MXPA99004070A - 3-CARBOXAMIDE DERIVATIVES OF 5H-PYRROLO[2,1-c][1,4]-BENZODIAZEPINES - Google Patents

Abstract

This invention relates to 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, the compounds having general structure (I).

Description

DERIVATIVES 3-CARBOXAMIDE OF 5H-PIRROLO [2, 1-c] [1,4] - BENZODIACEPINES FIELD OF THE INVENTION: This invention relates to non-peptidic tricyclic vasopressin antagonists, which are useful for the treatment of conditions where lower effects of vasopressin are desired, such as in congestive collapse, in conditions of disease with resorption. excessive renal water, and in conditions with increased vascular resistance and coronary vasoconstriction.

Background of the Invention Vasopressin is released from the posterior pituitary, either in response to increased plasma osmolarity detected by cerebral osmoreceptors or decreased blood volume and blood pressure detected by volume and low pressure receptors and arterial baroreceptors. The hormone exerts its action through two well-defined types of receptors: vascular Vla receptors and renal epithelial V2. The vasopressin-induced antidiuresis, mediated by the renal epithelial receptors V2, helps maintain normal osmolarity, blood volume and blood pressure. Vasopressin is involved in some cases of congestive collapse where resistance REF. 29901 is increased peripherally. V? A receptor antagonists can decrease systemic vascular resistance, increase cardiac output, and prevent coronary vasoconstriction induced by vasopressin. Thus, under conditions with an increase induced by vasopressin in total peripheral resistance and altered local blood flow, VXa receptor antagonists can be therapeutically useful agents. Vla receptor antagonists can lower blood pressure, induce hypotensive effects, and thus be therapeutically useful in the treatment of some types of hypertension. Blockade of V2 receptors is useful for the treatment of diseases characterized by an excess of renal reabsorption of free water. Antidiuresis is regulated by the hypothalamic release of vasopressin (antidiuretic hormone), which binds to specific receptors on the cells of the renal collecting tubules. This binding stimulates adenylate cyclase and promotes the cAMP-mediated incorporation of water pores into the lumenal surface of these cells. V2 antagonists can correct fluid retention in congestive collapse, liver cirrhosis, nephritic syndrome, central nervous system damage, lung disease and hyponatremia.

Elevated vasopressin levels occur in congestive collapse, which is more common in elderly patients with chronic collapse. In patients with hyponatremic congestive collapse and elevated vasopressin levels, a V2 antagonist may be beneficial in promoting the excretion of free water by antagonizing the action of the antidiuretic hormone. On the basis of the biochemical and pharmacological effects of the hormone, vasopressin antagonists are expected to be therapeutically useful in the treatment and / or prevention of hypertension, heart failure, coronary vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis, the syndrome of inappropriate antidiuretic hormone secretion (SIADH), congestive collapse, nephritic syndrome, cerebral edema, cerebral ischemia, cerebral hemorrhagic shock, thrombotic hemorrhage and abnormal states of water retention. The following prior art references describe peptide antagonists of vasopressin: M. Manning et al., J. Med. Chem., 35, 382 (1992); M. Manning et al., J. Med. Chem., 35, 3895 (1992); H. Gavras and B. Lam e, U.S. Patent 5,070,187 (1991); M. Manning and W. H. Sawyer, U.S. Patent 5,055,448; (1991) F. E. Ali, U.S. Patent 4,766,108 (1988); R. Ruffolo et al., Drug News and Perspective, 4 (4), 217, (May) (1991). P. D. Williams et al., Have reported potent hexapeptide antagonists of oxytocin [J. Med. Chem., 35, 3905 (1992)], which also exhibit weak vasopressin antagonist activity by binding to Vx and V receptors. Peptide antagonists of vasopressin suffer from a lack of oral activity and selectivity. Some exhibit a partial agonist activity. No peptide antagonist of vasopressin has been recently described, Y. Yamamura et al., Science, 252, 579 (1991).; Y. Yamamura et al., Br. J. Pharmacol, 105, 787 (1992); J. D. Albright et al. U.S. Patent 5,536,718A, U.S. Patent 5,532,235A, U.S. Patent 5,516,774A, U.S. Patent 5,512,563A, U.S. Patent 5,459,131A; A. Venkatessan et al. U.S. Patent 5,521,173A; Ogawa et al., (Otsuka Pharm Co., LTD). EP 0514667-A1, EPO 382185-A2, WO 9105549 and U.S. 5,258,510, WO 9404525; Ya anouchi Pharm. Co., Ltd., WO 9420473, WO 9412476, WO 9414796; Fujisawa Co. Ltd., EP 620216-A1; Ogawa et al, (Otsuka Pharm. Co.). EP 470514A describes carbostyril derivatives and pharmaceutical compositions containing the same. The non-peptide antagonists of oxytocin and vasopressin have been described by Merck and Co .; M. G. Bock and P. D. Williams, EP 0533242A; M. G. Bock et al., EP 0533244A; J. M. Erb, D. F. Verber, P. D. Williams, EP 0533240A; K. Gilbert et al., EP 0533243A. U.S. Patent 5,436,333 (Venkatesan et al.) Teaches a process for the preparation of tricyclic heterocycles, which are useful as intermediates in the production of cardiovascular agents. The present invention relates to novel tricyclic derivatives, which exhibit vasopressin antagonist activity, in vitro to V2 receptors and exhibit vasopressin antagonist activity in vivo. In addition, these compounds have greater solubility in water when compared to the 3-acylpyrrolobenzodiazepine derivatives described above.

Brief Description of the Invention This invention relates to novel compounds selected from those of the general formula I: Formula I wherein R is selected from -OH, -NR1R3, -NHORi, -NH- (CH2) -COOH, Ri and R2 are independently hydrogen or lower alkyl; R3 is X is CH2, NRi, 0, S; n is from 1 to 4; p is from 1 to 4; q is from 2 to 4; R4 and R5 are independently selected from hydrogen, lower alkyl, halogen, cyano, trifluoromethyl, amino, hydroxy, or lower alkoxy; R6 is a portion of the formula: Ar is a selected portion of R7 and R8 are independently selected from hydrogen, halogen, cyano, lower alkyl, lower alkoxy, hydroxy, or trifluoromethyl; R9 is a portion of the formula: Rio is selected from C3-C7 cycloalkyl, cyclopentenyl, cyclohexenyl, or the portion of the formula Ar 'is a selected portion of Rn and R12 are independently selected from hydrogen, F, Cl, Br, cyano, lower alkyl, lower alkoxy, trifluoromethyl, phenoxy or substituted phenoxy as in the - in which Rn is selected from hydrogen, halogen, cyano, lower alkyl, lower alkoxy, hydroxy, or trifluoromethyl; Ar "is selected from 1. phenyl, 2. a five-membered aromatic heterocyclic ring (unsaturated) having one or two heteroatoms selected from N, O, S, 3. a five-membered aromatic heterocyclic ring (unsaturated) having three or four nitrogen atoms, or 4. a six-membered aromatic heterocyclic ring (unsaturated) having one, two or three nitrogen atoms, and Ar "may be optionally substituted with halogen, lower alkyl, hydroxy, lower alkoxy, or trifluoromethyl; or pharmaceutically acceptable salts, esters or forms of prodrugs thereof. For the purposes of this specification, the lower alkyl is a Ci to C6 alkyl, preferably Ci to C4, straight or branched chain, such as methyl, ethyl, n-butyl, tert-butyl, and lower alkoxy is Ci to C6 alkoxy, preferably Ci to C4, straight or branched chain, such as methoxy, ethoxy, n-butoxy, or tert-butoxy. Halogen is fluorine, chlorine, bromine, or iodine. Cycloalkyl refers to monocyclic cycloalkyl portions of C3 to C7. It should be further understood that the definition of R3, above, includes portions of the following structures: It should be understood that the Ar "substituents of this invention, which are five-membered aromatic heterocyclic rings (unsaturated) having one or two heteroatoms selected from N, O, S include, but are not limited to, thienyl, furyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, isothiazolyl, isoxazolyl, and imidazolyl The Ar "groups comprising a five-membered aromatic heterocyclic ring (unsaturated) having three or four nitrogen atoms include the triazole and tetrazole portions. The Ar "groups comprising a six-membered aromatic heterocyclic ring (unsaturated) having one, two or three nitrogen atoms including, but not limited to, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,3-triazine groups , 1,2,4-triazine and 1,3,5-triazine Among the most preferred compounds of this invention are those having the following Formula I: Formula I wherein R is selected from -OH, -NRXR3, -NH- (CH2) -COOH, -N i - R ai. ? -M 5-N - - Ri and R2 are independently hydrogen or lower alkyl; R3 is X is CH2, NRi, O, S; n is from 1 to 4; q is from 2 to 4; R4 and R5 are independently selected from the group of hydrogen, lower alkyl, halogen, amino, hydroxy, cyano, trifluoromethyl or lower alkoxy; R6 is a portion of the formula: Ar is a selected portion of R7 and R8 are independently selected from hydrogen or halogen; R9 is a portion of the formula: Rio is a portion of Ar "of the formula: J Ar 'is a selected portion of Rn, 12 are independently selected from hydrogen, F, Br, Cl or lower alkyl; Ar "is selected from phenyl or a five-membered aromatic heterocyclic ring (unsaturated) having one or two heteroatoms selected from N, O, S, or a pharmaceutically acceptable salt, ester or prodrugs thereof. this invention are those of the formula: in which R is selected from OH, NRXR3 or \ - N-Ri Rio is 2-Ar "-cyclopentenyl, and R, R2, R3, Rd, R, R9, Rio, Rn, R12 / X / - p, p, q, Ar, Ar 'and Ar" are as defined in more generic group, above, and preferably, as defined in the subgeneric group, above; or the pharmaceutically acceptable salts, esters or prodrugs thereof.

Detailed Description of the Invention The present invention comprises the compounds described above, as well as the pharmaceutical compositions containing the compounds and one or more carriers, excipients, etc., pharmaceutically acceptable. This invention also encompasses methods for treating conditions in a mammal, preferably a human, where lesser effects of vasopressin are desired, the methods comprising administering to a mammal in need thereof a therapeutically effective amount of one or more of the compounds of the invention. 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 organic acids, such as hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, organic acids such as acetic acid, oxalic acid , citric acid, tartaric acid, succinic acid and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium, or with organic bases. The compounds can also be used in the form of conventional esters, carbamates and other forms of 'prodrug', which, when administered in such form, are converted to the active portion in vivo.When the compounds are used for the above purposes, can be combined with one or more pharmaceutically acceptable carrier excipients, for example, solvents, diluents and the like, and can be administered orally in forms such as tablets, capsules, dispersible powders, granules or suspensions containing, for example, about 0.05 to 5% suspending agent, syrups containing for example, from about 10 to about 50% sugar, and elixirs containing, for example, from about 20 to 50% ethanol and the like, or parenterally in the form of injectable solutions or suspensions sterile, containing approximately 0.05 to 5% of suspending agent in an isotonic medium. Pharmaceuticals can 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 dose 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 in a daily dose of about 0.5 to about 500 mg / kg of body weight of the mammal, preferably given in divided doses two to four times a day. , or in a sustained release form. For most large mammals, the total daily dose 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 can be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced according to the requirements of the therapeutic situation. These active compounds can be administered orally as well as by intravenous routes, intramuscular or subcutaneous. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, nonionic surfactants and edible oils, such as corn, peanut and sesame oils, as appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants commonly employed in the preparation of the pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preservatives and antioxidants, for example vitamin E, ascorbic acid, BHT and BHA. Preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly hard and liquid filled tablets and capsules. Oral administration of the compounds is preferred. These active compounds can also be administered parenterally or intraperitoneally. Solutions or suspensions of those active compounds as free base or pharmacologically acceptable form, 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 injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that it easily comes out of the syringe. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oil. As mentioned above, the new tricyclic non-peptide vasopressin antagonists of this invention are useful for treating conditions where a lesser effect of vasopressin is desired, such as in congestive collapse, under disease conditions with excessive renal water reabsorption and in conditions with increased vascular resistance and coronary vasoconstriction.

In particular, the vasopressin antagonists of this invention are therapeutically useful in the treatment and / or prevention of hypertension, heart failure, coronary vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis, the syndrome of inappropriate antidiuretic hormone secretion (SIADH ), congestive collapse, nephritic syndrome, cerebral edema, cerebral ischemia, cerebral hemorrhagic shock, thrombotic hemorrhage and abnormal states of water retention. This invention also provides the processes for preparing the compounds of the general formula I as defined above. More particularly, this invention provides a process for preparing a compound of formula I, which comprises one of the following: a) reacting a compound of formula: wherein R4, R5 and e are as defined above, and hal is a halogen, for example, chloro with an amine of the formula HNZiZ2 in which -NZXZ2, can be -NRjRa, NHORi, -NH- (CH2) n-C00H, wherein n, X, R2, R2 and R3 are as defined above, to give a corresponding compound of formula I, wherein R is as defined above; or b) treating a compound of formula: wherein R4, R = and R6 are as defined above, and hal is a halogen, for example chlorine, with an aqueous base to give a corresponding compound of formula I, in which R is OH, or c) acylate a compound of formula: wherein R, R4 and R5 are as defined above, with the exception that R is not OH; Rn is wherein R7 and Rs are as defined above, with an acid of formula HO) ^ v ^^ - AAf? »HnO? ^^^ Rpiioo H« Ou ^^^^^ O or a reactive derivative thereof, for example acid halide or anhydride, and to give a corresponding compound of formula I, wherein R9 is as defined herein above.

The compounds of this invention, pyrrolobenzodiazepine derivatives acylated in the 3-position in 1_ (Scheme I), can be prepared using two procedures from a 3-trihalomethyl ketone derivative (example 4). The synthesis of this intermediate and its precursor has been described (EP 636625 A2). Reaction of the 3-trihalomethylketone derivative 4 directly with a primary or secondary amine provides the desired product 1_. Alternatively, the 3-trihalomethylketone derivative 4_ is treated with an aqueous base, such as sodium hydroxide, to obtain, by acidification, the corresponding carboxylic acid 5. The carboxylic acid group can be activated by coupling by conversion to an acid, bromide or anhydride chloride, reacting first with an activating reagent such as N, N-dicyclohexylcarbodiimide, diethyl cyanophosphonate and related activating reagents used in the formation of 'peptide amide bonds. "The method of acid activation it is chosen on the basis of compatibility with other substituent groups in the molecule.One example can be the treatment of acid 5 with oxalyl chloride / di-ethylformamide to obtain the acid chloride 6, which, when treated with a primary amine or secondary, provides the desired product 1_, where -NZ1Z2, can be -NR1R3, NHORi, -N- (CH2) n-C00H, - \ _ / - B ', "V \. -V0-N < Ri and R2 are independently hydrogen or lower alkyl; R3 is n is from 1 to 4; p is from 1 to 4; q is from 2 to 4; Scheme I The 3-trihalomethylketone derivative 4_ is obtained by acylation of the 3-position of the pyrrolobenzodiazepine 3_ using the appropriate trihaloacetyl halide reagent. The compound substituted at the 3-3 position can be a fully assembled target compound, wherein? 7 is selected from Rβ of Formula I or an intermediate, wherein R 7 7 is In the case where Ri7 is the compound can be prepared following the procedures described in Scheme II, followed by the appropriate steps in Scheme I. The compounds of general formulas 4a and _ can be prepared as shown in Scheme II. The reaction of the tricyclic derivative 1 with a 4-nitroaryl carbonyl chloride substituted or unsubstituted with 6-nitropyridine-3-carbonyl chloride gives the intermediate 8a or 8b. Reduction of the nitro group in intermediates 8a and 8b gave the corresponding amino derivatives _9a and 9b. The reduction of the nitro group in 8a and J3b, can be carried out under conditions of catalytic reduction (ie, hydrogen / Pd / C, hydrazine-ethanol / Pd / C) or under conditions of chemical reduction (ie, stannous chloride / ethanol, zinc / acetic acid-trichloride titanium) or related reducing conditions known in the art. The conditions for the conversion of the nitro group to amino are chosen based on the compatibility with the preservation of other functional groups in the molecules. The reagents of pyridine and aryl carboxylic acid HO they are activated by coupling by conversion to a chloride, bromide or acid anhydride or by first reacting with an activating reagent, such as N, N-dicyclocarbodiimide, diethyl cyanophosphonate and related activating reagents used in the formation of 'peptide amide bonds' The method for activating the acids for coupling to the tricyclic derivatives 9a and 9b is chosen on the basis of compatibility with other substituent groups in the molecule.The method of choice is the conversion of the carboxylic acids to the corresponding acid chlorides. Acid chlorides they can be prepared by standard procedures known in the art, such as the reaction with thionyl chloride, oxalyl chloride and the like. The coupling reaction is carried out in halogenated solvents, such as chloroform, dichloromethane, ethereal solvents, such as dioxane, tetrahydrofuran or hydrocarbon solvents such as toluene in the presence of pyridine or tertiary amine base, such as triethylamine and similar. Alternatively, the acid chlorides, prepared from the carboxylic acids, can be reacted with the derivatives 9a and 9b in pyridine with or without 4- (dimethylamino) pyridine to give the compounds 10a and 10b. The reaction of the compounds of formula 9a and 9b with aroyl, arylacetyl, or cycloalkenylcarbonyl chloride or the corresponding activated carboxylic acids; in halogenated solvents such as chloroform, dichloromethane, ethereal solvents such as dioxane, tetrahydrofuran or hydrocarbon solvents such as toluene; in the presence of a tertiary amine base such as 2β triethylamine, diisopropylethylamine or pyridine and the like gives derivatives 10a and 10b. Reaction of the derivatives 10a and 10b with trihalomethyl acyl chloride in an inert solvent such as chloroform, dichloromethane or an ether solvent such as tetrahydrofuran between 0 ° and the reflux temperature of the solvents gives the trihalomethyl ketone derivatives 4a and 4b .

Scheme II An alternative sequence of steps can be used to prepare the title compounds as shown in Scheme Ilb. The reduction of the nitro group in intermediates 12a and 12b, wherein -NZ? Z2, can be -NRR3, NHORi, -N- (CH2) n -COOH and R7 and R8 are independently selected from hydrogen, halogen, cyano, alkyl lower, lower alkoxy, hydroxy, or trifluoromethyl, giving the corresponding amino derivatives 13a and 13b. The reduction of the nitro group at 12a and 12b can be carried out under conditions of catalytic reduction (i.e., hydrogen / Pd / C, hydrazine-ethanol / Pd / C) or under conditions of chemical reduction (ie, stannous chloride / ethanol) , zinc / acetic acid-titanium trichloride) or the related reduction conditions known in the art. The conditions for the conversion of the nitro group to amino are chosen based on the compatibility with the preservation of the other functional groups in the molecules. Acylation of the amino derivatives 13a and 13b with pyridine and appropriately substituted aryl carboxylic acids, gives the objective compounds 14a and 14b. Pyridine and aryl dicarboxylic acid reagents HO are activated for coupling by conversion to a chloride, bromide or acid anhydride or by first reacting with an activating reagent, such as N, N-dicyclocarbodiimide, diethyl cyanophosphonate and related activating reagents used in the formation of peptide amide bonds The method for activating the acids for coupling to the tricyclic derivatives 13a and 13b is chosen on the basis of compatibility with other substituent groups in the molecule.The method of choice is the conversion of the carboxylic acids to the corresponding acid chlorides. The acid chlorides they can be prepared by standard procedures known in the art, such as the reaction with thionyl chloride, oxalyl chloride and the like. The coupling reaction is carried out in solvents such as halogenated hydrocarbons, toluene, xylene, tetrahydrofuran or dioxane in the presence of pyridine or tertiary amine bases such as triethylamine and the like. Alternatively, the acid chlorides prepared from the carboxylic acids can be reacted with the 13a and 13b derivatives in pyridine with or without 4- (dimethylamino) pyridine to give the compounds 14a and 14b.

Scheme IIb Alternatively, intermediate 1_ (Scheme III) can be converted to the more reactive fluorine derivatives 15_. Reaction of 15_ with a substituted amine NHRi (Ri = lower alkyl) gives the corresponding aminonicotinyl derivatives 1_6. The acylation of these derivatives 1_6 leads to a molecule 17. This compound can be treated with trihalomethyl acetyl chloride to give the corresponding products of formula 4b of Scheme II.

Scheme III As an alternative method for the synthesis of the compounds of this invention as described in Formula I, wherein R6 is as shown below The coupling of the pyridyl or aryl carboxylic acids of the general formula 18 with the tricyclic derivatives 1, will give the objective compounds 2_0, which when reacted with trihalomethyl acetyl chloride give the intermediate 4_ of Scheme I. The pyridine and aryl carboxylic acids are activated by coupling by conversion to a chloride, bromide or acid anhydride or by first reacting with an activating reagent, such as N, N-dicyclocarbodi ida, diethyl cyanophosphonate and related activating reagents used in the formation of peptide amide bonds. The method for activating the acids 18 for the coupling to the tricyclic derivatives L (Scheme IV) is chosen based on the compatibility with other substituent groups in the molecule.The method of choice is the conversion of the carboxylic acids 1 to 8 to the chlorides of corresponding acids 1_9. Acid chlorides _19 can be prepared by the procedures known in the art, such as the reaction with thionyl chloride, oxalyl chloride and the like. The coupling reaction is carried out in halogenated solvents such as chloroform, dichloromethane, ethereal solvents such as dioxane, tetrahydrofuran or hydrocarbon solvents such as toluene, in the presence of pyridine or tertiary amine bases such as triethylamine and the like (Scheme IV). Alternatively, the acid chlorides 19, prepared from the carboxylic acids, can be reacted with the JL derivatives in pyridine with or without 4- (dimethylamino) pyridine. In general, when JL_8 acids are reacted with the "peptide type" activating reagents, higher temperatures are required than when acid chlorides are used.

Scheme IV 19 X = C, N HO R10 The acids Y T ° (represented in part by 23, ^ 6, 29) can be prepared by the methods shown in Scheme V.

Scheme V 21 22 23 2d 24 25 n = l, 2 n = l, 2 n = l, 2 29 27 28 An aryl (or heteroaryl) borane, borate, magnesium, trialkyltin or zinc reagent is coupled to an aryl compound 2JL_ or pyridyl 24, wherein Q is selected from bromine, iodine, fluorosulfonate or trifluoromethylsulfonate and Rn is hydrogen, fluorine, chlorine or bromine, using a zero valent palladium or nickel catalyst in the presence or absence of coordinating ligands such as triphenylphosphine and an organic or inorganic base. The resulting methyl bis aryl (heteroaryl) 22 or arylpyridyl (heteroarylpyridyl) compound can then be oxidized using reagents such as KMn04 to provide the corresponding carboxylic acids 23 and _26. Derivatives of 23 and 2_6, wherein Rn is lower alkyl, can be prepared by the treatment of methyl ester 23 and 26, wherein Rn is bromine with the corresponding lower alkyl borane in the presence of a zero valent palladium catalyst. In the case of the cycloalkyl portion, the compound 29, the material can be prepared starting from the appropriate ketoester 27. Reaction of the ketoester 27_ with phosphorus trihalide (bromine, iodine) or triflic anhydride, for example, gives the compound ß-halo or corresponding β-trifluoromethylsulfonate 2_8. Compound 28_ can be reacted with borane aryl (heteroaryl) reagent, borate, magnesium, trialkyltin or zinc in the presence of a palladium or zero-valent nickel catalyst and an organic or inorganic base to give the objective compound 2 as the ester. Hydrolysis of the ester portion in 29 with an alkali metal hydroxide in an aqueous alcoholic or etheral solvent provides the carboxylic acid 29. Alternatively, the compound of general formula I, may be worked up as shown in Scheme VI, in where J is selected from B (OH) 2, Sn (lower alkyl) 3, R is selected from Br, I, OS02CF, and Ar "is selected as defined above.

Scheme VI The intermediate 3_0 can be coupled to an aryl tin or boron reagent under the Stille or Suzuki conditions, respectively, using zero valent palladium in the presence or absence of coordinating ligands and a base to give the compounds of the general formula 31. The present invention it will be better understood in view of the following non-limiting examples.

EXAMPLE 1 10- [2-Chloro-4- (5-fluoro-2-methyl-benzoylamino) -benzoylj-10,1-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodi cepin- 3- carboxylic Step a) N-. { 3-Chloro-4- [3- (trichlorocarbonyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl] -phenyl.}. -5-fluoro-2-methyl -benzamide A suspension of N- [3-chloro-4- (5H, HH-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-carbonyl) -phenyl] -5-fluoro-2-methyl- Benzamide (4.73 g, 10 mmol) in dichloromethane (300 ml) was stirred at room temperature with trichloroacetyl chloride (1.81 g, 10 mmol) for 6 hours under nitrogen. A second equivalent of trichloroacetyl chloride (1.81 g, 10 mmol) was added, and the reaction was stirred at room temperature overnight. After dilution with dichloromethane (500 ml), the reaction mixture was filtered through a plug of silica gel (2x), and the filtrate was evaporated in vacuo to a residue. The residue was redissolved in dichloromethane (300 ml), washed with 0.5N sodium hydroxide and water, and dried (MgSO). Filtration through a plug of silica gel (2x), and evaporation of the filtrate in vacuo gave 6.2 g (10 mmol) of the 3-trichloromethyl ketone as a tan amorphous powder, which was used without further purification as in Example 1, step b.

Step b) 10- [2-Chloro-4- (5-fluoro-2-methyl-benzoylamino) -benzoyl] -10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine acid -3-carboxylic The N-. { 3-chloro-4- [3- (trichlorocarbonyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepine-10-carbonyl] -phenyl.}. -5-fluoro-2- methyl-benzamide (1.22 g, 2 mmol) was stirred in acetone (5 ml) under nitrogen at room temperature for 45 minutes with 2.5 N sodium hydroxide (1.6 ml, 4 mmol) The reaction mixture was neutralized to pH 7.0 with 2N HCl (2 mL, 4 mmol) After the addition of water (10 mL), the precipitate was filtered, washed sequentially with cold water, ethanol, and diethyl ether to give, after air drying, a product crude as a colorless powder (750 mg, 72%). Recrystallization of the crude product from methanol-water (3: 1, 10 ml) gave, after drying in vacuo at 25 ° C for three hours, 600 mg ( 1.2 mmol) of the title compound as a colorless, homogeneous, crystalline solid, mp 218 ° C (with decomposition) MS (+ BAR), m / z: 520/518 (M + H) Analysis for: C28H21CIF 3O40.62 H20 Calculated: C, 63.55; H, 4.24; N, 7.94, Found: C, 63.53; H, 4.21; N, 7.82.

EXAMPLE 2 10- [2-Chloro-4- (5-fluoro-2-methyl-benzoylamino) -benzoyl] -10,1-dihydro-5H-pyrrolo [2, 1-c] [1,4-benzodiasepin-3-acid] carboxylic, potassium salt (1: 1) A suspension of the product of Example 1, step b, 10- [2-chloro-4- (5-fluoro-2-methyl-benzoylamino) -benzoyl] -10, 11-dihydro acid -5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-3-carboxylic acid (517 mg, 1 mmol), in methanol (10 mL) was treated with 1N potassium hydroxide (1 mL, 1 mmol), and it leaked. After evaporation of the solvent in vacuo, the residue was redissolved in acetone (50 ml), refiltered (2x), and concentrated to a smaller volume (20 ml). The addition of diethyl ether and cooling gave, after filtration of the solid and drying in vacuo at 70 ° C for three hours, 270 mg (0.49 mmol) of the potassium salt of the acid as a lightly colored amorphous powder, e.g. F. 195-205 ° C. MS (+ BAR), m / z: 520/518 (M + H). Analysis for: C28H2oClFKN304 3.2 H20. Calculated: C, 60.48; H, 3.63; N 7.56. Found: C, 59.22; H, 4.03; N, 7.30.

EXAMPLE 3 N-. { 3-Chloro-4-t3- (NA, N '-dimethyl-hydrazinocarbonyl) -5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl] -f nil} -5- fluoro-2-meti1-benzamide The N-. { 3-chloro-4- [3- (trichlorocarbonyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl] -phenyl} -5-fluoro-2-methyl-benzamide (1.86 g, 3 mmol) was stirred under nitrogen with an excess of N, N-dimethylhydrazine (5 ml) for 3 hours at 60 ° C. The excess N, -dimethylhydrazine was removed under high vacuum. The residue was dissolved in ethyl acetate, filtered through a short plug of silica gel, and the filtrate was evaporated in vacuo to give 1.63 g (2.9 mmol, 97%) of a crude product. Purification by flash column chromatography on silica gel (150 g), and eluting with ethyl acetate, gave, after drying in vacuo at 25 ° C overnight, 1.15 g (2.1 mmol) of the title compound as a light yellow amorphous powder, which retained 0.33 mol of ethyl acetate, p. F. 133-135 ° C. MS (-ESI), m / z: 560/558 (M-H) ~. Analysis for: C3oH27ClFN503-0.33 C4 H8 02. Calculated: C, 63.85; H, 5.07; N, 11.88. Found: C, 63.17; H, 5.10; N, 11.77.

EXAMPLE 4 2- [[10- [2-Chloro-4- [(5-fluoro-2-methylbenzoyl) amino] benzoyl] -10,1-dihydro-5H-pyrrolo yodide. { 2, 1- c] [1,4] benzodiazepin-3-yl] carbonyl] -1, 1,1-trimethylhydrosinium The product of Example 3, N-. { 3-chloro-4- [3- (N, N '-dimethylhydrazinocarbonyl) -5H, HH-pyrrolo [2, 1-c] [1,4] benzo-diazepin-10-carbonyl] -phenyl} 5-Fluoro-2-methyl-benzamide (700 mg, 1.25 mmol) was treated with an excess of iodomethane (5 g, 35 mmol) in dichloromethane (100 mL) and stirred under nitrogen at room temperature for 60 hours. The precipitate was filtered, and washed sequentially with cold dichloromethane and diethyl ether, to give, after drying in vacuo at 25 ° C overnight, 700 mg (1.0 mmol) of the title compound as a colorless amorphous powder, e.g. F. (188) 193 ° C. MS (-ESI), m / z: 828 (MI + I) "MS (+ BAR), m / z: 574 (M + H) + Analysis for: C31H3oClFIN503? 20 0.6 CH2C12 Calculated: C, 49.23; H , 4.34; • N, 9.08; I, 16.47, Found: C, 48.83; H, 4.00; N, 9.11; I, 17. 02.

EXAMPLE 5 Intense salt of 2- [[10- [2-chloro-4- [(5-fluoro-2-methylbenzoyl) amino] benzoyl] -10,1-dihydro-5H-pyrrolo [2,1-c] [ 1,4] Enzydiacepin-3-yl] hydroxymethylene] -1,1,1-trimethylhydrazinium The product of the Example, 4, 2- [[10- [2-chloro-4- [(5-fluoro-2) iodide] -methylbenzoyl-amino] bnezol] -10, 11-dihydro-5H-pyrrolo {2, 1-c] [1,4] Enzydiacepin-3-yl] carbonyl] -1, 1, 1-trimethylhydrazinium (400 mg 0.57 mmol), treated with 0.1 N sodium hydroxide (5.7 ml, 0.57 mmol) in a methanol-water mixture (10 ml: 10 drops) After concentration in vacuo, additional water was added. precipitate was filtered, and washed sequentially with water, cold methanol, and diethyl ether to give, after drying in vacuo at 25 ° C for 5 hours, 160 mg (0.28 mmol) of the title compound as a colorless amorphous powder, mp. 255 ° C MS (+ ESI), m / z: 576/574 (M + H) + Analysis for: C3iH29ClFN5? 3: Calculated: C, 64.86; H, 5.09; N, 12.20 Found: C, 63.44; H, 5.09; N, 12.15.

EXAMPLE 6 N- [5- [3-Trichloromethylcarbonyl] - [5H-pyrrolo- [2, lc] - [1,4] -benzodiazepin-10 (11H) -yl] carbonyl] -2-chlorophenyl] -2-phenylbenzamide To a stirred solution of 2-phenyl-N- [4- (5H-pyrrole [2, 1-c] [1,4] benzodiazepin-10 (11H) -i-carbonyl] -2-chlorophenyl] -benzamide ( 5.00 g, 9.7 mmol) in dichloromethane (55 ml) under nitrogen, N, N-diisopropylethylamine (3.39 ml, 19.4 mmol) was added, followed by trichloroacetyl chloride (3.25 ml, 29.1 mmol) by dripping for five minutes. The reaction mixture was allowed to stir overnight at room temperature, the reaction mixture was washed three times with water, the combined aqueous extracts were washed with dichloromethane, and the organic extract was dried and the solvent was removed to give the crude product (8.05 g. g) The crystallization from ethyl acetate-hexane gave a crude product (5.12 g) .An analytical sample obtained from recrystallization had a mp of 168-170 ° C. MS (+ ESI), m / z: 663 M0 Analysis for : C34H27N 3O5 Calculated: C, 61.56; H, 3.49; N, 6.33. Found: C, 61.28; H, 3.22; N, 6.32.

EXAMPLE 7 Acid 10-. { 4- [biphenyl-2-carbonyl) -amino] -2-chloro-benzoyl) -10,11-dihydro-5H-benzo [e] pyrrolo [1,2-a] [1,4] diazene-3-carboxylic acid To a solution of N- [5- [3-trichloromethylcarbonyl] - [5H-pyrrolo- [2, 1-c] - [1,4] -benzodiazepin-10 (11H) -yl] carbonyl-2-chlorophenyl] - 2-Phenylbenzamide (2.24 g, 3.4 mmol) in acetone (22 ml) was added aqueous sodium hydroxide (2.48 ml, 2.5 N, 6.2 mmol) and the reaction was stirred at room temperature for 1.25 hours. The reaction was acidified with HCl (3.47 ml, 2N) and the solvent was removed under vacuum. The residue was partitioned between ethyl acetate-water, dried and the solvent was removed to give the crude product (2.41 g). Trituration with ether-hexane gave a solid (1.9 g). A sample of chloroform-methanol-ether p. F. 216-218. MS (+ BAR), m / z: 562/564 (M + H) +. Analysis for: C34H27N3? 5 Calculated: C, 70.52; H, 4 30; N, 7.48. Found: C, 69.25; H, 4.39; N, 7.14.

EXAMPLE 8 Acid-10- (4- [(biphenyl-2-carbonyl) -amino] -2-chloro-benzoyl) -10,1-dihydro-5H-benzo [e] irrolo [1,2-a [1, 4] diasepin-3-carboxylic-1, 1-dimethylhydrazide To a suspension of N- [5- [3-trichloromethylcarbonyl] - [5H-pyrrolo- [2, 1-c] - [1,4] -benzodiazepine-10 (11 H) -yl] carbonyl-2-chlorophenyl] -2-phenylbenzamide (0.941 g, 1.5 mmol) in dichloromethane (2 ml) was added 1,1-dimethylhydrazine (1.1 ml, mmol) and the reaction was stirred for 24 hours. The solid was put into solution and finally turned into a suspension. The solvent was evaporated and the excess hydrazine was removed in vacuo. The residue was purified using column chromatography on silica gel in methanol-ethyl acetate (1:20) and the product was eluted with the same solvent to give 0. 8 g of the compound. Two methanol-ether crystallizations gave 0.454 g of the crude product p. F. 173-176. MS (+ BAR), m / z: 604 (M + H) 0 Analysis for: C34H27N3O5 Calculated: C, 69. 59; H, 5. 01; N, 11 59. Found: C, 69. 40; H, 5. 01; N, 11 60 EXAMPLE 9 10- (4- [(Biphenyl-2-carbonyl) -amino] -2-sloro-benzoyl) -10,1-dihydro-5H-benzo [e] pyrrolo acid [1, 2-a [1, 4] ] diacepin-3-carboxylic-piperazine-N-me i1 amide Method A. A suspension of carboxylic acid (Example 7) (4g, 7.12 mmol) in dichloromethane (27 ml) and dimethylformamide (0.66 ml, 8.54 mmol) was cooled to about 0-5 ° under nitrogen. Oxalyl chloride (0.75 mL, 8.54 mmol) in dichloromethane (3 mL) was added gradually. The mixture was stirred at room temperature for 1.5 hours. To a solution of N-methylpiperazine (3.2 ml, 28.5 mmol), in dichloromethane (30 ml) containing the diisopropylethylamine (7.45 ml, 42.72 mmol) was added dropwise a freshly prepared solution of acid chloride for about 15 minutes under nitrogen . The reaction was allowed to stir for 1.5 hours at room temperature. The mixture was diluted with dichloromethane (20 ml) and the mixture was washed with water, 5% sodium bicarbonate, and 25% saline. The aqueous extract was washed again with dichloromethane and the combined organic solution was dried and the solvent was removed under vacuum to give the crude product (5.8 g). The residue was purified by column chromatography on silica gel (140 g) in methanol-ethyl acetate (1:20). The product was eluted with methanol-ethyl acetate (1:10) to give the pure compound as a white matte foam. A sample (0.97 g, 1.51 mmol) dissolved in a mixture of methanol-ether (1: 1, 6 ml) and methanolic hydrogen chloride (1 N, 2 ml, 1.96 mM) was added. After stirring for 45 minutes all the solvent was removed in vacuo. The residue was triturated overnight with ether containing a few ml of methanol. The resulting amorphous solid was filtered to give the crude hydrochloride salt (0.876 g). Reprecipitation of ethanol-ether gave (0.516 g) of the salt. MS (El) m / z: 604 (M + H) 0 Analysis for: C38H34CIN5O3? CI. 1.5 H20 Calculated: C, 64.44; H, 5.22; N, 9.89. Found: C, 64.15; H, 5.39; N, 9.61. Method B. To a suspension of the product of Example 7 (2.0 g, 3.56 mmol) in dichloromethane (150 ml) was added successively N-methyl piperazine (0.414 ml, 3.74 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl (0.716 g, 3.74 mmol), and 4-dimethylaminopyridine (catalyst). The reaction was stirred at room temperature for 36 hours, diluted with dichloromethane, washed with water, NaOH (1 N), brine, and dried (MgSO4). Purification by flash chromatography (silica gel, eluting with a 50: 1 chloroform-methanol solvent and then 20: 1) gave a white foam (1.55 g).

EXAMPLE 10 Acid 10-. { 4- [(Biphenyl-2-carbonyl) -amino] -2-chloro-benzoyl} - 10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-3-carboxylic- (2-dimethylamino-ethyl) -methyl-amide The compound of Example 10 was prepared in the same way wherein it was described in Example 9, Method A, except that the N-methylpiperazine was replaced by N, N, N-trimethylethylenediamine. The title compound was obtained as a matt white amorphous solid. P. f. 100-120 °, MS (+ BAR), m / z: 646 (M + H) +.

EXAMPLE 11 Biphenyl-2-carboxylic acid. { 3-Chloro-4- [3- (4-piperidinyl-piperidine-1-carbonyl) -5H, IIH-pyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl] -phenyl} Amide The compound of Example 11 was prepared in the same manner as described in Example 9 Method A, except that the N-methylpiperazine was replaced by 4-piperidinyl-piperidine. The title compound was obtained as a matt white amorphous solid. P. f. 209-219 °. MS (+ BAR), m / z: 712/714 (M + H) +.

EXAMPLE 12 Biphenyl-2-carboxylic acid f3-chloro-4- [3- (4-dimethylamino-piperidine-1-carbonyl) -5H, IIH-pyrrolo [2,1-c] [1,4] benzodiazepine-10- carbonyl] -phenyl} -amide The compound of. Example 12 was prepared in the same manner as described in Example 9, Method A, except that the N-methylpiperazine was replaced by 4-dimethylamino piperidine. The title compound was obtained as a brown amorphous solid. P. f. 138-152 °. MS (+ BAR), m / z: 672 (M + H) 0 Analysis for: C4oH38ClN5? 3"HCl.H20 Calculated: C, 66.04; H, 5.64; N, 9.63 Found: C, 65.22; H, 5.49; N, 9.32.

EXAMPLE 13 Biphenyl-2-carboxylic acid. { 3-Chloro-4- [3- (4-methyl-piperazin-1-aminocarbonyl) -5H, IIH-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl] -f nil} Amide The compound of Example 13 was prepared in the same manner as described in Example 9, Method A, except that the dimethylhydrazine was replaced by 4-N-methyl-N-amino piperazine. The title compound was obtained as a pale yellow solid. P. f. 172-182 °. MS (+ BAR), m / z: 660 (M + H) +.

EXAMPLE 14 Acid 10-. { 4- [(biphenyl-2-carbonyl) -amino] -2-sloro-benzoyl} - 10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-3-carboxylic acid (2-dimethylamino-ethyl) -amide The compound of Example 14 was prepared in the same manner as described in Example 9, Method A, except that the N-methylpiperazine was replaced by N, N-dimethylethylene diamine. The title compound was obtained as a white solid. P. f. 85-94. MS (+ BAR), m / z: 632 (M + H) 0 Analysis for: C37H34ClN5? 3"2H20 Calculated: C, 66.45; H, 5.69; N, 10.47 Found: C, 64.57; H, 5.50; N , 9.28.

EXAMPLE 15 Biphenyl-2-carboxylic acid. { 3-chloro-4- [3- (4-morpholino-piperidine-1-carbonyl) -5H, IIH-pyrrolo [2, l-c] [1,4] benzodiazepine-10-carbonyl] -phenyl} Amide The compound of Example 15 was prepared in the same manner as described in Example 9, Method A, except that the N-methylpiperazine was replaced by 4-morpholino-piperidine. The title compound was obtained as an amorphous solid. MS (+ BAR), m / z: 714 (M + H) +.

EXAMPLE 16 10- (4- [(Biphenyl-2-carbonyl) -amino] -2-methoxy-benzoyl) -10,1-dihydro-5H-benzo [e] pyrrolo acid [1, 2-a [1, 4] ] diacepin-3-carboxylic piperazine-N-methyl amide Step a) 2-Methoxy-4-nitrobenzoic acid methyl ester Thionyl chloride (13.9 ml, 190 mmol) was added via syringe to a solution of 4-methoxy-4-nitrobenzoic acid. nitro-2-methoxybenzoic acid (50 g, 250 mmol) and methanol, which was stirred at room temperature. The reaction was stirred at room temperature for 16 hours. The volatiles were removed in vacuo. The residue was dissolved in dichloromethane, washed with sodium hydroxide (1N), and the organic layer was separated and dried (MgSO). Evaporation in vacuo gave a light yellow solid (50 g), p. F. 80-81 ° C, which was taken directly for the next step. Analysis for: C9H9NO5 Calculated: C, 51.19; H, 4.30; N, 6.63. Found: C, 50.97; H, 4.11; N, 6.51.

Step b) 4-Amino-2-methoxy-benzoic acid methyl ester A mixture of 2-methoxy-4-nitrobenzoic acid methyl ester (12 g, 57 mmol) palladium (10% on activated carbon), and ethanol (150 ml) was stirred at room temperature under 50 psi (3.515 kgf / cm2) of hydrogen for 2 hours. The reaction was filtered through diatomaceous earth, and the diatomaceous earth was washed with chloroform. Evaporation of the washings with chloroform gave a yellow solid. Purification by crystallization gave a pale yellow crystalline solid (8.76 g), p. F. 148-149 ° C. Analysis for: C9H11NO3 Calculated: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.42; H, 6.02; N, 7.69.

Step c) 4- [(Biphenyl-2-carbonyl) -amino] -2-methoxy-benzoic acid methyl ester In a solution under reflux of 2-biphenylcarboxylic acid (9.2 g, 46 mmol) in dichloromethane, dimethylformamide was added ( 0.1 ml, 1.4 mmol) and then pure oxalyl chloride (8.1 ml, 92 mmol) via syringe.

The reaction was refluxed for 10 minutes, then volatile compounds were removed in vacuo.

The residue was redissolved in dichloromethane, concentrated and dried under high vacuum for 15 minutes. The acid chloride was dissolved in dichloromethane (50 ml) and added to a 0 ° C solution of 4-amino-2-methoxy-benzoic acid methyl ester (8.4 g, 46 mmol), diisopropyl ethylamine (10.5 ml, 60 mmol) and dichloromethane (200 ml). The reaction was warmed to room temperature and stirred for 16 hours. The reaction was diluted with dichloromethane, washed with water, sodium hydroxide (1N), hydrochloric acid (1N) and brine, and dried (MgSO). Evaporation gave a yellow foam, which was crystallized from methane to give a pale yellow solid (16.08 g) p. F. 141-142 ° C. Analysis for: C22H? GN0 Calculated: C, 73. 12; H, 5 30; N, 3 88 Found: C, 72.93; H, 5.20; N, 3.83.

Step d) 4- [(Biphenyl-2-carbonyl) -amino) -2-methoxy-benzoic acid Sodium hydroxide (1N) (38 mL, 38 mmol) was added to a solution under reflux of 4-methyl ester. [(biphenyl-2-carbonyl) -amino] -2-methoxy-benzoic acid (11.6 g, 32 mmol) in methanol (200 ml). The reaction was refluxed for 2 hours. The volatiles were removed in vacuo, and the residue was extracted into ethyl acetate / HCl (aq). The aqueous layer was extracted again with ethyl acetate, and the organic extracts were combined and dried (MgSO). Evaporation gave a pale orange foam, which was crystallized from methanol to give a white solid (9.33 g), p. F. 158-159 ° C. Analysis for: C2? H? 7N04 Calculated: C 72.61; H, 4.93; N, 4.03. Found: C, 72.20; H, 4.61; N, 3.96.

Step e) Acid [3-methoxy-4 - (SH, IIH-pyrrolo [2, 1-c] [1,4] benzodi cepin-10-carbonyl) -enyl] -biphenyl-2-carboxylic acid amide In a solution under reflux of 4 - [(biphenyl-2-carbonyl) -amino] -2- etho-benzoic acid (3.29 g, 9.5 mmol) and dichloromethane (50 ml) was added dimethylformamide (0.02 ml, 0.28 mmol) and then chloride of pure oxalyl (0.87 ml, 10 mmol) via syringe. The reaction was refluxed for 10 minutes and then the volatile compounds were removed in vacuo. The residue was evaporated with fresh dichloromethane and then dried under high vacuum for 15 minutes. The acid chloride was dissolved in dichloromethane (50 ml) and added to a 0 ° C solution of 10,11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine (1.57 g, 8.55 g). mmol), N, N-diisopropylethylamine (1.93 ml, 12.35 mmol) and dichloromethane (200 ml). The reaction was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane, washed with water, sodium hydroxide (1N), hydrochloric acid (1N) and brine, and dried (MgSO4). Evaporation gave a yellow foam, which was crystallized from methanol to give a white solid (2.05 g), p. F. 224-226 ° C. Analysis for: C33H? 7N3? 3 Calculated: C 76.87; H, 5.35; N, 8.07. Found: C, 76.82; H 5.23; N, 8.04.

Step f) N- [5- [3-Trichloromethylcarbonyl] - [5H-pyrrolo- [2, 1-c] - [1,4] -benzodiazepin-10 (11H) -yl] sarbonyl] -2-methoxy-nil] -2-phenylbenzamide To a solution of the product from Step e of Example 357 (2.5 g, 4.87 mmol) in dichloromethane (50 ml) at 0 ° C was added trichloroacetyl chloride (1.09 ml, 9.74 mmol) via a syringe, and the The reaction was stirred at room temperature for 4 hours. The reaction was diluted with dichloromethane, washed with sodium bicarbonate and brine, and the organic extracts were dried (MgSO4). Evaporation and filtration of the residue through a pad of silica gel followed by washing with ethyl acetate / hexane 1/1, gave the desired product as a white foam (1.5 g), e.g. F. 139-143 ° C.

Analysis for: C35H26CI3 3O4 + 0.25 H20. Calculated: C, 63.36; H, 4.03; N, 6.33. Found: C, 63.05; H, 4.03; N, 6.21.

Step g) Acid 10-. { 4- [(biphenyl-2-carbonyl) -amino] -2-methoxybenzoyl) -10,1-dihydro-5H-benzo [eJpyrrolo [1,2-a] [1,4] -diacepi -3-carboxylic acid Sodium hydroxide (1N) (2.0 ml, 1.92 mmol) to a room temperature solution of N- [5- [3-trichloromethylcarbonyl] - [5H-pyrrolo- [2, 1-c] - [1, 4] - benzo-diazepin-10 (11H) -yl) carbonyl] -2-methoxyphenyl) -2-phenylbenzamide (0.8 g, 1.2 mmol) in tetrahydrofuran (10 ml), and the reaction was stirred for 1.5 hours. Hydrochloric acid (1N) was added and the reaction was diluted with ice. The volatiles were removed in vacuo and the white solid was filtered and dried to give (0.8 g) of the title compound, p. F. 149-151 ° C. Analysis for: C34H27N305 Calculated: C, 70.21; H, 5.14; N, 7.22. Found: C, 70.20; H, 4.89; N, 7.31.

Step h) 10- (4- [(Biphenyl-2-sarbonyl) -amino] 2-methoxy-benzoyl) -10,1-dihydro-5H-benzo [e] pyrrolo [1, 2-a [1,4] acid) Jdiacepin-3-carboxylic-piperazine-N-me-il-amide A solution of 10- [4- [(biphenyl-2-carbonyl) -amino] -2-methoxybenzoyl) -10,1-dihydro-5H-benzo acid [] e] pyrrolo [1,2-a] [1,4] diazepine-3-carboxylic acid (0.434 g, 0.778 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.157 g, 0.8 mmol), 4 dimethylaminopyridine (catalyst) and N-methyl piperazine (0.91 ml, 0.814 mmol) in dichloromethane was stirred at room temperature for 3.5 hours. The reaction was diluted with dichloromethane, and washed with water and brine. The organic extracts were dried (MgSO) and concentrated to give a white foam. Purification by flash chromatography (silica gel; elution solvent of chloroform-methanol 50: 1 then 20: 1) and crystallization of ethanol gave a white solid (0.23 g) p. F. 139-140 ° C. Analysis for: C39H37N5O4 + 1.0 H20 Calculated: C, 71.21; H, 5.98; N, 10.65. Found: C, 71.25; H, 5.99; N, 10.64.

EXAMPLE 17 10- (4- [(Biphenyl-2-carbonyl) -amino] -2-methoxy-benzoyl) -10,1-dihydro-5H-benzo [e] pyrrolo acid [1, 2-a [1, 4] ] diacepin-3-carboxylic-1, 1-dimethylhydrazine A solution of the product of Step h of Example 16 (1.0 g, 1947 mmol) in dichloromethane (20 ml) at 0 ° C was added trichloroacetyl chloride (0.434 ml, 3.89 mmol) via syringe, and the reaction was stirred at room temperature for 4 hours. The reaction was diluted with dichloromethane, washed with sodium bicarbonate and brine, and the organic extracts were dried (MgSO4). Evaporation and filtration of the residue through a pad of silica gel, washing with 1: 1 ethyl acetate-hexane, gave the trichloroketone as a white foam when concentrated. The foam was dissolved in pure N, N-dimethylhydrazine at room temperature, and then heated to reflux for 25 minutes. The volatiles were removed in vacuo, and the residue was adsorbed on silica gel and purified by flash chromatography (eluting with 1: 1 ethyl acetate-hexane solvent and then 4: 1 ethyl acetate-methanol). Crystallization of ethanol gave a tan solid (0.23 g), p. F. 164-165 ° C. Analysis for: C36H33N5O4 + 1.0 H20 Calculated: C, 70.0; H, 5.71; N, 11.34. Found: C, 70.01; H, 5.62; N, 11.29.

EXAMPLE 18 Acid 10-. { 4- [(biphenyl-2-carbonyl) -amino] -2-chloro-benzoyl} - 10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-3-carboxylic (glyc1) -amide The compound of Example 18 was prepared in the same manner as described in Example 8, except that dimethylhydrazine was replaced by t-butyl glycine as the reagent. The resulting t-butyl ester (0.725 g) of the title compound thus obtained was hydrolyzed by treatment with formic acid (2.3 ml) at room temperature for 48 hours to give the title compound as a white amorphous solid, e.g. F. 176-186. MS (ESI) m / z 617 (N + H) +. Analysis for: C36H30N4O6 Calculated: C: 67.9, H: 4.40, N: 9.05. Found: C: 66.51, H: 4.23, N: 8.44.

EXAMPLE 19 10- [2-Chloro-4- (2-thiophen-2-yl-benzoylamino) -benzoyl] -10,1-dihydro-5H-pyrrolo [2, lc] [1,4] benzodiazepine-3- acid carboxylic-1, 1-dimethylhydrazine N- [3-Chloro-4- (5H, llH-pyrrolo [2, 1-c] [1,4] benzodiasepin-10-carbonyl) -phenyl] -2-thiophen-2 il-benzamide Step a) 2-Bromobenzoyl chloride To a solution of bromobenzoic acid (1.88 g, 9.35 mmol) in anhydrous tetrahydrofuran (20 ml), under nitrogen, was added 1 drop of dimethylformamide followed by the addition of oxalyl chloride (1 ml, 11.4 mmol). The mixture was stirred at room temperature until gas evolution ceased and then heated to reflux. The solution was cooled to room temperature before being concentrated in vacuo to yield a gold-colored oil (1.87 g), which was used without further purification.

Step b) 2-Bromo-N- [3-chloro-4- (10,11-dihydro-5H-pyrrolo [2, ls] [1,4] benzodiazepine-10-carbonyl) -phenyl) -benzamide To one solution with stirring of 10, 11-dihydro-10- (2-chloro-4-aminobenzoyl) -5H-pyrrolo [2, 1-c] [1,4] benzodiazepine (2.25 g, 6.66 mmol) in dichloromethane (40 ml under nitrogen, triethylamine (1.19 ml, 8.53 mmole) was added.The mixture was cooled to 0 ° C before a solution of 2-chloro chloride was added dropwise. bromobenzoyl (1.87 g, 8.52 mmol) in dichloromethane (20 ml) The cooling bath was stirred and continued stirring for 14 hours.The reaction mixture was poured into water.The organic layer was separated and washed sequentially with water, bicarbonate saturated sodium and water before being dried (Na2SO) .The material was filtered and concentrated in vacuo, to give a pale orange foam. (2.00 g). Purification by flash chromatography on silica gel with hexane-ethyl acetate (1: 1) as the mobile phase resulted in a white powder (1.39 g), e.g. F. 188-189 ° C. EM (El), m / z; 519 (M +). Analysis for: C26Hi9BrClN302 + 0.5 H20 Calculated: C, 58.93; H, 3.80; N, 7.93 Found: C, 59.12; H, 3.62; N, 7.75.

Step c) N- [3-Chloro-4- (5H, 11H-pyrrolo [2, lc] [1,4] benzodiazepine-10-carbonyl) -phenyl] -2-thiophen-2-yl-benzamide The 2- bromo-N- [3-chloro-4- (10,11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -phenyl] -benzamide (1.04 g, 2.0 mmol ), thiophene-2-boronic acid (0.32 g, 2.4 mmol), and barium hydroxide octohydrate (0.88 g 2.8 mmol) were suspended in ethylene glycol dimethyl ether (28.8 ml) and water (4.8 ml). The heterogeneous mixture was stirred at room temperature and purged with nitrogen for ten minutes before adding bis (triphenylphosphine) palladium (II) chloride (0.17 g, 0.24 mmol) and the reaction was placed under a static nitrogen pressure. The reaction was heated in an oil bath at 70 ° C. 20 hours later, additional thiophene-2-boronic acid (0.13 g, 1 mmol) was added to the reaction. 24 hours after the total reaction time, additional bis (triphenylphosphin) -palladium (II) chloride (84 mg, 0.12 mmol) was added to the reaction vessel. The reaction was cooled to room temperature, and the mixture was extracted into benzene. The combined organic extracts were washed with brine, dried (MgSO 4), filtered or concentrated in vacuo, to give a brown solid (1.42 g). The solid was triturated with ethyl acetate and filtered. The filtrate was purified by flash chromatography using silica gel with hexane-ethyl acetate (1: 1) as the mobile phase to give a pale yellow solid, which was dried under vacuum at 78 ° C for two days (0.59 g) , p. F. 132-136 ° C. MS (El), m / z: 523 (M +). Analysis for: C30H22CIN3O2S + 0.5 H20 Calculated: C, 67.53; H, 4.36; N, 7.88 Found: C, 67.53; H, 4.08; N, 7.90.

Step d) N-. { 3-Chloro-4- [3- (trichlorocarbonyl) - (5H, 11H-pyrrolo- [2, 1-c] [1,4] benzodiasepin-10-sarbonyl] -phenyl.} -2-thiophene-2- il-benzamide The product from step C was converted to the corresponding trichloro ketone according to the protocol set forth in step A of Example 1.

Step e) 10- [2-Chloro-4- (5-thiophen-2-yl-benzoylamino) -benzoyl] -10, l-dihydro-5H-pyrrolo [2, 1-s] [1,4] benzodiazepine acid -3-carboxylic acid The trichloro ketone prepared in step D was hydrolyzed to the title acid according to the protocol set forth in step B of Example 1.

Step f) 10- [2-Chloro-4- (2-thiophen-2-yl-benzoylamino) -benzoyl] -10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine acid 3-carboxylic acid 1,1-dimylhydrazide The trichloroketone prepared in step D was reacted with N, N dimethyl hydrazide according to the protocol of Example 8.

EXAMPLE 20 10- [2-Chloro-4- (3-pyridin-2-yl-benzoylamino) -benzoyl] -10,1-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine- 3- carboxylic piperazine-N-methyl amide N- [3-chloro-4- (5H, 11H-pyrrolo [2,1-c] [1,4] benzodiazepin-10-carbonyl) -phenyl] -3-pyridin-2-yl-benzamide Step a) The Compound of Example 20a was prepared in the same manner as described in Example 19 following steps 19a, 19b. In Step 19a, 2- (pyridin-3-yl) -benzoic acid was replaced by 2-bromobenzoic acid. The preparation of 2- (pyridin-3-yl) -benzoic acid was carried out in the manner of Timari, et al (Chem. Ber, 1992, 125, 929), substituting 3-bromopyridine instead of 2- Bromopyridine The title compound was obtained as a white matte powder (0.21 g), p. F. 155-158 ° C. Analysis for: C31H23CIN4O2 + 0.85 H20 Calculated: C, 69.68; H, 4.66; N, 10.49 Found: C, 69.69; H, 4.70; N, 10.16 N-. { 3-Chloro-4- [3- (trichlorosarbonyl) - (5H, 11H-pyrrolo [2, 1-s] [1,4] -benzodiazepine-10-carbonyl) -phenyl} 3-pyridin-2-yl-benzamide Step b) The product of step A was converted to the corresponding trichloro ketone according to the protocol set forth in step A of Example 1.10- [2-Chloro-4- (3-pyridin-2-yl-benzoylamino) -benzoyl] -10, l-dihydro-5H-pyrolo [2, 1-c] [1,4] benzodiazepine-3 acid -carboxylic Step c) The trichloro ketone prepared in step B was hydrolyzed to the acid of the title according to the protocol set forth in step B of Example 1. - [2-Chloro-4- (3-pyridin-2-yl-benzoylamino) -benzoyl] -10, l-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-3- acid carboxylic-piperazine-N-methyl amide Step d) The acid prepared in step C was converted to an amide using method A of Example 9.

EXAMPLE 21 10- [2-Chloro-4- (4-pyridin-2-yl-benzoylamino) -benzoyl] -10, -dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-3 acid - carboxylic (2-dimethylamino-ethyl) -methyl amide N- [3-Chloro-4- (5H, llH-pyrrolo [2, lc] [1,4] benzodiazepine-10-carbonyl) -phenyl] -2-pyridine -4-yl-benzamide Step a) The compound of Example 21a was prepared in the same manner as described in Example 19 following steps 19a and 19b. In Step 19a, 2- (pyridin-4-yl) -benzoic acid was replaced by 2-bromobenzoic acid. The preparation of 2- (pyridin-4-yl) -benzoic acid was carried out in the manner of Timari, et al (Chem. Ber, 1992, 125, 929) substituting 4-bromopyridine hydrochloride and an additional equivalent of base instead of 2-bromopyridine. The title compound was obtained as a pale yellow solid (1.21 g), p. F. 165-168 ° C. Analysis for: C3iH23ClN402 + 0.47 H20 Calculated: C, 70.59; H, 4.57; N, 10.62 Found: C, 70.58; H, 4.50; N, 10.33 N- (3-Chloro-4- [3- (trichlorocarbonyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepin-10-carbonyl) -phenyl] -2-pyridin-4- il-benzamide Step b) The product from step A was converted to the corresponding trichloro ketone according to the protocol set forth in step A of Example 1. - [2-Chloro-4- (4-pyridin-2-yl-benzoylamino) -benzoyl] -10, l-dihydro-5H-pyrrolo [2, 1-s] [1,4] benzodiazepine-3-acid Step s) The trichloro ketone prepared in step B was hydrolyzed to the title acid according to the protocol set forth in step B of Example 1. - [2-Chloro-4- (4-pyridin-2-yl-benzoylamino) -benzoyl] -10, l-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-3-acid carboxylic (2-dimethylaminoethyl) -methyl-amide Step d) The acid prepared in step c was converted to its 2-dimethyl amino-ethyl-methyl amide according to the protocol in Example 10.

EXAMPLE 22 10- [2-Chloro-4- (2-pyridin-2-yl-benzoylamino) -benzoyl] -10,1-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine- 3- carboxylic-piperazine-Nm i1 amide N- (4- (3-Methoxy-5H, llH-pyrrolo [2, lc] [1,4] benzodiazepine-10-carbonyl) -phenyl] -2-pyridine-2- il-benzamide Step a) 2-Methoxy-4- [(2-pyridin-2-ylbenzoyl) -amino] benzoyl chloride To a solution of 2-methoxy-4- [(2-pyridin-2-ylbenzoyl) amino acid ] benzoic acid (0.92 g, 2.64 mmol) in anhydrous tetrahydrofuran (25 ml), under nitrogen, was added 1 drop of dimethylformamide followed by the addition of oxalyl chloride (0.28 ml, 3.17 mmol). The mixture was stirred at room temperature until the evolution of gas ceased. The solution was concentrated in vacuo to yield a tan solid (1.16 g), which was used without further purification.

Step b) N- [4- (3-Methoxy-5H, llH-pyrrolo [2, lc] [1,4] benzodiazepine-10-carbonyl) -phenyl] -2-pyridin-2-yl-benzamide To one solution with stirring of 10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine (0.405 g, 2.20 mmol) in dichloromethane (30 ml), under nitrogen, triethylamine was added (0.37 ml, 2.64 mmol). The mixture was cooled to 0 ° C and a solution of crude 2-methoxy-4- [(2-pyridin-2-ylbenzoyl) amino] benzoyl (1.16 g) in dichloromethane (30 ml) was added dropwise. After 5 hours, the reaction mixture was poured into water. The organic layer was separated and washed sequentially twice with water and aqueous sodium bicarbonate, and once with water and dried (Na 2 SO 4). The material was filtered and concentrated in vacuo to give a brown solid (1.1 g). Purification by flash chromatography on silica gel with hexane-ethyl acetate-methylene chloride, methanol (3: 6: 2: 0.5) as the mobile phase, followed by concentration under vacuum resulted in a pale purple solid (0.88 g). ), p. F. 138-140 ° C. MS (BAR), m / z: 515 (M + H). Analysis for: C32H26N4O3 + 0.43 H20 Calculated: C, 73.58; H, 5.18; N, 10.73. Found: C, 73.59; H, 5.05; N, 10.47.

N-. { 3-Chloro-4- [3- (trichlorocarbonyl) - (5H, 11H-pyrrolo [2,1-c] [1,4] -benzodiazepine-10-carbonyl) -phenyl} -2-pyridin-2-yl-benzamide Step c) The product from step B was converted to the corresponding trichloro ketone according to the protocol set forth in step A of Example 1. - [2-Chloro-4- (2-pyridin-2-yl-benzoylamino) -benzoyl] -10, l-dihydro-5H-pyrrolo [2, l-s] [1,4] benzodiazepine-3-sarboxylic acid Step d) The trichloroketone prepared in step C was hydrolyzed to the title acid according to the protocol set forth in step B of Example 1. - [2-Chloro-4- (2-pyridin-2-yl-benzoylamino) -benzoyl] -10, l-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-3- acid carboxylic-piperazine-N-methyl amide Baso d) The acid prepared in step D was converted to its N-methyl piperazine amide via Method B of Example 9.

EXAMPLE 23 10- [2-Bromo-4- (2-pyridin-2-yl-benzoylamino) -benzoyl] -10,1-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-3 acid - carboxylic-1, 1-dimethylhydrazide N- [3-Bromo-4- (5H, llH-pyrrolo [2, lc] [1,4] benzodiazepine-10-carbonyl) -phenyl] -2-pyridin-2-yl -benzamide Step a) 2-Bromo-4-aminobenzoate methyl A solution of 2- (pyridin-2-yl) benzoic acid (2.85 g, 14.3 mmol) in dry tetrahydrofuran (20 ml) was treated with 1 drop of dimethylformamide followed by oxalyl chloride (1.5 ml, 17.1 mmol) in dry tetrahydrofuran (5 ml).

When the gas evolution ceased, the mixture was refluxed for 5 minutes and cooled to room temperature and concentrated in vacuo to a bright yellow solid. The solid was suspended with tetrahydrofuran (20 ml) and concentrated again. The crude acid chloride was used in the next step without further purification.

Step b) Methyl 2-Bromo-4- [(2-pyridin-2-yl-benzoyl) amino] -benzoate A solution of methyl 2-brom.o-4-am.-benzoate (3 g, 13 mmol) and triethylamine (2.5 ml, 18 mmol) in dichloromethane (50 ml) was cooled to 0 ° and reacted with a suspension of 2- (pyridin-2-yl) benzoyl chloride in dichloromethane ( 20 ml). Stirring was maintained at room temperature for 4 hours. The reaction was quenched with 20% acetic acid, washed sequentially with saturated aqueous sodium bicarbonate, water and then saturated brine solution. The solution was dried (MgSO4), filtered and concentrated in vacuo to give 5.23 g of a white foam. MS (+ BAR) m / z 411/413 (M + H) 0 Analysis for: C2oH? 5Br 2? 3 Calculated: C, 58.41; H, 3.68; N, 6.81. Found: C, 57.73; H, 3.66; N, 6.54.

Step c) 2-Bromo-4- [(2-pyridin-2-yl-benzoyl) -amino) enzoic acid A solution of methyl 2-bromo-4- [(2-pyridin-2-yl-benzoyl) amino] Benzoate in methanol (100 ml) was treated with 1N sodium hydroxide (15 ml, 1.2 eq). The solution was heated to reflux for 3.5 hours and additional 1N sodium hydroxide (10.4 ml., 2 equivalent in total) was added. Reflux was maintained for an additional 2 hours and the reaction was stirred at room temperature overnight. The mixture was concentrated in vacuo to a syrup and diluted with water. The aqueous solution was washed with ethyl acetate and the aqueous layer was adjusted to a pH of 4.5-5 with acetic acid. The product was precipitated, filtered and dried to give a tan solid (4.43 g). MS (El) m / z: 397/399 (M +).

Step d) 2-Bromo-4- [(2-pyridin-2-yl-benzoyl) -amino] -benzoyl chloride To a solution of 2-bromo-4- [(2-pyridin-2-yl-benzoyl) acid ) -amino] -benzoic acid (1.4 g, 3.52 mmol) in anhydrous tetrahydrofuran (25 ml), under nitrogen, a drop of dimethylformamide was added followed by the addition of oxalyl chloride (0.37 ml, 4.23 mmol). The mixture was stirred at room temperature until there was no further evolution of gas and then heated to reflux. The reaction mixture was cooled to room temperature and concentrated in vacuo to yield a tan solid (1.385 g), which was used without further purification.

Step e) N- [3-Bromo-4-5H, IIH-pyrrolo [2, lc] - [1,4-benzodiazepine-10-carbonyl) -phenyl] -2-pyridin-2-yl-benzamide To one solution with stirring of 10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine (0.54g, 2.93 mmol) in dichloromethane (35 ml), under nitrogen, triethylamine was added (0.49 ml, 3.52 mmol). The mixture was cooled to 0 ° C before dropping a suspension of crude 2-methoxy-4- [(2-pyridin-2-ylbenzoyl) -amino] benzoyl chloride (1.4 g) in dichloromethane (5 ml). After the addition was complete, the reaction mixture was allowed to warm to room temperature. 18 hours later the reaction mixture was poured into water and washed sequentially with water, saturated aqueous sodium bicarbonate, twice with 10% aqueous acetic acid, once with saturated aqueous sodium bicarbonate and once with water.

The organic solution was dried (Na2SO4), filtered and concentrated in vacuo to give a dark purple foam (1.73 g). Purification by flash chromatography on silica gel with hexane-ethyl acetate (1: 2) as the mobile phase, followed by concentration in vacuo, resulted in a white solid (1.23 g), m.p. 227.5-229 ° C. MS (ESI), m / z: 563 (M +). Analysis for: C3iH23Br 402 Calculated: C, 66.08; H, 4.11; N, 9.94 Found: C, 65.84; H, 3.86; N, 9.85 N-. { 3-Bromo-4- [3- (trichlorocarbonyl) - (5H, 11H-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl) -phenyl} -2-pyridin-2-yl-benzamide Step f) The product of step E was converted to the corresponding trichloroacetone according to '. to the protocol set forth in step A of Example 1. - [2-Brcmo-4- [2-pyridin-2-yl-benzoylamino) -benzoyl] -10,11-dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepine-3-acid carboxylic Step g) The trichloro ketone prepared in step F was hydrolyzed to the acid of the title according to the protocol set forth in step B of Example 1. - [2-Bromo-4- [2-pyridin-2-yl-benzoylamino) -benzoyl] -10,11-dihydro-5H-pyrrolo- [2,1-c] - [1,4] -benzc acid iazepine-3-carboxylic-1, 1-dimethylhydrazide Step h) The trichloroketone prepared in step F was treated with 1,1-dimethylhydrazine according to the protocol set forth in Example 8.

EXAMPLE 24 10- [2-Chloro-4- [8-quinoloinyl-amino) -benzoyl] -10,11-dihydro-5H-pyrrolo- [2, 1-c] - [1,4] -benzodiazepine-3-carboxylic acid -piperazine-N-methylamide Quinoline-8-carboxylic acid- [4- (5H, 11H-pyrrolo [2, 1-s] [1,4] -benzodiazepine-10-carbonyl) -3-chloro-phenyl] - amide Step a) The compound of Example 24 was prepared in the same manner as described in Steps 19a and 19b of Example 19. In Step 19a, quinoline-8-carboxylic acid was replaced by 2-bromobenzoic acid. The title compound was obtained as a white powder (0.69 g) m.p. 230-231 ° C. Analysis for: C29H21CIN4O2 + 0.33 H20 Calculated: C, 69.81; H, 4.38; N, 11.23 Found: C, 69.81; H, 4.09; N, 11.14 Quinoline-8-carboxylic acid-4- [3- (trichlorocarbonyl) (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepine-10-carbonyl) -3-chloro-phenyl] -amide b) The product of step A was converted to the corresponding trichloro ketone according to the protocol set forth in step a of Example 1. - [2-Chloro-4- [8-quinolinecarboxamino] -benzoyl] -10, 11-dihydro-5H-pyrrolo- [2, 1-c] - [1,4] -benzodiazepine-3-carboxylic acid Step c) The trichloroketone prepared in step b was hydrolyzed to the title acid according to the protocol set forth in step b of Example 1. - [2-Chloro-4- [8-quinolinylamino) -benzoyl] -10,11-dihydro-5H-pyrrolo- [2, 1-c] - [1,4] -benzodiazepine-3-carboxylic-piperazine acid -N-methyl-amide Step d) The acid prepared in step c was converted to its N-methyl piperacinamide using method B of Example 9.

Calculated: C, 69.81; H, 4.38; N, 11.23 Found: C, 69.81; H, 4.09; N, 11.14 Quinoline-8-carboxylic acid-4- [3- (trichlorocarbonyl) (5H, 11H-pyrrolo [2, 1-c] [1,4] -benzodiazepine-10-carbonyl) -3-chloro-phenyl] -amide b) The product of step A was converted to the corresponding trichloro ketone according to the protocol set forth in step a of Example 1. - [2-Chloro-4- [8-quinolinecarboxamino] -benzoyl] -10, 11-dihydro-5H-pyrrolo- [2, 1-c] - [1,4] -benzodiazepine-3-carboxylic acid Step c) The trichloroketone prepared in step b was hydrolyzed to the title acid according to the protocol set forth in step b of Example 1. - [2-Chloro-4- [8-quinolinylamino] -benzoyl] -10,11-dihydro-5H-pyrrolo- [2, 1-c] - [1,4] -benzodiazepine-3-carboxylic-piperazine acid -N-methy1-amide Step d) The acid prepared in step c was converted to its N-methyl piperazine ida using method B of Example 9.

EXAMPLE 25 2-Phenyl-cyclopent-1-enecarboxylic acid- [3-chloro-4- (3-carboxylic acid) (2-dimethylamino-ethyl) -methyl-amide-5H, HH-pyrrolo- [2, 1-] c] - [1,4] -benzodiazepine-10-carbonyl) -phenyl] -amide Step a) [2-phenyl-cyclopent-1-enecarboxylic acid] Sodium hydroxide (1N) (10.7 ml, 11.8 mmol) was added to a refluxing solution of 2-phenyl-cyclopent-1-enecarboxylic acid methyl ester (2.32 g, 10.7 mmol) (Lin et al., J. Chin.Chem.Soc., 1993, 40, 273-282) in methanol (40 ml). The reaction was refluxed for 2 hours. The volatiles were removed in vacuo and the residue partitioned between ethyl acetate and hydrochloric acid (1N). The aqueous layer was extracted again with ethyl acetate, and the organic extracts were combined and dried (MgSO). Evaporation of the solution in vacuo gave a pale yellow solid, which was recrystallized from acetone / hexane to give a white solid (1.27 g) m.p. 145-146 ° C. Analysis for: C12H12O2 Calculated: C, 76.57; H, 6.43; N, Found: C, 76.47; H, 6.35; N, Step b) 2-phenyl-cyclopentyl-1-carbonyl chloride To a solution of 2-phenyl-cyclopent-1-enecarboxylic acid (0.43 g, 2.28 mmol) in dichloromethane (20 ml) was added dimethylformamide via a syringe (1 drop). ) and then pure oxalyl chloride (0.4 ml, 4.56 mmol). The reaction was stirred at room temperature for 2 hours and then the volatiles were removed in vacuo. The residue was dissolved in dichloromethane, concentrated in vacuo and dried under high vacuum for 15 minutes to give an amber oil which was used directly in the next step without further purification.

Step c) 2-Phenyl-cyclopentyl-enecarboxylic acid- [4- (5H, 11H-pyrrolo- [2, 1-c] - [1,4] -benzodiazepine-10-carbonyl) -3-chloro-enyl ] -amide The product of Example 25, step b, 2-phenyl-cyclopentylcarbonyl chloride was dissolved in dichloromethane (20 ml) and added at room temperature to a solution of , 11-dihydro-10- (2-chloro-4-aminobenzoyl) -5H-pyrrolo [2, 1-c] - [1,4] benzodiazepine (0.77 g, 2.28 mmol, 4-dimethylaminopyridine (catalyst) in dichloromethane (20 ml)). Then triethylamine (0.38 ml, 2.74 mmol) was added via syringe. The reaction was stirred for 16 hours, diluted with dichloromethane and washed with sodium bicarbonate, hydrochloric acid (1N), and brine. The dichloromethane solution was dried (MgSO4) and concentrated in vacuo to give a yellow solid. Purification by flash chromatography (elution solvent of chloroform / methanol 50/1 and hexane / ethyl acetate 2/1) gave a white solid (0.70 g), m.p. 121-122 ° C. Analysis for: C31H26CIN3O2 Calculated: C, 73.29; H, 5.16; N, 8.27 Found: C, 73.18; H, 5.02; N, 8.11 2-phenyl-cyclopent-1-enecarboxylic acid- [3-chloro-4- (3-trichloro-carbonyl) -5H, IIH-pyrrolo [2, 1-c] - [1,] -benzodiazepine-10-carbonyl) phenyl] -amide Step d) The product from step C was converted to the corresponding trichloro ketone according to the protocol set forth in step A of Example 1. 2-phenyl-cyclopent-1-enecarboxylic acid- [3-chloro-4- (3-carboxylic acid) -5H, llH-pyrrolo [2,1-s] - [1,4] -benzodiaaepin-10-caribonyl ) -phenyl] -amide Step e) The trichloroketone prepared in step D was hydrolyzed in the title acid according to the protocol set forth in step B of Example 1. 2-f-enyl-cislopent-1-incarboxylic acid- [3-chloro-4- (3-carboxylic acid) (2- ii? Nylamino-ethyl) -methyl-amide-5H, llH-pyrrolo [2, 1- c] - [1,4] -benzodiazepine-10-carbonyl) -phenyl] -amide Step f) The amide was prepared by the reaction of the acid prepared in step e, above, according to the protocol set forth in Example 10.

Effects on Response Antagonism Antidiuretic of Arginine Endogenous Vasopressin (V2) in Conscious Rats with Free Access to Water Consumption Before but Not During the Experiment: Male or Female Normotensive Sprague-Dawley Rats (Charles River Laboratories, Inc., Kingston, NY) of 400-450 g of body weight were supplied with food for Laboratory Rodents # 5001 (PMI Feeds, Inc., Richmond, IN) and water ad libi tum. On the day of the test, the rats were placed individually in metabolic cages equipped with stainless steel grids (to separate feces from the urine) and funnels for urine collection. The vehicle or reference agent was given in several oral doses. During the test, no water or food was provided to the rats. The urine was collected for four hours after dosing the test compound. At the end of four hours, the volume of urine was measured. The osmolality of the urine was determined using a Fiske Ten-in-One Osmometer (Fiske Associates, Norwood, MA, 02062), or an Advanced CRYOMATIC Osmometer, Model 3C2 (Advanced Instruments, Norwood, MA). Na +, K + and Cl "ion determinations were carried out using specific electrodes for the ions in a Beckman SYNCRON EL-ISE Electrolyte System analyzer In the following results, an increased urine volume and reduced osmolality AVP control indicates activity The results of this test on the representative compounds of this invention are shown in Table 5.

Binding to the Membranes of the Mouse Fibroblast Cell Line (LV-2) Transfected with cDNA Expressing the Human Vasopressin Receptor V2 Preparation of the Membrane Bottles of 175 ml capacity, containing bound cells that grew to confluence, cleaned of half culture by aspiration. The bottles containing the bound cells were rinsed with 2x5 ml of phosphate buffered saline (PBS) and the liquid aspirated each time. Finally, 5 ml of a Hank-based enzyme-free dissociation solution (Specialty Media, Inc., Lafayette, NJ) was added and the bottles were left undisturbed for 2 minutes. The contents of all the bottles were poured into a centrifuge tube and the cells were pelleted at 300 x g for 15 min. The Hank-based solution was aspirated from the cell homogenate with a # 6 adjusted polytron 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 was centrifuged at 1500 x g for 10 min. to remove traces of membrane. The supernatant fluid was centrifuged at 100,000 x g for 60 min to pellet the receptor protein. After completion, the pellet was resuspended in a small volume of 50.0 mM Tris.HCl buffer, pH 7.4. The protein content was determined by the Lowry method and the receptor membranes were suspended in 50.0 mM Tris-HCl buffer with a content of 0.1 mM phenyl methyl sulfonyl fluoride (PMSF) and 0.2% bovine sero albumin (BSA) to give 2.5 mg of receptor protein per ml of suspension.

Receptor Binding For the binding experiments, the following volume in ml was added to the wells of a 96-well format of a microtiter plate: 100.0 ml of 100.0 mM Tris.HCl buffer with a 0.2% content of BSA inactivated by heat, 10.0 mM MgCl 2 and a mixture of protease inhibitors; 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 [3H] Arginine8, vasopressin (S.A, 75.0 Ci / mmol) at 0.8 nM and the reaction was initiated by the addition of 80.0 ml of tissue membranes (200.0 mg of tissue protein). The plates were left undisturbed on the test bench for 120 minutes until equilibrium was reached. The specific binding was not evaluated in the presence of 1.0 mM unlabelled ligand, added in a volume of 20 ml. For the test compounds, these were solubilized in 50% dimethylsulfoxide (DMSO) and a volume of 20.0 ml was added to a final incubation volume of 200 ml. After completion of the union, the contents of each well were filtered, using a Brandel® Cell Harvester (Gaithersburg, MD). The radioactivity trapped on the filter disc by the ligand-receptor complex was evaluated by flash count in liquid phase in a Packard LS Counter, with an efficiency of 65% for tritium. The data were analyzed to determine the values of the IC0 by the LUNDON-2 program for the competition (LUNDON SOFTWARE, OH). The results of this test on the representative compounds of this invention are shown in Table 5.

Table 5 Rat Urine Volume Data * and Binding Assay Membranes of the Cell Lineage of the Mouse Fibroblast (LV-2) Transfected with the cDNA Expressing the Human V2 Receptor Number < Example Urine Volume Vasopressin Receptor (ml / 4 hours) Human V2 Binding 10 mg / kg rat po nM Example 1 13.2 14 Example 2 11.5 Example 3 22 15 Example 4 9.2 60 Example 5 9.1 60 Example 6 5.6 Use 7 19.2 4.3 Example 8 40.9 8.6 Example 9 23.7 3.3 Example 10 22.2 5.5 Example 11 20.5 9.3 Example 12 21.4 Example 13 16.8 Example 14 11.3 Example 15 19.3 10.7 Example 16 24.3 Example 17 9.4 Example 18 7.8 7.6 Volume of urine produced in a period of time of 4 hours by the oral administration of a dose of 10 mg / kg to the rats. 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 (33)

1. RE IVINDICATIONS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of formula: characterized in that: R is selected from -OH, -NR? R3, -NHORi, -NH- (CH2) -COOH, Ri and R2 are independently hydrogen or lower alkyl; R3 is selected from the group of: ^^^ H ° ^ O p is 1 to 4; q is from 2 to 4; R4 and Rb are, independently, selected from hydrogen, lower alkyl, halogen, amino, cyano, trifluoromethyl, hydroxy, or lower alkoxy; R6 is a portion of the formula: Ar is a selected portion of R7 and Re are independently selected from hydrogen, halogen, cyano, lower alkyl, lower alkoxy, hydroxy, or trifluoromethyl; R9 is a portion of the formula: Rio is selected from C3-C7 cycloalkyl, cyclopentenyl, cyclohexenyl, or the Ar 'portion is a selected portion of Rn and R12 are independently selected from hydrogen, F, Cl, Br, cyano, lower alkyl, lower alkoxy, phenoxy or substituted phenoxy, or trifluoromethyl; Ar "is selected from a) phenyl; b) a five-membered aromatic heterocyclic ring (unsaturated) having one or two heteroatoms selected from N, 0, S; c) a five-membered aromatic heterocyclic ring (unsaturated) having three or four nitrogen atoms; or d) a six-membered aromatic heterocyclic ring (unsaturated) having one, two or three nitrogen atoms, and Ar7 'may be optionally substituted with halogen, lower alkyl, hydroxy, lower alkoxy, or trifluoromethyl; or pharmaceutically acceptable salts, esters or forms of prodrugs thereof.
2. 2. A compound according to claim 1, characterized in that it has the formula: wherein R is selected from -OH, -R1R3, -NH- (CH2] COOH, Rj and R2 are, independently, hydrogen or lower alkyl; R-is n is from 1 to 4; q is from 2 to 4; Ri and R5 are independently selected from hydrogen, lower alkyl, halogen, amino, hydroxy, cyano, trifluoromethyl, or lower alkoxy; R6 is a portion of the formula: Ar is a selected portion of R7 and R8 are independently selected from hydrogen or halogen; lower alkoxy; R9 is a portion of the formula: Rio is a portion of the formula Ar 'is a selected portion of R p and R 12 are independently selected from hydrogen, F, Cl, Br, cyano, lower alkyl, lower alkoxy, trifluoromethyl, phenoxy or substituted phenoxy having the structure: < Ru ° - wherein, Rn is selected from hydrogen, halogen, cyano, lower alkyl, lower alkoxy, hydroxy, or trifluoromethyl; Ar "is selected from phenyl 2-pyridyl or a five-membered aromatic heterocyclic ring (unsaturated) having one or two heteroatoms selected from N, 0, S, or a pharmaceutically acceptable salt, ester or prodrugs thereof. compound according to claim 1, characterized in that it has the formula: in which R is selected from OH, NR! R3, or -N N-R, Ri and R2 are independently hydrogen or lower alkyl; (CH2) -NNRl R2 q is from 2 to 4; R6 is a portion of the formula: or \ l -C-Ar Ar is a selected portion of R7 and R8 are independently selected from hydrogen or halogen; R9 is Rio is a portion of the formula: Ar * is a selected portion of phenyl or a five-membered aromatic heterocyclic ring (unsaturated) having one or two heteroatoms selected from N, O, S; or a pharmaceutically acceptable salt, ester or prodrugs thereof. 4. The compound according to claim 1, characterized in that it is 10- [2-chloro-4- (5-fluoro-2-methyl-benzoylamino) -benzoyl] -10, 11-dihydro-5H-pyrrolo acid. 2, 1-c] [1,] benzodiazepine-3-carboxylic acid or a pharmaceutically acceptable salt, ester or prodrugs thereof. 5. The compound according to claim 1, characterized in that it is 10- [2-chloro-4- (5-fluoro-2-methyl-benzoylamino) -benzoyl] -10, 11-dihydro-5H-pyrrol'o [2, 1-c] [1 , 4] benzodiazepine-3-carboxylic, potassium salt (1: 1). 6. The compound according to claim 1, characterized in that it is N-. { 3-Chloro-4- [3- (N ', N'-dimethyl-hydrazinocarbonyl) -5H, llH-pyrrolo [2, 1-c] [1,4] -benzodiazepine-10-carbonyl] -phenyl} -5-fluoro-2-methyl-benzamide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 7. The compound according to claim 1, characterized in that it is 2- [[10- [2-chloro-4- [(5-fluoro-2-methylbenzoyl) amino] benzoyl] -10, 11-dihydro iodide -5H-pirrolo. { 2, 1-c] [1,] benzodiazepin-3-yl] carbonyl} - 1, 1, 1-trimethylhydrazinium or a pharmaceutically acceptable salt, ester or prodrugs thereof. 8. The compound according to claim 1, characterized in that it is the inert salt of 2- [[10- [2-chloro-4- [(5-fluoro-2-methylbenzoyl) amino] benzoyl] -10, 11- dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepin-3-yl] hydroxy-methylene] -1,11-trimethylhydrazinium or a pharmaceutically acceptable salt, ester or prodrugs thereof. 9. The compound according to claim 1, characterized in that it is N- [5- [3-trichloromethylcarbonyl] - [5H-pyrrolo- [2, 1-c] - [1,4] -benzodiazepine-10 (11H ) -yl] carbonyl] -2-chlorophenyl] -2-phenylbenzamide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 10. The compound according to claim 1, characterized in that it is the acid 10-. { 4- [bipheni-2-carbonyl) -amino] -2-chloro-benzoyl) -10,1-dihydro-5H-benzo [e] pyrrolo [1,2-a] [1,4] diazene-3-carboxylic acid or a pharmaceutically acceptable salt, ester or prodrugs thereof. 11. The compound according to claim 1, characterized in that it is 10- (4- [(biphenyl-2-carbonyl) -amino] -2-chloro-benzoyl) -10,11-dihydro-5H-benzo acid. e] pyrrolo [1, 2-a [1,4] diazepine-3-carboxylic acid-N-methyl amide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 12. The compound according to claim 1, characterized in that it is the acid 10-. { 4- [(Biphenyl-2-carbonyl) -amino] -2-chloro-benzoyl} -10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-3-carboxylic- (2-dimethyl-amino-ethyl) -methyl-amide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 13. The compound according to claim 1, characterized in that it is biphenyl-2-carboxylic acid. { 3-Chloro-4- [3- (4-piperidinyl-piperidine-1-carbonyl) -5H, IIH-pyrrolo.2, 1-c] [1,4] benzodiazepine-10-carbonyl] -phenyl} -amide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 14. The compound according to claim 1, characterized in that it is biphenyl-2-carboxylic acid. { 3-Chloro-4- [3- (4-dimethylamino-piperidine-1-carbonyl) -5H, IIH-pyrrolo [2, 1-c] [1,] benzodiazepine-10-carbonyl] -phenyl} -amide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 15. The compound according to claim 1, characterized in that it is biphenyl-2-carboxylic acid. { 3-Chloro-4- [3- (4-methyl-piperazin-1-aminocarbonyl) -5H, IIH-pyrrolo [2, 1-c] [1,] benzodiazepine-10-carbonyl] -phenyl} -amide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 16. The compound according to claim 1, characterized in that it is the acid 10-. { 4- [(biphenyl-2-carbonyl) -amino] -2-chloro-benzoyl} -10,11-dihydro-5H-pyrrolo [2, 1-c] [1,4] benzodiazepine-3-carboxylic (2-dimethylamino-ethyl) -amide or a pharmaceutically acceptable salt, ester or prodrugs thereof . 17. The compound according to claim 1, characterized in that it is biphenyl-2-carboxylic acid. { 3-Chloro-4- [3- (4-morpholino-piperidine-1-carbonyl) -5H, IIH-pyrrolo [2, 1-c] [1,4] benzodiazepine-10-carbonyl] -phenyl} - amide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 18. The compound according to claim 1, characterized in that it is 10- (4- [(biphenyl-2-carbonyl) -amino] -2-methoxy-benzoyl) -10,11-dihydro-5H-benzo [e] pyrrolo acid [1, 2-a] 1,4] diazepine-3-carboxylic piperazin-N-methyl amide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 19. The compound according to claim 1, characterized in that it is 10- (4- [(biphenyl-2-carbonyl) -amino] -2-methoxy-benzoyl) -10,11-dihydro-5H-benzoic acid [e] pyrrolo [l / 2-a [1,4] diazenete-3-carboxylic-1, l-dimethyl-hydrazine or a pharmaceutically acceptable salt, ester or prodrugs thereof. 20. The compound according to claim 1, characterized in that it is the acid 10-. { 4- [(biphenyl-2-carbonyl) -amino] -2-chloro-benzoyl} -10, 11-dihydro-5H-pyrrolo [2, 1-c] [1,] benzodiazepine-3-carboxylic (glycyl) -amide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 21. The compound according to claim 1, characterized in that it is 10- [2-chloro-4- (2-thiophen-2-yl-benzoylamino) -benzoyl] -10, 11-dihydro-5H-pyrrolo acid. 2, 1-c] [1,] benzodiazepine-3-carboxylic-1, 1-dimethylhydrazine or a pharmaceutically acceptable salt, ester or prodrugs thereof. 22. The compound according to claim 1, characterized in that it is 10- [2-chloro-4- (3-pyridin-2-yl-benzoylamino) -benzoyl] -10, l-dihydro-5H-pyrrolo acid. 2, 1-c] [1,4] -benzodiazepine-3-carboxylic piperazin-N-methyl amide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 23. The compound according to claim 1, characterized in that it is 10- [2-chloro-4- (4-pyridin-2-yl-benzoylamino) -benzoyl] -10, 11-dihydro-5H-pyrrolo acid. 2, 1-c] [1,4] benzodiazepine-3-carboxylic (2-dimethylamino-ethyl) -methyl amide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 24. The compound according to claim 1, characterized in that it is 10- [2-chloro-4- (2-pyridin-2-yl-benzoylamino) -benzoyl] -10, 11-dihydro-5H-pyrrolo acid. 2, 1-c] [1,4] benzodiazepine-3-carboxylic-piperazin-N-methyl amide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 25. The compound according to claim 1, characterized in that it is 10- [2-bromo-4- (2-pyridin-2-yl-benzoylamino) -benzoyl] -10, 11-dihydro-5H-pyrrolo acid [2] , 1-c] [1,4] benzodiazepine-3-carboxylic-1, 1-dimethyl-hydrazide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 26. The compound according to claim 1, characterized in that it is 10- [2-chloro-4- [8-quinoloinyl-amino) -benzoyl] -10,1-dihydro-5H-pyrrolo- [2, 1-c] - [1,4] -benzodiazepine-3-carboxylic-piperazin-N-methyl amide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 27. The compound according to claim 1, characterized in that it is 2-phenyl-cyclopent-1-enecarboxylic acid- [3-chloro-4- (3-carboxylic acid) (2-dimethylamino-ethyl) -methyl-amide. -5H, llH-pyrrolo- [2, 1-c] - [1,4] -benzodiazepine-10-carbonyl) -phenyl] -amide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 28. ' The compound according to claim 1, characterized in that it is the acid 10-. { 4- [(bifeni1-2-carbonyl) -amino] -2-chloro-benzoyl} -10, 11-dihydro-5H-pyrrolo- [2, 1-c] [1,4] -benzodiazepine-3-carboxylic- (glycyl) -amide or a pharmaceutically acceptable salt, ester or prodrugs thereof. 29. A pharmaceutical composition useful for treating diseases in mammals, characterized by excessive renal water reabsorption, the pharmaceutical composition is characterized in that it comprises an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, ester or prodrugs of it, and a suitable pharmaceutical carrier. 30. The pharmaceutical composition according to claim 29, characterized in that the disease in a mammal characterized by an excessive renal absorption of water is congestive collapse, nephrotic syndrome, hyponatremia, coronary vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis, syndrome of inappropriate antidiuretic hormone secretion, cerebral edema, cerebral ischemia or cerebral stroke. 31. Bear of a compound according to claim 1 or a pharmaceutically acceptable salt, ester or prodrugs thereof, for the preparation of a medicament for treating a disease in a mammal characterized by excessive renal reabsorption of water. 32. The use according to claim 31, wherein the disease in a mammal characterized by excessive renal water reabsorption is congestive collapse, nephrotic syndrome, hyponatremia, coronary vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis, Secretion syndrome of Inappropriate Antidiuretic Hormone, cerebral edema, cerebral ischemia or cerebral hemorrhagic shock. 33. A process for preparing the compound of formula I according to claim 1, characterized in that it comprises one of the following: a) reacting a compound of formula: wherein R4, R5 and Re are as defined in claim 1, and hal is a halogen, for example, chloro with an amine of the formula in which -NZ2Z2, it can be -NR1R3, NHORx, -NH- (CH2) n-C00H, wherein n, X, Ri, R2 and R3 are as defined in claim 1, to give a corresponding compound of formula I, wherein R is as defined above; or b) treating a compound of formula: wherein R4, R5 and Re are as defined in claim 1, and hal is a halogen, for example chlorine, with an aqueous base to give a corresponding compound of formula I, in which R is OH, or c) acylated a compound of formula: wherein R, R4 and R3 are as defined in claim 1, with the exception that R is not OH; Rn is wherein R7 and R8 are as defined in claim 1, with an acid of formula ) Af HC .R, or HO? " or a reactive derivative thereof, for example acid halide or anhydride, and to give a corresponding compound of formula I, wherein R9 is as defined in claim 1.