NONPEPTIDE SUBSTITUTED BENZOTHIAZEPINES AS VASOPRESSIN ANTAGONISTS

Abstract: The invention is directed to nonpeptide substituted benzodiazepines of Formula (I), wherein A, X, Z, Bp, W, n, R<1> and R<2> are as described in the specification, which are useful as vasopressin receptor antagonists for treating conditions involving increased vascular resistance and cardiac insufficiency. Pharmaceutical compositions comprising a compound of Formula (I) and methods of treating conditions such as hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, or water retention are also disclosed.

Description: NONPEPTIDE SUBSTITUTED BENZOTHIAZEPINES AS VASOPRESSIN ANTAGONISTS Cross Reference to Related Applications This application claims priority from U.S. Serial No, 60/163,544, filed November 4, 1999. Field of the Invention This invention relates to novel nonpeptide substituted vasopressm receptor antagonists. More particularly, the compounds of the present invention interrupt the binding of the peptide hormone vasopressm to its receptors and are therefore useful for treating conditions involving increased vascular resistance and cardiac insufficiency. Background of the Invention Vasopressm is a nonapeptide hormone that is secreted primarily from the posterior pituitary gland. The hormone effects its actions through the vascular V-1 and renal V-2 receptor subtypes. The functions of vasopressm include contraction of uterine, bladder, and smooth muscle; stimulation of glycogen breakdown m the liver; release of corticotropm from the anterior pituitary; induction of platelet aggregation; and central nervous system modulation of behaviors and stress responses. The V-1 receptor mediates the contraction of smooth muscle, and hepatic glycogenolytic and central nervous system effects of vasopressm. The V-2 receptor, presumably found only m the kidney, effects the antidiuretic actions of vasopressm via stimulation of adenylate cyclase. Elevated plasma vasopressm levels appear to play a role m the pathogenesis of congestive heart failure (P. A. Van Zwieten, Progr. Pharmacol . Clm . Pharmacol . 1990, 7, 49) . As progress toward the treatment of congestive heart failure, nonpeptide vasopressm V-2 receptor antagonists have induced low osmolality aquaresis and decreased peripheral resistance conscious dogs with congestive heart failure (H. Ogawa, J. Med. Chem. 1996, 39, 3547) . In certain pathological states, plasma vasopressm levels may be inappropriately elevated for a given osmolality, thereby resulting m renal water retention and hyponatremia. Hyponatremia, associated with edematous conditions (cirrhosis, congestive heart failure, renal failure) , can be accompanied by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) . Treatment of SIADH- compromised rats with a vasopressm V-2 antagonist has corrected their existing hyponatremia (G. Fujisawa, Kidney Int . 1993, 44 ( 1 ) , 19). Due m part to the contractile actions of vasopressm at its V-1 receptor m the vasculature, vasopressm V-1 antagonists have reduced blood pressure as a potential treatment for hypertension as well. Thus, vasopressm receptor antagonists could be useful as therapeutics m the conditions of hypertension, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, and water retention. SUMMARY OF THE INVENTION The present invention is directed to compounds represented by the following Formula I: wherem R 1 is selected from -COOH, formyl, o-mesylate, -S0OH, alkoxysulfonyl, alkylcarboxy, substituted alkylcarboxy, aralcarboxy, substituted aralcarboxy, - NR 4 R 5 , -OH, cyano, N-morpholmo, alkoxy, aralkoxy, alkylcarbamoyl, substituted alkylcarbamoyl, alkoxycarbonyl, substituted alkoxycarbonyl, -NHCOR 6 and -CONR 7 R 8 , wherein R 4 , R r , R U , R 7 , and R P are independently selected from the group consisting of H, alkyl, and aryl; A is S, SO or S0 2 ; X is CH 2 or carbonyl; Z is CH 2 , S0 2 or carbonyl, with the proviso that X is B is (CH 2 )m, NH or 0; W is aryl, substituted aryl, heteroaryl or substituted heteroaryl ; R 2 is -N(H)YR ' ' or -YN(H)R 3 wherem Y is H or carbonyl; R 3 is H, alkyl, substituted alkyl, aryl or substituted aryl; n is 1-5 ; and The compounds of the present invention are vasopressm receptor antagonists useful as aquaretics and, m general, m disease states of vascular resistance. Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. Illustrating the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier. An example of the invention is a method of treating congestive heart failure m a subject m need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. Another example of the invention is a method of inhibiting the onset of a condition of vascular resistance m the subject, which comprises administering to the subject a prophylactically effective dose of the pharmaceutical composition of a compound of Formula I . Further exemplifying the invention is the method of treating congestive heart failure, wherem the therapeutically effective amount of the compound is about 1 to about 30 mg/kg/day. Still further exemplifying the invention is the method of inhibiting the onset of congestive heart failure, wherein the prophylactically effective amount of the compound is about 1 to about 30 mg/kg/day. An additional illustration of the invention is a method of treating a condition selected from hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, or water retention m a subject m need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. Preferably, the therapeutically effective amount of the compound administered for treating any of these conditions is about 1 to about 30 mg/kg/day. Also included m the invention is the use of any of the compounds described above for the preparation of a medicament for treating a condition selected from inner ear disorders, hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, or water retention m a subject m need thereof. Detailed Description of the Invention The present invention provides nonpeptide substituted benzothiazepine compounds which are useful as antagonists of vasopressin. More particularly, the compounds of Formula I inhibit the binding of vasopressin to V-1 and V- 2 receptors, and are therefore useful in treating conditions with increased vascular resistance. Examples of conditions with increased vascular resistance include, but are not limited to, congestive heart failure, edema, water retaining states, and the like. More particularly, the present invention is directed to compounds of Formula I: wherein R 1 is selected from -COOH, formyl, o-mesylate, -S00H, alkoxysulfonyl, alkylcarboxy, substituted alkylcarboxy, aralcarboxy, substituted aralcarboxy, - NR M R 5 , -OH, cyano, N-morpholino, alkoxy, aralkoxy, alkylcarbamoyl, substituted alkylcarbamoyl, alkoxycarbonyl, substituted alkoxycarbonyl, -NHCOR° and -CONR 7 R 8 , wherein R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of H, alkyl, and aryl; A is S, SO or S0 2 ; X is CH 2 or carbonyl; Z is CH 2 , S0 2 or carbonyl, with the proviso that X is not CH 2 when Z is CH 2 ; B is (CH 2 ) m , NH or 0; W is aryl, substituted aryl, heteroaryl or substituted heteroaryl; R 2 is -N(H)YR 3 or -YN(H)R 3 wherein Y is H or carbonyl; R 3 is H, alkyl, substituted alkyl, aryl or substituted aryl; m is 1-3 ; n is 1-5; and p is 0 or 1. The nonpeptide substituted benzodiazepine compounds of the present invention are vasopressin receptor antagonists, in a preferred embodiment, the compounds are orally active. As demonstrated by the results of the pharmacological studies described hereinafter, the compounds show the ability to block vasopressin binding to recombinant V-1 and V-2, and therefore are useful as therapeutics in or prophylactics against the conditions of hypertension, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, and water retention. In particular, compounds of Formula I, wherein R 1 is - COOH, formyl, o-mesylate, -S0 2 OH, alkylcarboxy, substituted alkylcarboxy, aralcarboxy, substituted aralcarboxy, cyano, N-morpholmo, alkoxy, aralkoxy, alkylcarbamoyl, or substituted alkylcarbamoyl, are embodiments of the present invention. More particularly, compounds of Formula I wherem A is S, p is 0, and n is 1 or 2 are embodiments of this invention. Compounds of Formula I wherem X is CH 2 and Z is carbonyl, are also particular embodiments of this invention . Compounds of Formula I wherem is phenyl, substituted phenyl, benzyl, substituted benzyl, pyridmyl, substituted pyridmyl, naphthyl or substituted naphthyl, are still particular embodiments of this invention. Compounds of Formula I, wherem R 2 is -N(H)YR 3 m which Y is carbonyl and R 3 is substituted phenyl, are further particular embodiments of the present invention. In particular, compounds of Formula I wherem R" is -NHCO(2- Ph) Ph are yet other embodiments of the present invention. Compounds of Formula I, wherem R J is phenyl or substituted phenyl, are still other embodiments of the present invention. In addition, compounds of Formula I, wherem R is amme, substituted amme, -NHCOR D or -CONR 7 R 8 wherem R n , R and R 8 are as described hereinabove, are particular embodiments of the present invention. More particularly, compounds of Formula I wherein R 1 is selected from -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHBOC, - N(BOC) 2 , -NHCOC(CH 3 ) 2 NH 2 , -N (COC (CH 3 ) 2 NH 2 ) 2 and - NCH 2 (2, 5-OCH 3 ) Ph; W is Ph or substituted Ph; R 2 is -NH 2 , -NHAc, -NHCO (2-CH 3 ) Ph or -NHCO (2-Ph) Ph; and p is 0 are also particular embodiments of the present invention . Compounds of Formula I wherein R 1 is -OH are particular embodiments of the present invention, too. More particularly, compounds of Formula I wherein R 1 is -OH; W is heteroaryl, Ph or substituted Ph; R 2 is -NH 2 , -NHAc, -NHCOCH^, -NHCO (2-CH 3 ) Ph, -NHCO (2- Ph)Ph, -NHCO(2-CH 3 , 5-F) Ph, or -NHCO ( 3, 4-C1 ) Ph; and p is 0 are also particular embodiments of the present invention. Compounds of Formula I wherein R 1 is alkoxycarbonyl, substituted alkoxycarbonyl, or -CONR'R 8 wherein R ^ and R 8 are as described hereinabove, are particular embodiments of the present invention as well. More particularly, compounds of Formula I wherein R 1 is alkoxycarbonyl, substituted alkoxycarbonyl, or - CONR 7 R 8 wherein R 7 and R 8 are as described hereinabove; Z is carbonyl; W is Ph or substituted Ph; R 2 is -NHCO(2-Ph)Ph; and p is 0 are also particular embodiments of the present invention. The following compounds are further particular embodiments of the present invention: Compound 24: 2-Carboxymethyl-l-oxo-5- ( 4- (2- phenylbenzoylamino) benzoyl) -1 , 5-benzothiazepme Compound 29: 2-Carboxymethyl-5- (4- (2- phenylbenzolylamino) benzoyl) -1, 5-benzothiazepme 0 \ OH N- O' / / o " • '" ' ., y y Compound 31: 2- (2-Carboxyethyl ) -5- [ 4- (2- phenylbenzoylamino) benzoyl] -1 , 5-benzothiazepme Compound 33 and Compound 34: 2-Carboxymethyl-5- [4- (2- phenylbenzoylammo) benzoyl] -1, 5-benzothιazepme The compounds of the present invention may also be present m the form of a pharmaceutically acceptable salt or salts. For use m medicine, the salt or salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salt or salts." Other salts may, however, be useful m the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuπc, nitric, phosphoric, acetic, propionic, glycolic, lactic, succmic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic, 2-naphthalenesulfonιc, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid. Representative basic/cationic salts include, but are not limited to, benzathine, chloroprocaine, choline, diethanolamine, ethylenedia ine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc. Where the compounds according to this invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers . It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment . As used herein, "treating" a disorder means eliminating or otherwise ameliorating the cause and/or effects thereof. To "inhibit" or "inhibiting" the onset of a disorder means preventing, delaying or reducing the likelihood of such onset. Methods are known m the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition. The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response m a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. The term "prophylactically effective amount" refers to that amount of active compound or pharmaceutical agent that inhibits m a subject the onset of a disorder as being sought by a researcher, veterinarian, medical doctor or other clinician, the delaying of which disorder is mediated by the reduction of increased vascular resistance. Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Unless otherwise noted, "alkyl" and "alkoxy" as used herein, whether used alone or as part of a substituent group, include straight and branched chains having 1 to 8 carbon atoms, or any number withm this range. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n- pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl . Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. Cycloalkyl groups contain 3 to 8 ring carbons and preferably 5 to 7 ring carbons. The term "Ar" or "aryl" as used herein, whether used alone or as part of a substituent group, refers to an aromatic group such as phenyl and naphthyl. When the Ar or aryl group is substituted, it may have one to three substituents which are independently selected from Cι~C 8 alkyl, Cι-C 8 alkoxy, fluormated Cι-C 8 alkyl (e.g., trifluoromethyl) , fluormated Cι~C 8 alkoxy (e.g., trifluoromethoxy) , halogen, cyano, hydroxy, ammo, nitro, C1-C alkylammo (i.e., -NH-C1-C4 alkyl), C1-C4 dialkylammo (i.e., -N- [C1-C4 alkyl] 2 wherem the alkyl groups can be the same or different) , or unsubstituted, mono-, di- or tπ-substituted phenyl wherem the substituents on the phenyl are independently selected from Cι~C 8 alkyl, Cι-C 8 alkoxy, fluormated Cι-C 8 alkyl, fluormated C]-C 8 alkoxy, halogen, cyano, hydroxy, ammo, nitro, alkylammo, dialkylammo or heteroaryl. "Ph" or "PH" denotes phenyl. The term "heteroaryl" as used herein represents a stable five or six membered monocyclic aromatic ring system which consists of carbon atoms and from one to three heteroatoms selected from N, 0 or S . The heteroaryl group may be attached at any heteroatom or carbon atom which results m the creation of a stable structure. Examples of heteroaryl groups include, but are not limited to pyridmyl, pyrazmyl, pyπdazmyl, pyrimidmyl, thiophenyl, furanyl, lmidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, tπazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, indolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl or quinolinyl. Prefered heteroaryl groups include pyridinyl, thiophenyl, furanyl and quinolinyl. When the heteroaryl group is substituted, the heteroaryl group may have one to three substituents which are independently selected from Cι-C 8 alkyl, halogen, aryl, heteroaryl, alkoxy, alkylammo, dialkylammo, arylamino, nitro, and hydroxy. The term "aralkoxy" indicates an alkoxy group substituted with an aryl group (e.g., benzyloxy) . The term "acyl" as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group . The term "halogen" shall include iodine, bromine, chlorine and fluorine. The terms "substituted alkylcarboxy, " "substituted aralcarboxy" and "substituted alkylcarbamoyl" denote alkylcarboxy, aralcarboxy and alkylcarbamoyl substituted with radicals including, but not limited to, halogen, alkyl, alkoxy, amino, and the like. Whenever the term "alkyl", "acyl", or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aralkyl, dialkylammo) it shall be interpreted as including those limitations given above for "alkyl", "acyl", and "aryl." Designated numbers of carbon atoms (e.g., Ci-Cβ) shall refer independently to the number of carbon atoms m an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent m which alkyl appears as its prefix root. It is intended that the definition of any substituent or variable at a particular location m a molecule be independent of its definitions elsewhere m that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill m the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known m the art as well as those methods set forth herein. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients m the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients m the specified amounts. The utility of the compounds to treat disorders of increased vascular resistance can be determined according to the procedures described herein. The present invention therefore provides a method of treating vascular resistance disorders m a subject m need thereof which comprises administering any of the compounds as defined herein m a quantity effective to treat vascular resistance disorders. The compound may be administered to a patient by any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, mtradermal and parenteral. The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention m association with a pharmaceutically acceptable carrier . To prepare the pharmaceutical compositions of this invention, one or more compounds of Formula I or salt thereof of the invention as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions m oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease m administration, tablets and capsules represent the most advantageous oral dosage unit form, m which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, m which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 1 mg to 30 mg/kg and may be given at a dosage of from about 1 to 30 mg/kg/day (preferred 3 to 15 mg/kg/day) . The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed. Preferably these compositions are m unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, automjector devices or suppositories; for oral parenteral, mtranasal, sublmgual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented m a form suitable for once- weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. The liquid forms m which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alg ate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl- pyrrolidone or gelatin. Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared m racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a stereogenic HPLC column. During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. This invention will be better understood by reference to the schemes and examples that follow, but those skilled in the art will readily appreciate that these are only illustrative of the invention as described more fully in the claims which follow thereafter. Scheme 1 As set forth m Scheme 1, wherem R is -COOH, formyl , alkoxy, aralkoxy, or -0(CO)R 9 , R 9 is alkyl, substituted alkyl, aryl or substituted aryl, R 2' is nitro, -N(H)YR 3 or -YN(H)R 3 , and A, X, Z, Bp, W, Y, R 2 , R 3 , n are as described above, a base such as tπethylamme is added to a mixture of 2-ammothιophenol and a compound of Formula II, such as 5, 6-dιhydro-2H-pyran-2-one, all of which are either commercially available or may be readily prepared by known methods. The mixture can be dissolved m an appropriate non-polar solvent like methylene chloride and then heated m refluxmg xylene to obtain the corresponding compound of Formula III. The compound of Formula III can be alkylated under basic conditions (such as with potassium carbonate or NaH) to yield the corresponding compound of Formula IV, such as by treatment with an alkylatmg agent including but not limited to substituted benzyl bromide or chlorides refluxmg acetone, dimethylformamide (DMF) , or tetrahydrofuran (THF) . Alternatively, the compound of Formula III can be treated with an appropriate reducing agent such as diborane or lithium aluminum hydride m an appropriate solvent such as tetrahydrofuran, ether or 1,4-dιoxane to obtain the corresponding compound of Formula V. The compound of Formula V can be alkylated or acylated preferably at a temperature m the range of 0-60°C to form the corresponding compound of Formula VI, such as by adding either substituted benzyl, substituted benzene sulfonyl, or phenacyl halides to a solution of the corresponding compound of Formula V m tetrahydrofuran, ether or methylene chloride pretreated with N, 0- bis (trimethylsilyl) acetamide. Compounds of Formulae IV and VI wherem R 2' is nitro or acetamide can be converted to substituted anilines via standard procedures such as catalytic hydrogenation or acid treatment. The aniline can then be further substituted with a variety of substituted phenacyl halides m an appropriate solvent such as methylene chloride or THF and a base such as triethylamme once treated with N, O-bis (trimethylsilyl) acetamide to form the corresponding compounds of Formula la wherein R 2 is -N(H)YR 3 or -YN(H)R . The compounds of Formulae IV and VI can be alkylated, acylated, or oxidized to form compounds of Formula la. Alkylation or acylation at the hydroxyl position can be accomplished by the addition of an alkyl or acylhalide in the presence of a base such as sodium hydride, potassium hydride or triethylamine in an appropriate solvent such as THF, DMF or methylene chloride. Phenyl or substituted phenyl ethers can be formed by the addition of phenol or substituted phenols to compound of Formulae IV and VI using triphenylphosphine and diethyl azodicarboxylate in a solvent such as tetrahydrofuran. Oxidation can be executed by using oxidizing agents such as pyridinium chlorochromate, pyridinium dichromate or Jones reagent using known procedures for this transformation. To make compounds of Formula I wherein R 1 is o- mesylate, -S0 2 OH, alkoxysulfonyl, alkoxycarbonyl, substituted alkoxycarbonyl, -NR 4 R°, -OH, cyano, N- morpholino, -NHCOR 6 or -CONR 7 R 8 , the compounds of Formula III or V may be used as the starting material and can be further converted to the corresponding compounds of Formula I or VIII according to Scheme 2. vπ lb As set forth in Scheme 2, wherein E is -NR 7 R π °δ or -OR" R 10 is alkyl or substituted alkyl, and A, X, Z, Bp, W, R 2 , R 7 , R 8 , n are as described above, the intermediates (III and V) may be oxidized to form the corresponding compounds of Formula VII using oxidizing agents such as 3- chloroperoxybenzoic acid m an appropriate solvent such as methylene chloride. Alkylation or acylation on the ring nitrogen of Formula VII can be achieved preferably at a temperature m the range of 0-60°C to form the corresponding compound of Formula lb, such as by adding either substituted benzyl, or phenacyl halides to a solution of the corresponding compound of Formula VII m tetrahydrofuran, ether or methylene chloride pretreated with N, O-bis (trimethylsilyl) acetamide . The hydroxyl group the compound of Formula lb can be converted under basic conditions such as TEA to the mesylate m the compound of Formula lc. The mesylate can then be displaced with a variety of substituted amines or morpholme preferably at a temperature between 60 and 80°C m an appropriate solvent such as tetrahydrofuran or dimethylformamide to give compounds of the Formula Id. The mesylate can also be heated under similar conditions with ammonium hydroxide to afford compounds of the Formula Ih which can be further functionalized by treatment with substituted acylhalides and tπethylamme m non-polar solvents such as THF or methylene chloride to give the corresponding compounds of the Formula Ii. Alternatively, the mesylate of Formula lc can be treated with sodium cyanide m an appropriate solvent such as dimethylformamide to give the compound of Formula Ie. The compound of Formula Ie can be further hydrolyzed to form the compound of Formula If under basic conditions such as NaOH. 7Λn alternative way to extend the CH 2 chain connecting R 1 is reduction of the compound of Formula If with an appropriate reducing agent such as lithium aluminum hydride (LAH) to obtain the compound of Formula VIII, which can then be used m place of lb for making the compounds of Formulae Ic-Ik. Esters of Formula Ig can be prepared by treating the carboxylic acids of Formula If with an alkylhalide under basic conditions (such as with NaH or potassium carbonate) m dimethylforamide or tetrahydrofuran. The unsubstituted amides of Formula Ig can be prepared by treating the carboxylic acids of Formula If with di-tert-butyl dicarbonate, ammonium hydrogen carbonate and pyridme m a suitable solvent such as dioxane. Substituted amides of Formula Ig can be obtained by forming the acid chlorides of Ig using thionylchloride as the reagent. The acid chloride can then be reacted with substituted amines. Alternatively, the mesylate of Formula lc can also be converted to a bromide using a metal halide such as lithium, potassium, or sodium bromide m dry tetrahydrofuran, dimethylforamide or acetonitπle . This can then be converted to the sulfonic acid m the compound of Formula I by treating the bromide with sodium sulfite an appropriate solvent such as ethanol/water . The sulfonic acids can be converted to sulfonyl chlorides by treatment with thionyl chloride or phosphorous pentachloride followed by treatment with an alkanol using a base such as pyridme under known conditions to give the corresponding compounds of Formula Ik. The compounds of this invention exist m a racemic form as well as (-) and (+) enantiomers. The racemate can be resolved into the optical antipodes by known methods, such as chiral HPLC methods, conversion and separation of diastereomeric salts, or formation and separation of diastereomeric esters or carbamates. As exemplified m Scheme 3 below, wherem compounds of Formula II may be made according to Schemes 1 and/or 2 and (*) represents a stereogenic center, the diastereomeric carbamates of Formula Im can be formed by the addition of a chiral auxiliary such as (S) - (-) -1-phenylehtylιsocyanate to the starting substituted benzothiazepme of Formula II m refluxmg toluene. Once separated by column chromatography each pure diastereomer can be hydrolyzed under basic conditions (sodium ethoxide) to obtain each enantiomer of Formulae In and Ip m pure form. Scheme 3 ip The method of treating vascular resistance disorders described m the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 100 mg and 1000 mg, preferably about 100 to 500 mg, of the compound, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions. Advantageously, compounds of the present invention may be administered m a single daily dose, or the total daily dosage may be administered divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered mtranasal form via topical use of suitable mtranasal vehicles, or via transdermal skin patches well known to those of ordinary skill m that art. To be administered m the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. For instance, for oral administration m the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The liquid forms can be m suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired. The compound of the present invention can also be administered m the form of liposome delivery systems, such as small unilamellar vesicles, large unila ellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines . Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy- ethylaspartamidephenol, or polyethyl eneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders of vascular resistance is required. The daily dosage of the products may be varied over a wide range from 100 to 1000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing the active ingredient in the amount sufficient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 1 mg/kg to about 30 mg/kg of body weight per day. Preferably, the range is from about 3 to about 15 mg/kg of body weight per day, most preferably, from about 5 to about 10 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 2 times per day. Optimal dosages to be administered may be readily determined by those skilled m the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result m the need to adjust dosages. The following examples are intended to illustrate the invention but not to limit it. Example 1 2- (2-Hydroxyethyl) -benzothιazepιn-4-one 2-Ammothιophenol (51g, 410mmol) and 5,6- dιhydropyran-2-one (40g, 410mmol) were combined with triethylamme (1ml) m CH 2 C1 2 (500ml) causing an exothermic reaction that was allowed to cool to room temperature (RT) . The mixture was stirred at room temperature for two days. The reaction was washed with dilute NH 4 C1 then with brine and dried over Na 2 S0 4 . The volatiles were removed in vacuo . The resulting yellow oil (91 g) was diluted with xylene (500 ml) and stirred at reflux for 5 days, chilled and the resulting light brown crystals, collected by filtration. 52g, 61% . mp 173 - 175°C. 1 H NMR (300MHz, CDC1 3 ) 9.66 (broad s, 1H) , 7.60 - 6.85 (m, 4H) , 4.45 (t, 1H) , 3.77 (m, 1H) , 3.67 - 3.13 (m, 2H) , 2.63 - 2.00 (m, 2H) , 1.90 - 1.53 (m, 2H) ; IR (KBr) 3400, 2200, 1600 cm "1 ; MS: m/z (MH + )224 Example 2 2- (2-Hγdroxyethyl) -1 ,5-benzothiazepine A borane THF solution ( IM solution; 600ml) was slowly added to a cooled (0°C) solution of 2- (2-hydroxyethyl) - benzothiazepin-4-one as prepared in Example 1 (50g, 0.22M)in dry THF (500ml). The ice bath was removed and the mixture was stirred at reflux overnight then allowed to cool to room temperature. The mixture was cooled in an ice bath and quenched with IN NaOH. The THF was removed under reduced pressure and the aqueous mixture extracted with ethyl acetate (EtOAc) (2 x 300ml) . The combined EtOAc extracts were washed with brine, dried (MgS04), filtered and evaporated in vacuo to give a yellow oil. ^H NMR (300MHz, CDC13) δ7.36 (d, 1H) ; 7.046 (t, 1H) ; 6.766 (t, 1H) ; 6.725 (d, 1H) ; 4.413 (s, 1H) ; 3.915 - 3.773 (m, 2H) ; 3.646 - 3.57 ( m, 1H) ; 3.317 - 3.227 (m, 1H) ; 3.119 - 3.051 (m, 1H) , 2.248 - 2.186 (m, 1H) ; 1.934 - 1.789 (m, 1H) . MS: m/z (MH+) 210. Example 3 2- (2-Hydroxyethyl) -5- (4- (2-phenylbenzoylamιno) benzoyl) - 1 , 5-benzothιazepιne (Compound 17) A mixture of 2-bιphenylcarboxylιc acid (25g, 0.13M) thionyl chloride (80ml) was stirred at room temperature overnight and the excess S0C1 2 removed under reduced pressure to give the acid chloride as a yellow oil. The oil was dissolved methylene chloride (60ml) and slowly added through an addition funnel to a solution of methyl (4-ammo) benzoate (20g, 0.13M) and tπethylamme (28ml, 0.198M) dissolved methylene chloride (400ml). The resulting mixture was stirred at room temperature for 4 - 5 hours and water (500ml) was added. Layers were separated, the CH 2 C1 2 layer dried (MgSθ ) and solvent removed under reduced pressure. The resulting solids were washed with diethyl ether and dried to give a tan solid benzyl ester (37g, 89%) . M.P. 160 - 161°C. To a stirred solution of the ester (37g, 0.11M) CH30H (400ml) was slowly added 6.6N NaOH (100ml). Stirring was continued till all solids dissolved (6 hours). The methanol was removed under reduced pressure, the solids dissolved m H->0 and concentrated HCl was slowly added to the stirred solution. The mixture was stirred at RT overnight and the resulting white solid precipitates collected and dried to give the desired p-substituted benzoic acid as a white crystalline solid (34.4g, 97%). MS: m/z (M + ) 318. The acid chloride was prepared by stirring the acid (34 g, 0.1M) m thionyl chloride (260ml) with gentle heating (40°C oil bath) for 4 hours. The residual semi solid was diluted with toluene and filtered to give the acid chloride product as white solid (33.6g, 93.5%). M.P. 148 - 150°C. To a cold (ice bath) solution of 2- (2- hydroxyethyl) -1 , 5-benzothιazepme as prepared m Example 2, (17g, 0.082M) in dry THF (100ml) was slowly added N, 0- bis (trimethylsilyl) acetamide (36ml, 0.16M). The resulting mixture was stirred at room temperature for 1.5hr and the prepared 4- (2-phenylbenzoylammo) -benzoylchloride (27g, 0,082M) dissolved m methylene chloride was slowly added through an additional funnel over a 45 mm. period. Stirring was continued for an additional two hours and H 2 0 was slowly added. The aqueous mixture was stirred overnight and the resulting solid precipitates were collected by filtration and dried to give the desired substituted benzothiazepme product (35.4g, 85%). M.P. 224- 228°C. Compound exists as a pair of rotamers . ^H NMR (300MHz, DMS0d 6 )δ 10.26 (s, 1H) ; 7.62 - 6.88 ( , 18H) , 4.85, 4.54 (m, 2H) ; 3.59 (m, 2H) ; 3.07, 2.96, 2.14 (m, 2H) ; 2.27, 2.14 (m 1H) ; 1.94 (m, 1H) ; 1.76 (m, 1H) ; 1.54 (m, 1H) . MS: m/z (MH+) 509. Example 4 2-Carboxymethyl-5- (4- (2-phenylbenzolylamιno) benzoyl) -1 , 5- benzothiazepine (Compound 29) Pyridinium dichromate (38g, 0.1M) was slowly added to a solution of Compound 17 as prepared m Example 3 (10.2g, 0.02M) dimethylformamide (50ml) . The resulting mixture was stirred at room temperature for 4 - 6 hours and diluted with methylene chloride (200ml) . The mixture was stirred at room temperature for 30 minutes and filtered through a short column (EM silica gel 60/Celιte) elutmg further with methylene chloride then ethyl acetate. The solvents were removed under reduced pressure to give a crude semi-solid. Flash column chromatography (EM silica gel 60; 5% MeOH CH 2 C1 2 ) followed by recrystallization, gave pure product as a white solid (9.2g, 88%) . M.P. 204- 208°C. Compound exists as a pair of rotamers . -'-H NMR (400MHz, DMSOd 6 ) δ 10.29 (s,lH); 7.52 - 7.07 (m, 18H) ; 6.90 (m, 1H) ; 4.83, 4.62 (m, 1H) ; 3.55, 3.30 (m, 1H) ; 2.99, 2.78 (m, 1H) ; 2.63, 2.52 (m, 1H) ; 2.46, 2.37 (m, 1H) ; 2.24, 2.13 (m, 1H) ; 1.99, 1.88 (m, 1H) . m/z (MH + ) 523. Example 5 2-Carboxymethyl-l-oxo-5- (4- (2-phenylbenzoylammo) benzoyl) - 1 , 5-benzothιazepιne (Compound 24) Excess Jones reagent (5.0ml) prepared by a slow addition of concentrated sulfuric acid (150ml) to a cold solution (0-5°C) of Cr0 3 (180g, 1.8M) in ice water (1.21) and stirred for one hour at 0°C, was slowly added to a cold mixture of Compound 17 as prepared m Example 3 (4.0g, 7.8mM) m acetone (60ml) . The resulting mixture was stirred at room temperature overnight. Water (100ml) was then slowly added and the volatile solvents removed in vacuo . The aqueous mixture was extracted with ethyl acetate (2 x 100ml) . The combined EtOAc extracts were dried (MgS0 4 ), filtered and evaporated m vacuo to give a crude product. Purification by flash column chromatography (EM silica gel 60; 10% EtOAc m CH?C1 ) gave the desired product as a white solid, m/z (MH + ) 539. Example 6 2- (2-Methanesulfonylethyl) -5- (4-nitrobenzoyl) -1 ,5- benzothiazepine Methanesulfonyl chloride (1.8ml, 23mM) was slowly added to a cold solution of 2- (2-hydroxyethyl) -1, 5- benzothiazepine as prepared in Example 2 (5g, 23mM) and triethylamine (6.6ml, 47mM) in methylene chloride (100ml). The mixture was stirred at 0°C for three hours then poured into ice water (100ml) . The layers were separated and the methylene chloride layer dried (MgS0 4 ) . Once filtered, the solution containing the desired mesylate product was treated with triethylamine (4.8ml, 34mM) then with 4- nitrobenzoylchloride (4.2g, 23mM) . The mixture was stirred at room temperature overnight, poured into water (150ml) and layers were separated. The methylene chloride was dried (MgS0 4 ), evaporated in vacuo and purified by column chromatography to give the desired product (8.7g, 86%) . m/z (MH + ) 437 Example 7 2- (2-Dimethylaminoethyl) -5- (4-aminobenzoγl) -1 , 5- benzothiazepine (Compound 12) A mixture of 2- (2-methanesulfonylethyl) -5- (4- nitrobenzoyl) -1, 5-benzothiazepine as prepared in Example 6 (0.9g, 2.1mM) and dimethylamine (40% solution in water, 3.0ml) in tetrahydrofuran (10ml) was heated in a sealed tube with stirring in an 80°C oil bath for 16 hours. The mixture was cooled to room temperature, evaporated to dryness, diluted with water (30ml) and extracted with ethyl acetate (2x35ml) . The combined ethyl acetate extracts were dried (MgS0 4 ) and evaporated m vacuo to give the desired product (0.78g, 97%). This product (0.78g, 2. O M) was dissolved m ethanol, and a catalytic amount of 10% Pd/C was added. The mixture was hydrogenated m a PARR apparatus under 30psι of H 2 pressure for 16hr, filtered through Celite and evaporated m vacuo to give the desired product (0.64g, 90%). m/z (M+) 356. Example 8 2- (2-Dιmethγlamιnoethyl) -5- (4- (2- phenylbenzoylamino) benzoyl) -1 ,5-benzothιazepme (Compound 11) 2-Phenylbenzoyl chloride (0.36g, 1.67mM) (prepared from 2-bιphenylcarboxylιc acid as described Example 3) was slowly added to a solution of Compound 12 as prepared m Example 7 (0.5g, 1.4mM) and triethylamine ( 0.38ml, 3.3mM) m methylene chloride (30ml) . The mixture was stirred at room temperature for 16 hours and water (80ml) was added. The layers were separated. The methylene chloride layer was dried (MgS0 4 ) , filtered and evaporated m vacuo to give a crude product. Purification by flash column chromatography (EM silica gel 60; 30% EtOAc m CH 2 C1 2 ) yielded the desired product as a white solid, m/z (MH + ) 536. Example 9 2- (2-Dιmethylamιnoethyl) -5- [4- (2- methylbenzoylamino) benzoyl ] -1 , 5-benzothιazepme (Compound 9) Compound 12 as prepared in Example 7 (0.118mg, 0.37mM) was treated following the procedure of Example 8, with 2-toluoyl chloride (0.04ml, 0.33mM) substituted for 2-phenylbenzoyl chloride, to give a white solid product. m/z (MH+) 474. Example 10 2- (2-Methanesulfonylethyl) -5- (4- (2- methylbenzoylamino) benzoyl) -1 , 5-benzothiazepine (Compound 13) 2- (2-Methanesulfonylethyl) -5- ( -nitrobenzoyl) -1, 5- benzothiazepine as prepared in Example 6 (0.3g, 0.68mM) was dissolved in ethanol, and a catalytic amount of 10% Pd/C was added. The mixture was hydrogenated in a PARR apparatus under 30psi of H 2 pressure for 16hr, filtered through Celite, evaporated in vacuo, then treated with as described in Example 8 with 2-toluoyl chloride substituted for 2-phenylbenzoyl chloride to give the desired mesylate product as a white solid (0.22g, 56%) . m/z (MH + ) 525. Example 11 2- (2-Methanesulfonγlethyl) -5- [ (4- (2- phenylbenzoylammo) benzoyl) ] -1 , 5-benzothiazepine (Compound 16) 2- (2-Methanesulfonylethyl) -5- (4-nitrobenzoyl) -1, 5- benzothiazepine as prepared in Example 6 was dissolved in ethanol, and a catalytic amount of 10% Pd/C was added. The mixture was hydrogenated in a PARR apparatus under 30psi of H 2 pressure for 16hr, filtered through Celite, evaporated in vacuo, then treated as described in Example 8 to give the desired mesylate as a white solid, m/z (MH + ) 587. Example 12 2- (2-Methylaminoethyl) -5- [4- (2- methylbenzoylamino) benzoyl ] -1 , 5-benzothiazepine (Compound 14) Compound 13 as prepared in Example 10 (0.045g, 0.08mM) and methylamine (40% solution in water; 1ml) in tetrahydrofuran (4ml) was heated in a sealed tube with stirring in an 80°C oil bath for 16 hours. The mixture was cooled to room temperature, evaporated to dryness, diluted with water (30ml) and extracted with ethyl acetate (2x35ml) . The combined ethyl acetate extracts were dried (MgS0 4 ) and evaporated in vacuo to give a crude mixture. Purification by chromatography (EM silica Gel 60; 10% EtOAc in CH 2 C1 2 ) gave the product as a white solid, m/z (MH + ) 460. Example 13 2- (2-Aminoethyl) -5- [4- (2-methylbenzoylamino) benzoyl ] -1 , 5- benzothiazepine (Compound 15) A mixture of Compound 13 as prepared in Example 10 (0.050g, 0.09mM) in tetrahydrofuran (4ml) was treated as described in Example 12 with ammonium hydroxide (1ml) substituted for dimethylamine to give a white solid product, m/z (MH + )446 Example 14 2- (2-Aminoethyl) -5- [4- (2-phenylbenzoylamino) benzoyl] -1 ,5- benzothiazepine (Compound 28) Compound 16 as prepared in Example 11 was treated as described in Example 13 to give a white solid product, m/z (MH+) 508. Example 15 2- [2-Amino-2-methyl propionamido] -ethyl-5- [4- (2- phenylbenzoylamino) benzoyl ] -1 , 5-benzothiazepine Hydrochloride (Compound 39) A mixture of Compound 28 as prepared in Example 14 (O.lδOg, 0.36mM), 2- ( tert-butoxycarbonylaminoisobutyric acid (0.072g, 0.36mM), 1-hydroxybenzotriazole (0.05g, 0.36mM) and 1- [3- (dimethyamino) propyl] -3-ethylcarbodiimide hydrochloride (0.169g, 0.9mM)in methylene chloride (30ml) was stirred at room temperature for 6 hours and a saturated potassium carbonate solution was added. Water was added and the layers were separated. The methylene chloride layer was dried (MgS0 4 ), evaporated in vacuo and the resulting semi-solid purified by chromatography. The BOC group was removed with trifluoroacetic acid to give the desired amine . The HCl salt was prepared and recrystallized from methanol/diethyl ether to give the desired product as a white crystalline solid, m/z (MH + ) 593. Example 1 6 2- [5- [4- (2-Phenylbenzoylamino) benzoyl] -1 ,5- benzothiazepine] acetaldehyde (Compound 25) A mixture of Compound 17 as prepared in Example 3 (0.24g, 0.47mM), Celite and pyridinium chlorochromate (0.2g, 0.90mM) in methylene chloride (30ml) was stirred at RT overnight, filtered through Celite. The methylene chloride was removed under reduced pressure and the residue chromatographed (EM silica gel 60; 30% EtOAc in CH 2 C1 2 ) to give the title product (160mg, 67%) . m/z (MH + ) 507 Example 17 2- (2-Cyanoethyl) -5- [4- (2-phenylbenzoylamino) benzoyl] -1 ,5- benzothiazepine (Compound 30) A mixture of Compound 16 as prepared in Example 11 (0.115g, 0.197mM) and sodium cyanide (20mg) in dimethylformamide was stirred in a 70°C oil bath for 4 hours. The reaction mixture was then cooled to RT and the DMF was removed under reduced pressure. The residual semi-solid was diluted with water (30ml) and extracted with ethyl acetate (2x30ml) . The combined ethyl acetate extracts were dried (MgS0 4 ), filtered and evaporated in vacuo . The crude mixture was purified by chromatography to give pure product as a white solid (71mg, 70%) . m/z (MH+) 518 Example 18 2- (2-Carboxyethyl) -5- [4- (2-phenylbenzoylamino) benzoyl] - 1 , 5-benzothiazepine (Compound 31) A 6.6N NaOH solution (0.5ml) was added to a mixture of Compound 30 as prepared in Example 17 (0.05g, 0.096mM) in methanol. The mixture was stirred at reflux overnight, cooled to room temperature and evaporated in vacuo . The residue was diluted with water and enough 6N HCl was added drop-wise to precipitate the product. The solid product was collected by filtration and dried, m/z (MH + )537 Example 19 2-Ethyl [5- [4- (2-phenylbenzoylamino) benzoyl ] -1 , 5- benzothiazepin] sulfonic acid (Compound 32) A mixture of Compound 16 as prepared in Example 11 (0.31g, 0.5) and lithium bromide (46mg) in dry tetrahyrofuran (30ml) was stirred at reflux for 6 hours, cooled to room temperature and evaporated in vacuo . The residue was diluted with water and extracted with ethyl acetate. The ethyl acetate extract was dried (MgS0 4 ), filtered and evaporated in vacuo to give the bromide. The bromide was diluted with an ethanol/water mixture (20/10) and treated with two equivalence of sodium sulfite. The mixture was stirred at reflux for 16 hours, cooled to room temperature and the ethanol was removed under reduced pressure. Another 30ml of water was added then 2N HCl. The aqueous mixture was extracted with ethyl acetate (2x50ml) . The ethyl acetate extracts were dried (MgS0 4 ), filtered and evaporated in vacuo . The crude semi-solid was chromatographed (EM silica gel 60; 10% MeOH in CH 2 C1 2 ) to give the product, m/z (MH + )573 Example 20 2-Acetamido-5- [4- (2-phenylbenzoylamino) benzoyl ] -1,5- benzothiazepine (Compound 38) Ammonium hydrogen carbonate (0.029g, 0.36mM) was added to a mixture of Compound 29 as prepared in Example 4 (0.160g, 0.31mM), di-tert-butyl dicarbonate (0.078g, 0.36mM) and pyridine (0.2ml) in dioxane (10ml). The mixture was stirred at room temperature overnight and water was added. The precipitates were collected and dried to give a white solid product (0.11g,68%) m/z (MH + )522 Example 21 2- (2-Hydroxyethyl) -5- (4-aminobenzyl) -1 , 5-benzothiazepine- 4-one A mixture of 2- (2-hydroxyethyl) -benzothiazepin-4-one as prepared in Example 1 (3g, 13.5mM), potassium carbonate and p-nitrobenzyl bromide (3.0g, 13.8mM) in acetone (100ml) was stirred at reflux for 48 hours, cooled to room temperature, diluted with water (80ml) and evaporated in vacuo to remove the acetone. The aqueous mixture was extracted with ethyl acetate (2 x 80ml. The combined organic extracts were dried (MgS0 4 ), filtered and evaporated in vacuo to give the desired product as an oil (4.2g, 87.5%). m/z (M+) 359. The oil (1.2g, 3.4mM) was dissolved in ethanol and a 5 mole% of 10% Pd/C was added. The mixture was hydrogenated under H 2 pressure in a Parr apparatus for 16 hours, filtered through Celite and evaporated in vacuo to give the desired product (l.lg, 100%) as an oil. m/z (MH + ) 329. Example 22 2- (2-Hydroxγethyl) -5- (4- (2-phenylbenzoylamino) benzyl) -1,5- benzothiazepine-4-one (Compound 23) To a cold (ice-bath) solution of 2- (2-hydroxyethyl) - 5- (4-aminobenzyl) -1, 5-benzothiazepine-4-one as prepared in Example 21 (0.865g, 2.6mM) in dry THF was added N, 0- bis (trimethylsilyl) acetamide (1.16ml, 5.2mM). After 1 hour, 2-phenylbenzoyl chloride (0.570g, 2.6mM), prepared from 2-biphenylcarboxylic acid as described in Example 3, was added and stirring was continued for an addition hour. Water (80ml) was added and the mixture was extracted with ethyl acetate (2 x 80ml) . The organic extract was dried (MgS0 4 ), filtered and evaporated in vacuo to give a crude product. Purification by flash column chromatography (EM silica gel 60; 30% EtOAc in CH 2 C1 2 ) yielded the desired product as a white solid (l.lg, 83%) m.p .116-120°C 1 H NMR (300MHz, DMSOd 6 ) δ 7.8 (d, J = 7Hz, 1H) ; 5.09 (d, J=15Hz,H); 4.89 (d, J=15Hz, 1H) ; 3.79 (m, 3H) ; 2.69 - 2.24(m, 2H) ; 1.71 (m, 2H) ; m/z (MH + ) 509. Example 23 2- (2-Hydroxyethγl) -5- (4- (2-methylbenzoylamino) benzyl) -1 ,5- benzothiazepine-4-one (Compound 22) 2- (2-Hydroxyethyl) -5- ( 4-ammobenzyl) -1, 5- benzothιazepme-4-one as prepared m Example 21 (0.105g, 0.31mM) was treated using the procedure described m Example 22, with o-toluoyl chloride (0.04ml, 0.33mM) substituted for 2-phenylbenzoyl chloride, to yield the title product as a white solid (0.086g, 64%) m/z (MH + ) 447 Example 24 2- (2-Hydroxyethyl) -5- (4-acetamιdobenzenesulfonyl) -1,5- benzothiazepme To a mixture of 2- (2-hydroxyethyl) -1, 5- benzothiazepme as prepared m Example 2 (3g, 14.4mM) m pyridme (30ml) was slowly added N-acetylsulfanilyl chloride (6.7g, 28.7mM) . The resulting mixture was stirred at room temperature for 16 hours and the excess pyridme was removed under reduced pressure. The residual semi-solid was diluted with H 2 0 (80ml) and extracted with CH 2 C1 2 (2 x 80ml) . The combined methylene chloride extracts were dried (MgS0 4 ), filtered and evaporated vacuo to give a crude oil. Flash column chromatography (EM silica gel 60; 2% MeOH m CH 2 C1 2 ) gave the desired product as a white solid (2.9g, 50%). m/z (MH+)407 Example 25 2- (2-Hydroxyethyl) -5- (4-amιnobenzenesulfonyl) -1 ,5- benzothiazepine (Compound 4) 2- (2-Hydroxyethyl) -5- ( 4-acetamιdobenzenesulfonyl) - 1, 5-benzothιazepme as prepared m Example 24 was dissolved m a 10% HCl/MeOH (100ml) solution and stirred at reflux for 2^ hours. The mixture was cooled and a saturated NaHC0 3 solution (60ml) was added. The methanol was removed under reduced pressure and the aqueous mixture extracted with EtOAc (2 x 80ml) . The combined EtOAc extracts were dried (MgS0 4 ), filtered and evaporated in vacuo to give the desired product as a solid (2.4g,92%) m.p. 145 - 148°C. ^U NMR (300MHz, DMSOd 6 ) δ 7.50 ( d, J=7Hz, 1H) ; 7.41 (d, J=8.6Hz, 2H) ; 7.33 - 7.19 (m, 3H) ; 6.59 (d, J=8.6Hz, 2H) ; 6.05(s, 2H) 4.51 (t, J=5Hz, 1H) ; 3.45 - 3.35 (m, 4H) ; 2.96 (m, 1H) , 2.07 (m, 1H) ; 1.81 (m, 1H) ; 1.49 (m, 2H) . m/z (MH + ) 365. Example 26 2- (2-Hydroxyethyl) -5- [4- (2-phenylbenzoylamino) - benzenesulfonyl ] -1 , 5-benzothiazepine (Compound 19) Compound 4 as prepared in Example 25 (0.6g, 1.5mM) was treated with N, O-bis (trimethylsilyl) acetamide (0.65g, 3.0ml) then with 2-phenylbenzoyl chloride ( 0.39g, 1.8mM) as described in Example 22 to yield the title product as a white solid, m.p. 1 NMR (300MHz, CDC1 3 ) δ 7.92 (d, J=7.4Hz,lH); 7.60 -7.04 (m, 17H) ; 3.76 (m, 2H) ; 2.89 ( , 1H) ; 2.08 (m, 1H) ; 1.90 (m, 1H) ; 1.64 (m, 4H) . m/z (MH+) 545 Example 27 2- (2-Hydroxyethyl) -5- [4- (2-methylbenzoylamino) benzenesulfonyl ] -1 , 5-benzothiazepine (Compound 5) Compound 4 as prepared in Example 25 (0.55g, 1.5mM) was treated as described in Example 26 with 2-toluoyl chloride (0.3ml) substituted for 2-phenylbenzoyl chloride to give the desired product m/z (MH + )483 Example 28 2- (2-Hydroxyethyl) -5- [4- (3, 4-dichlorobenzoylamino) benzenesulfonyl] -1 , 5-benzothiazepine (Compound 10) Compound 4 as prepared in Example 25 was treated as described in Example 26 with 3, 4-dichlorobenzoyl chloride (0.085g, 0.41mM) substituted for 2-phenylbenzoyl chloride to give the product, m/z (MH + )537 Example 29 2-Ethyl- (2-methanesulfonyl) -1 , 5-benzothiazepine-4-one Methanesulfonyl chloride (3.6ml, 45mM) was slowly added to a cooled (0°C) solution of 2- (2-hydroxyethyl) - benzothiazepin-4-one as prepared in Example 1 (lOg, 45mM) and triethylamine (4.5ml, 32mM) dissolved in methylene chloride. The mixture was stirred at room temperature for 1.5 hours, cooled in an ice bath and water was added. The aqueous mixture was extracted with ethyl acetate. The organic phase was dried (MgS0 4 ), filtered and evaporated in vacuo to give a solid product 14. Ig, 94%) . m/z (MH + ) 302 Example 30 2- [N-(tert-butoxycarbonyl) -ethyl] -5- [4- (2- methylbenzoylamino) -benzyl] -1 , 5-benzothiazepine-4-one (Compound 6) Sodium azide (5.9g, 92mM) was slowly added to a mixture of 2-ethyl- (2-methanesulfonyl) -1, 5- benzothiazepine-4-one as prepared in Example 29 (14. Og, 46.5mM) in dimethylforamide (100ml). The mixture was stirred at room temperature for fifteen minutes then heated in an 80°C oil bath for an additional four hours. The mixture was cooled to room temperature, poured into ice water (300ml) and stirred for one hour. The resulting precipitates were collected and dried to give the azide as an off-white solid (8.2g, 72%). The azide (8.0g, 32.2mM) dissolved in dry tetrahydrofuran (60ml) was added to a cooled solution of lithium aluminum hydride (48ml; IM solution in THF) in THF (100ml) . The mixture was stirred at room temperature for three hours and a saturated K 2 C0 3 solution was slowly added. The mixture was filtered through Celite and the THF was removed under reduced pressure. The resulting mixture was diluted with ethyl acetate (250ml) and washed with water (1x250ml) then with brine (1x250ml) . The ethyl acetate extract was dried (MgS0 4 ) , filtered and evaporated in vacuo to give the amine as a yellow oil (3.96g, 56%). To a cold (0°C) mixture of the amine (3.9g, 17.8mM) in dry THF (80ml) was added di-tert-butyl dicarbonate (3.89g, 17.8mM). The mixture was slowly warmed up to room temperature, stirred for one hour. The mixture was again cooled in an ice-bath and water (80ml) was added. The THF was removed under reduced pressure and the aqueous mixture extracted with ethyl acetate (2x80ml) . The combined ethyl acetate extracts were dried (MgS0 4 ), filtered, evaporated in vacuo . Purification by flash column chormatography (EM silica gel, 10% EtOAc in CH 2 C1 2 ) gave the desired product (3.7g, 65%) . Further treatment with 4-nιtrobenzyl bromide, catalytic hydrogenation as described m Example 21 followed by acylation with o-toluoyl chloride as described m Example 23 gave the desired product as an off-white solid, m/z (MH+)546. Example 31 2- (2-Ammoethyl) -5- [4- (2-methylbenzoylamino) -benzyl ] -1 , 5- benzothιazepιne-4-one (Compound 7) Compound 6 as prepared m Example 30 was dissolved m methylene chloride and treated with excess trifluoroacetic acid. The mixture was stirred at room temperature overnight and diluted with saturated soαium bicarbonate. The layers were separated and the methylene chloride layer dried (MgS0 4 ), filtered and evaporated m vacuo to give the desired product as a solid m/z (MH + ) 446. Example 32 2- [2- (2,4-Dιmethoxybenzylammo)ethyl] -5- [4- (2- methylbenzoylamino) -benzyl ] -1 , 5-benzothιazepme-4-one (Compound 8) A mixture of Compound 7 as prepared m Example 31 (0.105g, 0.24mM), 2, 4-dιmethoxybenzaldehyde (0.040g, 0.240mM) and acetic acid (0.05ml) m methanol was stirred at room temperature for three hours and 2.5 equivalence of sodium cyanoborohydride was added. The mixture was stirred at room temperature for an additional 4 hours and a 6N NaOH (0.5ml; adjusted to pH8) was added. The methanol was removed under reduced pressure and the residue diluted with water (50ml) and extracted with ethyl acetate (2x50ml) . The ethyl acetate extracts were dried (MgSU4), evaporated in vacuo and purified by flash column chromatography (EM silica gel 60; 5% MeOH in CH 2 C1 2 ) to give a white solid product, m/z (MH + ) 596. Example 33 2- (2-Dimethylaminoethyl) -5- (4-acetamidobenzenesulfonyl) - 1, 5-benzothiazepine (Compound 1) 2- (2-Hydroxyethyl) -5- (4-acetamidobenzenesulfonyl) - 1, 5-benzothiazepine as prepared in Example 24 (1.2g, 2.77mM) was treated with triethylamine (0.6ml) and methanesulfonyl chloride (0.2ml, 3.05mM) as described in Example 29 to give a yellow solid mesylate product. A mixture of the mesylate ( 0.20g, 0.41mM) and dimethylamine (40% in water solution; 3ml) dissolved in tetrahydrofuran (4ml) was heated in a sealed tube with stirring in an 80°C oil bath for 16 hours. The mixture was cooled to room temperature, evaporated to dryness, diluted with water (30ml) and extracted with ethyl acetate (2x35ml) . The combined ethyl acetate extracts were dried (MgS0 4 ) and evaporated in vacuo to give a solid product, m.p. 78 - 80°C. m/z (MH + )434. Example 34 2- (2-Hydroxyethyl) -5- [2-chloro-4- (2-methyl-5- fluorobenzoylamino) benzoyl] -1 , 5-benzothiazepine (Compound 43) A mixture of 2- (2-hydroxyethyl) -1, 5-benzothiazepine as prepared in Example 2 (0.070g, 0.34mM) and N, 0- bis (trimethylsilyl) acetamide (0.15ml, 0.67mM)was treated as described in Example 3 with 2-Chloro-4- (2-methyl-5- fluorobenzoylamino) benzoyl chloride (O.llg, 0.32mM) substituted for 4- (2-phenylbenzoylamino) benzoyl chloride to give the product as a white solid, m/z (MH + ) 500. Example 35 2- (2-Dimethylaminoethyl) -5- [4- (2-methylbenzoylamino) - benzenesulfonyl ] -1 , 5-benzothiazepine (Compound 2) 2- (2-Dimethylaminoethyl) -5- (4-acetamidobenzenesulfonyl) -1 , 5-benzothiazepine as prepared in Example 33 was further treated as described in Examples 25 and 27 to give the desired product as an off-white solid m/z (MH + ) 510. Example 36 2- [2- (N-Morpholino) -ethyl] -5- [4- (2-methylbenzoylamino) - benzenesulfonyl ] -1 , 5-benzothiazepine (Compound 3) 2- (2-Hydroxyethyl) -5- ( 4-acetamidobenzene-sulfonyl ) - 1, 5-benzothiazepine as prepared in Example 24 was treated as described in Example 33 with morpholine substituted for dimethylamine . Then the product was further treated as described in Examples 25 and 27 to give the product as a solid, m/z (MH+) 552. Example 37 2- (2-Hydroxyethyl) -5- (4- (2-phenylbenzoylamino) -pyπdinoyl) - 1 ,5-benzothιazepιne (Compound 40) 5-Carboxy-2- (2-methyl-5-fluorobenzoylammo) pyridme (0.66g, 2.4mM) was treated with thionyl chloride then added to a mixture of 2- (2-hydroxyethyl) -1, 5-benzothιazepme as prepared m Example 2(0.7g, 3.3mM) and N, 0- bis (trimethylsilyl) acetamide (1.5ml, 6.6mM) m tetrahydrofuran and the solid product isolated, m/z (MH + ) 466 Example 38 2- (2-Hydroxyethyl) -5- (4- (2-methylbenzoylamino) benzoyl) -1 ,5- benzothiazep e (Compound 18) A mixture of 2- (2-hydroxyethyl ) -1 , 5-benzothιazepme as prepared m Example 2 was treated as described m Example 3 with 2-toluoyl chloride substituted for 2- phenylbenzoylchloride to give the product as a white solid. m/z (MH+) 447 Examples 39 and 40 2- (2-Hydroxyethyl) -l-dιoxo-5- (4- (2-phenylbenzoylammo) - benzoyl) -1 , 5-benzothιazepιne (Compound 35) and 2- (2- hydroxyethyl) -l-oxo-5- (4- (2-phenylbenzoylammo) -benzoyl) - 1 ,5-benzothiazepme (Compound 36) 3-Chloroperoxybenzoιc acid (0.34g, 1.97mM) was added to a mixture of Compound 17 as prepared Example 3 (l.Og, 1.97mM) m methylene chloride. The mixture was stirred at RT overnight and an aqueous sodium sulfite solution was added. The layers were separated and the methylene chloride layer further extracted with saturated potassium carbonate, dried (MgS0 ) , filtered and evaporated in vacuo to give a mixture of two products. Purification by chromatography (EM silica gel 60, 50% EtOAc in methylene chloride) give the sulfone product (0.650g) and the sulfoxide product (0.43g); m/z (MH + ) 541 and 525, respectively. Example 41 2- (2-Methanesulfonylethyl) -5- [ (4- (2-phenylbenzoylamino) - benzyl) ] -1 ,5-benzothiazepin-4-one (Compound 21) Methanesulfonyl chloride (0.04ml, 0.55mM) was added to Compound 23 as prepared in Example 22 (0.280g, 0.55mM) and triethylamine (0.15ml, 1. litiM) following the procedure described in Example 29 to give the solid product, m/z (MH+) 587. Example 42 2- (2-Methanesulfonylethyl) -5- [ (4- (2-phenylbenzoylamino) - benzenesulfonyl) ] -1 , 5-benzothiazepine (Compound 20) Methanesulfonyl chloride (0.02ml, 0.278mM) was added to Compound 19 as prepared in Example 26 (0.151g, 0.278 mM) and triethylamine (0.07ml, 0.55mM) following the procedure described in Example 29 to give the solid product, m/z (MH + ) 623. Example 43 2-Methyl- [5- (4- (2-phenylbenzoylammo) benzoyl) -1 ,5- benzothiazepine] acetate (Compound 37) Methyl iodide (0.06ml, 0.96mM)was added to a mixture of Compound 29 as prepared m Example 4 (0.5g, 0.96mM) and potassium carbonate (0.26g, 1.88mM) m dimethyl formamide (10ml) . The mixture was stirred at room temperature overnight and slowly added to water (80ml) . The white solid precipitates were collected and dried to give the product, m/z (MH + ) 537. Example 44 - 47 Preparation of Enantiomers of 2- (2-Hydroxyethyl) -5- (4- (2- phenylbenzoylamino) benzoyl) -1 , 5-benzothιazepme (Compounds 26 and 27) and 2-Carboxymethyl-5- [4- (2- phenylbenzoylamino) benzoyl ] -1 , 5-benzothιazepιne (Compounds 33 and 34) (S) - (-) -1-Phenylethyl isocyanate (2.6ml) was added to a suspension of Example 3 (7.8g, 15.4mM) and a catalytic amount of N, N-dimethylethanolamme m toluene (150ml). The resultant mixture was stirred at reflux for 48 hours, cooled to room temperature and filtered to remove unreacted starting material. The filtrate was evaporated in vacuo and the residual semi-solid chromatographed (EM silica gel 60, 10% tert-butyl ethyl ether m methylene chloride) to give each diastereomer pure. Each single diastereomer was then dissolved m ethanol and added to a sodium ethoxide solution. The mixture was stirred a reflux overnight and cooled to room temperature. The ethanol was removed under reduced pressure, the mixture diluted with IN HCl and extracted with ethyl acetate. The ethyl acetate extract was dried (MgS0 4 ) and filtered. Removal of the solvent under reduced pressure and drying of the resulting solid gave the pure enantiomers of Compounds 26 and 27. Each enantiomer was then treated following the procedure described m Example 4 to give the pure enantiomers of Compounds 33 and 34. Example 48 In-Vitro Binding Assay Assay buffer is 50mM Tπs-Cl, 5mM MgCl2, 0.1% BSA (pH 7.5) containing 5ug/ml of aprotmm, leupeptm, pepstatm, 50ug/ml bacitracm, and ImM Pefabloc. H3 vasopressin is 3 H- argmme-8-vasopressm ( 68.5Cι/mmol, final concentration m assay is 0.65-0.75nM) . Into wells of 96-well round bottom polypropylene plates are added buffer, test compound, membrane (containing cloned human V2 receptor) , and H3 vasopress . The reaction plates are allowed to sit at room temperature for one hour. The samples are filtered through Unifliter GF/C plates (presoaked m 0.3 polyethyleneimme) . The plates are washed 5 times with cold physiological saline containing 0.05% Tween 20. After drying, the bottom of the filter plates are sealed and 0.025ml of Mιcroscmt-20 is added to each filter. The top of the plate is sealed, and the plate is counted. Non-specific binding is determined by the addition of 1.25uM argmme-8-vasopressm m those wells. %Inh. is calculated as follows: peak response after drug inhibition = 100 - 100 x peak response before drug Example 49 Reversal of Vasopressin-Induced Hypertension in Rats. The anti-hypertensive activity of a compound may be assessed using an anesthetized model of vasopressin- induced hypertension. Male Long Evans, normotensive rats of between 350 and 450 g in body weight may be anesthetized with pentobarbital (35 mg/kg, ip) and maintained throughout the procedure with an ip infusion of 10 mg/kg/hr. Arginine vasopressin can be infused at 30 ng/kg/min, iv, to induce a stable hypertensive state (ca. 50 mmHg increase in mean arterial blood pressure) . Compounds of interest can be administered in an ascending dose fashion and the maximum decrease in mean arterial blood pressure can be recorded. An ED 50 may be determined from the linear portion of the dose-response relationship for each animal . This model can be modified slightly to assess the bioavailability of compounds of interest. Rather than dosing the animals iv in an ascending dose fashion, a single dose per animal cab be administered directly into the duodenum. The anti-hypertensive effects can be then monitored for 60 minutes and the maximum percent reversal can then be calculated. Tables I and II below set forth the vasopressin receptor binding data of some compounds of the instant invention. Table I - 59 - Table I I 'ICso value s ( μM) 'Enantiomers While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Claims: WHAT IS CLAIMED IS 1. A compound of Formula I wherem R 1 is selected from -COOH, formyl, o-mesylate, -S0 2 OH, alkoxysulfonyl, alkylcarboxy, substituted alkylcarboxy, aralcarboxy, substituted aralcarboxy, - NR 4 R 5 , -OH, cyano, N-morpholmo, alkoxy, aralkoxy, alkylcarbamoyl, substituted alkylcarbamoyl, alkoxycarbonyl, substituted alkoxycarbonyl, -NHCOR 6 and -CONR 7 R 8 , where R 4 , R", R 6 , R , and R 8 are independently selected from the group consisting of H, alkyl, and aryl; A is S, SO or S0 2 ; X is CH 2 or carbonyl; Z is CH 2 , S0 2 or carbonyl, with the proviso that X is W is aryl, substituted aryl, heteroaryl or substituted heteroaryl; R 2 is -N(H)YR 3 or -YN(H)R 3 wherem Y is H or carbonyl; R 3 is H, alkyl, substituted alkyl, aryl or substituted aryl; m i s 1 - 3 ; n is 1 - 5 ; and p i s 0 or 1 ; or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt thereof. 2. The compound of Claim 1 wherein R 1 is selected from - COOH, formyl, o-mesylate, -S0 2 OH, alkylcarboxy, substituted alkylcarboxy, aralcarboxy, substituted aralcarboxy, cyano, N-morpholino, alkoxy, aralkoxy, alkylcarbamoyl and substituted alkylcarbamoyl. 3. The compound of Claim 2 wherein p is 0, A is S, and n is 1 or 2. 4. The compound of Claim 2 wherein X is CH 2 and Z is carbonyl . 5. The compound of Claim 2 wherein W is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridinyl, substituted pyridinyl, naphthyl and substituted naphthyl . 6. The compound of Claim 2 wherein R 2 is -N(H)YR 3 wherein Y is carbonyl and R 3 is substituted phenyl. The compound of Claim 6 wherein R 2 is -NHCO (2-Ph) Ph. 8. The compound of Claim 2 wherem R 3 is phenyl or substituted phenyl. 9. The compound of Claim 1 wherein R 1 is -NR 4 R 5 , -NHCOR 5 or -CONR 7 R 8 where R 4 , R 5 , R δ , R 7 and R 8 are as claimed m Claim 1. 10. The compound of Claim 9 wherem R 1 is selected from -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHBOC, - N (BOC ) 2 , -NHCOC (CH 3 ) 2 NH 2 , -N (COC (CH 3 ) 2 NH 2 ) 2 and - NCH 2 (2,5-OCH 3 ) Ph; W is Ph or substituted Ph; R 2 is -NH 2 , -NHAc, -NHCO(2-CH 3 ) Ph or -NHCO (2-Ph) Ph; and 11. The compound of Claim 1 wherem R 1 is -OH. 12. The compound of Claim 11 where W is heteroaryl, Ph or substituted Ph; R 2 is -NH 2 , -NHAc, -NHCOCH 3 , -NHCO (2-CH 3 ) Ph, -NHCO (2- Ph)Ph, -NHCO(2-CH 3 , 5-F) Ph, or -NHCO (3, 4-Cl ) Ph; and 13. The compound of Claim 1 wherem R 1 is alkoxycarbonyl, substituted alkoxycarbonyl or -CONR 7 R 8 wherem R 7 and R 8 are as claimed m Claim 1. 14. The compound of Claim 13 wherein Z is carbonyl; W is Ph or substituted Ph; R 2 is -NHCO (2-Ph) Ph; and p is 0. 15. The compound of Claim 1 which is 2- (2-carboxyethyl) - 5- [4- (2-phenylbenzoylamino) benzoyl] -1, 5-benzothiazepine . 16. The compound of Claim 1 which is 2-carboxymethyl-l- oxo-5- (4- (2-phenylbenzoylamino) benzoyl) -1,5- benzothiazepine . 17. The compound of Claim 1 which is 2-carboxymethyl-5- (4- (2-phenylbenzolylamino) benzoyl) -1 , 5-benzothiazepine . 18. A substantially pure single enantiomer of the compound of Claim 17. 19. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier. 20. A method of treating a subject suffering from a condition of vascular resistance, which comprises administering to the subject a therapeutically effective amount of the compound of Formula I as defined in Claim 1. 21. A method of inhibiting in a subject the onset of a condition of vascular resistance in the subject, which comprises administering to the subject a prophylactically effective dose of a compound of Formula I as defined in Claim 1. 22. The method of Claim 20 or 21 wherein said condition is selected from inner ear disorders, hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, and water retention. 23. The method of Claim 22 wherein said condition is congestive heart failure or cardiac insufficiency. 24. A process for preparing a compound of Formula la, la wherein R 1' is -COOH or formyl, alkoxy, aralkoxy, or -0(CO)R 9 wherein R 9 is alkyl, substituted alkyl, aryl or substituted aryl; A is S, SO or S0 2 ; X is CH 2 or carbonyl; Z is CH 2 , S0 2 or carbonyl, with the proviso that X is not CH 2 when Z is CH 2 ; B is (CH 2 ) m , NH or 0; W is aryl, substituted aryl, heteroaryl or substituted heteroaryl; R 2 is -N(H)YR 3 or -YN(H)R 3 wherein Y is H or carbonyl; R 3 is H, alkyl, substituted alkyl, aryl or substituted aryl; m is 1-3 ; n is 1-5; and p is 0 or 1 which process comprises: [a) reacting with a compound of Formula II to form a compound of Formula III; II III (b) converting the compound of Formula III to a compound of Formula IV wherein R 2' is nitro, -N(H)YR 3 or -YN(H)R 3 ; IV and (c) converting the compound of Formula IV to the compound of Formula la. 25. A process for preparing a compound of Formula la la wherein R 1' is -COOH or formyl, alkoxy, aralkoxy, or -0(CO)R 9 wherein R 9 is alkyl, substituted alkyl, aryl or substituted aryl; A is S, SO or S0 2 ; X is CH 2 or carbonyl; Z is CH 2 , S0 2 or carbonyl, with the proviso that X is not CH 2 when Z is CH 2 ; B is (CH 2 )m, NH or 0; W is aryl, substituted aryl, heteroaryl or substituted heteroaryl; R 2 is -N(H)YR 3 or -YN(H)R 3 wherein Y is H or carbonyl; R 3 is H, alkyl, substituted alkyl, aryl or substituted aryl; m is 1-3 ; n is 1-5; and p is 0 or 1 which process comprises: (a) reacting with a compound of Formula II to form a compound of Formula III; II III (b) converting the compound of Formula III to a compound of Formula V; V (c) converting the compound of Formula V to the compound of Formula VI wherein R 2' is nitro, -N(H)YR 3 or -YN(H)R 3 ; and (d) converting the compound of Formula VI to the compound of Formula la. 26. A process for preparing a compound of Formula III πi which comprises reacting with a compound of Formula II. II 27. A compound of Formula III III wherein n is 1-5

Inventors: CHEN ROBERT H K, URBANSKI MAUD J, CHEN, ROBERT, H., K., URBANSKI, MAUD, J.
Applicants: ORTHO MCNEIL PHARM INC, ORTHO-MCNEIL PHARMACEUTICAL, INC.
Application year: 2000
Main classification: C07D281
IPC codes: A61K31, A61P1, A61P7, A61P9, A61P13, A61P25, A61P27, C07D281