WO2009117144A1 - Benzazepine compounds - Google Patents

Abstract

This invention relates to novel compounds that are benzazepines derivatives and pharmaceutically acceptable salts thereof. More specifically, this invention relates to novel benzazepines derivatives that are derivatives of conivaptan. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering a dual antagonist of arginine vasopressin (AVP) Vi A and V2 receptors, such a conivaptan.

Description

DEUTERATED CONIVAPTAN

RELATED APPLICATION

[1] This application claims the benefit of U.S. Provisional Application No. 61/070,075, filed on March 20, 2008. The entire teachings of the above application is incorporated herein by reference.

BACKGROUND OF THE INVENTION

[2] Conivaptan, also known as [1 ,1 '-biphenyl]-2-carboxamide, τV-[4-[(4,5- dihydro-2- methylimidazo[4,5 <i][l]benzazepin-6(lH)-yl)carbonyl]phenyl]-,monohydrochloride, acts as a dual inhibitor of arginine vasopressin (AVP) through binding at the Vi _A and V₂ receptors. AVP, also known as anti-diuretic hormone (ADH), is critical in regulating water and electrolyte balance. Through its V₂ receptors, this hormone's effect largely is to cause retention of water, but not of sodium, and thus to maintain plasma osmolality within the normal range. Inhibition of AVP through V₂ antagonism can lead to excretion of free water, not sodium, thus increasing blood sodium levels. (See FDA label and Summary Basis of Approval for vaprisol at http://www.fda.gov/cder) {last visited 02/21/08).

[3] Conivaptan is currently approved for euvolemic and hypervolemic hyponatremia in hospitalized patients as an IV formulation. The oral formulation is currently undergoing clinical trials for the treatment of euvolemic and hypervolemic hyponatremia. [4] In humans, the metabolism of conivaptan occurs primarily at CYP 3A4 to produce 4 main metabolites: the product of hydroxylation to the imidazo-methyl-group (Ml), the product of hydroxylation to the 4-methylene position of the benzazepine ring (M2), the product resulting from hydroxylation at both aforementioned sites (M4), and the product of oxidative de-amination resulting in the benzazepine-cleaved carboxylic acid (M7). Relative to parent, Ml has similar binding affinity at Vi₃ and V₂ receptors, M2 and M4 have 5 to 38% less affinity and M7 has no affinity. The combined exposure of the metabolites is only 7% that of conivaptan and thus their contribution to overall clinical effect is minimal. The metabolites are believed, however, to play a major role in the potent inhibition of CYP 3 A4 observed in patients dosed with conivaptan. Studies involving pre- incubation of human microsomes with conivaptan showed greater inhibition of 3A4 than without pre-incubation; also inhibition occurred only under conditions where the parent could undergo biotransformation leading to the conclusion that the parent is not a direct 3A4 inhibitor. Due to this potent CYP 3A4 inhibition, the co-administration of conivaptan with other potent CYP 3A4 inhibitors is contraindicated and concomitant use of conivaptan with drugs that are primarily metabolized by CYP 3A4 are to be closely monitored or avoided. (See FDA label and Summary Basis of Approval for vaprisol at http://www.fda.gov/cder) {last visited 02/21/08). [5] The most common adverse reactions reported with conivaptan administration include but are not limited to, infusion site reactions (occurring in 73% and 63% of subjects treated with conivaptan 20 mg/day and 40 mg/day, respectively), diarrhea, vomiting, peripheral edema, pyrexia, hypokalemia, hyponatremia, headache, hypertension, and orthostatic hypotension. (See FDA label for vaprisol at http : //www. fda. go v/cder) .

[6] Despite the beneficial activities of conivaptan, there is a continuing need for new compounds to treat the aforementioned diseases and conditions.

SUMMARY OF THE INVENTION

[7] This invention relates to novel compounds that are benzazepines derivatives and pharmaceutically acceptable salts thereof. More specifically, this invention relates to novel benzazepines derivatives that are derivatives of conivaptan. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering a dual antagonist of the arginine vasopressin (AVP) Vj _A and the V₂ receptors, such a conivaptan.

DETAILED DESCRIPTION OF THE INVENTION

[8] The terms "ameliorate" and "treat" are used interchangeably and include both therapeutic treatment and prophylactic treatment (reducing the likelihood of development). Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.

[9] "Disease" means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.

[10] It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of conivaptan will inherently contain small amounts of deuterated and/or ^l3C-containing isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention. See, for instance, Wada E et al., Seikagaku 1994, 66:15; Ganes LZ et al.,

Comp Biochem Physiol MoI Integr Physiol 1998, 119:725.

[11] In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated specifically as "D" or "deuterium", the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium).

[12] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[13] In other embodiments, a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3

(99.5% deuterium incorporation).

[14] The term "isotopologue" refers to a species that differs from a specific compound of this invention only in the isotopic composition thereof.

[15] The term "compound," when referring to a compound of this invention, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound. [16] The invention also provides salts, solvates or hydrates of the compounds of the invention.

[17] A salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt. [18] The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient. [19] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para- toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid. [20] As used herein, the term "hydrate" means a compound which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[21] As used herein, the term "solvate" means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.

[22] The compounds of the present invention (e.g., compounds of Formula I), may contain an asymmetric carbon atom, for example, as the result of deuterium substitution or otherwise. As such, compounds of this invention can exist as either individual enantiomers, or mixtures of the two enantiomers. Accordingly, a compound of the present invention will include both racemic mixtures, and also individual respective stereoisomers that are substantially free from another possible stereoisomer. The term "substantially free of other stereoisomers" as used herein means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers, or less than "X"% of other stereoisomers (wherein X is a number between 0 and 100, inclusive) are present. Methods of obtaining or synthesizing an individual enantiomer for a given compound are well known in the art and may be applied as practicable to final compounds or to starting material or intermediates. [23] The term "stable compounds," as used herein, refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein

(e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).

[24] "D" refers to deuterium.

[25] "Stereoisomer" refers to both enantiomers and diastereomers.

[26] "Tert", " * ", and "t-" each refer to tertiary.

[27] "US" refers to the United States of America.

[28] "FDA" refers to Food and Drug Administration.

[29] "NDA" refers to New Drug Application.

[30] Throughout this specification, a variable may be referred to generally (e.g., "each

R") or may be referred to specifically (e.g., R ₅ R ₅ R , etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable.

THERAPEUTIC COMPOUNDS

[31] The present invention provides a compound of Formula I:

or a salt thereof, wherein: each Z is independently hydrogen or deuterium; R¹ is CD₃, CD₂H, CDH₂, or CH₃; and when R¹ is CH₃, at least one Z is deuterium.

[32] In another embodiment of a compound of formula I, Z^{I a} and Z^lb are the same; and Z^2a and Z^2b are the same.

[33] In another embodiment of a compound of formula I, Z^la and Z^lb are deuterium; and Z^2a and Z^2b are hydrogen.

[34] In another embodiment of a compound of formula I, Z^la and Z^lb are hydrogen; and

Z^2a and Z^2b are deuterium.

[35] In another embodiment of a compound of formula I, Z^la and Z^Ib are deuterium; and

₇2a and Z^2b are deuterium.

[36] In yet another embodiment, the compound is selected from any one of the compounds (Cmpd) set forth in Table 1 (below):

Table 1 : Exemplary Embodiments of Formula I

[37] In another set of embodiments, any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance. [38] The synthesis of compounds of Formula I can be readily achieved by synthetic chemists of ordinary skill. Relevant procedures and intermediates are disclosed, for instance in: JP 1996198879

JP 2002087962(A)

Boeglin, D. et al. J. Comb. Chem. 2007, 9, 3, 487-500

Tsunoda, Takashi; Tanaka, Akihiro; Mase, Toshiyasu; Sakamoto, Shuichi. Heterocycles (2004), 63(5), 1113-1 122.

Tsunoda, Takashi; Yamazaki, Atsuki; Iwamoto, Hidenori; Sakamoto, Shuichi. Organic Process Research & Development (2003), 7(6), 883-887.

Tsunoda, T.; Yamazaki, A.; Mase, T.; Sakamoto, S. Org Process Res Dev 2005, 9(5): 593

Norman, P.; Leeson, P. A.; Rabasseda, X.; Castaner, J.; Castaner, R.M. Drugs Fut 2000, 25(11): 1121

Matsuhisa, A.; Taniguchi, N.; Koshio, H.; Yatsu, T.; Tanaka, A. Chem Pharm Bull 2000, 48(1): 21

[39] Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.

EXEMPLARY SYNTHESIS

[40] A convenient method for synthesizing compounds of Formula I is depicted in

Scheme 1.

Scheme 1 : General Route to Compounds of Formula I.

Formula I

(39} As depicted in Scheme 1 , a general route to preparing compounds of Formula I commences with carboxylic acid I. Following the general procedures of Tsunoda, T.; et al. Org Process Res Dev 2005, 9(5): 593, known carboxylic acid I is treated first with thionyl chloride in acetonitrile, then with deuterated amine IX to afford compounds of Formula I.

[40] A convenient method for synthesizing Intermediate Amine IX is depicted in Scheme 2.

Scheme 2: Preparation of amine IX.

V Vt

[41] As depicted in Scheme 2, deuterated amine IX can be prepared following the general procedures of Boegiin, D. et al. J. Comb. Chem. 2007, 9, 3, 487-500. Commercially-available methylanthranilate II is tosylated with TsCl and pyridine to afford ester III. Ester III is treated with NaH and deuterated halo-ester IV in DMF, followed by treatment with NaH in MeOH and toluene, followed by microwave heating in the presence of HCl, AcOH and aqueous EtOH to afford ketone V. Following the methods of Tsunoda, T.; Yamazaki, A.; Mase, T.; Sakamoto, S. Org Process Res Dev 2005, 9(5): 593, bromination of ketone V is achieved via treatment with pyridinium hydrobromide perbromide in chloroform to yield bromoketone VI. Cyclization with deuterated amidine VII in the presence of potassium carbonate in toluene yields tricycle VIII. Deprotection of the nitrogen with H₂SO₄ affords amine IX.

NH

[42] Referring again to Scheme 2, the known ethanimidamide-2,2,2-d3, ^D3^C X ^NH2 , [Liu, M. T. H.; et al. Journal of Organic Chemistry (1980), 45(22), 4515.] may be used as amidine VII to ultimately provide compounds of Formula I wherein R¹ is CD₃. [43] Referring again to Scheme 2, other desired deuterated amidines VII (R¹ is CD₂H or CDH₂) may be prepared from deuterated acetonitrile following the methods of Liu, M. T. H.; et al. Journal of Organic Chemistry (1980), 45(22), 4515. The deuterated acetonitrile reagents may be prepared as described in Anthoni, U.; et al. Journal of Labelled Compounds and Radiopharmaceuticals (1984), 21(4), 375-80. [44] Referring again to Scheme 2, the known Br(CD₂)₃CO₂Me [T. Tanaka, et al. Journal of Labeled Compounds and Radiopharmaceuticals, 29(6), 667-80; 1991] may be used as halo-ester IV to ultimately provide compounds of Formula I wherein all Z are deuterium.

[45] Alternatively, Br(CD₂)₃CO₂Et may be synthesized from commercially-available Br(CD₂)₃CO₂H and iodoethane according to the methods of T. Tanaka, et al. Journal of Labeled Compounds and Radiopharmaceuticals, 29(6), 667-80; 1991 and used as halo- ester IV to ultimately provide compounds of Formula I wherein all Z are deuterium. [46] Referring again to Scheme 2, the known 4-chloro-butyric-4,4-d2 acid, ethyl ester, D D

Cl CO₂Et₅ [_Harj Harold; et al. Journal of the American Chemical Society (1963),

85(20), 3269-73 or Paquett, Leo A. Journal of the American Chemical Society (1963), 85(20), 3288-92.] may be used as halo-ester IV to ultimately provide compounds of Formula I wherein Z¹ are deuterium and Z² are hydrogen. [47] Referring again to Scheme 2, the known 4-chloro-butanoic-2,2,3,3-d4 acid,

methyl ester,

_} [Ohya, Kazumi; Sano, Mitsuji. Biomedical Mass

Spectrometry (1977), 4(4), 241-7.] may be used as halo-ester IV to ultimately provide compounds of Formula I wherein Z¹ are hydrogen and Z² are deuterium. [48] The specific approaches and compounds shown above are not intended to be limiting. The chemical structures in the schemes herein depict variables that are hereby defined commensurately with chemical group definitions (moieties, atoms, etc.) of the corresponding position in the compound formulae herein, whether identified by the same variable name (i.e., R¹, R², R³, etc.) or not. The suitability of a chemical group in a compound structure for use in the synthesis of another compound is within the knowledge of one of ordinary skill in the art.

[49] Additional methods of synthesizing compounds of Formula I and their synthetic precursors, including those within routes not explicitly shown in schemes herein, are within the means of chemists of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the applicable compounds are known in the art and include, for example, those described in Larock R, Comprehensive Organic Transformations, VCH Publishers (1989); Greene TW et al., Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley and Sons (1999); Fieser L et al., Fieser andFieser 's Reagents for Organic Synthesis, John Wiley and Sons (1994); and Paquette L, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. [50] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.

COMPOSITIONS

[50] The invention also provides pyrogen-free compositions comprising an effective amount of a compound of Formula I (e.g., including any of the formulae herein), or a pharmaceutically acceptable salt of said compound; and an acceptable carrier. Preferably, a composition of this invention is formulated for pharmaceutical use ("a pharmaceutical composition"), wherein the carrier is a pharmaceutically acceptable carrier. The carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the • formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

[51] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[52] If required, the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be enhanced by methods well-known in the art. One method includes the use of lipid excipients in the formulation. See "Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences)," David J. Hauss, ed. Informa Healthcare, 2007; and "Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples," Kishor M. Wasan, ed. Wiley-Interscience, 2006. [53] Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States patent 7,014,866; and United States patent publications 20060094744 and 20060079502.

[54] The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques). Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985). [55] Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product. [56] In certain embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a nonaqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. [57] In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

[58] Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[59] Compositions suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit- dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. [60] Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed . including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long- chain alcohol diluent or dispersant.

[61] The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[62] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g.: Rabinowitz JD and Zaffaroni AC, US Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.

[63] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.

[64] Application of the subject therapeutics may be local, so as to be administered at the site of interest. Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.

[65] Thus, according to yet another embodiment, the compounds of this invention may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein. [66] According to another embodiment, the invention provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal. [67] According to another embodiment, the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention. Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.

[68] According to another embodiment, the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active.

[69] According to another embodiment, the invention provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this invention, such that said compound is released from said device and is therapeutically active.

[70] Where an organ or tissue is accessible because of removal from the patient, such organ or tissue may be bathed in a medium containing a composition of this invention, a composition of this invention may be painted onto the organ, or a composition of this invention may be applied in any other convenient way.

[71] In another embodiment, a composition of this invention further comprises a second therapeutic agent. The second therapeutic agent may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as conivaptan. Such agents include those indicated as being useful in combination with conivaptan, including but not limited to, those described in WO 1999065525, WO

2001054677, WO 2004108138, and WO 2005039565.

[72] Preferably, the second therapeutic agent is an agent useful in the treatment or prevention of a disease or condition selected from diseases impacted by arginine vasopressin such as heart failure, hyponatremia, syndrome of inappropriate vasopressin secretion (SIADH), hypertension, pulmonary hypertension, renal diseases (nephrosis, nephritis, diabetic nephropathy, chronic or acute renal failure), edema, brain edema, ascites, hepatic cirrhosis, hypokalemia, water metabolism disorder, diabetes, various ischemic diseases, cerebrovascular disease, cyclothymic failure, gastric ulcer, nausea, vomiting, syncope, renal function disorder and the like, sequelae of cerebral infarction, intracerebral bleeding and the like, dysmenorrhea!, vision disorders based on ocular circulatory disorders such as intraocular hypertension and glaucoma, and vision disorders based on ciliary tension such as shortsightedness.

[73] In another embodiment, the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described second therapeutic agents, wherein the compound and second therapeutic agent are associated with one another. The term "associated with one another" as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).

[74] In the pharmaceutical compositions of the invention, the compound of the present invention is present in an effective amount. As used herein, the term "effective amount" refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat (therapeutically or prophylactically) the target disorder. For example, and effective amount is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.

[75] The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in Freireich et al., (1966) Cancer Chemother. Rep 50: 219. Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N. Y., 1970, 537.

[76] In one embodiment, an effective amount of a compound of this invention can range from about 0.1 mg to about 600 mg per treatment. In more specific embodiments the range is from about 1 mg to 300 mg, or from about 2 mg to 120 mg, or most specifically from about 10 mg to about 60 mg per treatment. Treatment typically is administered as a continuous infusion for 1-4 days in the case of the IV formulation of conivaptan, or is administered twice daily in the case of the oral formulation of conivaptan. Duration of treatment is not to exceed 4 days.

[77] Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the patient, excipient usage, the possibility of co- usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information for conivaptan. [78] For pharmaceutical compositions that comprise a second therapeutic agent, an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent. Preferably, an effective amount is between about 70% and 100% of the normal monotherapeutic dose. The normal monotherapeutic dosages of these second therapeutic agents are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are incorporated herein by reference in their entirety. [79] It is expected that some of the second therapeutic agents referenced above will act synergistically with the compounds of this invention. When this occurs, it will allow the effective dosage of the second therapeutic agent and/or the compound of this invention to be reduced from that required in a monotherapy. This has the advantage of minimizing toxic side effects of either the second therapeutic agent of a compound of this invention, synergistic improvements in efficacy, improved ease of administration or use and/or reduced overall expense of compound preparation or formulation.

METHODS OF TREATMENT

[80] In another embodiment, the invention provides a method of inhibiting the activity of arginine vasopressin (AVP) through binding at its V_{I A} and V₂ receptors in a cell, comprising contacting a cell with one or more compounds of Formula I herein. [81] According to another embodiment, the invention provides a method of treating a disease that is beneficially treated by conivaptan in a patient in need thereof comprising the step of administering to said patient an effective amount of a compound or a composition of this invention. Such diseases are well known in the art and are disclosed in, but not limited to the following patents and published applications: WO 1995003305, WO 1999038533, US 2002128259, and WO 2005039565. Such diseases include, but are not limited to, heart failure, hyponatremia, syndrome of inappropriate vasopressin secretion (SIADH), hypertension, pulmonary hypertension, renal diseases (nephrosis, nephritis, diabetic nephropathy, chronic or acute renal failure), edema, brain edema, ascites, hepatic cirrhosis, hypokalemia, water metabolism disorder, diabetes, various ischemic diseases, cerebrovascular disease, cyclothymic failure, gastric ulcer, nausea, vomiting, syncope, renal function disorder and the like, sequelae of cerebral infarction, intracerebral bleeding and the like, dysmenorrhea, vision disorders based on ocular circulatory disorders such as intraocular hypertension and glaucoma, and vision disorders based on ciliary tension such as shortsightedness.

[82] In one particular embodiment, the method of this invention is used to treat a disease or condition selected from euvolemic and hypervolemic hyponatremia. [83] Methods delineated herein also include those wherein the patient is identified as in need of a particular stated treatment. Identifying a patient in need of such treatment can be in the judgment of a patient or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method). [84] In another embodiment, any of the above methods of treatment comprises the further step of co-administering to said patient one or more second therapeutic agents. The choice of second therapeutic agent may be made from any second therapeutic agent known to be useful for co-administration with conivaptan. The choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of second therapeutic agents that may be employed in the methods of this invention are those set forth above for use in combination compositions comprising a compound of this invention and a second therapeutic agent.

[85] The term "co-administered" as used herein means that the second therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the second therapeutic agent(s) are administered by conventional methods. The administration of a composition of this invention, comprising both a compound of the invention and a second therapeutic agent, to a patient does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said patient at another time during a course of treatment.

[86] Effective amounts of these second therapeutic agents are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein, as well as in Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, it is well within the skilled artisan's purview to determine the second therapeutic agent's optimal effective-amount range.

[87] In one embodiment of the invention, where a second therapeutic agent is administered to a subject, the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.

[88] In yet another aspect, the invention provides the use of a compound of Formula I alone or together with one or more of the above-described second therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment or prevention in a patient of a disease, disorder or symptom set forth above. Another aspect of the invention is a compound of Formula I for use in the treatment or prevention in a patient of a disease, disorder or symptom thereof delineated herein.

PHARMACEUTICAL KITS

[89] The present invention also provides kits for use to treat euvolemic and hypervolemic hyponatremia. These kits comprise (a) a pharmaceutical composition comprising a compound of Formula I or a salt thereof, wherein said pharmaceutical composition is in a container; and (b) instructions describing a method of using the pharmaceutical composition to treat euvolemic and hypervolemic hyponatremia. [90] The container may be any vessel or other sealed or sealable apparatus that can hold said pharmaceutical composition. Examples include bottles, ampules, divided or multi -chambered holders bottles, wherein each division or chamber comprises a single dose of said composition, a divided foil packet wherein each division comprises a single dose of said composition, or a dispenser that dispenses single doses of said composition. The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle, which is in turn contained within a box. In one embodiment, the container is a blister pack.

[91] The kits of this invention may also comprise a device to administer or to measure out a unit dose of the pharmaceutical composition. Such device may include an inhaler if said composition is an inhalable composition; a syringe and needle if said composition is an injectable composition; a syringe, spoon, pump, or a vessel with or without volume markings if said composition is an oral liquid composition; or any other measuring or delivery device appropriate to the dosage formulation of the composition present in the kit.

[92] In certain embodiment, the kits of this invention may comprise in a separate vessel of container a pharmaceutical composition comprising a second therapeutic agent, such as one of those listed above for use for co-administration with a compound of this invention. EVALUATION OF METABOLIC STABILITY

[93] Certain in vitro liver metabolism studies have been described previously in the following references, each of which is incorporated herein in their entirety: Obach, RS, Drug Metab Disp, 1999, 27:1350; Houston, JB et al., Drug Metab Rev, 1997, 29:891; Houston, JB, Biochem Pharmacol, 1994, 47:1469; Iwatsubo, T et al., Pharmacol Ther, 1997, 73: 147; and Lave, T, et al., Pharm Res, 1997, 14:152.

[94] Microsomal Assay: Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, KS). β -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl₂), and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich. The incubation mixtures are prepared according to Table 2: Table 2. Reaction Mixture Composition for Human Liver Microsome Study

[95] Determination of Metabolic Stability: Two aliquots of this reaction mixture are used for a compound of this invention. The aliquots are incubated in a shaking water bath at 37⁰C for 3 minutes. The test compound is then added into each aliquot at a final concentration of 0.5 μM. The reaction is initiated by the addition of cofactor (NADPH) into one aliquot (the other aliquot lacking NADPH serves as the negative control). Both aliquots are then incubated in a shaking water bath at 37°C. Fifty microliters (50 μL) of the incubation mixtures are withdrawn in triplicate from each aliquot at 0, 5, 10, 20, and 30 minutes and combined with 50 μL of ice-cold acetonitrile to terminate the reaction. The same procedure is followed for Compound 1 and the positive control,. Testing is done in triplicate.

[96] Data analysis: The in vitro half-lives (t^s) for test compounds are calculated from the slopes of the linear regression of % parent remaining (In) vs incubation time relationship. in vitro t ._/2= 0.693/k k = -[slope of linear regression of % parent remaining(ln) vs incubation time]

Data analysis is performed using Microsoft Excel Software.

[97] The metabolic stability of compounds of Formula I is tested using pooled liver microsomal incubations. Full scan LC-MS analysis is then performed to detect major metabolites. Samples of the test compounds, exposed to pooled human liver microsomes, are analyzed using HPLC-MS (or MS/MS) detection. For determining metabolic stability, multiple reaction monitoring (MRM) is used to measure the disappearance of the test compounds. For metabolite detection, Ql full scans are used as survey scans to detect the major metabolites.

[98] SUPERSOMES™ Assay. Various human cytochrome P450-specific SUPERSOMES™ are purchased from Gentest (Woburn, MA, USA). A l.O raL reaction mixture containing 25 pmole of SUPERSOMES™, 2.OmM NADPH, 3.OmM MgCl, and l μM of a compound of Formula I in 10OmM potassium phosphate buffer (pH 7.4) is incubated at 37 ⁰C in triplicate. Positive controls contain 1 μM of dimebolin instead of a compound of formula I. Negative controls used Control Insect Cell Cytosol (insect cell microsomes that lacked any human metabolic enzyme) purchased from GenTest (Woburn, MA, USA). Aliquots (50 μL) are removed from each sample and placed in wells of a multi-well plate at various time points (e.g., 0, 2, 5, 7, 12, 20, and 30 minutes) and to each aliquot is added 50μL of ice cold acetonitrile with 3μM haloperidol as an internal standard to stop the reaction.

[99] Plates containing the removed aliquots are placed in -20 ⁰C freezer for 15 minutes to cool. After cooling, 100 μL of deionized water is added to all wells in the plate. Plates are then spun in the centrifuge for 10 minutes at 3000 rpm. A portion of the supernatant (100 μL) is then removed, placed in a new plate and analyzed using Mass Spectrometry. [100] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples merely present a detailed description of certain preferred embodiments. It will be apparent to those of ordinary skill in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention. All the patents, journal articles and other documents discussed or cited above are herein incorporated by reference.

Claims

CLAIMSWhat is claimed is:

1. A compound of formula I:

or a salt thereof, wherein: each Z is independently hydrogen or deuterium; R¹ is CD₃, CD₂H, CDH₂, or CH₃; and when R¹ is CH₃, at least one Z is deuterium.

2. The compound of claim 1 , wherein: Z^{l a} and Z^lb are the same; and

Z^2a and Z^2b are the same.

3. The compound of claim 1, wherein: Z^{l a} and Z^lb are deuterium; and

Z^2a and Z^2b are hydrogen.

4. The compound of claim 1, wherein: Z^la and Z^Ib are hydrogen; and

Z ₇2a and Z ,2b are deuterium.

5. The compound of claim 1, wherein: Z^la and Z^Ib are deuterium; and Z^2a and Z^2b are deuterium.

6. The compound of claim 1 which is a compound depicted in the following table:

or a salt thereof.

7. A composition comprising a compound of claim 1 or a pharmaceutically acceptable salt of said compound; and an acceptable carrier.

8. A method of inhibiting the activity of arginine vasopressin (AVP) through binding at its V_1A and V₂ receptors in a cell, comprising contacting a cell with a compound of claim 1.

9. A method of treating a disease or conditions selected from heart failure, hyponatremia, syndrome of inappropriate vasopressin secretion (SIADH), hypertension, pulmonary hypertension, renal diseases, edema, brain edema, ascites, hepatic cirrhosis, hypokalemia, water metabolism disorder, diabetes, ischemic disease, cerebrovascular disease, cyclothymic failure, gastric ulcer, nausea, vomiting, syncope, renal function disorder, sequelae of cerebral infarction, intracerebral bleeding, dysmenorrhea!, vision disorders based on ocular circulatory disorders, and vision disorders based on ciliary tension, in a patient in need thereof comprising administering to said patient an effective amount of a compound of claim 1 or a composition of claim 7.

10. The method of claim 9, wherein the disease or conditions is euvolemic and hypervolemic hyponatremia.

1 1. A kit for use to treat euvolemic and hypervolemic hyponatremia, comprising:

(a) a pharmaceutical composition comprising a compound of claim 1; and

(b) instructions describing a method of using the pharmaceutical composition to treat euvolemic and hypervolemic hyponatremia.