.uce a single dose .may vary depending upon the subject being treated, and the particular mode of administration.
(0076] -Methods of preparing these formulation.s or compositions include the step of 196i-12;41g into association subject coinpositions with the carrier and.;
optionally, one or more accessory ingredients in general, the formulations are prepared by uniformly and intimately bringing into as.sociation a subject composition with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product, 10077] The compounds of .formula 1 described herein may be administered in inhalant.
or aerosol formulations. The inhalant or aerosol formulations may comprise one or more agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in inhalation therapy. The final aerosol formulation may for example contain 0.005-9Wo wirw, for instance 0.005-50%, 0,005-5% \WIN-, or 0.01-1.0% wfw, of medicament relative to the total weight of the: formulation.
100781 In solid dosage thrills for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or mare pharmaceutically acceptable carriers andlor any of the following: (I) fillers or extenders, such as starches, lactose, sucrose, glucose, rnannitol, and/or silicic acid;
(2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl .pyrrolidone, sucrose andlor acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, cal.ci UM 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 tale, 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 be employed as fillers in soli and hard-filled gelatin capsules using lactose or mili-. sugars, as weli as high mol e:cul.ar weight polyethylene glycols and the likeõ
10079" Liquid dosage fornis tor oral administration include pharmaceutically acceptable emulsions, microem ul si on s, solutions, suspensions, sy nips and elixirs. In a.ddi tin to the subj.ect compositions, the ii c1uid dosage forms .may contain inert diluents COMMonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol., benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseedõ COM, peanut, sunflower, soybean, oliveõ castor, and .sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and .fatty acid esters of sorbitan, and mi xtures thereof 10080.1 Suspensions, in addition to the subject compo.sitionsõ may contain suspending agents such as, for example, ethoxylated isosteatyl alcohols., polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
[0081] 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) Formulations which are suitable for vaginal administration also include .pessaries, tampons, creams, gels, pastes, foams, or spray .formulations containing such. carriers as are known in the art to be appropriate.
10082] Dosage forms for transdermal administration include powders, sprqs, ointments, pastes, creams, lotions, gels, solutions, patche.s, 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.
[0083] The ointments, pastes, creams and gets 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 a ddi t onal y con Lain cutithill a ry propellants, such as chlo.rofluorohydrocarhons a.nd volatile 13nsubsfituted hydrocarbons, such as butane and propane.
10084] 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, 6,440454, 6,267,983, 6,239,180, and 6,103,275.
100851 in another embodiment, a transdemal patch may comprise: a. substrate sheet comprising a composite :film formed of a resin composifion comprising 100 parts by eiti,ht of a polyvinyl chloride-polyurethane composite and 2-10 parts by weight of a styreneeethylene-butylene-styrene copolymer, a first adhesive layer on the one side of the composite film, and a polyalkyiene terephthalate film adhered to the one side of the composite film by means of the first adhesive layer, a primer layer which coinprises a.
saturated polyester resin and is formed on the surface of the polyalkylene terephthalate -film; and a second adhe.sìe 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 filin 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 terep hth al ate film 1.00861 Another type of patch comprises incorporating the drug directly in a phannac eutical y acceptable adhesive and laminating the drug-containing adhesive onto a suitable backing member, eg. 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.
100871 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( i on top hore si s) for large-molecule drugs.
10088j lontophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current. One example of an iontophoretic Membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by which iontophoresis enhances molecular transport across the skin are (a) repelling a charged ion from an electrode of the same charge, (b) electroosmosis, the convective movement of solvent that occurs through a 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.
10089] 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 p a c ket, Typically the lit com ph se s di recti ohs for the ad.ininistralion of the separate components. 717he kit form is particularly advantageous -when the separate components are preferably administered in different dosage forms (e.g., oral and parent:era:I). are administered at different dosage intervals, or when titration of the individual components athe combination is desired by the prescribing physician.

100901 An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging Indus-by and are widely used for the packaging a pharmaceutical unit.
dosag.e forms (tablets, capsules.,. and the like). Blister packs generally consist of a sheet of relative! V stiff material covered \vial, a foil of a plastic material that may be transparent..
[00911 Methods and compositions for the suppression of carbonic anhydrase activity.
Among other things, herein is provided a method of treating complications or diseases manifested from carbonic anhydrase enzyme activity, comprising administering to a pati.ent in need thereof a therapeutically effective amount of compound of Formula HN

N¨N
Formula 'Wherein., R1 each independently represents D, H, iSSN'OWNX

c.<1\0/\sss _________________________ A...L0-H \:s -=-.. ,..... '1.1.L.," LI
csS5 0 õrµ

H H
N "It.a ¨0.--A*0 H , H H
N

H H
.;22;INN's=...,,,,NN,.o,,.-N-..,%.õ.-- s' ¨
{2Z, 0 0 sSS
OH

H H i or H
, R2 each independently represents "....., SH

..,---0 N/ s H3C .,,,,,.
4,, 0 ...../...N'e 1 ,HS H2N
, .
..7,N.,,,NNs,..õ...7.CH 3 OH
HO
OH

l'N'...../..
H
H
0 0 N õsS
\esS:\ HO
OH HS \\........õ,.......... ....... \

H
OH
: =

0 .2..
0 e S -...,,, S
, i' 0 t ..i.sS5 , :SS'S
-i 9 0 , H. OH 0 1:-1, HO ...o S s .1 0 0 0 c., 100 CO2 H
OH A to rss. ococH3 coNH2 0.,..
o=??...
. , r CH 3 C1-E3 OH 0 14. 10 01 CH;
11,5C ¨N........._õ7-N.N.,...",s5' 0 0 OH
o tiVI\ NH
Ea 0 Matt s HN if 0 , NH2 , o = b a 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-a1kyl, or -COCH3;
R3 independently represents H, D, methyl, F. CI, ethyl or acetyi.
Aletimxis fix using compoinds offortmila 10021 The invention .also includes methods for treating glaucoma, epileptic seizures, Idiopathic intracranial hypertension (pseudotumor cerebri), altitude sickness, cystinuria, periodic paralysis and dual ectasia, congestive heart failure, drug induced edema., diuretic, intermittent claudication resulting from obstructed arteries in the limbs, and vascular dementia, improves blood flow through peripheral blood. vessels and therefore helps with blood circulation in the arms and legs (e.g. intermittent.
claudication), and the brain (hence its use in vascular dementia), .VerlOUS disease, Peyronie's disease, neuropathic injuries, strokes, sickle celi disease, nausea and headaches in the mountains (altitude sickness), non-alcoholic steatohepatitis and alcoholic liver disease, fibrotic lesions induced by radiation therapy for breast cancer, cytokine release syndrome, type I
diabetes and type 2 diabetes, asthma., bronchodilationõ kidney diseases., renal protection, vascular ischemia, .neuroprotection, va.sodilation, Alzheimer's disease, dementia, stroke, and treatm ent of en dam etri o.si s.
METHO.DS OF MAKING
1009311 Examples of synthetic pathways useful for making compounds of formula t are set forth in example below and generalized in scheme -1:

Scheme-I:

N -NN KOH -N
. (CH3C0)20 N -N
H2N S Et0H H H2N C 3COOH ZN S
Ph 1 rt- 0 C ,30m in 2 60 C, 10 min 3 C0nc.HC1 50% aq.CH3000H Et0H
-N 0 reflux, 4.5 h - 0 C, 30 min 0 4/ NH7 NN .1/
2) Liquid NH3 /L-N"--S 0 2) 5M aq.NaOH

oxalyi chloride rt, 2h +
DMF

5 7 100 C, 8 h sS¨<
N

10094] Step-1: Synthesis of campou nd 2:

N KOH N -N
õIL ¨S H j===-S\
H2N S Et0H H2N S
H20 Ph rt- 0 C,30m 100951 .Addition of 301 n of (5.36 moles) of 85%potassilIM hydroxide to a slurry of 608 g(4.56 moles) of 2-amill0-1,3,4-thiadiazole-5-thio1 1 in 456 cc of water produced a brown.
solution. This solution was clarified .with Darco (g-60 (for filtration) and diluted .with 1300 cc of ethanol. Benzyl chloride (575 g, 4.56 moles) was added rapidly with stirring.
The thick reaction mixture was tbrmed almost immediately was stirred and cooled to 0 C.
for 30 minutes and then diluted with 2 1., of cold water_ The solid compound 2 was removed by filtration and washed with water and ether..
10096] Step-2: Synthesis of com.pound N --N (CH3C 0)20 N -N

H,N S
Phi Phi 2 60 C. 10 min 3 (00971 A slurry of 4.0 moles of compound 2 in 4..4 .Moles of acetic anhydride and 1500 cc of acetic acid was heated at 60 C. for 10 minutes to get clear solution. The solution was gradually cooled and at the first appearance of ciy.stals, 2l. of µvater .was added. 'The suspension was cooled to 0 C and the solid compound 3 was collected by filtration.
[00981 Step-3: Synthesis of compound 4:

0 N-N 50% aciCH3COOH 0 5 C: 30 min C)11 NF¨S 0 Ph 2) Liquid NH3.

100991 A suspension of 0.50 g of compound. 3 in 40 cc of 50% aqueous acetic acid was chlorinated for 0.5 h at 5 0 C. The solid was filtered off after this time and added to 20 cc of liquid ammonia. After evaporation of ammonia and dilution of the dry residue with water, the aqueous solution was filtered. Acidification with hydrochloric acid gave solid compound 4 with nicking point 260 [001001 Step-4: Synthesis of compound SI

1) Conc.FIC
Et.OH
-N 0 reflux.; 4.5 hN 0 N-11"---'S
2) 51V1 aq,Na01-1 2N

solution of compound 4 (15 g, 67.5 mmol ,j) in a mixture of ethanol (100 nilL) and concentrated 'hydrochloride acid (30 ml.) was heated at reflux for 4_5 h, during which time a solid slowly deposited. Upon cooling the solution, the solvents were removed in vacuo and the solid residue was redissolved in F120 (75 mt.). The SO1101.011 \vas basified to pH 7 Ivith 5 IM sodium hydroxide, the precipitated product.
.was collected by filtration, and then recrystallized from water to give =the product 5 (10.6 g, 58.9 minol, 87%), mp 228-229 C (lit15 mp 230-232 ()C), 1001.02j Step-5: Synthesis of compound 7:
O
otreylcIlloncte.
¨
HO

6 CH Clz rt. 2h

7 (001031 To a .soluti on of 605 nig of 5,8,11,14,17-eicosapentaenic acid 6 in 6 ml of dry chloroform was added 0,25 1111 of oxalyi chloride under argon at room temperature.
The mixture was reacted for 2 hours, From the reactio.n mixture were removed the c.hloroform and the remaining oxaly1 chloride by distillation under reduced pressure to give 5,8,1 1,14,17-eicosapentaenoyl chloride 7, which was then directly used for the next step, 1001.041 Step-6: Synthesis of compound 8:
NH kloo;
+

6 7 100 `t, 8 h HA p N-1,4 0

8 1001051 A solution of compound 5 (2 mmol.) in dry .DMF (I 0 mr) was suspended in of anhydrous potassium carbonate (2,2 nunol) at room. temperature. To the reaction mixture was added the .DMIF solution 2 mmol of of 5,8, 4,17-eicosapentaenoy1 chloride 7 in 2 rul DIMIF prepared above d.ropwise over 15 min., and the mixture was heated at iO C for 8 hours. From the reaction mixture was removed insolubles by filtration, and water Was added to the filtrate. The mixture was extracted two times with ethyl acetate (2x10 .ml).
Organic laver of the extract was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation under reduced pressure to get the residue was subjected to silica gel column chromatography to obtain the pure compound 8.
1001061 The term "sample" refers to a sample of a body flu-id, to a sample of separated cells or to a sample from a tissue or an organ. Samples of body fluids can be obtained by vell known techniques and include, preferably, samples of blood, plasma, serum, or urine, more preferably, samples of blood, plasma or SertIM.
:EQUIVALENTS
[001.071 'The present disclosure provides among other things compositions and methods for treating diseases manifested from carbonic anydrase enzyme activity and their complications. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. :M.any variations of the systems and methods herein will become apparent to those skilled in the art upon review of this specification. The full scope of the claimed systems and methods should be determined by reference to the claims, along with their .full scope of equivalents, and the specification, along with such variations.
INCORPORATION BY REFER.ENCE
1.001081 All publications and patents mentioned herein, including those .items listed.
above, are hereby incorporated by reference in their entirety as if each individuai publication or patent was specifically and individually indicated -to be incorporated by reference. hi case of conflict the present application, including any definitions herein, will control,

Claims (14)

1. A compound of Formula I:
or a pharmaceutically acceptable salt, hydrate, polymorph, solvate, prodrug, enantiomer, or stereoisomer thereof, wherein:
R1 represents D, H, R2 represents a is 2,3 or 7;
each b is independently 3, 5 or 6;
e is 1, 2 or 6;
c and d are each independently H, D, -OH, -OD, C1-C6-alkyl, -NH2 or -COCH3;
and R3 independently represents H, D, methyl, F, CI, ethyl or acetyl.

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

3. The pharmaceutical composition of claim 2, wherein said pharmaceutical composition is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration.

4. A method for treating a disease with carbonic anhydrase activity as the underlying etiology, the method comprising administering to a patient in need thereof an effective amount of pharmaceutical composition of claim 3.

5. The method of claim 4, wherein the disease with carbonic anhydrase activity as the underlying etiology is selected from glaucoma, epileptic seizures, Idiopathic intracranial hypertension (pseudotumor cerebri), altitude sickness, cystinuria, periodic paralysis and dural ectasia, congestive heart failure, drug induced edema, diuretic, intermittent claudication resulting from obstructed arteries in the limbs, and vascular dementia, osteoporosis, improves blood flow through peripheral blood vessels and therefore helps with blood circulation in the arms and legs (e.g.
intermittent claudication), and the brain (hence its use in vascular dementia), venous disease, neuropathic injuries, strokes, sickle cell disease, nausea and headaches in the mountains (altitude sickness), non-alcoholic steatohepatitis and alcoholic liver disease, fibrotic lesions induced by radiation therapy for breast cancer, cytokine release syndrome, type 1 diabetes and type 2 diabetes, asthma, bronchodilation, kidney diseases, renal protection, vascular ischemia, neuroprotection, vasodilation, Alzheimer's disease, dementia, stroke, and treatment of endometriosis.

6. The pharmaceutical composition of claim 2, further comprising a molecular conjugate of azolamide compounds selected from a group consisting of acetazolamide and methazolamide, and carboxylic acid compounds selected from a group consisting of R-Lipoic acid, eicosapentaenoic acid, docosahexaenoic acid, acetyl cysteine, salsalate and fumaric acid.

7. The molecular conjugate of claim 6, wherein the carboxylic acid compound is R-Lipoic acid.

8. The molecular conjugate of claim 6, wherein the carboxylic acid compound is eicosapentaenoic acid.

9. The molecular conjugate of claim 6, wherein the carboxylic acid compound is docosahexaenoic acid.

10. The molecular conjugate of claim 6, wherein the carboxylic acid compound is acetyl cysteine.

11. The molecular conjugate of claim 6, wherein the carboxylic acid compound is salsalate.

12. The molecular conjugate of claim 6, wherein the carboxylic acid compound is fumaric acid.

13. The molecular conjugate of claim 6, wherein the compound is acetazolamide.

14. The molecular conjugate of claim 6, wherein the compound is methazolamide.