Patent Description:
Vasopressin regulates urea transport through the activation of two cyclic AMP (cAMP) dependent signaling pathways: protein kinase A (PKA) and exchange protein activated by cAMP (Epac). Vasopressin acts by increasing the phosphorylation and apical plasma membrane accumulation of the UT-A1 urea transporter protein. Vasopressin has also been shown to regulate water transport via increasing phosphorylation and apical plasma membrane accumulation of the aquaporin-<NUM> (AQP2) water channel. Thus, the inability of the kidney to respond to vasopressin manifests itself in irregularities in urea and water transport, leading to improper urine concentration.

Metformin has been shown to improve urine concentration in rodents with NDI. Metformin has a potential side effect that it causes lactic acidosis in select cases. Thus, there is a need for improved therapeutic treatments of NDI.

Aside from lifestyle modifications that include increased water consumption and changes in diet, hydrochlorothiazide and amiloride are diuretics that manage the dehydration associated with NDI. Currently, there exist no therapies specifically targeted towards NDI. Therefore, there is a need for therapeutic treatments that address the kidney function in NDI cases.

In embodiments, this disclosure relates to methods of treating or preventing nephrogenic diabetes insipidus in a subject in need thereof comprising administering a therapeutically effective amount of a compound of formula I:
<CHM>
its stereoisomers or pharmaceutically acceptable salts thereof, wherein R<NUM> and R<NUM> are independently selected from a group consisting of hydroxy, alkoxy, NHR' wherein R' is hydrogen, alkyl, cycloalkyl, SO<NUM>R or COR, wherein R is selected from alkyl or cycloalkyl; R<NUM> and R<NUM> or R<NUM> and R<NUM> are independently selected from hydrogen, or alkyl; R<NUM> and R<NUM> and/or R<NUM> and R<NUM> may form a cyclic ring of <NUM>-<NUM> carbon atoms; n is independently selected from <NUM> or <NUM>; Li is independently a linear aliphatic chain optionally containing from <NUM> to <NUM> carbon atoms; wherein one or more symptoms of nephrogenic diabetes insipidus is treated. In embodiments, a compound of Formula I is <NUM>,<NUM>'-(dodecane-<NUM>,<NUM>-diyl)bis(cyclopropane-<NUM>-carboxamide) (also known as NDI-<NUM>), derivatives, prodrugs, or salts thereof.

In embodiments, the symptoms to be treated include the production of large quantities of dilute urine, excessive urination, and/or excessive thirst.

In embodiments, the subject is diagnosed with nephrogenic diabetes insipidus.

In embodiments, the compound of Formula I or derivative thereof is administered in combination with a cGMP-specific phosphodiesterase inhibitor, metformin, a diuretic, or a P2Y purinergic receptor antagonist.

Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.

Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.

Prior to describing the various embodiments, the following definitions are provided and should be used unless otherwise indicated. Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claims.

The compounds of the present disclosure may form one or more salts, tautomers, solvates, or contain one or more chiral centers and exist in different optically active forms. When the compound contains one chiral center, the compound comprises an enantiomer. The present disclosure includes mixtures of salts, stereoisomers, enantiomers, diastereomers, tautomers, or solvates. Enantiomers can be resolved by methods known in the art, such as crystallization, chiral chromatography and the like. When the compound contains more than one chiral centers, diastereomers may be present. The present disclosure includes specific optically pure isomers which have been resolved, as well as mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.

Unless the context requires otherwise, throughout the specification and claims which follow, the word "comprise" and variations thereof, such as, "comprises," "comprising" "including," "containing," or "characterized by," are to be construed in an open, inclusive sense, that is, as "including, but not limited to" and does not exclude additional, unrecited elements or method steps. By contrast, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. In embodiments or claims where the term comprising is used as the transition phrase, such embodiments can also be envisioned with replacement of the term "comprising" with the terms "consisting of" or "consisting essentially of.

In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent.

The word "about" when immediately preceding a numerical value means a range of plus or minus <NUM>% of that value, e. g, "about <NUM>" means <NUM> to <NUM>, "about <NUM>,<NUM>" means <NUM>,<NUM> to <NUM>,<NUM>, etc, unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as "about <NUM>, about <NUM>, about <NUM>, "about <NUM>" means a range extending to less than half the interval(s) between the preceding and subsequent values, e. g, more than <NUM> to less than <NUM>. Furthermore, the phrases "less than about" a value or "greater than about" a value should be understood in view of the definition of the term "about" provided herein.

The terms "administer," "administering" or "administration" as used herein refer to either directly administering a compound (also referred to as an agent of interest) or pharmaceutically acceptable salt of the compound (agent of interest) or a composition to a subject.

The term "carrier" as used herein encompasses carriers, excipients, and diluents, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical, cosmetic or other agent across a tissue layer.

As used herein, the terms "urine of the subject does not contain elevated glucose" refers to a comparison to subject with normal levels of glucose in their urine. A human subject may have glucose in urine depending on the timing, amount, and particular sugars consumed by the subject. It is normal for non-diabetics while fasting to have blood glucose levels of about <NUM> to <NUM>/dL. The average renal threshold is at a blood glucose level of about <NUM>-<NUM>/dL; thus, when blood glucose levels reach <NUM>-<NUM>/dL some glucose may appear in the urine. Blood sugar levels for those without diabetes and who are not fasting is typically below <NUM>/dL more than two hours after eating. A normal subject may have high blood sugar levels and glucose in urine soon after consuming a sugary drink. However, blood sugar levels after two hours of consuming a sugary drink are typically less than <NUM>/dL.

As used herein the term "lithium" refers to lithium salts typically used in the treatment of manic bipolar disorder. Examples include lithium carbonate, lithium citrate, lithium orotate, lithium bromide, and lithium chloride.

As used herein, the terms "prevent" and "preventing" include the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.

As used herein, the terms "treat" and "treating" are not limited to the case where the subject (e.g., patient) is cured and the disease is eradicated. Rather, embodiments, of the present disclosure also contemplate treatment that merely reduces symptoms, and/or delays disease progression.

As used herein, the term "combination with" when used to describe administration with an additional treatment means that the agent may be administered prior to, together with, or after the additional treatment, or a combination thereof.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. The salts can be prepared in situ during the isolation and purification of the compounds of the disclosure, or separately by reacting the free base or free acid of a compound of the disclosure with a suitable base or acid, respectively. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydro bromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, <NUM>-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methane-sulfonate, <NUM>-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, <NUM>-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and aryl sulfonate.

As used herein, the term "derivative" refers to a structurally similar compound that retains sufficient functional attributes of the identified analogue. The derivative may be structurally similar because it is lacking one or more atoms, substituted, a salt, in different hydration/oxidation states, or because one or more atoms within the molecule are switched, such as, but not limited to, adding a hydroxyl group, replacing an oxygen atom with a sulfur atom, or replacing an amino group with a hydroxyl group, oxidizing a hydroxyl group to a carbonyl group, reducing a carbonyl group to a hydroxyl group, and reducing a carbon-to-carbon double bond to an alkyl group or oxidizing a carbon-to-carbon single bond to a double bond. A derivative optional has one or more substitutions. Derivatives may be prepared by any variety of synthetic methods or appropriate adaptations presented in synthetic or organic chemistry text books, such as those provide in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (<NUM>) Michael B. Smith or Domino Reactions in Organic Synthesis, Wiley (<NUM>) Lutz F.

The terms "effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to an amount of a compound that, when administered to a subject, is capable of reducing a symptom of a disorder in a subject or enhance the texture, appearance, color, sensation, or hydration of the intended tissue treatment area. The actual amount which comprises the "effective amount" or "therapeutically effective amount" will vary depending on a number of conditions including, but not limited to, the severity of the disorder, the size and health of the patient, and the route of administration. A skilled medical practitioner can readily determine the appropriate amount using methods known in the medical arts.

The phrase "pharmaceutically acceptable" or "cosmetically acceptable" is employed herein to refer to those agents of interest/compounds, salts, compositions, dosage forms, etc, which arewithin the scope of sound medical judgment--suitable for use in contact with the tissues of human beings and/or other mammals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In some aspects pharmaceutically acceptable means approved by a regulatory agency of the federal or a state government, or listed in the U. Pharmacopeia or other generally recognized pharmacopeia for use in mammals (e. g, animals), and more particularly, in humans.

As used herein the language "pharmaceutically acceptable excipient" is intended to include any and all carriers, solvents, diluents, excipients, adjuvants, dispersion media, coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like, compatible with pharmaceutical administration.

As used herein, "pharmaceutical formulation" and "pharmaceutical composition" can be used interchangeably.

The term "patient" and "subject" are interchangeable and may be taken to mean any living organism which may be treated with compounds of the present invention. As such, the terms "patient" and "subject" may include, but is not limited to, any non-human mammal, primate or human. In some embodiments, the "patient" or "subject" is a mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans. In some embodiments, the patient or subject is an adult, child or infant. In some embodiments, the patient or subject is a human.

The composition may be administered to patients in an amount effective, especially to enhance pharmacological response in an animal or human organism. As used herein, the term "effective amount" refers to an amount sufficient to realize a desired biological effect. The appropriate dosage may vary depending upon known factors such as the pharmacodynamic characteristics of the particular active agent, age, health, and weight of the host organism; the condition(s) to be treated, nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, the need for prevention or therapy and/or the effect desired. The dosage will also be calculated dependent upon the particular route of administration selected. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely made by a practitioner, in the light of the relevant circumstances. The titer may be determined by conventional techniques.

As used herein, the term "AMPK activator" refers to a substance that activates adenosine monophosphate kinase, AMPK.

A "linking group" refers to any variety of molecular arrangements that can be used to bridge two molecular moieties together.

As used herein, "alkyl" means a noncyclic straight chain or branched, unsaturated or saturated hydrocarbon such as those containing from <NUM> to <NUM> carbon atoms. A "higher alkyl" refers to unsaturated or saturated hydrocarbon having <NUM> or more carbon atoms. A "C8-C18" refers to an alkyl containing <NUM> to <NUM> carbon atoms. Likewise a "C6-C22" refers to an alkyl containing <NUM> to <NUM> carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, nbutyl, n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl" or "alkynyl", respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, <NUM>-butenyl, <NUM>-butenyl, isobutylenyl, <NUM>-pentenyl, <NUM>-pentenyl, <NUM>-methyl- <NUM>-butenyl, <NUM>-methyl-<NUM>-butenyl, <NUM>,<NUM>- dimethyl-<NUM>-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, <NUM>-butynyl, <NUM>-butynyl, <NUM>-pentynyl, <NUM>-pentynyl, <NUM>-methyl-<NUM>-butynyl, and the like.

Non-aromatic mono or polycyclic alkyls are referred to herein as "carbocycles" or "carbocyclyl" groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, and the like.

The term "aryl" refers to aromatic homocyclic (i.e., hydrocarbon) mono-, bi- or tricyclic ring-containing groups preferably having <NUM> to <NUM> members such as phenyl, naphthyl and biphenyl. Phenyl is a preferred aryl group.

"Alkoxy" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n- pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, s-butoxy, tbutoxy.

"Alkoxyalkyl" refers an alkyl group as defined above with the indicated number of carbon atoms attached through an alkyl bridge (i.e., -CH<NUM>-O-CH<NUM>CH<NUM>).

The terms "cycloalkyl" and "cycloalkenyl" refer to mono-, bi-, or tri homocyclic ring groups of <NUM> to <NUM> carbon atoms which are, respectively, fully saturated and partially unsaturated.

The term "substituted" refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are "substituents. " The molecule may be multiply substituted.

The term "prodrug" refers to an agent that is converted into a biologically active form in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. Typical prodrugs are pharmaceutically acceptable esters. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.

By way of example only, appropriate prodrugs can be prepared by reacting a non-derivatized compound with a suitable carbamylating agent, such as, but not limited to, <NUM>,<NUM>-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like. Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a derivative as set forth herein.

Pharmaceutically acceptable prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters. Compounds having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. In certain instances, all of these prodrug moieties incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.

In some embodiments, prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e. , two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the present disclosure. The amino acid residues include but are not limited to the <NUM> naturally occurring amino acids and also includes <NUM>-hydroxyproline, hydroxylysine, demosine, isodemosine, <NUM>-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, ornithine and methionine sulfone.

For example, if a disclosed compound or a pharmaceutically acceptable form of the compound contains a carboxylic acid functional group, a prodrug can comprise a pharmaceutically acceptable ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)alkanoyloxymethyl, <NUM>-(alkanoyloxy)ethyl having from <NUM> to <NUM> carbon atoms, <NUM>-methyl-<NUM>-(alkanoyloxy)-ethyl having from <NUM> to <NUM> carbon atoms, alkoxycarbonyloxymethyl having from <NUM> to <NUM> carbon atoms, <NUM>-(alkoxycarbonyloxy)ethyl having from <NUM> to <NUM> carbon atoms, <NUM>-methyl-<NUM>-(alkoxycarbonyloxy)ethyl having from <NUM> to <NUM> carbon atoms, N-(alkoxycarbonyl)aminomethyl having from <NUM> to <NUM> carbon atoms, <NUM>-(N-(alkoxycarbonyl)amino)ethyl having from <NUM> to <NUM> carbon atoms, <NUM>-phthalidyl, <NUM>-crotonolactonyl, gamma-butyrolacton-<NUM>-yl, di-N,N-(C<NUM>-C<NUM>)alkylamino(C<NUM>-C<NUM>)alkyl (such as beta-dimethylaminoethyl), carbamoyl-(C<NUM>-C<NUM>)alkyl, N,N-di(C<NUM>-C<NUM>)alkylcarbamoyl-(C<NUM>-C<NUM>)alkyl and piperidino-, pyrrolidino- or morpholino(C<NUM>-C<NUM>)alkyl.

If a disclosed compound or a pharmaceutically acceptable form of the compound contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C<NUM>-C<NUM>)alkanoyloxymethyl, <NUM>-(( C<NUM>-C<NUM>)alkanoyloxy) ethyl, <NUM>-methyl-<NUM>((C<NUM>-C<NUM>)alkanoyloxy)ethyl(C<NUM>-C<NUM>)alkoxycarbonyloxymethyl, N-(C<NUM>-C<NUM>)-alkoxycarbonylaminomethyl, succinoyl, (C<NUM>-C<NUM>)alkanoyl, alpha-amino(C<NUM>-C<NUM>)alkanoyl, arylacyl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where each alpha-aminoacyl group is independently selected from naturally occurring L-amino acids, P(O)(OH)<NUM>, -P(O)(O(C<NUM>-C<NUM>)alkyl)<NUM>, and glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

If a disclosed compound or a pharmaceutically acceptable form of the compound incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C<NUM>-C<NUM>)alkyl, (C<NUM>-C<NUM>)cycloalkyl, benzyl, a natural alpha-aminoacyl, -C(OH)C(O)OY<NUM> wherein Y<NUM> is H, (C<NUM>-C<NUM>)alkyl or benzyl, -C(OY<NUM>)Y<NUM> wherein Y<NUM> is (C<NUM>-C<NUM>) alkyl and Y<NUM> is (C<NUM>-C<NUM>)alkyl, carboxy(C<NUM>-C<NUM>)alkyl, amino(C<NUM>-C<NUM>)alkyl or di-N,N-(C<NUM>-C<NUM>)alkylaminoalkyl, -C(Y<NUM>)Y<NUM> wherein Y<NUM> is H or methyl and Y<NUM> is mono-N- or di-N,N-( C<NUM>-C<NUM>)alkylamino, morpholino, piperidin-<NUM>-yl or pyrrolidin-<NUM>-yl.

Embodiments of the invention are directed to compounds of Formula IA according to claim <NUM> for use in methods of treating or preventing a condition in a subject in need thereof which comprises administering a therapeutically effective amount of a compound of formula IA as described herein.

In embodiments, the condition to be treated is characterized by the production of large quantities of dilute urine, excessive urination, and/or excessive thirst. In embodiments, the subject is treated and does not produce large quantities of dilute urine. In embodiments, when the subject is treated by the administration of the compound of Formula IA, the subject does not experience excessive urination. In embodiments, when the subject is treated by the administration of the compound of Formula IA, the subject does not experience excessive thirst. In embodiments, when the subject is treated by administration of the compound of Formula IA, the urine of the subject does not contain elevated glucose.

According to the invention, when the subject is treated by the administration of the compound of formula IA, it does not alter blood sugar levels, it does not induce hypoglycemia in a fasting condition, and/or the urine of the subject does not contain elevated glucose. In embodiments, when the subject is treated by the administration of the compound of Formula IA, the subject does not experience gastrointestinal distress.

According to the invention, the condition is nephrogenic diabetes insipidus (NDI). In embodiments, the subject has been diagnosed with NDI using a test where the subject is restricted from drinking water and the hourly increase in osmolality of urine of the subject is less than <NUM> mOsm/kg per hour for at least <NUM> hours. Nephrogenic diabetes insipidus (NDI), a form of diabetes insipidus, is a disease characterized by the production of large quantities of dilute urine, which results from the inability of the kidney to respond to vasopressin, the primary hormone known to enable urine concentration. To avoid dehydration, those diagnosed with NDI must consume enough fluids to equal the amount of urine produced, which may be as high as <NUM> of water per day. A symptom of NDI is the production of large quantities of dilute urine. The concentration of urine, or how dilute a subject's urine is, as measured by the osmolality of the urine. In severe cases of NDI the subject's urine concentration is less than <NUM> mOsm/kg. In mild cases of NDI the subject's urine concentration is less than <NUM> mOsm/kg. In embodiments, the subject is treated and the osmolality of the urine is greater than <NUM> mOsm/kg, greater than <NUM> mOsm/kg, greater than <NUM> mOsm/kg, greater than <NUM> mOsm/kg, greater than <NUM> mOsm/kg, greater than <NUM> mOsm/kg, greater than <NUM> mOsm/kg, greater than <NUM> mOsm/kg, greater than <NUM> mOsm/kg, greater than <NUM> mOsm/kg, or greater than <NUM> mOsm/kg. In embodiments, the subject is treated and daily urine osmolality is increased by about <NUM>% per day, increased by about <NUM>% per day, increased by about <NUM>% per day, or increased by about <NUM>% per day. In severe cases of NDI the subject produces as much as or greater than <NUM> of urine per day. In mild cases of NDI the subject produces greater than <NUM> of urine per day. In embodiments, the symptom of excessive urination is treated, and the amount of urine produced is less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, less than <NUM>/day, or less than <NUM>/day. In embodiments, the subject experiences a reduction in the daily volume of urination selected from the group consisting of reducing the daily volume of urination by <NUM>%, reducing the daily volume of urination by <NUM>%, reducing the daily volume of urination by <NUM>%, reducing the daily volume of urination by <NUM>%, reducing the daily volume of urination by <NUM>%, reducing the daily volume of urination by <NUM>%, reducing the daily volume of urination by <NUM>%, reducing the daily volume of urination by <NUM>%, reducing the daily volume of urination by <NUM>%, reducing the daily volume of urination by <NUM>%. In embodiments, the subject experiences a reduction in the daily frequency of urination selected from the group consisting of reducing the daily frequency of urination by <NUM>%, reducing the daily frequency of urination by <NUM>%, reducing the daily frequency of urination by <NUM>%, reducing the daily frequency of urination by <NUM>%, reducing the daily frequency of urination by <NUM>%, reducing the daily frequency of urination by <NUM>%, reducing the daily frequency of urination by <NUM>%, reducing the daily frequency of urination by <NUM>%, reducing the daily frequency of urination by <NUM>%, reducing the daily frequency of urination by <NUM>%.

In embodiments, the condition is acquired NDI. Acquired NDI is most commonly thought to stem from chronic lithium treatment, a classic treatment for bipolar disorders. Those undergoing chronic lithium treatment display no mutations in either the UT-A1 or AQP2 proteins. Thus, it is the inability to respond to vasopressin, and subsequently undergo phosphorylation of UT-A1 and AQP2, that leads to defects in urine concentration. In embodiments, nephrogenic diabetes insipidus is prevented or severity reduced in a subject being treated with lithium for a psychiatric disorder, wherein the subject is administered a therapeutically effective amount of lithium in combination with a therapeutically effective amount of a compound of Formula IA or derivative thereof as described herein. In certain embodiments, the subject is diagnosed with a psychiatric disorder such as major depressive disorder, manic episodes, or bipolar disorder. In embodiments, a therapeutically effective amount of compound of Formula IA is administered to a subject to treat nephrogenic diabetes insipidus induced by lithium therapy.

In embodiments, the condition is congenital NDI. Congenital NDI arises from mutations in the vasopressin receptor, V2R, causing it to malfunction, or in the kidney water channel AQP2, resulting in a decreased ability to absorb water. Those possessing V2R mutations display no mutations in either the UT-A1 or AQP2 proteins. Thus, it is the inability to respond to vasopressin, and subsequently undergo phosphorylation, that leads to defects in urine concentration.

Embodiments of the invention are directed to compounds of formula IA for use in methods of treating or preventing acquired NDI in a subject in need thereof comprises administering a therapeutically effective amount of a compound of Formula IA as described herein. In embodiments, the subject is being administered lithium. In embodiments, the subject is being administered lithium and is at risk of developing acquired NDI or has developed acquired NDI. In embodiments, the subject is diagnosed with a psychiatric disorder and the subject is administered a therapeutically effective amount of lithium. In certain embodiments, the subject is diagnosed with a psychiatric disorder such as major depressive disorder, manic episodes, or bipolar disorder. In embodiments, the lithium is administered in combination with a therapeutically effective amount compound of Formula IA or derivative thereof as described herein to prevent development of or treat NDI. In embodiments, the lithium and the compound of Formula IA or derivative thereof as described herein are administered in a single pharmaceutical composition or in separate pharmaceutical compositions.

In embodiments, the subject is an adult. In embodiments, the subject is a non-adult or a child.

In embodiments, the class of compounds are classified as AMPK activators, since they enable the phosphorylation of both the UT-A1 and AQP2 proteins.

The compounds according to the invention are compounds of formula IA,
<CHM>
its stereoisomers or pharmaceutically acceptable salts thereof, wherein R<NUM> and R<NUM> are independently selected from a group consisting of hydroxyl, alkoxy, or NHR' wherein R' is hydrogen, alkyl, or cycloalkyl.

In embodiments, the compound of Formula IA is <NUM>,<NUM>'-(dodecane-<NUM>,<NUM>-diyl)bis(cyclopropane-<NUM>-carboxamide) or derivatives or salts thereof. This compound is also referred to as NDI-<NUM> and is depicted as having the following structure:
<CHM>.

In embodiments, the compound of Formula IA is <NUM>,<NUM>'-(decane-<NUM>,<NUM>-diyl)bis(cyclopropane-<NUM>-carboxylic acid) or derivatives or salts thereof. This compound is also referred to as NDI-<NUM> and is depicted as having the following structure:
<CHM>.

In embodiments, the compound of Formula IA is <NUM>-(<NUM>-(<NUM>-(cyclopropylcarbamoyl)cyclopropyl)decyl)cyclopropane-<NUM>-carboxylic acid or derivatives or salts thereof. This compound is also referred to as NDI-<NUM> and is depicted as having the following structure:
<CHM>.

In certain embodiments, a compound of Formula IA include the following examples. The preparation of these examples are provided for in <CIT> and <CIT>. <CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

In embodiments, the therapeutically effective amount of a compound of Formula IA may be from about <NUM>/day to about <NUM>,<NUM>/day. In embodiments, the therapeutically effective amount of a compound of Formula I may be from about <NUM>/day to about <NUM>,<NUM>/day. In embodiments, the therapeutically effective amount of a compound of Formula IA may be from about <NUM>/day to about <NUM>/day. In embodiments, the therapeutically effective amount of a compound of Formula IA may be from about <NUM>/day to about <NUM>/day. In embodiments, the therapeutically effective amount of a compound of Formula IA may be from about <NUM>/day to about <NUM>/day. In embodiments, the therapeutically effective amount of a compound of Formula IA may be from about <NUM>/day to about <NUM>,<NUM>/day. In embodiments, the therapeutically effective amount of a compound of Formula IA may be from about <NUM>/day to about <NUM>/day. In embodiments, the therapeutically effective amount of a compound of Formula IA may be from about <NUM>/day to about <NUM>/day. In embodiments, the therapeutically effective amount of a compound of Formula IA may be from about <NUM>/day to about <NUM>/day. In embodiments, the therapeutically effective amount of a compound of Formula IA may be from about <NUM>/day to about <NUM>/day. In embodiments, the therapeutically effective amount of a compound of Formula IA may be from about <NUM>/day to about <NUM>,<NUM>/day.

In embodiments, the therapeutically effective amount of a compound of Formula IA for an adult subject may be from about <NUM> to about <NUM>,<NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for an adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for an adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for an adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for an adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for an adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for an adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for an adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for an adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for an adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for an adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for an adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for an adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for a non-adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for a non-adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for a non-adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for a non-adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for a non-adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for a non-adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for a non-adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for a non-adult subject may be from about <NUM> to about <NUM> per day. In embodiments, the therapeutically effective amount of a compound of Formula IA for a non-adult subject may be from about <NUM> to about <NUM> per day.

In embodiments, for the administrations disclosed herein similar amounts converted to molar equivalents of the salts are contemplated. In embodiments, administrations may include an amount of less than <NUM>%, <NUM>%, or <NUM>% variation by weight.

In embodiments, the therapeutically effective amount of a compound of Formula IA may be administered in a single dose or a dose repeated one or several times after a certain time interval. In embodiments, the therapeutically effective amount is administered daily or every two or three days, or once a week. Administration may be one, twice, or three times daily, e.g., single dose of <NUM> daily, single dose of <NUM>, <NUM> twice daily, or <NUM> my three times daily, single dose of <NUM>,<NUM> daily, single dose of <NUM> daily, single dose of <NUM>, single dose of <NUM>, <NUM> twice daily, or <NUM> three times daily. In embodiments, the therapeutically effective amount is administered daily or every other day for more than two weeks, ten weeks, thirty weeks, a year, or as long as symptoms or the disease are present. In embodiments, the therapeutically effective amount is administered daily or every other day for more than thirty weeks.

In embodiments, the compound of Formula IA may be administered systemically or locally. For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, intranasally, intravaginally, by inhalation, by depot injections, or by implants. In embodiments, the compound of Formula I is suitable for oral administration. In embodiments, the compound of Formula I is administered in the form of a pill, tablet, capsule, gel, gummy, liquid, or in the form of an aqueous saline buffer. In embodiments, the pharmaceutically acceptable excipient is a saccharide or polysaccharide.

In embodiments, the compound of Formula IA is in a pharmaceutical composition. In embodiments, a pharmaceutical composition of the disclosure comprises a carrier and/or diluent appropriate for its delivering by injection to a human or animal organism. Such carrier and/or diluent is non-toxic at the dosage and concentration employed. It is selected from those usually employed to formulate compositions for parental administration in either unit dosage or multi-dose form or for direct infusion by continuous or periodic fusion. It is typically isotonic, hypotonic or weakly hypertonic and has a relatively low ionic strength, such as provided by sugars, polyalcohols and isotonic saline solutions. Representative examples include sterile water, physiological saline (e.g. sodium chloride), bacteriostatic water, Ringer's solution, glucose or saccharose solution, Hank's solution, and other aqueous physiologically balanced salt solutions (see for example the most current editions of <NPL>). The pH of the composition of the disclosure is suitably adjusted and buffered in order to be appropriate for use in humans or animals, typically at a physiological or slightly basic pH (between about pH <NUM> to about pH <NUM>, with a special preference for pH <NUM>). Suitable buffers include phosphate buffer (e.g. PBS), bicarbonate buffer and/or Tris buffer. A typical composition is formulated in <NUM> saccharose, <NUM> NaCl, <NUM> MgCl2, <NUM>/l Tween <NUM>, <NUM> Tris pH <NUM>. Another typical composition is formulated in <NUM>/ml mannitol, <NUM>/ml HAS, <NUM> Tris, pH <NUM>, and <NUM> NaCl.

The pharmaceutical composition of the disclosure can be in various forms, e.g. in solid (e.g. powder, lyophilized form), or liquid (e.g. aqueous). In the case of solid compositions, the typical methods of preparation are vacuum drying and freeze-drying which yields a powder of the active agent plus any additional desired ingredient from a previously sterile-filtered solution thereof. Such solutions can, if desired, be stored in a sterile ampoule ready for reconstitution by the addition of sterile water for ready injection.

Nebulized or aerosolized formulations also form part of this disclosure. Methods of intranasal administration include the administration of a droplet, spray, or dry powdered form of the composition into the nasopharynx of the individual to be treated from a pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer (see for example <CIT>). Enteric formulations such as gastroresistant capsules and granules for oral administration, suppositories for rectal or vaginal administration also form part of this disclosure. For non-parental administration, the compositions can also include absorption enhancers which increase the pore size of the mucosal membrane. Such absorption enhancers include sodium deoxycholate, sodium glycocholate, dimethyl-beta-cyclodextrin, lauroyl-<NUM>-lysophosphatidylcholine and other substances having structural similarities to the phospholipid domains of the mucosal membrane.

The pharmaceutical composition can also contain other pharmaceutically acceptable excipients for providing desirable pharmaceutical or pharmacodynamic properties, including for example modifying or maintaining the pH, osmolarity, viscosity, clarity, color, sterility, stability, rate of dissolution of the formulation, modifying or maintaining release or absorption into an the human or animal organism. For example, polymers such as polyethylene glycol may be used to obtain desirable properties of solubility, stability, half-life and other pharmaceutically advantageous properties (<NPL>; <NPL>). Representative examples of stabilizing components include polysorbate <NUM>, Larginine, polyvinylpyrrolidone, trehalose, and combinations thereof. Viscosity enhancing agents include sodium carboxymethylcellulose, sorbitol, and dextran. The composition can also contain substances known in the art to promote penetration or transport across the blood barrier or membrane of a particular organ (e.g. antibody to transferrin receptor; <NPL>). A gel complex of poly-lysine and lactose (<NPL>) or poloxamer <NUM> (<NPL>) can be used to facilitate administration in arterial cells.

In embodiments, the methods may include the co-administration of a second active agent. In embodiments, co-administration may be part of the same pharmaceutical composition or separated pharmaceutical compositions described herein. In embodiments, co-administration may be at the same time, substantially the same time, before or after administration of the compositions described herein.

In embodiments, the second active agent may be selected from the group consisting of a cGMP-specific phosphodiesterase inhibitor, an AMPK activator, a diuretic, a P2Y purinergic receptor antagonist, and lithium.

In embodiments, lithium is administered in an amount selected from the group consisting of <NUM>, <NUM>, <NUM>, and <NUM>.

In embodiments, the cGMP-specific phosphodiesterase inhibitor is selected from the group consisting of sildenafil, vardenafil, tadalafil, and avanafil.

In embodiments, the AMPK activator is selected from the group consisting of metformin, Proguanil, cryptotanshinone, <NUM>-aminoimidazole-<NUM>-carboxamide-<NUM>-beta-D-ribofuranoside, A-<NUM> [<NUM>-hydroxy-<NUM>-(<NUM>'-hydroxy-[<NUM>,<NUM>'-biphenyl]-<NUM>-yl)-<NUM>-oxo-<NUM>,<NUM>-dihydrothieno[<NUM>,<NUM>-b]pyridine-<NUM>-carbonitrile], D942 [<NUM>-(<NUM>-(<NUM>-(<NUM>-(<NUM>- Fluorophenyl) ethoxy)phenyl)propyl)furan-<NUM>-carboxylic acid], WS070117 [O2',<NUM>',<NUM>'-tri-acetyl-N6-(<NUM>-hydroxylaniline)adenosine], PT1 [<NUM>-Chloro-<NUM>-[[<NUM>-[[<NUM>-(<NUM>,<NUM>-Dimethyl-<NUM>--nitrophenyl)-<NUM>-furanyl]methylene]-<NUM>,<NUM>-dihydro-<NUM>-ox-o-<NUM>-thiazolyl]amino]benzoic acid] and salts thereof. Metformin (also known as Fortamet®, Glucophage®, Glumetza®, Riomet®) was previously used as a treatment for type II diabetes. Proguanil (also known as Paludrine®) is an example of an AMPK activator and has been used as a prophylactic antimalarial drug.

In embodiments, the diuretic is selected from the group consisting of thiazide, amiloride, and other diuretics.

In embodiments, the P2Y purinergic receptor antagonist is selected from the group consisting of suramin, clopidogrel, reactive blue <NUM>, acid blue <NUM>, acid blue <NUM>, and pyridoxalphosphate-<NUM>-azophenyl-<NUM>',<NUM>'-disulfonic acid (PPADS).

Rats were given tolvaptan to induce NDI. Tolvaptan binds to and blocks the vasopressin type <NUM> receptor (V2R) and renders the animals insensitive to vasopressin-induced antidiuresis. The efficacy of three compounds of Formula I were evaluated. Each rat was gavage fed with <NUM>/kg/day of tolvaptan in the carrier solution (<NUM>% hydroxypropylmethyl cellulose in water) for <NUM> days to prepare the NDI model. The drugs were added to the gavage feeding solution and delivered daily for <NUM> days (NDI-<NUM>, <NUM>/kg/day; NDI-<NUM> or NDI-<NUM>, <NUM>/kg/day). Control rats were sham gavage fed. The bar graph shows the response to the drugs expressed as the percent of the untreated, fully concentrating rats (basal, set to <NUM>%). As shown in Figure 1B, the tolvaptan successfully produced a situation of nephrogenic diabetes insipidus, reducing the urine osmolality to <NUM>% of the normal animal. Both NDI-<NUM> and NDI-<NUM> showed efficacy, NDI-<NUM>, improved urine concentrating ability to <NUM>% of normal.

NDI-<NUM> was tested to determine an initial time course and sustainability of the anti-diuretic response. Rats were given tolvaptan to initiate NDI. They were then fed <NUM>/kg/day with NDI-<NUM> for <NUM> days (<FIG>). Basal bar shows urine osmolality for fully concentrating rats. Tolvaptan shows minimal concentration in this model. Data indicates that NDI is effective within <NUM> hours of initial treatment and is sustained for <NUM> days. To ensure that the observed efficacy is not compromised by potential binding of NDI-<NUM> to V2R, NDI-<NUM> was given to mice in which the V2R was genetically knocked out yielding a genetic model of NDI (<FIG>). Control mice received no drug. NDI-<NUM> was given by injection to the mice and <NUM>-hour urine collected and assessed for urine osmolality. NDI-<NUM> produced a <NUM>% improvement in urine concentration.

Tolvaptan induced NDI rats were prepared and fed with doses of NDI-<NUM> from <NUM> to <NUM>/kg/day in a series of experiments. The drug NDI-<NUM> showed statistically significant improvements in urine concentrations at <NUM>/kg/day and above (<FIG>). To confirm the effectiveness of the <NUM>/kg/day dose, NDI-<NUM> was given to V2R knock-out NDI mice and <NUM>-hour urines were assessed for urine osmolality (<FIG>). The osmolality was increased in NDI mice after treatment with <NUM>/kg/day of NDI-<NUM>.

An experiment was designed to approximate hypoglycemia in the tolvaptan-treated rat NDI model to look for hypoglycemia. A timeline for the experiment is illustrated in <FIG>. The rats were given tolvaptan beginning Day negative <NUM>. On Day zero half of the rats started to receive <NUM>/kg/day of NDI-<NUM>. After observing an improvement in the urine concentration, the animals were exercised daily for <NUM> days. Food was removed from the animals and NDI-<NUM> was given, then <NUM> hours later rats were subjected to <NUM> minutes of treadmill running. Blood glucose measurements were taken before and after the bout of exercise. Food was restored. The process was repeated daily for <NUM> days. The average urine osmolality and urine volumes in the NDI rats not receiving NDI-<NUM> (control) or receiving <NUM>/kg/day NDI-<NUM> is shown in <FIG>. Urine osmolality was increased (p<<NUM>) and urine volume decreased (p<<NUM>) upon drug treatment. <FIG> shows the blood glucose values for rats that were exercised. For each day, patterned bars are from rats not receiving NDI-<NUM>. The leftmost bar (diagonal) is before and to the right is after exercise. The next two bars show blood glucose values for rats receiving NDI-<NUM>. Solid black is before and solid white is after exercise.

Claim 1:
A compound of Formula IA,
<CHM>
its stereoisomers or a pharmaceutically acceptable salt thereof,
wherein R<NUM> and R<NUM> are independently selected from a group consisting of hydroxyl, alkoxy, or NHR' wherein R' is hydrogen, alkyl, or cycloalkyl;
for use in a method of preventing or treating nephrogenic diabetes insipidus in a subject,
wherein at least one symptom of nephrogenic diabetes insipidus is treated, and wherein administering the compound to the subject does not alter blood sugar levels in the subject.