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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/06—Antiabortive agents; Labour repressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
  • C07D223/20—Dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
  • C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
  • C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
  • C07D223/28—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a single bond between positions 10 and 11
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
  • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
  • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
  • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D267/02—Seven-membered rings
  • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
  • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
  • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
  • C07D267/20—[b, f]-condensed
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems

Definitions

• This invention relates to new tricyclic non-peptide vasopressin antagonists which are useful in treating conditions where decreased vasopressin levels are desired, such as in congestive heart failure, in disease conditions with excess renal water reabsorption and in conditions with increased vascular resistance and coronary vasoconstriction.
• Vasopressin is released from the posterior pituitary either in response to increased plasma osmolarity detected by brain osmoreceptors or decreased blood volume and blood pressure sensed by low-pressure volume receptors and arterial baroreceptors.
• the hormone exerts its action through two well defined receptor subtypes: vascular V 1 and renal epithelial V 2 receptors.
• Vasopressin-induced antidiuresis mediated by renal epithelial V 2 receptors, helps to maintain normal plasma osmolarity, blood volume and blood pressure.
• Vasopressin is involved in some cases of congestive heart failure where peripheral resistance is increased.
• V 1 antagonists may decrease systemic vascular resistance, increase cardiac output and prevent vasopressin induced coronary vasoconstriction.
• V 1 -antagonists may be therapeutic agents.
• V 1 antagonists may decrease blood pressure, induced hypotensive effects and thus be therapeutically useful in treatment of some types of hypertension.
• V 2 receptors The blockage of V 2 receptors is useful in treating diseases characterized by excess renal
• Antidiuresis is regulated by the hypothalamic release of vasopressin (antidiuretic hormone) which binds to specific receptors on renal collecting tubule cells. This binding stimulates adenylyl cyclase and promotes the cAMP-mediated
• V 2 antagonists may correct the fluid retention in congestive heart failure, liver cirrhosis, nephritic syndrome, central nervous system injuries, lung disease and hyponatremia.
• V 2 antagonist may be beneficial in promoting free water excretion by antagonizing the action of antidiuretic hormone, On the basis of biochemical and pharmacological effects of the hormone, antagonists of vasopressin are expected to be
• Non-peptide vasopressin antagonists have recently been disclosed, Y. Yamamura et al., Science, 252, 579(1991); Y. Yamamura et al., Br. J. Pharmacol, 105, 787(1992); Ogawa et al., (Otsuka Pharm Co., LTD.) EP 0514667-A1; EPO 382185-A2; WO9105549 and
• the present invention relates to novel tricyclic derivatives which exhibit antagonist activity at V 1 and/or V 2 receptors and exhibit in vivo
• vasopressin antagonist activity The compounds also exhibit antagonist activity at oxytocin receptors.
• This invention relates to new compounds selected from those of the general formula I:
• Y is (CH 2 ) n , O, S, NH, NCOCH 3 , N-lower alkyl (C 1 -C 3 ), CH-lower alkyl (C 1 -C 3 ), CHNH-lower alkyl (C 1 -C 3 ), CHNH 2 , CHN[lower alkyl (C 1 -C 3 H 2 , CHO-lower alkyl(C 1 -C 3 ), CHS-lower alkyl (C 1 -C 3 ), wherein n is an integer from 0-2:
• Ri is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S-lower alkyl(C 1 -C 3 ), -SH, -SO lower alkyl(C 1 -C 3 ), -SO 2 -lower alkyl(C 1 -C 3 ), -CO-lower alkyl(C 1 -C 3 ), -CF 3 ; lower alkyl(C 1 -C 3 ); O-lower alkyl(C 1 -C 3 ), -NO 2 , -NH 2 , -NHCO lower alkyl (C 1 -C 3 ), -N-[lower alkyl(C 1 -C 3 )] 2 , -SO 2 NH 2 ; -SO 2 NH lower
• R 2 is hydrogen, Cl, Br, F, I. -OH, lower alkyl(C 1 -C 3 ), O-lower alkyl(C 1 -C 3 ), or R 1 and R 2 taken together are methylenedioxy or ethylenedioxy;
• R 3 is the moiety:
• Ar is a moiety selected from the moiety
• R 4 is hydrogen, lower alkyl(C 1 -C 3 ); -CO-lower alkyl(C 1 -C 3 );
• R 5 and R 7 are selected from hydrogen, (C 1 -C 3 ) lower alkyl, (C 1 -C 3 ) lower alkoxy and halogen;
• R 6 is selected from (a) moieties of the formula:
• cycloalkyl is defined as C 3 to C 6 cycloalkyl, cyclohexenyl or cyclopentenyl;
• R a is hydrogen, CH 3 , C 2 H 5 , moieties of the formulae:
• R 10 is lower alkyl(C 3 -C 8 ), lower alkenyl
• X is O, S, NH, NCH 3 , or a bond
• R 5 and R 7 are as previously defined
• K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen (C 1 -C 3 )lower alkoxy, -CO-lower alkyl( C 1 -C 3 ), CHO, (C 1 -C 3 )lower alkoxy, -CO 2 -lower alkyl(C 1 -C 3 ), and R a and R b are as hereinbefore defined; (d) a moiety selected from those of the formulae:
• R c is selected from halogen, (C 1 -C 3 )lower alkyl
• R b is as hereinbefore defined;
• Ar' is a moiety selected from the group
• R 8 and R 9 are independently hydrogen, lower alkyl (C 1 -C 3 ); O-lower alkyl(C 1 -C 3 ); S-lower alkyl(C 1 -C 3 ),
• W is O, S NH, N-lower alkyl(C 1 -C 3 ), NCO-lower
• R 25 is selected from the moieties
• heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C 1 -C 3 ) lower alkyl, formyl, a moiety of the formula:
• the fused heterocyclic ring may be represented by furan, pyrrole, pyrazole, thiophene, thiazole, oxazole, imidazole, pyrimidine or pyridine ring which may be substituted or unsubstituted.
• R 5 , R 6 and R 7 are as hereinbefore defined.
• R 8 , R 9 , R 25 and W' are as hereinbefore defined.
• Y in Formula I is -(CH 2 ) n - and n is zero or one;
• A-B is or and R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as hereinbefore defined; and m is an integer from 1-2.
• R 3 is the moiety: Ar is and
• R a , R b and W' are as previously defined and R 8 and R 9 are preferably ortho CF 3 , Cl, OCH 3 , CH 3 , SCH 3 or OCF 3 substituents or Ar' is a disubstituted
• R 8 and R 9 are independently Cl, OCH3 , CH 3 and F.
• Y is -(CH 2 ) n -, n is zero or one and represents a phenyl, substituted phenyl, thiophene, furan, pyrrole or a pyridine ring;
• R 3 is the moiety: wherein Ar is
• R 6 is selected f rom the group
• R a , R b , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 25 and W' are as previously defined.
• R 3 is the moiety: wherein Ar is selected from moieties of the formulae: and
• cycloalkyl is defined as C 3 -C 6 cycloalkyl, cyclohexenyl or cyclopentenyl and wherein Ar' is selected from the moieties:
• R a is independently selected from hydrogen, CH 3 or -C 2 H 5 ; and R 5 , R 7 , R 8 , R 9 , R 10 , R 25 , X and W are as hereinbefore defined.
• R 3 is the moiety: wherein Ar is selected from moieties of the formulae:
• cycloalkyl is defined as C 3 to C 6 cycloalkyl, cyclohexenyl or cyclopentenyl and wherein Ar' is selected from the moieties:
• Ra is independently selected from hydrogen, CH 3 or -C 2 H 5 ; and R 5 , R 7 , R 8 , R 9 , R 10 , R 25 , X and W are as hereinbefore defined.
• aryisulfonyl chlorides diarylphosphinyl chlorides, diphenoxyphosphinyl chlorides, alkyl (C 3 -C 8 ) carbonyl chlorides, alkenyl (C 3 -C 8 )carbonyl chlorides,
• alkoxy(C 3 -C y )carbonyl chlorides alkenyloxy(C 3 -C 8 ) carbonyl chlorides, alkyl(C 3 -C 8 )sulfonyl chlorides, alkenyl(C 3 -C 8 )sulfonyl chlorides cycloalkylcarbonyl chlorides, arylcarbamoyl chlorides or heteroarylcarbamoyl chlorides as illustrated in Scheme 1, gives the novel compounds 8a and 8b of this invention.
• the reactions may be carried out in solvents such as chloroform, dichloromethane, dioxane, tetrahydrofuran, toluene and the like in the presence of a tertiary base such as triethylamine, diisopropylethylamine or pyridine at 0°C to 50°C. If more than one aroyl, heteroaroyl or aryisulfonyl group, etc. is introduced during the reaction, mild base treatment (NaOH, KOH etc.) in a lower alkancl removes the second such group to give the products 8a and 8b.
• solvents such as chloroform, dichloromethane, dioxane, tetrahydrofuran, toluene and the like
• a tertiary base such as triethylamine, diisopropylethylamine or pyridine at 0°C to 50°C.
• mild base treatment NaOH, KOH etc.
• R b is H, CH 3 or C 2 H 5 .
• the intermediates 13a and 13b may be reacted with R 10 X- (14) wherein R 10 is as previously defined and X is O, S, NH or NCH 3 to give derivatives of 15a and 15b as shown in Scheme 4.
• R 6 wherein R 6 is as previously defined may be prepared as shown in Scheme 5 by first synthesizing the pyridinyl moieties 16 which are to be attached to the tricyclic benzazepine units.
• the preformed pyridinyl moieties 16 may be activated for coupling by reaction with peptide coupling reagents or preferably activated by conversion to the pyridine-3-carbonyl chlorides 17.
• the coupling may be carried out in inert solvents such as chloroform, dichloromethane, tetrahydrofuran, dioxane, toluene and the like in the presence of a tertiary amine such as triethylamine.
• the reactions may also be carried out in pyridine and related alkyl pyridines.
• the starting materials 3a and 3b in Scheme 1 can be made by literature methods.
• intermediate 6,11-dihydro-5H-dibenz[b,e]azepines and substituted derivatives are prepared according to literature procedures: L.H. Werner, et al., J. Med. Chem. ,8,74-80 (1965); A.W.H. Wardrop et al., J. Chem. Soc. Perkins Trans I, 1279-1285 (1976).
• Substituted 5,11-dihydrodibenz[b,e]azepin-6-one are prepared by literature procedures: J. Schmutz et al., Helv. Chim. Acta., 48, 336 (1965); and reduced to substituted 6,11-dihydro-5H-dibenz[b,e]azepines with lithium aluminum hydride, borane, borane-dimethylsulfide and agents know to reduce an amide carbonyl to a
• dibenz[b,f][1,4]thiazepin-11(10H)-ones - J . Schmutz et al., Helv. Chim. Acta., 48, 336 (1965); may be carried cut with lithium aluminum hydride in inert solvents such as dioxane and the like.
• the tricyclic 6,7-dihydro-5H-dibenz [b, d] azepine intermediates of Formula 30 may be prepared by the literature procedures: T. Ohta et al., Tetrahedron Lett., 26, 5811 (1985); Wiesner et al., J. Amer. Chem. Soc., 77, 675 (1955); or derivatives may be prepared by coupling procedures illustrated in Scheme 7.
• 4,10-Dihydro-5H-thieno [3,2-c][1]benzazepine 21a and 9,10-dihydro-4H-thieno[2,3-c][1]benzazepine 21b may be prepared by coupling tributyltin derivatives 19 and 20 with 2-nitrobenzyl bromide in the presence of tetrakis (triphenylphosphine) palladium(O) as shown in Scheme 6.
• tricyclic lactam intermediates 29 and 32 may be reduced with lithium aluminum hydride (LAH) or borane to give the tricyclic azepines 30 and 33.
• LAH lithium aluminum hydride
• Tricyclic intermediates 42 for the synthesis of selected vasopressin antagonists of this invention wherein Y in Formula I is -CH 2 - and m is one, may be prepared as shown in Scheme 8.
• Suitable 1-nitro-2-chloro or 1-nitro-2-bromo heterocycles 35 undergo halogen exchange when reacted with a alkyllithium reagent such as t-butyllithium, s-butyllithium or n-butyllithium to give intermediates 37 which react with anhydrides of Formula 38.
• R 12 is tert-butyl, secondary butyl, n-butyl, 2,6-dimethylpiperidine or a hindered non-nucleophilic dialkylamine.
• the nitro products 39 are reduced with hydrogen and a suitable catalyst or chemically reduced (Zn-acetic acid, TiCl 3 etc.) to the amino intermediates 40.
• Ring closure to the cyclic lactams 41 is conveniently carried out by heating in xylene or an inert solvent at 100oC to 200°C.
• the cyclic lactams of structure type 41 are readily reduced by borane in tetrahydrofuran, borane-dimethylsulfide in tetrahydrofuran or lithium aluminum hydride in a suitable solvent such as dioxane to give the tricyclic compounds 42.
• derivatives 38b wherein Z is as previously defined.
• Derivatives 38b are prepared by standard procedures such as ring closure of 1-amino-2-carbcxy heteroaromatic compounds or 1-amino-2-benzoic acid derivatives, with acetic anhydride (Scheme 8).
• some of the tricyclic derivatives of structural type 42 may be prepared by "palladium” type coupling or “copper” induced coupling of halogenated derivatives 43 to give tricylic lactams 44 . Reduction of the lactam carbonyl group gives the intermediates 42. Coupling of halogen derivatives 45 to effect ring closure with activated copper or "palladium' type reagents which induce aryl coupling gives lactams 46 . Borane reduction of lactams 46 gives derivatives 47.
• Tetrahydro-1H-1-benzazepin-5-ones 51 and the tetrahydro-1H-1-benzazepin-2,5-d5iones 52 are useful compounds for the synthesis of intermediate tricyclic heterocyclic structures 53 and 54 (Scheme 10).
• the tetrahydrobenzazepin-5-ones 51 and 52 may be formulated to give hydroxymethylene derivatives or reacted with either the Vilsmeier reagent or the N, N-dimethylformamide dimethyl acetal to give the
• tetrahydrobenzazepin-2-ones are known compounds which are prepared by reaction of a-tetralones with sodium azide under acidic conditions.
• Chlorine gas is bubbled into a mixture
• tetrahydrofuran is added 4.0 ml of 10 molar borane-dimethylsulfide in tetrahydrofuran.
• the mixture is stirred at room temperature for 18 hours, 50 ml of anhydrous methanol added and the solvent removed. An additional 30 ml of methanol is added and the solvent removed to give white crystals.
• a sample is purified by chromatography on silica gel with hexane-chloroform-ethyl acetate (2:1:1) as solvent to give white crystals, m.p. 145-148°C.
• tetrahydrofuran-dichloromethane (1:1) is added 3.75 ml of 2.0 molar borane-dimethylsulfide in tetrahydrofuran. The solution is stirred 1 hour at room temperature and then relfuxed for 16 hours. The mixture is cooled and water slowly added dropwise until gas evolution ceases. The volatile are removed under vacuum and the aqueous residue made alkaline with 2N sodium hydroxide. The mixture is extracted with ether (50 ml) and the extract is washed with brine and dried (Na 2 SO 4 ). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter pad is washed with ether and the filtrate evaporated. The residual solid is washed with isooctane to give 1.20 g of white solid.
• reaction mixture is stirred for 6 hours. At the end, reaction mixture is filtered and the residue washed with acetone and concentrated. The brown residue is extracted with chloroform and washed well with water. The organic layer is dried (Na 2 SO 4 ) and filtered and concentrated. The product is isolated by silica gel column chromatography by eluting with 20% ethyl acetate: hexane to give 2.0 g of the desired product as a pale yellow crystalline solid, m.p. 86°C. Mass Spectrum;
• the product obtained is pure enough for further transformation.
• the oil product, 4,5-dihydro-4,4-dimethyl-2-[3- (tributylstannyl)-2-thienyl]-oxazole is mixed with 2-nitrobenzyl bromide (5.5 g 25 mmol) in toluene and refluxed in the presence of tetrakis
• a mixture of 4.0 g of methyl-2-methylfurane-3-carboxylate, 30 ml of 2 N NaOH and 15 ml methanol is refluxed for 1.5 hours.
• the solvent is removed under vacuum to give a solid.
• the solid is extracted with dichloromethane (discarded).
• the solid is dissolved in water and the solution acidified with 2 N citric acid to give a solid.
• the solid is washed with water and dried to give crystals 1.05 g of crystals of 2-methylfuran-3-carboxylic acid.
• the preceding compound (0.95 g) and 3 ml of thionyi chloride is refluxed fcr 1 hour.
• the solvent is removed, toluene added (20 ml, three times) and the solvent removed to give the product as an oil.
• Methyl 6-aminopyridine-3-carboxylate Dry methanol (400 ml) is cooled in an ice bath and HCI gas is bubbled into the mixture for 25 minutes. To the MeOH-HCl is added 30 g of 6-aminopyridine-3-carboxylic acid and then the mixture is stirred and heated at 90°C for 2 hours (all the solid dissolved). The solvent is removed under vacuum and the residual solid dissolved in 100 ml of water. The acidic solution is neutralized with saturated sodium bicarbonate (solid separated) and the mixture chilled and filtered to give 30 g of white crystals, m.p. 150°-154°C.
• 6-Amino-5-bromopyridine-3-carboxylic acid (10 g, 50 mmol) is dissolved in saturated methanolic HCI (100 ml) and refluxed for 24 hours.
• the solvent, methanol, is re-moved under reduced pressure and the residue is dis-solved in ice cold water.
• the aqueous solution is neutralized with 0.1 N NaOH and the solid which separates is filtered; washed well with water and air dried to yield 10 g of product as a solid: mass spectrum 231 (M + ).
• tetrahydrofuran is added slowly 18 ml of 2 N NaOH.
• the mixture is stirred at room temperature overnight and brought to pH 5 with glacial acetic acid.
• the mixture is concentrated, acidified to pH 2-3 with 1 N HCI and extracted with 250 ml of ethyl acetate.
• the extract is washed with 50 ml of brine, dried (Na 2 SO 4 ) and the solvent removed under vacuum.
• the residual white solid is triturated with 15 ml of ethyl acetate to give 3.35 g of white crystals, m.p. 215-217°C.
• 6-aminopyridine-3-carboxylate and 12.6 ml of diiso-propylethylamine in 50 ml of dichloromethane under argon is added a solution of 9.7 ml of cyclohexylcarbonyl chloride in 10 ml of dichloromethane.
• the mixture is stirred at room temperature overnight and diluted with 200 ml of dichloromethane and 60 ml of water.
• the organic layer is separated, washed with 60 ml of brine and dried (Na 2 SO 4 ).
• the solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated under vacuum to give 12.8 g of a solid.
• Methyl 2-[N-(4-ethoxy-4-oxobutyl)-N-(2- methylphenylsulfonyl)amino)benzoate A mixture of 2.65 g of methyl 2-[(4-ethoxy-4-oxobutyl)amino]benzoate, 2.0 g of 2-methylphenylsulfonyl chloride and pyridine is heated on a steam bath for 16 hours. The mixture is concentrated under a vacuum (remove pyridine) and 1N HCI added. The mixture is extracted with dichloromethane and the extract washed with 1NHCl, H 2 O, 1 M NaHCO 3 , brine and dried (Na 2 SO 4 ).
• 1,4,5,6-Tetrabydropyrazolo-[4,3-d][1]benzazepine A mixture of 1.0 g of 1,4,5,6-tetrahydro-6- [(2-methylphenyl)sulfonyl]pyrazolo[4,3-d][1]benzazepine in 60 ml of 40% (V/v)H 2 SO 4 in glacial acetic acid is heated at 60°C for 12 hours or until the tosyl group is removed. The mixture is poured into 100 ml ice and water with cooling. Solid NaOH is added portionwise (temperature kept below 30°C) with efficient stirring and the pH brought to 8. The mixture is extracted with ethyl acetate and the extract dried (Na 2 SO 4 ) and the solvent removed to give a solid.
• the mixture is refluxed for 2 hours ana extracted with ethyl acetate.
• the extract is washed with 2H citric acid, H 2 O, brine and dried (Na 2 SO 4 ).
• the solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness under vacuum.
• the residue is chromatographed on a column (2" ⁇ 18") of silica gel (32° g) with hexane-ethyl acetate (1:1) as solvent to give 0.78 g of crystals, m.p. 172-174°C.
• tetrahydrofuran cooled to -78°C, is added 20 ml of a 2.5 molar solution of n-butyl lithium in hexane. The mixture is stirred -78°C for 15 minutes and at 0°C for 30 minutes. To the stirred solution is added 6.0 g of 2-methylbenzoxazepine-4-one. The mixture is stirred at room temperature for 16 hours quenched with ice cold water and extracted with chloroform. The extract is concentrated to dryness and 100 ml of 40% H 2 SO 4 is added.
• a mixture of 5.0 g of 2-(phenylmethyl)benzoic acid in 5.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are evaporated in vacuo to give 5.70 g of an oil.
• a 2.85 g portion of the above oil in 25 ml of methylene chloride is added to a solution of 50 ml of methylene chloride containing 1.85 g of methyl 4-amino-2-chlorobenzoate and 1.65 g of N,N-diisopropylethylamine by stirring at room temperature for 18 hours.
• the reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried (Na 2 SO 4 ).
• Methyl 3-Methoxy-4-[([4'-trifluoromethyl)[1,1'- biphenyl]-2-carbonyl)amino]benzoate A solution of 3.56 g of [4'- (trifluoromethyl)[1,1'-biphenyl]-2-carbonyl chloride in 25 ml of methylene chloride is added dropwise to an ice cold solution of 1.81 g of methyl 4-amino-3-methoxybenzoate and 1.62 g of N,N-diisopropylethylamine in 50 ml of methylene chloride.
• the reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried (Na 2 SO 4 ).
• the organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 3.9 g of the desired product as a crystalline solid, m.p. 112-113°C.
• Methyl 2-Chloro-4-[([4'-(trifluoromethyl)[1,1'- biphenyl]-2-carbonyl)aminolbenzoate A solution of 3.56 g of [4'- (trifluoromethyl)[1,1'-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.86 g of methyl 2-chloro-4-aminobenzoate and 1.6 g of N,N-diisopropylethylamine in 50 ml of methylene chloride.
• reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO 3 and the organic layer dried (Na 2 SO 4 ).
• the organic layer is passed through a pad of hydrous magnesium silicate (3X) and hexane added to the filtrate at the boil to give 4.0 g of the desired product as a crystalline solid, m.p. 130-132°C.
• 2-(2-Pyridinyl)benzoic Acid A mixture of 3.0 g of methyl 2-(2-pyridinyl)benzoate and 600 mg of sodium hydroxide in 50 ml of 9:1 methanol : water is refluxed for 4 hours. The reaction mixture is concentrated in vacuo and the residue dissolved in 50 ml of cold water. The solution is neutralized with glacial acetic acid and the
• Example 2 As described for Example 1, a mixture of 4,10-dihydro-5H-thieno[3,2-c][1]benzazepine and triethylamine in dichloromethane is reacted with 6-[(5-fluoro-2-methylbenzoyl)amine]pyridine-3-carbonyl chloride to give the product as a solid.
• 1,4,5, 6-tetrahydropyrazolo [4,3-d][1]benzazepine is reacted with 5 mmol of [ 1,1'-biphenyl]-4-carbonyl chloride.
• the product is stirred in methanol with 2N NaOH fcr 16 hours and the mixture concentrated and extracted with ethyl acetate.
• the extract is washed with 1 M citric acid, NaHCO 3 , H 2 O, dried (Na 2 SO 4 ) and the solvent removed to give the product of the example as a solid.
• To a mixture of 0.197 g of 10,11-dihydroaibenz[b,f][1,4]oxazepine and 0.402 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]benzoyl chloride in 5 ml of dichloromethane (cooled in ice bath) is added dropwise 0.154 g of N, N-diisopropylethylamine in 2 ml of dichloromethane.
• the mixture is stirred at room temperature under argon for 2 hours.
• the mixture is poured into water and the organic layer separated.
• the organic extract is washed with 2N Na 2 CO 3 , water, brine and dried (Na 2 SO 4 ).
• the solution is filtered through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane.
• the filtrate is concentrated to dryness to give 0.65 g of solid.
• the solid is purified by thick layer chromatography on silica gel with hexane-ethyl acetate (2:1) as solvent to give 0.110 g of a glass, m.p. 107°C-122°C. Anal.
• N,N-diisopropylethylamine in 7 ml of dichloromethane is stirred at room temperature for 3 hours.
• the mixture is poured into water and extracted with dichloromethane.
• the extract is washed with 2N Na 2 CO 3 , water, brine and dried (Na 2 SO 4 ).
• the solution is filtered through a thin pad of hydrous magnesium silicate (pad washed with dichloromethane).
• the filtrate is concentrated to dryness to give a yellow solid.
• the solid is purified by chromatography on thick layer silica gel plates with hexane-ethyl acetate (1:1) as solvent to give 0.12 g of
• Example 65 As described for Example 48 the following compounds can be prepared. Example 65
• Example 88 N-[5-(Pyrido[2,3-b][1,5]benzoxazepin-6(5H)-ylcarbonyl)- 2-pyridinyl]-2-(dimethylamino)-4-pyridinylcarboxamide As described for Example 67, the following compounds can be prepared.
• Example 88 N-[5-(Pyrido[2,3-b][1,5]benzoxazepin-6(5H)-ylcarbonyl)- 2-pyridinyl]-2-(dimethylamino)-4-pyridinylcarboxamide As described for Example 67, the following compounds can be prepared.
• Example 88 N-[5-(Pyrido[2,3-b][1,5]benzoxazepin-6(5H)-ylcarbonyl)- 2-pyridinyl]-2-(dimethylamino)-4-pyridinylcarboxamide
• Example 67 As described for Example 67, the following compounds can be prepared.
• Example 66 As described for Example 66., the reaction of 5,6-dihydropyrido[2,3-b][1,4]benzoxazepine (0.198 g) with 6-[([1,1'-biphenyl]-2-carbonyl)amino]pyridine-3-carbonyl chloride (0.404 g) in dichoromethane in the presence of ⁇ . N-diisopropylethylamine (0.155 g) gives the product as a solid.
• the solid is purified by chromatography on silica gel to give the product as a solid.
• a 4.85 g sample of crude product is triturated with ether to give 2.68 g of 6,11-dihydropyrido[2,3-b][1,5]benzodiazepine as a solid.
• dichloromethane is stirred at room temperature for 1.5 hours.
• the mixture is poured into water and extracted with dichloromethane.
• the extract is washed with H 2 O, saturated NaHCO 3 , H 2 O, brine and dried (Na 2 SO 4 ).
• the solution is filtered through a thin pad of hydrous megnesium silicate and the filtrate concentrated to dryness.
• the residue is purified on thick layer silica gel plates with hexane-ethyl acetate (1:2) as solvent to give the product as a solid which is crystallized from ethyl acetate to give off-white crystals, m.p. 220°C-221°C.
• dichloromethane is stirred at room temperature for 1.5 hours.
• the mixture is poured into water and extracted with dichloromethane.
• the extract is washed with H 2 O, saturated NaHCO 3 , H 2 O, brine and dried (Na 2 SO 4 ).
• the solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness.
• the residue is chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1:2) to give 0.160 g of solid, m.p. 147°C-165°C.
• Hydrogen chloride gas is bubbled into 50 ml of anhydrous chilled methanol for 15 minutes. A 25 ml sample of the methanolic hydrogen chloride is added to 0.30 g of N-[4-(6,11-dihydropyrido[2,3-b][1,5]benzodiazepin-6(5H)-ylcarbonyl)phenyl][1,1'-biphenyl]-2-carboxamide. The mixture is stirred at 0°C for 0.5 hours and allowed to warm to room temperature. The solvent is removed and the solid dried under vacuum to give 0.31 g of solid, m.p. 195°C-210°C.
• Example 134 the following compounds can be prepared by reaction of 6,11-dihydropyrido[2,3-b][1,5]benzodiazepine with the
• Example 302 the following compounds can be prepared by reaction of 6,11-dihydro-5H-dibenz[b,e]azepine with the appropriate substituted or unsubstituted 4-[(arycarbonyl)amino]benzoyl chloride or the appropriate substituted or unsubstituted 6-[(arycarbonyl)amino]pyridine-3-carbonyl chloride
• Example 352 the following compounds can be prepared by reaction of 6,11-dihydro-5H-pyrido[2,3-b][1,4]benzodiazepine with the appropriate substituted or unsubstituted 4-[(arylcarbonyl)amino]benzoyl chloride or the appropriate substituted or unsubstituted 6-[(arylcarbonyl)amino]pyridine-3-carbonyl chloride
• LAH LAH
• dichloromethane which contains 7 ml of N,N-diisopropylethylamine.
• the mixture is stirred at room temperature for 16 hours and then is washed with water, 1N HCI, saturated sodium bicarbonate solution, water and dried (Na 2 SO 4 ).
• the solvent is removed and the residue purified by chromatography on silica gel with ethyl acetate-hexane (1:3) to give 1.1 g of a solid, m.p.
• Rat liver plasma membranes expressing the vasopressin V 1 receptor subtypes are isolated by sucrose density gradient according to the method described by lesko et al., (1973). These membranes are quickly suspended in 50.0 mM Tris.HCl buffer, pH 7.4, containing 0.2% bovine serum albumin (BSA) and 0.1 mM
• BSA bovine serum albumin
• phenylmethylsulfonyifluoride (PMSF) and kept frozen at -70°C until used in subsequent binding experiments.
• PMSF phenylmethylsulfonyifluoride
• the following is added to the wells of a ninety-six well format micrctiter plate: 100 ml of 100.0 mM Tris.HCl buffer containing 10.0 mM MgCl 2 , 0.2% heat inactivated BSA and a mixture of protease
• leupeptin 1.0 mg%; aprotinin, 1.0 mg %; 1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mM PMSF, 20.0 ml of [phenylalanyl-3,4,5,- 3 H] vasopressin (S.A. 45.1 Ci/mmole) 0.8 mM, and the reaction initiated by the addition of 80 ml of tissue membranes containing 20 mg of tissue protein. The plates are kept undisturbed on the bench top at room temperature for 120 min. to reach equilibrium. Non-specific samples are assayed in the presence of 0.1 mM of the unlabeled antagonist phenyialanylvasopressin, added in 20.0 ml volume.
• test compounds For test compounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 ml volume to a final incubation volume of 200 ml. Upon completion of binding, the content of each well is filtered off, using a Brandel® cell Harvester (Gaithersburg, MD). The radioactivity trapped on the filter disk by the ligand-receptor complex is assessed by liquid scintillation counting in a Packard LS Counter, with an efficiency of 65% for tritium. The data are analyzed fcr IC 50 values by the LUNDON-2 program for competition (LUNDON).
• DMSO dimethylsulfoxide
• Medullary tissues from rat kidneys are dissected out, cut into small pieces and soaked in a 0.154 mM sodium chloride solution containing 1.0 mM EDTA with many changes of the liquid phase, until the solution is clear of blood.
• the tissue is homogenized in a 0.25 M sucrose solution containing 1.0 mM EDTA with many changes of the liquid phase, until the solution is clear of blood.
• the tissue is homogenized in a 0.25 M sucrose solution containing 1.0 mM EDTA and 0.1 mM PMSF using a Potter-Elvehjem homogenizer with a teflon pestle.
• the homo ⁇ enate is filtered throu ⁇ h several layers (4 layers) of cheese cloth.
• the filtrate is rehomogenized using a dounce homogenizer, with a tight fitting pestle.
• the final homogenate is centrifuged at 1500 X g for 15 min.
• the nuclear pellet is discarded and the supernatant fluid recentrifuged at 40,000 ⁇ g for 30 min.
• the resulting pellet formed contains a dark inner part with the exterior, slightly pink.
• the pink outer part is suspended in a small amount of 50.0 mM Tris.HCl buffer, pH 7.4.
• the protein content is determined by the Lowry's method (Lowry et al., J. Biol. Chem., 1953).
• the membrane suspension is stored at - 70°C, in 50.0 mMTris.HCl, containing 0.2% inactivated BSA and 0.1 mM PMSF in aiiquots of 1.0 ml containing 10.0 mg protein per ml of suspension until sue in subsequent binding experiments.
• Frozen platelet rich plasma received from the Hudson Valley Blood Services, are thawed to room temperature.
• Platelet Source Hudson Valley Blood Services, Westchester Medical Center, Valhalla, NY.
• the tubes containing the PRP are centrifuged aa
• KC1 to give 1.0-2.0 mg protein per ml of suspension.
• the flasks containing the attached cells are rinsed with 2 ⁇ 5 ml of phosphate buffered saline (PBS) and the liquid aspirated off each time.
• PBS phosphate buffered saline
• 5 ml of an enzyme free dissociation Hank's based solution (Specialty Media, Inc., Lafayette, NJ is added and the flasks are left undisturbed for 2 minutes.
• the content of all flasks is poured into a centrifuge tube and the cells pelleted at 300 ⁇ g for 15 minutes.
• the Hank's based solution is aspirated off and the cells homogenized with a polytron at setting #6 for 10 sec in 10.0 mM Tris.HCl buffer, pH 7.4 containing 0.25 M sucrose and 1.0 mM EDTA.
• the homogenate is centrifuged at 1500 ⁇ g for 10 minutes to remove ghost membranes.
• the supernatant fluid is centrifuged at 100,000 ⁇ g for 60 minutes to pellet the receptor protein. Upon completion, the pellet is resuspended in a small volume of 50.0 mM Tris.HCl buffer, pH 7.4.
• the protein content is determined by the Lowry method and the receptor membranes are suspended in 50.0 mM Tris.HCl buffer containing 0.1 mM phenylmethylsulfonylfluoride (PMSF) and 0.2% bovine serum albumin (BSA) to give 2.5 mg receptor protein per ml of suspension.
• PMSF phenylmethylsulfonylfluoride
• BSA bovine serum albumin
• Fcr binding experiments the following is added in ml volume to wells of a 96 well format of a microtiter plate: 100.0 ml of 100.0 mM Tris.HCl buffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl 2 and a mixture of protease inhibitors: ieupeptin, 1.0 mg%; aprotinin, 1.0 mg%; 1,10-phenanthroline, 2.0 mg %;
• trypsin inhibitor 10.0 mg % and 0.1 mM PMSF., 20.0 ml of [ 3 H] Arginine 8 , vasopressin (S.A. 75.0 Ci/mmole) at 0.8 nM and the reaction initiated by the addition of 80.0 ml of tissue membranes (200.0 mg tissue protein).
• tissue membranes (200.0 mg tissue protein).
• the plates are left undisturbed on the bench top for 120 minutes to reach equilibrium. Non specific binding is assessed in the presence of 1.0 mM of unlabeled ligand, added in 20 ml volume. For test compounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 ml volume to a final incubation volume of 200 ml.
• DMSO dimethylsulfoxide
• Conscious hydrated rats are treated with compounds under study from 0.1 to 100 mg/kg orally or vehicle. Two to four rats are used for each compound. One hour later, arginine vasopressin (AVP, antidiuretic hormone, ADH) dissolved in peanut oil is administered at 0.4 mg/kg intraperitoneally. Two rats in each test would not receive arginine vasopressin but only the vehicle (peanut oil) to serve as water-loading control. Twenty minutes later each rat is given 30 mL/kg of deionized water orally by gavage and is placed
• Urine volume is measure and osmolality analyzed by use of a Fiske One-Ten osmometer (Fiske Assoc.., Norwood, MA, USA).
• Urinary sodium, potassium, and chloride are analyzed by use of ion-specific electrodes in a Beckman E3 (Electrolye 3) Analyzer.
• a Fiske One-Ten osmometer Fiske Assoc.., Norwood, MA, USA.
• Urinary sodium, potassium, and chloride are analyzed by use of ion-specific electrodes in a Beckman E3 (Electrolye 3) Analyzer.
• Vasopressin V 1 Antagonist Activity in Conscious Rats
• Conscious rats are restrained in a supine position with elastic tape.
• the area at the base of the tail is locally anesthetized by subcutaneous
• 2% procaine 0.2 ml
• a cannula made of FE 10 and 20 (heat-fused) tubing is passed into the lower abdominal aorta.
• the cannula is secured, heparinized (1000 iu/cc), sealed and the wound closed with one or two stitches of Dexon 4-0.
• the caudal vein is also cannulated in the same manner for intravenous drug administration. The duration of the surgery is approximately 5 minutes. Additional local anesthesia (2% procaine or iidocaine) is provided as needed.
• the animals are placed in plastic restraining cages in an upright position.
• the cannula is attached to a Statham P23Db pressure transducer and pulsatile blood pressure is recorded.
• each rat is dosed orally with compounds under study 0.1-100 mg/kg (10 cc/kg) or intravenously 0.1-30 mg/kg (1 cc/kg).
• the vasopressin injections are repeated 30,60,90,120,180,240 and 300 minutes later. Percentage of antagonism by the compound is calculated using the pre-drug vasopressin vasopressor response as 100%.
• mice Female Sprague-Dawley rats weighing approximately 200-250 g are injected intramuscularly (i.m.) with 0.3 mg/kg of body weight of
• DES diethylstilbestrol
• the rats are sacrificed 18 hours later under pentobarbital anesthesia.
• the uteri are dissected out, cleaned of fat and connective tissues and rinsed in 50 ml of normal saline.
• the tissue pooled from six rats is homogenized in 50 ml of 0.01 mM Tris.
• HCI containing C .5 mM dithiothreitol and 1.0 mM EDTA, adjusted to pH 7.4, using a polytron at setting 6 with three passes of 10 sec each.
• the homogenate is passed through two (2) layers of cheesecloth and the filtrate centrifuged at 1000 ⁇ g for 10 minutes.
• the clear supernatant is removed and recentrifuged at 165,000 ⁇ g for 30 minutes.
• the resulting pellet containing the oxytocin receptors is resuspended in 50.0 mM Tris.HCl containing 5.0 mM MgCl 2 at pH 7.4, to give a protein concentration of 2.5 mg/ml of tissue suspension. This preparation is used in subsequent binding assays with [ 3 H] oxytocin.
• Binding of 3,5-[ 3 H]Oxytocin ([ 3 H]OT) to its receptors is done in micrctiter plates using [ 3 H]OT, at various concentrations, in an assay buffer of 50.0 mM Tris.HCI, pH 7.4 and containing 5.0 mM MgCl 2 , and a mixture of protease inhibitors: BSA, 0.1 mg; aprotinin, 1.0 mg; 1,10-phenanthroiine, 2.0 mg; trypsin, 10.0 mg; and PMSF, 0.3 mg per 100 ml of buffer solution.
• Non-specific binding is determined in the presence of 1.0 uM unlabeled OT.
• the binding reaction is terminated after 60 minutes, at 22°C, by rapid filtration through glass fiber filters using a Erandel® cell harvester
• V 2 Vasopressin Antidiuretic
• mice Male or female normotensive Sprague-Dawley rats (Charles River Laboratories, Inc., Springfield, NY) of 400-450 g of body weight were supplied with Laboratory Rodent Feed #5001 (PMI Feeds, Inc., Richmond, IN) and water ad libitum. On the day of test, rats were placed
• DMSO dimethylsulfoxide
• the compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases.
• These salts include, but are not limited to, the following: salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maieic acid.
• Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium cr magnesium or with organic bases.
• the compounds can also be used in the form of esters, carba.mates and other conventional "pro-drug" forms, which, when administered in such form, convert to the active moiety in vivo .
• the compounds When the compounds are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers, fcr example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectabie solutions cr suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium.
• Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
• the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in a sustained release form. For most large mammals the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg.
• Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
• active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes.
• Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glyccls, non-ionic surfac tants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.
• Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
• compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
• active compounds may also be administered parenterally or intraperitoneally.
• Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
• Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectabie solutions or dispersions.
• the form must be sterile and must be fluid to the extent that easy syringability exits. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi.
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.
• the new tricyclic non-peptide vasopressin antagonists of this invention are useful in treating conditions where decreased vasopressin levels are desired, such as in congestive heart failure, in disease conditions with excess renal water reabsorption and in conditions with increased vascular resistance and coronary vasoconstriction.
• vasopressin antagonists of this invention are therapeutically useful in the treatment and/or prevention of hypertension, cardiac insufficiency, coronary vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis, congestive heart failure, nephritic syndrome, brain edema, cerebral ischemia, cerebral hemorrhage-stroke, thrombosis-bleeding and abnormal states of water retention.
• the oxytocin antagonists of this invention are useful in the prevention of preterm labor and premature birth which is a significant cause of infant health problems and infant mortality.

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