MXPA98004765A - Gonadotrop liberating hormone antagonists - Google Patents

Abstract

there are disclosed compounds of the formula (See Formula) and pharmaceutically acceptable salts thereof, which are useful as antagonists of the gonadotropin-releasing hormone and therefore may be useful for the treatment of a variety of disorders related to sex hormones and other disorders. both in men and in women

Description

GONADOTROPINE LIBERATING HORMONE ANTAGONISTS BACKGROUND OF THE INVENTION Gonadotroin-releasing hormone (GnRH) »also called luteinizing hormone-releasing hormone (LHRH) is a decapeptide that plays an important role in human reproduction. The hormone is released from the hypothalamus and acts on the pituitary gland to stimulate the biosynthesis and the secretion of luteinizing hormone (LH) and of the hormone stimulator of the -follicle (FSH). The LH released from the pituitary gland is the main responsible for the regulation of gonadal steroid production in both sexes, while FSH regulates spermatogenesis in men and follicular development in women. GnRH agonists and antagonists have been shown to be effective in the treatment of certain conditions that require inhibition of LH / FSH release. In particular, GnRH-based therapies have been shown to be effective in the treatment of endometriosis »uterine fibroids» polyacotic ovarian disease »early puberty and several gonadal steroid-dependent neoplasms; very mainly cancers of the prostate, breast and ovaries. GnRH agonists and antagonists have also been used in various assisted fertility techniques and have been investigated as potential contraceptives in both men and women. They have also shown a possible usefulness in the treatment of gonadotropic adenomas of the pituitary »in sleep disturbances. such as sleep apnea »in irritable bowel syndrome» in premenstrual syndrome, in benign prostatic hyperplasia »hirsutism» as an adjunct to growth hormone therapy in children deficient in growth hormone »and in models of lupus in murids. The compounds of the invention can also be used in combination with bisphosphonates (bi-osphonic acids) and other agents, such as growth hormone secretagogues, for example, MK-0677 »for the treatment and prevention of metabolic disorders of the body. calcium and phosphate in the bones »in particular» for the prevention of bone loss during therapy with the GnRH antagonist. and in combination with estrogens »progesterones» antiestrogens »antiprogestins and / or androgens» for the prevention or treatment of bone loss or hypogonadal symptoms. such as hot flushes during therapy with the GnRH antagonist. Additionally, a compound of the present invention can be coadministered with a 5al a-reductase 2 »inhibitor such as finasteride or epristeride; an inhibitor of 5alpha-reductase 1, such as 4'7beta-d -methyl-4-aza-5alpha-col-3-one, 3-oxo-4-aza-4'-7beta-di eti-16beta- ( 4-chlorophenoxy) -5alpha-androstane and 3-oxo-4-aza-4, 7beta-dimethyl-1-6beta- < phenoxy) -5alpha-androstane "which are described in WO 93/23420 and WO 95/11254; double inhibitors of 5alpha-reductase 1 and 5alpha-reductase 2'-such as 3-oxo-4-aza-17beta- (2,5-trifluoromethyl-lfeni-1-carbamoyl-1) -5alpha-androstane, which is described in WO 95/07927 » antiandrogens »such as flutamide» casodex and cyproterone acetate »and alpha-l blockers. such as prazosin »terazosin» doxazosin. ta sulosin and alfuzosin. Additionally, a compound of the present invention can be used in combination with the growth hormone »growth hormone releasing hormone or growth hormone secretagogues, to retard puberty in children deficient in growth hormone» which will allow them to continue to gain weight before the fusion of the epiphyses and the cessation of growth at puberty. The present GnRH antagonists are GnRH-like decapeptides which are generally administered intravenously or subcutaneously, presumably because of their nonsignifying oral activity. They have amino acid substitutions usually in positions 1 »2» 3 »6 and 10. Non-peptide GnRH antagonists offer the possible advantage of oral administration. GnRH antagonists that are not peptides have been described in European application O 219 292 and in De. B and co-authors. J. Med. Chem., 32, 2036-2038 < 19B); in WO 95/28405, WO 95/29900 and EP 0S79642 »all by Takeda Chemical Industries, Ltd.

The substituted characters known in the art include those described in the following patents and patent applications: U.S. Patent No. 5,030,640 describes ethanola-indole-alpha-heterocyclic indoles "which are potent beta-agonists. U.S. Patent No. 4,544,663 discloses i ndol amine derivatives that are purportedly useful as agents against male fertility. WO 90/05721 discloses a-amino or 3-acetic acids useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents. French patent 2,181,559 describes indole derivatives with sedative, neuroleptic, analgesic, hypotensive, antiserotonin and adrenol activity. Belgian patent 879381 describes derivatives of 3-aminoalkyl 1-1H-i dol-5-thioamide and -carboxyamide, as cardiovascular agents used to treat hypertension, Raynaud's disease and migraine.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds that are GnRH antagonists that are not peptides, which can be used to treat a variety of conditions related to the sex hormone in both men and women; to methods for their preparation and to methods and pharmaceutical compositions containing those compounds for use in mammals. Due to its activity as antagonists of the hormone GnRH. The compounds of the present invention are useful for treating a variety of conditions related to the sex hormone in both men and women. These conditions include: endometriosis. uterine fibroids. Ovarian poliquíicos disease. hirsutism »precocious puberty, gonadal steroid-dependent neoplasms» such as cancers of the prostate, breast and ovaries, gonadotrophic pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome and benign prostatic hypertrophy. They are also useful as adjuncts for the treatment of growth hormone deficiency and short stature, and for the treatment of systemic lupus erythematosus. In addition, the compounds of the present invention may be useful in in vitro fertilization and as contraceptives. The compounds may also be useful in combination with androgens, estrogens, progesterones, antiestrogens, and antiprogestogens, for the treatment of endometriosis. the fibroids and in contraception. They are also useful in combination with testosterone or other androgens or in anti-progestogens in men »as a contraceptive. The compounds can also be used in combination with an angiotensin-converting enzyme inhibitor such as Enalapril or Captopril, an angiotensin II receptor antagonist such as Losartan, or a renin inhibitor for the treatment of uterine fibroids. Additionally, the compounds of the present invention can also be used in combination with bisphosphonates (bis-osphonic acids) and other agents »for the treatment and prevention of alterations in calcium metabolism» phosphate and bone, in particular for the prevention of bone loss during therapy with the GnRH antagonist; and in combination with estrogen »progesterone and / or androgen» for the prevention or treatment of bone loss or hypogonadal symptoms. such as hot flushes during therapy with the GnRH antagonist. Additionally, a compound of the present invention can be coadministered with an inhibitor of 5alpha-reductase 2. such as finasteride or epristeride; an inhibitor of 5alpha-reductase 1. such as 4, 7beta-dimeti l-4-aza-5al a-col estan-3-one, 3-o? o-4-aza-4.7beta-dimeti l-16beta- ( 4-cl orophenoxy) 5alpha-androstane and 3-oxo-4-a? A-4 »7beta-dimet l-16beta- (phenoxy) -5alpha-androstane» as described in WO 93/23420 and WO 95/11254; double inhibitors of 5alpha-reductase 1 and 5alpha-reductase 2 »such as 3-oxo-4-aza-17beta- (2» 5-trif luorometi Ifen 1-carbamoi 1) -5alpha-androstane »as described in WO 95 / 07927; antiandrogens »such as flutamide, casodex and cyproterone acetate, and alpha-1 blockers» such as prazosin, terazosin »doxazosin» tamsulosin and alfu? osin. Additionally, a compound of the present invention may be used in combination with the growth hormone "growth hormone releasing hormone and growth hormone secretagogoe" to retard puberty in growth hormone-deficient children. it will allow them to continue to gain weight before the fusion of the epiphysis and the cessation of development at puberty.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds of the general formula: wherein: A is alkyl of 1 to 6 carbon atoms, substituted alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, substituted cycloalkyl of 3 to 7 carbon atoms, alken it of 3 to 6 atoros of carbon, substituted alkenyl of 3 to 6 carbon atoms, to the one of 3 to 6 carbon atoms, substituted alkynyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or alkyl of Co_- S (0)) -alcome from 0 to 5 carbon atoms »alkyl from Co_ß-0-alkylo from 0 to 5 carbon atoms, alkyl from Co_ß-0-a 1 qui 1 or from 0 to 5 carbon atoms »C0_ß-NRxa-alkyloxy of O to 5 carbon atoms» where R ß and alkyl of O to 5 carbon atoms can be joined to form a ring, «16 or a simple gadget; R is hydrogen, alkyl of 1 to 6 carbon atoms, substituted alkyl of 1 to 6 carbon atoms "wherein the substituents are as defined below; aryl »substituted aryl aralkyl or substituted aralkyl "wherein the substituents are as defined for R3» R ^ and Rβ; R. is Ris R_. is hydrogen, alkyl of 1 to 6 carbon atoms, substituted alkyl of 1 to 6 carbon atoms. aralkyl. substituted aralkyl, aryl »substituted aryl, alky 1-0R JL» < NRi; LRi2) of 1 to 6 carbon atoms "(CONRi; LRi2) of 1 to 6 carbon atoms, or C (NRiiRX2) NH; R_. and A taken together form a ring of 5 to 7 atoms; R3. R <and R> are independently hydrogen, alkyl of 1 to 6 carbon atoms, substituted alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, substituted alkenyl of 2 to 6 carbon atoms »CN. nitro. perfluoroalkyl of 1 to 3 carbon atoms »perfluoroalkoxy 1 to 3 carbon atoms »aryl» substituted aryl »aralkyl» • ": the replaced" R i0 (CH2) p-. RiiC (0) 0 (CHa¡) (; > -, 0) (CH2) p-. - (CHa p-SCO ^ R ^ - (CH2) p, C (0) NRi, LRi2 or halogen, where R ^ is hydrogen »alkyl of 1 to 6 carbon atoms» perfluoroalkyl of 1 to 3 carbon atoms »Aryl or substituted aryl, R3 and R4 taken together form a carbocyclic ring of 3 to 7 carbon atoms or a heterocyclic ring containing 1 to 3 heteroatoms selected from N 'O and S; R & hydrogen; alkyl of 1 to 6 carbon atoms »substituted alkyl of 1 to 6 carbon atoms» aryl »substituted aryl, per loroalkyl of 1 to 3 carbon atoms» CN »NO-, halogen» R? aO (CH2) ß- NR2AC < 0) R2O, NR2; LC (O) NR2CJR2JL or S02R2O; R. "is hydrogen, alkyl of 1 to 6 carbon atoms or substituted alkyl of 1 to 6 carbon atoms, unless X is hydrogen or halogen; so. R ... "will be absent; Rβ is C (0) 0R2O. C (O) NR20R2, NR20R2 »C (0) R2O» NR2xC (0) R2O.

NR2xC (0) NR2OR2X, 0C (0) R2O, 0C (O) NR20R2X, 0R2O, S0"R2O, S (0) nR2oRz? ' a heterocyclic ring or a bicyclic heterocyclic ring with 1 to 4 heteroatoms selected from Ni O or S. which may be optionally substituted with R 3, R 4 and R 7, alkyl of 1 to 6 carbon atoms or substituted alkyl of 1 to 6 carbon atoms; or R-, and R ?, all together »form a heterocyclic ring containing one or more heteroatoms selected from N» O or S »which may be optionally substituted with R3» R ^ and Rβ; R "and R" "are independently hydrogen" alkyl of 1 to 6 carbon atoms "substituted alkyl of 1 to 6 carbon atoms" aryl or substituted aryl, aralkyl or substituted aralkyl when m is different from O; or »and Rβ« taken together »form a carbocyclic ring of 3 to 7 atoms or when m is different from O; R. and A. all together »form a heterocyclic ring containing from 3 to 7 carbon atoms and one or more heteroatoms» when m is different from O; or Ra.o and R or * 'taken together, form a carbocyclic ring of 3 to 7 carbon atoms or; R »R3LO taken together form a carbocyclic ring of 3 to 7 carbon atoms or a heterocyclic ring containing one or more heteroatoms when m is different from zero; or R "and R2" taken together, form a heterocyclic ring containing from 3 to 7 carbon atoms and one or more heteroatoms "when m is different from zero; or R or Rz 'taken together' form a heterocyclic ring containing from 3 to 7 carbon atoms and one or more heteroatoms; Rxo and A »taken together» form a heterocyclic ring containing from 3 to 7 carbon atoms and one or more heteroatoms; or Ra-x and Ra.substantially hydrogen "alkyl of 1 to 6 carbon atoms" substituted alkyl of 1 to 6 carbon atoms »aryl» substituted aryl. aralkyl »substituted aralkyl» a carbocyclic ring of 3 to 7 carbon atoms or a substituted carbocyclic ring containing from 3 to 7 atoms; R and Ri2 taken together can form a ring of 3 to 7 atoms »optionally substituted; R 3 is hydrogen, OH, NR7Ra, RRxxS02 (at 1 i of 1 to 6 carbon atoms), NRx S02 (substituted alkyl of 1 to 6 carbon atoms »NRxxS02 (ari lo)» NRx S02 (ari substituted ) »NRxxS02 (perfluoroalkyl of 1 to 3 carbon atoms)» S02NRxx (alkyl of 1 to 6 carbon atoms) »S02NRxx (substituted alkyl of 1 to 6 carbon atoms» S02IMRxx (ari lo), S02NRx (ary lo) substituted) »S02NR x (perfluoroal qui 1 or 1 to 3 carbon atoms)» S02NRxx (C (0) -alqulo of 1 to 6 carbon atoms); S02NRxx (alkyl substituted with C (0) > 1 to 6 carbon atoms); S02NRxx (C (0) -ari lo); S02f \ IRxx (ari substituted with C (0)); S (0) "(alkyl of 1 to 6 carbon atoms); S (0) "(substituted alkyl of 1 to 6 carbon atoms)» S (0) r. (Ari 1 o), S (0) r? (Substituted aryl), perfl oroalkyl of 1 to 3 carbon atoms, per luoroal coxi of 1 to 3 carbon atoms, alkoxy of 6 carbon atoms, substituted alkoxy of 1 to 6 carbon atoms »COOH, halogen, N02 or CN; Rx-t and R x β are i dependently hydrogen, alkyl of 1 to 6 carbon atoms, substituted alkyl of 1 to 6 carbon atoms »alkenyl of 2 to 6 carbon atoms, substituted alkenyl of 2 to 6 carbon atoms. CN »nitro, perfluoroalkyl of 1 to 3 carbon atoms, perfolyoroalkyl of 1 to 3 carbon atoms» aryl »substituted aryl» aralkyl »substituted aralkyl» Rxx0 (CH2) p, - »RxxC (0) 0 < CH2) p-, Rxx0C (0) (CH2) ,,, -, (CH2) pS (0) r, RX7, - < CH2 > , .--, C (0) NRxxRx2 or halogen; wherein Rx7 is hydrogen, alkyl of 1 to 6 carbon atoms, perfluoroalkyl of 1 to 3 carbon atoms, aryl or substituted aryl; Rxß is hydrogen, alkyl of 1 to 6 carbon atoms or N (RX RX2); Rxß is hydrogen, alkyl of 1 to 6 carbon atoms, substituted alkyl of 1 to 6 carbon atoms. C (0) 0R x, C (0) NRxxR 2. C (0) Rx, SCO ^ R ^; Rxw has the definition of Rx3 or Rx- ^? R2"and R2X are independently hydrogen, alkyl of 1 to 6 carbon atoms» substituted alkyl of 1 to 6 carbon atoms »aryl» substituted aryl »aralkyl» substituted aralkyl »a carbocyclic ring of 3 to 7 atoms» a substituted carbocyclic ring containing from 3 to 7 atoms, a heterocyclic ring or a b-cylic ring with the 4 heteroatoms selected from N, 0 or S. which may be optionally substituted with R3, R ^ and RB; C 1 -C 6 -alkyl substituted with a heterocyclic ring or a bicyclic heterocyclic ring of 1 to 4 heteroatoms »selected from N, 0 or S» which may be optionally substituted with R 3 »R 4 and RÍ ..; Rao and R? ' taken together »can form a ring c.:. - substituted from 3 to 7 carbon atoms; Á __ •? \ L »0» S (0) "» C (0), < CR XR 2) 0 »a single bond to Rβ" alkenyl of 2 to 6 carbon atoms, substituted alkenyl of 2 to 6 carbon atoms, alkenyl or substituted alkynyl of 2 to 6 carbon atoms; when X is 0 »SCO) ,,. C (0) or CRXXR 2 »only Rß is possible; Z is 0 »S or NRXX; is 0 to 3; n is 0 to 2; P is 0 to 4; and the alkyl, cycloalkyl, alkenyl and alkynyl substituents are selected from alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aryl. substituted aryl »aralkyl» substituted aralkyl. hydroxy. oxo. cyano. alkoxy of 1 to 6 carbon atoms, fluoro. C (0) ORXX. aryl-alkoxy of 1 to 3 carbon atoms »aryl-substituted alkoxy of 1 to 3 carbon atoms; and the aryl substituents are as defined for R3 »R ^ and Rβ; or a pharmaceutically acceptable salt and / or hydrate thereof; or when applicable »a geometrical or optical isomer or a racemic mixture thereof. Unless otherwise specified or indicated, the following definitions will apply throughout the specification and the claims. When any variable (for example »aryl» heterocycle, etc.) occurs more than once in any constituent or in formula I. its definition. in each occurrence. it is independent of its definition in each of the other occurrences. Combinations of substituents and / or variables »are also permissible only if such combinations result in stable compounds. The term "alkyl" is intended to include Straight-chain branched chain saturated aliphatic hydrocarbon "having the specified number of carbon atoms" for example »methyl (Me), ethyl (Et)» propyl »butyl» pentyl »hexyl» heptyl »octyl. nonyl decilo. undecide dodecyl and its isomers, such as isopropyl (i-Pr) »isobutyl (i-Bu), secondary butyl (s-Bu), tertiary butyl (t-butyl), isopentane, isohexane, etc. The term "aryl" includes phenyl and naphthyl. Preferred aryl is phenyl. The term "halogen" or "halo" is intended to include fluorine, chlorine, bromine and iodine. The term "heterocycle" or "heterocyclic ring" is defined by all heterocyclic, non-aromatic rings, of 3 to 7 atoms, containing 1 to 3 heteroatoms »selected from N» 0 and S »Such as oxirane» oxetane »tetrahydro uran» tetrahydropyran »pyrrolidine» piperidine, tetrahydropyridine »tetrahydropyridine» tetrahydrothioene »tetrahydrothiopyran, morpholine» hydantoin »valerolactam» pyrrole idinone and sims. As used herein, the term "composition" is intended to comprise a product comprising the specified ingredients in the specified amounts, as well as any product that is the result, directly or indirectly. of the combination of the specified ingredients in the specified quantities. Further. those skilled in the art are well aware that many of the preceding heterocyclic groups may exist in more than one tautomeric form. It is intended that all those tautoms are included within the scope of this invention. Optically isomeric forms, ie, mixtures of enantiomers, for example, racemates or diastereomers, as well as the individual enantiomers or diastereomers of the compounds herein are included. These individual enantiomers are designated according to the optical rotation they perform »by the symbols (+) and (-). (L) and (D) »(1) and (d) or their combinations. These isomers can also be designated according to their absolute spatial configuration by (S) and (R). which represent "left" and "right", respectively.

The individual optical isomers can be prepared using conventional resolution methods, for example, by treatment with an optically active acid, appropriate; separation of the diastereomers and then recovery of the desired isomer. Additionally, individual optical isomers can be prepared by asymmetric synthesis. Additionally, a given chemical formula or a given chemical name will encompass its pharmaceutically acceptable addition salts and solvates. such as hydrates. The compounds of the present invention, although effective themselves, can be formulated and administered in the form of their pharmaceutically acceptable addition salts for purposes of stability, convenience or crystallization, increased solubility and other properties. * - > ies The compounds of the present invention can be administered in the form of their pharmaceutically acceptable salts. The term "cacerously acceptable carrier salt" is intended to include all acceptable salts. Examples of the acid salts are those of hydrochloric »nitric» sulfuric acid. phosphoric »formic» acetic »tri-luoroacetic. propionic maleic succim'co »malonic» methanesulfonic acid and the like »which can be used as a dosage form to modify the solubility or hydrolysis characteristics» or can be used in sustained release or prodrug formulations. Depending on the particular functionality of the compound of the present invention, the pharmaceutically acceptable salts of the compounds of this invention include those formed of cations such as sodium potassium, aluminum. calcium, lithium. magnesium, zinc, and bases such as ammonia, ethylenediamine. N-meti Iglutamine. lysine Arginine ornithine »choline» N.N'-dibenci leti lendiamine »chloroprocaine» diethanolamine »procaine» N-benzylphenethiol »diethylamine» pipera? ina. tris (hydroxymethi 1) aminomethane and tetramethylammonium hydroxide. These salts can be prepared by common and ordinary methods, for example by reacting a free acid with a suitable organic or inorganic base or alternatively. reacting a free base with a suitable organic or inorganic acid. Also in the case that an acid group (-C00H) or alcohol is present. the pharmaceutically acceptable esters can be employed. for example »those of methyl» ethyl, butyl »acetate» maleate »pi valoi loxi eti lo and the like; and those esters known in the art because they modify the solubility or hydrolysis characteristics for use as sustained release or prodrug formulations. The compounds of the present invention can have chiral centers and other centers whose stereochemistry is illustrated in formula I y. consequently, racemic mixtures and individual enantiomers or diastereomers may be present as racemates; all of these isomeric forms are included in the present invention, as well as their mixtures. Additionally, some of the crystalline forms for the compounds of the present invention can exist as polymorphs and "as such" are intended to be included in the present invention. Additionally, some of the compounds of the present invention can form solvates with water or common organic solvents. Said solvates are within the scope of the invention. The compounds of the invention are prepared by the following reaction schemes. All substituents are as previously defined unless indicated otherwise.

SCHEME. TO REACTION SCHEME A As shown in reaction scheme A »the treatment of tryptamine (1) with N-carboxyphtalimide in an inert organic solvent» such as tetrahydrofuran. at a temperature of 20-65 ° C. preferably 65 ° C. during a period of 12-48 hours. gives the corresponding N- derivative to imidotriptamine (2). The N-tal i i dotriptamine (2) could be further modified by treatment with a brominating agent. such as pyridinium hydrobromide. perbromide. pyrrolidone hydrobromide or the like, in an inert organic solvent. such as tetrahydro uran. dimethyl chloride. chloroform or mixtures thereof, at 0-25 ° C for a period of 30 minutes to 4 hours, to give 2-bromotriptamine (3). The bromide (3) can be reacted with an arboronic acid (prepared essentially as described in Gronowitz, S; Hornfeldt »A.-B; Yang» Y. -H »Chem. Ser.» 19B6 »26» 311- 314) with palladium catalysis (O) »a weak base» such as aqueous sodium carbonate or the like, and a source of chloride, such as lithium chloride in an inert solvent such as toluene »benzene» ethanol »propanol or its n. = Zinc "at a temperature of 25 to 100 ° C", preferably 80 ° C, for a period of 1-6 hours "to give the derivative (4) of 2-ary1-triptamine. Finally. the phthalic group can be removed by treating (4) with aqueous hydrazine in an inert solvent such as methanol or ethanol, at 0 ° C at 25 ° C, for a period of 4-24 hours, to give the tryptamine (5).

SCHEME B triethylamine CH2CI2 REACTION SCHEME B As shown in reaction scheme B », 2-ary1 triptamine can be condensed with a carboxylic acid of type (6) using the l- (3-dimet laminopropyl) -3- hydrochloride coupling reagent. eti Icarbodi imida (EDC) l »3-dicyclohexy Icarbodiimide (DCC) or the like» with or without l-hydroxybenzotriazole (HOBt) and a tertiary amine base »such as N-methylmorpholine (NMM), triethylamine or the like» in an inert organic solvent »such as methylene chloride »chloroform» dimethylformamide or mixtures thereof »at room temperature or in its vicinity» during a period of 3-24"•" to give the corresponding amide derivative (7). .- .. Dente can be treated 2-ary 1 tryptamine (5) with an active ester or with an active acid chloride of type (i), in an inert organic solvent »such as methylene chloride» chloroform »tetrahydrofuran» ether diethyl ether or the like, and a tertiary amine base such as triet lane »diisopropylethylamine. pyridine or the like, at a temperature of 0 to 25 ° C for 30 minutes to 4 hours, to give (7).

SCHEME C REACTION SCHEME C As shown in reaction scheme C », the amide carbonyl of (7) can be reduced by treatment with borane, lithium aluminum hydride or with equivalent hydride sources in an inert organic solvent, such as tetrahydrofuran» diethyl ether »1,4-dioxane or the like, at 25-100 ° C, preferably 65 ° C, for a period of 1-8 hours, to give the corresponding amine compound (9).

SCHEME D REACTION D SCHEME As shown in reaction scheme D », 2-ary1 riptamine (5) can be modified by treatment with an aldehyde or a ketone of type (10) in the presence of a weak acid. such as tri luoroacetic acid (TFA). acetic acid or the like »with or without a desiccator, such as 3Á molecular sieves or magnesium sulfate, and a hydride source. such as sodium borohydride or sodium cyanoborohydride, in an inert organic solvent. such as methanol. Ethanol, isopropanol. tetrahydro uran. dichloromethane. chloroform or mixtures thereof, at a temperature of 0 to 25 ° C for a period of 1-12 hours. to give the corresponding secondary or tertiary amine derivative (1).

SCHEME E REACTION SCHEME E As shown in the reaction scheme E 'the treatment of an aryl hydrazine or an aridihydrazine hydrochloride (12) with an aryl cyclopropyl Icetone of type (13) in a polar organic solvent such as methane !. ethanol »n-propanol. isopropanol »n-butanol. t-butanol »preferably n-butanol» at a temperature of 70 to 120 ° C for a period of 8 to 24 hours »gives 2-ary1 tri ptamine (5). Alternatively, when treating anhydrous hydroxide or anhydrous hydrochloride (12) with an arylbuthane Icetona of type (14) containing a substitutable group (chloride, bromide, iodide »O-methanesulfonate, 0-tri-chloroethanesulfonate or similar), in position 4. in a polar solvent, such as methanol »ethanol» n-propanol »isopropanol» n-butanol, terbutanol or their mixtures »at room temperature, for a period of 30 minutes to 2 hours, followed by heating at a temperature of 65-100 ° C for 4-24 hours »2-ary1-triptamine (5) is produced.

SCHEME F Re REACTION SCHEME F As shown in the reaction scheme F, it is possible to react iodoanilines of the type (15) with arylactides "an appropriate palladium (O) catalyst such as tetrakisky tri-enylans) palladium" a copper halide (1) »such as cuprous bromide» in an inert organic solvent »such as triethylamine» at a temperature of 50-8B ° C for a period of 30 minutes to 5 hours »to give the diari leti leño (16). Acetylene (16) can be further modified by treatment with palladium (II) catalyst such as palladium (II) chloride or palladium (II) acetate. in an inert organic solvent »such as acetonitrile» at a temperature of 50 to 82 ° C »for a period of 30 minutes to 6 hours» to give 2-ari pretty! (17) B SCHEME Q REACTION SCHEME 6 As shown in the reaction scheme G »the treatment of 2-ari cute! (17) with net oxalyl chloride or in an inert organic solvent such as methylene chloride, chloroform, d-chloroethane, tetrahydrofuran or the like at a temperature of 25-65 ° C for a period of 3-24 hours, the adduct (18) of acyl chloride. The crude product (IB) can be reacted with an amine of type (19) in an inert organic solvent such as diethyl ether, tetrahydrofuran, methylene chloride, chloroform or the like, and an amine base, such as eti lamina »diisopropylethylamine or pyridine» at a temperature of 0 to 25 ° C for a period of 30 minutes to 4 hours »to give the amide derivative (20). The amide (20) can be further modified by treatment with a reducing agent »such as borane or lithium aluminum hydride» in an inert organic solvent »such as tetrahydrofuran» at elevated temperatures »preferably at reflux» for a period of 1 hour. to 5 hours »to give the compound (21).

SCHEME H REACTION SCHEME H As shown in the reaction scheme H », it is possible to reduce N-benzyl derivatives of type (22a) or N-benzylcarboxylic derivatives of type (22b)» to give the secondary amine analogs (7) by treatment with hydrogen (1 atmosphere) and an appropriate catalyst »such as palladium on carbon» palladium hydroxide on carbon or the like »in an inert organic solvent» such as or tetrahydrofuran »ethyl acetate» methanol »ethanol or mixtures thereof» to which a weak acid "such as 30% aqueous acetic acid" has been added over a period of 10 minutes to 3 hours or until the "aryl group" has been removed to give the secondary amine. SCHEME I REACTION SCHEME I As shown in reaction scheme I »the treatment of a nitroindol of type (24) with hydrogen (1 atmosphere) and an appropriate catalyst» such as Raney nickel < R > in an inert organic solvent »such as ethanol» methanol or the like »at room temperature for a period of 2-12 hours, gives e! derivative (25) of a corresponding inoindole.

SCHEME J REACTION SCHEME J As shown in the reaction scheme J, the amino- or hydroxy indole (25) can be modified by acylation under a variety of conditions. For example »the treatment of (25) with? Acid chloride» active acid or ester anhydride and an amine base, such as triethylamine »di sopropylethylamine» pyridine or the like »in an inert organic solvent» such as methylene chloride »Chloroform» tetrahydrofuran or its mixtures »at 0 ° C to room temperature» for a period of 1 to 12 hours, gives the corresponding amide or ester derivatives (26). Alternatively (25) can be coupled with a carboxylic acid by one of the many commonly used dehydrating agents. For example, the treatment of aminoindole (25) with an appropriate carboxylic acid and l- (3-dimethylaminopropy 1) -3-et Icarbodiimide hydrochloride (EDC). 1.3-di ciel ohe i Icarbodi imida (DCC) or the like, with or without 1-hydroxybenzotriazole (HOBt) and a tertiary amine base, such as N-methyl or olin (NMM), triethylamine or the like, in a solvent inert organic, such as methylene chloride. chloroform »dimethylformamide or mixtures thereof» at or near room temperature »for a period of 3 to 24 hours» gives e! amide derivative or corresponding ester (26).

SCHEME K '° REACTION SCHEME K As shown in e! reaction scheme K, it is possible to prepare urea or carbamate derivatives of (25) by treatment with a carbamoyl chloride of type (27a) or »alternatively. with an isocyanate reagent of type (27b) and an amine base. such as pyridine. triethylamine. "* opi 1 eti 1 amine, N-methylmorpholine or the like" in an "inert organic" such as methylene chloride » ^ xj x. ioro +, ..o »dimethyl ormamide, tetrahydrofuran or mixtures thereof" at a temperature of 0-65 ° C "for a period of 1-72 hours, to give (28). The compound (25) can also be modified by treatment with a bisylectrophile reagent such as phosgene, triphosgene, 1,1'-carbon imidazole, carbonate μL, N'-disuccinimidyl or the like, with or without addition of an amine base, such as pyridine, triethylamine, diisopropylellamine, N-methylmorpholyl, in an inert solvent, such as methylene chloride, chloroform or similar »at a temperature of -20 ° C to 0 ° C. during a period of 20 minutes to 2 hours. After this time, the reaction mixture is treated with a suitable mono- or disubstituted amine at -20 to 25 ° C for a period of 1-5 hours to give the analogue (28) of urea or carbamate.

SCHEME L etlamna REACTION SCHEME L As shown in the reaction scheme L », the amine (25) can be modified by treatment with an appropriate sulfonyl chloride of type (29) or a sulfamyl chloride of the type (30)» with an amine base »such as pyridine. triet i lamina. diisopropylethylamine. N-methylmorpholine »in an inert solvent. such as methylene chloride. chloroform »dichloroethane or the like» at a temperature of -20 ° C to 25 ° C »for a period of 20 minutes to 2 hours» to give the corresponding derivatives of N-sulphonamide (31) or of N-sulfani lamide (32) ) »Respectmente amente. SCHEME M REACTION SCHEME M As shown in reaction scheme M ", 2-ary1-tryptamine (33) can be modified by treatment with an epoxide such as (34) in an inert organic solvent, such as methanol, ethanol, isopropanol, butanol. erbutane or mixtures thereof "at a temperature of 65 to 110 ° C" for a period of 8 to 20 hours "to give the am-non-alcohol derivative (35) correspondingly.

SCHEME N REACTION SCHEME N As shown in reaction scheme N., the amide derivatives of an indo derivative can be prepared. containing acid »such as (36)» by treatment with an appropriate amine (R- ^ R ^ H) and a suitable coupling agent, such as benzotriazole-1-i loxi-tri s hexafluorophosphate (pyrrole and diene) phosphonium (PyBOP), benzotr azole-1-yl hexafluorophosphate 1-tris (dimethylane) phos (BOP), l- (3-di eti laminopropy 1) -3-ethylcarbonate (EDC) hydrochloride ) »L» 3-dicyclohexy Icarbodiimide (DCC) or the like »with or without 1-hydroxybenzotriazole (HOBt) and a tertiary amine base» such as N-methylmorpholine (NMM) »triethylamine or the like» in an inert organic solvent » such as methylene chloride »chloroform» tetrahydrofuran »dimethylformamide or mixtures thereof, at room temperature or close to it» during a period of 3 to 24 hours »which provides the corresponding amide derivative (37). The compounds of the present invention are useful in the treatment of various conditions related to sex hormone in men and women. This utility manifests itself in its ability to act as antagonists of the neuropeptide hormone GnRH »as demonstrated by the act-. i .ad in the following n vitro analyzes.

Analysis of binding to the GnRH receptor in the rat pituitary: Raw plasma membranes »prepared from rat pituitary tissues» were incubated in a Tris buffer. HCl (50 mM »pH 7.5) containing bovine serum albumin (0.15 * 4)» CI-125DD-t-Bu-Ser6-Pro9-eti-GnRH-lamide and the desired concentration of? N test compound. The analysis mixtures were incubated at 4 ° C for 90 to 120 minutes »followed by rapid filtration and repeated washing through a glass fiber filter. The radioactivity of the radioligands bound to the membrane was determined in a gamma counter. From these data the IC 50 of the igand radiol that binds to the GnRH receptors in the presence of the test compound was estimated.

Analysis of inhibition of LH tolerance The active compounds of the GnRH receptor binding assay were further evaluated with an LH release assay in vitro, to confirm their antagonist activity (blockade of LH release induced by GnRH). 1. Preparation of the sample. The compounds to be analyzed were dissolved and diluted in DMSO. The final concentration of DMSO in the incubation medium was 0.5%. 2. The analysis Wistar male rats (150-200 g) were obtained from Charles River Laboratories (Wilmington, MA). The rats were kept at a constant temperature (25 ° C) at a cycle of 12 hours of light and 12 hours of darkness. Food and water were left ad libitum to the rats. The animals were sacrificed by decapitation and the pituitary glands removed aseptically and placed in Hank's balanced salt solution (HBSS) in a 50 ml polypropylene centrifuge tube. The collection tube was centrifuged for 5 minutes at 250 x g and the HBSS was removed by aspiration. The pituitary glands were transferred to a disposable petri dish and fragmented with a scalpel. The fragmented tissue was then transferred to a 50 ml disposable centrifuge tube by suspending the tissue fragments in three successive 10 ml aliquots of HBSS containing 0.2% collagenase and 0.2% hyaluronidase. The dispersion of the cell was carried out in a water bath at 37 ° C with moderate agitation for 30 minutes. At the end of the incubation, the cells were aspirated 20 to 30 times with a pipette and the undigested pituitary fragments allowed to settle for 3 to 5 minutes. The suspended cells were removed by aspiration and then subjected to a centrifugation at 1200 x g for 5 minutes. The cells were resuspended in the culture medium. The undigested pituitary fragments were treated with 30 ml aliquots of the digestion enzymes "as before" for a total of 3 digestions with the collagenase / hyaluronidase mixture. The resultant cell suspensions were pooled and counted and diluted to a concentration of 3 x 10 cells / ml and 1.0 ml of this suspension was placed in each concavity of a tray of 24 concavities (Costar, Cambridge, MA, USA). ). The cells were kept in a humidified atmosphere of 5% C03./95% air, at 37 ° C »for 3 to 4 days. The culture medium consisted of DMEM containing 0.37% NaHC03 »10% horse serum» 2.5% fetal bovine serum »1% non-essential amino acids» 1% glutamine and 0.1% gentamicin. On the day of the experiment, the cells were washed three times 1.5 hours before and twice more immediately before starting the experiment. with DMEM containing 0.37% NaHCO3 »10% horse serum» 2.5% fetal bovine serum »1% non-essential amino acids (100X)» 1% glutamine (100) »1% penicillin / streptomycin (10,000 units of penicillin and 10,000 micrograms of streptomycin per ml). and 25 M of HEPES. pH 7.4. The release of LH was initiated in the presence of 2 nM GnRH in each concavity, in duplicate. Incubation was carried out at 37 ° C for 3 hours. After incubation, the medium was removed and centrifuged at 2000 x g for 15 minutes to remove any cellular material. The supernatant fluid was removed and analyzed for the LH content with a double procedure ... - I RÍA. using materials obtained from Dr. A. F. Parlo (Harbor-UCLA Medical Center, Torrance, CA. E. U. A.). The compounds of formula I are useful in numerous areas affected by GnRH. They can be useful in conditions related to the sexual hormone, in cancers that depend on the sexual hormone. in benign prostatic hypertrophy or fibroids of the uterus. Sex hormone-dependent cancers, which may benefit from the administration of the compounds of this invention include prostatic cancer. uterine cancer. breast cancer and gonadotrophic adenomas of the pituitary. Other "sex hormone dependent" conditions that may benefit from the administration of the compounds of this invention include: endometriosis »ovarian diseases» healthy »uterine fibroids and precocious puberty. The compounds can also be used in combination with an angiotensin-converting enzyme inhibitor. such as Enal april or Captopril; with an angiotensin II receptor antagonist »such as Losartan» or with a renin inhibitor »for the treatment of uterine fibroids. The compounds of the invention may also be useful for controlling e! pregnancy »as a contraceptive in both men and women» for fertility and HIV »in the treatment of premenstrual syndrome» in the treatment of lupus erythematosus »in the treatment of hirsutism» in e! treatment of irritable bowel syndrome »and for the treatment of sleep disorders» such as sleep apnea. Another use of the compounds of this invention is as an adjunct in growth hormone therapy »in children deficient in growth hormone. The compounds can be administered with growth hormone or with a compound that increases endogenous production or that releases growth hormone. It has developed certain compounds that simulate the release of endogenous growth hormone. Peptides known to stimulate the release of endogenous growth hormone include growth hormone releasing hormone, growth hormone releasing peptides GHRP-6 and GHRP-1 (described in U.S. Patent 4,411,890. PCT Patent Publication No. WO 89/07110 and in PCT Patent Publication No. WO 89/07111) and GHRP-2 (described in TCP Patent Publication No. WO 93/04081). as well as hexarelin (J. Endocrine!. Invest. 15 (supplement 4) .45 (1992)). Other compounds that stimulate the release of endogenous growth hormone are described, for example, in the following: U.S. Patent No. 3,239,345; U.S. Patent 4,036,979; U.S. Patent 4,411; 890 U.S. Patent U.S. Patent 5 U.S. Patent: US Patent 5,284,241 U.S. Patent U.S. Patent 5,284,841 U.S. Pat. U.S. Patent 5,310,737; U.S. Patent No. 5, 317,017; U.S. Patent 5,374,721; U.S. Patent No. 5,430,144, U.S. Patent 5,434,261, U.S. Patent No. 5,438,136, EPO Patent Publication No. 0, 144, 230; EPO patent publication No. 0.513.974; TCP patent publication No. WO 94/07486; TCP patent publication No. WO 97/08583 »TCP patent publication No. WO 94/11012; Patent Publication of TCP No. WO 94/13696; TCP patent publication No. WO 94/19367; TCP patent publication No. WO 95/032B9; TCP patent publication No. WO 95/03290; TCP patent publication No. WO 95/09633 »TCP patent publication No. WO 95/11029; TCP patent publication No. WO 95/12598; TCP patent publication No. WO 95/13069; TCP patent publication NO. WO 95/14666; TCP patent publication No. WO 95/16675; TCP patent publication No. WO 95/16692; TCP patent publication DO NOT. WO 95/17422; TCP patent publication NO. WO 95/17423; Science »260» 1640-1643 (June 11, 1993); Ann.

Rep. Med. Chem., 2B, 177-1B6 (1993); Bioorg. Med. Chem. Ltrs. » 4 (22) »2709-2714 (1994); and Proc. Nati Acad. Sci. USA, 92. 7001-7005 (July 1995). Preferred growth hormone secretagogues "representatives" employed in the combination herein include the following: 1) N-Cl- (R) -C (1,2-dihydro-1-methansulon 1 spiroC3H-i ndol- 3.4 '-piperidin.] - 1-i) carboni 13-2- (lH-indol-3-i 1) eti 1 D-2-amino-2-methyl-1-propanamide. 2) N-Cl- (R) -C (1,2-dihydro-l-methancarboni 1 spiroC3H-i ndol-3 »4'-piperidin-II-1-1) carboni 1 ZI-2- (lH-ndol-3) -i 1) eti 1] -2-amino-2-meti 1 ropanamide. 3) N-Cl- (R) -C (1 »2-dihydro-1-benzenesulfonyl 1 spiroC 3 H -indo! -3,4'-piperidin.] - 1-1) carbonyl 3-2- (1H- i ndo1-3-i 1) eti 13-2-arnino-2-meti 1propanamide. 4) N-CKR) -i: (3 »4-dihi ro-spiroC2H-l-benzopyran-2» 4'-piperidinH-l'- 1) carboni 13-2- (lH-indol-3-i 1) eti 1: -2-am no-2-methyl ipropanamide; 5) N-Cl (R) -C (2-acetyl 1-1, 2 »3» 4-te rahidroespi roCi soquino-1 in-4,4'-piperidinD-l'-i 1) carbonyl D-2- (i dol-3-yl) ethyl] -2-am.no-2- et 1propanamide; 6) N-Cl- (R) -C (1, 2-dihydro-l-methansulfoni lespiroC3H-indole-3,4'-piperidin3-l-1) carbom "1 D-2- (feni lmeti loxi) -Item 13-2-amino-2-methylpropanamide, 7) N-Cl- (R) -C-methanesulfonate (1,2-dihydro-1-methan-sulonyl-1-i-iC3H-i ndo1 -3 »4'- pi peri din -1'-i 1) -carboni 13-2- (feni lmeti lox) -et 13-2-amino-2-methylpropropanamide 8) N-Cl- (R) -C (1 »2- di i dro-1-metansul foni 1 esp roC3H-i ndol-3,4'-piperidin3-l'-i 1) carboni 13-2- (2 '.6'-difluorofem' 1 eti lo i) -eti 1 -2-amino-2-methyl-1-propanamide 9) N-Cl- (R) -C (1,2-dihydro-l-methanesulfoni! -5-f1) uoro-spiroCSH-i dol-S .4'-piperidi n3-l '-i 1) carboni 13-2- (feni lmeti loxi) -ei 13-2-amino-2-meti 1 propanam da 10) N-C1- (R) -C (1,2-di) idro-l-methansulfoni 1espiroC3H-i ndol-3.4'-pi eridin3-l'-i 1) carboni 13-2- (feni Imeti 1 thio) -ethyl 3-2-amino-2-meti ipropanamide 11) N- Cl-R) -C (1,2-dihydro-l-methanesulfoni 1 spiroC3H-i ndol-3,4'-piperidin3-l'- 1) carboni 1 -3- eni Ipropi 13-2-amino-2- et lpropanamide 12) N-Cl- (R) -C (1 , 2-di hi-dro-1-methansul oni 1 espi roC3H-i ndol-3,4'-piperidin3-l'-i 1) carboni 1 -3-cyclohexy Ipropi 13-2-amino-2- et Ipropana ida . 13) N-Cl- (R) -C (1,2-dihydro-l-methanesulfonyl spiroCSH-i ndol -3 »4'-p peri in3-l'-i 1) carboni 1 -4- eni l ut 13-2 -am no-2-methyl lpropanamide. 14) N-Cl- (R) -C (l »2-dihydro-l-metans? Lphoni lespiroC3H-indol-3,4'-piperidin3-l- 1) carboni 13-2- (5-fluoro- lH-indol-3-i 1) -eti 1 -2-a ino-2-methyl-1-propanamide. 15) N-C1- (R) -C (1,2-dihydro-l-metansu1 onyl-5-1-uoroscopy C3H-indol-3 »4'-piperidin3-l-1) carboni 1 -2 - (5- luoro-lH-indol-3-i 1) -eti 13-2-amino-2-methypropanamide. 16) N-Cl- (R) -C (l »2-dihydro-l- (2-ethoxycarbonyl) methyl-sulfoni lespiroC3H-indol-3» 4'-piperidin3-l-1) carboni 1 -2- (5-f! Uoro-lH-indol-3-yl) -ethyl-2-amino-2-methyl-1-propanamide. 17) N-Cl- (R) -Cl »2-dihydro-l» 1-di oxoespi oC3H-benzothiophen-3,4'-piperidin-3-l-1) carboni 1 -2- (eni lmeti loxi) eti 1 -2-amino-2-methylpropanamide; and their pharmaceutically acceptable salts. The compounds of the present invention can also be used in combination with bis-osphonates (bis-ionic acids) and other agents »such as growth hormone secretagogues, for example. MK-0677 »for the treatment and prevention of alterations in calcium, phosphate and bone metabolism» in particular to prevent bone loss during therapy with the GnRH antagonist »and in combination with estrogen» progesterone and androgens » for the treatment of bone loss or hypogonadal symptoms »such as hot flashes during therapy with the GnRH antagonist. It is known that bis-bisphosphonates (bisphosonic acids) inhibit bone resorption and are useful for the treatment of bone stones. as described in U.S. Patent 4,621,077, Rosini and co-inventors.The literature describes a variety of bisphosphonic acids that are useful in the treatment and prevention of diseases involving bone resorption. Representative examples can be found in the following: U.S. Patent No. 3, 251, 07; U.S. Patent No. 3, 422, 137; U.S. Patent No. 3 »584, 125; U.S. Patent No. 3,940,436; U.S. Patent No. 3,944,599; U.S. Patent No. 3,962,442; U.S. Patent No. 4,054,598; U.S. Patent No. 4,267,108 »U.S. Patent No. 4,327,039; U.S. Patent No. 4 »407» 76i; U.S. Patent No. 4,578,376 »U.S. Patent No. 4,621,077; U.S. Patent No. 5,624,654; U.S. Patent No. 4,746,654; US Patent No. 4,761,696; U.S. Patent No. 4,922,007; U.S. Patent No. 4,942,157; U.S. Patent No. 5,227,506; U.S. Patent No. 5,270,365; EPO patent publication No. 0.252.5045 and J. Qrg. Chem., 36, 3843 (1971). The preparation of bis-ionic acids and halogenobisophonic acids is well known in the art. Representative examples can be found in the references mentioned above, which describe the compounds that are useful for the treatment of alterations in e! calcium or phosphate metabolism »in particular as inhibitors of bone resorption. Preferred bisphosphonates are selected from the group of the following compounds: alendronic acid »etidronon acid» clodronic acid. pamidronic acid »tiludronic acid» risedronic acid »6-amino-1-hydroxy-1-hydroxy-1-bisphosphonic acid and 1-hydroxy-3-hydroxy-3-methoxy-1-propyphosphonic acid; or any of its pharmaceutically acceptable salts. A particularly preferred bisphosphonate is alendronic acid (alendronate) or a pharmaceutically acceptable salt thereof. A particularly preferred bisphosphonate is sodium alendronate, which includes sodium alendronate trihydrate. Alendronate sodium has received regulatory approval for sale in the United States under the brand name F0SAMAX R > . Additionally, a compound of the present invention can be coadministered with a 5alpha-reductase-2-inhibitor such as finasteride or epristeride; an inhibitor of Salfa-reductase 1 »such as 4.7beta-dimeti l-4-aza-5alpha-cholestan-3-one» 3-oxo-4-aza-4 »7beta-dimeti 1-16beta- (4-c1 orophenoxy) ) -5a1 fa-androstane »and 3-oxo-4-aza-4» 7beta-dimeti l-16beta- (phenoxy) -5alpha-androstane, which were described in WO 93/23420 and in WO 95/11254; the double inhibitors of 5al a-reductase 1 and Salfa-reductase 2, such as 3-oxo-4-aza-17beta- (2 »5-trifluoromethylphen-1-carbamoyl) -5al a-androstane» which was described in WO 95/07927; antiandrogens. such as flutamide »casodex and cyproterone acetate» and alpha-1 blockers »such as prazosin, tetazosin, doxazosin. tamsulosin and alf? zos n.

Additionally a compound of the present invention can be used in combination with growth hormone, growth hormone hormone or growth hormone secretagogues, to retard puberty in growth hormone-deficient children, which will allow them to continue to increase in height before the fusion of the epiphysis and the cessation of growth at puberty. For the combination treatment with more than one active agent, wherein the active agents are in separate dose formulations, the active agents can be administered separately or jointly. In addition, the administration of one element may be prior to »concurrent with» or subsequent to the administration of the other agent. The compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, candies, troches, aqueous or oily suspensions, powders or dispersible granules, emulsions, hard or soft capsules, or syrups or elixirs. . Compositions intended for oral use can be prepared according to any method known in the art., for the manufacture of pharmaceutical compositions, and said compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives, in order to provide pharmaceutically elegant and palatable preparations. The tablets contain the active ingredient in admixture with pharmaceutically acceptable, non-toxic excipients which are suitable for the manufacture of tablets. These excipients, for example, can be inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.; granulating or disintegrating agents, for example »corn starch or alginic acid; agglutinating agents »eg» starch »gelatin or acacia gum; and lubricating agents »for example» magnesium stearate »stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to retard disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a "time delay material" such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated by the technique described in U.S. Patents 4,256,108,14,446,452 and 4,265,874 to form osmotic therapeutic tablets to control irradiation. Formulations for oral use can also be presented as gelatin capsules' wherein the active ingredient is mixed with an inert solid diluent 'eg' calcium carbonate 'calcium phosphate or kaolin' or as soft gelatine capsules, wherein the Active ingredient is mixed with water or with an oily medium, for example. peanut oil paraf na liquid or olive oil. Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Said excipients are suspending agents »for example» sodium carboxymethylcellulose »methylcellulose» hydroxypropylmethylcellulose »sodium alginate» polyvinylpyrrolidone »gum tragacanth and acacia gum; dispersing agents or humectants »can be a phosphatide that occurs in nature» for example, lecithin. or products of the condensation of an alkylene oxide with fatty acids »for example» polyoxyethylene stearate »or the condensation products of ethylene oxide with long chain aliphatic alcohols» for example, heptadecaeti leno-oxyketanol. or the condensation products of ethylene oxide with partial esters. fatty acid derivatives and a hexitol. such as polyoxyethylene lensorbi tol monooleate, or the condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents »one or more flavoring agents» and one or more sweetening agents, such as sucrose, saccharin or aspartame. Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil; or in mineral oil, such as liquid paraffin. Oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those noted above, and flavoring agents can be added to give a palatable oral preparation. These compositions can be preserved by the addition of an anti or "idante" such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Other excipients may also be present, for example sweetening, flavoring and coloring agents. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be naturally occurring phosphatides, for example, soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides., for example, sorbitan monooleate, and the condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with sweetening agents »for example, glycerol. propylene glycol. sorbitol or sucrose. Said formulations may also contain a demulcent a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile, injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known technique, using the dispersing or wetting agents and the suitable suspending agents, which have been mentioned hereinabove. The sterile injectable preparation can also be a sterile, injectable solution or suspension, in a non-toxic, parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the vehicles and acceptable solvents, which can be used, are water, Ringer's solution and isotonic sodium chloride solution. Additionally, sterile, fixed oils, such as solvents or suspension media, are conventionally employed. For this purpose, any soft fixed oil may be used, which includes the synthetic mono- or diglycerides. Additionally, fatty acids. such as oleic acid »have use in the preparation of injectables. The compounds of formula I can also be administered in the form of a suppository for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is "solid at ordinary temperatures" but which is liquefied at the rectal temperature and therefore melts in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For this topic, creams are used, ointments, jellies, solutions or suspensions, etc., which contain the compound of formula I. (For the purposes of this application, topical application will include mouth rinses and gargles). The compounds for the present invention can be administered in intranasal form "by topical use of intranasal vehicles is suitable" or by "transdermal routes" using those forms of skin transdermal patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system. the administration of doses. Of course, it will be continuous instead of intermittent »throughout the dosing regimen. The compounds of the present invention can also be supplied as a suppository using bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. The dosage regimen using the compounds of the present invention is selected according to a variety of factors including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration, the renal and hepatic function of the patient »and the particular compound of the present to be employed. Anyone who is a doctor or veterinarian with ordinary experience can easily determine and prescribe the effective amount of the drug necessary to prevent. counter. stop or reverse the progress of the condition. The optimal precision to obtain the concentration of the drug within the scale that produces efficacy without toxicity, requires a regimen based on the kinetics of the availability of the drug for the sites to which it is destined. This involves a consideration of the distribution, equilibrium and elimination of a drug. Preferably, the doses of the compound of the structural formula I "useful in the method of the present invention" vary from 0.01 to 1,000 mg per adult human, per day. Very preferable »doses vary from 0.1 to 500 mg / day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01 to 1000 mg of the active ingredient, in particular 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0. 25.0 »50.0» 100 and 500 mg of active ingredient for the symptomatic adjustment of the dose to the patient to be treated. An effective amount of the drug is ordinarily provided at a dose level of about 0.0002 mg / kg to about 50 mg / kg of body weight per day. The scale is more particularly from 0.001 mg / Kg to 1 mg / Kg of body weight »per day. Advantageously »the active agent of the present invention can be administered in a single daily dose» or the total daily dose can be administered in divided doses of two »three or four times a day. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the patient being treated and the particular mode of administration. However, it will be understood that the specific dose level for any particular patient will depend on a variety of factors including age, body weight, avalanche in general, sex, diet, time of administration, route of administration, the rate of excretion, the combination of drugs and the severity of the particular disease that is undergoing therapy. The following examples illustrate the preparation of some of the compounds of the invention, and should not be taken as a limitation to the invention described herein.

EXAMPLE 1 C2- (3 > 5-DIMETHYLPHENYL) -3-C2 ~ (4-PYRIDIN-4-ILBUTILAMIN0) ETIL3 ~ lH-IND0L-5-IL3-M0RF0LIN-4-ILMETAN0NA P3SQ J I Ethyl 3- (2-am? Noeti 1) -2- (3? 5-dimethyl-1-phenyl) -1H-indo-1-5-carboxylic acid ethyl ester. A mixture of 7.60 g (50 mmol) of 4-hydroazinobenzoic acid, 10.55 g (50 mmol) of 3-chloropropyl 1-3, 5-dimethyl-lignin ketone and 200 ml of absolute ethanol was stirred under nitrogen and heated to reflux. . After 12 hours the mixture was cooled and filtered. The solid remaining in the filter was washed with small additional volumes of ethanol. The filtrate was treated with 4 ml of concentrated sulfuric acid and stirred at reflux under nitrogen for 4 days. The cooled mixture was stirred in an ice bath as a sodium ethoxide solution (21% w / w in ethanol). and it was added dropwise, until the mixture was basic by means of pH paper. The mixture was filtered and concentrated in vacuo at 30 ° C. The residue was partitioned between diethyl ether and water. A little saturated aqueous solution of sodium chloride was added to aid in the separation of the layers. The aqueous phase was washed with an additional 100 ml of ether. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residual gum was purified by flash chromatography on silica gel (elution with 97: 3: 0.3 and then with 95: 5: 0.5 of methylene chloride: methanol: ammonium hydroxide) to give 4.8 g of the title compound. NMR with AH at 400 MHz was consistent with the assigned structure. The mass spectrum (PB-NH ,, / CI): m / e = 337 (M + H).

Step IB: 2- (3 »5-d? Meti Ifeni 1) -3-C2-C4- (pyridin-4-i 1) bu ethyl ester lami o3-eti 13-lH-indo1-5-carboxylic acid To the dry flask was added 5.0 g (14.9 mmoles) of 3- (2-aminoeti 1) -2- (3,5-dimet Ifeni 1) -lH-indole-5-carboxylic acid ethyl ester. 1.98 g (13.5 mmol) of 4- (pyrid n-4-yl) b-tyraldehyde (diluted with 0.5 ml of CDC13 »8.12 g (67.7 mmoles) of anhydrous magnesium sulfate and a magnetic stirring bar. nitrogen, cooled to -10 ° C and agitated as 11.5 ml of dry CDC13 was gradually introduced by syringe, the mixture was stirred under nitrogen for about 20 minutes, then the septum was removed and 670 mg (17.6 mmol) was rapidly added. ) of sodium borohydride The septum was immediately replaced and the system was re-flushed with nitrogen The mixture was stirred under nitrogen at about -5 ° C as 10 ml of dry methanol was added gradually by syringe. After a few minutes at this temperature, the reaction was removed from the cooling bath and partitioned between 80 ml of ethyl acetate and 100 ml of water, the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The mediant residue was purified and flash chromatography on silica gel (elution with a gradient of 4-9% methanol in methylene chloride; was repeated using 5-15% methanol in methylene chloride) to give 3.19 g of the title compound. NMR with 500 MHz XH (CDCl ..,.) Was consistent with the assigned structure. Mass spectrum (PB-NH3 / CI): m / e = 470.4 (M + H). Another 1.91 g of less pure material was also isolated.

Payment I Ethyl ester of 3-C2-Cbencyloxycarbonyl 1-C4- (pyridin-4-yl) but? 1] ap > ino3eti13-2- (3,5-dimei1feni1) -lH-indo1-5-carboxylic acid.

A solution of 3.19 g (6.83 mmol) of 2- (3,5-dimethyl-l-phenyl) -3-C2-C4- (pyridin-4-y1) butylamino-3-yl 131H-ndol-5- ethyl ester was stirred under nitrogen. carboxy 1 in 25 ml of dry methylene chloride, and cooled to -78 ° C in a dry ice-acetone bath, as 2.38 ml (1.76 g, 13.7 mmoles) of N »N-di isoprop leni lam was added. na »followed by the gradual addition of 3.4 ml (4.06 g» 23.7 mmoles) of chlorine benzyl orbonate »by syringe» in portions. After about 2.5 hours the solution was removed from the ice bath and allowed to warm to room temperature. It was then partitioned between ethyl acetate and 5% aqueous solution of potassium bisulfate. The organic phase was dried over magnesium sulfate, it was filtered and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (elution with a gradient of 0.5-10% methanol in methylene chloride) produced a quantitative yield of the product, such as a yellow foam. The NMR with AH »at 500 MHz» was complex »due to the existence of rotamers» but was consistent with the assigned structure. Mass spectrum (PB-NH3 / CI >;: m / e = 604.3 (+ H).

Step ID 3-CZ-Cbenzyloxycarbonyl acid acid chloride 1-C4- (Pyrid n-4- l) but lam no3-eti13-2- < 3,5-dimethyl in l) -lH-indo-1-5-carboxyl co.

A solution of 4.11 g (6.83 mmol) of the ethyl ester of 3-2-t-benzyloxycarbonyl-C4- (pyridin-4-1) butylamino3eti 13- was stirred at about 60 ° C. 2- (3 »5-dimethyl-1-phen-1) -lH-indole-5-carboxylic acid in 161 ml (80.5 mmol) of 0.50 N KOH. as 19 ml of water was gradually added. Stirring was continued at reflux overnight. The cooled mixture was concentrated in vacuo to give a yellow solid, which was divided between 250 ml of an i: i mixture of ethyl acetate: tetrahydrofuran and 250 ml of 0.5 N HCl. The organic phase was washed twice with O.5N HCl. then it was dried over magnesium sulfate. it was filtered and concentrated in vacuo. The resulting solid was triturated with diethyl ether and collected on a filter to give (after drying) 3.46 g of a yellow solid, m.p. 133.5-137.5 ° C; homogeneous by TLC (95: 5: 0.5 of CH ^ la ^ eHO ^ cOH). The NMR with AH at 500 MHz (DMSO-dβ) was consistent with the assigned structure. Mass spectrum (ESI): m / e = 576.4 (M + H) *.

Step 1E Benzyl Ester of C2-CZ- (3 »5-diroet Ifeni 1) -5- (morfo1 in-4-carbonyl) -1H-i do1-3-i 13e i13- (4-pi i -4- i1buti 1) carbamic.

It was stirred under nitrogen at room temperature. in a capped flask. a mixture of 100 mg (0.163 mmol) of 3-C2-Cbencyloxycarbonyl-1C4- (pyridin-4-1) -buty1-amino-3-ethyl-1-2- (3 »5-di eti Ifeni 1) -lH- hydrochloride indole-5-carboxyl ico, 101.7 mg (0.196 mmol) of the PyBOP reagent »0.085 ml (85.2 mg, 0.978 mmol) of orpholine and 1 ml of dry methylene chloride. After 5 days the solution was partitioned between ethyl acetate and saturated aqueous solution of aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the crude product by flash chromatography on silica gel (gradient elution with 1-4% MeOH in CH2C12) yielded a quantitative yield of the title compound as a yellow gum; homogeneous by TLC in 95: 5 CH2Cl2-MeOH. The NMR with AH at 500 MH? (CDCl .. ,,) was complex due to the rotamers »but was consistent with the assigned structure. Mass spectrum (ESI): m / e = 645.6 (M + H).

Step IF C2- < 3 > 5-dimet? Lfen? 1) -3-C2- (4-Pyrid-4-ylbt? T? 1am) o) -eti-13-lH-indol-5-yl-3-norfolol-4-l-methanone A mixture of 113 mg (0.175 mmol) of the benzyl ester of C2-C2- (3 »5-dimeti-lfeni-1) -5- (morph in-4-carboni 1) was shaken with hydrogen (approximately 3.5 Kg / cm 2 gauge). ) -lH-indol-3- 1 -eti 13- (4-p ri i -4butyl) 1) carbamic, 50 mg of 20% palladium hydroxide on carbon and 10 ml of 2-ethoxyethanol, in a container Pressed for 2.5 hours. The catalyst was removed by filtration through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution from 99: 1: 0.1 to 94: 6: 0.6 of CH.-L. ^ MeO concentrated NH ^ OH), which yielded 53.2 mg (60%). ) of a rigid white »foam; homogeneous by TLC in 95: 5: 0.5 of concentrated CH2Cl3. The NMR with * H at 500 MHz (CDC13) was consistent with the assigned structure. Mass spectrum (ESI): m / e = 511.5 (M + H).

PREPARATION OF SYNTHESIS INTERMEDIARIES Step A 4- (-pyr di 1) -3-pentin-l-o1 5.5 g of the hydrochloride salt of 4-bromopyridine was dissolved in a mixture of solvents comprising 50 ml of triethyl lamine and 10 ml of water To the pyridine salt was added 100 mg of anhydrous lithium chloride, 100 mg of copper bromide powder (I) and 2.17 g of but-3-in-1-ol, and the mixture was stirred as it was passed through. A gaseous stream of active nitrogen was passed through the solution for about 15 minutes, after which 250 mg of tetrakis (triphenylphosph) palladium was added, the reaction mixture was heated to reflux under a nitrogen atmosphere and at reflux for 2.5 hours, after which the heating was stopped and the reaction was allowed to cool to room temperature.The mixture was concentrated in vacuo and the residue was treated with 3M sodium hydroxide, extracted with chloroform and concentrated to the The purification of the residue by rapid chromatography on silica gel e (ethyl acetate) gave 3.74 g of the title compound.

Step B 4- (4-pir d 1) -butan-l-ol 3.5 g of 4- (4-pyridyl) -3-butin-1-ol in 100 ml of methanol was dissolved in a Parr hydrogenation bottle and platinum (IV) oxide was added - Adams catalyst (0.3 g) 3. The Parr bottle was placed in a Parr hydrogenation apparatus and the solution was hydrogenated at 2.8 kg / cm * for 2.5 hours "and after that time it was judged by TLC that the starting material had been consumed. The spent catalyst was removed by filtration through a pad of Celite and the pad was carefully washed with more methane! The combined filtrates were evaporated under reduced pressure on a rotary evaporator and the oily residues were then subjected to column chromatography on a short column of silica using pure ethyl acetate as eluent to give 3.0 g of the title compound.

Step C 4- (pyr? Din-4-i1) butyraldehyde 1.45 ml of a 2M solution of oxalyl chloride in dry methylene chloride was placed. in an oven-dried flask and cooled to -78 ° C using a dry ice and acetone chill bath and a 0.413 ml solution was added dropwise.

DMSO in 1 ml of methylene chloride. to oxalyl chloride. for 3 minutes and stirred for another 3 minutes. A solution of 400 g of 4- (4-pyridyl-1) butan-1-ol in 5 ml of dry methylene chloride was added to the reaction flask for about 3 minutes, and the reaction was stirred for 15 minutes. 2.03 ml of anhydrous triethylamine was added and the reaction mixture was stirred for another 2 hours and during that time the cold bath had warmed to room temperature. The reaction is quenched by adding saturated brine and then dividing with methylene chloride. The aqueous layer was discarded and the methylene chloride extract was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to leave an oily residue. The product was isolated by column chromatography on silica gel »using 301 mg of ethyl acetate as eluent. Following a procedure similar to that described in example 1, the following compounds were prepared: EXAMPLE 2 DICLQRHYDRATE OF l- (7-AZABICICL0C2.2.13HEPT-7-IL) -2-C2- (3,5-DIMETHYLEN) -3-C2-C4- (4-PIRIDIN-3-IL) BUTILAMIN03ETIL31h-IND0L- 5-IL3- 2-METILPR0PAN-1-0NA Step 2A 2-C2- (3,5-dimet 1-ene-1) -3-CZ-C4- (Pyridin-3-y1) butylamino-3-yl-13-lH-indo-1-yl-2-methyl-ethyl acid ethyl ester nico A dry flask containing 3.00 g (7.903 mmoles) of the ethyl ester of 2-C3- (2-aminoet-1) -2- (3 »5-di eti I in 1) -lH_ ndol-5- 13- 2-methopropionic acid (prepared essentially as described in Example 1) from 2- (4-hydrazinofen) 2-meth Ipropionate »4.76 g (39.7 mmol) of anhydrous magnesium sulfate and a magnetic stirring bar» with a septum and a needle adapter that leads to a Firestone valve. The flask was thoroughly purged with nitrogen and the mixture was cooled in an ice-methane bath! at -10 to -5 ° C and stirred vigorously as a solution of 1.32 g (8.88 mmoles) of 4- (pyridin-3-yl) butyraldehyde in 15 ml of CDCl 3 was added via the syringe for 10 minutes. -15 minutes. The resulting mixture was stirred under nitrogen at -10 to -5 ° C for 40-45 minutes. Then the septum was removed just enough to add 390 mg (10.3 mmol) of sodium borohydride. The mixture was stirred under nitrogen at -10 to -5 ° C. 10 ml of dry methanol was added dropwise by the syringe for several minutes. After 30 minutes the mixture was separated from the cooling bath and partitioned between 90 ml of ethyl acetate and 90 ml of water. The organic layer was washed with 2 x 30 ml of brine, then dried over anhydrous sodium sulfate. The filtered solution was concentrated in vacuo and the residue was flash chromatographed on silica gel (gradient elution with 0-10% methanol in methylene chloride). The fractions containing the product and a small amount of unreacted starting material were combined and concentrated to give 3.00 g of a rigid »light beige» foam and used directly in the next step without further purification or characterization . Step 2B 2-C3-C2-Cbenzyloxycarbonyl ethyl ester-C4- <pyridin-3-y1) butyl 3-amino-3-ethyl-2- (3,5-dimet-1-phenyl) -lH-do-1-5- 1 -2-methyl-1-methylene. It was stirred under nitrogen »while cooling in a dry ice-acetone bath. a solution of 3.00 g (maximum 5.86 mmol) of the ethyl ester of 2-C2- (3 »5-dimet lfeni 1) -3-C2-C4C (pyridin-3-yl) butylamino3eti 1 -lH-ind? l-5-1 -2-methylpropionic in 30 ml of dry methylene chloride. It was added to that solution, by means of syringe. 1,106 ml (820 mg, 6.36 mmoles) of N »N-di isopropi leti lamina. Then 0.956 ml (1.14 g, 6.36 mmoles) of benzyl chloroformate was added dropwise by syringe for 5 to 10 minutes. After 20 minutes the solution was removed from the cooling bath and allowed to warm to room temperature. After 2 hours the solution was diluted with 50 ml of methylene chloride, transferred to a separatory funnel and shaken with 80 ml of water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography of the residual gum on silica gel (gradient elution with 0.2-2% methanol in methylene chloride) gave 2.81 g (55% overall for steps 1 and 2) of pale golden yellow gum »virtually homogeneous by TLC in 95: 5 of CH ^ Cljj-MeOH. The NMR with AH at 500 MHz was complex due to the rotamers »but appeared to be consistent with the assigned structure. Mass spectrum (ESI): m / e = 646 (M + H). Step 2C Acid 2-C3-C2-Cbenzyloxycarboni 1-C4- (pyridin-3-y1) buty 13 a m? N3 -et? 1-2 (3,5-dimet 1 in 1) -lH indol-5- 1 -2-met lproponic. A mixture of 2.78 g (4.30 mmol) of the ethyl ester of 2-C3-C2-C-benzyloxycarbonyl-C4- (pyridin-3-y1) buty-13-amino-3-di-13-2- (3 »5-dimethyl) was stirred under nitrogen. lfen 1) -lH-indol-5-yl 3-2-methylpropionic acid in 43.0 ml (21.5 mmol) of 0.5 M potassium hydroxide in methanol and 25 ml of tetrahydrofuran; and heated to reflux. 18 ml of water was gradually added to the resulting solution and the solution was refluxed for 39 hours. Then it cooled and concentrated to a small volume »accompanied by precipitation. The mixture was treated with 10.75 ml (21.5 mmol) of 2N hydrochloric acid and stirred for a few minutes. The solid was then collected on a filter and washed thoroughly with water. After drying by suction under nitrogen the solid was triturated and washed with diethyl ether and dried under vacuum to give 2.43 g (92% of a cream-colored powder »mp 152-154 ° C (with partial decomposition), homogeneous by TLC in 90: 10 of CH ^ Cl ^ - eDH NMR with 500 MHz AH (DMS0-dβ) was consistent with the assigned structure Mass Spectrum (ESI): m / e = 618 (M + H).

Step 2D Benzyl Ester of C2-C5-C2- (7azab? CycloC2.2.l3hept-7-yl) -l, l-dimethyl-2-oxoethyl3-2- (3> 5-dimeti lfeni 1) -lH acid indo1-3-l -et 1 -C4- (pyridin-3-yl) but-13-carbamic acid. A mixture of 92.7 mg (0.15 mmoles) of 2-C3-C2-C2-Cbenc-loxycarbon l-C4- (pyridine-3-y1) but 13- was stirred at room temperature in a stoppered flask for 48 hours. amino3eti 1 -2- (3,5-dimeti-lfen-1) -lH-indol-5-13-2-methylpropionic acid. 80.2 mg (0.6 mmol) of 7-azabicycloC2.2 hydrochloride. 13-heptane, 83.2 mg (0.16 mmol) of PyBOP reagent, 0.107 ml (77.8 mg, 0.77 mmol) of tri- 1 amine and 0.75 ml of dry methylene chloride. The solution was partitioned between 10 ml of ethyl acetate and 10 ml of 0.5N hydrochloric acid. The organic phase was washed with 10 ml of saturated aqueous sodium bicarbonate solution and then with 5 ml of saturated aqueous sodium chloride solution. . The ethyl acetate phase was dried (over magnesium sulfate), filtered and concentrated in vacuo at room temperature. The residue was purified by TLC on six Analtech tapered silica gel plates (20 x 20 cm). which were revealed in 95: 5 CH2Cl2-MeOH. The product band of each plate was isolated, combined and extracted with 95: 5 CHßCl2-MeOH. Concentration of the extracts in vacuo produced 85.9 g (82%) of a very pale yellow glass, virtually homogeneous by TLC. in 95: 5 of CH ^ Cl ^ -MeOp, NMR with 500 MHz XH (CDC13) was complex due to the rotamers. but it was consistent with the assigned structure.

Mass spectrum (ESI): m / e = 697.6 (M + H). Step 2E- (7-azabicycloC2.2.13hePt-7-i1) -2-C2f (3.5-dimeti-lfen-1) -3-C2-C4- (pyr? Di -3-yl) butylamino3et 13-lH-indole 5-i 13-2-methyl Ipropan-1-one. A mixture of 80.2 mg (0.115 mmoles) of the benzyl ester of C2-C5-C2- (7-azabicycloC2.2.13hept-7-i1) -l-l-dimeti 1 was shaken with hydrogen (3.23 Kg / cm2). -2-oxoet 13-2- (3,5-dimeti Ifeni 1) -lH- nd? L-3-i 13-ethi 13-C4- (pyridin-3-yl) butyl 13-carbamic acid, 40 mg palladium al 10% on coal. 4 ml of absolute ethanol and 4 ml of ethyl acetate, for six hours, in a pressure vessel. The catalyst was filtered through Celt under nitrogen and the filtrate was concentrated in vacuo at room temperature. The residue was purified by preparative TLC on 4 Analtech tapered silica gel plates (20 x 20 cm). which were revealed in 92.5: 7.5: 0.75 of CHS? ClS? -Me0H-NH ^ 0H concentrated. The product band of each plate was isolated, combined and extracted with 92.5: 7.5: 0.75 of concentrated CHa.Cl-2-MeOH-H ^OH. Concentration of the extracts in vacuo yielded 43.8 mg (81%) of a rigid gum or pale yellow glass, esenc to the homogeneous entity by TLC in 92.5: 7.5: 0.75 of concentrated CH2Cl2-MeOH-NH OH. The NMR with 500 MHz XH (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m / e = 563.5 (M + H).

Step f l- < D-hydrochloride 7-azabicycloC2.2.13hePt-7-i 1) -2C2- < 3,5-dimethylphenyl) -3-C2-C4- (Pyridin-3-yl) but lamino3e and 13-lH-indol-5-yl-2-methylpropan-1-one. A solution of 42.8 g (0.0760 mmoles) of l- (7-azabicycloC.2.13hept-7-yl) -2-C2- (3,5-dimet lfen 1) -3-C2-C- (pi) was treated. idin-3-i 1) but 1 amino3eti 1-lH-ndol-5-1 -2-methypropan-1-one in 1.5 ml of methanol with 0.152 ml (0.304 mmol) of 2N hydrochloric acid. and allowed to stand briefly before filtering, the filtrate was evaporated to dryness under nitrogen, and the residue was triturated with diethyl ether, the resulting solid was collected on a filter, washed with more ether and dried to give 46.5 mg ( 96%) of light golden cinnamon powder, pf greater than 160 ° C (gradual. "Preliminary softening) The NMR with 500 MHz XH (DMSO-d ^) was consistent with the assigned structure.

PREPARATION OF SYNTHESIS INTERMEDIARIES Step A (±) -2- < 4-ni ro eni 1) ethyl propionate To a solution of 9.76 g (50 mol) of (±) -2- (4-nitropheni 1) propionic acid in 150 ml of absolute ethanol, 3.0 ml of concentrated sulfuric acid was added. . The resulting solution was stirred at reflux, under nitrogen. After 6 hours the solution was cooled and stirred vigorously as 250 ml of saturated aqueous sodium bicarbonate solution was gradually added (caution: foam). The mixture was then divided between 750 ml of ethyl acetate and 500 ml of water. The organic layer was washed with 100 ml of saturated aqueous sodium bicarbonate solution and then with 100 ml of saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give 10.86 g (97%) of an oil.; homogeneous by TLC in 9: 1 hexane-ethyl acetate. The NMR with 400 MHz H-CDC13 was consistent with the assigned structure Step B 2-met-1-2- (4-n-1-n-1) ethyl proponate A suspension of 924 was stirred under nitrogen. my (23 m moles) of sodium hydride (60% in oil) in 21 ml of dry N »N-dimet Iformamide» in an ice bath »as a solution of 4.6B g (21 mmol) of ( ±) -2- (4-nitrophenol 1) ethyl proponate in 20.5 ml of dry Ntti-dimeti ormamide, for about 10 minutes.An intense violet color was developed during the addition. room temperature After about an hour, the mixture was cooled again in an ice bath as a solution of 1.44 ml (3.28 g, 23 mmoles) of methyl iodide was added dropwise by means of a syringe. in 5 ml of dry NN-dimethylformamide for about 10 minutes while maintaining the internal temperature at 10-15 ° C. The mixture was allowed to warm to room temperature and the color changed to coffee, after another hour another 1B7 ml (426 mg. 3 mmole) of iodomethane. The next day the mixture consisted of a suspension of some grayish solid in a golden liquid. It was vigorously stirred and quenched by the gradual addition of 10 ml of a 5% aqueous solution of potassium bisulfate. The mixture was divided between 400 ml of diethyl ether and 400 ml of water. The organic layer was washed with another 3 x 400 ml of water and then with 50 ml of saturated aqueous sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography of the residue on silica gel (elution with 19: 1 hexane-ethyl acetate) yielded 4.31 g (87%) of an oil; homogeneous by TLC in 9: 1 hexane-ethyl acetate. The NMR with 400 MHz AH (CDC13) was consistent with the assigned structure. Step C 2- (4-aminopheni 1) -2-methyl ethylpropionate A mixture of 4.27 g (18 mmoles) of 2-methyl-2- (shaken with hydrogen (initial pressure of 3.30 kg / cm 2 gauge) was shaken. 4-ni trofeni 1) ethyl propionate. 200 mg of 10% palladium on carbon and 120 ml of absolute ethanol, in a pressure vessel, for two hours. The catalyst was removed by filtration through celite. under nitrogen and the filter cake was washed with more ethanol. Concentration of the filtrate in vacuo to 50 ° C gave 3.74 g (100% of an oil) homogeneous by TLC in 4: 1 hexane: EtOAc NMR with 400 MHz AH (CDC13) was consistent with the assigned structure. Mass Spectrum (ESI): m / e = 208 (M + H) Step D 2- (4-h? Raz or enyl) -2-methyl ethylpropionate Stirred at -10 to -5 ° C, an ice-acetone bath, a solution of 3,725 g (18 mmol) of ethyl 2- (4-aminophenyl) -2-methylpropionate in 18 ml of concentrated hydrochloric acid, as added dropwise, for about 15 minutes a solution of 1.29 g (18.7 mmoles) of sodium nitrite in 7.5 ml of water was stirred at that temperature for another 30 minutes, then a small amount of insoluble solid was filtered off into a cold receiving flask. The filtrate was added dropwise over 10-15 minutes to a solution of 20.3 g (90 mmol) of dihydrate of stannous chloride in 14.6 ml of concentrated hydrochloric acid, under nitrous. geno »in an ice-acetone bath. The addition was carried out at such a rate that the internal temperature remained at about -5 ° C. A gummy material was separated during the addition. After the addition was complete, stirring was continued at -10 to -5 ° C for one hour. The aqueous phase was decanted and the residual gum dissolved in 250 ml of ethyl acetate. The ethyl acetate solution was treated cautiously with 250 ml of saturated aqueous sodium bicarbonate solution in a separating funnel. The ethyl acetate layer was washed with 50 ml of saturated aqueous sodium chloride solution. The whole mixture was filtered before the separation of the phases. The ethyl acetate phase was dried over magnesium sulfate, filtered and concentrated in vacuo at room temperature to yield 2.59 g (65%) of an oil. NMR conAH at 500 MHz (CDCl ..,) was consistent with the assigned structure, and indicated that only minor impurities were present. Following a procedure similar to that described in example 2, the following compounds were prepared: EXAMPLE 3.1 -C2- (3,5-PIMETHYLPHENYL) -3-C2-C4- (PIRIDIN-3-IL) BUTILAMIN03-ETHYL-1H-IND0L-5-IL3-2-ETHYL-4, -DIMETHYL-2.4-DIHYDROPYRAZ0L- 3-0NA Step 3.1A 2-et 1-4.4-dimethyl-5- (4-n trofen l) -2.4-? H? DroPirazol-3-one A mixture of 1.00 g was stirred under nitrogen at moderate reflux for 24 hours. (4 mmoles) of the methyl ester of 2,2-dimeti 1-3- (4-nitrophen-1) -3-oxopropyonic acid (Yang »C.-Y, WneK, GE Polymer, 1992, 33, 4191-4196 ), 3.00 g (20 mmoles) of oxalate of Ihydrazine, 8 ml of 2-methoethanol and 4 ml of glacial acetic acid. The cold solution was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. Ethyl acetate was washed with additional water and then with saturated aqueous sodium chloride solution. The organic solution was dried over magnesium sulfate, filtered and concentrated in vacuo to give 703 mg (67%) of pale yellow crystals, m.p. 121-122 ° C; homogeneous by TLC in 2: 1 hexane-EtOAc. The NMR with * H at 500 MHz (CDC13) was consistent with the assigned structure. Mass spectrum (PB-NH3 / CI): m / e = 232.1 (M-Et), 265.1 (M + H). Step 3. IB 5- (4-am or enyl) -2-eti l-4.4-dimet 1-2.4-d? H? 'Drop? Razo1-3-one. Hydrogenation of 2-ethi 1-4,4-di et 1-5- (4-nitropheni-1) -2,4-dihydropyl-3-one, according to the procedure of Example 3.2, step E »Produced a quantitative yield of solid light yellow-cinnamon» pf 118-120.5 ° C; homogeneous by TLC in i: i of hexane-EtOAc and 9B: 2 of CHZC12-MeOH. The NMR with 500 MHz XH (CDCl ..,) was consistent with the assigned structure. Mass spectrum (ESI): m / e = 232.1 (M + H).

Step 3.1C 2-et l-5- (4-hydrazinophenyl) -4,4-dimeti 1-2,4-d h drop razol-3-one. This material was prepared from 5- (4-a-inofeni-1) -2-eti-1-4,4-dimethyl-l-2 »4-dihydropyrazol-3-one according to the procedure of Example 2» REACTION INTERMEDIARIES . Step D »except that the entire reaction mixture from the reduction with stannous chloride» was stirred in an ice bath and treated cautiously with excess saturated sodium carbonate solution (CAUTION: produces foam) which resulted in the precipitation. This material was transferred to a separatory funnel and shaken with 2: 1 Etβ-CHßCl 2. The mixture was filtered before phase separation. The aqueous phase was extracted further with several portions of ethyl acetate. The combined organic fractions were concentrated in vacuo to give an 80% yield of an amorphous light yellow-orange solid »m.p. 131.5-135 ° C »with decomposition; poorly defined by TLC in 95: 5 NMR with * H at 500 MHz (CDC13) was consistent with the assigned structure. Step 3.ID 5- 3- (2-am? Noet 1) -2- (3,5- et lfeni 1) -lH-i dol-5-i 13-2-et 1-4.4-d me 1- 2.4-dih dropirazol-3-one This compound was prepared from 2-ethi 1-5- (4-idrazinophenyl) -4,4-di eti-2'-4-dihydropyrazol 3-one and 3-chloropropi 1-3.5 -dimeti 1 phen ketone "according to the procedure of example 3.2, step A" except that the reaction time was 15 hours. Rapid chromatography of the crude product on silica gel (elution with gradient, with 97: 3 and 95: 5 of CHßCl2-MeOH) followed by 95: 5: 0.5 and 92.5: 7.5: 0.75 of CHaCl3-MeOH-NH "OH concentrate ) gave a 27% yield of a rigid homogeneous light brown foam by TLC in 92.5: 7.5: 0.75 of concentrated CHiZClat-MeOH-NH..OH. The NMR with • »+! at 500 MHz (CDCl3) was consistent with the assigned structure. Mass spectrum (PB_NH3 / CI): m / e = 403.2 (M + H). Step 3.1E 5-C2- (3.5-dimet lfeni 1) -3-C2-C4- (Pyrid? N-3-y1) buty1am or 3et 1-lH-indo1-5-il3-2-et? L- 4.4-d? Met? 1-2.4-d? H? Dropirazo1-3-one A mixture of 82.5 mg (0.205 mmoles) of 5-C3- (2-aminoeti 1) -2- (3 »5) was purged with nitrogen. -dimeti 1-phenyl) -lH-i dol-5-i 13-2-ethyl-4 »4-dimet l-2» 4-dihydropyrol-3-one and 124 mg (0.475 mmol) of magnesium sulfate »and stirred in an ice-methanol bath at about -10 to -5 ° C »as a solution of 34.3 mg (0.23 mmoles) of 4- (pyridin-4-yl) butyraldehyde in 0.500 was gradually added» by syringe » my CDCl .., dry. The mixture was stirred under nitrogen at that temperature for 30 minutes. The septum was removed sufficiently to add 10.0 mg (0.265 mmoles) of sodium borohydride and the solution was re-purged with nitrogen. The mixture was stirred at -10 to -5 ° C during the gradual addition of 350 ml of dry methanol, and stirring was continued at that temperature. After 45 minutes the mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine. it was then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC on six GF silica gel plates of 1000 micras (revealed in 87.5: 12.5 to CHaCl2-Me0H). Isolation of the product band (by extraction with 90: 10: 1 of CH ^ Cl -, - concentrated MeOH-NH ^ OH) gave 49.8 mg (45%) of a rigid, light beige, essentially homogeneous foam before TLC in 90:10 of CH2Cl2-MeOH. The NMR with - "- H at 500 MHz (CDC13) was consistent with the assigned structure: Mass spectrum (ESI): m / e = 536.4 (M + H).

EXAMPLE 3.2 l-f2- (3.5-PIMETYLPHENYL-3-C2- (4-PYRIDIN-3-IL-BUYLAMIN0) ETIL3-lh-IND0L-5-IL1-4-METHYL-1.4-DIHYDROTETRAZ0L-5-0NA Step 3.2A 2-C2- (3> 5-d? Methylphenyl) -5-nitro-lH-indol-3-i1 eti1ami a To a solution of 3-chloropropi 1-3,5-dimeti lfeni leetone (2.5 g in 13.5 ml of terbutanol) was added 1.65 g of 4-n-trofem'lhydrazine and stirred for 20 minutes at room temperature. At that time 10B ml of 90% aqueous methanol was added and the mixture was heated to reflux in an oil bath. After 16 hours the mixture was cooled to room temperature and removed in vacuo or volatiles. The residue was triturated with ethyl acetate and allowed to stand at 0 ° C for 8 hours. Filtration of the resulting suspension gave the crude title compound, such as the hydrochloride salt (1.4 g). Step 3.2 B N-f2-C2- (3.5-d? Methy1fem'l) -5-n? Tro-lH-indo1-3-i1 -met? -benzamide. To a solution of 2-C2- (3.5-dimeti Ifen 1) -5-ni tro-lH-indole-3-yl 3-ylmelate (3.0 g in 80 ml of dry methylene chloride) at 0 ° C, added 4.0 ml of triethylamine, followed by 1.5 ml of benzoyl chloride, and the mixture was stirred at room temperature. After 20 minutes the reaction was quenched by adding saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with water and concentrated in vacuo to give 1.43 g of crude title product. Pqgp 3,? C Benc l-f2-C2- (3.5-diraet lfeni 1) -5-n? ro-lH-ndol-3-i 1 -eti 11-ami a To a stirred solution of N- £ 2-C3.5-dimeti lfen 1) -5-ni tro-lH-indol-3-yl 3 -eti l} benzamide (1.7 g in 130 ml of dry tetrahydrofuran) was added 35 ml of a 1M solution of borane in tetrahydrofuran and the mixture was heated slowly to reflux in an oil bath. After 2 hours the mixture was cooled to room temperature and the excess borane was quenched by the careful addition of methanol. The mixture was concentrated to half the volume, treated with 13 ml of N.N-dimethylethanolamine and heated to reflux in an oil bath. After three hours the mixture was cooled to room temperature and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride: methanol, 97: 3) gave 1.5 g of the title compound. Pa, sp 3.2P Benz l-f2-C2- (3.5-dimeti lfeni 1) -5-n tro-lH-? dol-3-i 1 eti 11- (4-pir? d? -3- 1.-bu i 1) ami a. A mixture of 700 mg of benzyl-C2-C2- (3 »5-dimeti Ifeni 1) -5-ni tro-lH-i ndol-3- 13eti 1) amine and 314 mg of 4-pi Ridinol was solvated. 3-i-butyraldehyde in 30 ml of dry methanol to which 2 g of powdered molecular sieves of 3A had been added. The pH of this mixture was adjusted to 5 by the addition of trifluoroacetic acid and then 441 mg of sodium cyanoborohydride was added and the mixture was stirred at room temperature. After 48 hours the mixture was filtered through diatomaceous earth. it was concentrated in vacuo and purified by flash chromatography on silica gel (methyl chloride: methanol: ammonium hydroxide, 96: 4: 0 »then 96: 4: 1) to give 676 mg of the title compound.

Step 3.2E 3-f2-Cbenc 1- (4-pyr-di-3-1-buty1) amino3eti 1 l-2- (3t5-dimet 1-phen 1) -lH-indo1-5-i lam na A stirred solution of benz l-C2-C2- (3 »5-dimet 1-pheny1) -5-ni tro-lH-ndol-3-i 13-eti 1} - (4-pridin-3-y1-butyl) amine (360 mg in 30 ml of absolute ethanol) was added approximately 30 mg of Raney4 R > . The reaction flask was fitted with a hydrogen tank, evacuated and re-charged with hydrogen (3 times) and stirred at room temperature. After 3 hours the reaction was flushed with nitrogen, filtered through diatomaceous earth and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride: methanol: ammonium hydroxide: 96: 4: 1) gave 246 mg of the title compound. Step 3.2F Benzyl-f2-C2- (3,5-dimethyl-1-phenyl) -5-isocyanato-lH-indol-3-yl-3-yl- (4-pyridin-3-yl-butyl-1) amine A solution of 3-C2-Cbenzyl- (4-pyridin-3-yl-butyl) -amino et l} -2- (3 »5-dimet lfeni 1) -! H-indol-5-i-lamine (120 mg in 8 ml of dry methylene chloride) at 0 ° C» 26.6 mg of triphosgene was added »followed by 0.050 ml of pyridine and the mixture was stirred at room temperature. After 50 minutes the mixture was concentrated in vacuo to give 120 mg of the crude title compound.

Step 3.gG l-C3-f2-Cbenc l- (4-pyridin-3-y1-buty1) -araino3etiT > -2- (3,5-Diroetilfeni 1) -lH-indole-5-yl -1,4-dihydrotetrazo1-5-one To a solution of the freshly prepared aluminum azide (0.6 mmoles in 6 ml of dry tetrahydrofuran) was added 120 mg of benz l-C2-C2- (3,5-dimet lfeni 1) -5-isocyanato-lH-indol-3-i 13-eti 1} - (4-pyridyl-3-yl-1-butyl) amine and the mixture was refluxed in an oil bath. After 20 hours the mixture was cooled to room temperature, concentrated, poured into a mixture of 1M sodium potassium tartrate and on ice, stirred vigorously for 40 minutes and then partitioned between ethyl acetate and water. The organic portion was washed successively with 1M sodium and potassium tartrate with water and with brine and then dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride: methanol 1. 88:12) gave 58 mg of the title compound. Step 3.2H l-C3-f2-Cbenc? 1- (4-Pyrid? N -3? 1 -but? L) am? No3et? 1- > -2- (3.5-dimet 1 enyl) -lH-dol-5-i 13-4-methi 1-1.4-dih? Drotetrazo-1-5-one. To a solution of 1-C3- £ 2-1-.benzyl- (4-pyridin-3-yl-butyl) -aminoethyl} -2- (3,5-di eti 1-phenyl) -lH-indol-5-i 13-1.4-dihydrotetrazol-5-one (25 mg in 1.5 ml of dry N, N-dimethylformamide) at 0 ° C, added 13 mg of potassium carbonate, followed by 0.033 ml of a 10% solution of iodomethane in methylene chloride. and the mixture was stirred at low temperature. After 2 hours the reaction was quenched by the addition of saturated aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic portion was washed successively with water and with brine, dried over sodium sulfate and concentrated in vacuo. Purification of the concentrate by flash chromatography on silica gel (methylene chloride: methanol: 95: 5) gave 20 mg of the title compound. Step 3.2 l-f2- (3 »5-dimethylphenyl) -3-C2- (4-pyrid n-3-y1-butylamino) eti 1-lH-indol-5-y1 '> -4-me i1-l > 4-dihi rotetrazo1-5-one To a stirred solution of l-C3-. { 2-Cbenci l- (4-p ridin-3-i 1 -buti 1) amino eti l} -2- (3 »5-di eti lfeni 1) -lH-indol-5- 13-4-methyll» 4-dihydrotetrazol-5-one (20 mg in 4 ml of methanol) »15 mg of catalyst was added of 10% palladium hydroxide on carbon, followed by acetic acid (0.020 ml of a 30% solution in water). The reaction flask was equipped with a hydrogen tank, evacuated and re-charged with hydrogen (3 times) and stirred at room temperature. After 30 minutes the reaction was flushed with nitrogen, filtered through diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (methylene chloride: methanol: ammonium hydroxide: 90: 6.5: 1) gave 16 mg of the title compound, m / e = 496 (M + H).

PREPARATION OF SYNTHESIS INTERMEDIARIES Step A 4-chloro-N-methoxy-N-methyl-1-bumeramide To a solution of 4-chlorobutyl chloride (10.0 g in 200 ml of methylene chloride) was added 10.5 g of N-O-dimethyl hydrochloride. 1 hydro 1 amine. The mixture was stirred under nitrogen and kept below 25 ° C by cooling in an ice bath »as necessary, while 29.1 ml of triethylamine was added dropwise, for about 20 minutes, which resulted in a precipitation . After 1.5 hours at room temperature, the mixture was concentrated in vacuo. The residue was partitioned between 100 ml of diethyl ether and 100 ml of saturated aqueous sodium bicarbonate solution. The organic layer was washed with another 100 ml of saturated sodium bicarbonate and the aqueous fractions were re-extracted with ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 10.5 g (90%) of an oil having a satisfactory purity by NMR with AH (CDC13). Mass spectrum (PB-NH3 / CI): m / e = 166 (M + H). Step B 3-chloropropyl 1-3,5-dimethyl enyl ketone. It was stirred under nitrogen at -78 ° C. a solution of 10.2 ml (13.9 g, 72 mmoles) of 5-bromo-m-i-ene in 200 ml of anhydrous tetrahydrofuran was added as 35.8 ml (85 mmoles) of n-butyllithium 2.5 M »in tetrahydrofuran was added dropwise. .

After 15 minutes at -7 B ° C, a solution of 10.0 g (60 mmoles) of 4-chloro-N-methoxy-N-methyl-1-butyramide in 30 ml of anhydrous tetrahydro-urane was added dropwise over 25-30 minutes. minutes The resulting solution was kept at -78 ° C for 45 minutes, and then briefly warmed to room temperature. The reaction was quenched by the addition of 40 ml of 2N hydrochloric acid. and then it was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution. The organic solution was dried over sodium sulfate, filtered and concentrated in vacuo. Rapid chromatography of the residue yielded 8.91 g (70%) of an oil, which had satisfactory purity by NMR with XH (CDCl ..,).

EXAMPLE 3.3 f2-C5-C2-BUTILPENTAZ0L-1-IL) -2- (3.5-DIMETHYLENHYL) -lh-IND0L-3- IL3ETIL1-C4-PYRIDIN-3-IL-BUTIL) AMIN Pasp 3? 3A Ester terbut l co of benz acid 1-f2-C2- (3 »5-di et lfeni 1) -5-nitro-lH-indol-3-i 1 -et? 11-carbamic To a solution of benzyl-2-C2- (3.5-dimet ifeni 1) -5-ni tro-lH-dol-3- 1 et 1} -am Na (example 3.2 »step C, 450 mg in 10 ml of tetrahydrofuran and 3 ml of water) at 0 ° C was added a solution of 491 mg of diterbutyl dicarbonate. followed by 236 mg of potassium carbonate and the resulting suspension was stirred vigorously at 0 ° C. After 50 minutes the reaction was quenched by the addition of saturated aqueous ammonium chloride in excess and the mixture was extracted with ethyl acetate. The organic portion was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane: ethyl acetate »3: 1) to give 530 mg of the title compound. Step 3.3B Terbutyl ester of f2-C5-ami or-2- (3,5-Dimeti Ifeni 1) -lH-indole-3-yl-1-benzylcarbamate acid ester. It was prepared essentially as described in example 3.2E »starting from 530 mg of the terbutyl ester of benzyl acid. {; 2-C2- (3.5-di eti lfem'1) -5-ni tro-lH-ndol-3-i 13-eti 1} carbohydrate "to give 387 mg of the title compound. Step 3.3C Terbutilic ester of benz acid 1-f2-C2- (3,5-dimeti1 eni1) -5-pentanoi-1ami o-lH-indo1-3-i 13-eti 11-carbamide. To a solution of the terbutyl ester of C2-C5-amino-2- (3 »5-dimet? Ifen 1) -lH_ ndol-3-i 13eti 1.}. Carbamic benzyl (200 mg in 10 ml of dry-loam chloride) at 0 ° C was added 0.18 ml of triet sheet, followed by the dropwise addition of 0.06 ml of chloride and the mixture was stirred at After 17 minutes the reaction was quenched by the addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate.The organic portion was washed successively with saturated sodium bicarbonate and with saturated ammonium chloride, then dried over Sodium sulfate The purification of the concentrate by flash chromatography on silica gel (hexane: ethyl acetate »3: 2) gave 230 mg of the title compound.

Step 3.3D Terbutyl ester of benzyl 1-f-C5- (2-but lpentazol-1-yl) -2- (3,5-dimethylphen-1) -lH-indol-3-yl-ethyl-n-carbamic acid. To a solution of the terbutyl ester of benzyl l-2-C- (3 »5-d eti I eni 1) -5-pentanoi lamyl o-lH-dol-3- 1} -eti 1 } Carbamic (BO mg in 3 ml dry methylene chloride) was added, in this order. 76.6 mg triphenylphosphine. 21 mg of imidazole. 72 mg of zinc azide (complex with pyridine) and 0.048 ml of diethyl azodicarboxylate were added and the mixture was stirred at room temperature. After 15 hours an additional portion of zi c_2-pyridine azide (29 mg) was added. After a further reaction time of 1 hour, the vessel was cooled to room temperature and the reaction mixture was applied directly to a column of silica gel for purification by flash chromatography (hexane: methylene chloride: ethyl acetate »3: 4: i, then 2: 0: 1) to give 57 mg of the title compound. Pasp 3-3E Benzy1-r2-C5- (2-butylpentazol-1-l) -2- (3,5-dimethyl eni 1) -lH-indol-3-yl 3-et Tí-ami a To a solution of the terbutyl ester of benzyl-C2-C5- (2-butylpentazol-l-yl) -2- (3,5-dimeti lfen 1) -lH-indol-3-i 13- eti l} Carbamic acid (57 mg in 3.5 ml of methylene chloride) at 0 ° C was added 0.12 ml of anisole followed by 0.80 ml of trifluoroacetic acid and the mixture was stirred at 0 ° C. After 1.5 hours the mixture was concentrated in vacuo and the residual acid was removed by azeotroping with toluene to give the crude title compound in quantitative yield. Pagp 3.3F Benc 1-f2-C5- (2-butylpentazo1-l-i1) -2- (3,5-dimeti l eni 1) -lH-i dol-3-yl 3et? ~ N- (4-pyridi -3) -? 1-buti 1) amine. It was prepared essentially as described in Example 3.2D from 58 mg of benzyl-C2-C5- (2-butylpentazol-1-l) -2- (3 »5-dimet lfeni 1) -lH- ndol -3- 13ethyl} -amine to give 43 mg of the title compound. Step 3.36 f2-C5- (2-butylPentazo1-l-i1) -2- (3.5-dimeti-lfeni-1) -! H -indole-3-1-eti1 ^ - (4-pyr-3-y1-buty1) amine . It was prepared essentially as described in Example 3.21 »from benzyl-C2-C5- (2-butylpentazol-1-y1) -2- (3» 5-dimet Ifeni 1) -lH-ndol-3 - 13eti 1} - (4-pi rid n-3-yl-butyl) -amine (43 mg) to give 34 mg of the title compound, m / e = 522 (M + H).

EXAMPLE 3.4 f2-C2- (3.5-DIMETHYLPHENYL) -5- (5-IS0BUTIL-C1.2.430XADIAZ0L-3-IL) - lh-IND0L-3-IL3ETIL - < 4-PYRIDIN-3-IL-BUTIL) AMINE Step 3.4A Terbutilus ester of f2-C5-cyano-2- (3.5-d? Eti Ifeni 1) -lH-i do1-3-i1 ethynocarbamic ester Prepared essentially as described in Example 3.3A. from 3- (2-aminoeti 1) -2- (3.5-dimet lfen 1) -1H. ndol-5-carbon tri lo (prepared essentially as described in Example 3.2 »step A)» to give 300 mg of the title compound. Step 3.4B Terbutilic ester of f2-C2- acid < 3.5-dimet I eni 1) -5- (N-droxycarbamimidoi 1) -lH-indol-3-yl 13eti-13-carbamic acid. A solution of 300 mg of the C2-C5-cyano-2- (3 »5-dimeti Ifeni 1) -lH-indol-3- 13eti 1 terbutyl ester was added} -carbamic acid in 5 ml of ethanol, to a suspension of 725 mg of potassium carbonate and 273 mg of hydroxamine hydrochloride in 7 ml of ethanol, and the total was heated to reflux in an oil bath. After 21 hours the mixture was cooled to room temperature and filtered to remove the solids. The filtrate was concentrated in vacuo, then partitioned between ethyl acetate and water. The organic portion was washed with water, dried over sodium sulfate and the concentrate was purified by flash chromatography on silica gel (methyl chloride or: methanol, 92.8) to give 105 mg of the title compound. Step 3.4C Terbutilic ester of fZ-C2- (3.5-Dimeti Ifen 1) -5- (5-isobuty 1-C1.2.43 oxadiazo1-3-i1) -lH-indo1-3-i 13eti1 -carbamic acid ester. To a stirred solution of 0.025 ml of isovaleric acid in 4 ml of methylene chloride »was added 37.8 mg of l-hydroxybenzotriazole and 43.6 mg of l- (3-dimeti inopropy 1) -3-et? 1 carbodi mide "and the reagents were allowed to mix for 30 minutes. At that time, a solution of 81 mg of the terbutyl ester of C2-E2- (3 »5-dimeti Ifeni 1) _5- (-hydroxycarba imidoi 1) -lH-do1-3-yl 3eti 1 was added} Calcium chloride in 3 ml of methylene chloride was added and the reaction was stirred at room temperature. After 2 hours the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride: methanol: 96: 4) to give 81 mg of the title compound. 2-C2- (3.5-d? 'Methy1phenyl) -5- (5-isobut l-C1.2.43 oxadiazol-3-i1) -lH-i ndol-3-i 1 t-ethyl-1-amine It was prepared essentially as described in Example 3.3E »from 67 mg of the f-2-C2- (3» 5-dimethyl-l-pheny1) -5- (5-isobutyl-C1.2.43-oxadiazol-3-y1) terbutyl ester - lH-indol-3-i 13et 1} carbohydrate "to give 48 mg of the title compound. Step 3.4E f2-C2- (3.5-dimet? 1fen? L) -5- (5- sobuti1-C1.2,43 oxadiazo1-3-i 1) -1H indo1-3-i1 eti1V- (4-pir? ' din-3-i1-but? 1.amine To a solution of 22 mg of 2-C2- (3 »5-dimethylphenyl) -5- (5-isobutyl 1 C1.2.43 oxadiazol-3-yl) -lH -i ndol-3-i 13eti was laminated in 1.5 ml of chloroform »at 0 ° C» 38 mg of anhydrous magnesium sulfate was added, followed by 11 mg of 4- (3-pyridyl) butanal and the mixture was stirred at At room temperature, 3.7 mg of sodium borohydride in 0.50 ml of methane was added and the mixture was stirred at 0 [deg.] C. After 30 minutes, the reaction was quenched by the addition of water and The mixture was extracted with ethyl acetate, the organic portion was washed successively with saturated potassium carbonate and with brine, then dried over sodium sulfate, purification of the concentrate by flash chromatography on silica gel (methylene chloride: methanol). 92: 8) gave 26.5 mg of the title compound, m / e = 522 (M + H).

E ^ PLO 3.5 (2-f2- (3,5-DIMETHYLPHENYL) -5-Cl-METHYL-l- (4-METHYL-lH-IMIDAZO-2-I) -ETIL 3-lh-IND0L-3-IL1-ETI) - < 4-PIRIDIN-4-IL-BUTIL) -AMINE Ethyl ester of 2-C3- < 2-terbutoxicarboni lami oeti 1) -2- (3,5-dime111fen 1) -1H-indo-1-5-i-1-methyl-1-ppr-ionic It was prepared essentially as described in Example 3.3A, from 1.13 g of the 2- C3- (2-aminoeti 1) -2- (3,5-dimeti lfeni 1) -lH- ndol-5- ethyl ester 13-2-methy1-propionic (example 2) »to give 1.28 g of the title compound. Step 3.5B Acid 2-C3- (2-terbutox carboni lam o-eti 1) -2- (3 »5-d? Meti Ifeni 1) -1H-i dol-5-yl-2-methopropionic acid. To a stirred solution of 1.28 g of the ethyl ester of 2-C3- (2-terbuto-icarboni la inoeti 1) -2- (3 »5-dimeti-1-pheny1) -lH-indole-5-13-2- Ipropionic met. in 25 ml of ethanol, 30 ml of 0.5N sodium hydroxide was added and the mixture was heated to 90 ° C in an oil bath. After 30 hours the mixture was concentrated in vacuo, diluted with water and extracted 3 times with diethyl ether. The aqueous layer was then made acidic by the addition of 0.5N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and with brine, dried over sodium sulfate and concentrated in vacuo to give 1.23 g of the crude title compound. Step 3.5C Terbutyl ester of the acid (2-f2- (3,5-dimeti-1-phenyl) -5-Cl- (methoxymethylcarbamoyl) -1-methyl-1-ethyl-1H-i-dol-3-? T) -ei 1 -carbamic. To a suspension of 1.23 g of 2-C3- (2-tert-butoxycarboni) inoet-1) -2- (3 »5-dimet Ifeni 1) -lH-indol-5-i 13-2-methylpropionic acid in 15 ml of N »N-dimethylformamide) at 0 ° C, 60B mg of 1-hydroxybenzotriazole (HOBt) »0.48 ml of 4- ethyl orfolin and 352 mg of N-0-di and 1-idroxy hydrochloride were added and the mixture was stirred at low temperature. After 15 minutes 826 mg of l- (3-di eti the inopropy 1) -3-ethylcarbodiimide hydrochloride (EDC) was added and the mixture was warmed to room temperature. The reaction was quenched after 3.5 days' by concentration in vacuo, resuspended in ethyl acetate and washed sequentially with water, with 0.3N sodium bisulfate, with water with saturated sodium bicarbonate and with brine. The organic portion was dried over sodium sulfate and the concentrate was purified by flash chromatography on silica gel (hexane: ethyl acetate, 3: 1) to give 905 mg of the title compound. Step 3.5D Terbutyl ester of f2-C5- acid (l >l-dimeti 1-2-oxo-eti 1) -2- (3,5-d? met? lfen l) -lH indol-3-1 eti ncarbámico. To a solution of 296 mg of the terbutyl ester of the acid (2- (3,5-d and lfeni 1) -5-Cl- (meto met Icarba oi 1) -l- eti 1-eti 1 -1H- ndo1- 3-1.) -eti 1) in 5 ml of dry tetrahydrofuran, at 0 ° C, and added 1.8 ml of a 1M solution of lithium aluminum hydride in tetrahydroanhydrate and the mixture was stirred at low temperature. After one hour the reaction is quenched by the careful addition of 0.3M aqueous sodium bisulfate solution. The resulting mixture was extracted with ethyl acetate and the organic portion was washed successively with 0.3M aqueous sodium bisulfate, with water and with brine. This was then dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel (hexane: ethyl acetate, 85:15), to give 253 mg of the title compound. Step 3.5E Terbutilic ester of the acid (2-f2- (3,5-dimet? Ifen l) -5-Cl-met? 1-l- (4-methy1-lH-imidazo1-2 -? '1) eti13-lH- indo1-3-i eti1) -carbamic. To a solution of 475 mg of the terbutyl ester of acid. { 2 - [. 5- < l.l- dip.et l-2-oxo-eti 1) -2- (3,5-dimeti Ifeni 1) -lH-indole-3- 13eti 1} charcoal in 15 ml of ethanol, 1 ml of a 40% aqueous solution of pyruvic aldehyde was added. followed by 2.2 ml of ammonium hydroxide "and the mixture was stirred at room temperature. After 2 days, another portion was added plus 0.50 ml of 40% aqueous pyruvic aldehyde and 1.1 ml of ammonium hydroxide. Finally »after 4 days» the reaction mixture was concentrated in vacuo. The residue was solvated in ethyl acetate and washed sequentially with water and with brine. The combined organic washings were dried over sodium sulfate and the concentrate was purified by flash chromatography on silica gel (hexane: ethyl acetate »1: 4) to give 402 mg of the title compound. Pflsq 3.5F 2-f2- (3 »5-dimethyl-phenyl) -5-C1-methyl-1-1- (4-methyl-1H-imi azol-2-yl) eti 13-lH-i ndol-3 1 Veti 1 amine It was prepared essentially as described in example 3.3E »from 353 mg of the terbutyl ester of (2-C2C (3» 5-dimethylphenyl) -5-Cl-methyll- ( 4-met 1-1H-ii dazol-2-i 1) eti 131H-i ndol-3-1.] Eti 1) carbamic "to give 198 mg of the title compound Step 3.56 It was prepared essentially as described in Example 3.2D »from 97 mg of 2-f_2- (3» 5-dimethylfem "1) -5-Cl- eti 1 -1 (4-methy1-lH-i my day? -2- 1) et 13-lH-i ndol -3-i 1} eti lamina »and using 4-pyridin-4-i 1-b? -raldehyde. to give 73 mg of the title compound »m / e = 520 (m + 1). Following a procedure similar to that described in Examples 3.1-3.5, the following compounds were prepared: EXAMPLE 4 l- (7-A2ABICICL0C2.2.13HEPT-7-IL) -2- 2- (3,5-DIMETHYLENE) -3-C2- (II-DIMETHYL-4-PIRIDIN-4-IL-BUYLAMIN0) -ETIL -) - lh -IND0L-5-IL ^ -2- METHYL-PROPAN-10 A Step 4A l- (3-methyl-1-but-2-eni-1) -tetrahydrothio enium bromide To a solution of 2.9 g of precursor bromide in 10 ml of dry tetrahydro uran, at 0 ° C t was added 1.8 ml of tetrahydrothiophene and the mixture was allowed to warm to room temperature. After 22 hours the mixture was concentrated in vacuo and the remaining starting materials were removed by azeotroping with toluene, to give the crude title compound, as a white solid (2.2 g).

Step 4B 4-C3- (Z-met Ipropen l) oxirani1 pyridine To a suspension of 381 mg of 1- (3-methyl-1-but-2-enyl) -tetrahydrothiophene bromide or in 5 ml of dry tetrahydrofuran at 0 ° C was added 0.31 ml of pyridine-4-carboxyaldehyde »Followed by 111 mg of sodium hydride and the mixture was allowed to warm to room temperature After 1.5 hours another 0.15 ml of pyridine-4-carboxyaldehyde was added and after 30 minutes the reaction was quenched by the addition of water. The mixture was partitioned between ethyl acetate and water and the organic portion was washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate The purification of the concentrate by flash chromatography on silica gel (hexane: ethyl acetate 1: 2) ) gave 138 mg of the title compound.

Step 4C l- (7-azabicycloC2.2.13hePt-7-i1) -2-f2- (3,5-dimeti1 in 1) -3-C2- (4-hydroxy-lt -dimeti 1-4-pyrid? N-4 -i l-but-2-en 1amino) eti13-1H-indol-5-i 11-2-meti lpropan-1-one To a solution of 70 mg of 2-C3- (2-aminoeti1) -2- (3,5-dimeti Ifeni 1) -lH-ind? L-5-i 13-l- (7-a? Abicyclic? C2.2.13hept-7-i 1) -2-methyl-1-propan-1-one (prepared essentially as described in Example 2) in 6 ml of tetrahydrofuran. 2 ml of a solution of 86 mg of 4-C3- (2-eti Ipropeni 1) oxirani 13pyridine in tetrahydrofuran was added. followed by 24 mg of tetrakis (trifeni i osphine) palladium 'and the mixture was heated to 65 ° C' in an oil bath. After 2 hours the mixture was cooled to room temperature, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (methyl chloride: ethanol, 92: 8, then 88:12) to give 91 mg of the title compound.

Step 4D l- (7-azabicic1oC2.2.13hept-7.i1) -2-f2- (3.5-dimeti1 eni 1) -3-C2- (1,1-d? Meti 1-4-Piridin-4-i 1- buti lam no) -et? '131H-indol-5-yl t-2-met lpropan-1-one.

To a solution of 27 mg of l- (7-azabicicl? _2.2.13hept-7- 1) -2-C2- (3 »5-dimeti-lfeni-1) -3-C2- (4-hydroxy-1.1) -dimeti 1-4-pi r din-4-i l-but-2-eni no) eti 13-1H-indol-5-i 13-2-methyl-1-propan-1-one in a mixture of 2 ml of tetrahydrofuran and 2 ml ethyl acetate) at 0 ° C. 0.010 ml of tri-luoroacetic anhydride was added »followed by 0.009 ml of triethylamine and the mixture was stirred at low temperature. After 15 minutes, 0.03 ml of acetic acid was added, together with 28 mg of palladium hydroxide on carbon. The reaction flask was equipped with a hydrogen tank, evacuated and re-charged with hydrogen (3 times) and stirred at room temperature. After 8 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography on silica gel (methyl chloride or: methanol: ammonium hydroxide, 94: 6: 1) gave 15 mg of the title compound, m / e = 591 (M + H). Following a procedure similar to that described in examples 4 and 2, the following compounds were prepared: Example * X-R7.R8 - (A) -R? me EXAMPLE 5.1 l- (7-AZABICICL0C2.2.1 HEPT-7-IL) -2-f2- (3,5-DIMETHYLPHENYL) -3-Cl- METHYL-2- (4-PYRIDIN-4-IL-BUYLAMIN0) ETIL3-lh- IND0L-5-IL-y-2- METILPROPAN-l-ONA P3SQ g.jA N-methoxy-methylamide of 2-methyl-1-cyclopropanecarbon acid To a solution of 10 g of 2-methyl-1-methylcyclopropane-carboxylic acid in a mixture of 200 ml of benzene and 2 ml of N, N -dimeti lformamide, at 0 ° C, 10.5 ml of oxalyl chloride was added and the mixture was stirred at 0 ° C for 30 minutes, then warmed to room temperature for 30 minutes. At this time 14.6 g of N, 0-dimeti hydrohydroxylamina hydrochloride was added, followed by 41 ml of triethylamine. The mixture was stirred at room temperature for one hour, then quenched by the addition of saturated sodium bicarbonate. The aqueous portion was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The product was purified by distillation under reduced pressure to give 8.9 g of an oil. Step 5.IB (3.5-dimet Ifen 1) - (2-methyl cyclopropy 1) methanone To a solution of 5.7 ml of 5-bromo-meta-log in 120 ml of dry tetrahydrofuran, at -78 ° C, 30.6 ml was added. of a 1.4M solution of n-butyl-1-1-yl in hexane and the mixture was stirred at low temperature. After 15 minutes a solution of 5.0 g of N-methoxy-N-methyl-2-ethyl-1-cyclopropanecarboxylic acid in 50 ml of tetrahydrofuran was added dropwise for 5 minutes and then the mixture was allowed to slowly warm to room temperature. ambient. After one hour the reaction was quenched by adding 20 ml of 2N hydrochloric acid and 40 ml of water. This was extracted with ethyl acetate and washed with saturated sodium bicarbonate solution and with brine, then dried over sodium sulfate to give 6.95 g of the title compound (crude). Pasp 5. + C 2-C3- (2-ami-ol-methyl-ethyl) -2- (3.5- dimet Ifeni 1) -lH-i do1-5-i 1 -2-met 1pro ionic acid ethyl ester To a 5.7 g solution of the ethyl ester of the acid 2- (4-hydrazinofen 1) -2-methylpropionic acid in 20 ml of n-butanol »was added 4 g of (3» 5-dimethy Ifeni I) - (2-methylcyclopropi 1) -methanone, followed by 1.3 ml. of concentrated hydrochloric acid and the mixture was heated at 110 ° C in an oil bath. After 16 hours the mixture was cooled to room temperature and washed sequentially with 0.5 N sodium hydroxide with water and with brine. The combined organic washes were dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride: methanol: 95: 5) gave 2.5 g of the title compound. Step 5.ID 2- (3,5-d-methyl-1-eny1) -3-Cl-methyl 1-2- (4-Pyr? D? N-4-yl-butylamino) -ethyl ethyl ester -eti13-lH-indo1-5-irv-2-met? lpropio-nico. It was prepared essentially as described in example 2 »step A» from 233 mg of the ethyl ester of 2-C3- (2-amino-1-met leti 1) -2- (3 »5-dimeti Ifeni 1) -IH-indol-5-13-2-methylpropionic acid to give 258 mg of the title compound. Step 5.1E 2-C3-f2-Cbenzylcarbonyl ethyl ester 1- (4-pyridin-4-yl-butyl) amino3-eti1 -2- (3,5-dimet? "1-pheny1) -lH-indole-5 -r> -2-methylpropionic acid was prepared essentially as described in example 2. step B »from 258 mg of the ethyl ester of 2-C2- (3» 5-d-methyl-1-phenyl) -3 -Cl-methyl-2- (4-pyridin-4-yl-butylamino) -eti 13-lH-i-dol-5-yl.] -2-methyl-propionic acid »to give 240 mg of the title compound.

Step 5.1F Acid 2-C3-f2-Cbenzyloxycarboni 1- (4-pyridin-4-1-butyl) -amino3-1-methylate 11-2- (3.5-d ethyl in 1) -! H-indo1- 5- 13-2-methyl-1-propanol. It was prepared essentially as described in example 2 »step C» from 240 mg of 2-C3- £ 2-Cbenc loxylcarbonyl- (4-pyridine-4-i-butyl) ethyl ester. 1) amino3-ethi 13-2- (3 »5-dimet Ifem" 1) -lH-ido-5-1.] -2-methylpropionic acid to give 222 mg of the title compound Step 5.1G Ester benzyl acid f2-C5-C2- (7-azab? c? doC2.2.13hept-7-i1) -ll-d met? 1-2-oxo-eti1 -2- (3,5-d met 1phen1) -lH i do1-3-yl 3propi 1 ~) - (4-pyr d? n-4-y1-but? 1) carbamino was prepared essentially as described in example 2 »step D. from 91 mg of the acid 2-C3-C2-Cbenci loxicarboni l- (4-piridin-4-i 1-but 1) -amino3-l-met leti 1.}. -2- (3 »5-dimeti lfeni 1) -lH-ndol-5-yl-2-methyl-1-propionic acid "to give 66 mg of the title compound Step 5.1 H- (7-azabicic1 or 2.2.13hePt-7-i1) -2- 2- (3.5 -dimeti1feni1) -3-Cl-met 1-2- (4-pyr-di-4-i-butylamide) and 13-lH-ndo1-5-? TV-2-methyl-1propan-1-one. prepared essentially as described in the example or 2 »step E» from 62 mg of the benzyl ester of C2-C5-C2- (7-a? abic clo-: 2.2.13hept-7-yl) -l, 1-dimeti 1-2-oxo -eti 1 -2- (3, 5-di met Ifeni 1) -lH_ ndol-3-i 13propi 1} - (4-pyridin-4-y 1-but 1) carbamic »to give 27 mg of the title compound, m / e = 577 (M + H).

EXAMPLE 5.2 l- (7-AZABICICL0C2.2.13HEPT-7-IL) -2-C2- (3,5-DIMETHYLEN) -3-C2-CMETIL-C4- (PIRIDIN-4-IL) BUTIL3AMIN03ETIL31H-IND0L-5-IL) -2- METILPROPAN-1-ONA A dry flask "containing 120 mg (0.21 mmol) of l- (7-azabicycloC2.2.13hept-7-i1) -2-C2- (3,5-dimet lfeni 1) -3-C2-C4 was added. - (pyridin-4-? 1) butylamino3eti 1-lH-indol-5-i 1) -2-methyl-1-propan-1-one (prepared essentially as described in example 2) »63.0 mg (2.1 mmol) of paraformaldehyde and 200 mg of molecular sieves powder 3 &, with a septum and purged perfectly with nitrogen. Then 5 ml of methanol and 0.121 ml (126.1 mg »2.1 mmoles) of glacial acetic acid were added, and the mixture was stirred at room temperature for 15 minutes. Then 52.8 mg (0.84 mmol) of sodium cyanoborohydride was added, after an additional 25 minutes, 2.5 ml of anhydrous tetrahydrofuran was added.

After one day the mixture was filtered and the filter cake was thoroughly washed with methylene chloride. The filtrate was shaken in a separating funnel with water. The aqueous phase was extracted three more times with methylene chloride. The combined organic fractions were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed rapidly on silica gel (gradient elution with 99: 1: 0.1 to 95: 5: 0.5 of CHjjCljj.MeOH-concentrated NH ^OH) to give 95.4 mg (79%) of a rigid foam. yellow; homogeneous by TLC in 95: 5: 0.5 of concentrate. The NMR with 500 MHz XH (CDC13) was consistent with the assigned structure. Mass spectrum (ESI): m / e = 577.5 (M + H). Following a procedure similar to that described in examples 5.1 and 5.2, the following compounds were prepared:EXAMPLE 6 Following procedures similar to those described in Examples 1 to 5 »the following compounds were prepared:

Claims (9)

NOVELTY OF THE INVENTION CLAIMS 1. - A compound of the formula: characterized in that: A is alkyl of 1 to 6 carbon atoms »substituted alkyl of 1 to 6 carbon atoms» cycloalkyl of 3 to 7 carbon atoms »substituted cycloalkyl of 3 to 7 carbon atoms» alkenyl of 3 to S atoms carbon »alken the substituted of 3 to 6 carbon atoms» alkynyl of 3 to S carbon atoms »alky substituted of 3 to 6 carbon atoms» alkoxy of 1 to 6 carbon atoms or alkyl of C0_ß-SiOJ ^ - alky from O to 5 carbon atoms »alkyl of Co_ß-0-alkyl of 0 to 5 carbon atoms» alkyl of Co_ß-0-alkylo of 0 to 5 carbon atoms »alkyl of C0_ß-NR; t. β-alkyl from 0 to 5 carbon atoms »where R 1 and the alkyl of 0 to 5 carbon atoms can be linked to form a ring» or a simple ligature; R0 is hydrogen »alkyl of 1 to 6 carbon atoms» substituted alkyl of 1 to 6 carbon atoms, wherein the substituents are as defined below »aryl» ar substituted »aralkyl or substituted aralkyl» wherein the substituents are as defined for R »R ^ and R '; R- ,. is
1. R_. it is hydrogen »alkyl of 1 to 6 carbon atoms, substituted alkyl of 1 to 6 carbon atoms» aralkyl »substituted aralkyl, aryl. substituted aryl, alkyl-ORxa .. (NR? a.R 2) from 1 to S carbon atoms. (CONR1ARY) of 1 to 6 carbon atoms, or C (NR: L1R a) NH; Rz and A taken together form a ring of 5 to 7 atoms; R3 »R and Rβ are independently hydrogen, alkyl of 1 to 6 carbon atoms, substituted alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, substituted alkenyl of 2 to G carbon atoms. CN »nitro» perfluoroalkyl of 1 to 3 carbon atoms »perfluoroalkoxy of 1 to 3 carbon atoms, aryl. it's substituted, aralkyl. substituted aralkyl »Rxa.O < CHat) (? -. Ri C (0) 0 (CH2) p-, R ^ OCCO) (CH2) p-, - (CH3!) |: > S (0) "RiV" - (CH2) "C (O) NRX1RX2 or halogen; wherein R x - is hydrogen »alkyl of 1 to S carbon atoms» perfluoroalkyl of 1 to 3 carbon atoms »aryl or substituted aryl; R.:; And R ^ taken together form a carbocyclic ring of 3 to 7 carbon atoms or a heterocyclic ring containing from 1 to 3 heteroatoms selected from N, O and S; R ,,. is hydrogen »alkyl of 1 to G carbon atoms» substituted alkyl of 1 to 6 carbon atoms, aryl »substituted aryl, perfluoroalkyl of 1 to 3 carbon atoms. CN. Ojg. halogen R x0 (CH2) o-. NR ^^ O ^. ^. NRaxC (0) NRaoR2x or SO ^ R-jt ,; R- is hydrogen "alkyl of 1 to 6 carbon atoms or substituted alkyl of 1 to S carbon atoms. unless X is hydrogen or halogen; so. R7 will be absent; Rβ is C (0) ORao »C (0) NR3? OR2-: L, NRaoR2i. C (0) R2O. I \ IR21C (O) Rao, NR2iC (0) NRaoRz; iL. OC.OJRjgo, OC (O) NRsloRs: L. 0R2o. SO ^ R. ^, S (0) r, R2oR-za. ' A heterocyclic ring or a bi-cyclic heterocyclic ring with 1 to 4 heteroatoms selected from N.O or S "which may be optionally substituted with R3I and R3. alkyl of 1 to S carbon atoms or substituted alkyl of 1 to 6 carbon atoms; or R--, and Rß. taken together they form a heterocyclic ring containing one or more heteroatoms selected from N. 0 or S. which may be optionally substituted with R 3.
2. R ^ and RB; R, and Rβ are independently hydrogen, alkyl of 1 to 5 carbon atoms, substituted alkyl of 1 to 6 carbon atoms, aryl or substituted aryl, aralkyl or substituted aralkyl when different from O; or Rß and Rßß taken together »form a carbocyclic ring of 3 to 7 atoms or 0 I! when it is different from 0; R ,, and A. taken together, form a heterocyclic ring containing from 3 to 7 carbon atoms and one or more heteroatoms, when m is different from 0; or Rxo and R10.? taken together, they form a carbocyclic ring of 3 to 7 carbon atoms or 0 II. R9 and R or taken together form a carbocyclic ring of 3 to 7 carbon atoms or a heterocyclic ring containing one or more heteroatoms when m is different from zero; or R9 and Rz, taken together, form a heterocyclic ring containing from 3 to 7 carbon atoms and one or more heteroatoms. when m is different from zero; or Rxo and Ra. taken together, they form a heterocyclic ring containing from 3 to 7 carbon atoms and one or more heteroatoms; Rxo and A. taken together form a heterocyclic ring containing from 3 to 7 carbon atoms and one or more heteroatoms; or R x and Rxa! they are independently hydrogen. alkyl of 1 to S carbon atoms. substituted alkyl of 1 to 6 carbon atoms, aryl. substituted aryl. aralkyl. substituted aralkyl, a carbocyclic ring of 3 to 7 carbon atoms or a substituted carbocyclic ring containing from 3 to 7 atoms; Rxx and R 2 taken together can form a ring of 3 to 7 atoms, optionally substituted; Rx3 is hydrogen. OH. NR- ^ R ,,, RR S02 (at the one of 1 to 6 carbon atoms), NR S02 (substituted alkyl of 1 to 6 carbon atoms, NRx S02 (ari lo), NR xS02 (ari substituted) NRxxS02 (perfluoroalkyl of 1 to 3 carbon atoms) S02NRxx (alkyl of 1 to 6 carbon atoms) S02NRx (substituted alkyl of 1 to G carbon atoms S02NRx (arylo) »S02NR (ary lo) replaced) »S02NRxx (perfluoroal qui 1 or 1 to 3 carbon atoms)» S02NRxx (C (0) -alqulo of 1 to G carbon atoms) »S02NRxx (alkyl substituted with C (0)» of 1 to 6 carbon atoms); S02NRxx (C (0) -ari lo); S02NRx (ari substituted with C (0)); S (0) r (alkyl of 1 to G carbon atoms) JSíO) ^ (alkyl substituted from 1 to 6 carbon atoms) .S (O).,. (arylo), S (0) "(substituted aryl), perfluoroalkyl of 1 to 3 carbon atoms, perfluoroalkoxy of 1 to 3 carbon atoms, alkoxy of 1 to 6 carbon atoms, the co substituted of 1 to G carbon atoms »COOH» halogen »N02 or CN; R - and Rxß are independently hydrogen , alkyl of 1 to G carbon atoms, substituted alkyl of 1 to 6 carbon atoms »alkenyl of 2 to 6 carbon atoms, substituted alkenyl of 2 to 6 carbon atoms. N > nitro, perfluoroalkyl of 1 to 3 carbon atoms, per loroalkoxy of 1 to 3 carbon atoms, ar lo. it's replaced. aralkyl. substituted aralkyl »RxxO (CH2)" -, RxxC (0) 0 (CH2) ^ -, RxxOC (0) (CH2) p-, (CH2), S0 0 J ^ R ^ "- (CHJÜ) ,, C (0) NRxxRX2 or halogen; wherein R xv is hydrogen »alkyl of 1 to 6 carbon atoms» perfluoroalkyl of 1 to 3 carbon atoms »aryl or substituted aryl; Rxß is hydrogen »alkyl of 1 to 6 carbon atoms or N (RXXRX2); Rxß is hydrogen »alkyl of 1 to G carbon atoms» substituted alkyl of 1 to 6 carbon atoms. C (0) ORx. C (0) NRxxRX2. C (0) R »S (0) r, Rxx; Rxß > has the definition of Rx3 or Rx- »» R2C > and R2X are independently hydrogen, alkyl of 1 to 6 carbon atoms, "substituted alkyl of 1 to 6 carbon atoms," aryl. substituted aryl »aralkyl» substituted aralkyl »a carbonic anion of 3 to 7 atoms» a substituted carbocyclic ring containing from 3 to 7 atoms »a heterocyclic ring or an organic ring with the 4 heteroatoms selected from N 0 or S »which may optionally be substituted with R3, R ^ and Rβ; C 1-6 -alkyl substituted with a heterocyclic ring or a bicyclic heterocyclic ring of 1 to 4 heteroatoms »selected from N» O or S, which may be optionally substituted with R 3 »R and Rβ; "20 and RZI * taken together, can form an optionally substituted ring of 3 to 7 carbon atoms; X is N» O. S (0) "» C (0) »<CRXXRX2) 0» a single ligature to Rß »Alkenyl of 2 to 6 carbon atoms» substituted alkenyl of 2 to 6 carbon atoms »alkynyl or substituted alkyne of 2 to G carbon atoms, when X is 0» SiO) ^ »C (0) or CRXXR 2. only Rβ is possible, Z is 0 »S or NRX, m is 0 to 3, n is 0 to 2» p is 0 to 4, and the substituents "alkylcycloalkyl" and alkenyl are selected from alkyl of 1 to 6 carbon atoms »with 3 to 7 carbon atoms» aryl »substituted aryl» aralkyl »substituted aralkyl» hydroxy »oxo» cyano »alkoxy with 1 to G carbon atoms» fluoro »C (0) 0R x »aryl-alkoxy of 1 to 3 carbon atoms, aryl-alkoxy substituted of 1 to 3 carbon atoms; and the aryl substituents are as defined for R3. R ^ and Rβ; or a pharmaceutically acceptable salt and / or hydrate thereof; or when applicable, a geometric isomer? optical or a racemic mixture of them. 2. The compound in accordance with the rei indication 1, of the formula: further characterized in that Rx and X-R7, Ra are as indicated in the following table:
3. 3. - The compound according to claim 1, of the formula: further characterized in that R and X-R7 »Rß are as indicated in the following table:
4. 4. - The compound according to claim 1 »of the formula: further characterized in that R and X-R7, Rβ are as indicated in the following table:
5. 5. - The compound in accordance with the rei indication 1 »of the formula: further characterized in that A, R and X-R7 »Rß are as indicated in the following table:
6. 6. - The compound according to claim 1 »of the formula: further characterized because Rx, R2. Rß »R9 > m > Rxo »R or« »X-R-, R, and A are as indicated in the following table:
7. 7. - The compound according to claim 1 »of the formula: further characterized in that Rx »R2, R9, R9m, R0, RXOß, X-R ^R, and A are as indicated in the following table: A pharmaceutical composition characterized in that it comprises an effective amount of compound as defined in re-indication 1, and a pharmaceutically acceptable carrier therefor. 9. The use of an effective amount of compound according to claim 1 to prepare a composition for treating a patient suffering from an alteration derived from the gonadotropic hormone. 10. The use according to claim 9 »further characterized in that the alteration derived from the gonadotropin-releasing hormone is a condition related to the sexual hormone. 11. The use according to the rei indication 9. also characterized because the alteration derived from the gonadotropin-releasing hormone is a cancer dependent on the sex hormone »a benign prostatic hypertrophy or a myoma of the uterus. 12. The use according to the rei indication 11"further characterized because the cancer dependent on the sexual hormone belongs to the group consisting of prostatic cancer» uterine cancer »breast cancer and gonadotrophic adenomas of the pituitary. 13. The use according to claim 10, further characterized in that the condition related to the sexual hormone is selected from the group consisting of endometriosis, polyacitic ovarian disease. uterine fibroids and precocious puberty. 14. The use of an effective amount of a compound as defined in rei indication 1. to prepare a composition to prevent pregnancy in a subject who needs it. 15. The use of an effective amount of a compound as defined in claim 1 for preparing a composition for treating lupus erythematosus in a subject in need thereof. 16. The use of an effective amount of a compound as defined in claim 1 to prepare a composition for treating irritable bowel syndrome in a subject in need thereof. 17. The use of an effective amount of a compound as defined in claim 1 for preparing a composition for treating premenstrual syndrome in a subject in need thereof. 1
8. 8. The use of an effective amount of a compound as defined in claim 1"to prepare a composition for treating hirsutism in a subject in need thereof. 1
9. 9. The use of an effective amount of a compound that stimulates the endogenous production or release of growth hormone and an effective amount of a compound as defined in claim 1 to prepare a composition for treating short stature. or a deficiency in growth hormone of a subject that needs it. 20. The use of an effective amount of a compound as defined in claim 1 to prepare a composition for treating sleep disturbances. such as sleep apnea in a subject that needs it. 21.- A pharmaceutical composition. characterized in that it comprises an inert carrier and an effective amount of a compound that stimulates the endogenous production or the release of the growth hormone, in combination with a compound as defined in claim 1. 22.- A pharmaceutical composition »characterized in that it is prepared by combining the compound of claim 1 with a pharmaceutically acceptable carrier therefor.