MXPA06007563A - Compounds useful in therapy - Google Patents

Abstract

Compounds of formula (I), or a pharmaceutically acceptable derivative thereof, wherein:X represents NR or O;R represents hydrogen, C1-8 alkyl or SO2[C,1-8 alkyl];W represents N or CH;Y and Y'independently represent hydrogen, halogen, OH, CF3, OCF3, CN, NH2 C1-8 alkyl, C1-8 alkyloxy or C3-8cycloalkyl;Ring A represents a heterocyclic ring containing at least one nitrogen atom;Z represents a direct link, C1-8 alkyl or C3-8 cycloalkyl;R1 represents R2, OR2, OR 3-R4, N(R2)[C1-8 alkylene]aR4;NCOR2, or SR4;R2 and R4 independently represent hydrogen, C3-8 cycloalkyl, CF3, Ar or Het;R3 represents a direct link or C1-8 alkyl;is 0 or 1;Ar represents an aromatic ring, optionally fused to a heterocyclic ring, and/or optionally substituted with one or more groups as described below;Het represents a heterocyclic ring optionally substituted with one or more groups as described below, and/or optionally fused to an aromatic ring which is optionally substituted with one or more groups as described below;at each occurrence C1-8alkyl, C1-8alkylene and C3-8cycloalkyl may be independently optionally substituted with one or more groups as described below;substituent groups for Ar, Het, C1-8alkyl, C1-8alkylene and C3-8cycloalkyl referred to the above are independently selected from hydrogen, halogen, C1-8alkyl, C1-8alkyloxy, S[C1-8alkyl], CN, CF3, NH2 and OH;are useful for treating anxiety, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhoea (primary and secondary), endometriosis, emesis (including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), mittelschmerz, preclampsia, premature ejaculation, premature (preterm) labor and Raynaud's disease.

Description

USEFUL COMPOUNDS IN THERAPY FIELD OF THE INVENTION This invention relates to new compounds useful in therapy. A processes for the preparation of such compounds and intermediates used in their preparation. Additionally, it refers to compositions containing such compounds and their use. BACKGROUND OF THE INVENTION WO 01/87855 discloses triazole derivatives as inhibitors of glycine transporter activity. WO 01/58880 and JP2000-63363 describe thiazole derivatives useful as antagonists of the arginine vasopressin V? A receptor. Kakefuda et al., Bioorg.

Med. Chem. 10 (2002) 1905-1912 and Kakefuda et al., J. Med. Chem., 2002, 45, 2589-2598 analyze the utility of 4,5-diphenyl-1,2,4-triazole derivatives as selective antagonists for the human V-IA receptor and comment that the structure of 4,5-diphenyl-1,2,4- triazole plays an essential role in the affinity of VIA. It has been found that the compounds of the present invention have useful pharmaceutical properties. They can be used to treat one or more diseases selected from aggressiveness, Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder, asthma, atherosclerosis, autism, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypematremia), cataracts , central nervous system disease, cerebrovascular ischemia, cirrhosis, dysmenorrhoea (primary and secondary), emesis (including motion sickness), endometriosis, gastrointestinal disease, glaucoma, gynecological disease, heart disease, intrauterine growth retardation, inflammation (including rheumatoid arthritis) ), ischemia, ischemic heart disease, lung tumor, micturition disorder, ovulation pain, neoplasm, nephrotoxicity, non-insulin dependent diabetes, obesity, obsessive / compulsive disorder, ocular hypertension, preeclampsia, premature ejaculation, preterm delivery (preterm ), lung disease, disease of Raynaud, kidney disease, renal failure, male or female sexual dysfunction, septic shock, sleep disorder, spinal cord injury, thrombosis, urogenital tract infection and urolithiasis. Of particular interest are the following diseases or disorders: anxiety, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhea (primary and secondary), endometriosis, emesis (including motion sickness), delay in intrauterine growth, inflammation (including rheumatoid arthritis), ovulation pain, preeclampsia, premature ejaculation, premature delivery (preterm) and Raynaud's disease. In particular, the compounds of the present invention show vasopressin antagonist activity and can be used in the treatment of dysmenorrhoea (primary and secondary).

There is a great unmet need in the area of menstrual disorders and it is estimated that up to 90% of all women of menstrual age are affected to some degree. Up to 42% of women miss work or stop doing other activities due to menstrual pain and it has been estimated that, as a result, approximately 600 million work hours are lost per year in the United States. { Coco, A. S. (1999). Primary dysmenorrhea. [Review] [30 refs]. American Family Physician, 60, 489-96 ..}. . Menstrual pain in the lower abdomen is due to hyperactivity of the myometrium and a reduction in uterine blood flow. These pathophysiological changes produce abdominal pain that branches to the back and legs. This can make women feel nauseous, have headaches and suffer from insomnia. This condition is called dysmenorrhea and can be classified as primary or secondary dysmenorrhea. A primary dysmenorrhoea is diagnosed when no anomaly that causes this state is identified. This affects up to 50% of the female population. { Coco, A. S. (1999). Primary dysmenorrhea. [Review] [30 refs]. American Family Physician, 60, 489-96,; Schroeder, B. & Sanfilippo, J. S. (1999). Dysmenorrhoea and pelvic pain in adolescents. [Review] [78 refs]. Pediatríc Clinics of North America, 46, 555-71} . When an underlying gynecological disorder is present, such as endometriosis, pelvic inflammatory disease (PID), fibroids or cancers, it will be diagnosed as secondary dysmenorrhea. Only secondary dysmenorrhea is diagnosed in approximately 25% of women who suffer from dysmenorrhea. Dysmenorrhea may occur along with menorrhagia, with approximately 12% of the referrals to outpatient gynecology departments assuming these cases. Currently, women suffering from primary dysmenorrhea are treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or the oral contraceptive pill. In cases of secondary dysmenorrhea, surgery can be performed to correct the underlying gynecological disorder. Women who suffer from dysmenorrhea have circulating levels of vasopressin that are higher than those observed in healthy women at the same time of the menstrual cycle. Inhibition of the pharmacological actions of vasopressin in the uterine vasopressin receptor can prevent dysmenorrhea. DETAILED DESCRIPTION OF THE INVENTION According to the present invention there is provided a compound of formula (I), (i) or a pharmaceutically acceptable derivative thereof, wherein: R represents hydrogen, C? -8 alkyl or SO2 [C? -8 alkyl]; W represents N or CH; Y and Y 'independently represent hydrogen, halogen, OH, CF3, OCF3, CN, NH2, C? -8 alkyl, C? -8alkyloxy or C3-8 cycloalkyl; Ring A represents a heterocyclic ring containing at least one nitrogen atom; Z represents a direct bond, C alquilo? -8 alkyl or C 3-8 cycloalkyl; R1 represents R2, OR2, OR3-R4, N (R2) [C1-8 alkylene] aR4; NCOR2 or SR4; R2 and R4 independently represent hydrogen, C3-s, CF3, Ar or Het cycloalkyl; R3 represents a direct bond or C? -8 alkyl; a is 0 or 1; Ar represents an aromatic ring, optionally fused with a heterocyclic ring, and / or optionally substituted with one or more groups as described below; Het represents a heterocyclic ring optionally substituted with one or more groups as described below, and / or optionally condensed with an aromatic ring that is optionally substituted with one or more groups as described below; in each case, the C 1-8 alkyl, C 8 alkylene and C 3-8 cycloalkyl groups may be optionally and independently substituted with one or more groups as described below; the substituent groups for Ar, Het, C?-alkyl, C 1-8 alkylene, and C3.8 cycloalkyl indicated above are independently selected from hydrogen, halogen, C -? alquilo alkyl, C 1-8 alkyloxy, S [alquiloC1- alkyl 8], CN, CF3, NH2 and OH.

In the above definitions, halogen means fluorine, chlorine, bromine or iodine. Alkyl and alkyloxy groups containing the required number of carbon atoms, except where indicated, may be straight or branched chain. Examples of alkyl include methyl, ethyl, n-propyl, -propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, α-propoxy, n-butoxy, -butoxy, sec-butoxy and t-butoxy. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Unless otherwise indicated, the term heterocyclic ring, or heterocyclyl, means a saturated, unsaturated or aromatic, five or six member ring containing one or more heteroatoms selected from N, S and O. Preferred heterocycles included within the definition of "heterocycle" are pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl and quinoxalinyl , together with partially or fully saturated versions thereof, as well as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl and morpholinyl.

The term aryl ring means a five or six membered aromatic ring. Preferred groups of compounds are those in which one or more of the following apply: (i) X represents NR; (ii) R represents Me; (iii) W represents N; (iv) Ring A represents piperidinyl; (v) Z represents a direct link; (vi) R 'represents a phenyl ring substituted with halogen and / or alkyl; (vii) R 'represents a phenyl ring fused with a five-membered heterocycle containing nitrogen.

Preferred compounds according to the present invention are: [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) ) -piperidin-1 -yl] - (1 H -indol-3-yl) -methanone; 1- [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -piperidin-1-yl] -2-o-tolyl-ethanone; [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -piperidin-1-yl] - (1 -methyl-cyclohexyl) -methanone; 1- [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -piperidin-1H] - 2-cyclopropyl-ethanone; [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-ii) -piperidin-1-yl] - (1H) -indol-2-yl) -metanone; [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -piperidin-1-yl] - (2 -hydroxy-5-methyl-phenyl) -methanone; [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -piperidin-1-yl] - (1 H-indol-6-yl) -metanone; [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -piperidin-1-yl] - (3 -methoxy-phenyl) -methanone; [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5, 10b-tetraaza-benzo [e] azulen-1-yl) -piperidin-1 -yl] - (3 -fluoro-phenyl) -metanone; [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) piperidin-1-yl] - (4 -fluoro-phenyl) -metanone; 1- [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -piperidin-1-yl] - butan-1 -one; [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -piperidin-1-yl] -cyclopropyl- methanone; and pharmaceutically acceptable derivatives thereof.

Pharmaceutically acceptable derivatives of the compounds of formula (I) according to the invention include salts, solvates, complexes, polymorphs, prodrugs, stereoisomers, geometric isomers, tautomeric forms and isotopic variations of compounds of formula (I).

Preferably, pharmaceutically acceptable derivatives of compounds of formula (I) comprise salts, solvates, esters and amides of the compounds of formula (I). More preferably, the pharmaceutically acceptable derivatives of compounds of formula (I) are salts and solvates. The pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition salts and bases thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the salts acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate, borate, camsylate, citrate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glueuronate, hexafluorophosphate, hybienate, hydrochloride / chloride, hydrobromide / bromide , hydroiodide / iodide, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, palmate, phosphate, hydrogen phosphate, dihydrogen phosphate, saccharate, stearate, succinate, sulfate, D- and L-tartrate, tosylate and trifluoroacetate. A particularly suitable salt is the besylate derivative of the compounds of the present invention. Suitable base salts are formed from bases that form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

For a review of suitable salts see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Wiley-VCH, Weinheim, Germany (2002). A pharmaceutically acceptable salt of a compound of formula (I) can be prepared easily by mixing together solutions of the compound of formula (I) and the desired acid or base, as appropriate. The sai can precipitate from the solution and be collected by filtration or it can be recovered by evaporation of the solvent. The degree of ionization of the salt can vary from completely ionized to almost non-ionized. The compounds of the invention can exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term "hydrate" is used when said solvent is water. Within the scope of the invention are included complexes such as clathrates, drug-host molecule inclusion complexes where, in contrast to the solvates mentioned above, the drug and the host molecule are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes that contain two or more organic and / or inorganic components that may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized.

For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975). In the following, all references to compounds of formula (I) and pharmaceutically acceptable derivatives include references to salts, solvates and complexes thereof and to solvates and salt complexes thereof. The compounds of the invention include compounds of formula (I) as defined hereinabove, polymorphs, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as defined hereinbelow and compounds of formula (I) isotopically labeled. As stated, the invention includes all polymorphs of the compounds of formula (I) as defined above. Also within the scope of the invention are so-called "prodrugs" of the compounds of formula (I). In this way, certain derivatives of compounds of formula (I) having little or no pharmacological activity by themselves, when administered in or on the body, can be converted to compounds of formula (I) having the desired activity, for example, hydrolytic cleavage. . Said derivatives are referred to as "prodrugs". Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and" Bioreversible Carriers in Drug Design, "Pergamon Press, 1987 (ed. Roche, American Pharmaceutical Association.) Prodrugs according to the invention can be produced, for example, by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as "pro-moieties" as describes, for example, in "Design of Prodrugs "by H Bundgaard (Elsevier, 1985) Some examples of prodrugs according to the invention include: (i) where the compound of formula (I) contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with alkyl (CrC8); (i) where the compound of formula (I) contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with alkanoyloxymethyl (C? -C6) and (ii) where the compound of formula (I) contains a primary or secondary amino functionality (-NH2 or -NHR where R? H), an amide thereof, for example, replacement of one or both hydrogens with alkanoyl (C1-C10).

In the references mentioned above, other examples of replacement groups can be found according to the above examples and examples of other types of prodrug.

Finally, some compounds of formula (I) can act as prodrugs of other compounds of formula (I). Also within the scope of the invention are the metabolites of the compounds of formula (I) when they are formed in vivo. The compounds of formula (I) containing one or more asymmetric carbon atoms can exist in the form of two or more stereoisomers. When a compound of formula (I) contains an alkenyl or alkenylene group, cis / trans (or Z / E) geometric isomers are possible, and when the compound contains, for example, a keto or oxime group or an aromatic moiety, there may be tautomeric isomería ('tautomería'). It follows that a single compound can have more than one type of isomerism. Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds that display more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition salts or bases wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine. The cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, fractional crystallization and chromatography. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral HPLC. Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compounds of formula (I) contain an acid or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization and one or both diastereomers can be converted to the corresponding pure enanfomer (s) by means well known to a skilled person. The chiral compounds of the invention (and their chiral precursors) can be obtained enriched in one of the enantiomers using chromatography, typically HPLC, in an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing isopropanol of 0 to 50%, typically 2 to 20%, and 0 to 5% of an alkylamine, typically 0.1% of diethylamine. The concentration of the eluate produces the enriched mixture. Stereoisomeric conglomerates can be separated by conventional techniques known to those skilled in the art, see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994). The present invention also includes all pharmaceutically acceptable isotopic variations of a compound of formula (I) wherein one or more atoms are replaced with atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which is normally found in nature. Examples of suitable isotopes for inclusion in the compounds of the invention include hydrogen isotopes such as 2H and 3H, carbon such as 11C, 13C and 14C, nitrogen such as 13N and 15N, oxygen such as 15O, 17O and 13O, phosphorus such as 32P, sulfur such as 35S, fluorine such as 18F, iodine such as 123l and 125l, and chlorine such as 36CI. Certain isotopically-labeled compounds of formula (I), for example those that incorporate a radioactive isotope, are useful in studies of drug distribution and / or tissue substrates. The radioactive isotopes tritium, i.e. 3H, and carbon -14, i.e. 14C, are particularly useful for this purpose in view of the fact that they are easily incorporated and that detection means are available. In addition, replacement with heavier isotopes such as deuterium, i.e., 2H, may provide certain therapeutic advantages resulting from increased metabolic stability, for example a longer in vivo half-life or reduced dose requirements and therefore may be preferred in some circumstances Substitution with positron emission isotopes, such as 11C, 18F 15O and 13N, may be useful in positron emission topography (PET) studies to examine the occupancy of a receptor by a substrate. The isotopically-labeled compounds of formula (I) can be prepared in general by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically labeled reagents in place of the unlabeled reagent previously employed. . The pharmaceutically acceptable solvates according to The invention includes those in which the crystallization solvent can be isotopically substituted, for example D2O, d6-acetone and de-DMSO. Unless otherwise provided in this document: HBTU means O-benzotriazo-yl-N.N.N'.N 1 -tetramethyluronium hexafluorophosphate; Et 3 N means triethylamine; AcOH means acetic acid, TFA means trifluoroacetic acid; MeOH means methanol, EtOH means ethanol, and EtOAc means ethyl acetate; THF means tetrahydrofuran, DMSO means dimethylsulfoxide and DCM means dichloromethane, DMF means N, N-dimethylformamide, NMP means N-methyl-2-pyrrolidinone, DMA means dimethylacetamide; Boc means tert-butoxycarbonyl, CBz means benzyloxycarbonyl; Triflic anhydride means trifluoromethanesulfonic anhydride; p-TSA means p-toluenesulfonic acid; Dba means dibenzylidene acetone; Me means methyl, Et means ethyl; Cl means chlorine; OH means hydroxy; LG means a suitable outgoing group; and Prot means a suitable protective group.

The following schemes illustrate the preparation of compounds of formula (I), wherein Ring A etc. they are as defined earlier in this document: Scheme 1.0 Compound (II) is described in International Patent Publication No. WO 97/03986. Step (a): Cyclization of compound (II) is carried out under suitable dehydrating conditions, at elevated temperatures for up to 18 hours. Typically, dehydrating agents such as polyphosphoric acid, phosphorus oxychloride, triflic anhydride are used at temperatures of 20 to 120 ° C for 5 minutes to 12 hours. Optionally, the reaction can be carried out in the presence of a base such as pyridine and suitable solvents such as dichloromethane and acetonitrile. Alternatively, oxadiazole (III) can be prepared according to the method of Rigo et. to the. Synth Commun. 16 (13), 1665,1986. Preferred conditions are: Phosphorus oxychloride at 100 ° C for 8 hours, or 2.5 equiv. of triflic anhydride and 5 equiv. of pyridine in dichloromethane at 20 ° C for 3 hours. When X represents O, then LG is typically halo, preferably chlorine or bromine Scheme 2.0 Prot represents a suitable protecting group for nitrogen, for example Boc, CBz or allyl Carbamate. The conventional methodology for nitrogen-protecting groups is used, such as that found in textbooks (for example, "Protecting Groups in Organic Synthesis" by T. W. Greene and P. Wutz). Suitable compounds for use as compounds (IV) are known in the literature or can be prepared using a conventional methodology: for example, reduction of benzoic acids (see preparation 3 below).

Step (b): Compound (III) is reacted with an excess of compound (IV) in the presence of a base such as sodium hydride, potassium hexamethyldisilazide, "butyllithium or isopropylmagnesium chloride, in a suitable solvent such as THF, Toluene or NMP at temperatures of 0 ° C to 50 ° C for 1 to 24 hours, to give the compound (V) respectively, The preferred conditions are: 3 equiv of compound (IV) and 2.5 equiv of NaH in THF at 20 ° C for 2 hours. (vil1) Scheme 3.0 Prot represents a suitable protecting group for nitrogen, for example Boc, CBz or allyl Carbamate. The conventional methodology for nitrogen-protecting groups is used, such as that found in textbooks (for example, "Protecting Groups in Organic Synthesis" by T. W. Greene and P. Wutz).

Step (c): Oxadiazole (V) is reacted with an acid catalyst to give the compound of formula (VI). Typically, the reaction is carried out by heating the starting materials with a suitable acid catalyst (such as p-TSA), or Lewis acid catalyst (such as magnesium chloride), optionally using a high boiling solvent such as xylene, at an elevated temperature, such as 100-150 ° C, for 1 to 48 hours. Alternatively, the reaction can be subjected to microwave irradiation and heated at 150-200 ° C for 10-30 minutes in a high boiling solvent such as toluene or xylene. Preferred conditions are: Oxadiazole (V) and cat. P-TSA, in xylene at 140 ° C for 48 h.

Step (d): The deprotection of the compound (VI) is carried out using a conventional methodology, as described in "Protecting Groups in Organic Synthesis" by TW Greene and P. Wutz. "When Prot is Boc, the preferred methods are: chloride of hydrogen in a suitable solvent such as 1,4-dioxane at room temperature for 1-16 hours, or a solution of trifluoroacetic acid in dichloromethane for 1-2 hours.

When Prot is CBz, the preferred method is hydrogenolysis using a suitable palladium catalyst in a solvent such as ethanol.

When Prot is an allyl carbamate, the preferred conditions are thiobenzoic acid and a suitable palladium catalyst such as Pd2 (Dba) 3 with a suitable phosphine additive such as 1,4-bis (diphenylphosphino) butane in tetrahydrofuran for 20 minutes. When X represents N-alkyl, then Scheme 4.0 Step (e): Reacted commercially available 2-nitrobenzaldehyde (VIII) with methylamine hydrochloride to give the compound of formula (IX). Typically the reaction is carried out in methylene chloride in the presence of triethylamine for 16 hours.

Step (f): The amine (IX) is reacted in ethanol with hydrogen in the presence of PtO2 at 275,790 kPa (40 psi) for 2 hours to give the compound (X).

Step (g): The amine (X) is reacted with oxadiazole (III) to give a compound of formula (XI). Typically, the reaction is carried out by refluxing the starting materials in THF, in the presence of triethylamine, for 24 hours.

Step (h): The oxadiazole (XI) in toluene is reacted with TFA at 50 ° C for 1 hour to give a compound of formula (Vil ").

The compounds (Vil ') and (Vil ") correspond to the compounds of formula (VII) when X represents O and NR respectively The compounds of formula (VII) are used in a chemical library synthesis to provide compounds of formula (I) ): Scheme 5.0 The reactions are carried out in DMA, and a conventional peptide coupling reagent (HBTU) is used to cause the formation of the amide bond. The compounds of the present invention are useful because they possess pharmacological activity in animals. In particular, they are useful in the treatment of various conditions including aggression, Alzheimer's disease, anorexia nervosa, anxiety, anxiety disorder, asthma, atherosclerosis, autism, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia) , cataracts, central nervous system disease, cerebrovascular ischemia, cirrhosis, cognitive disorder, Cushing's disease, depression, diabetes mellitus, dysmenorrhoea (primary and secondary), emesis (including motion sickness), endometriosis, gastrointestinal disease, glaucoma, gynecological disease , heart disease, intrauterine growth retardation, inflammation (including rheumatoid arthritis), ischemia, ischemic heart disease, lung tumor, urination disorder, ovulation pain, neoplasm, nephrotoxicity, non-insulin dependent diabetes, obesity, obsessive / compulsive disorders , ocular hypertension, preeclampsia, eyac early, premature delivery (preterm), lung disease, Raynaud's disease, kidney disease, kidney failure, male or female sexual dysfunction, septic shock, sleep disorder, spinal cord injury, thrombosis, urogenital tract infection or urolithiasis, spinal cord injury, thrombosis, tract infection urogenital, urolithiasis. Dysmenorrhea (primary or secondary), more particularly primary dysmenorrhea, is particularly interesting. Thus, according to another aspect of the invention, there is provided a method of treating dysmenorrhea which comprises administering a therapeutically effective amount of a compound of the invention to a patient suffering from anxiety, cardiovascular disease (including angina, atherosclerosis). , hypertension, heart failure, edema, hypernatremia), dysmenorrhea (primary and secondary), endometriosis, emesis (including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), ovulation pain, preeclampsia, premature ejaculation, childbirth premature (preterm) or Raynaud's disease. The use of the compounds as a medicament and the use of the compounds of the present invention in the manufacture of a medicament for the treatment of anxiety, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia) are also provided. ), dysmenorrhea (primary and secondary), endometriosis, emesis (including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), ovulation pain, preeclampsia, premature ejaculation, preterm delivery (preterm) or Raynaud's disease, particularly dysmenorrhea. The compounds of the invention intended for pharmaceutical use can be administered in the form of crystalline or amorphous products. They can be obtained, for example, as solid plugs, powders or films by methods such as precipitation, crystallization, lyophilization, spray drying or evaporative drying. For this purpose, microwave or radio frequency drying can be used. They may be administered alone or in combination with one or more compounds other than the invention or combined with one or more other drugs (or in any combination thereof). The compounds of the present invention can be administered together with an oral contraceptive. Thus, in a further aspect of the invention, there is provided a pharmaceutical product containing a V1a antagonist and an oral contraceptive in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea. The compounds of the present invention can be administered together with a PDE5 inhibitor. Thus, in a further aspect of the invention, there is provided a pharmaceutical product containing a V1a antagonist and a PDEV inhibitor in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea. PDEV inhibitors useful for combining with V1a antagonists include, but are not limited to: (i) PDE5 inhibitors mentioned in the publications of International Patent Application No. WO03 / 000691; WO02 / 64590; WO02 / 28865; WO02 / 28859; W002 / 38563; WO02 / 36593; WO02 / 28858; WO02 / 00657; WO02 / 00656; WO02 / 10166; WO02 / 00658; WO01 / 94347; WO01 / 94345; WO / 15639 and WO / 15228; (ii) The PDE5 inhibitors mentioned in U.S. Patents 6,143,746; 6,143,747 and 6,043,252; (ni) the pyrazolo [4,3-d] pyrimidin-7-ones described in EP-A-0463756; the pyrazolo [4,3-d] pyrimidin-7-ones described in EP-A-0526004; the pyrazolo [4,3-d] pyrimidin-7-ones described in the published international patent application WO 93/06104; the isomeric pyrazolo [3,4-d] pyrimidin-4-ones described in the published international patent application WO 93/07149; the quinazolin-4-ones described in the published international patent application WO 93/12095; the pyrido [3,2-d] pyrimidin-4-ones described in the published international patent application WO 94/05661; the purin-6-ones described in the published international patent application WO 94/00453; the pyrazolo [4,3-d] pyrimidin-7-ones described in the published international patent application WO 98/49166; the pyrazolo [4,3-d] pyrimidin-7-ones described in the published international patent application WO 99/54333; the pyrazolo [4,3-d] pyrimidin-4-ones described in EP-A-0995751; the pyrazolo [4,3-d] pyrimidin-7-ones described in the published international patent application WO 00/24745; the pyrazolo [4,3-d] pyrimidin-4-ones described in EP-A-0995750; the hexahydropyrazorinyl, pyridyl, pyridinyl-1-diones described in published international application WO95 / 19978; the pyrazolo [4,3-d] pyrimidin-4-ones described in WO / 27848; the imidazo [5,1 - /] [1,2,4Jtriazine-opas described in EP-A-1092719 and published international application WO 99/24433 and the bicyclic compounds described in the published international application WO 93/07124; the pyrazoic [4,3-d] pyrimidin-7-ones described in the published international patent application WO 01/27112; the pyrazoles or [4,3-d] pyrimidin-7-ones described in the published international patent application WO 01/27113; the compounds described in EP-A-1092718 and the compounds described in EP-A-1092719; the tricyclic compounds described in EP-A-1241170; the alkylsulfone compounds described in published international application WO 02/074774; the compounds described in the published international application WO 02/072586; the compounds described in published international application WO 02/079203 and the compounds described in WO 02/074312. (iv) Preferably, 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4.3- d] pyrimidin-7-one (sildenafil, for example marketed as Viagra®) also known as 1 - [[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H- p; razolo [4,3-d] pyrimidin-5-yl) -4-ethoxyphenyl] sulfonyl] -4-methylpiperazine (see EP-A-0463756); 5- (2-ethoxy-5-morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrazolo [4,3-d] pyrimidin-7-one (cf. EP-A-0526004); 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxyphenl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO98 / 49166); 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl-2 , 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO99 / 54333); (+) - 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methyletoxy) pyridin-3-yl] -2-methyl-2 , 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, also known as 3-ethyl-5-. { 5- [4-ethylpiperazin-1-ylsulfonyl] -2 - ([(1 R) -2-methoxy-1-methyl-ethyl] oxy) pyridin-3-yl} -2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 99/54333); 5- [2-ethoxy-5- (4-etiIpiperazin-1-ylsuconyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dif? Idro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one, also known as 1-. { 6-Ethoxy-5- [3-ethyl-6,7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4,3-d] pyrimidin-5-yl] -3- pyridylsulfonyl} -4-ethylpiperazine (see WO 01/27113, Example 8); 5- [2-α-butoxyl-5- (4-ethyl-piperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- (1-methylpiperidin-4-yl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 01/27113, Example 15); 5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-etl-2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (see WO 01/27113, Example 66); 5- (5-Acetyl-2-propoxy-3-pyridinium) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-c | p] rmidmidon-7-one (see WO 01/27112, Example 124); 5- (5-acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4.3 -d] pyrimidin-7-one (see WO 01/27112, Example 132); (6R, 12aR) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) pyrazino [2 \ 1,1,1] pyrido [3,4-b] indole-1,4-dione (tadalafil, IC-351, Cialis®), ie compound of examples 78 and 95 of published international application WO 95/19978, as well as the compound of examples 1, 3, 7 and 8; 2- [2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1, 2,4] triazin-4-one (vardenafil, LEVITRA®) also known as 1 - [[3- (3,4-dihydro-5-methyl-4-oxo-7-propylimidazo [5,1- f] -as-triazin-2-yl) -4-ethoxyphenyl] sulfonyl] -4-ethylpiperazine, ie the compound of examples 20, 19, 337 and 336 of published international application WO 99/24433; the compound of example 11 of published international application WO 93/07124 (EISAI); compounds 3 and 14 of Rotella D P, J. Med. Chem., 2000, 43, 1257; 4- (4-chlorobenzyl) amino-6,7,8-trimethoxyquinazoline; N - [[3- (4,7-Dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] -pyrimidin-5-yl) -4-propoxyphenyl] sulfonyl] - 1-methy1-2-pyrrolidinepropanamide ["DA-8159" (Example 68 of WO00 / 27848)]; and 7,8-dihydro-8-oxo-6- [2-propoxyphenyl] -1H-imidazo [4,5-g] quinazoline and 1- [3- [1 - [(4-fluorophenyl) methyl] -7, 8-Hydro-8-oxo-1H-imidazo [4,5-g] quinazoln-6-yl] -4-propoxy-phenyl] carboxamide. (v) 4-bromo-5- (pyridylmethylamino) -6- [3- (4-chlorophenyl) -propoxy] -3 (2H) pyridazinone; 1- [4 - [(1,3-benzodioxol-5-ylmethyl) ammonium] -6-chloro-2-quinozolinyl] -4-piperidinecarboxylic acid, monosodium salt; (+) - cis-5,6a, 7,9,9,9a-hexahydro-2- [4- (trifluoromethyl) -phenyimethyl-5-methyl-cyclopent-4,5] imidazo [2,1-b] purin -4 (3H) ona; furazolocillin; cis-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydrocyclopent [4,5] -imidazo [2,1-b] purin-4-one; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole-6-carboxylate; 4-bromo-5- (3-pyridylmethylamino) -6- (3- (4-chlorophenyl) propoxy) -3- (2H) pyridazonone; 1- methyl-5 (5-morpholinoacetyl-2-n-propoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-one; 1- [4 - [(1,3-Benzodioxol-5-methyl) amino] -6-chloro-2-quinazolinyl] -4-piperidinecarboxylic acid, monosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa Hakko, see WO 96/26940); Pharmaprojects No. 5069 (Schering Plow); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer); FR229934 and FR226807 (Fujisawa); and Sch-51866.

The contents of the published patent applications and of the articles of journals and, in particular, the general formulas of the therapeutically active compounds of the claims and of the compounds exemplified herein, are incorporated therein in their entirety by way of reference. Preferably, the PDEV inhibitor is selected from sildenafil, tadalafil, vardenafil, DA-8159 and 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7 H -pyrazolo [4,3-d] pyrimidin-7-one. More preferably, the PDE5 inhibitor is sildenafil and pharmaceutically acceptable salts thereof. Sildenafil citrate is a preferred salt. The compounds of the present invention can be administered together with a NO donor. Thus, in a further aspect of the invention, there is provided a pharmaceutical product containing a V1a antagonist and a NO donor in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea. The compounds of the present invention can be administered together with L-arginine, or in the form of an arginate salt. Thus, in a further aspect of the invention, there is provided a pharmaceutical product containing an antagonist of V1a and L-arginine in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea. The compounds of the present invention can be administered together with a COX inhibitor. Thus, in a further aspect of the invention, there is provided a pharmaceutical product containing a V1a antagonist and a COX inhibitor in the form of a combined preparation for simultaneous, separate or sequential use in the treatment of dysmenorrhea. The COX inhibitors useful to be combined with the compounds of the present invention include, but without limitation: (i) ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, prapoprofen, miroprofen, thioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucilloxic acid, indomethacin, sulindac, tolmetin, zomepirac, diclofenac, fenclofenec, alclofenac, bufenac, isoxepac, furofenac, tiopinac, zidometacin, acetylsalicylic acid, indomethacin, piroxicam, tenoxicam, nabumetone, ketorolac, azapropazone, mefenamic acid, tolfenamic acid, diflunisal, podophyllotoxin derivatives, acemetacin, droxicam, floctafenin, oxyphenbutazone, phenylbutazone, proglumetacin, acemetacin, fentiazac, clidanac, oxipinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flufenisal, sudoxicam, etodolac, piprofen, salicylic acid, choline trisalicylate, magnesium, salicylate, benorilate, fentiazac, clopinac, feprazone, isoxicam and 2-flu acid Gold-to-methyl [1,1-biphenyl] -4-acetic, 4- (nitrooxy) butyl ester (see Wenk, et al., Europ. J. Pharmacol. 453: 319-324 (2002)); (ii) meloxicam, (CAS Registry Number 71125-38-7, described in U.S. Patent No. 4,233,299), or a pharmaceutically acceptable salt or prodrug thereof; (iii) Substituted benzopyran derivatives that are described in U.S. Patent No. 6,271,253. Also the benzopyran derivatives described in U.S. Pat. Nos. 6. 034,256 and 6,077,850 together with the International Publications No. WO 98/47890 and WO 00/23433; (iv) COX2 selective chromene inhibitors described in U.S. Patent No. 6,077,850 and U.S. Pat. 6. 034,256; (v) The compounds described in the Application Publications of International Patent No. WO 95/30656, WO 95/30652, WO 96/38418 and WO 96/38442, and the compounds described in European Patent Application Publication No. 799823, together with the pharmaceutically acceptable derivatives thereof; (vi) celecoxib (U.S. Patent No. 5,466,823), valdecoxib (U.S. Patent No. 5,633,272), deracoxib (U.S. Patent No. 5,521,207), rofecoxib (U.S. Patent No. 5,474,995), etoricoxib (International Patent Application Publication No. WO 98/03484), JTE-522 (Japanese Patent Application Publication No. 9052882), or a pharmaceutically acceptable salt or prodrug thereof; (vii) Parecoxib (described in U.S. Patent No. 5,932,598), which is an effective therapeutic prodrug of the selective tricyclic Cox-2 inhibitor valdecoxib (described in U.S. Patent No. 5,633,272), particular parecoxib sodium; (viii) ABT-963 (described in the Patent Application Publication International No. WO 00/24719) (ix) Nimesulide (described in U.S. Patent No. 3. 840,597), flosulide (described in J. Cárter, Exp. Opin. Ther.

Patents. 8 (1), 21-29 (1997)), NS-398 (described in U.S. Patent No. 4,885,367), SD 8381 (described in the US Pat.

United States No. 6,034,256), BMS-347070 (described in U.S. Patent No. 6,180,651), S-2474 (described in European Patent Publication No. 595546) and MK-966 (described in US Pat. U.S. Patent No. 5,968,974); (x) The pharmaceutically acceptable compounds and derivatives described in U.S. Patent No. 6,395,724, U.S. Patent No. 6,077,868, U.S. Patent No. 5,994,381, U.S. Patent No. 6,362. 209, U.S. Patent No. 6,080,876, U.S. Patent No. 6,133,292, U.S. Patent No. 6,369,275, U.S. Patent No. 6,127,545, U.S. Patent No. 6,130. 334, U.S. Patent No. 6,204,387, U.S. Pat. No. 6,071,936, U.S. Patent No. 6. 001,843, U.S. Patent No. 6,040,450, International Patent Application Publication No. WO 96/03392, International Patent Application Publication No. WO 96/24585, U.S. Patent No. 6,340,694, U.S. Pat. United States No. 6,376,519, United States Patent No. 6. 153.787, U.S. Patent No. 6,046,217, U.S. Patent No. 6,329,421, U.S. Patent No. 6,239,137, U.S. Patent No. 6,136,831, U.S. Patent No. 6,297. 282, U.S. Patent No. 6,239,173, U.S. Patent No. 6,303,628, U.S. Pat.

US 6,310,079, U.S. Patent No. 6,300,363, U.S. Patent No. 6,077,869, U.S. Patent No. 6,140,515, U.S. Patent No. 5,994,379, U.S. Pat. United States No. 6,028,202, United States Patent No. 6,040,320, United States Patent No. 6. 083,969, U.S. Patent No. 6,306,890, U.S. Patent No. 6,307,047, U.S. Patent No. 6,004,948, U.S. Patent No. 6,169,188, U.S. Patent No. 6,020. 343, U.S. Patent No. 5,981,576, U.S. Patent No. 6,222,048, U.S. Patent No. 6,057,319, U.S. Patent No. 6,046,236, U.S. Patent No. 6,002. 014, U.S. Patent No. 5,945,539, U.S. Patent No. 6. 359,182, International Patent Application Publication No. WO 97/13755, International Patent Application Publication No. WO 96/25928, International Patent Application Publication No. WO 96/374679, International Patent Application Publication No. WO 95/15316, International Patent Application Publication No. WO 95/15315, International Patent Application Publication No. WO 96/03385, International Patent Application No. WO 95/00501, International Patent Application No. WO 94/15932, Publication of International Patent Application No. WO 95/00501, International Patent Application Publication No. WO 94/27980, International Patent Application Publication No. WO 96/25405, International Patent Application Publication No. WO 96/03388 , International Patent Application Publication No. WO 96/03387, United States Patent No. 5,344, 991, International Patent Application Publication No. WO 95/00501, International Patent Application Publication No. WO 96/16934, International Patent Application Publication No. WO 96/03392, International Patent Application Publication No. WO 96/09304, International Patent Application Publication No. WO 98/47890 and Application Publication of Pate International No. WO 00/24719.

The contents of any of the patent applications, and in particular the general formulas of the therapeutically active compounds of the claims and compounds exemplified therein, are incorporated herein by reference in their entirety. Generally, the compounds of the present invention will be administered as a formulation together with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound (s) of the invention. The choice of excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on the solubility and stability and the nature of the dosage form. Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be obvious to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in "Remington's Pharmaceutical Sciences ", 19th Edition (Mack Publishing Company, 1995).

Thus, according to another aspect of the present invention, there is provided a pharmaceutical formulation comprising a compound of formula (I) mixed with a pharmaceutically acceptable adjuvant, diluent or carrier. The compounds of the invention can be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or a buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particles, liquids, or powders, lozenges (including liquid-filled), chewing gum, multi and nanoparticles, gels, solid solution, liposomes, films (including muco-adhesives) ), ovules, sprayers and liquid formulations. Liquid formulations include suspensions solutions, syrups and elixirs. These formulations can be used as fillers in soft or hard gelatin capsules, and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and / or suspending agents . Liquid formulations can also be prepared by reconstituting a solid, for example, from a sachet. The compounds of the invention can also be used in rapidly dissolving and rapid disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001). For dosage forms of tablets, depending on the dose, the drug can be from 1% by weight to 80% by weight of the dosage form, more typically from 5% by weight to 60% by weight of the dosage form. dosage. In addition to the drug, the tablets generally contain a disintegrant. Examples of disgregates include: sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methicellulose, microcrystalline cellulose, hydroxypropylcellulose substituted with lower alkyl, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will constitute from 1% by weight to 25% by weight, preferably from 5% by weight to 20% by weight of the pharmaceutical form. Binders are generally used to impart cohesion qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

The tablets may also optionally comprise surfactants, such as sodium laurisulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactants may constitute 0.2 wt% to 5 wt% of the tablet, and the glidants may constitute 0.2 wt% to 1 wt% of the tablet. The tablets generally also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium laurisulfate. The lubricants generally constitute from 0.25% by weight to 10% by weight, preferably from 0.5% by weight to 3% by weight of the tablet. Other possible ingredients include anti-oxidants, colorants, flavoring agents, preservatives and flavor masking agents. The model tablets contain up to about 80% of the drug, from about 10% to about 90% by weight of binder, from about 0% by weight to about 85% by weight of diluent, from about 2% by weight to about 10% by weight. weight of disintegrant and from about 0.25% by weight to about 10% by weight of lubricant. The tablet mixtures can be compressed directly or by means of a roller to form tablets. Blends of tablets or portions of mixtures may, alternatively, be wet, dry, or melt granulated, coagulated in the molten state, or extruded prior to the formation of the tablets. The final formulation may comprise one or more layers and may be covered or uncoated; It can even be encapsulated. Tablet formulation is described in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y, 1980 (ISBN 0-8247-6918-X). Solid formulations for oral administration can be formulated for immediate release and / or for modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. US Pat. No. 6,106,864 describes modified release formulations suitable for the purposes of the invention. In Verma et al, Pharmaceutical Technology On-line, 25 (2), 1-14 (2001) are found other appropriate release technologies such as alpha energy dispersions and osmotic and coated particles. In document WO 00/35298 the use of a chewing gum is described to achieve conirro release. The compounds of the invention can also be administered directly in the bloodstream, in the muscle or in an organ inerrn. Suitable means for parenteral administration include intravenous, intra-arterial, infraperiponeal, intravenous, intraventricular, in-radicular, intraserial, infrarenal, intramuscular and subcutaneous administration. Suitable devices for parenteral administration include needle injections (including microneedles), needleless injections and infusion techniques. Parenteral formulations typically are aqueous solutions which may contain natural excipients such as salts, carbohydrates and lamponan agents (preferably at a pH of 3 to 9), but for some applications, may be more adequately formulated as a sterile non-aqueous solution or as a dry form to be used June with a suitable vehicle as sterile water without pyrogens. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can be easily performed using conventional pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds of formula (I) used in the preparation of parenteral solutions can be increased by suitable processing, for example, the use of atomized dispersions of alia energy (see WO 01/47495) and / or by the use of appropriate formulation techniques, as the use of agents that increase the solubility. Formulations for parenteral administration can be formulated to be of immediate and / or modified release. Modified release formulations include rereebar, sustained, pulsed, conirmed, directed and programmed release. In this manner, the compounds of the invention can be formulated as a solid, semi-solid or hydroxy-liquid for administration as an implanted reservoir that provides for the modified release of the active compound. Examples of such formulations include stenis coated with drugs and PGLA microspheres. The compounds of the invention can also be administered topically in the skin or mucosa, via the dermal or fransdermal route. Physical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, fine powder, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, poly-ethylene glycol and propylene glycol. Penetration enhancers can be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999). Other means of topical administration include delivery by iontophoresis, electroporation, phonophoresis, sonophoresis and injection with microneedles or without needles (for example, Powderjecl ™, Biojecí ™, etc.). Formulations for topical administration can be formulated to be of immediate and / or modified release. Modified release formulations include reframed, sustained, pulsed, conirmed, directed and programmed release. The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (alone, as a mixture, for example, in a dry mixture with lactose, or as a mixed particulate component, for example , mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, sprayer, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1, 1,2-tetrafluoroethane or 1, 1,1, 2,3, 3,3-hepiafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example chitosan or cyclodextrin. The pressurized pack, pump, spray, atomizer or nebulizer contains a solution or suspension of the compound (s) of the invention comprising, for example, ethylene, aqueous ethylene or a suitable allergenic agent to disperse, solubilize or prolong the liberation of the active principle, one or more propelenders as dissolved and an optional fensioaclivo, fal as írioleafo de sorbiíán, oleic acid or an oligolácíico acid. After use in a dry powder or suspension formulation, the pharmaceutical product is micronized at an adequate size for delivery by inhalation (preferably less than 5 micrometers). This can be achieved by any suitable heating method, such as spiral jet mill, fluid bed jet mill, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

Capsules (made, for example, of gelatin or HPMC), ampoules and cartridges for use in an inhaler or a dissolver can be formulated to confer a mixture of powder of the compound of the invention, a powder base suitable as lacíosa or starch and a modifier of the output such as: -leucine, manilol or magnesium esiearaio. The lacíosa can be anhydrous or esíar in the form of the monohidraío, preferably esío úlfimo. Other suitable excipients include dexirane, glucose, maltose, sorbiol, xylitol, fructose, sucrose and trehalose. A solution formulation suitable for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of the compound of the invention per operation and the operation volume may vary from 1 μl to 100 μl. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, eneol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol. To the formulations of the invention screened for inhaled / inorganic administration, suitable flavors may be added, such as menyol and levomenlol or sweeteners, such as saccharin or sodium saccharin. Formulations for shallow / infranasal administration can be formulated to be immediate and / or modified release using, for example, DL-lactic-coglycolic poly-acid (PGLA). Modified release formulations include relaxed, sustained, pulsed, controlled, directed and programmed release. The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, vaginal suppository or enema. A traditional suppository base is cocoa butter, but several alternatives may be used when appropriate. Formulations for rectal / vaginal administration can be formulated to be of immediate and / or modified release. Modified release formulations include rereebar, sustained, pulsed, conirro, directed and programmed release. The compounds of the invention can also be administered directly to the eyes or to the ears, preferably in the form of gofas of a suspension or micronized solution in sterile saline solution, pH adjusted, isoonic. Ofras suitable formulations for ocular and otic administration include ointments, implanides biodegradable (for example, absorbable gel sponges, collagen) and non-biodegradable (for example silicone), wafers, lenses and systems of particles or vesicles, such as niosomes or liposomes. A polymer may be incorporated as re-polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a polymer of heyopolysaccharide, for example, gellan, June with a preservative, as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

Formulations for ocular / optical administration can be formulated to be of immediate and / or modified release. Modified release formulations include reliever, sustained release, pulsed, controlled, directed or programmed release. The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrin or polyethylene glycol-containing polymers to improve their solubility, rate of dissolution, taste masking, bioavailability and / or stability for use in any of the aforementioned modes of administration. It has been found that drug-cyclodextrin complexes, for example, are generally useful for most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to the direct formation of complexes with the drug, cyclodextrin can be used as an auxiliary additive, that is, as a vehicle, diluent or solubilizer. The most commonly used for these purposes are alpha-, beta- and gamma cyclodextrins, examples of which can be found in International Patent Applications No. WO 91/11172, WO 94/02518 and WO 98/55148, to the extent that it may be convenient to administer a combination of active compounds, for example, for the purpose of bringing a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions can be conveniently combined, of which at least one contains a compound according to the invention, in the form of a ki? suitable for coadministering the compositions. Thus, the kiln of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) according to the invention and means for keeping said compositions separate, such as a container , divided bottle or divided sheet package. An example of such a kit is the family blister used for packaging tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the different compositions at different dosage intervals, or for evaluating the separate compositions therein. To assist in monitoring the treatment, the kit typically comprises instructions for administration and may have a so-called reminder. For the administration to patients. In humans, the total daily dose of the compounds of the invention will preferably be in the range of about 0.01 to about 15 mg / kg of body weight, depending on the mode of administration. The daily dose may be administered in a single dose or in divided doses throughout the day. These dosages are based on an average human subject weighing approximately 65 kg to 70 kg. The doctor can easily determine doses of subjects whose weights are outside of this range, such as children and the elderly. As used herein, the terms "traisation" and "bring" mean alleviating the symptoms, eliminating the cause temporarily or permanently, or preventing or slowing the onset of symptoms. The term "treatment" includes relief, elimination of the cause (temporarily or permanently) or prevention of symptoms and disorders associated with primary and / or secondary dysmenorrhea. Treatment may be a pretreatment as well as a procedure at the onset of symptoms. The compounds of the present invention can be tested in the investigations presented below: 1. 0 Sampling of Union to V in filter 1. 1 Preparation of the Membrane Receptor binding assays were performed on cell membranes prepared from CHO cells that expressively expressed the human VIA receptor, (CHO-hV? A). The CHO-hV1A cell line was kindly provided under a license agreement by Maro Thibonnier, Depl. of Medicine, Case Western Reserve University of Medicine, Cleveland, Ohio. CHO-hV | A cells were routinely manipulated at 37 ° C in a humidified atmosphere with 5% CO2 in a mixture of DMEM / Hams F12 supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 15 mM HEPES and G418 400 μg / ml. For the production of large amounts of cell pellets, adherent CHO-hV1A cells were grown to a confluence of 90-100% in cylindrical flasks of 850 cm2 containing a mixture medium of DMEM / Hams F12 supplemented with 10% fefal bovine serum. , 2 mM L-glufamine and 15 mM HEPES. Confluent CHO-hV? A cells were washed with phosphate buffered saline (PBS), harvested in ice-cold PBS and centrifuged at 1,000 rpm. Cell pellets were stored at -80 ° C until use. The cell pellets were thawed on ice and homogenized in membrane preparation buffer consisting of 50 mM Tris-HCl, pH 7.4, 5 mM MgCl 2 and supplemented with a cocktail of protease inhibitor (Roche). The cell homogenate was centrifuged at 1000 rpm, 10 min, 4 ° C and the supernatant was removed and stored on ice. Residic sediment was homogenized and cooled as indicated above. The supernatans met and centrifuged at 25,000 x g for 30 min at 4 ° C. The pellet was resuspended in freezing buffer made up of 50 mM Tris-HCl, pH 7.4, 5 mM MgCl2 and 20% glycerol and stored in small aliquots at -80 ° C until use. The concentration of proteins was determined using Bradford reagent and BSA as pairo. 1. 2 Union V1A in Filter Protein linearity studies were performed followed by salivary binding studies in each new batch of membrane. A membrane concentration was chosen that provided a specific binding in the linear portion of the curve. Saíuración binding studies were then performed using various concentrations of [3 H] -arginine vasopressin, [3 H] -AVP (0.05 nM - 100 nM) and the values of d and Bma were determined - The effects of the compounds were tested about the union of [3 H] -AVP to CHO-hV? A membranes, (3 H-AVP, specific activity 65.5 Ci / mmol, NEN Life Sciences). The compounds were solubilized in dimethylsulfoxide (DMSO) and were diluted to a concentration of 10% DMSO with a test buffer conferring 50 mM Tris-HCl, pH 7.4, 5 mM MgCl 2 and 0.05% BSA. 25 μl of compound and 25 μl of [3 H] -AVP, (final concentration at or below the KA value of the membrane for the membrane lot, 0.5 nM -0.6 nM) were added to a polypropylene plate. 96-well round bottom. The binding reaction was initiated by the addition of 200 μl of membrane and the plates were gently shaken for 60 min at ambient temperature. The reaction was terminated by rapid filtration using a Filirmaie cell harvester (Packard Instruments) through a 96-well UniFilier GF / B plate that had been pre-wetted in 0.5% polyphenyleneimine to prevent peptide adhesion. Filters were washed 1 x with 1 ml of ice-cold wash buffer containing 50 mM Tris-HCl, pH 7.4 and 5 mM MgCl 2. The plates were dried and 50 μl of Microscint-0 (Packard instruments) was added to each well. The plates were hermetically sealed and counted in a TopCount Microplate scintillation counter (Packard Inslrumenls). Non-specific binding (NSB) was determined using d (CH2) 5Tyr (Me) unlabeled AVP 1 μM ([β-mercapio-β, β-cyclopeniamefyllenpropionyl, 0-Me-Ty? ^, Arg8] -vasopressin) (ßMCPVP), (Sigma). The radioligand binding data were analyzed using a logistic equation of four parameters with the minimum forced at 0%. The slope was smoothly adjusted and fell en -re -0, 75 and -1.25 for the valid curves. The specific binding was calculated by dissolving the mean NSB cpm of the mean fob cpm. For the test compounds, the amount of ligand bound to the receptor was expressed as bound% = (sample cpm - mean NSB cpm) / specific binding cpm x 100. The% binding was plotted against the concentration of compound of trial and adjusted to a sigmoid curve. The inhibitory dissociation constancy (Ki) was calculated using the Cheng-Prusoff equation: where [L] is the concentration of ligand present in the well and d is the radioligand dissociation constancy obtained from the analysis of the Scafchard plot. 2. 0 Functional Test of VIA: Inhibition of Ca2 * mobilization mediated by AVP / VIA-R by FLIPR (Fluorescent Plate Reader) (Molecular Devices) The intracellular calcium release was measured in CHO-hV? A cells using FLIPR , which allows the rapid detection of calcium after the activation of receptors. The cell line CHO-hV? A was kindly provided under a license agreement by Marc Thibonnier, Depí. of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio. CHO-V? A cells were routinely manipulated at 37 ° C in a humidified atmosphere with 5% CO2 in a mixture of DMEM / Hams F12 supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 15 mM HEPES and G418 400 μg / ml. On the afternoon before the test, the cells were plated at a density of 20,000 cells per well in 96-well sterile black plates with clear bottoms to allow inspection of the cells and fluorescence measurements at the bottom of each well. Wash buffer containing Dulbecco's Phosphate Buffered Saline (DPBS) and 2.5 mM probenecid and charged dye was prepared by cell culture which conferred 4 μM Fluo-3-AM (dissolved in DMSO and pluronic acid) , (Molecular Probes) and 2.5 mM probenecid recently on the day of the assay. Compounds were solubilized in DMSO and diluted in assay buffer made up of DPBS conferring 1% DMSO, 0.1% BSA and 2.5 mM probenecid. Cells were incubated with 100 μl of loading dye per well for 1 hour at 37 ° C in a humidified atmosphere with 5% CO2. After loading, the cells were washed in 100 μl of wash buffer using a Denley plate washer. In each well, 100 μl of wash buffer was left. The cellular fluorescence was measured using FLIPR. Fluorescence readings were obtained at 2s intervals by adding 50 μl of the test compound after 30s. Then, 155 additional measurements were taken at intervals to 2s to detect any agonist activity of the compounds. Then 50 μl of arginine vasopressin (AVP) was added so that the final assay volume was 200 μl. In addition, additional fluorescence readings were collected at 1s intervals for 120s. The responses were measured as maximum fluorescence intensity (Fl). For pharmacological characterization, the basal Fl value of each fluorescence response was subtracted. For the dose-response curves to AVP, each response was expressed as a% of the response to the maximum concentration of AVP in that row. For Clso determinations, each response was expressed as a% of the response to AVP. The IC50 values were converted to a modified Kb value using the Cheng-Prusoff equation that takes into account the agonist concentration, [A], the agonist CE5o and the slope: Kb = Cl5o / (2+ [A] / A5o] n) 1 / n-1 where [A] is the concentration of AVP, A50 is the EC50 of AVP obtained from the dose-response curve and n = slope of the dose-response curve to AVP. The compounds of the invention may have the potential to be more powerful, have a longer duration of action, have a greater activity activity, be more flexible, have fewer side effects, be more selective or have properties that are more useful than compues of the prior art. The invention is illustrated by means of the following preparations and examples: Preparation 1: 4- [N '- (2-Chloro-acetyl) -hydrazinocarbonyl] -piperidine-1-carboxylic acid ferc-bufyl ester (11) 4-Hydrazinocarbonyl-piperidine-1-acid eup-buyl ester was dissolved carboxylic acid (see reference WO 9703986 A1 19970206) (25 g, 103 mmol) in dichloromelane (300 ml) and 4-methylmorpholine (12.5 ml, 113 mmol) was added. The mixture was cooled using an ice bath and chloroacetyl chloride (8.2 ml, 103 mmol) was added dropwise. The reaction was heated to ambient temperature and agglomerated for 4 hours. The reaction mixture was partitioned with an aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate, filtered and the filtrate was evaporated to give the title compound as an off-white solid (29.6 g). Experimental; C, 48.01; H, 6.91; N, 12.85; C? 3H22N3O4CI-0.3 H2O requires; C, 48.02; H, 7.01; N, 12.92%; APCl MS m / z 318 [M-H] + Preparation 2: 4- (5-Chloromethyl- [1,3,4] oxadiazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester (lll) Hydrazide (II) (5.0 g, 15.6 mmol) was suspended in dichloromean (200 ml) and pyridine (6.4 ml, 78 mmol) was added before cooling the mixture to 10 ° C. Gase was added to glyphuraceous anhydride (6.6 ml, 39 mmol) for 15 min. And then stirred at room temperature for 3 hours. The reaction mixture was partitioned with water (50 ml), the organic layer was dried over magnesium sulfate, then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluent (2:98) to yield the title compound as a white solid (2.95 g). 1 H NMR (400 MHz, CD 3 OD): d 1.45 (s, 9H), 1.74 (m, 2H), 2.19 (m, 2H), 3.04 (m, 2H), 3.24 ( m, 1H), 4.09 (m, 2H), 4.85 (s, 2H) Preparation 3: (2-Amino-5-methoxy-phenyl) -melanol (IV) 2-Amino-5-methoxy-benzoic acid (2.0 g, 12 mmol) in lerahydrofuran (20 ml) was added to an ice-cold 1 molar solution of lithium aluminum hydride (14.4 ml) in tetrahydrofuran and stirred at 5 ° C for 2 hours. Water (0.5 ml) was added dropwise, followed by a 2 molar aqueous solution of sodium hydroxide (0.5 ml). The resultant emulsion was dried over magnesium sulfate, filtered and then evaporated under reduced pressure to yield the thixture compound as a yellow solid (766 mg). 1 H NMR (400 MHz, CD 3 OD): d 3.70 (s, 3 H), 4.55 (s, 2 H), 6.65-6, 78 (m, 3 H), APCl MS m / z 154 [M + H] + Preparation 4: 4- [5- (2-Amino-5-chloro-benzyloxymethyl) - [1.3.4] oxad-azole-2-yl} -carboxylic acid ester ] -piperidine-1-carboxylic acid (V) A solution of (2-Amino-5-chloro-phenyl) -melanol (1 g, 6.4 mmol) in diethylhydrofuran (10 ml) was added dropwise to an ice-cooled suspension of sodium hydride (60% strength). mineral oil, 215 mg, 5.4 mmol) in ureahydrofuran (5 ml) was added and stirred for 1 hour. A solution of oxadiazole (III) (1 g, 5.3 mmol) in diethylhydrofuran (5 mL) was added dropwise to gofa and the mixture was agitated at room temperature for 2 hours. The reaction mixture was partitioned between dichloromethane (50 ml) and a solution of sodium hydrogencarbonate (25 ml). The aqueous solution was washed with dichloromethane (2x20 ml) and the combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methianol in dichloromethane (5:95) as eluyeny to give the title compound (1.3 g) as a yellow solid. 1 H NMR (400 MHz, CDCl 3): d 1.47 (s, 9 H), 1.81 (m, 2 H), 2.07 (m, 2 H), 2.96 (m, 2 H), 3.08 ( m, 1H), 4.12 (m, 2H), 4.23 (s, 2H), 4.58 (s, 2H), 4.68 (s, 2H), 6.62 (d, 1H), 7.07 (s, 1H), 7.12 (d, 1H); APCl MS m / z 423 [MH] +, 323 [M-Bocf Preparation 5: 4- (8-Chloro-4H, 6H-5-oxa-2,3, 10b-Iriaza-benzo [4-hydroxy] -ary acid eic acid. e] azulen-1-yl) -piperidine-1-carboxylic acid (VI) Foluene-4-sulfonic acid (80 mg, 0.46 mmol) was added to a solution of oxadiazole (V) (1.28 g, 3.0 mmol) in xylene and heated at 140 ° C for 18 hours. The xylene was redissolved under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and sodium hydrogen carbonate solution (25 ml). The aqueous solution was washed with dichloromethane (2 x 20 ml) and the combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5: 0.5: 95) as eluent to give the title compound (730 mg) as a pale yellow foam. 1 H NMR (400 MHz, CDCl 3): d 1.43 (s, 9 H), 1.85 (m, 2 H), 1.96 (m, 2 H), 2.92 (m, 2 H), 3.08 ( m, 1 H), 4.18 (m, 2H), 4.40 (s, 2H), 4.66 (s, 2H), 7.36 (d, 1H), 7.58 (m, 2H) , Experimental; C, 57.98; H, 6.17; N, 13.40; C20H25N4O3CI 0.5H2O requires; C, 58.04; H, 6.33; N, 13.54%; APCl MS m / z 405 [MH] +, 305 [M-Boc] + Preparation 6: 8-Chloro-1-piperidin-4-yl-4H, 6H-5-oxa-2,3,1 Ob-triaza-benzo [e] azulene (Vil ') Iriazole (VI) (700 mg, 1.73 mmol) was dissolved in 1,4-dioxane (6 ml) and hydrochloric acid (4 M in 1,4-dioxane, 12 ml) was added. The reaction mixture was stirred at ambient temperature for 4 hours. The 1,4-dioxane was reduced under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and a solution of sodium hydrogencarbonate (25 ml). The aqueous solution was washed with dichloromethane (2 x 20 ml) and the combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure to give the compound of the extract (410 mg) as a pale yellow foam. 1 H NMR (400 MHz, CD 3 OD): d 1.83 (m, 4 H), 2.65 (t, 2 H), 3.09 (m, 2 H), 3.24 (m, 1 H), 4.41 ( s, 2H), 4.58 (s, 2H), 7.58 (m, 3H); APCl MS m / z 305 [MH] + Preparation 7: (5-Chloro-2-nitro-benzyl) -methyl-amine (IX): To a solution of 15.0 g of 5-chloro-2-nitrobenzaldehyde (VIII) (81 mmol, 1 equiv.) In 400 ml of methylene chloride was added 33.8 ml of eryrylamine (243 mmol, 3 equiv. ) and 16.4 g of methylamine hydrochloride (243 mmol, 3 equiv.). The reaction mixture was stirred for 16 hours. An aqueous solution of sodium bicarbonate was added, the methylene chloride phase was dried (MgSO) and the volatiles were removed under reduced pressure. The residue was dissolved in meianol, the solution was cooled to 0 ° C and 2.4 g of sodium borohydride (65 mmol, 0.8 equiv.) Were added portionwise. The solution was stirred for 4 hours, the solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and an aqueous solution of sodium bicarbonate. The organic phase was dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure yielding 14.8 g of the title compound as a brown solid (91%). 1 H NMR (400 MHz, CDCl 3): d 2.45 (s, 3 H), 4.00 (s, 2 H), 7.40 (d, 1 H), 7.65 (s, 1 H), 7.95 ( d, 1 H); LCMS: m / z APCI +, 201 [MH] + Preparation 8: 4-Chloro-2-methylaminomethyl-phenylamine (X) To a solution of 14.6 g of the compound (IX) (73 mmol, 1 equiv.) In 350 ml of ethanol was added 500 mg of PtO2. The mixture was stirred at 275,790 kPa (40 psi) of hydrogen for 2 hours, filtered over Celite® and then the volatiles were removed under reduced pressure, yielding 12.1 g of a green oil. This oil was purified by column chromatography on silica gel using methylene chloride / methanol / aqueous ammonia as eluent (90: 10: 1 v / v / v: 95: 5 v / v) to yield 11.40 g of the compound of the tíulo in the form of an oil (92%). 1 H NMR (400 MHz, CDCl 3): d 2.40 (s, 3 H), 3.70 (s, 2 H), 4.65 (m, 2 H), 6.60 (d, 1 H), 7.00 ( s, 1H), 7.05 (d, 1H); LCMS: m / z APC \ +, 171 [MH] + Preparation 9: 4- (5 { [(2-amino-5-chloro-benzyl) -mef-l-amyl) ferric acidic acid ester no] -melil.} - [1.3.4] oxadiazol-2-yl) -piperidine-1-carboxylic acid (XI): To a solution of 10.0 g of oxadiazole (III) (33 mmol, 1 equiv.) In 220 ml of THF was added 6.8 g of phenylamine (X) (40 mmol, 1.2 equiv.) And 6 g. , 9 ml of ethyrylamine (50 mmol, 1.5 equiv.). The solution was refluxed for 24 hours, the solvent was removed under reduced pressure and the residue partitioned between methylene chloride and an aqueous solution of sodium bicarbonate. The organic phase was separated, dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride / mefanol / aqueous ammonia as eluent (97: 3: 0.3 v / v / v at 95: 5: 5 v / v / v), to yield 10.7 g of the title compound (74.1%). H NMR (400 MHz, CDCl 3): d 1.40 (s, 9H), 1.80 (m, 2H), 2.00 (m, 2H), 2.25 (s, 3H), 2.90 ( m, 2H), 3.05 (m, 1H), 3.60 (s, 2H), 3.80 (s, 2H), 4.05 (m, 2H), 6.60 (d, 1H), 7.00 (s, 1H), 7.05 (d, 1H); LCMS: m / z APCf, 436 [MHf Preparation 10: 8-Chloro-5-methyl-1-piperidin-4-yl-5,6-dihydro-4H-2,3,5,10b-ioaraza-benzo [e] azulene (Vil ") A solution of 10 7 g of the ester (XI) (25 mmol, 1 equiv.) In 200 ml of toluene was heated to 50 ° C and 2.84 ml of TFA (38 mmol, 1.5 equiv.) Was added. The mixture was heated at reflux for 1 hour and the solvent was removed under reduced pressure, the residue was partitioned between methylene chloride and an aqueous sodium hydroxide solution.The aqueous phase was concentrated under reduced pressure and purified by column chromatography on silica gel. using methylene chloride / meianol / aqueous ammonia as eluyenie (80: 20: 2 v / v / v at 90: 10: 1 v / v / v), to produce 4.6 g of the title compound (59%) 1H NMR (400 MHz, CD3OD): d1, 80-2.20 (m, 4H), 2.50 (s, 3H), 2.60-2.90 (m, 2H), 3.00 (m, 2H) ), 3.40 (m, 3H), 3.40-3.80 (m, 2H), 7.60 (m, 3H), LCMS: m / z APC, 318 [MH] + Examples 1 to 92: Examples 1 to 92, illustrated in Table 1, were synthesized as a library from intermediates of formula (VII). The following monomer solutions were used: carboxylic acids: Dissolutions in dimefilacelamide (DMA) (anhydrous) plus 3.75% of amyrylamine at a concentration of 0.2 M Amines: Dissolvents in DMA (anhydrous) plus 3.75% of 0.2 M Concentration in the form of Salts: Dissolvations in DMA (anhydrous) + 3.75% of erytylamine at a concentration of 0.2 M HBTU: Dissolved in DMA (anhydrous) at a concentration of 0.2 M N.B. Soft sonication was used in a hot water bath (temp <40 ° C) to dissolve the monomers when necessary.

Experimental Procedure: The reaction scale was between 20 and 30 micromoles per well (experimental details are shown for the 20 μmol reaction, therefore the scale can be adjusted within this range). The reactions were carried out in a 96-well polypropylene plate. a) To the wells were added amine solutions (0.1 ml, 20 μmol, 1 equiv.) b) To the wells were added carboxylic acid solutions (0.15 ml, 30 μmol, 1.5 equiv. ) c) To each well was added HBTU solution (0.15 ml, 30 μmol, 1.5 equiv.) d) The 96-well polypropylene plate was sealed with a PTFE and a rubber syringe and fastened between a pair of metal plates, e) The plate was heated in an oven for 6 hours at 60 ° C and then allowed to cool in the oven overnight. f) When cooled, the plate was released and placed in a Genevac to remove the solvent, g) The samples were re-dissolved in DMSO / water (9: 1) (500 μl) and any particles were retired by filiration. h) The purification was carried out by RP-HPLC.

HPLC purification conditions: Column: Phenomenex Luna C18, 10 μm, 150 x 10 mm di Temperature: ambient Eluent A: 0.05% diethylamine in water Eluent B: acetoniiryl Samples dissolved in: 90% dimethylsulfoxide in water. Sample loaded using Gilson Autosampler with an Injection Volume of 550 μl Initial Conditions of Gilson LC Pump: Solvents A% 80,0 B% 20,0 Flow (ml / min) 8,000 Table of Gilson Pump Gradient LC periods: Time A% B% Flow (ml / min) 0.00 80.0 20.0 8,000 0.20 80.0 20.0 8,000 7.00 5.0 95.0 8,000 9.00 5.0 95.0 8,000 9.10 80.0 20.0 8,000 10.20 80.0 20.0 8,000 Detector uv Gilson 119 controlling at 254 nm: Collector adjusted to 225 nm Dual sensitivity 200 Maximum sensitivity 80 Peak width 0.3 min.

Conditions of HPLC analysis and delays of the Mass Spectromere: Column: Phenomenex Luna C18, 5 μm, 30 x 4.6 mm di. Eluyenie A: 0.05% Diethylamine in Water Eluyenie B: Aceophylloyl Dissolved Mills in: 90% Dimefilsuiphoxide in Water Muesira loaded using Gilson Quad Z with an Injection Volume of 5 μL Initial conditions of Waiers 1525 LC binary pump: Solvents A% 95.0 B% 5.0 Flow (ml / min) 2.5 (per channel) Temperature (° C) ambient Table of Events of the LC Pump Gradient: The class of days of the gradient contains 4 entries that are: Total mode time 4.50 min Detection: Wavelength detector Waters 2488 dual UV1 (nm) 225 UV2 (nm) 255 and ELSD: PolymerLabs, Temperalura: 75 ° C gas flow: 1.2 bar Mass Specs: Waters ZQ 20004 MUX tracks, ES + cone voltage: 26 v Capillary: 3.85 kV ES-: -30 v Capillary voltage: -3.00 kV Desolvation gas: 800 l / min Temperaure of source: 300 ° C. Scan interval 160-1000 Da Table 1 Example 93: [4- (8-Chloro-5-mephyl-5,6-dihydro-4H-2,3,5,1 Ob-feirazazabenzo [e] azulen-1-yl) -piperidin-1 -yl] - (3-meioxy-phenyl) -meanone To a solution of 3-methoxybenzoic acid (72 mg, 0.47 mmol) in dichloromethane (10. ml) was added HBTU (O-benzoyriazole-1-yl-NNN'.N'-ephrameryluronium hexafluorophosphate, 180 mg 0.47 mmol), followed by 30 min after the amine in Preparation 10 (Vil ") (100 mg, 0.315 mm) The reaction mixture was stirred at ambient temperature overnight, dimethylformamide (2 mL) was added. ) to aid solubilization and 3-methoxybenzoic acid (48 mg, 0.315 mmol) and HBTU (119 mg, 0.315 mmol) were further added.The reaction mixture was stirred at ambient temperature overnight and then distributed over night. dichloromethane and saturated aqueous sodium carbonate solution The organic layer was collected, evaporated under reduced pressure and purified by column chromatography on silica gel eluting with dichloromethane: methanol: ammonia (95: 5: 0.5 to 90). : 10: 1 v: v: v) to provide the title compound (55 mg, 39%). 1H NMR ( 400 MHz, CDCl 3): d1, 94-2.05 (day, 4H), 2.48 (s, 3H), 3.05 (sa, 2H), 3.18 (m, 1H), 3.32 ( sa, 2H), 3.67 (sa, 2H), 3.82 (s, 3H), 3.93 (sa, 1H), 4.64 (sa, 1H), 6.94 (m, 3H), 7.29 (m, 2H), 7.51 (m, 2H); LRMS: m / z APCI +, 474 [MNaf Example 94: [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,1 Ob-tetraazabenzo [e] azulen-1-yl) -piperidin-1-yl ] - (3-fluoro-phenyl) -meyenone To a solution of the amine of preparation 10 (VH ") (110 mg, 0.35 mmol), in dichloromethane (10 ml) was added triethylamine (73 μl, 0.52 mmol), followed by 3-fluorobenzoyl chloride (73 μl, 0.49 mmol). The reaction mixture was stirred at room temperature overnight. Then, it was washed with an aqueous solution of saturated sodium carbonate. The organic layer was collected, evaporated under reduced pressure and purified by column chromatography on silica gel eluting with dichloromethane: methanol: ammonia (90: 10: 1 v: v: v) to provide the title compound (52 mg , 3. 4%). 1 H NMR (400 MHz, CDCl 3): d 1.99 (br s, 4 H), 2.48 (s, 3 H), 3.07 (br s, 2 H), 3.18 (m, 1 H), 3.32 ( sa, 2H), 3.66-3.88 (sa, 3H), 4.59 (sa, 1H), 7.11 (m, 2H), 7.18 (m, 1H), 7.28 (m , 1H), 7.36 (m, 1 H), 7.51 (m, 2H); LRMS: m / z APCI +, 440 [MHf Example 95: [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5, 10b-tetraazabenzo [e] azulen-1-yl) -piperidin-1-yl] - (4-fluoro-phenyl) -metanone The title compound was prepared by a method similar to that described for example 94 using the amine of preparation 10 (Vil ") and 4-fluorobenzoyl chloride. 1 H NMR (400 MHz, CDCl 3): d 1.98 (br, 4H ), 2.48 (s, 3H), 3.06 (sa, 2H), 3.18 (m, 1H), 3.32 (sa, 2H), 3.67 (sa, 2H), 4.07 (sa, 1H), 4.51 (sa, 1H), 7.09 (t, 2H), 7.29 (m, 1H), 7.41 (m, 2H), 7.52 (m, 2H); LRMS: m / z APCI +, 440 [MHf Example 96: 1- [4- (8-Chloro-5-mephyl-5,6-dihydro-4H-2,3,5,10b-teiraaza-benzo [e] azulen-1-yl) -piperidin-1 - il] -bulan-1 -one The compound of the extract was prepared by a method similar to that described by Example 94 using the preparation amine (Vil ") and butyryl chloride. 1 H NMR (400 MHz, CDCl 3): d 0 , 96 (t, 3H), 1.65 (sexf., 2H), 1.82-2.02 (ma, 4H), 2.30 (m, 2H), 2.49 (s, 3H), 2 , 75 (sa, 1H), 3.12 (m, 2H), 3.34 (sa, 2H), 3.68 (sa, 2H), 3.98 (day, 1 H), 4.52 (sa , 1 H), 7.26 (m, 1H), 7.52 (m, 2H), LRMS: / 77 / zAPCf, 388 [MHf Example 97: [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,1 Ob-teirazazabenzo [e] azulen-1-yl) -piperidin-1-yl ] -cyclopropylmeanone The compound of the formula was prepared by a similar method to that described for Example 94 using the preparation amine (VII ") and cyclopropanecarbonyl chloride, 1 H NMR (400 MHz, CDCl 3): d 0.75 (m, 2H), 0.97 (m, 2H), 1.74 (m, 1H), 1.86-2.03 (ma, 4H), 2.48 (s, 3H), 2.80 (sa, 1H), 3.13 (m, 2H), 3.33 (ma, 2H), 3.66 (sa, 2H), 4.33 (da, 1 H), 4.48 (sa, 1H), 7.29 ( d, 1H), 7.51 (m, 2H), LRMS: m / z APCf, 386 [MHf All the compounds exemplified above showed a Ki value of less than 500 nM when tested in study 1.0 (assay of binding to V-? A in filter) as described above. In Table 2 shown below, examples of specific compounds are illustrated.

Table 2

Claims (14)

CLAIMS:

1. - A compound of the formula (I), ( or a pharmaceutically acceptable derivative thereof, wherein: X represents NR or O; R represents hydrogen, C? -8 alkyl or SO2 [C? -8 alkyl]; W represents N; Y and Y 'independently represent hydrogen, halogen, OH, CF3, OCF3, CN, NH2, C? _8 alkyl, C? _ 8 alkyloxy or C3_8 cycloalkyl; Ring A represents a heterocyclic ring containing at least one nitrogen atom; Z represents a direct bond, C 3-8 alkyl or C 3-8 cycloalkyl; R1 represents R2, OR2, OR3-R4, N (R2) [C1-8 alkylene] aR4; NCOR2 or SR4; R2 and R4 independently represent hydrogen, C3-8 cycloalkyl, CF3, Ar or Hei; R3 represented a direct bond or C -? - 8 alkyl; a is 0 or 1; Ar represents an aromatic ring, optionally condensed with a heterocyclic ring, and / or optionally substituted with one or more groups as described below; Hel represents a heterocyclic ring optionally substituted with one or more groups as described below, and / or optionally condensed with an aromatic ring that is optionally substituted with one or more groups as described below; in each case, the C?-8 alkyl, C?-8 alkylene and C 3-8 cycloalkyl groups can optionally and independently be substituted with one or more groups as described below; the susfiluyeníes groups for Ar, Hef, C? -8 alkyl, C? -8 alkylene and C3-8 cycloalkyl indicated above are independently selected from hydrogen, halogen, C? -8 alkyl, C?? 8 alkyloxy, S (alkyl) C? _8), CN, CF3, NH2 and OH.

2. - A compound according to claim 1, wherein X represented NR and R represented Me.

3. - A compound according to claims 1 or 2, wherein Ring A represented piperidinyl.

4. - A compound according to any of claims 1 to 3, wherein Z is a direct link.

5. - A compound according to claim 1, selected from [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-ioaraza-benzo [e] azulen- 1-yl) -piperidin-1-yl] - (1H-indol-3-yl) -meyenone; 1 - [4- (8-Chloro-5-meityl-5,6-dihydro-4H-2,3,5, 10b-eeryaraza-benzo [e] azulen-1-yl) piperidin-1-yl] -2 -o-yl-olyenone; [4- (8-Chloro-5-meityl-5,6-dihydro-4H-2,3,5,10b-eeryza-benzo [e] azulen-1-yl) -piperidin-1-yl] - (1 -methyl-cyclohexyl) -mephanone; 1 - [4- (8-Chloro-5-meiiii-5,6-dihydro-4H-2,3,5, 10b-fef-raaza-benzo [e] azulen-1-yl) -piperidin-1-yl] -2-cyclopropyl-euryone; [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo [e] azulen-1-yl) -piperidin-1-yl] - (1 H-indol-2-yl) -methanone; [4- (8-Chloro-5-methyl-5,6-dihydro-4H-2,3,5,10b-letraza-benzo [e] azulen-1-yl) piperidin-1-yl] - (2- hydroxy-5-methyl-phenyl) -methanone; [4- (8-Chloro-5-mephyl-5,6-dihydro-4H-2,3,5, 10b-eeryza-benzo [e] azulen-1-yl) piperdin-1 -yl] - ( 1 H-indol-6-yl) -meyenone; [4- (8-Chloro-5-mephyl-5,6-dihydro-4H-2,3,5, 10b-ioaraza-benzo [e] azulen-1 -ii) -p -peridin-1-yl] - (3-mephoxy-phenol) -melanone; [4- (8-Chloro-5-mephyl-5,6-dihydro-4H-2,3,5, 10b-ioaraza-benzo [e] azulen-1-l) -piperidin-1-yl] - ( 3-fluoro-phenyl) -meyenone; [4- (8-Chloro-5-meityl-5,6-dihydro-4H-2,3,5,10b-eeryaraza-benzo [e] azulen-1-yl) -piperidin-1-yl] - (4 -fluoro-phenyl) -meanone; 1- [4- (8-Chloro-5-meityl-5,6-dihydro-4H-2,3,5,10b-ephaza-benzo [e] azulen-1-yl) piperin-1-yl] -bulan-1 -one; [4- (8-Chloro-5-meityl-5,6-dihydro-4H-2,3,5, 10b-ephaza-benzo [e] azulen-1-yl) -piperidin-1-yl] -cyclopropyl- melanone; and pharmaceutically acceptable derivatives thereof.

6. - The use of a compound according to any of claims 1 to 5 as a medicament.

7. - A period of anxiety, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatraemia), dysmenorrhoea (primary and secondary), endometriosis, emesis (including motion sickness), retardation of inimeric growth, inflammation (including rheumatoid arthritis), ovulation pain, preeclampsia, premature ejaculation, premature delivery (pre-term) or Raynaud's disease, which comprises administering an effective ferapéuíicameie caníidad of a compound according to any of claims 1 to 5 to a patient suffering from said írasíorno.

8. - A method according to claim 6 wherein the frasforne is dysmenorrhea (primary or secondary).

9. - A method according to claim 9 wherein the disorder is primary dysmenorrhea.

10. The use of a compound according to any of claims 1 to 5 in the manufacture of a medicament for the eradication of anxiety, cardiovascular disease (including angina, atherosclerosis, hypertension, heart failure, edema, hypernatremia), dysmenorrhea (primary and secondary), endometriosis, emesis (including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), ovulation pain, preeclampsia, premature ejaculation, premalign delivery (pre-term) or Raynaud's disease.

11. - Use according to claim 10 wherein the disorder is dysmenorrhea (primary or secondary).

12. - Use according to claim 11 wherein the disorder is primary dysmenorrhea.

13. - A pharmaceutical formulation that includes a compound according to any of claims 1 to 5 or a pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable excipient, diluent or carrier;

14. A pharmaceutical prodrug containing a V1a antagonist according to any of claims 1 to 5 together with a compound selected from (a) an oral contraceptive, (b) a PDE5 inhibitor, (c) a NO donor, (d) ) L-arginine, or (e) a COX inhibitor, in the form of a combined preparation for simultaneous, separate or sequential use! in the treatment of dysmenorrhea. SUMMARY: The compounds of formula (I), (0 or a pharmaceutically acceptable derivative thereof, wherein: X represents NR or O, R represents hydrogen, C 1-8 alkyl or SO 2 [C 8 alkyl], W represents N or CH, Y and Y independently represent hydrogen, halogen, OH, CF3, OCF3, CN, NH2, C? -8 alkyl, C? -8alkyloxy or C3-8 cycloalkyl, Ring A represents a heterocyclic ring containing at least one nitrogen atom, Z represents a direct bond C3-8 alkyl or C3-8 cycloalkyl, R1 represents R2, OR2, OR3-R4, N (R2) [C ^ -8 alkylene] R4, NCOR2 or SR4, R2 and R4 independently represent hydrogen, C3-8 cycloalkyl, CF3, Ar or Het; R3 represents a direct bond or C-? 8 alkyl; a is O or l; Ar represents an aromatic ring, optionally condensed with a heterocyclic ring, and / or optionally substituted with one or more groups as describes below; Het represents a heterocyclic ring optionally substituted with one or more groups as described below, and / or optionally condensed with an aromatic ring that is optionally substituted with one or more groups as described below; in each case, the C?-8 alkyl, C?-8 alkylene and C 3-8 cycloalkyl groups may optionally and independently be substituted with one or more groups as described below; the substituent groups for Ar, Het, C? -8 alkyl, C? _8 alkylene and C3-8 cycloalkyl indicated above are independently selected from hydrogen, halogen, C1-8 alkyl, alkyloxy C-i-β, S (C?-8 alkyl), CN, CF 3, NH 2 and OH; They are useful for the treatment of anxiety, cardiovascular disease (including angina, aerosol, hypertension, heart failure, edema, hypernatremia), dysmenorrhoea (primary and secondary), endometriosis, emesis (including motion sickness), intrauterine growth retardation, inflammation (including rheumatoid arthritis), ovulation pain, preeclampsia , premature ejaculation, premature delivery (preterm) and Raynaud's disease.