MXPA01007918A - Pyridobenzodiazepine and pyridobenzoxazepine carboxyamide vasopressin agonists - Google Patents

Abstract

The present invention provides benzoheterocyclic carboxyamides, particularly pyridobenzodiazepine and pyridobenzoxazepine carboxyamides, of general formula (I), wherein:W is O or NH, optionally substituted, as well as methods and pharmaceutical compositions utilizing these compounds for providing a temporary delay of urination or for the treatment of disorder which may be remedied or alleviated by vasopressin agonist activity, including diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence, bleeding or coagulation disorders.

Description

AGRONISTS OF CARBOXYAMIDE VASOPRESSIN OF PIRIDOBENZODIAZEPINA AND PIRIDOBENZOXAZEPINA This invention relates to benzoheterocyclic carboxyamides, particularly carboxyamides of pyridobenzodiazepine and pyridobenzoxazepine, which act as vasopressin agonists V2, as well as treatment methods and pharmaceutical compositions using these compounds.

BACKGROUND OF THE INVENTION Vasopressin (antidiuretic hormone, ADH), a nonapeptide hormone and a neurotransmitter, is synthesized in the supraoptic nuclei of the hypothalamus of the brain and transported through the supraoptic-pituitary tract to the posterior pituitary where it is stored. Upon sensing an increase in plasma osmolality by brain osmoreceptors or a decrease in blood volume or blood pressure (detected by baroreceptors and volume receptors), vasopressin is released into the bloodstream and activates the receptors of vasopressin V? a in blood vessels causing vasoconstriction to raise blood pressure; and the vasopressin V2 receptors of the REF: 131753 Nephron of the kidney causing the reabsorption mainly of water and to a lesser degree of electrolytes, to expand the volume of the blood (Cervoni and Chan, Di uretic Agents, in Kirk-Othmer, Encyclopedia of Chemical Technology, 4th edition, Wiley, Volume 8, 398-432, (1993)). The existence of vasopressin in the pituitary is known as early as 1895 (Oliver and Schaefer, J. Physiol. (London), 18, 277-279, (1985)). The determination of the structure and total synthesis of vasopressin were carried out by du Vigneaud et al. In 1954 (du Vigneaud, Gish and Katsoyannis, J. Am. Chem. Soc., 76, 4751-4752, (1954)). The actions of Via vasopressin receptors are mediated through the phosphatidylinositol pathway. Activation of vasopressin VXa receptors causes contraction of the smooth muscle of blood vessels to raise blood pressure. The actions of the vasopressin V2 receptors are mediated through the activation of the adenylate cyclase system and the elevation of the intracellular levels of cAMP. Activation of vasopressin V2 receptors by vasopressin or vasopressin-like compounds (peptidic or non-peptidic) increases the water permeability of the collecting ducts of the nephron and allows the reabsorption of a large amount of free water. The final result is the formation and excretion of a concentrated urine, with a decrease in the volume of urine and an increase in urine osmolality. Vasopressin plays a vital role in water conservation by concentrating urine at the site of the collecting ducts of the kidney. The collecting ducts of the kidney are relatively impervious to water without the presence of vasopressin in the receptors and therefore, the hypotonic fluid formed after filtering through the glomeruli, passing the coiled tubule proximal, the loops of Henle and the tubules distal coils will be excreted as diluted urine. However, during dehydration, volume depletion or blood loss, vasopressin is released from the brain and activates the vasopressin V2 receptors in the collecting ducts of the kidney making the ducts very permeable to water; therefore the water is reabsorbed and a concentrated urine is excreted. In patients and animals with central diabetes or insensitive neurogenic, the synthesis of vasopressin in the brain is defective and therefore, they produce very little or no vasopressin, but their vasopressin receptors in the kidneys are normal. Because they can not concentrate urine, they can produce as much as 10 times the urine volumes of their healthy counterparts and these are very sensitive to the action of the vasopressin and vasopressin V2 agonists. Vasopressin and desmopressin, which is a peptide analog of natural vasopressin, are being used in patients with central diabetes insipidus. Vasopressin V2 agonists are also useful for the treatment of nocturnal enuresis, nocturia, urinary incontinence and temporary urine retardation whenever it is desirable. Vasopressin, through the activation of its Via receptors, exerts vasoconstriction effects to raise blood pressure. An antagonist of vasopressin V? A receptors will counteract this effect. Vasopressin and vasopressin-like agonists release factor VIII and von Willebrand factor so that they are useful for the treatment of bleeding disorders, such as hemophilia. Vasopressin or vasopressin-like agonists also release the tissue-type plasminogen activator (t-PA) into the bloodstream so that they are useful in the dissolution of blood clots such as in patients with myocardial infarction. and other thromboembolic disorders (Jackson, "Vasopressin and other agents affecting the renal conservation of water", in Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9th edition, Hadman, Limbird, Molinoff, Ruddon and Gilman Eds., McGraw-Hill, New York, pages 715-731 (1996); Lethagen, Ann. Hema tol. 69, 173-180 (1994); Cash and collaborators, Bri t. J. Haema tol, 27, 363-364 (1974); David, Regula Tory Peptides, 45, 311-317 (1993); Burggraaf et al., CU. Sci. , 86, 497-503 (1994)). The following references in the prior art describe peptide vasopressin antagonists: Manning et al., J. Med. Chem. , 35, 382 (1992); Manning et al., J. Med. Chem. , 35, 3895 (1992); Gavras and Lammek, North American Patent No. 5,070,187 (1991); Manning and Sawyer, North American patent No. ,055,448 (1991); Ali, North American patent No. 4,766,108 (1988); Ruffolo et al., Drug News and Perspectives 4 (4), 217 (May 1991); Albright and Chan, Curr, Pharm. Des. 3 (6), 615 (1997). Williams et al. Have reported on potent hexapeptide oxytocin antagonists [J. Med. Chem. , 35, 3905 (1992)] which also exhibit an antagonistic activity of weak vasopressin in binding to Vi and V2 receptors. Peptide vasopressin antagonists suffer from a lack of oral activity and many of these peptides are nonselective antagonists since they also exhibit partial agonizing activity. Non-peptide vasopressin antagonists have recently been described. Albright et al. Describe tricyclic azepines as antagonists of vasopressin and oxytocin in U.S. Patent No. 5,516,774 (1996), tetrahydrobenzodiazepine derivatives as vasopressin antagonists are described in J.P. 0801460-A (1996); Ogawa et al. Describe benzoheterocyclic derivatives as antagonists of vasopressin and oxytocin, and as vasopressin agonists in WO 9534540-A; and Venkatesan et al. disclose tricyclic benzazepine derivatives as vasopressin and oxytocin antagonists in U.S. Patent No. 5,521,173 (1996). As mentioned above, desmopressin (l-deamino-8-D-arginine vasopressin) (Huguenin and Biossonnas, Helv. Chim. Acta, 49, 695 (1966)) is a vasopressin agonist. The compound is a synthetic peptide with variable bioavailability. An intranasal route is poorly tolerated and an oral formulation for nocturnal enuresis requires a dose 10-20 times greater than intranasal administration. Albright et al. Describe a subset of pyrido benzodiazepine and pyridooxazepine indole carboxyamides of the present application, as antagonists of the vasopressin Vi and / or V2 receptors and oxytocin receptor antagonists in U.S. Patent No. 5,521,563 (1996); U.S. Patent No. 5,686,445 (1997); U.S. Patent No. 5,736,538 (1998); European Patent No. EP 640592 Al (1995); WO 97/47624 Al; and WO 97/47625 Al, inter alia. The compounds of the general structure 16b in Reaction Scheme 4 of the above applications are taught by Albright et al. Which possess antagonistic properties of the vasopressin and oxytocin receptors. 16b, Scheme 4 (Albrigh et al.) Where Y = N or O; R = H, or lower alkyl (1 to 3 carbon atoms).

However, it has unexpectedly been found that the above indole carboxyamides of the general structure 16b are agonists of vasopressin V2 receptors in vivo, and thus have different biological profile and clinical utility from those originally described. In this way, preferably having an aquatic effect (elimination of water), these unexpectedly cause the resorption of water, that is, they reduce the volume of the urine and increase the osmolality of the urine. The compounds of this invention are non-peptidic and have good oral bioavailability. These are vasopressin V2 receptor agonists and as such these promote the reabsorption of water. These do not demonstrate agonist effects of vasopressin Via receptors and, thus, do not raise blood pressure. In contrast, the compounds of the prior art (except some in WO 9534540-A) are described as vasopressin antagonists at the receptors of both Via and V2.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to new and known compounds selected from those of the formula (I): wherein: X, Y and Z are independently selected from a group consisting of O, S, CH, CH2, N, or NR4; W is NR5 or O; Ri and R2 are independently hydrogen, straight chain alkyl (1 to 6 carbon atoms), branched chain alkyl (3 to 7 carbon atoms), cycloalkyl (3 to 7 carbon atoms), alkoxyalkyl (2 to 7 carbon atoms) carbon), halogen, straight or branched chain alkoxy (1 to 6 carbon atoms), hydroxy, CF3, or perfluoroalkyl (2 to 6 carbon atoms); R3 is hydrogen or a straight chain alkyl group (1 to 6 carbon atoms), branched chain alkyl (3 to 7 carbon atoms), cycloalkyl (3 to 7 carbon atoms, alkoxyalkyl (2 to 7 carbon atoms) , or hydroxyalkyl (1 to 6 carbon atoms), R 4 is selected from hydrogen, or lower alkyl (1 to 6 carbon atoms), and R 5 is independently selected from hydrogen, acyl (2 to 6 carbon atoms), straight chain (1 to 6 carbon atoms), or branched chain alkyl (3 to 7 carbon atoms), R6 is selected from hydrogen or halogen, or a pharmaceutically acceptable salt thereof. Formula (I) for the structure: are the following; Among the preferred compounds of this invention are: (5,11-Dihydro-pyrido [2,3-b] [1,5] benzodiazepin-10-yl) - (1-methyl-1H-indol-5-yl) - methanone; Benzo [1,3] dioxol-5-i1- (5,11-dihydro-pyrido [2,3-b] [1,5] benzodiazepin-10-yl) -methanone; (2,3-dihydro-benzofuran-5-yl) - (5,11-dihydro-pyrido [2, 3-b] [1, 5] benzodiazepin-10-yl) -methanone; Benzo [2] oxa [1,3] diazol-5-yl- (5,11-dihydro-pyrido [2, 3-b] [1,5] benzodiazepin-10-yl) -methanone; Benzothiazol-6-yl- (5,11-dihydro-pyrido [2, 3-b] [1,5] benzodiazepin-10-yl) -methanone; and (l-Methyl-lH-indol-5-yl) - (HH-5-oxa-4, 10-diaza-dibenzo [a, d] cyclohepten-10-yl) -methanone; It is understood by those practicing the art that some of the compounds of this invention, depending on the definition of Ri, R2, R, R4, and R5, may contain one or more asymmetric centers and thus may give rise to optical isomers and diastereomers. The present invention includes such optical isomers and diastereomers; as well as the enantiomerically pure, racemic and resolved R and S stereoisomers and pharmaceutically acceptable salts thereof, which possess the indicated activity. The optical isomers can be obtained in pure form by normal procedures known to those of skill in the art. It is also understood that this invention encompasses all possible regioisomers, and mixtures thereof which possess the indicated activity. Such regioisomers can be obtained in pure form by normal separation methods, known to those of skill in the art. The pharmaceutically acceptable salts are those derived from such organic and inorganic acids as; citric, lactic, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic and similarly known acceptable acids.

Also according to the present invention, methods of treatment, prevention or alleviation of disorders are provided which are corrected or alleviated by the agonizing activity of the vasopressin receptor. These methods for inducing vasopressin agonism in a mammal include, but are not limited to, methods of treating, preventing or alleviating diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence, bleeding disorders and coagulation, and to induce the time delay of urination whenever it is desirable, in humans or other mammals, which comprise administering to a human or other mammal an effective amount of a compound or a pharmaceutical composition of the invention. Accordingly, the present invention provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier or excipient. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier. The compositions are preferably adapted for oral administration. However, these can be adapted for other modes of administration, for example, parenteral administration for patients suffering from coagulation disorders. In order to obtain administration consistency, it is preferred that a composition of the invention be in the form of a unit dose. Suitable unit dosage forms include tablets, capsules and powders in pouches or flasks. These dosage unit forms may contain from 0.1 to 1000 mg of a compound of the invention and preferably from 2 to 50 mg. The still further preferred dosage unit forms contain from 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally in a dose range of about 0.01 to 100 mg / kg or preferably in a dose range of 0.1 to 10 mg / kg. These compositions can be administered from 1 to 6 times a day, more usually 1 to 4 times a day. The compositions of the invention can be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. These are formulated in a conventional manner, for example, in a manner similar to that used for known antihypertensive agents, diuretics and β-blocking agents.

Also according to the present invention, methods are provided for producing the compounds of the present invention.

PROCEDURE OF THE INVENTION The compounds of the present invention of the general formula (I) can be conveniently prepared according to the procedure shown in Reaction Scheme 1.

Reaction Scheme 1 In this manner, a pyridobenzodiazepine (benzoxazepine) of the formula (3, wherein W is O or NR5, and Ri R2 / R3 and n are as defined above) is treated with an appropriately activated heteroaryl carboxylic derivative of the formula (2). ) to provide the desired compounds of the formula (I) wherein Ri, R 2, R 3, R 4, R 5 R x / X, Y, Z, W and n are as defined above. The heteroaryl carboxylic acids of the general formula (1) can be activated as their acid halides, preferably the chloride (2, J = Cl), and can be reacted with the pyridobenzodiazepine (benzoxazepine) of the formula (3) in the presence of an inorganic base such as potassium carbonate in an aprotic, polar solvent such as N, -dimethylformamide; or an organic base such as 4-dimethylamino pyridine in an aprotic solvent such as dichloromethane or tetrahydrofuran at temperatures ranging from -40 ° C to 50 ° C. Alternatively, the acylation species of the formula (2) can be a mixed anhydride of the corresponding carboxylic acid, such as that prepared by treating the acid with 2, 6-trichlorobenzoyl chloride in an organic, aprotic solvent such as dichloromethane, according to the procedure of Inanaga and collaborators, Bull. Chem. Soc. Jpn. , 52, 1989 (1979). The treatment of the mixed anhydride of the general formula (2) with the pyridobenzodiazepine (benzoxazepine) of the formula (3) in an aprotic solvent such as dichloromethane and in the presence of an organic base such as 4-dimethylaminopyridine at temperatures ranging from 0 ° C to the reflux temperature of the solvent, produces a compound of the formula (I) wherein R 1 R2, R 3, R 4, R 5, R 6, X, Y, Z, W and n are as defined above. Alternatively, the activation of the carboxylic acids of the general formula (1) can be carried out by reacting the acids with other peptide coupling reagents known to those of skill in the art, in an aprotic, organic solvent such as dichloromethane, tetrahydrofuran, N, N-dimethylformamide, or the like, at temperatures ranging from -40 ° C to 120 ° C. The activation reagent for the carboxylic acids of the formula (1) is finally selected on the basis of its compatibility with the groups R4 and R5, and its reactivity with the tricyclic pyridobenzodiazepine (benzoxazepine) of the formula (3). Intermediates of carboxylic acid (1) of Reaction Scheme 1 are either commercially available, or are known in the art, or can be easily prepared by analogous methods for those in the literature for known compounds.

The compounds of the general formula (I) wherein R 4 is different from hydrogen; and W is NR5, and R5 is different from hydrogen; and Ri, R2, R3, X, Y, Z and n are as defined above, can be prepared by the alkylation or acylation of a compound of the formula (I, wherein W is NH, and R4 is different from hydrogen) of the Scheme 1, as summarized in Reaction Scheme 2 In this manner, the compound of the formula (I, W is NH, and R4 is not hydrogen) of Reaction Scheme 1 is alkylated by treatment with a base such as sodium (or potassium) hydride and an alkylating agent such as alkyl halide, preferably an alkyl chloride (bromide or iodide) in an aprotic solvent such as N, N-dimethylformamide or tetrahydrofuran at temperatures ranging from 0 ° C to 80 ° C to produce the compounds of the formula (I) in where W is NR5 and R5 is alkyl, R4 is different from hydrogen, and Ri, R2, R3, X, Y, Z and n are as defined above. Alternatively, the compounds of the formula (I, W is NH, and R is different from hydrogen) of Reaction Scheme 1 are acylated by treatment with a carboxylic acid halide or a carboxylic acid anhydride in the presence of an amine base such as pyridine or a trialkylamine such as triethylamine in an aprotic solvent such as dichloromethane or without the addition of a solvent when pyridine is used as the base, at temperatures ranging from 40 ° C to ambient, to produce the compounds of the formula ( 1) wherein W is R5 and R5 is acyl, R4 is different from hydrogen, and Ri, R2, R3, X, Y, Z and n are as defined above. The subject compounds of the present invention were tested for biological activity according to the following procedures.

Agonus Effects of Vasopressin V2 from Test Compounds in Water-Conscious, Normal-Conscious Rats Male or female normotensive Sprague-Dawley rats (Charles River Laboratories, Inc., Kingston, NY) of 350-500 g of body weight were supplied with a normal mouse diet (Purina Rodent Lab. Chow 5001) and water ad libitum. On the test day, rats were individually placed in metabolic cages equipped with devices to separate feces from urine and containers for collection of urine. A test compound or a reference agent was given in an oral dose of 10 mg / Kg in a volume of 10 mL / Kg. The vehicle used was 20% dimethyl sxide (DMSO) in preheated 2.5% corn starch. Thirty minutes after dosing the test compound, the rats were supercharged by means of a probe with water at 30 mL / Kg in the stomach using a feeding needle. During the test, the rats were not provided with water or feed. The urine was collected for four hours after dosing the test compound. At the end of the four hours, the volume of the urine was measured. Urine osmolality was determined using a Fiske One-Ten Osmometer (Fiske Associates, Norwood, MA, 02062) or an Advanced CRYOMATIC Osmometer, Model 3C2 (Advanced Instruments, Norwood, MA). The Na +, K + and Cl "ion determinations were carried out using ion-specific electrodes in a Beckman SYNCHRON EL-ISE Electrolyte System analyzer.The urine osmolality should be increased proportionally.In the selection test, two rats were used for Each compound If the difference in urine volume of the two rats was greater than 50%, a third rat was used.The results of this study are shown in Table 1.

Table 1 Decrease in the percentage of urine volume against the control in a dose of 10 mg / kg b Changes in osmolality expressed as the percentage of control in a dose of 10 mg / kg c Rat model used: Sprague-Dawley (CD) The following non-limiting examples further illustrate the invention.

Example 1 (5,11-Dihydro-pyrido [2,3-b] [1,5] benzodiazepin-10-yl) - (1-methyl-lH-indol-5-yl) -metanone Step A. Methyl ester of l-methyl-indole-5-carboxylic acid Under a nitrogen atmosphere, a solution of indole-5-carboxylic acid methyl ester (2.5 g, 14.3 mmol) in dry tetrahydrofuran (20 mL) was added dropwise to a stirred suspension of potassium hydride washed with hexane (1.63 g). , 14.3 mmol, 35% in oil). When the gas emission ceased, iodomethane (1.3 mL, 21.5 mmol) was added to the stirred solution. After an additional 30 minutes at room temperature, the precipitated product was filtered and washed with ethyl ether. The filtrate was concentrated in vacuo and the residue was triturated with hexane to give the title compound as a yellow solid (1.6 g). NMR (CDC13, 400 MHz): 5 3.82 (s, 3H), 3.93 (s, 3H), 6.58 (dd, 1H), 7.10 (d, 1H), 7.32 (d, 1H), 7.92 (dd, 1H) 8.39 (s, 1H) MS (El, m / z): 189 [M] +, 158, 130 Step B. l-Methyl-indole-5-carboxylic acid A solution of 1-methyl-indole-5-carboxylic acid methyl ester from Step A (2.5 g, 13.2 mmol) in ethanol (40 mL) containing 2.5N aqueous NaOH (3: 1, v / v) was heated to reflux for one hour. The reaction mixture was concentrated in vacuo, and the residue was partitioned between diethyl ether and IN HCl. The organic layer was washed with brine, dried over sodium ste and evaporated to dryness to give the title compound as an off-white solid (1.82 g). NMR (DMSO-de, 300 MHz): d 3.82 (s, 3H), 6.58 (dd, 1H), 7.42 (d, 1H), 7.48 (d, 1H), 7.75 (d, 1H), 8.22 (s, 1H), 12.38 (broad s, 1H) Step C. (5,11-Dihydro-pyrido [2,3-b] [1,5] benzodiazepin-10-yl) - (1-methyl-1H-indol-5-yl) -metanone Under anhydrous conditions, 2,4,6-trichlorobenzoyl chloride in one portion was added to a stirred solution of equimolar amounts of 1-methyl-indole-5-carboxylic acid (0.327 g, 1.87 mmol) from Step B, and triethylamine in dry dichloromethane (25-50 mL). When the anhydride formation was completed, 6,11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepine (0.519 g, 2.8 mmol) and N, N-dimethylaminopyridine were added to the clear solution. Agitation was continued until the reaction was completed (TLC). The reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. Removal of the solvent and chromatography with instantaneous evaporation of the residue (on Merck-60 silica gel, hexane-ethyl acetate 4: 1) afforded the title compound as a white solid (0.260 g), m.p. 147-148 ° C, in recrystallization with diethyl ether. NMR (DMSO-d6, 400 MHz): d 3.70 (s, 3H), 4.06 (broad d, 1H), 5.62 (broad d, 1H), 6.30 (s, 1H), 6.48 (t, 1H), 6.50 ( d, 1H), 6.73 (m, 1H), 6.89 (d, 1H), 7.05 (t, 1H), 7.20 (d, 1H), 7.33 (m, 2H), 7.43 (s, 1H), 7.51 (s) broad, 1H), 8.14 (m, 1H), 9.56 (s, 1H) MS (El, m / z): 354 [M] +, 158 Example 2 Benzo [1,3] dioxol-5-yl- (5,11-dihydro-pyrido [2, 3-b] [1,5] benzodiazepin-10-yl) -metanone Preparation of piperonyl acid (0.332 g, 2 mmol) and 6,11-dihydro-5H-pyrido [2,3-b] [1,5] benzodiazepine (0.398 g, 2 mmol) in an essentially identical manner as that of Example 1. The title compound was obtained as a white solid (0.400 g), mp 205-207 ° C, with recrystallization with diethyl ether. NMR (DMSO-d6, 400 MHz): d 4.06 (broad d, 1H), 5.54 (broad d, 1H), 5.97 (s, 2H), 6.57-6.75 (m, 6H), 7.07 (t, 1H), 7.30 (d, 1H), 7.51 (broad s, 1H), 8.09 (m, 1H), 9.56 (s, 1H) MS (El, m / z): 345 [M] +, 196, 181, 149 Calculated Analysis for C20H? 5N3O2: C 69. 56; H 4. 38; N 12 17 Found: C 69. 10; H 4. 58; N 12 04 Example 3 (2,3-Dihydro-benzofuran-5-yl) - (5,11-dihydro-pyrido [2, 3-b] [1,5] benzodiazepin-10-yl) -metanone Preparation of 2,3-dihydro-benzofuran-5-carboxylic acid (0.328 g, 2 mmol) and 6,11-dihydro-5 H -pyrido [2,3-b] [1,5] benzodiazepine (0.398 g, 2 mmol) ) in a manner essentially identical to that of Example 1. The title compound was obtained as an off-white solid, mp. 188 ° C, with recrystallization from diethyl ether. NMR (DMSO-d6, 400 MHz): d 3.05 (m, 2H), 4.06 (broad d, 1H), 4.47 (t, 2H), 5.60 (broad d, 1H), 6.51 (d, 1H), 6.60 ( m, 2H), 6.75 (m, 2H), 7.07 (m, 2H), 7.31 (d, 1H), 7.50 (broad m, 1H), 8.09 (m, 1H), 9.54 (s, 1H) EM (The , m / z): 343 [M] +, 196, 181, 147 Analysis Calculated for C2? H? 7N302: C 73.45; H 4.99; N 12.24.

Found: C 73.15; H 5.18; N 11.91 Example 4 Benzo [2] oxa [1,3] diazol-5-yl- (5,11-dihydro-pyrido [2, 3-b] [1,5] benzodiazepin-10-yl) -metanone Under a nitrogen atmosphere, an equimolar mixture of benzofurazan-5-carbonyl chloride (0.5 g, 2. 75 mmol), 6,11-dihydro-5H-pyrido [2, 3-b] [1,5] benzodiazepine (0.54 g, 2.75 mmol) and potassium carbonate in N, N-dimethylformamide (10 mL) was stirred at room temperature. environment for 1.5 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water and brine, and dried over sodium sulfate. The solution was filtered through a thin pad of Merck-60 silica gel and the filtrate was evaporated in vacuo. The residual oil was crystallized with diethyl ether to give the pure title compound as a yellow solid. (0.495 g), m.p. 193-194 ° C. NMR (DMSO-d6, 400 MHz): d 4.21 (d, 1H), 5.56 (d, 1H), 6.54 (t, 1H), 6.83 (m, 2H), 7.07 (t, 1H), 7.16 (d, 1H), 7.34 (d, 1H), 7.62 (d, 1H), 7.80 (s, 1H), 7.89 (d, 1H), 8.14 (m, 1H), 9.69 (s, 1H) MS (El, m / z): 343 [M] +, 196 Example 5 Benzothiazol-6-yl- (5,11-dihydro-pyrido [2, 3-b] [1,5] benzodiazepin-10-yl) -metanone Prepared benzothiazole-6-carbonyl chloride (0.55 g, 2.78 mmol) and 6,11-dihydro-5 H -pyrido [2, 3-b] [1,5] benzodiazepine (0.53 g, 2.7 mmol) in an essentially identical to that of Example 4. The title compound was obtained as a white solid (0.200 g), mp 237 ° C (with sintering at 233 ° C). NMR (DMSO-de, 400 MHz): d 4.17 (d, 1H), 5.60 (d, 1H), 6.47 (t, 1H), 6.61 (d, 1H), 6.77 (m, 1H), 7.03 (t, 1H), 7.10 (d, 1H), 7.32 (d, 1H), 7.60 (d, 1H), 7.84 (d, 1H), 8.06 (s, 1H), 8.12 (m, 1H), 9.40 (s, 1H) ), 9.62 (s, 1H) MS (El, m / z): 358 [M] +, 196, 181, 162 Example 6 (l-Methyl-lH-indol-5-yl) - (HH-5-oxa-4, 10-diaza-dibenzo [a, d] cyclohepten-10-yl-methanone) Under anhydrous conditions, 2,4,6-trichlorobenzoyl in one portion to a stirred solution of equimolar amounts of l-methyl-indole-5-carboxylic acid (0.124 g, 0.71 mmol) of Example 1, step B and triethylamine in dry dichloromethane (25-50) mL) After the formation of the anhydride was completed, 6,11-dihydro-5H-pyrido [2, 3-b] [1,5] benzodiazepine (0.141 g, 0.71 mmol) and N, N-dimethylamino were added. pyridine to the clear solution With the completion of the reaction (TLC), the mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate.The residue obtained in the evaporation of the solvent was flash chromatography on silica gel Merck-60 first with dichloromethane-ethyl acetate 4: 1, and then hexane-ethyl acetate. or was obtained as a white solid (0.045 g) • NMR (DMSO-d6, 400 MHz): d 3.71 (s, 3H), 5.11 (broad s, 2H), '6.38 (d, 1H), 6.91 (m , 2H), 7.05 (d, 1H), 7.22 (m, 2H), 7.27 (d, 1H), 7.32 (m, 2H), 7.56 (s, 1H), 8.24 (m, 1H) MS (El, m / z): 355 [M] +, 158 Example 7 Solvate of (6-bromo-benzo [1,3] dioxol-5-yl) - (5,1, -dihydropyrido [2, 3-b] [1 , 5] benzodiazepin-10-yl) -methanone with diethyl ether 0.23 Preparation of 6-bromo-l, 3-benzodioxol-5-carboxylic acid (0.150 g, 0.61 mmol) and 6,11-dihydro-5H-pyrido [2, 3-b] [1,5] enzodiazepine (0.119 g, 0.61 mmol) in a manner essentially identical to that of Example 1. The title compound was obtained as a white solid (0.075 g), mp. 249-250 ° C, with recrystallization from diethyl ether. NMR (DMSO-de, 400 MHz): d 4.10 (d, 1H), 5.38 (d, 1H), 5.99 (s, 2H), 6.58 (t, 1H), 6.80 (m, 2H), 7.02 (t, 2H), 7.24 (d, 1H), 7.34 (d, 1H), 7.56 (d, 1H), 8.08 ( d, 1H), 9.50 (s, 1H) MS (El, m / z): 423 [M] +, 344, 227 Anal. Calcd. For C20H26BrN2O2 + 0.23 C2H50: C 56.94; H 3.72; N 9.52. Found: C 56.57; H 3.61; N 9.40.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (11)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula (I): characterized in that X, Y and Z are independently selected from a group consisting of O, S, CH, CH2, N, or NR4; W is NR5 or O; Ri and R2 are independently hydrogen, straight chain alkyl (1 to 6 carbon atoms), branched chain alkyl (3 to 7 carbon atoms), cycloalkyl (3 to 7 carbon atoms), alkoxyalkyl (2 to 7 carbon atoms) carbon), halogen, straight or branched chain alkoxy (1 to 6 carbon atoms), hydroxy, CF3, or perfluoroalkyl (2 to 6 carbon atoms); R3 is hydrogen or a straight-chain alkyl group (1 to 6 carbon atoms), branched chain alkyl (3 to 7 carbon atoms), cycloalkyl (3 to 7 carbon atoms), alkoxyalkyl (2 to 7 carbon atoms) ), or hydroxyalkyl (1 to 6 carbon atoms); R 4 is selected from hydrogen, or lower alkyl (1 to 6 carbon atoms); and R5 is independently hydrogen, acyl (2 to 6 carbon atoms), straight chain alkyl (1 to 6 carbon atoms), or branched chain alkyl (3 to 7 carbon atoms); Re is H or halogen; or a pharmaceutically acceptable salt thereof.
2. 2. A compound according to claim 1, characterized in that it is (5,11-dihydro-pyrido [2, 3-b] [1,5] benzodiazepin-10-yl) - (1-methyl-1H-indol- 5-yl) -metanone.
3. 3. A compound according to claim 1, characterized in that it is benzo [1,3] dioxol-5-yl- (5,11-dihydro-pyrido [2,3-b] [1,5] benzodiazepine-10- il) -metanone. .
4. A compound according to claim 1, characterized in that it is (2,3-dihydro-benzofuran-5-yl) - (5,11-dihydro-pyrido [2,3-b] [1,5] benzodiazepine-10- il) -metanone.
5. 5. A compound according to claim 1, characterized in that it is benzo [2] oxa [1,3] diazol-5-yl- (5,11-dihydro-pyrido [2, 3-b] [1.5] benzodiazepin- 10-yl) -metanone.
6. 6. A compound according to claim 1, characterized in that it is benzothiazol-6-yl- (5,11-dihydro-pyrido [2, 3-b] [1,5] benzodiazepin-10-yl) -methanone.
7. 7. A compound according to claim 1, characterized in that it is (1-methyl-lH-indol-5-yl) - (HH-5-oxa-4, 10-diaza-dibenzo [a, d] cyclohepten-10) -il) -metanone.
8. 8. A compound according to claim 1, characterized in that it is a solvate of (6-bromo-benzo [1,3] dioxol-5-yl) - (5,11-dihydro-pyrido [2, 3-b] [1, 5] benzodiazepin-10-yl) -methanone with diethyl ether 0.23.
9. 9. The use of a compound according to claim 1 for the manufacture of a medicament for the treatment of disorders which are corrected or alleviated by the agonizing activity of vasopressin in a mammal.
10. 10. The use according to claim 9, characterized in that the disorder which is corrected or alleviated by the agonist activity of vasopressin is selected from the group of diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence, bleeding disorders and coagulation or the time delay of the urination.
11. 11. A pharmaceutical composition, characterized in that it comprises a pharmaceutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier or excipient. AGRONISTS OF THE CARBOXYAMIDE VASOPRESSIN OF PIRIDOBENZODIAZEPINA AND PIRIDOBENZOXAZEPINA SUMMARY OF THE INVENTION The present invention provides benzoheterocyclic carboxyamides, particularly carboxyamides of pyridobenzodiazepine and pyridobenzoxazepine, of the general formula (I), wherein: W is O or NH, optionally substituted, as well as also methods and pharmaceutical compositions using these compounds to provide a time delay of urination or for the treatment of a disorder which can be corrected or alleviated by the agonizing activity of vasopressin, which includes diabetes insipidus, nocturnal enuresis, nocturia, urinary incontinence, bleeding disorders and coagulation.