MXPA97001679A

MXPA97001679A - Derivatives of piperidine as antagonists of the neuroquin

Info

Publication number: MXPA97001679A
Application number: MXPA/A/1997/001679A
Authority: MX
Inventors: I Carruthers Nicholas
Original assignee: Schering Corporation
Priority date: 1995-06-06
Filing date: 1997-03-05
Publication date: 1997-06-01

Abstract

The present invention relates to compounds of the formula (I), wherein X, i, j, n, n ', A, A', R2, R3, and U are in accordance with what is described herein. The compounds of the present invention are antagonists of the NK1 or NK2 or NK3 receptors and as such are useful for the treatment of diseases such as, for example, ace

Description

DERIVATIVES OF P IPER I DINA AS ANTAGONISTS OF THE NEUPDQU? NTNA BACKGROUND OF THE INVENTION The present invention relates to a genus of "useful s or antagonists" of T. neurokinin receptors. Especially, these may be antagonists of the neuraqume-1 receptor (Nf 1), neuroqt.fi receptor antagonists, or na-2 < N 2), peuroquinine receptor antagonists -3 (Nr'3). The neurochemical receptors are found in the nervous system and in the circulatory system as well as in peripheral tissues of mammals, and therefore are involved in vain G? CTSOS biological. Accordingly, it is thought that neurokinin receptor antagonists are useful in the treatment or prevention of disease states in mammals, for example asthma, cough, bron aespas or, inflammatory diseases such as arthritis, migraine, nociception, and vain gastrointestinal disorders such as Crohn's disease, etc. Specifically, it has been indicated that the receptors of 1 and 2 are involved in microvascular leaks and mucus secretion, and the K2 receptors have been associated with 19. contraction of smooth muscles, making antagonists of the NK 1 and N 2 receptors especially useful for the treatment and prevention of asthma.

COMPENDIUM OF THE INVENTION The invention relates to compounds of the formula where each i and j is independently selected within the group consisting of 1 and 2; catáa n is independently selected within the. group consisting of 0, 1, 2 and 3? each n * is independently selected within the group consisting of 1, 2 and 3; where A and A 'are H, or b in A and A' together are = 0, = S; O well = N-R4; X is selected within the group consisting of O, CO, C (R, R1), C = C < R1, R8 > , NP.1 and S (0) e where e is 0, 1, or 2; P is selected within the. group consisting of H, 0P.8, C0N (P.8) 2, CN, S (0) eR8, S0eN (R8) 2, C02R8 and NR4C0R8? P.l is selected within the. group consisting of H, alkyl Cl-C?), Cycloalkyl C.3-C85 P2, P3, P5, R6 and R7 are independently selected from the group consisting of H, halogen, C1-C6 alkyl, CF3, C2F5, 0R8, C0R8, C02R8, C0N (R8, R8), N (R8, R8) , N (R8) C0R8, S < 0) eR8, 0C (0> R4, 0C fO) IFRS-P), NP8C02R4, NR8 < C0) (R8, P8), R15-phenol, R15-benzyl, N02, NR8S02R4, -S (0) 2NCR8) 2 or when P2 and R3 or any group of two of P5, P6 and R7 are found in adjacent carbons they can form a -0-CH2-0- group; each P4 is independently selected from the group consisting of alkyl, substituted alkyl, substituted alkyl, and substituted benZyl; each R8 is independently selected from the group consisting of H, alkyl, substituted alkyl, or their i, and benzyl; each R15 is independently H, halogen, lower alkyl, lower alkoxy; and Li is (A) (B) (Q • t • < ro 0 as) n "is independently selected within the group consisting of 0, 1, 2 3, the striped line is an optional carbon-carbon bond, R16 is H, C1-C6 alkyl, -S ( 0) 2R4, C0P.8, C02R4, C0N <P8) 2, R15-phenyl or R1.5-ben i.substituted means substituted with a substituent selected from the group consisting of H, CICA alkyl, 0CF3, CF3 and C2F5 The compounds of the formula I are also preferred, where i is 1 and j is 1. The compounds of the formula I are also preferred, where n is 1, n "is 0, 1, or 2, and n ' is 1. Also preferred are compounds of formula I, where n, n 'and n "are all 1. Also preferred are compounds of formula I, where n and n' are both 1 and n" is 0. Compounds of the formula are also preferred. I, where n and n 'are both 1 and n "is 2. Compounds of the formula I are also preferred, where A and A 'are both H. Compounds of formula I are also included, where A and A 'together they are = 0. Also preferred are compounds of the. Formula I, where X is C (R, R1). Also preferred are compounds of the formula I, where R is 0R8, C0N < R8) 2, CN, or NR8C0R8. Compounds of the formula I are also shown, where X is NRl. Also preferred are compounds of the formula I, wherein Rl. is Also preferred are compounds of the formula I, where n is 0 or 1 and R8 is H. Compounds of the formula I are also preferred, where R2, R3, R5, R6, and R7 are H, halogen, C1-C6 alkyl, CF3, 0R8, C0R8, C02P.8, CONRBRB, or NP.8R8. Also preferred are compounds of the formula I, where R 1? is H or tiien alkyl. Also preferred are compounds of the formula I, wherein each P.8 is H, C1-C6 alkyl or R15-phenyla. Also preferred are compounds of the formula I, wherein R8 is H or substituted alkyl. Also preferred are compounds of the formula I, where U is Exemplary compounds of the present invention are the following, as well as macromonically acceptable salts of The invention also relates to a composition comprising. an antagonist amount of the neutroxy molecule of a compound according to formula I and a pharmaceutically acceptable carrier material. The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in combination with a pharmaceutical vehicle and ice-tablet. The invention also relates to a method for inducing a neuroquinone antagonism comprising the administration of an antagonist effective amount of the neurokinin of a compound according to formula I to a mammal in need of such treatment. The invention also relates to a method for the treatment of chronic respiratory diseases with, for example, asthma and allergies; inflammatory diseases such as inflammatory bowel disease, psoriasis, asteoarteritis, and rheumatoid arthritis; migraine; disorders of the central nervous system such as depilation, psychosis, dementia, and Alzheimer's disease; Down's Syndrome; neuropathy; multiple sclerosis; ophthalmic disorders; conjunctivitis; autoimmune disorders; graft rejection; lupus in systemic issues; gastrointestinal disorders such as, for example, Crohn's disease and ulcerative colitis; disorders of bladder function; circulation disorders such as angina; Paynaud's disease; cough and pain. Especially, the invention also relates to a method for the treatment of asthma comprising administering to a mammal that requires such treatment an effective amount against asthma of a compound of formula I, such as pyropoxide. DETAILED DFSCPIPTION OF THE INVENTION As used herein, the term alkyl is a saturated, straight or branched hydrocarbon chain having from 1 to 6 carbon atoms. The number of carbon atoms can be indicated. For example, "Cl-Cé alkyl" represents a saturated, straight or branched hydrocarbon having from 1 to 6 carbon atoms. The term alchemyl refers to a stiff, straight or branched alchemist having 2 carbon atoms. The number of carbon atoms may be indicated. For example, "C2-C6 alkenyl" represents a straight or branched alkemyl having from 1 to? > carbon atoms. Asymmetric centers exist in compounds of the formula I of the invention. Accordingly, compounds of formula I include stereoisone. All of these isomeric and pissal forms of themselves are within the scope of the present invention. Unless otherwise indicated, the ion preparation methods presented here may result in distributions of product which include all possible structural isomers, even if B ti na that the physiological can vary in accordance with the steroid structure. mica The isomers may be separated by conventional means such as fractional crystallization, preparation plate or column chromatography on silica, alumina, or reverse-phase supports or HPLC (liquid chromatography on or off). m ño, separation of the enantiomers, when appropriate, by derivation or formation of salts with an optically pure reagent, followed by separation by one of the aforementioned methods. Alternately, the enantiomers can be separated by chromatography on a qui-ral support. The compounds of the formula I can be: -? St? R in unsolvated forms as well as in solvated forms, including hydrated forms, for example hemihydrate. In general, solvated forms, with pharmaceutically acceptable solvents such as for example water, ethanol and the like, are equivalent to unsolvated forms for the purposes of the present invention. Those compounds of formula II which contain a bSs group, such as for example -CH2NH2, form pharmaceutically reactable s. Preferred pharmaceutically acceptable salts are non-acid addition salts.;? ca- = > formed by the addition to a suitable compound of the present invention of an approximately stoichiometric amount of a mineral acid, such as for example HCl, v HBG, H2S04 or H3PQ4 or of a rganic acid such as for example acetic, propionic, maleic acid , oleic, palmitic, stearic, lupus, benzoic, lactic, p > ara-tol uensul fóni co, metansul phonic, citric, maleic, fumApco, its unique and similar, respectfully. GENERAL METHODS OF PREPARATION The compounds of the present invention can be prepared by one of the following general methods. Unless indicated otherwise, the variables found in the structural formulas below are as defined above. The compounds of the present invention can be prepared from an appropriately substituted benzaldehyde as shown in Scheme 1 or from an appropriately substituted phenylacetic acid as shown in Scheme 2.

Methods for the preparation of the compounds of the present invention are illustrated in the following scheme = > and examples. The compounds of the present invention can be separated from an appropriately substituted benzyl ester as shown in Scheme 1 or from an appropriately substituted acetic acid ester or as shown in Scheme 2. Accordingly As shown in Scheme 3, a beiraldehyde A is condensed with ethelacetsacetate in the presence of a base, for example an amine base as for example pj ipiepd ma, in a suitable solvent, for example an alcohol such as for example ethanol, as described in J. Indian Chem, Sa. , 397 ¿> , 53, 1122, to provide a bi acetoacetate to B. The hydrolysis of B ba or strongly acidic conditions using sodium hydroxide in an aqueous alcoholic solvent provides dissolved C. The dehydration of C using an appropriate dehydration agent for example, acetic acid or acetyl chloride, then provides the substituted glutaric anhydride D, Fl treatment of the anhydride D with an aniline or an ethyl acetate in a suitable solvent, for example a solvent for example, diethylene cell, in the presence of a suitable base, for example tpetilamipa or N, Nd? and i lamí nop r i d i na (DMAP), provides the acid F. The redurition of the Acid function r < The use of an appropriate method of reduction, for example by means of the m? d- oli do i.-ürresp ndienle or of mixed carbon dioxide and treatment with aqueous sodium borohydride, is obtains an alcohol G. The albohol G can then be converted into its halide well by the corresponding H, for example by the treatment with a sulphide halide in pre-seru of a L- »- 1 co or by Pipdin example. The intermediate product H should then be condensed with a heteroaryl amine in a suitable solvent, for example N, N-di and form it, in the presence of a base, for example potassium carbonate or N, N-d? isopropy let ila i na, if desired to provide J. In an alternative embodiment, the alcohol G can be oxidized, for example by means of the Smern process as described in Tetrahedron, 1978, 34, 1651, to provide an aldehyde. The aldehyde K can then be condensed with a heterocyclic amine I in a reductive amine reaction, for example using sodium ioboroborohydride in methanol in the presence of a dehydrating agent such as for example molecular sieves similar to that described in J. Am r. hem Soc. , 1971, 93, 1897, for pyropharmacy J. The amide functionality of J can be reduced, for example using borane-dimethyl sulfur in tetrahydrofuran, to provide the amine L.

SCHEME 1 In an alternative synthesis, scheme 2, a feni acid. Lactic acid M can be converted to acid at 1.1 ico N, for example as described in Bioorganic. Med. Chem. Letts., 1993, 3, 319. N acid can be homologated to acid P in accordance with. Arndt-Eistert procedure, for example as described in Chem. Pharm. Bu11., 1981, 29, 3249, and the acid P can be condensed with an aniline or an alkali lamin E to give 0 < n = 1). Condensation of acid P can be achieved by the corresponding acid chloride, prepared from P by treatment with oxalyl chloride and N, Nd imet i 1 catalytic formamide, which can be used when E is an aniline or an alkali. and it is the preferred method when E represents an aniline. In an alternative procedure, when a lamellar ari lalk is, the condensation can be achieved by means of a ca rbodi i mid, for example using the 1-e 11 -3- ( 3-dimet i lamí oapropí 1) carbod? I my in oetomethane The group of 0 can be dissociated in an oxidizing manner, for example with treatment with ozone in methanol, to provide the aldehyde. to be used in reductive animation reactions with amines I h ^ teroc i 1 i ca to provide compounds J as shown in scheme 3.

SCHEME 2 The invention presented here is exemplified by means of the following examples which should not be considered as limiting the scope of the present invention. Alternative alternative routes and analogous structures within the scope of the present invention will be apparent to those skilled in the art EXAMPLE 3 beta- (3, 4-d? Clar fni 1) -4-h? Dro; -Nm t I lN, 4-d? Fem 1-1 -piper i cl i npentami STEP A: d let i 1 -3, 4-di lorobenpa 1-b is-a etoacet or SIP treated 3, -dic orobenzal Diluted (100 g) in% ethanol (120 ml) with the lacetaac etato (346 ml) and stirred until a homogeneous solution was obtained.This solution was treated with rhodopine (8 ml) and allowed to stand for? 18 hours. The crude product was recrystallized from 95% ethanol to give the title compound (230 g) STEP B: 3- (3,4-du: lorafeni 1) glutamic acid co treated Di et i 1- 3, 4-d? C lorabenzal-bis-acetaaceta to (155 g) in ethanal (2 L) with 50% NaOH (2 L) and heated at reflux temperature for 4 hours. The reaction mixture was removed and approximately 1.5 L of solvent was removed by distillation. The remaining solution was drained on ice (1 Kg) and a sufficient amount of HCl was added to adjust the pH to 1. The resulting solution was extracted with EtOAc (3 X 1.5 L) and the combined extracts were dried on MgSO4, filtered and concentrates to provide 10Og of the tulip compound. STEP C: 3-anhydride 3, 4-d? Chloropheni 1) glutharic Acid 3- (3, 4-d? C 1 orofem 1) and lutA? i c o (100 g) with ethyl acetate (300 ml.) and the resulting mixture was heated to reflux for 5 hours. The cooled reaction mixture was then treated with toluene and confined to reduced pressure. The residue was formed into a paste with diethyl ether (250, nL 5 and filtered to provide the title compound (86 g) STEP D: 3,4-d? C3oro-b ta- < 2- ( (fepil) et 11 ammo) -2 ~ axo ti 1'benbenpropanoic Anhydride 3- (3,4-d? lorof ni 1> glutri co in CH2C1 (20 mL> at 0 ° C sec uenc) With N-met i laní 1 ma (0.518 g), tpeti lamina í? 489 g &and DMAP (traces), the mixture was stirred at 0 ° C for 2 hours and then allowed to warm to room temperature and stirred for 12 hours.The same time the reaction was washed with 1N HCl (2X20 mL) and water (20 L), the organic layers were dried over MgSO4, filtered and concentrated to give the title compound (1.2 g). 3,4-d? C.loro-beta < 2-h. Droiethile) -N-met? 1-N-phenylbenzenepropanamide It was treated 3,4-d? Chloro-beth acid (2- ((fem 1) met i lamí no) -2-oxoet i 1) benzenepropylene (0.98 g) in EtOAc <25 mL with CDI (0.653 g) and DMAP (traces). The resulting ion was stirred at room temperature for 15 minutes and then heated to 50 ° C for 2 hours. The reaction mixture was cooled to 0 ° C and treated with a solution of NaBH4 (.68 y) in H20 < 10 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with Ft20 and washed with 1N HCl (2 mL), saturated NaHCO3 (20 mL) and water (20 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (0.08 g). The mass spectrum (Cl): 352. STEP F: 3,4-? Gold-beta- (2-methansul foni 3 or? 11) -N-met 11-N-phen i-benzenepropane ida Cooled 3, -d-lor-beta - < 2-h idrox let 11) -N-met i 1-Nfeni Ibencenpropanamide (0.9 g) in CH2C12 '2 mL) at a temperature between -5 and -10 ° C and was treated sequentially with Et3N (0.332 g) and native methanesul chloride (0.365 g). After 2 hours, the reaction mixture was washed with water (2 × 20 mL) and the organic layer was separated, taken up in MgSO 4, filtered and concentrated under reduced pressure to give the title compound (1.1 g). STEP G: peotamide of beta- (3,4-d? Chloropheni 1> -4-h? Dro-? -N-me 11 -N, 4-di-phene 1-1-p? Pr? Di na It was treated 3, 4 ~ d- chloro ~ -beta- (2-metansul foni lo? I et 11) -N-met 11- N -pheni Ibencenpropanamide (ll g) in DMF (10 L) with 4-phenylane-4- h? dro- 'ipipieridine (1.14 g) and the mixture was heated at 60 ° C. for 18 hours. The cooled mixture of the reaction was diluted with EtOAc (100 mL) and the aqueous phase was removed. The aqueous layer was extracted with EtOAc (2X100 m) and the combined organic extracts washed with water (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. ida jra ropiorr j on r a areite. elution of i.i'OtM tog raphy on silica gel with 95: 5 (CH2C12: eOH) yielded the title compound (0.4 g). Melting point 67-72 *, mass spectrum (FAB): 513 (70%), 511 (100%). STEP H: 3,4-d? C3oro-bet - (2-o: < oethyl > -N-met 11-N-femlbencenprop nami oxalyl chloride (7.74 g) in CH2C12 (80 mL) was added a solution of DMSO (9.5 g) in CH2C12 <30 mL) for 35 minutes at a temperature of -78 * C. The mixture was stirred for 15 minutes after which a solution of CH2C12 (50 mL) of 3-di-loro-beta- (2-hydroxyl-11) -N-methyl-1-N-phen was added. 3 bencenpropanamide (17.15 g) for 20 minutes. The mixture was stirred for 30 minutes and then treated with a solution of Et3N (14.76 g) in CH2C12 < 20 mL) and stirred for an additional 30 minutes at a temperature of -78 ° C, followed by 1.5 hours at room temperature. The reaction mixture was washed with water (100 mL), the organic fraction was separated, dried over MgSO4, filtered and concentrated under reduced pressure to provide an oil. 20 g). Elution of the silica gel chromatography with 5-15% EtOAc Hex afforded the title compound (15.2 g). STEP I: Beta pentamide (3, -d? C loro eni 1) -4-h i dro; i-N- et 11-N, -di feni 1-1- iper id i na It was treated 3,4-d? c paroro-beta- (2-oxoet 13) - -met i -N-feni 1 b ^ pc n na apparel (0.43 g), in MeOH (20 L) sequentially with molecular sieves 3A (2. g), 4-phen? l-4-h? drox? p? pepd? na HCl ( 0.34 g) and NaBH3CN (0.32 g) The resulting mixture was stirred at room temperature for 18 hours.The reaction mixture was filtered through a pad of celite (trademark) and concentrated or reduced pressure. was divided between a solution of 10% NH40H and CH2C12 (25 L) .The organic layer was separated and the aqueous layer was extracted with CH2C12 (2X25 mL), the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. to give a crude oil (0.7 g) The elution from silica gel chromatography with 1-2% MeOH / CH2C12 gave the title compound (0.42 g) Mass Spectrum (Cl): 524. EXAMPLE 2 1 - (3- (3, -d iclorof nor 1) -5- ((met 11) feni lam? No) pent 11) -4-feni 1-4-p? Perid? Nol. Penta ida of beta- (3, 4-d? Chlorof nor 1) -4-hr idra-N ~ met 1 lN, 4-d 1 fem 1-1-p ipepdine (0.22 g) in THF was treated (25 L) with E ^ H3: DMS (0.212 ml; 10 M) and heated at reflux temperature for 18 hours. The cooled reaction was then treated with MeOH (2.0 L) and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOH (20 mL), treated with potassium carbonate (-'c g) and heated at reflux temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and partitioned between CH2C12 (20 mL) and a saturated NaHCO3 solution (20 L). The organic part was separated and the aqueous sample was reextracted with CH2C12 (2X20 mL). The organic phase was dried over MgSO, filtered and evaporated to give the title compound (0.20 g). Mass spectrum (FAB): 515. EXAMPLE 3 beta-1, 3-benzod? oxol-5-? 1) -4-h idroxy-N-met i l-N, 4-? fen? l-1-p > p ipiepdinpentamide STEP A: diethyl - (1, 3 ~ benzod? axal-5-? 1) -b? α-Acetoacetate Piperonal (0.2%) in ethanol 95% (30 mL) was treated with ethyl acetaacet (42.5 mL) and stirred until a homogeneous solution was obtained. Pipendine (2.3 L) was added and the resulting solution was stirred for 18 hours. The crude product was obtained by filtration and was subsequently recirculated from 95% ethanol to provide the title compound (35 g). STEP B: 3- (1,3-benzod? Oxol-5-? 1) glutaric acid Dietary 11-3, 4-met? lendioxy benzal-b i s-acetoacetate (3 <"> g) in ethanol (300 ml.) with NaOH?] 5% (300 mL) and heated to reflux for 4 hours.Approximately 250 ml of solvent was removed by distillation.The remaining solution was cooled to 0 [deg.] C. added a sufficient amount of HC1 dropwise to adjust the pH to 1. The resulting solution was extracted with EtOAc (3 x 500 mL) and the combined extracts were dried on MgSO4, filtered and concentrated or reduced pressure to provide ion r the title compound as a white solid <19 g) STEP C: 3- (1,3-benzod-loxol-5-i 1) glutaric acid anhydride 3- (1, ~ benzod? oxol-5-? 1) glutarium (3.2 g) with acetyl chloride (15 ml) and the resulting mixture was heated at reflux for 5 hours.The cooled reaction mixture was then azeotroped with toluene 2 x 100 ml) and concentrated under reduced pressure The residue was then formed into a paste with diethyl ether and filtered to provide the compound of the mixture. tul / (2.91 g) STEP D: Acid beta- (2- ((fen il) met i lam? no) -2 ~ oxoet 11) -l, 3-benzad? oxal-5- lpropanoi co Anhydride was treated 3- (1, 3-benzod? oxol -5-i 3) glutaric (2.91 y) in CH2C12 (100 mL) at 0 * C sequentially with N-methylanilma (1.68 L), tr i eti lamina (2.16 mL) and DMAP (150 mg). The mixture was stirred at 00C for 2 hours and then warmed to room temperature and stirred for 13 hours. The reaction mixture was diluted with CH2C1 (300 mL) and washed with 1N HCl d 150 mL) and agus < 1 x 150 mL). The organic layers were dried over MgSO4, filtered and concentrated to provide the title compound < 4.2 g). STEP E: beta (2-h idrox iet i 1) -N-me i 1-N-pheni 1 -1, 3-benzod ioxol-5- i 1 -propane amide Beta- (2- ((phenyl) acid was treated 1) met i lamí no) -2-oxoet i 1) -l, 3-tjenzad io? Ol-5-i 1 -propanoic acid (4.2 g) in EtOAc (100 ml.) With CDI (2.51 g) and DMAP ( 146 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated to S 'C for 2 hours. The reaction mixture was cooled to 0 ° C and treated with a solution of NaBH4 (2.34 g) in H20 (50 mL), warmed slowly to room temperature and stirred for 12 hours. The mixture in which the reaction was diluted with EtOAc (200 L) and washed with 1N HCl. (t x 1.50 ml.), stiff NaHCO3 (1 x 10 mL) and water (1 x 150 L). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give the crude compound as an oil. Chromatography elution on silica gel with 0-10% MeOH / CH2Cl proporated the title compound (2.36 g). Mass spectrum (Cl>: 328. STEP F: beta (2-oxoet 11) -N ~ met i 1-N-phenyll, 3-benzodiox 1-5-i 1-p apparel solution of beta- (2-h idro iet i 1) -N-me i 1-N-phene 1-1, 3-benzodi oxol -5- i 1 -propi nami da (5 0 mg) in CH2C12 (10 mL ) with PDC (570 m) and molecular sieves (4A, 570 mg) and stirred at room temperature for 2 hours, the reaction mixture was filtered through a pad of silica gel, rinsed with EtOAc (1.0O mL). ) and concentrated under reduced pressure to provide an oil The elution from silica gel chromatography with 50-75% EtOAc hexanes gave the desired title compound (374 mg) STEP G: beta- (1,3-benzodium) ol-5-i 1) -4 ~ h idrox i -N-me i 1-N, 4-di feni 1-1-piperi dinpe t mida Se or beta- (2-ox iet i 1) -N-met i 3 ~ N ~ ferti 1-1, 3-benzodio ol-5-i 1-p rop nam da (370 mg), in MeOH THF (1. s 1 ÍO L) sequentially with 3A molecular sieves (480 m) , 4-phenyl-4-hydroxypiperidine HCl (480) mg) and NaBH 3 CN (72 g). The resulting mixture was stirred at room temperature for 1.8 hours. The reaction mixture was then quenched with water (10 mL) and diluted with CH2C12 (50 mL). The organic layer was then separated and the aqueous layer was extracted with CH2C12 (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude oil. Elution by chromatography on silica gel with 1-2% MeOH / CH2C12 gave the title compound (310 m). Mass spectrum (Cl): 487. EXAMPLE 4 tiet- (3, 4-d? F luorofen 11) ~ 4-hi ro iNm ^ t? 3 ~ N, 4-? Fen? Ll-piper ii npepatamide STEP A: ? e? l-3,4- .: Was it treated 3, -d? f luorobenza ldehyde (5 g) in 95% ethanol (20 ml.) with etholacetoacetate (18 L) and stirred until a homogeneous solution was obtained. Pipetid (1 mL) was added and the resulting solution was stirred for 18 hours. The crude product was obtained by filtration and sufficiently recrystallized with 95% ethanol to provide the title compound (11 g). STEP B Acid 3- (3,4-d? F luorofeni 1) glutápca It was treated d i et i 1-3, -d? f l? orobenz 1-b is-acetoacetate (11 g) in ethanol (150 L) with 50% NaOH (150 mL) and heated at reflux for 4 hours. Approximately 100 mg of solvent was removed by distillation. The remaining solution was. cooled to 0 ° C and a sufficient amount of HCl was added dropwise to adjust the pH to 3. The resulting solution was extracted with EtOAc (3 x 300 L) and the combined extracts were dried over MgSO4, filtered ba or reduced pressure to provide the title compound as a white solid (7.4 g). STEP Anhydride 3- (3, 4-d? F luorofeni 1) glutApco 3- (3,4-difluoro-phenyl-1) glutaric acid (7.4 g) was treated with acetyl chloride (50 mL) and the resulting mixture it was heated at reflux for 5 hours. The mixture of the cooled reaction was then acetone coated with toluene (3 x 100 ml.) And concentrated under reduced pressure. The residue was formed into a paste with diethyl ether and filtered to propriate the title compound (6.5 g). STEP D: Acid 3, 4-ct? f luoro-beta- < ? - í í fem 1) met i lam? no) -3 ~ Mie 11 Ibencenpropanoi co Sej treated anhydride 3- (3,4-d? f luoro feni 1) glutApca (3.61 g) in CH2C12 (75 mL) a 0 * 0 sequentially 3 with N-met i lani 1 i na (2.16 mL), tpetilamma (2.78 L) and DMAP (195 mg). The mixture was stirred at 0 ° C for 2 hours and then allowed to warm to room temperature and stirred for 12 hours. The reaction was diluted with CH2C12 (300 L) and washed with 1N HCl (1 x 100 mL) and water (1 x 100 L). The organic layers were dried over MgSO4, filtered and concentrated to give the title compound (4.3 g). STEP E: 3, -d? f luoro-beta- (2-h? droethe 1) -N-met i 1-N-phenylebencenpropanamide Acid 3, 4-di f 1 uoro-beta- (2- ((geni 1) me i lam ? no > -2-oxoet i 1) bencenpropanoic (4.3 g) in EtOAc (100 ml.) with CDI (3.24 g) and DMAP (195 m). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50 ° C for 2 hours. The reaction mixture was cooled to 0 ° C and treated with a solution of NaBH 4 (3.02 g) in H 2 O (50 ml), slowly warmed to room temperature and stirred for 1 hour. 12 hours. The reaction mixture was diluted with EtOAc (200 mL) and washed with 1N HCl (1 x 100 L), saturated NaHCO 3 d x 10 mL) and water (1 x 10 mL). The organic phwas washed in MgSO 4, filtered and concentrated under reduced pressure to provide the crude compound in the form of an oil. Elution of the chromatography on silica gel with 0-1% MeOH / CH2C12 gave the title compound (3.64 g). Mass spectrum < CI) s 320, STEP F: 3,4-d? f luoro-beta- (2-oxoet 11 > -N-met? lNN-phene benzene propria) Oxalyl chloride (0.171 mL) in CH2C12 (10 mL) was added to a solution of DMSO (0.278 mL) in CH2C1 for 15 hours. minutes at a temperature of -78 ° C. The mixture was stirred for 15 minutes, a solution of CH2C1 of 3,4-d? f 1-chloro-bethane propanamide - (2-h? dro iti 1) -N was added. -met 11-N-pheni 1benzene (5 0 m) for 20 minutes. The mixture was stirred for 30 minutes and then treated with a solution of Et3N (0.655 mL) in CH2C12 and stirred for an additional 30 minutes at a temperature of -78 ° C, followed by 1.5 hours at room temperature. The reaction mixture was washed with 0.1 N HCl (1 x 50 mL) and brine (1; - 50 mL). The organic layer was dried on MgSO 4, filtered and concentrated under reduced pressure to provide an oil. Elution of chromatography on silica gel with 5-15% EtOAc Hex gave the title compound (388 mg).

STEP R: beta- (3,4-? F luorofeni 1) -4-h? Dro;, iN-met 11 ~ N, 4-di feni 1 -1-pp i per id i npep amide Sequence was treated 1 mind 3, 4-d? f luoro-beta- (2-or iet 11) -N-met i lN-phenylebencenpropamide (520 m), in MeOH / THF (1: 1, 15 mL) with 3A molecular sieves (70 mg), 4- phenol-4-hydroxypepdin HCl (700 mg) and NaBH 3 CN (103 mg). The resulting mixture was stirred at room temperature for IR hours. The reaction mixture was then quenched with water (20 mL) and diluted with CH2C12 (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2C12 (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude oil. Elution of the chromatography on silica gel with 1-2% MeOH / CH2C12 gave the title compound (570 mg). Mass spectrum (FAB): 479.2498. EXAMPLE 5 beta- (3,4-dichlorof n? 1) -4-h idrox i-N, 4-diphen? 1-1-pipepdi npentamide STEP A: 3,4-d? Chloro-beta- ((2-f or lam? Na) ~ 2-oxoet 11) -bencenpropanoi o Anhydride was treated 3- (3, -d? clsrof ni 1) glutArico (5 g, example 1, step c) in CH2C12 (100 ml.) at 0 ° C sequencing the corylaniline (2.19 mL), t pet i lamina (3.3 mL) and DMAP (236) mg). The mixture was stirred at 0 ° C for 2 hours and then > We were allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2C12 (300 mL) and washed with 1N HCl (1 x 150 mL) and water (1 x 1.50 mL). The organic layers were dried over MgSO4, filtered and concentrated to give the title compound (5.4). STEP B: 3,4-dichloro-beta- (2-hydroxyethyl) -Nf nor lbencenpropamide 3,4-dichloro-beta- ((2-phenylamino) -2-oxoet i 1) ~ benzenepropanoic acid (4.5 g) in EtOAc (100 mL) with CDO (2.6 g) and DMAP (156 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50 ° C for 2 hours. The reaction mixture was cooled to -10 * C and treated with a solution of NaBH4 (2.42 g) in H20 (50 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc (200 mL) and washed with 1N HCl (1 x 150 mL), stiff NaHCO 3 (1 x 150 mL) and water (1 x 150 mL). The organic phwas dried in concentrated MgSO4 under reduced pressure to give the crude compound as an oil. Elution of chromatography on silica gel with 0-1.0% MeOH CH2Cl2 gave the title compound (2 g). Mass spectrum (Cl): 338. STEP Cs 34-di. f lu.oro-beta- (2 ~ metansu.l foni lo i-1) -Nf or Ibencenprop namide It was cooled 3, 4-dichloro-beta- (2-h idrox i., and i 1) - N-Pheni Ibencenpropamide (340) in CH2C12 at a temperature between -5 ° C -1.0 * C and treated sequentially with Et3N (0.278 ml.) And ethansulphonic chloride 0.097 mL). After one hour, the reaction mixture was diluted with CH2C12 (75 ml.) And washed with saturated NaHCO3 (1 ml).; 50 mL). The organic layer was separated, dried over MgSO 4, filtered and concentrated under reduced pressure to yield the title compound (80 mg). STEP D: beta- (3, 4-dichloropheni 1.) -4-h idrox iN, 4-di feni 1-1-p iper id i npientamide 3, 4-dif luoro-beta- (2-metansulphide) loe iet i 1) -N-feni Ibencenprapanamide (480 mg) in DMF (5 mL) with 4-phenyl-4-hiroxy iper idine (177 m) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted in EtOAc (50 mL) and the aqueous phase was removed. The aqueous layer was extracted with EtOAc and the combined organic extracts, washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to provide an oil. Elution by chromatography on silica gel with 95: 5 (CH3C12: MeOH) provided the title compound (246 mg). Mass spectrum (Cl): 497. EXAMPLE 6 N- (4 ~ chloropheni 1) -beta- (3, 4-d ic. Lorofeni 3.) -4-h idrox i -4- feni 1- 1-p ipier id inpentamide STEP A: acid 3, 4-d? c 1 gold-beta- (2- (4-lorofem 1) to ino) ~ 2-ox oe 11) benzene no-co-acid 3-anhydride was treated , 4-d iclor f ni]) gutár io in CH2C12 (75 L a 0 * C sequencing Try 4-ck? Roan? 1 i na (2.25 g), trieti lamina (1.79 g) and DMAP (trace). The mixture was stirred at 0 ° C for 2 hours and then allowed to warm to room temperature and stirred for 2 hours.The reaction mixture was washed with 1N CH1 (3X50 mL) and water <5 mL). The organic layers were dried in MgsS04, filtered and concentrated to provide the title compound (4.9). STEP Bs 3,4-d? C3oro-beta- (2-h? Dro iet?]) -N- (4 ~ c lorofeni 1> benzephen? Anamd. 3,4-dichloro-beta acid was treated. 2- ((4- lorof nor 1) amn) -2-oxoet yl) bencenprop »ano? Co (4.0 g) in EtOAc (75 ml) with CDI (2.52 g) and DMAP (trace), the resulting solution was stirred at room temperature for 15 minutes and then heated at 50 ° C for 2 hours. The reaction mixture was cooled to 0 * 0 and treated with a solution of NaBH4 (2.59 g) in H20 (40 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with Et20 and washed with 1N HC1. (100 mL), NaHC03 sturado (100 mL) and water (100 L). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (3.81 g), STEP C: 3, 4-dichloro-beta-< 2-I annoyed him; < itil) -N- (4-c lorofeni i) bencer? propanamide 3, 4-di chloro-beta- (2-h idrox iet i 1) -N- (4-chloropheni 1) bencenpropanami (3.5 g) was cooled in CH2C12 (60 mL) at a temperature comprised between -5 ° C and -10 ° C and was treated seceuencia Try with Et3N (1.19 g), and chloride ethansul fon i lo (1.35 g). After 2 hours, the reaction mixture was washed with water (3X50 mL) and the organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to provide the thiol compound (3.8 g). . STEP D: N- (4-chloropheni 1) -beta- (3,4-di clorsfeni 1) -4-hydroxy-4- phenyl 1-1 -p iper idin-pentami a 3, -dic par-beta was treated - (2-me ansul fon i lo i i i i) -N-pheni 1 bencenpropane ida (3.8 g) in DMF (50 ml.) With 4-phenyl-4-hydroxipipter id would go (3.74 g) and me? Zcla was heated at 60 ° C for 18 hours. The cooled reaction mixture was diluted in EtOAc (100 mL) and water (100 L) and the aqueous phase was removed. The aqueous layer was extracted with EtOAc (2X100 mL), and the organic extracts were combined, washed with water (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide an oil. Elution of the chromatography on silica gel with 5% MeOH: CH2C] 2 or compound] compound (1.2 g).

Mass spectrum (FAE: 386. EJFMPl 0 7 1- (5- { -e lorofeni 1) a? Oo) ~ 3- (3,4-d? Chloroferu 1) fenit i 1) -4- feni 3 -4-p ipepd inol. The title compound was pre-prepared from N-Í4->. lorofe i 1) -bet - (3,4-d? lorofeni 1) -4-h? d o. ? -4-f n? 1-1-pi per icJin-penta ida, following the procedure of] example 2. Mass spectrum (FAB): 517. E TEMPLE 8 4-h? ro í-N-mei 11 -N, beta, -tr? f ni 1-1 -piper id i npen na ida STEP A: 3-phenyl anhydride If lutárico Was treated 3-Pheoyl acid (100 g) in CH2C12 (8 < X > mL) cartidohex and Icarbodi imide (104 g) in CH2C12 (400 mL) for 30 minutes. The resulting mixture was stirred at room temperature for * 48 hours. The reaction mixture was then diluted with hexane (800 mL '' and filtered.

The filtrate was concentrated to a reduced pressure and the residue was taken up from ethyl acetate / hexane to proporify the title compound (53 g). STEP B: beta- (2- ((phenyl 1) me i 1 i no) -2-oxoeti l) benzenepropan? Co 3-Fem Iglutárico anhydride (8.0 g) in CH2C12 (100 ml) at 0 ° Sequence was found with N-methanol (5.63 g, tetylamine (5.32 g) and DMAP (1.0 g) .The mixture was stirred at 0 ° C for 2 hours and then warmed to room temperature. and the mixture was stirred for 12 hours.The reaction mixture was washed with 1N HCl (2 × 50 ml.) and water (10 ml) .The organic layers were dried over MgSO.sub.4, filtered and concentrated to give the title compound. g) STEP C: beta- (2-h? drox? et? 1) - N-me il-Nf ni 3 bencenpropanami It was treated Beta- (2- ((f or 1) met i lanu no) -2-oxoeti 1) bencenpropane? Co (31.5 g) in EtOAc (225 ml) with CDI (11.68 g) and DMAP dO g). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50 ° C. for 2 hours.The reaction mixture was cooled to 0 ° C. and treated with a solution of NaBH 4 (9.74 g) in H 2 O (150 L), heated The reaction mixture was then diluted with Et20 and washed with 1N HCl (1.00 ml), stiff NaHCO3 (10 ml) and water (100 L). dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound <10.4) STEP D: beta- (2-methansulfen? leti]) -N-met-1-N-phenyi-benzenepropanamide Be- ( 2-h? Drax? Et 11) -N-met 11-N-phe- phenylbenzanpropanamide (5.0 g) in CH2C12 (100 ml) at a temperature of -5"C at -10 ° C and sequentially treated with; sEt3N (2.23 g) and methane chloride] foni 3 o (2.53 g). After 2 hours, the reaction mixture was washed with water (3X5 ml) and the organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (6.4 g). STEP E: 4-h? Drct? iN-met? nN, beta, 4-tp phen? l-1 -pipien di npe tanami da Se r tó b ta- (2-metart ylfontil ietil) -N-met 11-N-fem lbeneenpropanamide (2.0 g ) in DMF (10 L) with 4-phenol-4-hydroxypiperidine (1.44 g) and the mixture was heated at 60 ° C for 18 hours. The cooled mixture of the reaction was diluted with EtOAe (100 L) and water (100 mL) and the aqueous phase was removed. The aqueous layer was extracted with EtOAc (2X10O L) and the organic extracts were combined, washed with water (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide an oil. Silica chromatography on silica gel yielded the title compound (0.8 g). Mass spectrum (FAB): 443. EXAMPLE 9 1 - (5- ((fem 1) me i licked no) -3-feni lpept i 1) -4-f n? 1-4-pipepd mol The title compound was prepared from 4-h? Drox? -N-11-N, be a, 4-tr i feni 1 -1-pl ppdinpentane ida in accordance with the procedure of the example 2. Mass spectrum (CI): 429.

EXAMPLE 10 N- (-u lorofeni 1) -4-h i dro i-N-met i l-b t, 4-d? fen? l-1-pi er i inpent namide STEP A: beta- (2- <(4-c lorofeni 1) me J lamí) -2- or oet 11) bencenprop no? Anhydride 3-phenyl I lutap or (2, g) in CH2C32 (25 L) was treated at 0 ° C sequentially with 4-chloro-N-me i] ani 1 ina (1.86 g), tethylane (1.33 y) and DMAP (footprint). The mixture was stirred at 0 ° C for 2 hours and then allowed to warm to room temperature and s * --- »aided for 12 hours. The reaction mixture was washed with 1N HCl (2X50 mL) and water (100 mL). The organic layers were dried over MgSO4, filtered and concentrated to give the title compound (2.7 g). STEP B: N- (4-cl gold feni 1) -beta- (2 ~ hi drox íet i 1) -N-met i lbencenpropanamide Tieta- (2- ((4-c lorofem 1) met i lamino acid was treated ) -2-oxoet-yl) bencenprop-ico (1.3 g) in EtOAc (25 mL) with CDI (0.957 g) and DMAP (trace). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50 ° C for 2 hours. The reaction mixture was cooled to 0 ° C and treated with a solution of NaBH 4 (0.983 g) in H 2 O (15 mL), slowly warmed to room temperature and stirred for 12 hours. The reaction mixture was then diluted with Et20 and washed with HC1 N4 or (20 m), NaHC03 sturado (? < • mi) and u C'O mi). The urgAnit phase was e > _ada in MgSO4, filtration and concentrates to ba? p? * € ií > rón reduced p: -? pruporc ipnar the compue io of the titul (1.5 g). STEP C: N- (4-chlorofeni)) -bet a- (2-metansul oni lox ie? 3) -N-me i 3 bi.ni- enp na mide clothes N- (4-chlorof em 1) ~ beta- (2-h ictro; i et 11) -N-met 11-beni enpropananp d- «(1.25" in CH2C1 (25 ml) at a temperature of -5 ° C to -10 ' C and was treated sequentially with E13N (0.497 y) and chloride * - * metansul f opi 3 o (0.563 g).

After 2 hours, the acid mixture was washed with water (3 × 25 ml), saturated NaHCO 3 (20 ml) and the organic layer was separated, dried over MgSO 4, filtered and concentrated under pressure. Reduced par-a pyroparc ona i the compue-hto of the title í 1.44 g). STEP Ds N- (4-chlorophen? 1) -4 ~ h? Drox j -N-met j 1-betr *, 4-d? Pheni 3 -1-p rpr p p p p a n t i n t i n t It is tr or N ~ (4-e lorofeni 1) -beta- (2-m ta sul foni lox íe íl) -N- et i lbencenpr-opana ida < 1.44 g) in DMF (10 ml) with 4-phenol-4-hydroxyriform (1.61 g) 3rd mixture was heated at 80 ° C for 2 hor-3 = .. The ez lp cooled d *? the reaction was diluted with Ft0A > _ (50 mi) and water (50 mi.) And .- removed the oryánica. The aqueous layer was extracted > . EtOAc (2X5 ml.) and ln-3 organic extracts were combined, washed with water (5 <L), dried over MgSO4, filtered and concentrated or reduced to give an oil. elution of the ooma on silica gel with 10 * /.

Me H: CH2C12 gave the title compound (0.7 g).

Spectrum of mass (FAB): 477. EXAMPLE 11 1 - (5- ((4-c lorof ni 1) met il m no) -3-fm lpent i]) -4- f ni] -4-pii pendí ni 1 The compue o of the title was prepared from N-Í4-c lorofen i 1) -4-h? drox i-N-met 11-beta, 4-d? f ni 1-1-pi per? d? nintensive in accordance with the procedure of example 2. Mass spectrum (FAB): 463.3. EXAMPLE 12 4- (acet i] i no) -N-me i 1 -N, b ta, 4-ti feni 1 -1-pj iper id mpentanamide Fl composed of the title was prepared from beta- (2- e ansul foni lo it 11) -N-met 11-N-ben? lbenc nprop na ida, (which comes from] example 8, step D), using 4-acetyl lamium hydrochloride no-4-phenylepiper idine in a procedure analogous to the procedure of example 8, step E. Mass spectrum (FAB) ): 484. E TEMPLE 13 - (ac t i l? No) -N- (4-c lorof ni 1) -N-me i 1-bet, 4-d? feni 1-1-pipepd uipenta na ida The title compound was prepared from N- (4-chlorophen? l) -beta- (2-me nsul f oni lo iet i 1) -N-met i 1 bencertpropanamide ( Who pours the example JO, step C), using 4-acet i] m? no-4-fen hydrochloride? lp ipe id i na in a procedure similar to the procedure of example 10, page D. Mass spectrum (FAB): 518.3. FJEMP10 14 N-met i-N, beta-d? fem 1-4- (feni 1 met 11) - 1-p? pepd i npent tami da The title compound was prepared from beta- (2-me ns? l fom lxlti 1 '«-N-met i 1 -N-fem Ibenc nptroμ na ida (coming from example 8, step D), using a procedure similar to the procedure of example 8, step E. Mass spectrum (FAB): 441.1 EXAMPLE 15 N- (4-c) lorofeni 1) -N-met 11-b-fem 1 -4- (fem ethyl) -l-pipepdi pen amide The title compound was prepared from N- (4-c lorof ni 1) -beta- (2 -I ansu 1 foni lo íet i 1) -N- et i Ibencenpropanami da (coming from example 10, step O, using 4-benc i lp iper id ina in a procedure similar to the procedure of example 10, step D. Spectrum mass (FAB): 475.2 EXAMPLE 16 N-met il ~ N, b ad? feni 1-4- (feni 1 et 11) -l-p iperac i npentanamide The title compound was prepared from beta- ( 2- etansul foniloxieti l) -N-met? 1-N ~ fem lbencenpiropanamide (coming from example 8, step D), using N-phenylethylmethylpipep in a procedure s follow the procedure of step 8, step E. Mass spectrum (FAB): 442.1. EXAMPLE 17 N- (4-C lorofeni 1) -N-met i 1-beta-f n? l-4- (fen? lmet? l) -l-puperac i npentanamide E3 compound of the title was prepared from N- (4-c3 oropheni 1) -beta- (2-metansu3 foni lox let 13) -N- me i 1-benzene.) clothing (which comes in example l, ^ or C), using N-Fertile Imet 11 piperazine in a procedure similar to the procedure of Example 10, step D. Mass spectrum (FAB): 476.3. EJFMP10 18 bet a- (3, 4-d? Lorophenyl) -l, 2,3,4-tet rah idro-N-me 11-N-feni 1-2-? soqu exp iminpenta mol 3, 4-d? c parrot-beta- (2-ox? et i 1) -N-met 11-N-phenylebencenpropsamide (coming from example 1, step H) (0.53 g), in MeOH (35 L) sequencing the Try with 3A molecular sieves (5.5 g), isoquinoline HC1 (0.33 g) and NaBH3CN (0.4 g). The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered through a pad of celite (MR) and concentrated or reduced pressure. The residue was divided between a solution of NH40H at 3? 4 and CH2C12 (25 m). The organic layer was separated and the aqueous layer was extracted with CH2C12 (2 x 25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to provide a crude oil (0.7 g). The elution of the .rpn? Atoyrafla on silica gel co 2V. MeOH / CH2Cl2 gave the title compound (0.27 g). Mass spectrum (FAB): 467. E TEMPLE 19 3- (3,4-d? Chlor phen? L) -l, 2,3, 4-t trah id N-me 11 -N-pheny 1-2- i soqu mol mpentaoamina The title compound was prepared from beta- (3,4-di clor feni 1) -l, 2, 3, -tt rah ídro-N-me i] -N-feni 1 -2- í soqumol inpenta ida following the prouedimiepto of the example 2. Mass spectrum (FAB): 453. EXAMPLE 20 beta- (3, 4-d ic lorofeni 1) -3, 4-d? H? Dro-6-? Tt tox iN-met 11-4-oxa-N- feni 1-spi ro (2H-l-benzop? ran-2, '-p? p * epd? n) -l' -pentamide The compound of the title was pyreparated from 3,4-dichloro-tetha- (2-o;, oet 11) -N-met i 1-N-pheny] bencenpropanamide (coming from example 1, step H). ), using 3,4-d? h? dra-6-ethoxy-4-oxo-sp? ro (2H-l-benxopyran ~ 2, 4 '-pi pepd) HCl in a procedure similar to the procedure of example 18. Mass spectrum (FAB): 581. EXAMPLE 21 l '- (3- (3,4-D? cl orofeni 1) -5- í et i lfeni lam? no) pent i 1) -3,4 -d ih? dro-6-etox? -sp.nro (2H-l-benzop ir n-2,4 '-pi per id) -4-ol The title compound was prepared in beta-beta pair (3 , 4-dichlorophe and 1) -3, 4-d? H? Dro-6-methoxy-N-thi-4-oxo-N-phen? 1-iio (2H ~ l-bertzop? R no-2, 4 ', -p ipter id ma) -l' pentamide in accordance with the procedure of the pilot axis 2. Spectrum of more (FAB) c 569. EXAMPLE 22 Beta- (3,4-d? C lorofen11) -N-met 11- 4-axo-Nf or 1-1-pi pdinpent mida The compound of the title was prepared from 3, 4-di chloro- be - (2-oxo? 1) -N-met i 1-N-phen? lbencen clothing (from example 1, step H), mass spectrum (FAB): 433.1457. EXAMPLE 23 Beta- (3,4-d? Cl orof nor 1) -N-me 11 -Nf nor 1-4- (fm 1 et i 1) - 1-fnpepdinpenta ida The computest of the title was prepared on the basis of of 3,4-d-chloro-beta- (2-oxoet i 1) -N-met i lN-feni Ibencenptropanamide (coming from example 1, step H), using a procedure similar to the procedure of example 18. Spectrum mass (FAB): 509. EXAMPLE 24 N- (4-c lorofen i 1) -beta- (3, 4-d lcoropheni 1) -4-h idrox iN-met 11-4-fen? llp? pendí npent ida ida STEP A Acid 3,4-d? chloro-beta- (2- ((4-cl arofem 1) met i lamino) -2-oxoet 11) bencenpropane? Co 3- (3,4-d? cl orofeni 1) glutApco (10.0 g) anhydride was treated in CH2C12 (150 mL) at 0 ° C sequentially with 4-chloro-N-methyl-1-aniline (6.8 g) , tneti lamina (4.87 g) and DMAP (0.5 g).

The mixture was stirred at ßC for 2 hours and then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was washed with 1N HCl (3 X 100 mL) and water (100 mL). The organic layers were dried on MgSO4, filtered and rinsed to provide the title compound (14.9 g). STEP B 3,4-d? parrot-beta- < 2-hi dro let 11) -N- (4-cl orofeni 1) -N- et 11bencenp ida clothing 3,4-d? Chloro-beta- (2- ((4-the orofem 1) met i acid was treated no) ~ 2-oxoet 11) bencenpropane? co (14.9 g) in EtOAc (270 ml.) with CDI (9.1 g) and DMAP (trace). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50 ° C for 2 hours. The reaction mixture was cooled to 0 ° C and treated with a solution of Na H 4 (9.32 g) in H 2 O (140 mL), • slowly stirred at room temperature and stirred for 12 hours. The reaction mixture was then diluted with Et20 and washed with 1N HCl (3 X 10 mL), saturated NaHCO3 (250 mL) and water (250 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to propogate the title compound (12.64 g). STEP C 3,4-d? C 1 gold-beta- (2-metartsul foni lox let 11) -N- (4- l rofen i L) -N-met i lbencen rop na ida Cooled 3, 4- icloro -be a- (2-h? dro íe i 1) -N- (4- ._] urofertí 3) -N-met i lbencenpropartami da (2. 1 g) in CH2C12 (4O L) at a set temperature between -5ßC and -l * C and tried sequence with Et3N (0.69 g), and methan-iul fom chloride (0.78 g). After two hours, the mixture of the r-eaci. The mixture was washed with water (3X5 mL), the organic residue was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (2.3 g). STEP D N- (4-chlorofern 1) -beta- (3, 4-d icorofeni 1) -4-h? Dro; iN-met 11-4-fe * m 1-1-pifier id i npentane ida It is at 3, 4-di chloro-b a- (2-me nsul fomilloile) -N-met 11-N-fem Ibertcenpropanamide ( 1.6 g) in DMF (l mL) with 4-phenol-4-l? ? dro, < i p i pepdina (0.61 g) and 2C03 ("476 g). The mixture was stirred at room temperature * and then diluted with EtOAc dOO ml.) And washed with H20 (2X100 ml). The organic extracts were dried in MgSO4, it was filtered and concentrated under reduced pressure to pyriform an oil. elution of chromatography on silica gel with 95: 5 (CH2C 12: eOH) gave the title compound (0.56 g). Fspeetro de masa (FAB): 545.3. EXAMPLE 25 1- (5- (4-cl oropheni 1) (met 11) ammon) -3- (3,, 4-d icorofen11) ~ pent 11) ~ 4-phenyl-4-ppepdm . The compound of the title was prepared from N- (4-clarof nor 1) -beta- (3,4-d-lorofen i 1) ~ 4-h? Dro? -N-met i 1 -4- fern 1- 1-p? Per? d i npierttanamida in accordance with the procedure of example 2. Espect.ro mass (FAB): 531.1. EXAMPLE 26 N-4 4-dorQfem 1) -beta- (3, 4-d ic lorofeni 1) -N-met * .1- 4-oxo-l -p ipter id npentartamide STEP A 3, 4-d ic loro -beta- (-bromoeti 1) -Nm t? 1-N- (4-the orofeni 1) bertcenpropartam? Cla We rat 3,4-d? c parrot-be a- (2-methansulfonyloxy) -Nm t 11-N- (4-cl orof nor 1) benzenepropanamide (6.3 g, from example 27, step C) in THF (50 ml.) with lithium carbonate (2.0 g) and lithium bromide (2.34 g). The mixture was heated at reflux temperature for 2 hours. The mixture in the cooled reaction was diluted with CH2C12 (100 mL) and washed with H2O (2X100 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (5.6 g). STEP B N- (4-c lorofeni 1) -beta- (3,4-d? Lorafeni 1) -N-me 11-4-oxo-l-iper iddinptentanamide 3, 4-d-chloro-beta- ( 2-bromoe 11) ~ N-me i 1-N- (4-chloropheni-1) benzoproptanamide (4.6 g) in DMF (60 mL) with 4-p ?peridone monohydrate hydrochloride (3.94 g) and K2C03 (5.3 g). The mixture was stirred vigorously at room tempierature for 120 hours. The reaction mixture was poured into H20 (100 mL) and extracted with EtOAc (2X1O mi). The organic extr-acts were serored in MgSO4, filtered and concentrated. under reduced pressure pair-to provide urt oil. Elution of silica gel chromatography with 95: 5 (CH2C1: eOH) afforded the title compound (2.25 g). Mass spectrum (FAB): 467. I. EXAMPLE 27 N- (-1. Lorofeni 1) -beta- (3,4-? Chlorophen? L) -N-met i 1-4- <; f or 1 met 11) -l-p iperidi npentane ida STEP TO acid 3, 4-d? c parrot-beta- (2- ((4-chlorope i 1) met i lami no) ~ 2-oxoet 11> bencenprop no? co Sequence treatment Try anhydride 3- (3,4-dichlorophenyl) gluthac (5.0 g) in CH2.C12 (1O0 L) at a temperature of 0 ° C with 4-chlora-N-meth 11 and 1 ina (2.92 ml)), triethyl sheet (3.36 ml.) and DMAP (0.24 g). The mixture was stirred at 0 ° C for 2 hours and then warmed to room temperature and stirred for 12 hours.The reaction mixture was washed with 1N HCl (2X100 L) and water (2X100 Ml). The organic extracts were dried over MgSO4, filtered and concentrated to give the title compound (6.63 g) STEP B 3,4-d? ... parrot-beta- (2-h idrox let 11) -N-me? 1-N- (4-chlorofepi 1) -beneenpiropyamide It was treated with 3, 4-d-gold-beta- (2-γ (4-the orophenic 3) methalamy) -2-oxaet 13.) bencertpropanaic acid (4.0 ej) 5O in EtOAc (75 ml.) with CDI (2.43 g) and DMAP (0.122 g). The resulting solution was stirred at room temperature for 15 minutes and then heated to 50 ° C for 1 hour. The reaction mixture was cooled to 0 ° C and treated with a solution of NaBH 4 (2.45 g) in H 2 O (50 L), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with EtOAc (100 mL) and washed with H20 Q mi. ), 1N HCl (100 mL), and saturated NaHCOl (100 mL). The organic phase was dried over MgSO 4, filtered and concentrated under reduced pressure to give the title compound (3.69 g). STEP C 3, 4-d Ic parrot-beta- (2-me ansul fonilo ieti)) -N-met íl-N- (4-lorafen? 1) bencenp rop na ida Cooled 3, 4 ~ d? chloro-beta- (2-h? dro? et i)) -N-met i 1-N- (4-c 1 orofem]) -benzene ropanamide (3.6 g) in CH2C12 (100 mL) at a set temperature Between ~ 5 < , C y ~ 10 β C and treated sequentially with Et 3 N (1.62 L), and methanesulfonyl chloride (0.9 m). After two hours, the reaction mixture was washed with water (100 mL), brine (100 mL) and the organic layer was separated, dried over MgSO4, filtered and concentrated or reduced pressure to provide the title compound. title (4.3 g). STEP D N- (4-chlorophen? 1) -beta- (3, 4-d? C lorofem 1) -N-met? 1-4-i feni lmeti 3) -lp? Pendí nptent nami a 3, 4-di-loro-beta- (2-metansu) foni lo íet i 1) -N-met i] -N- (4- chlorofeni 1) bertcenp > clothes nam ida (1.6 g) ert DMF (ÍO mL) was treated with 4-f n? -4 ~ h idrox i iper id ina (1.14 g) y \ 2C03 (0.476 g> The mixture was heated to 60 * C for 38 hours.

The cooled reaction mixture was diluted with EtOAc (100 mL) and washed with H20 (2 X 100 mL). The organic extracts were dried on MgSO4, filtered and concentrated or reduced pressure to provide an oil. Elution of the chromatography on silica gel with 95: 2 (CH2C12: MeOH) gave the title compound (0.56 g). Melting point: 67-72", mass spectrum (C l): 543. EXAMPLE 28 N- (4-c lorofeni 1) -gamma- (3, -dic lorofen 11) -N-met 11 -4- ( feni l et i 1) -lp iper id inpent nami a The title compound was preptarated from N- (4-the oropheni 1) -beta- (3,4-d lorofeni 1) -N-me? l -4- (femlm til) - 1 -p ipepdi rtpentanamide using the procedure of example 2. Mass spectrum (Cl): 529. EXAMPLE 29 Beta- (3,4-d? Chlorophen? 1) -4-hi drox iNm i 1-N- (4-metho-pheny1) -4-phene-1-piperid-pentartate STEP A Acid 3, 4-d ic loro-beta- (2- í (4- eto i fe i 1) eneti lamí no) -2-oxoet i 1) bertcenpropanaic Anhydride 3- (3,4-d? C lorofem 1) glutaric (5.0 g) in CH2C1 (100 mL) was treated at 0 * C sequence 3 The mixture was stirred at 0 ° C for 2 hours and then allowed to warm to room temperature and stirred for 12 hours. The mixture of the reaction was washed with 1N HCl (10 mL), and water (2X100 mL). The organic layers were dried over MgSO4, filtered and concentrated to give the title compound (7.3 g), STEP B 3.4 ~ d-chlora-beta- (2 ~ h? Dro 1) -Nm ti 1 - N- (4- etox if ni 1) -benc n np rop na ida Acid 3, 4-d? Eloro-beta- (2- ((4-ethoxyphenyl) met 11 ami no) -2-oxoet? ]) bencenpropancnco (7.2 g) in EtOAc (125 ml) RDI (4.4 g) and DMAP (0.22 g). The resulting solution was stirred at temperature for 15 hours and then heated at 50 ° C. for 1 hour. The reaction mixture was cooled to 0 * C and treated with a solution of NaBH (4.46 g) in H20 (75 L), slowly warmed to room temperature and stirred for 12 hours. The reaction mixture was then diluted with EtOAc (100 L) and washed with H20 (1 mL), 1N HCl (100 L), and H20 UOO mL). The organic phase was dried over MgSO4, filtered and concentrated or reduced to give an oil. Elution of chromatography on silica gel with 60-100 * /. of EtOAc / hexane provided the title compound (5.43 g). STEP C 3, 4-d icloro-beta- (2-m - = - t nsu lfan i lox iet i 1) -N ~ met i l-N- (4-methoxy and feni 1) bertcenp >Na clothes went cold 3, 4 ~ d? chloro-beta- (2-h? drox? et 11) ~ N-met 11-N- (4-me tox-phene-1) -benzertpropartamide (2.0 g) in CH2C12 (50 ml) at a temperature comprised between -5 and -10 ° C and treated sequentially with Et 3 N (0.911 ml), and methansul fahyl chloride (0.64 ml). After two hours the reaction mixture was washed with water O mt * ', brine (100 ml) and the organic layer separated, dried in MgSO4, filtered and concentrated on the redressed solution to propitiate the solution. omptuesto of the title (2.56 g). STEP D beta- (3,4-d? C lorofem 1) - 4-h? drox i -N-met 11-N- < 4-methoxy-pheni-1) -4-phene-1-p-di-di-n-n-amide R-3-d-chloro-beta- (2-methansulfonic) -N-me 11-f-- ( 4-metax i feni 1) bencenprop na? da (4.2 g) in DMF (20 mL) with 4-phen? l-4-h idra? p iper idina U.53 g) and 1-2C03 (1.19 g). The mixture was heated at 60 ° C for 18 hours. The cooled reaction mixture was diluted in EtOAc (200 mL) and washed with H20 (3X150 mL). The organic extracts were dried on MgSO4, filtered. and concentrates under reduced pressure to provide an oil. Elution of the chromatography on silica gel with 90: 10 (CH2C12: MeOH) proptor-cy ortho the title compound (0.58 g). Mass spectrum (Cl): 541. FJFMPL0 30 N- (3,5-b? - (tpf luoromet i 1) fertile) -beta- (3, 4-d? The orofeni 1) -4 ~ hi dro iN -met i 1-4-feni l ~ lp i id id i id STEP AA gone 3, 4 ~ di 1 oro-beta - (2- ((3,5-b istrust luo ni 1 f or 1 ) a? no)) -2-oxoet 11) -benzeneprop3 noic Anhydride 3- (3,4-dl lorofem 1) g 3 ut (ca, 10 g, ptlo 1 axis, step C) was treated in CH2C32 (300 ml .) at a temperature of 0ßC sequencing Try 3, 5-b? s- (trif luoromet 11) an? 1 ina (7.5 mL), tpet llantina (6.7 mi) and DMAP (470 m). The mixture was stirred at O'C for two hours and then warmed to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2C12 (500 mL) and washed with 3N HCl (1 x 200 mL) and water (1 x 200 mL). The organic layers were dried over MgSO4, filtered and concentrated to give the title compound (18 g). STEP B acid 3, 4-d-chloro-beta-2-í (3,5-b? S-tp f 3 uoromet 11 phenyl) methylamino)) -2-oxoet 11) -benzene clothing ico He sighed Sodium hydride (2.16 g, 95tf) in THF UOO mL) and cooled to 0 * C. 3,4-d? Chloro-beta- (2- ((3,5-b? -tr if luoromet i 1 pheny1) mti lamino)) -2-oxoet-11) benzenepropane? Co is added dropwise. 18 g), in THF UOO mi). After the addition, the mixture was warmed to room temperature and stirred for 12 hours. The mixture was clearings heated to reflux for 1 hour. The mixture was cooled to room temperature and methyl iodide (2.6 mL) was added dropwise. The resin mixture was heated at reflux for 24 hours. It was cooled to 0 ° C and carefully quenched with H20 UOO mL). Extract with EtOAc (3 x 200 mL). The combined organic layers were dried on MgSO4, filtered and concentrated under reduced pressure to provide > =? 1 crude product. The elution ede the chromosome on silica gel1 with 0-50 * /. MeOH / CH2C12 afforded the title compound (8.5 g). STEP C N- (3,5-b? S-pf lucrómeti lf m 1) -3, 4-d icloro-beta- (2-h idroxet 11) -N-met 11-benc enp ropanani da A was treated < in 3, 4-d ic 3 gold-beta- (2- (3, - i s-tr if luoromet i lfem 1) met 13 amine)) -2-oxoet i 1) -benzene opane (7.8 g ) in EtOAc UOO mL) with CDI (3.16 g) and DMAP (19 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50 ° C. for 2 hours.The mixture of 3 to reactor was cooled to 0 * C and treated with a solution of NaBH4 (2.95 g "* in H20 (50 L), warmed slowly to room temperature and stirred for 12 hours.The reaction mixture was diluted with EtOAc (300 mL) and washed with 1N HC 2 x 20O mL) saturated NaHCO 3 U x 200 mL. and aejj.ua (1 x 200 L). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to provide crude crude in the form of an oil. Elution of chromatography on silica gel with 0-10 * 4 MeOH / CH2C12 afforded the title compound (6 g). Mass spectrum (Cl): 488. STEP D N- (3, 5-b? S-tr? F luoromet i 1 f i 1) -3, 4-d i chloro-beta- (2-o. >; oet? 1) -N-met 11-bencepprofjam? Da i na mixture of N- (3,5-b?) -trif] uoromet 13 feni 1 '• -3.4-d go loro-beta- (2-h idrox let 13) -N ~ met 11-bipyrin opane (1.3 g) and molecular sieves (4A, 624 mg) in CH2C12 (mt) was treated with TPAP (47 mg) and 4- N-oxide. The reaction was filtered through a pad of silica gel rinsed with EtOAc (100 mL) and concentrated under reduced pressure to proportionally evaporate the reaction mixture (624 mg) and stir at room temperature for 2 hours. - an oil The elution of chromatography on silica gel with 50-75V * of EOAc / hexanes gave the desired title compound (810 mg). STEP E N- (3,5-b s- tpf luoromet i 1) phenyl) -beta- (3,4-d? Lorof n? 1) -4-h idroxy-N-met 11-4-feni 1 -1 ~ p? iper idinpentami da Tr tó N- (3,5-b? -tp f luoroptet i 3 fem 1) -3, 4-d? c parrot-b ta ~ (2-oxoet 11) -N-met-1-benzenepropamide (810 mg), in MeOH / THF (1: 1, 20 ml) sequenced Try with 3A molecular sieves (534 mg), 4-phenol-4-hydroxpipepdine HCl (534 mg) and NaBH3CN U 4 rng). The test mixture was stirred at room temperature for 18 hours. The reaction mixture was piaged with water (20 mL) and diluted with CH2C12 (50 mL). The organic layer was spiked and the aqueous layer was extracted with CH2C12 (3 x 50 L). The combined organic extracts were dried over MgSO 4, filtered and concentrated under reduced pressure to provide the crude oil, elution of the rome was ographed on silica gel with 1-2 * /, MeOH / CH2C12 gave the title compound (70 m). tro more »(FAB): 647. 1663. EXAMPLE 31 v Beta- (, - i c loro n i 1) -4-h idro? -N ~ < 2-m tox i fern]) - N-met i 1-4-phen? Llp? Per? Di npenta ida STEP A Acid 3, -d ic loro-beta - (2- ((2-meto; - i feru 1) ammon) -2-oxoet 11) -benzenepraptan •: o 3 - (3, 4-d ic l rufem 1) anhydride g lutAr ico UO g, example 1, step C) was treated in CH2C12 (150 ml_ ) at 0 * C sequence. Ily with o-snisidine (6 ml.), triethylamine (6.7 ml) and DMAP (440 ml.). The mixture was stirred at 0 ° C for 2 hours and then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2C12 (500 ml) and washed with HC1 l \ -i U; 200 mi.) And water U x 200 mi). The orgArtic captures were dried in MgSO4, filtered and concentrated to give the title compound (14 g). STEP B 3, 4-d icloro-beta- (2- ((2-metho;: i fe i 1) met i lamino)) -2-fixoet 11) -benzenepropane? Sodium hydride is added (1.94 g, 95 * /.) In THF UOO L) and cooled 0 * 0. Acid 3, -dn: par-beta- (2- ((2-methoxy-fem-1) ammon) -2-o; -, oet i 1) -benzenepropa or? Co (14 mg) was added dropwise to Erjata. ), in THF U5 mL). After the addition, the mixture was heated to room temperature and stirred for 12 hours. The mixture was then heated to reflux during a hurricane. The mixture was cooled to ambient emperatu and methyl iodide (2.4 mL) was added dropwise. The resulting mixture was heated to reflux for 24 hours. It was cooled to 0 ° C and --.- > and turned off carefully with water (100 L). It is e; brought EtOAc (3 x 200 L). The combined organic layers were dried over MgSO 4, filtered and concentrated to give the crude product, elution of the chromium on silica gel with 0-50 * 4 MeOH CH2C1 piropiorne ionum. the compound of the 1 title (10 g) STEP C 3,4-d? cl gold-beta- (2-h? dro et i 1) -N- (2-meta? fem 1) -N-met i Ibencenprapanamide Acid 3, 4-d? C parrot-beta- (2- (1-metho: if ni 1) met i lamí)) -2-axoet 11) -bencenpropanoic acid (7.8 g) in EtOAc UOO mL) was treated with CDI (3.16 g) and DMAP U90 m). The resulting solution was stirred at room temperature for 15 hours and then heated at 50 ° C for 2 hours. The reaction mixture was cooled to 0 ° C and treated with a solution of NaBH 4 (2.95 g) in H 2 O (50 ml), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc (300 mL) and washed with 1N HCl (1 x 200 mL), saturated NaHCO 3 (1 x 2 mL) and U x 200 L water). The organic phase was. in MgSO4, filtered and stressed under reduced pressure to propound the crude compound as an oil. Elution chromatography on silica gel with -i < v /, MeOH / CH2C12 gave the title compound (8 g) "Mass Spec (Cl): 382. STEP D 3,4-d? chloro-beta-N- (2-etho? phenyl) -N-met 11- (2-oxoet-11) -benzenepropam. An oxal chloride chloride ion (1.14 ml.) Was cooled in CH2C12 (50 mL) at a temperature of -78 ° C and DMSO was added (1.85 mL) dropwise for 15 minutes. The mixture was stirred for 15 minutes. of which a solution of CH2C12 (10 L) of 3 was added for 20 minutes, 4-dic loro-beta- (2-h idrox let i 1) ~ N- (2-methox i fem l) -N- et i Ibencenp namide clothing (1.0 g). The mixture was stirred for 30 minutes and then treated with Ft3N (7.3 ml.) And stirred for an additional 30 minutes at a temperature of -78 ° C, followed by 1.5 hours at room temperature. The reaction mixture was quenched with water and diluted with CH2C12 OOO mL). The organic fraction was separated, washed sequentially with 1 N HCl (1 x 50 mL), saturated NaHCO 3 (1 x 50 mL) and brine (1 x 50 mL) and dried over MgSO 4, filtered and concentrated under reduced pressure to provide an oil. Elution of the silica gel chromatography with 5-15 * /. EtOAc / Hex provided the title compound 5 mg). STEP F beta- (3,4-d? C lor-ofeni 1) -4-h idrox i -N- (2-methoxy and feni 1) -N-met 11-4-fm 1- 1-p íp pdi npe t ida It was tr =? ot 3,4-ttn 1 ro-b ta-N- (2-mel, - i fepi 1) -N-met 11 - (2-oxoet il) -bencenpropamide (95 uty), in MeOH / THF (1: 1, 20 ml.) s Try to molecular sieves 3A (800 m), 4- phenyl 1 -4-h idro pipen dina HCl (ROO) and aBH3CN U56 g). The resulting mixture was stirred at room temperature for 18 hours. The rearrangement mixture was turned off with water (20 ml) and diluted with CH2C12 rum (50 ml). The organic layer was e a and the aqueous layer was extracted with CH2C12 (3 x 50 mi). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude oil. The elution of the chromosome in ge! of silica with 1.2 '/, MeOH-'CH2C12 gave the title compound (720 mg). Mass spectrum (Cl): 541. EXAMPLE 32 1- (3- (3,4-d? C lorof m 1) ~ 5- (4-hr-ox? -4-phenyl 1-1-? Per? d? n? 1) -1- or op nt 1) -l, 2,3, 4-tt rah idroqu ol r na STEP AA gone beta- (3, 4-d ic lorof ni 1) -1, 2, 3, 4-tetrah? a-oxo-quinolinic oleate-oleyl-3-anhydride 3- (3, 4-d? c 1 oropheni 1) g) ut neo (10 g, example 1, step C) was treated in CH2C12 (300 L) at 0? C sequentially. Try it with 1, 2,3,4-tetrahydroquinone (5.6 ml), tpetila ina (6.3 L) and DMAP (472 m). The mixture was stirred at 0 ° C for 2 hours and then it was warmed to room temperature and stirred for 12 hours.The reaction mixture was diluted with CH2C1 (500 ntL) and washed with 1N HCl U 200 mL) and water U x 200 ml), the organic layers were dried in MgSO, filtered and concentrated to give the compound of the tulle or U4.3 g) STEP B 1- (3- (3, 4-d ic lorofen 1) -5- hi dro? -1 -oxopertt il) - 1, 2,3,4-tet rahidroquinone ina Aci or beta- < 3, 4-d íc 1 orofeni 1) -1 was treated, , 3, 4-tetrahydro-of ts-c-o-quinol mpentanoic (14.3 g) in EtOAc (300 L) with CDI (7.42 g) and DMAP (450 m) The resulting solution was stirred at room temperature for 15 minutes. The reaction mixture was cooled to 0 C and treated with a solution of NaBH 4 (5.5 g) in H 2OOOOO), warmed slowly to room temperature and stirred for 12 hours and then heated at 50 ° C for two hours. The reaction mixture was diluted with Et OAc (500 mL) and washed with HC1 1N U x 20O mi), saturated NaHC03 U "200 mL) and water (1 x 2 < X * mi.). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to provide the crude compound as an oil. Elution of the chromatography on silica gel with 0-10V, of MeOH / CH2C12 gave the title compound (11.5 g). STEP Spectrum C l- (3- (3,4-d? Chlorophen? 1) -l, 5-? Oxopent 11) -l, 2,3,4-tet rah idroqu ol i na A solution was cooled of oxalyl chloride U.15 L) in CH2C12 (30 mL) at -78 ° C and then DMSO (1.87 mL) was added dropwise over 15 minutes. This mixture was stirred for 15 minutes. After which a solution of CH2C12 (30 ntl) of 1 - (3- (3, 4 ~ d? C.1 orof ni]) -5-hi drox iI-oxopent 11) -l, 2, 3 was added. , 4-tet rah i drejquinol i na (1. y) for 20 minutes. L = * mixture was stirred for 30 minutes and then tridated with Ft3N (7.4 ml) and stirred for an additional 30 minutes at a temperature of -78 ° C, followed for 1.5 hours at room temperature. The reaction mixture was quenched with water and diluted with CH2C12 OOO mL). The organic fraction was separated, washed sequentially with HC1 1N U x 50 mL), NaHCOT, saturated U x 50 mL) and brine (1 x 50 mL), dried on MgSO4, filtered and concentrated aunt or pressure reduced pair? provide an oil. Elution of the chromatography on silica gel with 5-15 * /, EtOAc / Hex ptroptctr-cisn the title compound (9 0 mg). STEP F l- (3 - (3,4-d? -alpha-phe-11) -5- (4-h id ra-, i -4-fen i] -1 -pi pendí ni 1) -l -ox-t -pent i 1) -l, 2, 3, 4-tet rah ídroquinol i na. 1 - (3- (3, 4-d-lorophen-1) -1, 5-d-iaxapent-11) -l, 2,3,4-tetrahydroquinoline (90O mg), in MeOH / THF U : l, 20 L) sequentially with molecular sieves 3A (67 mg), 4-phen? l-4-h? dro? ? pev-? HCl (767 mg) and NaBH3CN U50 y). The resulting mixture was stirred? ambie-rtte temperature for 18 hours. The reaction mixture was quenched with water (20 ml) and diluted with CH2C12 (50 ml). The organic layer was separated and the aqueous layer was e; brought with CH2C1 (3; 6" < "> mi.) The organic-r-organic layers were added in MgSO4, filtered and condensed b-? or reduced pressure to proprrx the raw ion. The elution of the romatograph in gel e 'il ice with 1-2.V, from MeOH / CH2C12 pt-opoi c the title compound (750 mg). Spectrum of m -r.3 'FAB): 537.2081. EJFMPI O 33 B trf- (3, 4-d? Cl orofen i 1) -4 ~ h? Drox í-N-met 11-4-fem] -N- í em l ti l) -1 -p ipepd inpentami gives STEP A Acid 3, 4-? chloro-bet a- (2- ((fem l et 11) met i] m? no) -2-oxoet yl) bencenpropane? co tr- atato artttldpdo 3- (3, 4-d chloroform 1) gl utAnco (5.0 g) in CH2C12 UOO mL) at 0ßC sequencing Try with N-me? LN ~ (feni Imet 11) am a (3.0 mi.), Tpeti lamina (3.36 L) and DMAP (0.26)). The mixture was stirred for 2 hours at 0 ° C and then warmed to room temperature and stirred for 12 hours. The reaction mixture was washed with 1N HCl UOO ml.) And water (2 x 10 i.). The organic layers were dried over MgSO4, filtered and concentrated to give the title compound (6.9 g). STEP B 3,4-d? Chloro-beta- (2-hr); let 11) -N-met i 1-N- (f or 1 met i 1) bencenpropanamide Acid 3, 4-ic 1 gold-beta- (2-((phenyl 1 met i 1) met i laa was treated ? o) ~ 2 ~ or oet i 1) bertcenptropa noico (6.9 g) in EtOAc (150 L) with CDI (4.4 g) and DMAP (0.22 g). The resulting solution was stirred at temptera tupa ambient for 15 minutes and then heated at 50 ° C for 1 hour. The reaction mixture was cooled to 0 ° C and treated with a solution of NaBH 4 (4.46 g) in H 2 O (7 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with Et-OAc (250 mL) and washed with 1N HCl (250 mL), H20 (250 mL) and added to MgSO4, filtered and reduced pressure to provide the title compound (6.29 g). STEP C 3,4-d? Chloro-b t- (2-oxoet 11) -N-met? L-N- (fi Imet i 1) bencenp ropanam ida Oxalila chloride (1.11 ml.) In CH2C12 UO mi ) to a solution of DMSO U.8 mL) in CH2C12 (75 ntL) for 15 minutes at a temperature of -78 ** C. This mixture was stirred for 15 minutes after which a solution of CH2C12 (20 ml.) Of 3,4-d? C] gold-beta- (2-hydroxiet 11) -N-met i 1 was added dropwise. -N-fe i Im 11) bencenp? ropanam i da (3.72 g). The mixture was stirred for 30 minutes and then treated with a solution of Et3N (4.24 L) in CH2C12 U0 L) and stirred for an additional 30 minutes at a temperature of -78 * C, and then heated to room temperature during the no The reaction mixture was washed with water (100 mL), the organic fraction was separated, dried over MgSO4, filtered and concentrated under reduced pressure to provide an oil (4.3 g). The elution of the ft * l chromate rafia ert ge3 silica on 1: 1 / FtOAc: Hex provided the title compound (3.09 g). STEP D beta- (3,4-d? Chlorofem 1) -4-h? Dro; i -N-met i 1 -4-fern 1-N- (fmlt 11) -1-μ iper id i pentami da 3, 4-dir par-beta- (2-o-> c? et i) ]) -N-met i 1-N- (pheni lme 11 Hiencenμ op na ida (1.21 g), in MeOH (10 mL) secuerter ia] ent with 3A molecular sieves (0. g). The resulting mixture was stirred at room temperature for 18 hours, and the reaction mixture was treated with a mixture of 1H-hydroxypropyl alcohol (0.92 g) and NaBH3CN (0.88 g). saturated solution of NaHCO 3 UO ml.) and concentrated under reduced pressure. The residue was divided between H20 (50 mL) and CH2C12 (10O mL). The organic layer was separated and dried over Na 2 SO 4, filtered and concentrated under reduced pressure to provide the title compound (0.77 g). Mass spectrum (Cl): 525. EXAMPLE 34 1- (3- (3,4-diclaraf m 1) -5- (met 11 í f ni lme 11) am? No) pent? 1) -4 ~ pheny1-4-p? Per id mol The title compound was prepared from beta- (3,4 ~ ioropheni 1) -4-h idrox iN-met 13 -4-phene 1- N- (f rule 11) -1-ptiperid i nptentamide according to the procedure of example 2. Mass spectrum (FAB): 511.4. EXAMPLE 35 2- (3- (3, 4-d) lorofert 11) -5- (4-hr idro, i -4-feru 1-1-p? Pep di ni 1) - 1- oi-opertt 13) -l, 2, 3, 4- tet rah droi -.nqnirt li na STEP A á-gone beta- (3, 4-d n. lorofeni l) - \, 2, 3, 4-tetrah idra -dl ao o- i ool i nol rtptent ncuco 3 - (3, 4-dic loroferu 1 Iglutápco anhydride (10 g, example t, step C) in CH2C12 (30 ml) at ßC was treated sequentially with 1, 2, 3, 4-tetrahydroquinone (6.0 mL), triethyl sheet (6.7 mL) and DMAP (472 m) The mixture was stirred at 0 ° C for 2 hours and allowed to warm to room temperature and stirred for 12 hr. - The reaction mixture diluted with CH2C12 (5 < ") ntL) and washed with 1N HCl U x 2 0 mi) and water (1 x 20 ml). The organic extracts were dried in MgSO4, filtered and concentrated to give the title compound (14 g). STEP B 2- (3- (3,4 ~ d? C 1 oropheni 1) -5-h? Dro i-1-oxopent 11) -1,2,3, 4 ~ t trah? Drai soqui nol a It was treated Acid beta- (3,4-d? C 3 orof nor 1) -l, 2, 3, 4-tetrahydric acid tara-oxo-i soquinol i nperttanoi co, (14 g) in EtOAc (300 mL) with CDI (7.25 g) and DMAP (440 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated at 5 ° C for 2 hours. The reaction mixture was cooled to 0 ° C and treated with a solution of NaBH 4 (6.7 g) in H 2 O (150 L), heated slowly to room temperature and then stirred for 12 hours. The reaction mixture was diluted with EtOAc (500 mL) and washed with 1N HCl U 200 mL), saturated NaHCO 3 (1: <20 tTtL) and U water; 200 6 The orgAm phase was dried in MgSO4, filtered and concentrated under reduced inlet to give the crude> as an oil.The elution of the chromatography on silica gel with 0-10 * / of MeOH / CH2C12 proposed, the title compound (12. g), mass spectrum (Cl): 378. STEP C 2- (3- (3,4-d? lorof m)) -1.5 -l loxopen 11) -l, 2,3,4-te rah idro i oqu rn 1 i na A solution of chloro chloride (.60 ml) in CH2C12 (20 ml) was cooled to -78 ° C. and then a drop was added to (O over 15 minutes of DMSO (0.749 mL) This mixture was stirred for 15 minutes, after which a solution of CH2C12 (10 mL) of 2 was added over 2 minutes. - (3- (3, 4-? Lorof rn 1) -5-h? Drox? -1-oxc? P? Ertt 11) -l, 2,3,4-tet rs h idroisoqu mol ia (1.0 g) The mixture was stirred for 30 minutes and then treated with Et3N (3 mL) and stirred for an additional 30 minutes at -78'C, followed by 1.5 hours at room temperature. The reaction mixture was quenched with water and diluted with CH2C12 (100 mL), the organic fraction was separated, washed sequentially with 1N HCl (1 x 50 mL), saturated NaHCO3 (1 x 5 mL) and brine. U x 50 ml), dried in MgSO4, filtered and concentrated under reduced pressure to provide an oil. Elution of the chromatography on silica gel rn 5-15 * /, EtOAc / Hex provided the title compound (800 m). STEP D 2- (3- (3,4-d? C lorofen i 3) -5- (4-hi droM -4-phen i 3-1-pii ep d mi l) -1-cxopent i 3) - l, 2, 3,4-tetr hi droisaqu mol ia It was treated .2- (3- (3, 4-d icl orofem 1) - 1, 5-d? opert + 11) -l, 2,3,4 -tetrahydr-oisoqumnl ina (800 m), in MeOH / THF (1: 1, 20 L) sequentially with molecular sieves 3A (900 mg), 4- phenyl] ~ 4 ~ h? drox? p? pepd? na HCl (900 m) and NaBH3CN U 30 m). The resulting mixture was stirred at room temperature • for 18 hours, the reaction mixture was piled with water (<5 ml) and diluted with CH2C12 (ml), the captain was separated and the aqueous layer was extracted with CH2C12 (3 x 50 ml), the combined organic layers were dried in MgSO4, filtered and concentrated under p re ion Reduced to reduce the crude oil. Elution of the silica gel chromatography with 1-2% MeOH / CH2C12 yielded the title compound (Blo me-,). Mass spectrum (FAB): 537. 075. EXAMPLE 36 Beta- (3,4- di lorofeni 1) -4-h idrox i -N- (3 ~ m tox i fem 1) mi 1-N-met 11- 4-phenyl-1-pi-pendant peptide STEP A Acid 3, 4-d ic loro-be - (2- ((3-tox i feni 1) met 11) met i lamí rto) -2-oxoet i 1 ) Bencen roμ noi co Anhydride 3- (3,4-d nr 1 gold fem 1) glutAr ico (6.7 g) in CH2C12 OOO ml) was treated to ßC ecuertc ia 1 mind with N-met 11-N- (3- met o; i fem 1) met 11) am? na (4.7 y), Lpel. lamina (3.27 g) and DMAP (0.32)). The mixture was stirred at 0 ° C for 2 hours and then allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was washed with HCl LN (75 ml.) And slurry (2x75 niL). The aryamic layers were serrated in MgSO4, filtered and concentrated to give the title compound U. 5 q). STEP B 3, 4 ~ d? chloro-beta- (2-hydroxyl) -N-me 11 -N- ((3-irt ox ifem 1) rtt 11) bencenp rapta nami da It was treated Acid 3, 4-d? 1 gold-beta- (2- (((3-methoxy-pheni-1) met-11) mnt-t-lam-no) -2-ox-ace-11) benc: enpteroparto? Co U. 5 g) in EtOAc (150 ml.) With CDI (6.22 g) and DMAP? ~ 3 g). The resulting solution was stirred at room temperature for 15 minutes and then heated to 500C for 1 hour. The reaction mixture was cooled to 0 ° C and treated with a solution of NaBH 4 (6.3 g) in water (75 ml), warmed slowly to room temperature and stirred for 12 hours, the reaction mixture was then diluted with EtOAe (250 L) and washed with 1N HCl (250 L), H20 (250 m) and extracted in MgSO 4, filtered and concentrated under reduced pressure to provide a crude oil (13 g). Elution of the silica gel with 5 '/, Me H / CH2C12 gave the title compound (9.35 g). STEP C 3, 4- ic loro-beta- (2-axoet 11) -N- et i 1 -N- ((3- etox i feni 1) met i 1) bencertp nam i da clothing The oru axalyl (3.23 g) in CH2C12 U < "< 0 mi.) a? 0 a solution of DMSO (4.14 g) in CH2C1 (20 mL) for 15 minutes at a temperature of -78 ° C. This mixture was stirred for 15 minutes after which s * > added dropwise a solution of CH2C12 (3 ml.) of 3, 4-dec 1 gold-beta- (2-hi '' Ir-ctx íet i 1) -N- ((3-metax i feni 1) met i 1) bencenp? ro anam gone (8.4 y). The mixture was stirred for 30 minutes and then treated with a solution of Et3N (6.43 g) in CH2C12 (30 mL) and stirred for an additional 30 minutes at a t-ur temperature of -78 ° C, and then allowed to warm up. at temp ra tur-3 atmosphere. The reaction mixture was washed with water UO L), the organic fraction was separated, sawn in MgSO 4, filtered and concentrated under reduced pressure to give an oil (11 g). Elution of silica gel chromatography with 10% EtOAc / CH2C12 gave the title compound (7.75 g). STEP D beta- (3, 4-d? C3 orafeni 1) -4-h? Drctx iN-i (3- ^ tox i feni 3) mti 1) -N-met 11-4-phene 1-1 ~ p iper id i npentana ida 3, 4-d-lor-beta- (2-ooti 1) -N-met 11-N- (3-methoxy-phenyl-1) -methyl) benc-enprop-anamide was treated ( 1.23 g), in MeOH (100 ml.) And sequencing Try molecular sieves 3A (4 g), 4-fe? Til-4-h? Drox ipipepdin? HC1 (0.87 g) and NaBH3CN (0.83 g). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was treated with a saturated solution of NaHCO3 (10 L) and concentrated under reduced pressure. The residue was partitioned between H20 (50 mL * and CH2C32 (100 mL). The urine layer was separated and dried in N2SO4, filtered and concentrated under reduced pressure to provide an oil (1.8 g). elution of the chromatography on silica gel with 5% MeOH / CH2C12 ptroport: yon the title compound ("2.77 g) m -sa spectrum (FAB): 555. EXAMPLE 37 l- (3- (, 4- ic lor f n11) -5- ((3 (methox if ni 1) met i 1) met i la no) pent 11) -4-f or 1-4- i in di no] The compound The title was prepared from beta- < 3,4-die lorofen 11) ~ 4-h idroxy -N-- ((3-methoxyl ferp 1) met 11) -N-met 11-4-pheni 1 - 1 p? The id is followed by the procedure of example 2. Mass spectrum (FAB): 541. FJEMPLO 38 N- (3, 5-B? s (tr-i f luoromet 11) f em 1) mt 11) ~ beta- (3,4-ic 1 orofe i 1) -4-hi dro; i -Nm t 11 -4-f in i 1-1 ~ p ipet- dinodientamide STEP A Ando 3, 4-d? c paroro-beta- (2- ((3,5-b? s- (tp f luoromet 11) f ui le 11) m il i no) ~ 2-oxaet i 1) -bertc enpt ropia no io Secondary treatment Try anhydride 3- (3,4-dic larofem]) glutArico (3.1 g, example 1, step C) in CH2C12 (50 i) at 0 * C with 3, 5-b is- (tp f] uorontet 11) benc i lamina (3.4 g), trieti lamina U.83 mi.) And DMAP i 15 ). The mixture was stirred at 0 ° C for 2 hours and then allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was diluted with CH2C32 (0 mL) and washed with 1N HCl (1 • 1O mi) and water (1 x 1 O L). The organic chases were dried on MgSO4, filtered and concordant to transform the title compound (6.1 y). STEP B N- (3,5-b? S- (tpfl uoromet i)) fem 1) met i 1) -3, 4-d íc parrot-bi- - (2 -ti idrax i «i 1) - N-met i 1-bencenpr or -ma uela Incidentally treated 3, 4-d? c parrot-beta- (2- ((3,5-bi s- (rif luoromet 11) fem I t 11) nt t 11 ai) -2-oxoet 11) -bencenpropanoi cu (6.1 q) in EtOAc (75 mi.) with CDI (2.43 g) and DMAP (150 m). The resulting solution was stirred at room temperature for 15 minutes and then heated to 50oC for? 2 hours. The reaction mixture was cooled to 0 ° C and treated with a solution of NaBH 4 (1.8 g) in H 2 O (3 m), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc (150 L) and washed with 1 N HCl (1 x 100 mL), saturated NaHCO 3 U x 10 0 i.) And water (1 x 100 L). The orgAruca phase was dried over MgSO4, filtered and concentrated under reduced pressure to give the crude compound in the form of an oil. Elution of silica gel chromatography with 0-10 * 4 MeOH / CH2C12 afforded the title compound (5.7 g). Mass Spectrum (FAB): 502.0791 STEP C - (3, 5-b? S- (tp f luoromet i 1) f ru 3 et i 1) -3, 4-d-chloro- / _-. >; beta- (2-oxoet 11) -N-met i-bencentre annu A mixture of N ~ ((3, -b is- (tp f luoromet 11) pheny1 »met 11 '-3, 4-di c 3 gold-beta- (2-hr-ethyl) -metha-1-benzenepropane (1. <"<" < g) &sieve-, molecular (4A, 460 nty), in CH2C12 (20 ml) It was treated with TPAP (36 m) and N-O, of 4-met 11 morpholine (460 mg) and stirred at room temperature for 2 h.The reaction mixture was filtered through a gel oha illa of silica rinsed with EtOAc (100 mL) and concentrated under reduced pressure psaia provide an oil.The elution of chromatin 3a togfia from silica gel with 50-75 * /, EtOAc / Hexanes yielded the io position of the desired title (615 mg STEP D N- ((3,5-bts- (tp f luorome i)) f nil) met? 1) ~ beta- (3,4- • di c 3 orofen11) ~ 4 ~ h? Drox i - Nm ti 1 -4-feru 1 -1-p-nd inpentamide N- (3,5-b? - (tnf luoroptet i 1 fem 1) -3,4-d-liter-beta- (2-oxyctet) ) ~ N ~ met i l-bencen ropami da (615 mg), in MeOH / TH F (1: 1, 15 L) sequentially with 3A molecular sieves (525 mg), 4-phenol-4-h? Draxip? Per? D? Na HCl (525 mg) and NaBH.sub.3 CN (104 m). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water (20 mL) and diluted with CH2C12 (50 mL). The organic capture was separated and the aqueous capture was extracted with CH2C12 (3 x 5 mL). The or-yAnica combined tops are ~ > erada = > ert MgSO4, filtered and concentrated under reduced cooling to provide the crude oil. Elution of silica gel chromatography with 1-2% MeOH CH2C12 afforded the title compound (50 (1) ntg). Fspectro de mas »a (FAB): 661.1811. EXAMPLE 39 Beta- (3, 4-d? C] oroferu 1) -N ~ ((3,5 ~ d? Me tox i fem 1) m t 11) -4-hydro; ß-N-methyl-4-phenyl] -1-p iper idinperttamide STEP A 3, 4-d-Cl-gold-be a- (2- ((3, 5-di ethoxy fem 1) met?]) met acid i am) ~ 2-o; oethyl) bencenpropane? co Sequentially anhydride 3- (3, 4-die l.iroferul) glutar? > - or (6.45 g) in CH2C12 (60 mL) at O'C with N-met 11 - N- (3, 5-d imethox i feni 1) me? 1) to ina (5.4 g), trieti lamina (3.14 g) and DMAP (0.3 g >). The mixture was stirred at 0 ° C for 2 hours and then warmed to room temperature and stirred for 20 hours, the reaction mixture was washed with 1N HCl (100 ml) and water (2x 100 ml). The organic layers were dried in MgSO 4, filtered and concentrated to provide the title compound. (11. g). STEP B 3,4-d? .clora ~ beta ~ (2-hydroxyethyl) -N-met 11-N- ((3, -dimethoxy and phenyl) met? 1) benzenepropartamide Acid 3, 4-die : par-beta- (2- (((3, -di methox? fe i 1) met i 3) mti lam? no) -2 ~ oxoet 11) ber? cenpropanaic (11.0 g) in EtOAc (150 m) with CDI (6.08 g) and DMAP (0.3 g). The resulting solution was stirred at room temperature for 15 minutes and then heated to 50 * C for 1 ttot-. The reaction mixture was cooled to 0 ° C and treated with a solution of NaBH 4 (6.2 q) in H 2 O (50 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with FtOAc (250 ml) and washed with HCl. 1N (250 ml), H20 (250 ml) and dried over MgSO4, filtered and concentrated under reduced pressure to give a crude oil (13 g). Chloride elution on silica gel with 2.5% e of MeOH / CH2C12 afforded the title compound (9.1 g). STEP C 3,4-d? Chlora-beta- (2-o;, oet? L) -N-met? lN- ((3,5-, Io) 1) met 11) Bencen ropanarr da Oxalyl chloride (3.2 g) in CH2C12 U25 L) was cooled to -78 * 'C and treated with a DMSO solution. (4.12 g) in CH2C12 (20 mL) for 15 minutes. This mixture was stirred for 15 minutes and a solution of CH2C32 (30 mL) of 3-d-chloro-beta- (2-hydroxyl-11) -N- ((3, -di ethoxy-pheni-1) met i was added. 1) Benzertpropartamide (9.0 g) dropwise. The mixture was stirred for 30 minutes and then treated with a solution of Et3N (6.4 g) in CH2C12 (25 L) and stirred for an additional 30 minutes at a temperature of -78 ° C., then it was allowed to warm up to room temperature. The reaction mixture was washed with water (125 L), the organic fraction was separated, dried over MgSO 4, filtered and concentrated under reduced pressure to pptptptor an oil (12 g). Elution of the ice gel with ice chromatography of FtOAc / CH2C12 yielded the title compound (8.2 g). STEP D Beta- (3, -4-d? C lor-oferu 1) -N ~ ((3, 5-d etox i feni 3) met? L) -4-h i roi '? ~ >; N- et 11-4-f m l-l ~ p ip r id i npentamide Was treated 3, 4-d? parrot-beta- (2-oxoet i 1) -N-met i] -N- ((3, -dimet ox i feni 3) met i l) bencertp? Weak clothing (1.5 g), in f1eOH (75 mL) Sequence Try molecular sieves 3A (5 g), 4-phenyl-4-h? d ?;? p? per? d? rn HCl (0. 8 g) ) and NaBH3CN (0.94 g). The resulting mixture was stirred at room temperature for 38 hours. The reaction mixture was treated with a saturated solution of NaHCO3 (10 mD and concentrated to a reduced pressure) The residue was dried between H20 (50 L) and CH2C12 (100 mL). Na2SO4, filtered and concentrated The pressure was reduced to give an oil (2.1 g) The elution of the chromatography on silica gel with 5 * 4 of MeOH / CH2C12 gave the title compound (1.2 g). Mass Spectrum (FAB): 585. EJFMPL0 40 Be-la- (3, 4-d? C lorofen11) -N- ((3-f 1 uoro-4-methoxy and feni 1) met 11) ~ 4- hydro i -N-met 11-4-fn? 1-1 -p iper id npertta ida STEP A Acid 3,4-d? c 1 oro-beta- (2- (((3-f luoro-4-ntotaxi fem 1) met 11) met i l-ame not) -2-oxo t 11) ben enpropane? co Anhydride 3 ~ (3, 4-dic 3 srofeni 3) gl? tAncs (4.15 g) in CH2C32 (150 mL) at 0'C 3 sequentially with N-met i 1-N- (3-fluoco-4-m or x i frm 1) mti 1 l mi na (3.25 y), triet llantina (2.0 g) and DMAP ( .2)). The mixture was stirred at ßC for 2 hours and then allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was washed with 1N HCl (75 ml) and water (2X75 ml). The organic layers were dried over MgSO4, filtered and concentrated to give the title compound (7.3 g). STEP B 3, 4-d go loro-beta- (2-h i dt o.íietil) -N-methyl-N-í (3-fluor or - 4 ~ me tox i feru 1) met i 1) bencenpropanam? It was treated Acid 3, 4-d lc-beta- (((3-fl uoro-4-grandson: i fem 1) met i 1) et i lamino) -2 -? '- oet 11) benzene? Co (7.3 g '&EtOAc USE mi.) with CDI (4.15 g) and N, N-dintet i lamí nopn r idina (0. 1 g). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50 ° C. for 1 hour. The reaction mixture was cooled to O'C and treated with a solution of NaBH 4 (4.2 g) in H 2 O (70 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with EtOAc (250 mL) and washed with 1N HC1 (250 mL), H20 (250 L) and dried over MgSO4, filtered and concentrated under reduced pressure to provide a crude oil (12 g). . Elution of silica gel chromatography with 2.5 * /, MeOH / CH2C12 afforded the title compound (.3-? G). STEP C Oxalyl chloride of 3, 4-d? chloro-beta- (2- '8 or; oe * t i 1) -N-met 11-N- ((3-m tox-phenyl) met 1) bencer? ptrop ant? d U.44 g) in CH2C12 OOO ml.) at a temperature of -78'C and treated with a solution of DMSO U.84 g) ert CH2C12 (20 mL) for 1? minutes F.-This mixture was stirred den-ante 1-5 minutes and then d * -1 ev > to - = > eg, dropwise added a solution of CH2C1 (3 ml.) of 3,4-d or:] wro-beta- (2-h idrox i and 11) -N- < (3-f luoro-4-methox i fem l) met i 1) benzoproptanamide (3.9 g). The mixture was stirred for 30 minutes, treated briefly with a solution of Et3N (2.85 g) in CH2C12 (20 mL), and then stirred for an additional 30 minutes at a temperature of -78 [deg.] C., then heated to a environment. The reaction was washed with water (100 L), the organic fraction was septated, dried in MgSO 4, filtered and concentrated under reduced pressure to give an oil (5. ""). in silica gel with 10 '/ Et0Ac: / CH2C 12 yielded the title compound (3.6 g) STEP D beta- (3,4-d? chlorophen? l) -N- (3-f luoro-4) -m tox enyl) me 11) -4-h idro i -N-met i l-4-fen? 1-1- ipen d mpentami da Se tr t 3,4-ed? c] gold-beta- (2 -oxaet 11) -N-met i 1-N ~ ((3-f luaro-4-meto; i feni 1) met 11) bencenpropanamide (1.05 g), in MeOH (50 ml) seenenc ia Try sieves Molecular 3A (3 y), 4-phenol-4-h? droMp? pepdma HCl (0.71 g) and NaBH3CN (0.7 g) The e-exultant mixture was stirred at room temperature for 18 hours, then the The reaction was treated with a -solu-unsaturated NaHC03 UO mL 'and concentrated under reduced pressure.The residue was divided between H20 (50 ml) and CH2C12 (100 ml) .The organic layer was separated and ecada in MgSO, filtered and concentrated or reduced pressure to provide an oil (1.2 q). Elution of the rom on silica gel with 5 '/, MeOH / CH2C12 yielded the title compound (0.92 g). Spectrum of maas (FAB): 573. EXAMPLE 41 1 - (3- (3, 4-d? 1 gold feni 1) -5- (4-h idro i-4-f or 1-1-p? Per? d? n? l) - opept 11) -l H-indole STEP A Acid 3, 4-di the gold-beta- ((2-U-? ndol thousand))) -2-oxoet 11) -bencenpropanoic or Anhydride 3- (3,4-d? Cl orofeni 1) glucan: (10 g, example 1, step C) was treated in CH2C12 (150 ml.) At 0 ° C secuertcicamente with indole (5.6), t pet i lamí na (6.7 mL) and DMAP (440 m). The mixture was stirred at O'C for two hours and then allowed to warm to room tempierature and stirred for 12 hours. The reaction mixture was diluted with CH2C12 (200 mL) and washed with 1N HCl (1 x 100 ntl) and water U-100 L), the organic capies were dried over MgSO4, filtered and concentrated to provide the compound of] title (14 STEP B acid 1- (3- (3,4-dichloro eru 1) ~ 5-h idroi i -1-oxopen 11) - 8 1H-i nd.il 3,4-d? C leu o-beta- ((2-U-idol nol))) -2-oxo t? 1) -ropianoic benzene (14 g) in EtOAc (3 < X < mi.) With CDI (12.5 g) and DMAP (470 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated for 2 hours at 50 ° C. the reaction mixture was cooled to ßC and treated with a solution of NaBH4 (7.3 g) ert H7O0 (100 ntL), slowly heated to room tempierature and stirred for 12 hours, the mixture of the reaction was diluted with FtOAc (300 ml) and washed with 1N HCl (1 x 200 L), saturated aHC03 U x 20-0 i) and water U x 200 ml). The organic phase was dried over MgSO 4, filtered and concentrated under recirculated pressure to give the crude compound in the form of an oil. The choice of chromatography on silica gel with 0-10% Me0H / CH2C12 yielded the thiol compound (5.5 g). STEP C 1- (3 ~ (3,4-d? Chlorofol) -l, 5 -di oxopent 11) -lH-mdol A mixture of 1- (3- (3,4-d? c lorofem 1) -5-h? drax i-l-oxopen il) -lH-? ndal (4.25 g) and molecular sieves (4A, 2.75 g) in CH2C1 (40 mt) with TPAP (50 mg) and N- 4-met i lmorphol oxide (2.75 m) and stirred at room temperature for 2 hours, the reaction mixture was filtered from a silica gel pad rinsed with EtOAc (100 ml!) and concentrated under reduced pressure to provide no oil, elution of silica gel chromatography with 30-75% EtOAc-H-hexanes gave the desired compound of the title (930 y). STEP D 1- (3- (3, 4-d? C 3o? Of m 1) -3- í -hid rax i -4-fni ll -pi per id mi 1) -to opient 11) -lH-? ndol Se t ra t 1 - (3- (3, 4 - ic 1 gold fem 1) -!, 5-d? oxoptertt 11) -lH-? rtdol (740 m), in MeOH / THF (1: 1, 30 ml) s-ec uenc i a] with molecular sieves 3A (880 mg), 4- fem l-4-h idro; ípipet-idina HCl (880 mg) and NaBH3CN U 30 m). The resulting mixture was stirred at room temperature for 10 horis. The mixture of the reaction was disengaged with water (2 utL) and diluted with CH2C12 (50 ml). the orgian cape? - t was separated and the watery capia was e; brought CJII CH2C12 (3; - 5 ml). The combined organic layers were dried in My804, fi ltered and rred in pils or reduced pressure to spray-U to the crude, elution of the chromatography in silica gel with 1- 2% MeOH / CH2Cl2 afforded the title compound (600 mg). Mass spectrum (Cl) s 521. F TEMPLE 42 Beta- (3, 4-d íc lorof eni 1) -4-h? ro-- 'iN- ((2-methox? fei 15met 11) - N-met i 1 -4-phen? 1 -1 -p iper id pentamide STEP AA gone 3, 4-? loro-beta- (2 - i ((? -meto; i phenyl) met 11) rat 11 a mo) -2 ~ o: 'oet 11) ben n rop noi. Co anhydride 3- (3, 4- ic lorof m 1> glu Anco (5.9 g) in CH 2 Cl 12 (80 nl) at 0 ° C was sequentially added with N-met 13 -N- (2 - etho ifti 1) met 13) am a (3.8 g), tneti lamina (3.5 mi) and DMAP (278 m). The mixture was stirred at 0 ° C for 2 hours and warmed-i was heated and stirred d? for hours. The reaction mixture was washed with 1N HCl U 10O ml * and brine U x 100 mL). LBS Aric layers were dried in Mg504, filtered and concented :: > to proport lunar the title compound (9.3 g). STEP B 3,4-d? Chloro-beta- (2-hydroxide; let 11) -N-met 11-N- ((2- ethoxy i fero 1) met i 1) bencer? Prop? Ana? It was treated Acid 3, 4-d ic 1 uro-beta-- (2- (((2-me l i ≤ 1) mt íl) met i 1 a? no) -2-oxa ti 1) bencenptropane? co (9.3 g "in FtOAc = 100 mL) and with CD? (4.62 g) and DMAP (345 m). The resulting solution was stirred at room temperature * for 15 minutes and then heated to 50 ° C • for 1 hot-a. The reaction mixture was cooled to 0 * C and treated with a solution of NaBH4 (3.45 g) in H20 (50 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with FtOAc 250 L) and washed with 1 N HCl 100 mL), H20 U x 100 mL) and dried over MgSO4, filtered and concentrated under reduced pressure to provide a crude oil (13). g). Elution of chromatography on silica gel with 5% MeOH-CH2C12 gave the title compound (8.7 g). Mass spec (FAB): 396.1124, STEP C 3, 4-d ic loro-beta- (2-oxoe? 1) -N-met? l ~ N- (2-methox i fem 1) m 11) benz. in na nate. A solution of oxalilct chloride (1.43 ml) in CH2C32 (30 ml.) was cooled to -78 * 0 after 3o which was added drop to got = t for 15 minutes--. DMSO (2.32 mi.). The mixture was stirred for 15 minutes. After this a solution of CH2C12 (20 ml.) Of 3,4-di-loro-beta- (2-hydroxyethyl) -N-met 11 -N- ((2- etox i feru l) met 11) bencenprapananuda (1.3 q) The mixture was stirred for 30 minutes and then treated with Et3N (9.2 iTiL) and stirred for 30 minutes at a temperature of ~ 78 ° C, followed by 1.5 hours at room temperature, the reaction mixture was quenched with 391.1a and diluted with CH2C12 (100 ml.) The organic fraction was separated, washed sequentially 1 a Try with 1N HCl (1 x 50 mL), saturated NaHCO3 (1 x 5 mL) and brine (1: - 50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to provide an oil.The elution of chromatography on silica gel with 50-1% EtOAc / Hex provided the title compound (950 mg) STEP D beta- (3,4-dichloropheni 1) -4-h idrox -N- < (2-ethoxy-1-pheny1) met i 1) -Nm 11 -4- fe i 1- 1-pt? pendí npenta ida It was treated 3, 4-d icl oro-beta- (2 -o; < oet 11) -N-met 11-N- ((2-ethoxy-1-fem-l -met-11) -ben-propyl-anam-ta (950 g), in MeOH / THF (30 ml. , 1: 1) sequentially with molecular sieves 3A (770 mg), 4-phenyl-4 ~ h? Droxip? Per? Dma HC3 (770 mg) and NaBH3CN (150 m. The resulting mixture was stirred at room temperature for 18 hours. The mep-ela of the reaction was quenched with water (20 ml) and diluted with CH2C12 (3.5 ml). The organic layer was separated and the aqueous layer was brought with CH2C12 (3, 5 ml). The combined organic rats were dried in MgSO4, filtered and concentrated under reduced pressure to provide the raw acid. The choice of silica gel on silica gel with 5% MeOH / CH2C12 yielded the title compound (720 g). Fspiectro dee masa (FAB): 553.2181. E TEMPLE 43 Beta- (3, - 1 chlorine faith 13) -4 -h 1dro 1 -N-met i 3-4-fen?] - N- (2- f or let 11) ~ l-p? P? Er? ? npentamide STEP A Acid 3, 4-d? c 1 gold-beta- (2-((2-phen? let i 1) met 11 amino) -2-? 1 l) benzenepropane? Ca 3- (3,4-dichloride 1) glutamate co (3.4 g) eri CH2C12 (50 i) was treated at 0 ° C sequentially with N-met 11 fene 1 sheet (2.4 mL), tpeti lamina (2.3 mL) and DMAP (162 m). The mixture was stirred at 0 ° C for 2 hours and then allowed to warm to room temperature and stirred for 20 hours. The reaction mixture was washed with 1N HCl (1 x 100 L) and U x 100 mL brine.). The organic layers were dried in MgSO4, filtered; and concentrated to provide the title compound (4.6 g), STEP B 3, 4-d ic loro-beta- (2-h? droaet? l) -N-me iN- (2-phene i 1) -bencer? Clothing was treated 3-3, 4-d? Chloro-beta- (2- ((2-phenet-1) met i 1 ai) -2-o; cn "t 11) benz in opioid (4.6 g) ert EtOAc (75 L) with CDI (2.6 g) and DMAP U 2) The resulting solution was stirred at room temperature for 15 minutes, and then heated to 50 ° C. for 1 hour. The reaction was cooled to "* 0 and treated with a solution of NaBH4 (2.5 g) in H20 (30 mL), slowly warmed to room temperature and stirred for 12 hours. The mixture of the reaction was then diluted with EtOAc: (250 ml) and washed with HC] 1N (1: 1 OO ml), H20 U x 100 ml) and dried over MgSO 4, filtered and concentrated under reduced pressure to give the reaction mixture. p provides a crude oil (5 g). Elution of 3a silica gel romatography with 2.5% MeOH / CH2C12 gave the title compound (3.5 g). Spectrum of ma sa sa (FAB): 380.1177. STEP C 3,4-d? C.3-chloro-beta- (2-oxoet? L) -N-met 13 -N- (2-phenet 11> -Lterteenpropanamide A solution of oxalyl loride U .25 ml was cooled ) in CH2C12 (25 mL) at a temperature of -78 ° C after which DMSO (2.03 mL) was added dropwise over 15 minutes. This mixture was stirred for 15 minutes. After this, a solution of CH2C12 (25 ml.) Of 3,4- i chloro-beta- (2-h? Ro.- i et i 1) -N-met 11-N- (2 -fenet i 1) -bencenpropanamide (1.1 g). The mixture was stirred for 30 minutes and then treated with Ft3N (9.2 ml.) And stirred for an additional 3 minutes at a temperature of -7 BßC, followed by 1.5 hours at room temperature. The reaction mixture was quenched with water and diluted with CH2C12 (100 L). The organic fraction was separated, washed sequentially with 1 N HCl; 50 mL), saturated NaHC03 or U x 50 L) and brine U x 50 L), mec d ert MyS04, filtered and concentrated under reduced pressure to propose an oil. The choice of chromatography on silica gel with 50-100% EtOAc / Hex afforded the title compound (900 m). STEP D beta- (3, 4-d? Chlorofem 1) ~ 4 ~ h 1 clrax? ~ N-? 2 ~ fenet 11 > -N- et 11-4- feni 1-1-p ipieridinpenta ida It was 3,4-d? 1 gold-bet a- (2-oxoe i 1) -N-met 11 -N ~ (2-phene i 1) -benzenepropanamide (900 m), in MeOH / THF (30 mL, 1: 1) seeuerte lal ertte with molecular sieves 3A (800 g), 4-phenyl-4-hydroxylpipepdine HCl (760 m) and NaBH 3 CN (150 mg). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was piaged with water (200 ml) and diluted with CH2C12 (50 ml.). The organic layer was separated and the oil layer was extracted with CH2C12 (3 x 50 mL). The eirganic capias were combined, dried in MgSO4, filtered and concentrated under reduced pressure to provide the crude oil. Elution of the chromatography on silica gel with 1-2% MeOH / CH2C12 on the title compound (680 mg). Spectrum of ..tasa (FAB): 539.2222. 8" The rn v 11 ro and in vivo of the quantities of the formula I can be determined by the following table: - PROCEDURE IN VITPO PAPA IDENTTFICAP L A NK ACTIVITY 1 Test compounds are tested for determine its ability to inhibit the activity of substance 0, agonist N 1, on the vas deferens island of guinea pig. Freshly cut deferential canals of Hartley male guinea pigs (230-350 g) are removed and are placed in baths 11 of 25 ml that contain a solution of reb. Heated to 37 ° C and constantly oxygenated with 95% of 02 and 5% of C0. The tissues are adjusted to O.5 g and allowed to equilibrate for a period of 30 minutes. the vas deferens is exposed to electric field stimulation dinner (stimulator S48 of Srass) every 6 seconds at an intensity that causes the tissue to contract at 80% of its maximum capacity. All responses are recorded isometically by means of a Grass force displacement transducer IFFT3) and a Harvard electronic recorder. Substance P inhibits skin contractions is imitated by the electric field of the guinea pig's deferential ducts. In studies not in pare ^ >;, all la-i. Tissues (control and drug-treated) are exposed to accumulated concentrations of the substance P ≤ l 10,000,000,000 M 7 l / l 0,000,000 t). The unique logarithmic concentrations of the test compounds are supplied to separate tissues and = > e allows to equilibrate for 30 minutes before generating a response curve to the concentration of the substance P. At least 5 separate tissues are used for each control and individual concentration of drug for each drug test. The inhibition of substance P is demonstrated by the displacement to the right of its c urva of respect to the on entry. These shifts are used to determine the pA2 value, which is defined as the negative logarithm of the molar concentration of the inhibited that would require twice the amount of agonist used to cause the chosen response dinner. This value is used to determine the relative potency of the antagonist. TRIAL NK2 TRIALS OF H MSTER ISOLATED TRAQUEA The general methodology as well as the characterization of the responses of the hamster trachea- to the neuroquimne agonists as provided by a monoreceptor assay of Nt'2 is found in CAMaggi et al. , Eur.: J. Pharmacol. 166 (1989) 435 and I.l.Ellis, et al., I. Phar. Exp. Ther. 267 1 1 93) 95. Continuous monitoring of the isometric tension is achieved with Grass force displacement transients FT-03 connected -t pn-eampl 1 Bu drivers; co Electronics integrated into a Gi-ctphtec L i rt rcorder Model WP 3310. Stun hamster male Charles River LAKct.VG (SYR), of J 3 2 grams in weight, by means of urt goal foot fast on the head. , e? -the loss of the corneal reflex is assured, the sters are sacrificed by means of aractomy and the heart is cut. Cervical segments of the trachea are removed in tw-ebs regulator at room temperature, pH 7.4, or igenado; < : an a g i consisting of 95% of 02 and 5% of C02 and clean d * -3 adhereutes tissues. The segments are cut into two or more "artillo" segments of 3-4 millimeters long. The rings * - * trachea are suspended from transducers and anchored in enamelled organ baths with water of 15.0 ml by means of stainless steel hooks and 6-0 wax. The baths are full of regulator of rebs, pH 7., maintained at a temperature of 37"C and with only one gas that consists of 95% of 02 and 5% of CO2.The tracheal rings are placed under an initial tension of 1.0 g and left for a period of 90 minutes with four straight 1 μM of NI A, washed and applied to recovery cycles at 20 minute intervals A pretreatment with 30 minute vehicle is followed by cumulative additions of increasing doses of NIA (final concentration 3 nM - 1 μji, additions at intervals of 5 minutes) The final response to NI A is followed by a 15 minute bath and a recovery period. pretr at at 30 minutes with test item or vehicle followed by cumulative doses of increasing doses of N (ert necessary case final concentration 3 nM - 10 ptM, add at intervals of 5 m? Nuto =). The final response to is followed by a 1 M carbon Utol challenge to obtain a response to the 3 rd maximum voltage at each tee time. The spreads of tissue to NI A are recorded as positive plunging of the pen in comparison to 3rd line b-? - to 1 and they become the tension in grams in broken ra-1 ó • on standing tables. The responses are normalized as a percentage of the maximum tissue tension. The ED50 for NI A are calculated from the responses to the treated N A doses and control and compared. Test compounds resulting in a dose ratio of agonist greater than igile to 2 at a sieving concentration of 1 piM (ie pA2-60) are considered active. Additional dose response data are obtained for active compounds in such a way that an apparent p? A2 estimate can be calcified. pA2 is already calculated - whether by estimation of \ i in accordance with that described by Furchgntt (where pA2 - - og i, PF Fur hgott, Phar. Pev. 7 (1995) 1R3) or by means of the Shild Graphic Art Analysis (O. Arunlafcshana &HO Shild, Br. J. Pharmacol. 14 (1959) 48) if the data are sufficient.

EFFECT OF ANTACONY TAS DF NIU SOBPE THE FIJGA MICPOVASOUL P OF THE RESPIRATORY IAS INDUCED POP THE SUBSTANCE P FN CONETILLOS DE INDIAS v Is re.lisan is ndio in guinea pigs, Hartley male Indies with a foot of 4? O 650 g. Animals receive food and water ad libitnm. The ammonia are in two sides by means of an injectable injection of dialurethane with an O.sub.m. content of A di dll Ib, 11%, 0.4 g / ml ethyl ester. ea and 0.4 g / ml methane). The trachea is intubated just below the larynx and the animals are ventilated (VT = 4 mi, f = 45 r sp i rae, i one - »/ mi n) with" respirator respirator Havar for rodents, vein jugulae It is used for the injection of drugs, using the blue praying role technique of Evans (a ni, G., et al., Pharmacal, Commun., 1,203-209, 1992) to measure the microvascu- lar leakage. »Respiratory pathways (AML, Evans' A zu l (3? Mg / lg) and injected intravenously, followed 1 minute by the iv injection of substance P UO μg / l * g) Five minutes later, The thorax is opened, and a needle of size 13 with a soft tip is passed into the aorta, an incision is made in the right atrium and the blood is driven by ep uage with 100 ml of a plin solution in the aortic catheter. The lungs and 3rd trachea are removed en bloc and the trachea and bronchi are then dried with piaptel filter and weighed, the blue of Ev-trtH is extracted by incubac tissue ion at 37 ° C for IR hours in 2 ml of amide in walled tubes. The absorbance of extraneous dye numbers at 62 n is measured. -The amount of dye is calculated by interpolation from a standard blue curve of Evan® within the range of 0.5-10 jag / ml in formauda. The concentration of dyes was skeletally colored dg per mg of tea i p -? damp. The test compounds are suspended in a cyclodextran urt vel tirul and i .v is provided. 5 minutes arit.es of the substance P. MEASUREMENT OF THE ACTIVITY OF N 2 IN LIVE Coneji l the Hartley male indians (400-500 gm) with access ad libi? Ma food and water are ane-iterated with an injection I nt rapten tortea of 0.9 ml / tg of citrate urethane (with urt content of 0.1 g / m of acid d iia ba rb i tunco, 0.4 g / ml of ethylurea and 0.4 g / ml of urethane). After the induction of surgical anesthesia, tubes are implanted in the trachea, esophagus and jugular vein to facilitate mechanical breathing, measurement of esophageal pressure and drug supplementation, respectively. The guinea pigs are placed inside a full-body topography and the cartridges are connected to the exit holes in the p3 et i sitograph. The flow of a i e is used using the differential ptresiort transducer <; V =? 1 iclyne, Northridge CA, model MP 45-1, range +/- 2 cnt H20) that ide 1 ^ pressure to you from a wire screen that covers a hole of 2.4 centimeters on the wall of the let i or r fo . . { The air flow signal is integrated into a flow proportional to the volume. The pulmonary pressure is measured as the pressure difference between the trachea and the esophagus using a differential pressure transducer (Validyne, Northridge, CA, model MP45-1, range "- / - 20 cm H20). Transpulsion signals are monitored by means of a pulmonary analysis computer (E'UKCO Electronics, Sha on, CT, model 6) and used for the derivation of pulmonary resistance (PL) as well as the cumc dynamic pulmonary lysis (CDyn) PP0NC0C0NST ICCT0N DEBIDA ANA Increasing doses of NA are administered iv at half logarithmic intervals (0.01-3 μg / lg), which allows recepiection of the baseline pulmonary mechanics between each Dosage The puco bronchial con- traction occurs within 3 seconds after each dose of agonist.The dose response stops when CDyn is reduced 80-90"from baseline. A two i -re-? Ptu * -a t- a NKA is found in each animal. the test compounds are suspended in a vehicle of c lox ano and administered iv 5 minutes before the start of the dose-response study for Nt-'A. For each animal, the curves of response to the dose pair Nt-A are constructed by the yraf ica i n of the percentage increase in PL or decrease in CDyn against the logarithmic dose of agonist. The =. doses of Nl'A that increase L in 10O * Á (.PL 10) or decrease CDyu by 40% (CDyn40) in 5 compared with Io baseline values! they are obtained by means of linear logarithmic interpolation of response curves to the dosi. FNLACE EYMSAYO (S) OF PECEPTOP OF NFÜP00UININA Cellos of Chinese Hamster Ovary < CH0) t ansf ct adas with C "? The coding regions for the human neuroquinone 1 (NI-1) of the human neurochemicals 2 (NK2) receptors are cultured in a minimum Dulbecco essential medium supplemented with 10 * / * ede of fetal calf serum, 0.1 rtM of non-essential amino acids, 2 mM of glutamine, 100 5 units / ml of penicillin and streptomycin, and (5.8 mg of 0418 ml at a temperature of 37 ° C in a humid atmosphere containing 5% C02.) The cells detach from the T-175 traits with a sterile solution. -il containing 5 mM EDTA in a phosphate-regulated saline solution.Cells are harvested by centrifugation and: washed in an RPMI medium at 40 * 0 for 5 minutes.The skin is resuscitated in TPS- HCl (pH7.4) that contains 1 uji of phosphoriirtidon and 4 μg / ml of qnimostat a at a cell density of 30; < 1 0,000,000 5 élul s s / nil. The suspension is homogenized in a Brirtlman Politrórt (setting 5) for 30-45 seconds. The homoyei? Ada is centp escaped to 80O. and for 5 minutes. »at A 9C to collect the broken na cells and nuclei. The supernatant is placed in a Sorvall RC5C at 19,000 rpm (44, v g) for 30 minutes at 4 ° C. The third pellet is suspended, the aliquot is removed for a protein determination (BCA) and washed again. . The resulting pellet is stored at -80 ° C. To test t-1 link with the receptor, 50 ptl of (3H) -Substance P (9-Sar, 1l ~ Met (02)) (specific activity 41 C? mmol) (Dupont-NFN) (0.8 nM for the NI-1 test), or (3H) ~ Neuroquine A (specific activity 114 Ci / m ol) (Tench) (1.0 nM for the NK-2 assay) is added to tubes containing regulator (50 mM Tps-HCl (ptH .4) with 1 M of Mr.C12 and 0.2 of bovine serum albumin) or DMSO or the test compound. The binding is carried out by the addition of 100 μl of membrane (10-20 μg) containing the Nl'-l or human NL-2 receptor in a final volume of 20 μl. After 40 minutes at room temperature, the reaction is stopped by means of filtration in filters Which are GF / C, which have been previously moistened in 0.3% pol. wash the filters twice with 3 ml of 50 M Tps-HCl (piH 7.4). Filters are added to 6 ml of a Reaiy-Bafe liquid scintillation me.-cla and quantified by liquid scintillation spectrometry in a L B 1219 Rae I-Beta counter. The non-specific binding is determined by the addition of either 1 μM and CF- < : '9994 (Nl "l) or bi n 1 μM of SB-489¿.8 (NI 2) (both synthesized by the Chemical Research Institute of the Research Institute of Scher i ng-Pl ough). the IC50 values of the ertlae curves: e of the pietenc la and the i values are determined in accordance with Cheng and Frusoff using the value determined at intent (5.8 nM for the receiver) - of NL '1 and 2.4 nM for The NK2 receptor Using the test procedures described above, the following data were obtained for representative compounds of formula I: For all compounds of the invention, the Nt-1 link is within a range of a; Imidally 7-97% inhibition at a concentration of 1 μM For all the compounds of the present invention, the N 2 bond is within a range of approximately 90% inhibition at a concentration of 1 μM. It will be understood that while linking Nl-2 for certain compounds of the present invention is up to 0% in concentration of 1 μM, in corn in r-ac i CJUT - 3 A ?. When these breaks are high, they may have a 3-fold inhibition effect on NL2. The activity "-1-" of the present compounds of the present invention, in the Neurokinin Receptor Binding Assay, are as follows: b ta- (3, 4- ic lorof in i 1 ) -4-h? Do; i -N- mt 11 -N, Ad if eni 1-1 -prp> rir id inpentamida Link: NI 1 tí i - 1 0 nM; Nt 2 M = 5.2 nM. - (3,4-? Chlorof n? L) -4-lt? O; if -N-met 11-4-fn?] -N- (f eni 1 met 11) -lp? P? Er id i npentamide Link: NM fci * 6.8 nM; N'2 Ci = 108 nM.beta- (3, 4-d ic lorof eru 1) -4-h? Dro--? - N- ((3-meto? If eni) ]) met 11) - N- et il -4-fem lt- i per id mpepla i »Fnlace; NL 1 M - 12 nM; Nt'2 tí i = 215 nM. beta- (3, 4-d? c 1 orof em 1) -4-h? dro: - i -N- ((-me ton íf eni 1) met 11) - N-met 11 -4-f in 11-1-p? iper id i npentanucJa Link; NL '1 Li = 7.5 nM; Nt'2 t i = 3 nM. beta- (3,4-d? c what ofeni 1) ~ 4-h? dro; - 'i -N-met i l-4-f n? 1-N- (2-f or lethyl) -l-p? pendí nptentami da Enlace: Nt 1 t: i = 70 nM; Nt'2 i = 46 nM. The t-i of a compound is the condition in which the excitement causes a 50% inhibition of NL 1 or of NL2. For the ampoules of the present invention having a inhibition of greater than 50% NL 1, the H i for Nt'l was determined. The NM for such compounds fall within a range of approximately 6.8 nM to approximately 215 nM. For the compounds of the present invention having an inhibition greater than 50% Nt, the =. t i for Nt 2, the Li pair-to Nt¡2 piara such contigs fall inside "Q from a range of approximately 5.2 nM to approx., - madamenle 215 nM. It will be recognized that the compound of the formula I exhibit an antagonistic activity of NL 1 and Nt 2 in vain degrees, e.g., certain cleavages having a strong antagonist activity with NK 1, but a weaker Nt 2 antagonist activity. . Others are strong antagonists of Nt 2 but deacetic antagonists of Nt-1. While c-initiates with an approximate strength are preferred, it is also within the scope of this invention to use compounds with an acronym activity. NM / NL2 unequal cu-indo is chemically approved. S > It has been found that the compounds of the formula I are antigens of the NL 1 receptors and of the Nt 2 receptors and are therefore useful for the treatment of conditions which have been proved or aggravated by the activity of the NM receptors. and NL "2. The present invention also relates to a pharmaceutical composition comprising a compound of the formula I and pharmaceutically acceptable carrier.The compounds of this invention can be administered in conventional oral dosing agents such as capsules, tablets or tablets. , powders, lozenge 4, suspensions or solutions, or in injectable dosage forms such as solutions, suspensions or polyesters for reconstitution, pharmaceutical adjuvants can be prepared with e;, ci. In addition to the use of standard formulations, the use of non-toxic fillers and excipients and additives is generally acceptable. chemically compatible?, binders, disintegrants, regulators, preservatives, artt i o¡ < lubricant, lubricants, formerly, thickeners, coloring agents, emu 1 s i f i > _a rttes and s 11 a re. The target dose of a compound of formula I for e3 treatment of asthma, cough, b orth = > ptasma, inflammatory disease, migraine, noc and ceptc ón a =. As gastrointestinal disorders, it is from about 0.1 mg to about 20 mg / kg of body weight per day, which is about 0.5 to 100% apyloid: 15 mg / kg, and with a higher preference of 0.5%. 5 mg / t < g. For an average body weight of 70 l < g, the dosing ranch is therefore from about 1 to about 15 g of drug per day, the preference being between 50 and about 100 mg intact, admistered in a single dose or in 2.-A doses divided. However, the exact dose is determined by the physician responsible for the patient and depends on the potency of the compound administered, the age, weight, condition and response of the patient.

Claims

RFIVTNDT0A0I0NES 1. L =? invention relates to compound. »of the formula where each i and j is independently selected within the group consisting of l and 2; ca to n - > e selects i dependently on the group consisting of 0, 1, 2 and; and each n 'is independently selected within the gretpo consisting of 1, 2 and where A and A 'are H, or A and A' together are = 0, -S; O well -N-R4s X is selected from the group consisting of 0, 00, 0 (R, R1), C - = - C (Pl, R8), NR1 and S (0) e where e is 0, 1, or 2; P is selected within the group consisting of H, 0R8, 00N (RR) 2, 0N, S (0) eP8, S0eN (R8) 2, 002R8 and NP400R8; Rl is selected from the group that you opted for t-t, rent 01-06, i loalqui 3o 03-08 $? ? R2, P, P5, P0 and P7: independently selected within] gr-upc »consisting of H, halogen, alkyl 01-06, 0F3, 02Fc ?, ORO, 00R8, 002P8, C0N (R8, P8), N (P8, R8), N (R8) C0R8, S (0) eR8, 00 (0) P4, 00 (0) N (R8, R4), NR8002R4, NR8 (C0) N (P8, P8), R15-fen ?, R15-benzyl, N02, NR8S02R4, -S (0) 2N (R8) 2 or when R2 and P3 or any group of two of R5, R6 > and R7 are in adjacent carbons can form a -0-CH2-0- group; each R 4 is independently selected from the group consisting of alkyl, substituted alkyl, substituted sulo, and substituted benzyl; each R8 is independently selected from the group consisting of H, alkyl, substituted alkyl, substituted aplo, and substituted benzyl; c-ida R15 is independently H, halogen, lower alkyl, aleo; i lower; and U is l < D) (E) n "is independently selected within the group consisting of 0, 1, 2 and 3, the dashed line is an optional carbon-carbon bond, R16 is H, alkyl Cl-C ?, -S (0) 2R4, C0R8, C02P4, C0N (R8) 2, R1 -f or Rl 5-benzyl Substituted means substituted with a selected substituent within the group consisting of H, CICA alkyl, 0CF3, CF3 and C2F5 2. A compound according to claim 1, wherein 1 i is 1 and is 1. 3. An i omposed in accordance with Id rei indication 1, where n is 1, n "is 0, 1 or 2, and n 'is 1. 4. A compound according to claim 1, wherein n, n' and n "are all 1. 5. A compound according to the rei indication 1, where rt, and n 'are both 1, and rt "e: -. 0. 6. A compound according to claim 1, wherein rt, rt 'are both 1, and n "is two 7. A compound according to claim 1, wherein A and A' are amitos H. 8 Urt composed in accordance with claim 1, where A and A 'together are -0 9. A compound according to claim 1, wherein X is C (P, P1) 10. A compound of cortforetti with claim 1, wherein R is 0R8, C0N (R8) 2 ON, or NP4C0P4 11. A compound according to claim 1, where X is NR1 12. A compound according to claim 1, wherein Rl is 13. A compound according to claim 1, wherein n is 0 or 1 and R8 is H, 14. A compound according to claim 10, wherein R2, P3, R5, R and P7 are H, halogen, C1-C6 alkyl, * -) CF3, 0RB, C0R8, 002R8, C0NP8, R8 or NR8, R8. 15. A compound according to the rei indication 10, wherein R16 is H or alkyl. 16. A compound according to claim 10, wherein each of R8 is selected from the group consisting of H, C1-C6 alkyl and R1 -f or lo. 17. A compound according to claim 10, wherein P.8 is H or substituted alkyl. 18. A comptu.e or in accordance with claim 10, wherein U is 19. A compound according to claim 1, selected from the group consisting of "D 25 ¿2N? or a pharmaceutically acceptable salt thereof. 20. A composition comprising an effective neurokinin antagonist amount of a compound in accordance with rei indication 1 and a pharmaceutically acceptable carrier material. 21. A od for inducing antagonism to neurokines comprising the administration of an effective neurokinin antagonist amount of a compound according to claim 1 to a mammal that requires it. 22. A od for the treatment of respiratory-, chronic- or co-operative asthma and allergies; inflammatory diseases such as inflammatory bowel disease, psoriasis, asteoart, and rheumatoid arthritis; migraine; disorders of the central nervous system such as by employd Depression, psychosis, dementia, and Alzheimer's disease; Doe-rn syndrome; neuropathy; multiple sclerosis; ophthalmic disorders; conjun ivi is; autoin disorders; graft rejection; lupus in systemic tissue; untreated gastrointestinal disorders, for example, illness • • • Crohn and colitis ulc rati a; Trainer of 1 -i function of 1 -i bladder; disorders of] H circulation such as angina; Raynaud's disease; cough and pain comprising administering an effective neuron-shrink antagonist amount of a compound according to claim 1 to a mammal that requires it.