MXPA00004956A - Substituted oximes as neurokinin antagonists - Google Patents

Abstract

Compounds within the genus represented by structural formula (I) or a pharmaceutically acceptable salt thereof, wherein:T is substituted phenyl or substituted pyridyl;R1 is H, methyl, ethyl, -CH2CN, -CH2C(O)NH2, -(CH2)3SO3H, -CH2C(O)NHCH3, -CH2C(O)NHOH, -CH2C(O)NHOCH3, -CH2C(O)NHCH2CN, -CH2F, -CH2C(O)NHCH2SO3H, (a), (b), (c), (d) or (e);R4 is methyl or ethyl;and Z is substituted piperidinyl.

Description

QXIMAS SUBSTITUTED AS ANTAGONISTS IN NEUROQUININE BACKGROUND OF THE INVENTION The present invention relates to a genus of substituted oximes useful as tachykinin receptor antagonists, in particular as neuropeptide antagonists neurokinin-1 receptor (NK-?) And / or neurokinin-2 receptor (NK2) and / or Neurokinin-3 receptor (NK3). Neurokinin receptors are found in the nervous system and in the circulatory system and peripheral tissues of mammals and are therefore involved in a variety of biological processes. Accordingly, neurokinin receptor antagonists are expected to be useful in the treatment or prevention of various diseases of mammals, for example asthma, cough, chronic obstructive pulmonary diseases (COPD), bronchospasm, emesis, neurodegenerative diseases, eye diseases, inflammatory diseases. such as arthritis, central nervous system conditions such as migraines and epilepsy, nociception, psychosis and various gastrointestinal disorders such as Crohn's disease. In particular, it has been reported that NKi receptors are involved in microvascular leakage and mucosal secretion, and NK2 receptors have been associated with smooth muscle contraction, which makes the NKi and NK2 receptor antagonists especially useful in the treatment and prevention of asthma. The NKi and NK2 receptor antagonists have been previously described: the arylalkylamines were described in U.S. Patent No. 5,350,852, issued September 27, 1994, and the spiro-substituted azacycles were described in WO 94/29309, published on 22 December 1994. U.S. Patent No. 5,696,267 describes compounds represented by the generic structure or a pharmaceutically acceptable salt thereof, wherein: a is 0, 1, 2 or 3; R is H, C -? - 6 alkyl, -OH or C2-C6 hydroxyalkyl; A is an optionally substituted oxime, hydrazine or olefin; X is a bond, -C (O) -, -O-, NR6 -, - S (O) e-, N (R6) C (O) -, -C (O) N (R6) -, -OC (O) NR6-, -OC (= S) NR6, -N (R6) C (= S) O-, -C (= NOR1) -, -S (O) 2N (R6) -, -N (R6) ) S (O) 2- N (R6) C (O) O- or -OC (O) -; b, d and e are independently 0, 1 or 2; T is H, phthalimidyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyl or bridged cycloalkyl; Q is -SR6, -N (R6) R7), -OR6, phenyl, naphthyl or heteroaryl; R6a, R7a, R8a, R9a R6 and R7 are H, C1-6 alkyl, C2-C6 hydroxyalkyl, Ci-C17 alky1 Ci-Cß alkoxy, phenyl or benzyl; or R6 and R7, together with the nitrogen to which they are attached, form a ring; R9a is R6 or -OR6; Z is morpholinyl, optionally N-substituted piperazinyl, optionally Substituted g is 0-3 and h is 1-4, with the proviso that the sum of h and g is 1-7; wherein the aryl, heterocycloalkyl, heteroaryl, cycloalkyl and bridged cycloalkyl groups are optionally substituted. It has been found that some compounds within this generic structure show surprisingly higher activity as neurokinin antagonists than those previously described in specific form.

BRIEF DESCRIPTION OF THE INVENTION The compounds of the present invention are represented by the formula or by a pharmaceutically acceptable salt thereof, wherein: T is R2-phenyl or R3-pyridyl; R1 is H, methyl, ethyl, -CH2CN, -CH2C (O) NH2, - (CH2) 3SO3H, CH2C (O) NHCH3, -CH2C (O) NHOH, -CH2C (O) NHOCH3, -CH2C (O) NHCH2CN , CH2F, -CH2C (O) NHCH2SO3H, R represents 2-3 substituents independently selected from the group consisting of chlorine, methyl and methoxy; R3 represents 2 to 3 substituents independently selected from the group consisting of chlorine and methyl; R 4 is methyl or ethyl; and Z is Z-isomers of the compounds of formula I are preferred. Compounds of formula I in which T is R2-phenyl are preferred, with compounds wherein R2 represents two chloro substituents, two methyl substituents (preferably 3,5-dichloro or 3,5-dimethyl), or two methoxy substituents and one methyl substituent (ie, 3,5-methoxy-4-methyl) considered to be the most preferred; especially preferred are compounds in which R2 represents two chloro groups. Also preferred are compounds of formula I in which R1 is methyl -CH2F, -CH2CN, - (CH2) 3SO3H, with methyl being most preferred. R 4 is preferably methyl. Another group of preferred compounds is one in which Z is with preferring even more preferred, especially preferred. This invention also relates to the use of a compound of formula I in the treatment of asthma, cough, chronic obstructive pulmonary diseases (COPD), bronchospasm, emesis, neurodegenerative diseases, eye diseases, inflammatory diseases such as arthritis, central nervous system conditions such as migraine and epilepsy, nociception, psychosis, and various gastrointestinal disorders such as Crohn's disease. In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I in a pharmaceutically acceptable carrier. The invention also relates to the use of said pharmaceutical composition in the treatment of asthma, cough, chronic obstructive pulmonary diseases (COPD), bronchospasm, emesis, neurodegenerative diseases, eye diseases, inflammatory diseases such as arthritis, central nervous system conditions such as migraine and epilepsy, nociception, psychosis, and various gastrointestinal disorders such as Crohn's disease.

DETAILED DESCRIPTION OF THE INVENTION In the structural formulas that are shown throughout the specification and claims the hydrogen atoms can be understood, for example, the partial structure. ap Some formulas can include a methyl group shown as a line and the point of adhesion to the other atom is shown as a line through which a wavy line is drawn, ie The compounds of formula I can have at least one asymmetric carbon atom and all isomers, including the diastereomers, enantiomers and rotational isomers as well as the E and Z isomers of the oxime, hydrazone and olefin groups, are contemplated as part of this invention. The invention includes the isomers d and I both in pure form and in mixture, including racemic mixtures. The isomers can be prepared using conventional techniques, either by reaction of optically pure or optically enriched materials or by separation of the isomers of a compound of formula I. Those skilled in the art will appreciate that for some compounds of formula I, an isomer will show an pharmacological activity superior to that of the other isomers. The compounds of the invention have at least one amino group which can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, citric acetic, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, tartaric, methanesulfonic and other mineral and carboxylic acids which are well known for those skilled in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form can be regenerated by treating the salt with a dilute aqueous base solution such as dilute aqueous sodium bicarbonate. The free base form differs from its respective salt form in some way with respect to some physical properties such as solubility in polar solvents, but on the other hand the salt is equivalent to its respective free base forms for the purposes of invention.

Some compounds of the invention are acids (for example, those compounds that possess a carboxyl group). These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of said salts are sodium, potassium, calcium aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, N-methylglucamine, and the like. The compounds of formula I can be prepared using methods that are well known to those skilled in the art for example by methods described in WO 96/34857. Those skilled in the art will recognize that other procedures may be applied, and that the process can be conveniently modified to prepare other compounds within the scope of formula I. The compounds of formula I defined above can be prepared as shown in the following reaction scheme related to the broader scope of the compounds which are described in WO 96/34857. In the reaction scheme, the variables are as defined above for the PCT application: Stage 1 : 46 (A: R '21: alkoxy B: R21 = Cl C: R21 = -N (CH3) OCH3) In step 1, a compound of formula 47A is reacted, where Q is as defined above, with a base such lithium diisopropylamide (LDA), KHMDS or KH in an inert organic solvent such as THF or DME for generate a dianion. An acid chloride, an ester or an amide of formula 46A, 46B, or 46C is added to obtain the ketone of formula 48. Preferably the reaction temperatures are between -78 ° C to 30 ° C. Alternatively, compounds of formula 48 can be generated by the reaction of a compound of formula 46, preferably 46C, with a metallized species of formula QCH2Mt in which Mt is a metal, such as lithium or MgHal, where "Hal" is halogen. Metallized species QCH2Mt can be generated by conventional methods, such as the treatment of compounds of formula QCH2Hal with Mg or by treating QCH3 with an organolithium base.

Stage 2: 49 In step 2, for the compounds described in the PCT application where R is not hydrogen, the ketone 48 is reacted with an appropriate base, such as LDA or KH in an inert organic solvent such as THF. For compounds wherein R is alkyl or hydroxyalkyl, a compound R-R17 ', wherein R17' is a leaving group such as Br, I or triflate. For compounds of the PCT application where R is OH, an appropriate oxidizing agent such as dimethyldioxirane or a Davis reagent is added. Preferred reaction temperatures are between -78 ° C to 50 ° C. For the compounds of the present invention, which correspond to the compounds of the PCT application, in which R is H, the ketone 48 is used directly in step 3.

Stage 3: In step 3, the ketone 49 is reacted with a base such as LDA in a solvent such as THF, and then an olefin of formula 50 is added, where R17"is as previously defined, to obtain the adduct 51 The preferred reaction temperatures are between -78 ° C to 60 ° C.

Stage 4: In step 4, the ketone 5_1 is reacted with HA ', where A' is NH-OR1, in an organic solvent such as pyridine or ethanol at a temperature between 25 ° C to 150 ° C to obtain a compound of formula 52 .

Stage 5: In step 5, a compound of formula 52 is oxidized by ozonophosis to obtain an aldehyde of formula 53. Suitable organic solvents include EtOAc, CH 3 OH, ethanol, CH 2 Cl 2 or the like. Preferred reaction temperatures are -78 to 0 ° C.

Stage 6: In step 6, an aldehyde of formula 53 is reacted with a compound of formula Z-H, wherein Z is as previously defined. The reaction is preferably carried out with a suitably substituted amine (such as its acid salt, for example, HCl or maleate or as its free base) and a hydride source such as NaBH 3 CN or sodium triacetoxyborohydride in an appropriate solvent (for example CH3OH, CH3CH2OH, or CF3CH2OH for NaBH3CN, or THF, 1,2-dichloroethane, CH3CN or CF3CH2OH for triacetoxyborohydride), with 3A sieves to obtain the desired product. Any suitable temperature can be used, with temperatures between 0 ° C and 25 ° C being preferred. Alternatively, a compound of formula I can be prepared from 51 by the following reaction scheme, wherein the variables are as defined for the cited PCT application.

Compound 51 is oxidized to a compound of formula 54 under conditions similar to those described for the preceding step 5. The aldehyde of formula 54 is reacted with a compound of formula ZH in a manner similar to that described in step 6 and the resulting ketone is then reacted with a compound of formula HA 'as described above in step 4 for obtaining the compound of formula I. Reactive groups not involved in the preceding processes can be protected during reactions with conventional protecting groups which can be removed by conventional procedures after the reaction. Table 1 below shows some typical protective groups: TABLE I The compounds of formula I proved to be antagonists of the NK- ?, and / or NK2, and / or NK3 receptors, and therefore, are useful for treating conditions caused or aggravated by the stimulation of said receptors. The present invention also relates to a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier. The compounds of this invention can be administered in conventional oral dosage form such as capsules, tablets, powders, seals, suspensions or solutions or in injectable dosage form such as solutions, suspensions, or powders to be reconstituted. The pharmaceutical compositions can be prepared with conventional excipients and additives, using well-known pharmaceutical formulation techniques. The pharmaceutically acceptable excipients and additives include non-toxic, chemically compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavors, thickeners, coloring agents, emulsifiers and the like. The daily dose of a compound of formula I for the treatment of asthma, cough, bronchospasm, inflammatory diseases, migraine, nociception and gastrointestinal disorders is from about 0.1 mg to about 20 mg / kg of body weight per day, preferably about 0.5. up to about 15 mg / kg. For an average body weight of 70 kg, the dosage range will therefore be from about 1 to about 1500 mg of drug per day, preferably about 50 to about 200 mg, and more preferably about 50 to about 500 mg / kg per day , administered in a single dose or in 2-4 divided doses. The exact dose, however, will be determined by the clinician and will depend on the potency of the compound administered, the age, weight, state and response of the patient. Examples are given below for preparing starting materials and compounds of formula I. As used herein, Me is methyl, Bu is butyl, Br is bromine, Ac is acetyl, Et is ethyl and Ph is phenyl.

PREPARATION 1 1-rr (3,5-bisftrifluoromethanophenimethoxy-3- (3,4-dichlorophenyl) -5- (4-hydroxy-4-phenyl-1-piperidinyl) -2-pentanone A solution of (c / s) -lll (3,5-bis (trifluoromethyl) phenyl] methoxy] methyl] -4- (3,4-dichlorophenyl) -4-hydroxy-4-phenol-1 is treated. -piperidinebutanol (2.0 g, 3.08 mmol) in acetone (90 ml, 0 ° C () with Jones's reagent (9 ml of H2CrO in H2SO (ca.8M).) The orange-colored suspension is stirred at 0 ° C. for 1 hour, and then divided between CH2Cl2 (150 ml) and saturated aqueous NaHCO3 (150 ml) The aqueous layers are extracted with CH2Cl2 (3 x 150 ml) and the combined organic layers are extracted again with saturated aqueous NaHC3. (150 ml), dried (Na2SO) and concentrated to give 1.94 g of crude product, purified by chromatography on silica gel (column: 4 cm x 15 cm, eluent: EtOAc: hexane: triethylamine (66:33: 2)) to obtain 1.64 g (2.53 mmol, 82%) of the title compound as a colorless foam HRMS (FAB, M + H +): m / e calculated for [C3? H3oNO3CI2F6] +: 648.1507, found 648.1496 .

PREPARATION 2 Step 1: Dissolve 4-aminomethyl-piperidine (30.00 g, 0.263 mol) in CH3OH (500 ml), cool to -30 ° C under N2, add di-t-butyl dicarbonate (38.23 g, 0.175 mol) in CH3OH (100 ml) dropwise, warm slowly to 23 ° C and stir for 16 hours. Concentrate, add CH2CI2 (700 mL), wash with saturated aqueous NaCl (2x200 mL), dry the organic solution (MgSO4), filter and concentrate to give 36.80 g of an 86:14 mixture of the title compound. and 4 - [(1,1-dimethylethyloxycarbonyl) methyl] -1-piperidinecarboxylate 1,1-dimethylethyl ester.

Step 2A: Dissolve the product (19.64 g, 0.0916 moles, 22.84 g of the mixture) from step 1 in dry CH2Cl2 (350 ml) and cool to 0 ° C under N2. Pyridine (10.87 g, 11.1 ml, 0.137 mol) is added, then chlorovaleryl chloride (15.63 g, 13.0 ml, 0.101 moles), is slowly heated to 23 ° C and stirred for 16 hours. Saturated aqueous NH4C (300 mL) is added, the layers separated and extracted with CH2Cl2 (2x250 mL). The combined organic extracts are dried (MgSO4), filtered and concentrated. Purify by chromatography (1000 ml of evaporative silica gel: eluent: 1: 1 EtOAc: hexane, then EtOAc): The appropriate fractions are combined and concentrated to give 25.36 g (0.0762 moles, 84%) as an oil colorless MS (CICH4): m / e 333 (M + 1).

Step 2B: Treat the product of step 1 in a procedure similar to that described for step 2A, using chlorobutyryl chloride. MS (FAB); m / e 319 (M + 1).

Stage 3 PREPARATION 2A Wash NaH (3.84 g, 0.160 moles, 6.40 g of 60% by weight) with hexane (25 ml), suspend in dry THF (150 ml) and cool to 0 ° C under N2. The product (25.35 g, 0.0762 mol) from step 2A in dry THF (150 ml) is added dropwise. It is stirred at 23 ° C for 30 minutes, refluxed for 6 hours, and stirred at 23 ° C for 16 hours. Cool to 0 ° C and add water (150 ml) and 1N HCl (150 ml). Concentrate and extract with EtOAc (3x200 ml). The combined organic extracts are washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated. Purify by chromatography (600 ml of evaporative silica gel); eluent: 5% CH3OH-CH2Cl2). The appropriate fractions are combined and concentrated to give 21.62 g (0.0729 mol, 96%) of the title compound as a yellow oil. MS (FAB): m / e 297 (M + 1).

PREPARATION 2B The product of step 2B is treated in a procedure similar to that described for prep. 2A. MS (FAB): m / e 283 (m + 1).

PREPARATION 2C The product (1.50 g, 5.06 mmol) of the prep is combined. 2A and Lawesson's reagent (1.13 g 2.78 mmoles) in dry THF (20 ml) under N2. Stir at 23 ° C for 20 hours. Concentrate and purify by chromatography (200 ml of evaporative silica gel: eluent 1: 3 EtOAc: hexane, 1: 2 EtOAc: hexane, and then 1: 1 EtOAc: hexane). The appropriate fractions are combined and concentrated to give 1.30 g (4.16 mmol, 82%) as a green oil. MS (FAB): m / e 313 (M + 1).

PREPARATION 2D Dissolve the product (2.50 g, 8.43 mmol) of the prep, 2A in dry THF (30 mL), add borane-DMS (16.9 mL of 2.0 M in THF, 33.74 mmol) and reflux for 20 hours. Cool to 0 ° C and add CH3OH (20 mL). Concentrate, add EtOH (50 mL) and K2CO3 (4.66 g, 33.74 mmol). It is refluxed for 4 hours and cooled to 23 ° C. Water (100 ml) is added, it is concentrated and extracted with CH? C (4x50 ml). The combined organic extracts are dried (MgSO4), filtered and concentrated. They are purified by chromatography (200 ml of evaporative silica gel, eluent: 7% CH3OH-CH2Cl2). Appropriate fractions are combined and concentrated to give 1.72 g (6.09 mmol, 72%) of the title compound as a colorless oil. MS (FAB): m / e 283 (m + 1).

PREPARATION 2E Dissolve the product (1.50 g, 5.06 mmol) of the prep. 2A in dry THF (20 ml) and cooled to -78 ° C under N2. Add [(CH3) 3S] 2NLi (5.5 mL of 1.0 M in THF, 5.5 mmol) and stir at -78 ° C for 1 hour. Add bromomethylcyclopropane (0.820 g, 0.59 ml, 6.07 mmol), heat slowly to 23 ° C and stir for 16 hours, add saturated aqueous NH4CI (40 ml), extract with EtOAc (3x30 ml), wash the Organic extracts combined with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated. Purify by chromatography (175 ml of evaporative silica gel, eluent: 2% CH3OH-CH2CI2 and then 4% CH3OH-CH2Cl2.) Combine the appropriate fractions and concentrate to give 0.93 g (2.65 mmol, 53%) of the Compound title in the form of a colorless oil, MS (FAB): m / e 351 (M + 1).

PREPARACON 2F It is the product of prep. 2A in a procedure similar to that described for prep. 2E, using allyl bromide. MS (CI / CH4): m / e 337 (M + 1).

Stage 4: The prep products are dissolved separately. 2 A to 2F in CH 2 Cl 2, add trifluoroacetic acid and stir at 23 ° C for 4 hours. Concentrate, add 1 N NaOH, extract with CH 2 Cl 2, dry the combined organic extracts (MgSO 4), filter and concentrate to obtain the corresponding substituted piperidines.

PREPARATION 3 Step 1: Using the procedures of Preparation 2, replace 4-aminomethyl-1- (1,1-dimethylethyloxycarbonyl) -piperidine with 4-amino-1-benzylpiperidine in prep. 2, stage 2A and continue through prep. 2, stage 3.

Step 2: Treat the palladium hydroxide (2.0 g) in EtOAc (100 ml) with the product of step 1 (25.0 g, 0.0918 mol) in EtOAc (200 ml) and (tBOC) 2O in EtOAc (200 ml) . To prepare, the resulting mixture is stirred on a Parr stirrer at 50 psi H2 pressure for 3 hours and then more palladium hydroxide catalyst (2 g) is added and stirred for 16 hours. The catalyst is removed by filtration and washed with EtOAc. Concentrate and purify by chromatography (silica gel, eluent 5% CH3OH-CH2Cl2). The appropriate fractions are combined and concentrated to give 24.37 g of the product as a white solid. MS (FAB): m / e 283 (M + 1).

Step 3: Treat the product of Step 2 according to a procedure similar to that described for preparation 2F. MS (CI / CH4): m / e 267 (M-55).

Step 4A: Treat the product of step 3 (5.17 g, 16.0 mmol) in EtOAc (90 ml) and H20 (90 ml) with Nal04 (20.57 g, 96.2 mmol) and Ru02 (0.064 g, 0.48 mmol). Stir at 23 ° C for 5 hours, add 1 N HCl (20 mL) and filter. The solid is washed with EtOAc and H2O. The filter layers are separated and extracted with EtOAc. The combined organic extracts are dried (MgSO), passed through charcoal and concentrated to give 5.10 g of the title compound. MS (FAB): m / e 341 (M + 1).

Step 4B Treat the product of preparation 2F according to a procedure similar to that described in step 4A to give the protected amino acid.

Step 5A: The substituted piperazines 3A5 to 3H5 as well as the 3N5 and 305 are prepared in a similar procedure using the appropriate amine. Treat the product of step 4A (1.00 g 2.94 mmole) in CH2Cl2 (20 ml) with carbonyldiimidazole (0.57 g, 3.53 mmol) and stir at 23 ° C for 4 hours. The appropriate amine is added and stirred for 16 hours. Add 1N HCl and extract with CH2Cl2. The combined organic extracts are dried (MgSO 4), filtered and concentrated. Purify by chromatography (silica gel: eluent: CH 3 -OH-CH 2 Cl 2). Appropriate fractions are combined and concentrated to give 3A5 to 3H5 and 3N5-3O5.

Step 5B Compounds 3I5 to 3K5 were prepared in a procedure similar to that described in step 5A by substituting the product from step 4A for the product of step 4B using the appropriate amine.

PREPARATION 3L5 The product of preparation 3, step 2 is treated according to the procedure similar to that described in preparation 2F, substituting the allyl bromide for the product of example 18L, step 2, to obtain the title compound.

Step 6 Compounds 3A6 to 3N6 are prepared by treating products 3A5 to 305 (step 5) according to the procedure similar to prep. 2, step 4. The preparation of 306 is carried out by treating the product of preparation 3, step 1, according to a procedure similar to that described for preparation 3, step 2, omitting (t-BOC) 2? to obtain the title compound. PREPARATION 4 PREPARATION 4A Step 1 Treat N-benzyl-piperidone (8.00 g, 0.0423 mol) in CH2Cl2 with (CH3) 3 SiCN (4.82 g, 0.0486 mol) and Znl2 (0.68 g, 0.0021 mol). It is stirred at 23 ° C for 16 hours and concentrated. Add saturated CH3OH NH3 (30 mL) and heat to 40 ° C. The resulting mixture is concentrated, CH2Cl2 (200 ml) is added, dried (MgSO4), filtered and concentrated to give 11.06 g of the desired product as a yellow oil. MS (CI / CH4): m / e 189 (M-26).

Step 2: Treat the product of step 1 according to a procedure similar to that of preparation 2, steps 2A and 3. EM (CI / CH). m / e 298 (M + 1).

Step 3: Treat the product from step 2 (1.50 g, 5.04 mmol) in t-BuOH (25 mL) with KOH (0.99 g, 17.64 mmol) and reflux for 30 minutes. It is cooled to 23 ° C and concentrated. Saturated NaCl (40 mL) is added, extracted with CH2Cl2 (3x40 mL), dried (MgSO4), filtered and concentrated. Purify by evaporative chromatography (silica gel, eluent: 10% CH3OH-CH2Cl2). The appropriate fractions were combined and concentrated to give 0.98 g of the desired product as a yellow solid. P.f. = 184-186 ° C. MS (FAB): m / e 298 (M-17).

Step 4: Treat the product of step 3 (0.97 g, 3.08 mmol) in CH3OH (25 ml) with palladium hydroxide (0.40 g). Stir on a Parr shaker at 50 psi under H2 pressure for 16 hours. Filter, wash with CH3OH and concentrate to give 0.69 g of the title compound as a white solid. P.f. = 180-185 ° C. MS (FAB): m / e 210 (M-15) PREPARATION 4B Step 1 Treat the product of the present preparation 4A, step 2 (1.50 g, 5.04 mmol) in CH2Cl2 (25 ml) with trichloroethyl chloroformate (TROC-CI) (1.39 g, 6.55 mmol). Stir at 23 ° C for 16 hours. Add 0.25 N NaOH (40 mL), extract with CH2Cl2 (3x40 mL), dry (MgSO4), filter and concentrate. Purify by evaporative chromatography (silica gel, eluent: 1: 1 EtOAc: hexane to 2: 1 EtOAc: hexane). Appropriate fractions are combined and concentrated to give 1.31 g of the desired compound as a white solid P.f. = 185-186 ° C, MS (CI / CH4): m / e 382 (M + 1).

Step 2 Treat the product of step 1 (1.30 g, 3.40 mmol) in THF (20 ml) with HOAc (1.9 ml, 34.0 mmol) and zinc (2.22 g, 34.0 mmol). Stir at 23 ° C for 18 hours. H2O (10 mL) is added, filtered and washed with EtOAc. 6.25 N NaOH is added to the filtrate, extracted with CH2Cl2, dried (MgSO4), filtered and concentrated to give 0.70 g of the title compound as a white solid. MS (CI / CH4): m / e 208. (M + 1).

PREPARATION 4C Step 1 Treat 4-cyano-4-phenylpiperidine in CH3OH with 50% KOH / H2O and heat in a sealed tube at 180 ° C for 2 hours. It is cooled to 23 ° C and concentrated to give the desired compound.

Step 2 Treat the product of step 1 with di-t-butyl-dicarbonate according to a procedure similar to that of preparation 2 step 1 to give the protected amino acid.

Step 3 The product of step 2 is coupled with morpholine according to a procedure similar to example 8 using DMF as a solvent.

Step 4 The amine is deprotected using a procedure similar to preparation 2, step 4, optionally substituting TFA for HCl 4D PREPARATION Step 1: Acetaldehyde (4.6 g, 105 mmol) and dimethylacetone dicarboxylate (7.1 g, 35 mmol) were cooled to 0 ° C and treated with benzylamine (5.2 g, 49 mmol), 12 N HCl, (4.1 mL), and H2O (3 ml). Stir at 23 ° C for 16 hours.

The reaction mixture is concentrated, acetone (20 ml) is added, filtered and concentrated. 6 N HCl (30 mL) is added and heated at 80 ° C for 16 hours.

The resulting solution is cooled to 23 ° C, basified to pH 10 with KOH granules and extracted with CH2Cl2 (3x80 ml). The combined organic extracts are dried (MgSO 4), filtered and concentrated. Purify by evaporative chromatography (silica gel, eluent: 10% EtOAc-hexane). The appropriate fractions are combined and concentrated to give 1.8 g of yellow oil. EM (FAB) m / e 218 (M + 1) Step 2 Treat the product from step 1 (1.7 g, 8.3 mmol) in CH3OH (10 mL) with H2NOH »HCl (1.2 g, 16.8 mmol) and CH3CO2 Na (2.05 g, 25 mmol). It is refluxed for 4 hours, then cooled to 23 ° C and concentrated. Saturated NH 4 Cl is added and extracted with CH 2 Cl 2. The combined organic extracts are dried (Na 2 SO 4), filtered and concentrated to give 1.6 g of a brown oil. MS (FAB) m / e 233 (M + 1). Step 3 Treat the product of step 2 (1.5 g, 6.46 mmol) in EtOH (20 ml) with Raney nickel (1 g, wash with EtOH). Stir on a Parr shaker at 41 psi of H2 pressure for 16 hours. The reaction mixture is filtered and concentrated. Purify by evaporative chromatography (silica gel, eluent: 7% CH 3 OH with NH 3 CH 2 Cl 2). The appropriate fractions are combined and concentrated to give 0.85 g of a clear oil. MS (FAB) m / e 217 (M + 1).

Stage 4 Continue in a similar manner to that described for the preparation 306 substituting 4-amino-N-benzylpiperidine for the product from step 3. MS (FAB) m / e 211 (M + 1).

PREPARATION 5 Step 1: A solution of (f?) - (+) - 4-benzyl-2-oxazolidinone (100 g, 563 mmol) and 1.10-phenanthroline (10 mg) in dry THF (1.25 I) is cooled to -78 ° C. and / 7-BuLi is added through an addition funnel at a rate such that the internal temperature remains <; -70 ° C. Add r? -BuL¡ (350 ml of 1.6 M in hexane, 350 mmol, 1 eq.) Until the reaction turns brown from the phenanthroline complex (about 349.5 ml). After 15 minutes, 3-carbomethoxypropionyl chloride (69.5 ml, 564 mmol, 1 eq.) Is added for 10 minutes through a syringe. The resulting solution is stirred for 30 minutes at -78 ° C. The mixture is allowed to warm to 23 ° C, then it is poured into EtOAc (2.5 L) / saturated NH 4 Cl (1 L). The organic layer is washed with saturated NH 4 Cl (1 L), saturated NaHCO 3 (2.5 L) and saturated NaCl (2.5 L), and then MgSO 4 is dried and concentrated to obtain a yellow solid. The solid is recrystallized from hot isopropanol (820 ml) to give 157.9 g (542 mmol, 96%) of the pure product as a colorless crystalline solid, m.p. 90-92 ° C.

Step 2: A solution of TiCl4 (419 ml of 1M in CH2Cl2, 419 mmol) in dry CH2Cl2 (1.35 I) is cooled to 0 ° C and treated with ti (O / -Pr) 4 (41.4 ml, 140 mmol) at through a syringe. After 10 minutes at 0 ° C, diisopropylethylamine (102.4 ml, 587 mmol) is added through a dry addition funnel. The resulting solution is stirred for 15 minutes at 0 ° C and then the product from step 1 (163.2 g, 561 mmol) is added in a single portion. The solution is stirred for 1 hour at 0 ° C and then freshly distilled acrylonitrile (147 ml, 2.24 moles) is added through an addition funnel. The resulting mixture is allowed to stand at 4 ° C for 18 hours and then the reaction mixture is poured into 25% aqueous NH 4 Cl (4 L) / EtOAc (6 L). The organic layer is washed with 12.5% aqueous NH 4 Cl (2 x 41), saturated NaHC 3 (4 l), and saturated NaCl (4 l), then dried (MgSO 4) and concentrated. The crude product is dissolved in EtOAc and filtered through a pad of silica gel (500 g). The filtrate is concentrated (6 I) and crystallized from hot CH3OH (4 ml / g) to give 116.5 g (338.3 mmol, 60%) of the pure product, as a colorless crystalline solid, m.p. 103-105 ° C.

Step 3 Treat a solution of the product from step 2 (25 g, 72.6 mmol) in CHCl3 (100 ml) and CH3OH (400 ml) with PtO2 (1.25 g) and place on the Parr @ 45 psi stirrer. It is stirred for 24 hours, then the mixture is filtered through a pad of Celite. The filtrate is concentrated to give 28.3 g of crude amine »HCl.

Step 4: Treat a solution of the product of step 3 (72.6 mmol) in 1,2-dichloroethane (500 ml) with HOAc (6 ml, 105 mmol, 1.4 eq.), Followed by? / - Boc-4-piperidone. (14.6 g, 73.5 mmol, 1.01 eq.) And NaB (Oac) 3H (25.7 g, 122 mmol, 1.7 eq.). It is stirred for 1.0 hour, then the mixture is poured into CH2Cl2 (1.4 I). Wash with saturated aqueous NaHCO3 (2x560 ml), dry (MgSO4) and concentrate to give 39.1 g of the product.

Step 5 A solution of the product from step 4 (72.6 mmol) in CH3CN (500 ml) is stirred for 72 hours at 50 ° C. Cool and concentrate to give 39.3 g of lactam.

Step 6 Treat a solution of the product of step 5 (39.3 g) (containing up to 72.6 mmoles of a mixture of N-benzyl and N.methyl-cyclohexyloxazolidinones) in CH 3 OH (150 ml), with NaOH (148 ml of NaOH aqueous 1 N, 2.2 eq.) It is stirred for 6 hours at 23 ° C and then it is concentrated. H20 (50 ml) is added and washed with EtOAc (3 x 200 ml) to remove the oxazolidinone. It is acidified to pH 2 with 40 ml of 15% aqueous HCl (4.4 M) and extracted with CH2Cl2 (4 x 200 ml). The combined extracts are dried (MgSO 4) and concentrated to give the pure acid as a colorless foam (22.3 g, 65.5 mmol, 96% ee). It is recrystallized from hot acetone (18 ml / g, reflulted, filtered, cooled, approximately 300 ml of solvent is extracted in rotoevaporator, seeded and sonicated, cooled to 10 ° C, isolated by filtration with 50 ml of cold acetone washes) to give 16.5 g (48.5 mmol) of the pure product as a colorless solid, 16.5 g (48.5 mmol, 67% from the product from step 2); p.f. 145-147 ° C, > 99% ee, on a chiral HPLC column; Daicel Chiracel OD, 85:15 hexane / isopropanol with 0.1% TFA).

Step 7 Treat a solution of the product of step 6 (10.0 g, 0.029 mol) in CH2Cl2 (100 ml) with HOBT (6.0 g, 0.044 mol), the appropriate amine in THF (or dioxane) (0.044 mol), and DDC (9.1 g, 0.044 moles). Stir at 23 ° C for 4 hours. It is filtered and washed with 0.5 N NaOH, the layers are separated, extracted with CH2CI, dried (MgSO4), filtered and concentrated. Purify by evaporative chromatography (silica gel, eluent: EtOAc and then with 5% CH3OH-EtOAc). The appropriate fractions are combined and concentrated to give the product.

Step 8 Treat a solution of the product of step 7 in CH2Cl2 (125 ml) with TEA (25 ml). It is stirred at 23 ° C for 4 hours and concentrated. H20 (25 ml) is added and basified with 20% in weight of NaOH. Extract with 20% EtOH in CH2Cl2 (7x100 ml). Dry (MgSO4), filter, and concentrate to give the products 5A to 5C.

PREPARATION 6 Step 1 Use the procedures of example 11, steps 1, 2 and 3, using 3,5-dichlorobenzoyl chloride in place of 3,5-bistrifluorobenzoyl chloride, to obtain the corresponding ketone product.

Step 2 Treat the product of step 1 with H2HOH HCl using a procedure similar to that described in example 1 to obtain the title compound. Separation of the Z / E oxime mixture was carried out by chromatography with SiO 2, eluting with EtOAc: CH 2 Cl 2 mixtures to obtain the pure Z-isomer as a colorless solid.

Method A Step 3A The product from step 2 (134 g) is dissolved in CH 2 Cl 2 (1.5 I). It is treated sequentially with HOBT (44.6 g), BOC-D-phenylglycine (86.3 g) and DEC (65.9 g). The mixture is stirred at 23 ° C for 18 hours, heated at reflux temperature for 2 hours, cooled again to 23 ° C, treated with a saturated solution of NaHCO3 (500 ml), the organic portion is separated, Dry (MgSO 4), filter and concentrate. The crude material is recrystallized, once from Et2O and twice from 'Pr2O to give 1, 1-dimethylethyl- [[[1 - [[(3,5-dichlorobenzoyl) methylamine] methyl] -2- ( 3,4-dichlorophenyl) -5-methyl-hexen-1-ylidene] amino] oxy] -2-oxo-1-phenylethyl] carbamate (51 g). MS (FAB): m / e 722 [a] D23 = -96.9 ° (c 0.4 CH2Cl2); p.f. 98-102 ° C (dec).

Step 4A: The product from step 3A (25.2 g) is dissolved in a 0.5 M solution of H2NNH2 in CH2CL2: CH3OH (2: 1) (200 ml) and stirred at 23 ° C for 30 minutes. The reaction mixture is diluted with CH2CL2 (100 ml), washed with H20 (100 ml), dried (MgSO4), filtered and concentrated. The product is purified by filtration through a pad of silica gel eluting with CH2CL2 to give the title compound (15.6) g. MS (FAB): m / e 647.

Method B Step 3B The product from step 2 (750 g) is dissolved in CH 2 Cl 2 (4.5 I) at 0 ° C. It is treated sequentially with Et3N (233 g), DMAP (2.8 g) and pivaloyl chloride (204 g). The mixture is stirred at low temperature, additional CH2Cl2 (41) is added to maintain homogeneity. After 20 minutes, add H2O (100 ml), stir for 10 minutes, wash with a solution of saturated NaHCO3 (21), H2O (21), dry (Na2SO4) and concentrate at 23 ° C. The oily product is purified by filtration through a pad of silica gel eluting with CH 2 Cl 2 to obtain 3,5-dichloro-N- [3- (3,4-dichloro-phenyl) -2 - [[(2,2 -dimethyl-3-oxo-propoxy] imino] -6-methyl-5-heptenyl] -N-methylbenzamide (846 g).

Step 4B The product of step 3B was solved using a column Chiralpak AD ™, eluting with mixtures of hexane / 'PrOH.

Step 5B The desired enantiomer of step 4B was treated according to a procedure similar to method A-step 4A to obtain the title compound.

PREPARATION 7 Step 1 Treat a solution of 3,4-dichlorophenylacetic acid (25 g) with Nt-BOC-sarcosine methyl ester (24.3 g) (prepared from HCl of sarcosine methyl ester and di-t-butyl dicarbonate) according to with a procedure similar to example 11, step 2, to obtain the desired product (36 g).

Step 2 Treat 2-bromoethanol (107 g) in CH2Cl2 (21) at 0 ° C with t-butyldimethylsilyl chloride (143 g), NET3 (130 g) and DMAP (11 g), allow the reaction mixture to warm at 23 ° C and stirred for 18 hours. The mixture is washed with H2O (250 ml), 20% HCl (250 ml), 20% NH4OH (250 ml), dried (MgSO4) and concentrated to give 2- (t-butylmethylsilyloxy) -ethyl bromide (197). ) g).

Step 3: Treat the product from step 1 (57 g) in DMF (500 ml) at -10 ° C with NaH (8.6 g, 60% disp. In oil) and stir for 1 hour. Add 2- (t-butyldimethylsilyloxy) ethylbromide (51.3 g) and Nal (6.4 g) and stir for 18 hours. EtOAc (400 mL) and a saturated NaCl solution (300 mL) are added. The organic portion is separated, dried (MgSO4), filtered and concentrated. The crude oil is purified by chromatography with silica gel eluting with EtOAc / hexane mixtures to give the product (60.1 g).

Step 4 Treat the product from step 3 (28 g) with HCl (17 g) of O-allylhydroxylamine according to a similar procedure to Example 1 to obtain the title compound (24.5 g).

EXAMPLE 1 O-Methyloxime of 1 -rr (3,5-bis (trifluoromethyl) pheninmethoxy-1,3- (3,4-dichlorophenyl) -5- (4-hiroxy-4-phenyl-1-piperidinyl) -2-pentanone Treat a solution of the product from Preparation 1 (270 mg, 0.417 mmol) in dry pyridine (5 mL) with O-methoxylamine HCl (52 mg, 0.626 mmol, 1.5 eq) and heat at 60 ° C for 30 minutes. . The vessel is allowed to cool to 23 ° C and the pyridine is removed in vacuo. The crude product is taken up in a minimum amount of CH2Cl2 (2 ml) and applied to the silica gel column (2.5 cm x 15 cm) loaded with hexane: EtOAc: triethylamine (66: 33: 1). It is eluted with the same solvent system to obtain 190 mg (0.281 mmol, 67%) of the title compound as a colorless foam. HRMS (FAB, M + H +): m / e for [C32H33N2? 3CI2F6] +: 677.1772, found 677.1785. Example 1A (Z isomer) is prepared from the product of preparation 1 in a procedure similar to that described for example 1, using hydroxylamine HCl as starting material: HRMS (FAB, M + H +): cale: 663.1616, found 663.1625.

EXAMPLE 2 Treat a solution of Example 1A (400 mg, 0.603 mmol) in dry DMF (12 mL) at 0 ° C with 60% NaH in mineral oil (48 mg), stir for 40 minutes and treat with methyl bromoacetate. (60 μL, 0.633 mmol, 1.05 eq). Stir for 30 minutes, pour into EtOAc (250 mL) / saturated NaHCO3 (200 mL) and extract. The organic layer is washed with water (2x100 ml), then with brine (10 ml) and dried over Na 2 SO 4. The crude mixture is purified by chromatography on silica gel (4x15 cm; hex / EtOAc 1: 1 w / 2% NEt3) to give 361.8 mg (0.492 mmol, 82%) of the pure product in the form of an oil. HRMS (FAB, M + H +): m / e cale, for [C34H34CI2F6N2? 5] +: 735.1827, found 735.1839. Using a similar procedure, treat the product of Example 1A with the appropriate alkyl halide to obtain the following compounds 2A-2C: * Followed by distillation with 1 M TBAF in THF (3 h, 23 ° C).

EXAMPLE 3 Treat a solution of the product of Example 2 (57 mg, 0.078 mmol) in MeOH (3 mL) at 0 ° C with gaseous ammonia for 5 minutes. After airing 2-3 times, the container is closed with a polypropylene lid and stirred until the TLC shows that the reaction is complete (20 hours) to give (56 mg, 0.078 mmol,> 99%) of the product pure in the form of a colorless powder. HRMS (FAB, M + H +): m / e calculated for [C33H33CI2N3? 4] +: 720.1831, found 720.1841.

EXAMPLE 4 A suspension of H2NOH »HCl (47 mg, 0.68 mmol, 5 eq) in ethanol is treated with KOH in MeOH (680 μL, 0.68 mmol, 5 eq), sonicated for 5 minutes and then added to a solution of Example 2A (95 mg, 0.135 mmol) in ethanol (5 ml). It is heated for 2.5 hours at 60 ° C, filtered, concentrated in vacuo and purified by chromatography on silica gel (2.5 x 14 cm; CH2CL2 / MeOH (NH3) 95: 5) to give 98.3 mg (0.134 mmol, 99%) of the product in the form of a film. HRMS (FAB): 735.1956 (M + H +).

EXAMPLES 5, 5A AND 5B Using the procedures described below, compounds of the preceding structural formula were prepared, where the definitions of R1 are shown in the following table: EXAMPLE 5 Step 1 Prepare the allyl oxime ether of the product of Example 6, step, using O-allyl hydroxylamine HCl as alkoxy amine.

Step 2 The silyl protecting group is removed in a procedure similar to that described in example 6, step 8.

Step 3 The hydroxyl group is alkylated with 3,5-dichlorobenzyl bromide in a procedure similar to that of Example 6, step 9.

Step 4: Treat a solution of the product of step 3 (285 mg, 0.426 mmol) in 80% aqueous EtOH with Pd (PPh3) 4 (25 mg, 0.021 mmol, 0.05 eq) and triethylammonium formate (2.13 ml of solution). 1 M in THF, 5 eq) and stirred at reflux for 4 hours. Cool, concentrate and purify by chromatography on silica gel (2.5 x 16.5 cm; hex / EtOAc 1: 1 p / 2% NET3) to give 185 mg (0.3095 mmol, 73%) as a film.

Step 5 Treat the product of step 4 in a similar manner to example 2 using BrC2CN as the alkyl halide.

EXAMPLE 5A Treat the product of example 5, step 4, similarly to example 2, using 2-bromo-1- (t-butyldimethylsiloxy) ethane as the alkyl halide followed by desilylation (3h, 23 ° C) with 1 M TBAF in THF EXAMPLE 5B Treat the product of example 5, step 5, similarly to example 4 to obtain the desired product.

EXAMPLE 6 Steps 1-6 3- (3,4-Dichlorophenyl) -1 - [[dimethyl (1,1-dimethyl-ethyl) silyl] oxy] -5- (4-hydroxy-4-phenol-1- piperidinyl) -2-pentanone as described in U.S. Patent 5,696,267.

Step 7 Treat a solution of the product of step 6 (6.6 g, 12.3 mmol) and NaOAc (6.05 g, 73.8 mmol) in EtOH (100 mL) and H20 (27 mL) with NH2OCH3 »HCl. The resulting solution is stirred for 12-18 hours at room temperature. Concentrate under reduced pressure and partition the resulting residue between CH2Cl2 (100 mL) and H20 (100 mL). The aqueous layer is extracted with CH2Cl2 (3x100 ml), the combined organic layers are dried over MgSO4, filtered and concentrated under reduced pressure to obtain the crude product as a pale oil. This product is passed without purification to the next stage. HRMS (FAB, M + H +): m / e calculated for [C29H43N203SiCl2] +: 565.2420, found 565.2410.

Step 8 Treat a crude oxime solution from step 7 (< 12.3 mmol) in THF (400 mL) with TBAF (15.4 mL, 15.4 mmol, 1 M in THF) at 0 ° C. The solution is stirred for 2 hours. The reaction is quenched with water and the aqueous phase is extracted with EtOAc (3x100 ml). The combined organic layers are dried over MgSO 4, filtered and concentrated under reduced pressure to give the crude product as a yellow oil. Purify by silica gel chromatography (column: 7.5 cm x 20 cm), load the column into CH2Cl2 and elute using a gradient of 100% CH2Cl2 at 5% CH3OH (NH3) / CH2Cl2 to obtain 16 g (29.9 mmol, 75% from step 6) of the desired compound as a white solid HRMS (FAB, M + H +): m / e calculated for [C 23 H 29 N 2 O 3 Cl 2] +: 451.1555, found 451.1553.

Step 9 Treat a solution of the product of step 8 (200 mg, 0.44 mmol) in DMF at 0 ° C with NaH (12 mg, 0.48 mmol). The resulting mixture is stirred for 30 minutes at 0 ° C. 2,4-Difluorobenzyl bromide (60 μL, 0.465 mmol) is added in a single portion and the cooling bath is removed. The reaction is stirred for 12-18 hours at room temperature. The reaction is quenched with H2O and extracted with EtOAc (3x30 mL). The combined organic layers are dried over MgSO, filtered and concentrated under reduced pressure to give the crude compound as a yellow oil. Purify by silica gel chromatography (column: 2.5 cm x 15 cm, load the column in 50% EtOAc / Hexane and elute using a gradient of 50-100% EtOAc / Hexane) to obtain 128 mg (0.22). mmoles, 50%) of the title compound in the form of a pale-colored oil. HRMS (FAB, M + H +): m / e calculated for [C30H33N2O3CI2F2] +: 557.1836, found 577.1832.

-EJEMPLO 7 Step 1 The product from example 6, step 8 (1.8 g) and TFA (0.31 μL) is added to the acid or yodoxibenzoic (2.24 g) in DMSO (20 ml). The mixture is stirred for 2 hours and ice / H 2 O (50 ml), concentrated NH 4 OH solution (5 ml) and EtOAc (50 ml) are added. The mixture is stirred and filtered to remove the solids. The solid residue is washed with H20 (2 × 20 ml) and EtOAc (2 × 20 ml). The filtrates are combined, the organic layer is separated and washed with H20 (2x25 ml), dried over MgSO4, filtered and evaporated to give 3- (3,4-dichlorophenyl) -5- (4-hydroxy-4). phenyl-1-piperidinyl) -2- (2-methoxyimino) pentanal (1.8 g) in the form of a foamy solid. Mass spectrum (FAB): 449 Step 2 Treat the product from step 1 (0.2 g) in CF3CH2OH (5 ml) with 3Á molecular sieves (1.0 g) and 3,5-bistrifluoromethylbenzylamine (0.14 g).

The mixture is stirred for 90 minutes and NaBHsCN (0.12 g) is added. After 18 hours the reaction mixture is filtered through a pad of Celite, rinse the pad of Celite with MeOH (10 ml) and evaporate the combined filtrates. The residue is partitioned between CH2Cl2 (15 mL) and 20% KOH (15 mL). The organic layer is separated and the aqueous layer is extracted with CH2Cl2 (2 × 20 ml). The organic extracts are combined, dried over MgSO4, filtered and evaporated to give a solid. Purify the crude product by chromatography with silica gel eluting with NH3 / MeOH / CH2Cl2 mixtures to obtain the title compound (0.1 g) HRMS (FAB, M + H +): m / e calculated for [C32H34N3O6CI2F6] +: 676.1932 , found 676.1940.

EXAMPLE 7A 3- (3,4-Dichlorophenyl) -5- (4-hydroxy-4-phenyl-1-piperidinyl) -1 -IT2-methoxyphenyl) methylaminol-2-pentanone O-methyloxime.

Using the product of example 7, step 1 as a starting material, the compound of example 7A is prepared using 2-methoxybenzylamine in a procedure similar to that described in example 7, step 2. HRMS (FAB, M + H +): m / e calculated for [C31H37N3? 3CI2] +: 570.2290, found 570.2291 EXAMPLE 8 Treat the product of example 7A (50 mg) in CH2Cl2 (5 ml) with HOBT (12.4 mg) and AcOH (1 ml) and cooled to 0 ° C. To the cold solution is added DEC (17.6 mg) and stirred for a further 18 hours. The reaction mixture is washed with a 10% solution of NH 4 OH (3 ml). The aqueous layer is extracted again with CH2Cl2 (3x3 ml), the organic portions are combined, dried over MgSO4, filtered and evaporated to give a solid. Purify the crude product by chromatography with silica gel eluting with mixtures of NH3 / MeOH / CH2CI2 to give the title compound (0.042 g). Analysis: Calculated for C33H39N304CI2. 0.5H2O; C, 63.76, H, 6. 49, N, 6.76. Found: C, 63.83, H, 6.85, N, 6.95.

EXAMPLE 9 Step 1-7 O - Methyloxime of 1 - [[3,5-bis (trifluoromethyl) phenyl] methoxy] -3- (3,4-dichlorophenyl) -5-hydroxy-2-pentanone is prepared as described in U.S. Patent 5,696,267.

Step 8 Oxalyl chloride (2.01 g, 15.82 mmol) is dissolved in dry CH2Cl2 (30 mL) and cooled to -78 ° C under N2, DMSO (2.47 g, 31.64 mmol) in dry CH2Cl2 (12 mL) is added per drip and stir at -78 ° C for 15 minutes. The product of step 7 (6.56 g, 12.66 mmol) in dry CH 2 Cl 2 (20 ml) is added dropwise and stirred at -78 ° C for 3 hours. Diisopropylethylamine (4.91 g, 37.97 mmol) is added and stirred at -78 ° C for 1 hour. Heat slowly to 0 ° C and stir at 0 ° C for 30 minutes. Water (150 ml) is added and extracted with CH2Cl2. The combined extracts are washed with saturated aqueous NaCl, dried (MgSO4), filtered, and concentrated to give 6.53 g (12.66 mmol, 100%) of a yellow oil. MS (FAB): m / e 516 (M + 1) - Step 9 Dissolve the product (1.05 g, 2.03 mmol) of step 8 and 4-phenylamino-piperidine (1.08 g, 6.13 mmol) in CF3CH20H (10 mL), add crushed 3A sieves (1 g) and NaBH3CN (0.26). g, 4.07 mmol), and stirred at 23 ° C for 4 hours. Concentrate and add water (60 ml) and EtOAc (60 ml). Filter through Celite, separate the filtrate layers and extract the aqueous solution with EtOAc. The combined organic extracts are dried (MgSO 4), filtered and concentrated. Purify by chromatography (200 ml of evaporative silica gel, eluent: 3% CH3OH-CH2Cl2). The appropriate fractions are combined and concentrated to give 0.98 g (1.45 mmol, 66%) of the title compound as a yellow oil. MS (FAB): m / e 676 (M + 1). The following compound of formula 9A is prepared by reaction of the product of example 9, step 8, with an appropriate amine according to the procedure of the example, step 9: MS (FAB): m / e 657 (M + 1) EXAMPLE 10 Dissolve the product (0.380 g, 0.578 mmol) of Example 9A in THF (3 mL) and CH3OH (1 mL). Add 1 N KOH (2.7 mL, 2.70 mmol) and reflux for 16 hours. It is cooled to 23 ° C and 1 N HCl (5 ml) and water (20 ml) are added. Extract with CH2Cl2 (3x20 mL), wash the combined organic extracts with saturated aqueous NaCl, dry (MgSO4), filter and concentrate to give 0.312 g (0.496 mmol, 86%) of the title compound as a foam yellow. MS (FAB): m / e 629 (M + 1) EXAMPLE 11 A suspension of sarcosine methyl ester hydrochloride (6.02 g, 43 mmol) in CH2CL2 (250 ml) is treated at 0 ° C with 3 5-bistrifluoromethyl benzoyl chloride (7.7 ml, 42.5 mmol) and Et3N (12.5 ml). , 89.7 mmoles). The mixture is stirred at 20 ° C for 1 hour. Water (150 ml) is added to the mixture and the organic layer is separated. Dry (MgSO4) and concentrate the organic layer to give the crude product. Purify by chromatography with silica gel (eluent: EtOAc: hexane (6: 4)) to obtain 12 g of the product (81%).

Stage 2: Treat a solution of 3,4-dichlorophenyl acetic acid (4.15 g, 20 mmol) in anhydrous THF (50 mL) at -60 ° C with [(CH 3) 3 Si] 2 NLi (46.2 mL, 46.2 mmol) and heat slowly. Mix at 0 ° C for 4 hours. This solution is transferred to a solution of the product from step 1 (5.46 g, 16 mmol) in anhydrous THF (8 ml) at -30 ° C. The reaction is heated at -10 ° C for 1 hour, stirred at 0 ° C for 1 hour and at 20 ° C for 4 hours. 50% aqueous HOAc (15 mL) is added and extracted with EtOAc. The organic layer is separated, dried (MgSO4) and concentrated to give the crude product. Purify by chromatography with silica gel (eluent: hexane / EtOAc, 6: 4) to give 5.21 g (69%) of the product. HRMS (FAB, M + H) = m / e calculated for [C19H14NO2CI2F6] + = 472.0306, found 472.0306.

Treat a solution of the product from step 2 (0.96 g, 2 mmol) in THF (6 ml) at -78 ° C with [(CH 3) 3 Si] 2 N Li (2.5 ml, 2.5 mmol) and stir at -78 °. C for 25 hours. A solution of 1-bromo-3-methyl-2-butene (0.42 g) in THF (1 ml) is added to the above anionic solution at -78 ° C, the solution is slowly heated to 0 ° C and stirred at 20 ° C for 2 hours. A saturated solution of NH 4 Cl (5 mL) is added, extracted with EtOAc twice and the combined EtOAc extracts are washed with brine, dried (MgSO 4) and concentrated to give a crude product. Purify by column chromatography (silica gel, eluent: EtOAc: hexane, 2: 8) to obtain 1 g of product (87%). MS (FAB, M + H +) m / e 540.

Treat a solution of the product from step 2 (0.22 g, 0.4 mmol) in pyridine (3 ml) at 70 ° C with methoxylamine HCl (95 mg, 1.14 mmol), stir at 70 ° C for 6.5 hours and then it is cooled to 20 ° C. Water is added to the reaction mixture, the solution is extracted with EtOAc, dried (MgSO4) and the EtOAc extracts are concentrated to give the crude product. Purify by chromatography with silica gel (eluent: hexane: Et20, 1: 1) to give 74 mg (32%) of the Z isomer and 130 mg (56%) of the E-isomeric oximes. MS (FAB, M + H +) = m / e 569.

Stage 5A Treat the product of step 3 (0.387 of E-isomer, 0.68 mmole) in a saturated EtOAc solution at 03 to -78 ° C for 5 minutes. The solution is purged with N2) (CH3) 2S is added and the solution is heated from -78 ° C to 20 ° C for 1 hour. The solution is concentrated to give the desired aldehyde which is used directly in the next reaction without further purification. MS (FAB M + H +) = m / e 543.

Stage 5B The Z-isomer is prepared using a procedure similar to that described in step 5A employing the Z-isomer product of step 4.

Step 6 Treat the product of step 5 with 4-hydroxy-4-phenylpiperidine in a procedure similar to that described in example 9, step 9, to obtain the title compound (Z-isomer) with a general yield of 77%. %. HRMS (FAB, M + H +) = m / e calculated for [C33H34N3? 3CI2F6] +: 704.1881, found 704.1875.

EXAMPLE 12 Step 1 Using the procedures of Example 11, using 3,5-dichlorobenzoyl chloride in place of 3,5-bistrifluorobenzoyl chloride in step 1, proceed through steps 2, 3, 4 and 5, to obtain the composed of the title. Alternatively, to prepare an optically active material, the product of preparation 6 is treated according to the procedure indicated in example 13, step 1.

Step 2 The following compounds of formula 12A to 12S are prepared by reaction of the product of step 1 with an appropriate amine (described in preparations 3 and 4) according to a similar procedure to example 9, step 9. The stereoisomers are separated HPLC on a chiral column using mixtures of hexane and isopropanol with 0.25% Et2NH adding to a Daicel AD and / or OD column.

EXAMPLE 13 Step 1 Treat the product of preparation 6 with CH3I using the procedure of Example 2, followed by a procedure similar to Example 11, step 5, to obtain the title compound.

Step 2 The following compounds are prepared by reaction of the product from step 1 with an appropriate amine (for 13A to 13C see preparation 5A-5C, for 13D see preparation 3O6, for 13F to treat the product of preparation 5, step 5, using a procedure similar to that described in preparation 2, step 4, to obtain the appropriate amino ester) according to a procedure similar to that of example 9, step 9, substituting NaBH3CN for NaB (OAc) 3H and trif I uore tanol for 1, 2-dichloroethane. 13 G are prepared by treatment of Example 13D with MCPBA in CH CI2 at 0 ° C for 3 hours; similarly prepared 13H by treatment of 13B. Example 13E is prepared from example 13F using conventional saponification conditions similar to those described in preparation 5, step 6.

EXAMPLE 14 EXAMPLE 14A Treat the product of Preparation 7 according to a procedure similar to that described in Example 6, Step 8. Continue in a manner similar to that described in Example 9, Steps 8-9, using the product of Preparation 5A or 3A6 in the place of 4-phenylamino-piperidine. The procedure is similar to that of preparation 2, step 4, optionally replacing TFA with HCl. The amine is acylated according to a procedure similar to preparation 2, step 2A using 3,5-dichlorobenzoyl chloride.

EXAMPLE 14B Treat the product of example 14A using a procedure similar to example 5, step 4, to obtain the oxime. Alternatively, for the preparation of the optically active material, the product of preparation 6 is treated according to a procedure such as that indicated in example 11, step 5B, followed by the procedure of example 13A, step 2.

EXAMPLE 14C Treat the product of Example 14B with BrCH2CN according to a procedure similar to Example 2A to give the title compound.

EXAMPLE 14D A procedure similar to that described in Example 4 is used using the product of Example 14C to obtain the title compound. The stereoisomers are separated by HPLC on a chiral column using mixtures of hexane and isopropanol with 0.25% Et2NH added on a Daicel AD and / or OD column.

EXAMPLE 14E Treat the product of Example 14C according to a procedure similar to that of Example 18M to obtain the title compound.

EXAMPLE 15 EXAMPLE 15A Step 1 Treat the product of preparation 7 using a procedure similar to that described in example 6, step 8. Continue in a manner similar to that described in example 9, steps 8-9, using the product of preparation 5B or 3B6 instead of 4-phenylamino-piperidine. The process is continued in a manner similar to the procedure indicated in Preparation 2, step 4, optionally substituting TFA for HCl. The amine is acylated according to the procedure similar to preparation 2, step 2A, using 3,5-dichlorobenzoyl chloride.

Step 2: Treat the resulting product using a procedure similar to Example 5, step 4, to obtain the title compound.

Alternatively, for the preparation of the optically active material, the product of preparation 6 is treated according to a procedure such as that indicated in example 11, step 5, followed by the procedure of example 13B, step 2.

EXAMPLE 15B The product of step 2 is treated with BrCH2CN according to a procedure similar to example 2A to obtain the title compound.

EXAMPLE 15C The product of Example 15A is alkylated and deprotected according to a procedure similar to Example 2B to give the title compound.

EXAMPLE 15D Step 1 The product is alkylated in Example 15A with allyl chloroacetate according to a similar procedure to Example 2 to obtain the resulting allyl ester.

Step 2: Treat a solution of the product from step 1 according to a procedure similar to that of example 3 to give the title compound.

EXAMPLE 15E Treat a solution of Example 15D, Step 1, with CH3NH2 according to a procedure similar to that of Example 3 to give the title compound.

EXAMPLE 15F A procedure similar to that described in Example 4 is used using the product of Example 15B to obtain the title compound. The stereoisomers are separated by HPLC on a chiral column using mixtures of hexane and urea propanol with 0.25% diethylamine added on a Daicel AD and / or OD column.

EXAMPLE 15G Step 1 The product of example 15D, step 1, is deprotected using a procedure similar to that of example 5, step 4.

Step 2: Treat a solution of the product from step 1 (82 mg) in dry CH 2 Cl 2 (1 ml) with NEt 3 (41 μl). followed by BOP-CI (36.5 mg). Stir 15 minutes at 23 ° C, then add 2-amino-1, 3,4-thiadiazole (14 mg). Stir for 2 hours, dilute with EtOAc (75 mL) and wash with 10% citric acid followed by H2O, and then with saturated NaHCO3. The organic layers are dried (Na2SO4), filtered, concentrated and purified by chromatography with silica gel to give the title compound.

EXAMPLE 15H The product of Example 15A is rented using a procedure similar to that described in Example 2 using 1,3-propane sulfone in place of methyl bromoacetate to obtain the title compound.

EXAMPLE 151 The product of example 15G, step 1, is coupled with H2NCH2CN using a procedure similar to that of example 8 to obtain the title compound.

EXAMPLE 15J The product of example 15G, step 1 is coupled with H2NCH2SO3H using the procedure similar to that of example 8 to obtain the title compound.

EXAMPLE 15K The product of Example 15A is rented using a procedure similar to that described in Example 2 using BrCH2F in place of methyl bromoacetate to obtain the title compound.

EXAMPLE 15L The product of Example 15A is treated with iodoethane according to a procedure similar to that of Example 2, to obtain the title compound.

EXAMPLE 15M Treat the product of Example 15B according to a procedure similar to that of Example 18M to obtain the title compound.

EXAMPLE 16 EXAMPLE 16A Step 1 Treat the product of preparation 7 using a procedure similar to that described in example 6, step 8. Continue in a manner similar to that described in example 9, steps 8-9, using the product of preparation 5C or 3C6 instead of 4-phenylamino-piperidine. The process is followed in a manner similar to the procedure indicated in Preparation 2, step 4, optionally substituting TFA for HCl. The amine is acylated according to a procedure similar to preparation 2, step 2A, using 3,5-dichlorobenzoyl chloride.

Step 2: Treat the resulting product using a procedure similar to Example 5, step 4, to obtain the title compound. Alternatively, for the preparation of the optically active material, the product of preparation 6 is treated according to a procedure indicated in example 11, step 5, followed by the procedure of example 13C, step 2.

EXAMPLE 16B The product of step 2 is treated with BrCH2CN according to a procedure similar to that of example 2A to obtain the title compound.

EXAMPLE 16C The product of Example 16A is alkylated and deprotected according to a procedure similar to that of Example 2B to obtain the title compound.

EXAMPLE 16D Step 1 The product of Example 16A is alkylated with allyl chloroacetate according to a similar procedure to Example 2 to obtain the resulting allyl ester.

Step 2: Treat a solution of the product from step 2 according to a procedure similar to that of example 3, to obtain the title compound.

EXAMPLE 16E Treat a solution of example 16D, step 1, with CH3NH2 according to a procedure similar to that of example 3 to obtain the title compound.

EXAMPLE 16F A procedure similar to that described in Example 4 is used using the product of Example 16B to obtain the title compound. The stereoisomers are separated by HPLC on a chiral column using mixtures of hexane and isopropanol with 0.25% Et2N added on a Daicel AD and / or OD column.

EXAMPLE 16G Step 1 The product of example 16D, step 1, is deprotected using a procedure similar to that of example 5, step 4.

Step 2: Treat the product of step 1 according to a procedure similar to that of example 15G, step 2, to give the title compound.

EXAMPLE 16H The product of Example 16A is alkylated using a procedure similar to that described in Example 2, using 1,3-propane sulfone in place of methyl bromoacetate to obtain the title compound.

EXAMPLE 161 The product of example 16G, step 1, is coupled with H2NCH2CN using a procedure similar to that of example 8, to obtain the title compound.

EXAMPLE 16J The product of example 16G, step 1, is coupled with H2NCH2SO3H using a procedure similar to that of example 8 to give the title compound.

EXAMPLE 16K The product of Example 16A is rented using a procedure similar to that described in. Example 2 employing BrCH F in place of methyl bromoacetate to obtain the title compound.

EXAMPLE 16L Treat the product of example 16A, step 2 with CH3CH2I according to a procedure similar to example 2 to obtain the title compound.

EXAMPLE 16M Treat the product of Example 16B according to a procedure similar to Example 18M to obtain the title compound.

EXAMPLE 17 EXAMPLE 17A Step 1 Treat the product of preparation 7 using a procedure similar to that described in example 6, step 8. The procedure is similar to that described in example 9, steps 8-9, using the product of preparation 306 in 4-phenylamino-piperidine. The process is followed in a manner similar to the procedure indicated in Preparation 2, step 4, by optionally substituting TFA for HCl. The amine is acylated according to a procedure similar to preparation 2, step 2A, using 3,5-dichlorobenzoyl chloride.

Step 2: Treat the resulting product using a procedure similar to Example 5, step 4, to obtain the title compound. Alternatively, for the preparation of the optically active material, the product of preparation 6 is treated according to a procedure indicated in example 11, step 5, followed by the procedure of example 13D, step 2.

EXAMPLE 17B Example 17A is rented with CH3I according to a similar procedure to Example 2 to give the title compound.

EXAMPLE 17C The product of Example 17A is alkylated and deprotected according to a procedure similar to Example 2B to give the title compound.

EXAMPLE 17D Example 17A is alkylated with BrCH2CN according to a similar procedure to Example 2A to give the title compound.

EXAMPLE 17E A procedure similar to that described in Example 4 is used, using the product of 17D to obtain the title compound.

EXAMPLE 17F Step 1: Example 17A is alkylated with allyl chloroacetate according to a similar procedure to Example 2 to give the resulting allyl ester.

Step 2: Treat a solution of the product from step 1 according to a procedure similar to that of example 3 to give the title compound.

EXAMPLE 17G Treat a solution of example 17F, step 1 with (CH3) 2NH according to a procedure similar to that of example 3 to obtain the title compound.

EXAMPLE 17H Treat a solution of example 17F, step 1 with CH3NH2 according to a procedure similar to that of example 3 to obtain the title compound.

EXAMPLE 171 Step 1 The product from example 17F, step 1, is deprotected using a procedure similar to that of Example 5, step 4.

Step 2 Treat the product of step 1 according to a procedure similar to example 15G, step 2 to give the title compound.

EXAMPLE 17J Example 17A is rented with 3-bromo-1-t-butyldimethylsilyloxypropane and deprotected using a procedure similar to that described in Example 2B to obtain the title compound.

EXAMPLE 17K Example 17A is rented using a procedure similar to that described in Example 2, employing 1,3-propane sulfone in place of methyl bromoacetate to obtain the title compound.

EXAMPLE 17L Step 1 The product of Example 17A is alkylated with methyl bromoacetate using a procedure similar to that described in Example 2 to obtain the methyl ester.

Step 2: Treat the product of step 1 according to a procedure similar to that of example 4 to obtain the title compound.

EXAMPLE 17M Step 1 The product of example 17A is alkylated with bromopropylphthalimide using a procedure similar to that described in example 2C to obtain the protected propylamine.

Step 2: Treat the product from step 1 with (CH3) NH2 according to a procedure similar to that of example 3 to obtain the primary amine.

Step 3 Treat the product from step 2 (150 mg) in CH2Cl2 (3 ml) with methyl isocyanate (14.7 mg) and stir for 1 hour. The solvent is evaporated and purified by chromatography with silica gel using CH 2 Cl 2 / CH 3 OH saturated with ammonia to provide 137 mg (86%) of the title compound.

EXAMPLE 17N Step 1: A solution of example 17J (1.0 g) in CH2Cl2 (20 ml) is cooled and then treated with Net3 (507 μl). The solution is heated to 0 ° C and stirred for 30 minutes. Pour into EtOAc / NaHCO3. The organic layer is washed with H2O, brine and dried (Na2SO4). The solvent is removed to provide the mesylate (quantitative).

Step 2 Treat a solution of the product from step 1 in dry DMF with NaSCH3. The solution is stirred for 45 minutes, and then the mixture is poured into EtOAc / aqueous NaHCO 3. The organic layer is washed with H20 and with brine, and dried (Na2SO4) and purified by chromatography with silica gel using EtOAc / Net3 to obtain 282 mg (86%) of the methyl sulfide.

Step 3: The product of step 2 (64 mg) is dissolved in THF (2 ml) and treated with t-butanol (500 μl), osmium tetroxide (56 μl of a 2.5% solution in t-butanol) and NMO (31.6 mg) and the mixture is stirred for 2 hours at 23 ° C. The mixture is poured into EtOAc / aqueous NaHSO4. The organic layer is washed with saturated aqueous NaHC03 and with brine, dried (Na2SO4), filtered, and concentrated and purified by chromatography with silica gel using EtOAc / Ne.3 to provide 57 mg (85%) of the title compound. Title.

EXAMPLE 170 The product from Example 17A is alkylated and deprotected according to a procedure similar to Example 17J by substituting 3-bromo-1-t-butyldimethylsilyloxy propane for 2-bromo-1-t-butyldimethylsilyloxy ethane. The product is converted to methyl sulfone according to a procedure similar to that described in example 17N.

EXAMPLE 17P The product of example 17N step 2 (128 mg) is dissolved in CH2CI2 (5 ml) and treated with ReOCI3 (PPh3) 4 (7.5 mg) and phenyl sulfoxide (51 mg). Stir for 3 hours at 23 ° C, and then add ReOCI3 (PPh3) 4 (7.5 mg) and phenyl sulfoxide (51 mg) and stir at 23 ° C for 15 hours. H 0 (20 ml) was added and extracted with CH 2 Cl 2. Dry the organic layer with MgSO 4 and concentrate. Purify using chromatography with silica gel (EtOAc / Net3 / CH3OH as eluent) to obtain 95 mg (72%) of the title compound.

EXAMPLE 17Q The product of example 17A is alkylated with the product of example 18L, step 2, using a procedure similar to that described in example 18L, step 3, to obtain the title compound.

EXAMPLE 17R Treat the product of example 17L with an excess of diazomethane in Et20 to obtain the title compound.

EXAMPLE 17S The product from Example 17A is rented using a procedure similar to that described in Example 2 using BrCH2F in place of methyl bromoacetate to obtain the title compound.

EXAMPLE 17T Treat the product of Example 17D according to the procedure similar to that of Example 18M to obtain the title compound.

EXAMPLE 18 EXAMPLE 18 A Step 1: Treat the product of Preparation 7 using a procedure similar to that described in Example 6, Step 8. Continue in a manner similar to that described in Example 9, Steps 8-9, using the product of Preparation 306 in Instead of 4-phenyl-piperidine. The process is followed in a manner similar to the procedure indicated in Preparation 2, step 4, by optionally substituting TFA for HCl. The amine is acylated according to a similar procedure in preparation 2, step 2A, using 3,5-dimethylbenzoyl chloride.

Step 2: Treat the resulting product using a procedure similar to Example 5, step 4, to obtain the title compound. Alternatively, for the preparation of the optically active material, the product derived from a procedure similar to that of preparation 6, steps 1 and 2, is treated, replacing the 3,5-dichlorobenzoyl chloride in stage 1 with 3,5-dimethylbenzoyl chloride , and solving the product of step 2 in a procedure similar to that described in preparation 6, step 4B. The procedure indicated in example 11, step 5 is continued, followed by the procedure of example 13D, step 2.

EXAMPLE 18B Example 18A is rented with CH3I according to a procedure similar to that of Example 2 to give the title compound.

EXAMPLE 18C The product from Example 18A is rented and deprotected using a procedure similar to Example 2B to give the title compound.

EXAMPLE 18D Example 18A is rented with BrCH2CN according to a procedure similar to example 2A to give the title compound.

EXAMPLE 18E A procedure similar to that described in example 4 is used, using the product 18D to obtain the title compound.

EXAMPLE 18F Step 1: Example 18A was alkylated with allyl chloroacetate according to a similar procedure to Example 2 to obtain the allyl ester.

Step 2 The product of step 1 is deprotected using a procedure similar to that of example 5, step 4.

Step 3 The product of step 2 is coupled with 2-amino-1,4-thiadiazole using a procedure similar to example 15G, step 2 to give the title compound.

EXAMPLE 18G Example 18A is rented with 3-bromo-1-t-butyldimethyl-silyloxypropane and deprotected using a procedure similar to that described in Example 2B to obtain the title compound.

EXAMPLE 18H Treat the product of example 18F, step 1, with morpholine at 65 ° C using a procedure similar to that of example 3 to give the title compound.

EXAMPLE 181 Treat the product of example 18F, step 1 at 23 ° C with n-methylpiperazine using a procedure similar to that of example 3 to obtain the title compound.

EXAMPLE 18J The product of Example 18F, Step 2, is coupled with thiomorpholine using a procedure similar to that of Example 8 to give the title compound.

EXAMPLE 18K The product from example 18F, step 2, is coupled with 2-aminothiazole using a procedure similar to that of example 18F, step 3, to obtain the title compound.

EXAMPLE 18L Step 1 Treat a solution of CH3ONH2 »HCl (2.5 g) in H20 (40 ml) with NaHCO3 (5 g). It is cooled to 0 ° and a solution of CICH2COCI (2.4 ml) in THF (20 ml) is added at a rate sufficient to maintain the internal temperature at 0-3 ° C. Upon completion of the addition, it is heated to 23 ° C and stirred for 2 hours. The pH is adjusted to 5 (Na 2 CO 3), the THF is removed in vacuo, and NaCl is added and extracted with CH 2 Cl 2. Dry the organic layer (Na2SO4), filter and concentrate to give the a-chloroamide.

Step 2: Treat a solution of the product of step 1 (131 mg) in acetone (1 ml) with Nal (158 mg). It is stirred for 7 hours at 23 ° C, the solvent is removed in vacuo, redissolved in THF, filtered through Celite and concentrated to give the iodoamide.

Step 3: Example 18A was alkylated with the product of example 18L, step 2, using a procedure similar to that described in example 2 using 2.5 equivalents of NaH to obtain the title compound.

EXAMPLE 18M A procedure similar to that described in Example 4 is used using the 18D product and the following modifications: HONH2"HCl is replaced by CH3ONH2» HCl, and 2,2,2-trifluoroethanol is used as the solvent, and is stirred at 70 °. C for a week to obtain the title compound.

EXAMPLE 18N The product of 18C is treated according to a procedure similar to that of example 17M, step 3.

EXAMPLE 19 EXAMPLE 19A Step 1 Treat the product of preparation 7 using a procedure similar to that described in example 6, step 8. Continue in a manner similar to example 9, step 8-9, using the product of preparation 5A or 3A6 instead of 4-phenylamino-piperidine. The procedure is similar to the procedure described in Preparation 2, step 4, optionally replacing TFA with HCl. The amine is acylated according to a procedure similar to preparation 2, step 2A, using 3,5, -dimethylbenzoyl chloride.

Step 2 Treat the product of step 1 using a procedure similar to that of example 5, step 4 to obtain the title compound. Alternatively, for the preparation of the optically active material, the product derived from a procedure similar to that of preparation 6, steps 1 and 2, is treated, replacing the 3,5-dichlorobenzoyl chloride of step 1 with 3,5-dimethylbenzoyl chloride , and solving the product of step 2 in a procedure similar to that described in preparation 6, step 4B. Continue with the procedure indicated in the example, 11, step 5, followed by the procedure of example 13A, step 2.

EXAMPLE 19B The product of Example 19A was alkylated with BrCH2CN using a procedure similar to that of Example 2A to give the title compound.

EXAMPLE 19C A procedure similar to that described in Example 4 is used using the product of Example 19B to obtain the title compound.

EXAMPLE 19D Step 1 The product of example 19A is alkylated with allyl chloroaceate according to a procedure similar to example 2 to give allyl ester.

Step 2 Treat the product of step 1 using a procedure similar to that of example 5, step 4.

Step 3 The product from step 2 is coupled with 2-amino-1,4-thiadiazole according to a procedure similar to example 15G, step 2 to give the title compound.

EXAMPLE 19E The product of example 19A is alkylated with the product of example 18L, step 2, using a procedure similar to that described in example 2 using 2.5 equivalents of NaH to obtain the title compound.

EXAMPLE 20 EXAMPLE 20A Step 1: Treat the product of preparation 7 using a procedure similar to that described in example 6, step 8. Continue in a manner similar to example 9, steps 8-9 using 4-hydroxy-4-phenylpiperidine in Place of 4-phenylamino-piperidine. Continue in a manner similar to the procedure of Preparation 2, step 4, optionally substituting TFA for HCl. The amine is acylated according to a procedure similar to preparation 2, step 2A, using 3,5-dimethyoxybenzolyl chloride.

Step 2 Treat the product of step 1 using a procedure similar to that of example 5, step 4.

Step 3 The product of step 2 is alkylated with BrCH2CN according to a procedure similar to that of example 2A to obtain the title compound.

Step 4 A procedure similar to that described in Example 4 is used using the product from step 3 to obtain the title compound.

EXAMPLE 20B The product of example 20A, step 2 is alkylated with 2-bromo-1 t-butyldimethylsilyloxy ethane and deprotected using a procedure similar to that of example 2B to obtain the title compound.

EXAMPLE 21 EXAMPLE 21A Step 1: Treat the product of preparation 7 using a procedure similar to that described in example 6, step 8. Continue in a manner similar to that described in example 9, steps 8-9, using the product of preparation 306 in place of 4-phenylamino-piperidine. The process is followed in a manner similar to the procedure indicated in Preparation 2, step 4, by optionally substituting TFA for HCl. The amine is acylated according to a procedure similar to preparation 2, step 2A, using 4-methyl-3,5-dimethoxybenzoyl chloride.

Step 2 Treat the product of step 1 using a procedure similar to example 5, step 4.

Step 3: Rent the product from step 2 with BrCH2CN using a procedure similar to example 2A to give the title compound.

EXAMPLE 21 B Treat the product of Example 21 A using a procedure similar to that described in Example 4 to obtain the title compound.

EXAMPLE 22 A procedure similar to that described in Example 20A was used using the product of preparation 306 instead of 4-h.drox.-4-phenylpiperidine in step 1 to obtain the title compound. HRMS (FAB, M + H +): m / e cale. To: 691.2778, found 691.2769.

EXAMPLE 23 A procedure similar to that described in Example 20A was used using 3,4,5-trimethoxybenzoyl chloride as the acid chloride in step 1 to obtain the title compound; MS (FAB): m / e 716 (M + 1).

EXAMPLE 24 A procedure similar to that described in Example 11 was used using the product of preparation 306 as an amine in step 6 to obtain the title compound HRMS (FAB, M + H +): m / e cale, for: 709.2147 found 709.2138.

EXAMPLE 25 Using a procedure similar to that of Example 2, the product of example 3H5 was methyl, replacing methyl iodide with methyl bromoacetate. The resulting product was deprotected and coupled to the product of example 12, step 1 using the procedure of example 9, step 9, to obtain the title compound. HRMS (FAB, M + H +): m / e cale, for: 798.2537; finding 798.2538.

EXAMPLE 26 A procedure similar to that described in Example 17B was used using 3-chloro-5-methyl-benzoyl chloride in place of 3,5-dichlorobenzoyl chloride (step 1, example 17A) to obtain the title compound. HRMS (FAB, M + H +): m / e cale, for: 621.2166; Found 621.2178.

EXAMPLE 27 A procedure similar to that described in Example 13A was used employing 3-chloro-5-methyl-benzoyl chloride in place of 3,5-dichlorobenzoyl chloride to obtain the title compound. HRMS (FAB, M + H +): m / e cale, for: 706.2694, found 706.2701.

EXAMPLE 28 Step 1: Glycine was condensed with 3,5-dichlorohezoic acid according to a similar procedure to Example 8. The resulting amide was treated with NaH followed by iodoethane according to Example 2. The resulting material was treated with diazomethane to give methyl ester of N-ethyl-N- (3,5-dichlorobenzoyl) -glycine.

Step 2 The procedures of example 11, steps 2-5 were used, substituting the product of step 1 for the product of example 11, step 1. An optically active material can be prepared using procedures similar to those of preparation 6. The compounds The following were prepared by reacting the product of step 2 with an appropriate amine (for 28A to 28C, see preparation 5A-5C; for 28D, see preparation 306) according to a procedure similar to example 9, step 9, substituting NaB3HCN for NaB (OAc) 3H and optionally substituting 2,2,2-trifluoroethanol for 1,2-dichloroethane.

EXAMPLE 29 Step 1 Carbonyldiimidazole (24g) was added to a solution of allyl-3,4-dichlorophenyl acetic acid (30.6g) in anhydrous THF (600 ml). The reaction mixture is stirred at 23 ° C for 1 hour. In a separate flask under N2, potassium t-butoxide (16.8 g) is dissolved in anhydrous THF (425 ml). The solution is cooled to 0 ° C and CH3N02 (200 ml) is added for 30 minutes. The acyl imidazole solution is added to the potassium nitranate solution through an addition funnel while maintaining the internal temperature between 0 ° C and 5 ° C. The cooling bath is removed and stirred at 23 ° C for 2 days. The reaction mixture is cooled to 0 ° C and poured into cold 1 M HCl (500 ml). The organic layer is separated, dried (MgSO 4) and concentrated to give 34 g of an orange oil. MS (CI + / CH4) m / e 288 (M + 1).

Step 2: A solution of the product from step 1 (12.2 g) in THF (34 ml) and HOAc (34 ml) is cooled to 0 ° C and H20 (17 ml) is added. Zn powder (15.6 g) is added in portions for 15 minutes. The reaction mixture is stirred for 15 minutes at 0 ° C and then heated to 23 ° C. The reaction mixture is heated at 40 ° C for 3 minutes. Heat is extracted and poured into H20 (150 mL) and THF (100 mL). The mixture is filtered and the solids are washed with THF and H20. The filtrate is concentrated and the resulting orange colored material is washed with Et20 and CH2CI2. The filtrate is concentrated to give 15.5 g of an orange oil. MS (CI + / CH4) m / e 259 (M + 1).

Step 3 A solution of the product from step 2 (15.5 g) in THF (55 ml) and H2O (10 ml) is cooled to 0 ° C and 3,5-dichlorobenzoyl chloride (8.2 g), base, is added. of Hunig (12 ml) and DMAP (0.25 g). The reaction mixture is heated to 23 ° C and stirred for 16 hours. EtOAc (300 mL) is added and washed with H2O (30 mL), 1 M HCl (3 x 30 mL), H2O (2 x 30 mL) and brine (2 x 40 mL), dried (MgSO4), and It is concentrated. Purify (Si02, elute with a gradient of 4% EtOAc / hexanes to give 25% EtOAc / hexanes) in order to obtain 8.8 g of a solid. MS (CI + / CH4) m / e 432 (M + 1) Step 4 Treat a solution of the product of step 3 (5.7 g, 13 mmol) in EtOH (100 ml) and H20 (25 ml) with CH3ONH2 »HCl (5.54 g, 66.3 mmol) and stir at 23 ° C for 2 days. The mixture is concentrated and EtOAc (200 ml) and H20 (20 ml) are added. Separate the layers and wash the organic layer with 1M NaHCO3 (2 x 20 ml) and brine (20 ml), dry (MgSO4) and concentrate to an oil. Purify (SiO2) eluting with a gradient of 4% EtOAc / hexanes to 15% EtOAc / hexanes to give 1.8 g of clear oil MS (CI + / CH4) m / e 461 (M + 1).

Step 5 Treat the product of step 4 according to a procedure similar to that of example 11, step 5, to obtain the title compound. MS (FAB): m / e 464 (M + 1). The following compounds of formula 29A to 29D were prepared by reaction of the product of step 5 with an appropriate amine (for 29A to 29C see preparation 5A-5C; for 29D, see preparation 306) according to a procedure similar to example 9, stage 9.

EXAMPLE 30 Treat the crude product of example 7, step 1, (1.65 g) with CH3NH2 according to a similar procedure to example 7, step 2, to obtain the desired product (0.6 g). MS (FAB): m / e 464. The product from step 1 is treated with the appropriate carboxylic acid according to a procedure similar to example 8 to give the following compounds: EXAMPLE 31 Step 1: Treat the product of preparation 7 according to a procedure similar to that described in example 6, step 8. Continue in a manner similar to that described in example 9, steps 8-9, using 4-phenyl-4 -hydroxypiperidine instead of 4-phenylamino-piperidine.

Step 2 Treat the product of step 1 using a procedure similar to example 5, step 4.

Step 3 Treat the product of step 2 in a procedure similar to that of preparation 2, step 4.

Step 4 Treat the product of step 3 (8.4 g) with 2-chloro-6-methylpyridine-4-carboxylic acid (3.84 g), according to a procedure similar to example 8 to give the product (5.9 g).

Step 5 Treat the product of step 4 (3.65 g) with BrCH2CN (0.725 g) according to a procedure similar to example 2A to give the product (1.9 g).

Step 6: Treat the product of step 5, (1.8 g) using a procedure similar to that of Example 4, to give the title compound (1.31 g.) MS (FAB): m / e 675 (M + 1).

EXAMPLE 32 The product of Example 31, Step 4, is rented and deprotected, using a procedure similar to Example 2B, to give the product. MS (FAB): m / e 647 (M + 1).

EXAMPLE 33 The title compound is prepared in a manner similar to the procedures of Example 32 substituting 2- (dimethylamino) -6-methylpyridine-4-carboxylic acid for 2-chloro-6-methylpyridine-4-carboxylic acid and 4-hydroxy-4 -phenyl piperidine by the product of the preparation 3O6. MS (FAB): m / e 661 (M + 1).

EXAMPLE 34 Treat the crude product of example 7, step 1, according to a similar procedure to example 30, substituting MeNH2 in step 1 for NH4OAc and using 3,5-bis (trifluoromethyl) benzoic acid in step 2 to obtain the composed of the title. MS (FAB): m / e 690.

EXAMPLE 35 A procedure similar to that described in Example 18B is used using the product of preparation 5B in place of the product of preparation 306 to obtain the title compound. HRMS (FAB): m / e 672 (M + 1).

EXAMPLE 36 Step 1 4-Piperidone hydrochloride (50 g) was treated in a solution of saturated NaHCO 3 (11) with a dioxane (30 ml) in a solution of benzyloxycarbonyl chloride (53.4 ml). The solution was stirred for 18 hours at room temperature and then extracted with EtOAc (2 x 500 ml). The organic fractions were combined, washed with 1 N HCl (500 ml) and with brine (500 ml), dried over MgSO 4, filtered and evaporated to give 1-benzyloxycarbonyl-4-piperidone (75 g).

Step 2: 2-Bromothioanisole (13.7 g) was cooled in TMF (120 ml) at -78 ° C (internal temperature) and treated with n-BuLi (36.5 ml, 2.5 M hexane solution). After 10-15 minutes, a solution of THF (120 ml) of the product from step 1 (12.5 g) was added through a cannula at -78 ° C. The combined mixture was stirred for a further 18 hours, during which time it was heated to room temperature. The solution was treated with a saturated NH 4 Cl solution (250 ml), EtOAc (250 ml) and the organic layer was separated. The aqueous portion was extracted with additional EtOAc (2 x 250 ml). The organic extracts were combined, washed with H2O (250 ml) and with brine (250 ml), dried over MgSO4, filtered and evaporated to give an oil. Chromatography with silica gel, eluting with EtOAc / hexane mixture, gave 1-benzyloxycarbonyl-4-hydroxy-4- (2-methylthiophenyl) piperidine (9.61 g).

Step 3 The product of step 2 (5.1 g) in CH2Cl2 (50 ml) was treated sequentially with trifluoroacetic acid (8.9 ml) and triethylsilane (34.5 ml). After 18 hours, the solution was treated with saturated NaHCO 3 (150 mk). After one more hour, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (100 ml). The organic extracts were combined, dried over Na 2 SO 4, filtered and evaporated. The crude product was purified by chromatography with silica gel eluting with EtOAc / hexane mixtures to obtain 1-benzyloxycarbonyl-4 (2-methylthiophenyl) piperidine (3.3 g).

Step 4 The product of step 3 (2.55 g) in CH2Cl2 (30 ml) was cooled to 0 ° C and treated with mCPBA (60%, 2.16 g) and stirred for 1 hour. The reaction mixture was treated with ice (20 g), with a saturated NH 4 OH solution (20 ml) and stirred for 10 minutes. The organic layer was separated and the aqueous layer was re-extracted with CH2Cl2 (2x30 ml). The combined organic portions were dried over MgSO4, filtered and evaporated to give a gum. Chromatography with silica gel eluting with EtOAc / CH 2 C 2 mixtures gave 1-benzyloxycarbonyl-4- (2-methylisulfinylphenyl) piperidine (0.5 g).

Step 5: The product of step 4 (0.5 g) was treated with trifluoroacetic acid (10 ml) and heated at reflux temperature for 45 minutes. The reaction mixture was cooled, diluted with toluene (40 ml) and evaporated. This procedure was repeated twice more. The residue was treated with CH2Cl2 (70 ml) and adjusted to alkaline pH through the addition of a solution of NH4OH. The organic layer was separated, dried over MgSO 4, and filtered and evaporated to give 4- (2-methylsulfinylphenyl) piperidine (0.3 g).

Step 6 Using a procedure similar to Example 9, step 9, the product of step 5 was coupled to the appropriate O-methyloxime to obtain the title compound. Mass spectrum (FAB) 684 (100%). Using the procedures of steps A through E of Example 36, starting with 3-bromothioanisole and 4-bromothioanisole, the corresponding 4- (3-methylsilfinylphenyl) piperidine and 4- (4-methylsulfonylphenyl) piperidine were obtained.

EXAMPLE 37 Step 1 Treat the product of preparation 7 as described in example 20A, adding the amine and using 3,4,5-trimethoxybenzoyl chloride.

Step 2 The product of step 1 was treated using a procedure similar to example 5, step 4.

Step 3: The product of step 2 is alkylated with BrCH2CN according to a similar procedure to example 2A.

Step 4: Treat a solution of the product from step 3 (2.5 g) in CH3OH (37 ml) with NaOCH3 (200 mg). Stir for 18 hours. The resulting solution is treated with CH3ONH2 * HCl and stirred for 3 hours. The solvent is removed and re-suspended in CH 2 Cl 2, dried over MgSO 4, filtered, concentrated in vacuo and purified by chromatography with silica gel (5x20 cm, 5% CH 3 OH / CH 2 Cl 2) to give 2.2 g of the desired product in the form of a white foam. HRMS (FAB) 730.2774 (M + H +). The following formulations exemplify some of the dosage forms of this invention. In each, the term "active compound" refers to a compound of formula I.

EXAMPLE A Tablets No. Inqredient ma / tablet mq / tablet 1 Active Compound 100 500 2 Lactose USP 122 113 Corn starch, food grade, 3 30 40 as 10% paste in purified water 4 Corn starch, food grade 45 40 5 Magnesium stearate 3 7 Total 300 700 Manufacturing method Items Nos. 1 and 2 are mixed in an appropriate mixer for 10-15 minutes. The mixture is granulated with item No. 3. The wet granules are crushed through a coarse sieve (e.g., inch inch, 0.63 cm) if necessary. The wet granules are dried. Dry granules are sieved if necessary and mixed with item No. 4 and mixed for 10-15 minutes. Item No. 5 is added and mixed for 1-3 minutes. The mixture is compressed to the appropriate size and weighed in a machine suitable for tablets.

EXAMPLE B Capsules No. Ingredient mg / tablet mg / tablet 1 Active Compound 100 500 2 Lactose USP 106 123 3 Corn starch, food grade 40 70 4 Magnesium stearate at Z Total 250 700 Manufacturing method Items Nos. 1, 2 and 3 are mixed in an appropriate mixer for 10-15 minutes. Item No.4 is added and mixed for 1-3 minutes. The mixture is filled into appropriate two-piece hard gelatin capsules in a suitable encapsulating machine.

EXAMPLE C Sterile powder for injection Ingredient mq / bottle mq / bottle Sterile active powder 100 500 For the reconstitution add sterile water for injection bacteriostatic water for injection. The in vitro and in vivo activity of the compounds of the formula I can be determined by various methods known in the art, such as an assay for determining the ability to inhibit the activity of the NKi agonist substance P, an NK2 assay of hamster trachea. isolated, an NKi antagonist effects test on a microvascular airway leak induced by substance P, measurement of NK2 activity in vivo in guinea pigs, measurement of bronchoconstriction due to NKA, and receptor adhesion assays Neurokinin Typical procedures have been described in W096 / 34857, published on November 7, 1996. Activity NK3 is determined following a procedure similar to that described in the literature, for example, Molecular Pharmacol., 48 (1995), p.711- 716 The percentage of inhibition is the difference between the percentage of maximum specific adhesion (MSB) and 100%. The percentage of MBS is defined by the following equation, where "dpm" is the disintegration per minute:% MBS = (dpm of unknown) - (non-specific adhesion dpm) X100 (total adhesion dpm) - (dpm of non-specific adhesion) It will be recognized that the compounds of the formula I exhibit NKi, NK2, and / or NK3 antagonist activity in various degrees, for example, some compounds have a strong NK-? Antagonist activity. but a weaker NK2 and NK3 antagonist activity, while others are strong NK2 antagonists but are weaker NKi and NK3 antagonists. Although compounds having approximate equipotence are preferred, it is also within the scope of this invention to use compounds of unequal NK? / NK / NK3 antagonist activity when clinically appropriate. Preferred compounds of the genus of this invention have a Ki < 10nM for the NK receiver. Also preferred are compounds of formula I having a K < 10 nM for the NK2 receiver. Compounds having a Ki < 10nM for each of the NK1 and NK2 receivers. More preferred are compounds having a Ki < 2 nM for the NK-i receiver and a Ki < 2 nM for the NK2 receiver. The compounds of the invention tested for NK3 have Ki in the range of 0.05 to 50 nM. The compound of Example 11, the only amide specifically described in U.S. Patent 5,696,267, has a Ki of 3.6 for the NK1 receptor and a Ki of 9.2 for the NK2 receptor. Using the test procedures described above, it was found that the exemplified compounds had Ki values in the range of 0.2 to 6 nM, preferably 0.2 to 1 nM, for the NKi receptor, and Ki values in the range of 0.2 to 2.7 nM , preferably 0.2 to 1 nM, for the NK2 receptor.

Claims (7)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound selected from the group consisting of and diastereomers, enantiomers, rotational isomers, E and Z isomers of the oxime, and pharmaceutically acceptable salts thereof. 2. - A compound of claim 1 selected from the group consisting of
2. AH, OH N
3. H3C, CH3 C! 3. - A compound of claim 2 selected from the group consisting of
4. 4. - A compound of claim 1 which is or a diastereomer, enantiomer, rotational isomer, E and Z isomer of the oxime, and pharmaceutically acceptable salt thereof. 5. - A compound represented by the formula. or a diastereomer, enantiomer, rotational isomer or E and Z isomer of the oxime, or a pharmaceutically acceptable salt thereof, wherein T is R2-phenyl or R3 -pyridyl; R1 is H, methyl, ethyl, -CH2CN, -CH2C (O) NH2, (CH2) 3SO3H, CH2C (O) NHCH3, -CH2C (O) NHOH, -CH2C (O) NHOCH3, CH2C (O) NHCH2CN, CH2F , -CH2C (O) NHCH2SO3H,
5. R represents 2-3 substituents independently selected from the group consisting of chlorine, methyl and methoxy; R3 is 2 to 4 substituents independently selected from the group consisting of chloro and methyl; R 4 is methyl, ethyl; and Z is
6. 6. - A compound of claim 5 wherein T is R-substituted phenyl, where R 2 consists of two chloro substituents, two methyl substituents, or two methoxy substituents and one methyl substituent, R 1 is methyl, -CH 2 F, -CH 2 CN, -CH2C (O) HCH2SO3H, R is methyl; Zes
7. 7. - A compound of claim 6 wherein R consists of two chlorine substituents, R1 is methyl and Z is